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Title:
MODIFIED RELEASE FORMULATIONS AND DOSAGE REGIMENS
Document Type and Number:
WIPO Patent Application WO/2021/186409
Kind Code:
A1
Abstract:
The present invention relates to pharmaceutical compositions containing a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof (hereinafter also referred to as the "Agent"), more particularly to certain modified release pharmaceutical compositions containing the Agent; to the use of said compositions as a medicament; to processes for the preparation of said compositions; to certain dosage regimens; and to certain medical uses involving administration of compositions containing the Agent.

Inventors:
STOTT PAUL (GB)
SINCLAIR ALEX (AU)
LOVERIDGE JASON (AU)
Application Number:
PCT/IB2021/052321
Publication Date:
September 23, 2021
Filing Date:
March 19, 2021
Export Citation:
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Assignee:
INVEX THERAPEUTICS LTD (AU)
International Classes:
A61K38/26; A61K9/00; A61K9/107; A61K38/22; A61K47/10; A61K47/14; A61K47/22; A61K47/44; A61P25/00; A61P43/00
Domestic Patent References:
WO2016034851A12016-03-10
WO2012177929A22012-12-27
WO2010028257A12010-03-11
WO2010032140A22010-03-25
Foreign References:
US20110091420A12011-04-21
Other References:
BOTFIELD HANNAH F., ULDALL MARIA S., WESTGATE CONNAR S. J., MITCHELL JAMES L., HAGEN SNORRE M., GONZALEZ ANA MARIA, HODSON DAVID J: "A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus", SCIENCE TRANSLATIONAL MEDICINE, vol. 9, no. 404, 23 August 2017 (2017-08-23), XP055860725, ISSN: 1946-6234, DOI: 10.1126/scitranslmed.aan0972
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Claims:
Claims

1 . A modified release pharmaceutical composition comprising the Agent, wherein said composition, after subcutaneous administration to a human subject in need of treatment thereof: a. maintains in the subject a geometric mean plasma concentration of the Agent of at least 2 pg/mL throughout at least a 20 hour period; and b. releases at least 50% by weight of the total amount of the Agent contained within the modified release pharmaceutical composition within a period of 36 hours after administration; wherein the Agent is a GLP-1 receptor agonist having a mean plasma terminal half- life of less than 9 hours.

2. A modified release pharmaceutical composition according to claim 1 , wherein said composition is administered in a dose of about 5 to 40 pg (such as about 10 pg, or about 20 pg).

3. A modified release pharmaceutical composition according to claim 1 or 2, wherein said composition, after administration, produces in the subject a geometric mean maximum plasma concentration (Cmax) of the Agent of less than 200 pg/mL, such as less than 150 pg/mL.

4. A modified release pharmaceutical composition according to any one of claims 1 to

3, wherein said composition, after administration, produces in the subject a geometric mean maximum plasma concentration (Cmax) of the Agent at a time (Tmax) more than 2.1 hours after administration, such as more than 2.5 hours after administration.

5. A modified release pharmaceutical composition according to any one of claims 1 to

4, wherein said composition, after administration, maintains in the subject a geometric mean plasma concentration of the Agent of at least 3 pg/mL throughout at least a 20 hour period (conveniently a 24 hour period) and more preferably at least 4 pg/mL throughout at least a 20 hour period (conveniently a 24 hour period).

6. A modified release pharmaceutical composition according to any one of claims 1 to

5, wherein said composition, after administration, releases at least 70%, 80%, 90% or 100% by weight of the total amount of the Agent contained within the modified release pharmaceutical composition within a period of 36 hours after administration.

7. A modified release pharmaceutical composition according to any one of claims 1 to

6, wherein said composition, after administration, produces in the subject for at least the first 3 hours after administration a geometric mean plasma concentration of the Agent of at least 3 pg/mL, preferably at least 5 pg/mL and more preferably at least 7 pg/mL.

8. A modified release pharmaceutical composition according to any one of claims 1 to

7, wherein said composition, after administration, produces in the subject a geometric mean plasma concentration of the Agent at 20 hours after administration (C20) of at least 5 pg/mL, preferably at least 6 pg/mL and more preferably at least 7 pg/mL

9. A modified release pharmaceutical composition according to any one of claims 1 to

8, wherein said composition, after administration, produces in the subject a geometric mean maximum plasma concentration (Cmax) of the Agent of between 10 pg/mL and 150 pg/mL.

10. A modified release pharmaceutical composition according to any one of claims 1 to

9, wherein said composition, after administration, produces in the subject a ratio of Cmax/AU Co-24 between 0.04 and 0.14 hr1, preferably between 0.06 and 0.12 hr1.

11. A modified release pharmaceutical composition according to any one of claims 1 to

10, wherein said composition contains 10-100 pg, preferably 10-55 pg, more preferably 10-40 pg and yet more preferably 10-35 pg of the Agent.

12. A modified release pharmaceutical composition according to any one of claims 1 to

11 , wherein said composition, after subcutaneous administration produces in the subject a geometric mean plasma concentration of the Agent at 1 hour after administration of at least 5 pg/mL.

13. A modified release pharmaceutical composition according to any one of claims 1 to

12, wherein after subcutaneous administration at a dose of about 20 pg to the subject the composition produces a geometric maximum plasma concentration (Cmax) of the Agent of between about 10 pg/mL and 200 pg/mL and an AUCo-24 of between about 100 pg.hr/ml_ and 2000 pg.hr/mL.

14. A modified release pharmaceutical composition according to any one of the preceding claims, wherein after administration to a subject in need of treatment thereof the composition produces a mean maximum plasma concentration (Cmax) at a time (Tmax) no later than 5 hours after administration. 15. A modified release pharmaceutical composition comprising the Agent, wherein said composition is an aqueous-based, an in-situ gelling system-based, an oil-based, a protein-binding based, a viscous depot-based or an emulsion-based pharmaceutical composition suitable for subcutaneous administration; wherein the Agent is a GLP- 1 receptor agonist having a mean plasma terminal half-life of less than 9 hours.

16. A modified release pharmaceutical composition according to claim 15, wherein the composition is an oil-based or emulsion-based pharmaceutical composition for subcutaneous administration.

17. A modified release pharmaceutical composition according to claim 16, wherein the composition is an oil-based pharmaceutical composition for subcutaneous administration.

18. A modified release pharmaceutical composition according to claim 17 comprising the Agent in an amount of 10-100 pg, preferably 10-55 pg, more preferably 10-40 pg and yet more preferably 10-35 pg.

19. A modified release pharmaceutical composition according to claim 17 or 18 comprising one or more oils selected from castor oil, sesame seed oil, safflower oil, cottonseed oil, soybean oil, peanut oil, corn oil, medium chain triglycerides and long chain triglycerides.

20. A modified release pharmaceutical composition according to claim 19 wherein the total amount of oil present is at a level of between about 60 to about 99% (conveniently about 70% to about 90%) by weight of the final composition.

21. A modified release pharmaceutical composition according to any one of claims 17 to 20 comprising one or more cosolvents selected from benzyl alcohol, ethanol, polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), propylene glycol and benzyl benzoate.

22. A modified release pharmaceutical composition according to claim 21 wherein the total amount of cosolvent present is at a level of between about 1 to about 50% (conveniently about 10% to about 30%) by weight of the final composition.

23. A modified release composition according to claim 17 comprising: a) the Agent at a concentration of between about 40 to 150 pg/mL (conveniently about 120 pg/mL); b) an oil selected from castor oil, cottonseed oil, safflower oil, sesame oil and soybean oil at a level of between about 50% to about 90% by weight of the final composition; and c) one or more cosolvents selected from benzyl alcohol, ethanol, propylene glycol, PEG 400 and benzyl benzoate wherein the total amount of cosolvent present is at a level of between about 10% to about 50% (conveniently about 20% to about 40%) by weight of the final composition.

24. A modified release pharmaceutical composition according to any one of the preceding claims, wherein the Agent is a GLP-1 receptor agonist having a mean plasma terminal half-life of less than 5 hours.

25. A modified release pharmaceutical composition according to any one of the preceding claims, wherein the Agent is selected from exendin-4, exenatide or lixisenatide.

26. A modified release pharmaceutical composition according to any one of the preceding claims, wherein the Agent is exenatide, or a pharmaceutically acceptable salt thereof.

27. A modified release composition according to claim 17, wherein the composition comprises: a) exenatide, or a pharmaceutically acceptable salt thereof; b) an oil selected from castor oil, cottonseed oil, safflower oil, sesame oil and soybean oil; and c) a cosolvent selected from benzyl alcohol, ethanol, propylene glycol, PEG 400 and benzyl benzoate.

28. A modified release pharmaceutical composition according to any one of claims 15 to 27, wherein the modified release pharmaceutical composition is a subcutaneous composition and the total volume of the modified release pharmaceutical composition is between about 100 pl_ to about 1500 mI_, conveniently about 100 mI_ to about 1000 mI_, more conveniently about 100 mI_ to about 500 mI_, yet more conveniently about 250 mI_.

29. A modified release pharmaceutical composition according to any one of claims 1 to 28 for use in therapy.

30. A modified release pharmaceutical composition according to any one of claims 1 to 28 for use in reducing elevated intracranial pressure (ICP), or treating a disorder associated with elevated intracranial pressure.

31. A modified release pharmaceutical composition for the use according to claim 30, wherein the disorder associated with elevated intracranial pressure is selected from idiopathic intracranial hypertension (IIH) and its various subtypes (e.g. idiopathic intracranial hypertension without papilloedema (IIHWOP), fulminant IIH, typical IIH, atypical IIH and IIH in ocular remission), secondary pseudo-tumour cerebri, hydrocephalus, normal pressure hydrocephalus, raised intracranial pressure secondary to a brain tumour or meningitis, raised intracranial pressure associated with primary mild traumatic brain injury, primary moderate traumatic brain injury or primary severe traumatic brain injury, venous sinus thrombosis, headache associated with raised intracranial pressure, raised intracranial pressure associated with primary intracerebral haemorrhage, ischemic or haemorrhagic stroke and raised intracranial pressure associated with subarachnoid haemorrhage.

32. A modified release pharmaceutical composition for the use according to claim 30, wherein the disorder associated with elevated intracranial pressure is idiopathic intracranial hypertension (IIH).

33. A modified release pharmaceutical composition for the use according to any one of claims 29 to 32, wherein the composition is administered once daily.

34. A modified release pharmaceutical composition for the use according to claim 33, wherein the composition is administered once daily within two hours prior to sleep onset.

35. A modified release pharmaceutical composition for the use according to claim 34, wherein the composition is administered once daily after a meal and within two hours prior to sleep onset.

36. A method of treating a warm blooded animal, preferably a human, suffering from a condition treatable by the Agent, the method comprising administering thereto a pharmaceutical composition according to any one of claims 1 to 28.

37. A pharmaceutical composition according to any one of claims 1 to 28, further comprising a second active agent selected from a carbonic anhydrase inhibitor

(such as acetazolamide, furosemide or topiramate), a DPP-IV inhibitor (such as vildagliptin, saxagliptin, azetidine, sitagliptin, omarigliptin, alogliptin and linagliptin) and a long acting GLP-1 receptor agonist (such as liraglutide, albiglutide, dulaglutide and semaglutide).

Description:
MODIFIED RELEASE FORMULATIONS AND DOSAGE REGIMENS

[0001] The present invention relates to pharmaceutical compositions containing a GLP- 1 receptor agonist or a pharmaceutically acceptable salt thereof (hereinafter also referred to as the “Agent”), more particularly to certain modified release pharmaceutical compositions containing the Agent; to the use of said compositions as a medicament; to processes for the preparation of said compositions; to certain dosage regimens; and to certain medical uses involving administration of compositions containing the Agent.

BACKGROUND

[0002] Intracranial pressure (ICP) is governed by various factors, including volumes of cerebral blood, cerebrospinal fluid (CSF) and brain tissue. Expansion of any of these volumes typically triggers compensatory changes in other compartments often resulting in limited change in ICP, at least initially. However, due to the rigid nature of the skull, ICP rises rapidly once these compensatory mechanisms are exhausted. Elevated ICP is a serious medical condition and increased pressure can lead to damage to the brain or spinal cord by pressing on important brain structures and by restricting blood flow.

[0003] Elevated ICP is associated with a range of disorders including idiopathic intracranial hypertension (IIH) and its various subtypes (e.g. idiopathic intracranial hypertension without papilloedema (IIHWOP), fulminant IIH, typical IIH, atypical IIH and IIH in ocular remission), secondary pseudo-tumour cerebri, hydrocephalus, normal pressure hydrocephalus, raised intracranial pressure secondary to a brain tumour or meningitis, raised intracranial pressure associated with primary mild traumatic brain injury, primary moderate traumatic brain injury or primary severe traumatic brain injury, venous sinus thrombosis, headache associated with raised intracranial pressure, raised intracranial pressure associated with primary intracerebral hemorrhage, ischemic or hemorrhagic stroke and raised intracranial pressure associated with subarachnoid hemorrhage. The extent to which elevated ICP contributes to symptoms and/or disease development and progression in these disorders can vary by disease subtype and severity.

[0004] Pharmacological options for treating elevated ICP are limited. For example, carbonic anhydrase inhibitors such as acetazolamide and topiramate, commonly used in the management of IIH, have been evaluated in vivo for their ability to lower ICP in existing animal models but evidence for their efficacy is inconclusive (Scotton Wet al., Topiramate is more effective than acetazolamide at lowering intracranial pressure, Cephalalgia, 2019 Feb;39(2): 209-218). Furthermore, serious side effects such as cognitive impairment, insomnia, paresthesia, fatigue and anxiety are often observed with treatment using these agents (Eftekhari S et al. , Preclinical update on regulation of intracranial pressure in relation to idiopathic intracranial hypertension, Fluids Barriers CNS, 2019; 16: 35).

[0005] More recently, incretins and incretin receptor agonists have been shown to offer potential for reducing elevated ICP. In International Patent Publication WO201 6/034851 A1 and also in Botfield et al. (A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus, Sci. Transl. Med. 2017, 9: 1-11 ) it has been demonstrated that the GLP-1 receptor agonist, exendin-4, when dosed subcutaneously as an immediate release formulation in a conscious rat model, reduced ICP when compared to a saline control.

[0006] Upon administration, immediate release formulations of GLP-1 receptor agonists exhibit a rapid increase in drug plasma concentration followed typically by rapid clearance and elimination of the drug from the body. For example, Byetta, which is an immediate release formulation of exenatide (a synthetic version of the GLP-1 receptor agonist, exendin-4) is approved for the treatment of type 2 diabetes and requires twice daily administration. Following subcutaneous administration of a 10 pg dose to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in about 2.1 hours. The mean peak exenatide concentration (Cmax) is about 211 pg/mL and the overall mean area under the curve (AUCo-inf) is 1036 pg*h/mL. The mean apparent clearance of exenatide in humans is 9.1 L/h and the mean terminal half-life is only 2.4 hours (Byetta product label, U.S. Food and Drug Administration, Issued 28 April 2005).

[0007] For disorders associated with elevated ICP, immediate release pharmacokinetics may in certain circumstances lead to sub-optimal therapy. For example, high plasma concentration levels immediately post administration may lead to adverse effects associated with over-treatment of elevated ICP, such as nausea and/or low pressure headaches, e.g. orthostatic headaches attributed to low cerebrospinal fluid pressure (classification code 7.2, The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018, Vol. 38(1 ) 1-211 ). Furthermore, fluctuations in plasma levels and periods of time during which plasma levels fall below sub-therapeutic concentrations can lead to inadequate control of ICP and this can have serious consequences. In addition to acute symptoms associated with a lack of control of ICP during day or night, a lack of adequate control over a prolonged period can have long-term consequences. For example, in patients with IIH, a lack of adequate control over a prolonged period can lead to the progression of serious complications such as the development or progression of papilloedema, which itself can lead to temporary or even permanent loss of vision (Corbett JJ et al. , Visual loss in pseudotumor cerebri. Follow-up of 57 patients from five to 41 years and a profile of 14 patients with permanent severe visual loss, Arch Neurol 1982; 39: 461-74).

[0008] From the forgoing, it is evident that a need exists for improved therapies for elevated ICP and associated conditions.

SUMMARY OF INVENTION

[0009] The Applicant has surprisingly found that modified release compositions exhibiting certain pharmacokinetic characteristics can provide efficacy and/or safety related benefits when employed to treat conditions associated with elevated ICP. Modified release compositions of the present invention are able to maintain therapeutic plasma concentrations of the active agent throughout an extended period of time. Furthermore, Applicant has surprisingly found that certain variations in ICP occur during wake and sleep patterns in patients with conditions associated with elevated ICP and particular compositions of the invention can be designed and used to provide a drug release profile that is tailored to and addresses these natural variations in ICP. Particular compositions may reduce or avoid the incidence or intensity of adverse effects associated with over treatment of ICP whilst also maintain adequate plasma levels to provide improved control of elevated ICP and thus help reduce the risk of serious consequences such as blindness from papilloedema.

[0010] The benefits provided by the modified release compositions of the present invention are not limited to a particular type of dosage form or a particular type of drug release mechanism. Flowever, the Applicant has also surprisingly found that certain types of modified release dosage forms are particularly well suited to providing the required release characteristics. Furthermore, certain compositions of the invention are also associated with additional benefits in respect to formulation preparation, manufacture, stability, tolerability and/or biopharmaceutical properties.

[0011] Surprisingly, the Applicant has also found that certain dosage regimens are advantageous when treating elevated ICP and associated disorders. For example, administration of compositions comprising the Agent within a short period prior to the onset of sleep can provide efficacy and safety related benefits when compared to other administration regimens. It has also been found that, unlike strict recommendations for products such as Byetta to be administered before food, administration of particular compositions of the present invention does not need to be limited to the timing of a meal.

[0012] Surprisingly, the Applicant has also found that administration of certain compositions comprising the Agent can lead to improvements in visual acuity in patients.

[0013] In a first aspect, the present invention provides a modified release pharmaceutical composition comprising the Agent, wherein said composition, after administration to a subject in need of treatment thereof: a) maintains in the subject a geometric mean plasma concentration of the Agent of at least 2 pg/mL throughout at least a 20 hour period; and b) releases at least 50% by weight of the total amount of the Agent contained within the modified release pharmaceutical composition within a period of 36 hours after administration.

[0014] In a further aspect of the present invention, the modified release pharmaceutical composition is a modified release pharmaceutical composition for subcutaneous administration.

[0015] In a further aspect of the present invention, there is provided a modified release pharmaceutical composition comprising the Agent, wherein said composition, after subcutaneous administration to a human subject in need of treatment thereof: a) maintains in the subject a geometric mean plasma concentration of the Agent of at least 2 pg/mL throughout at least a 20 hour period; and b) releases at least 50% by weight of the total amount of the Agent contained within the modified release pharmaceutical composition within a period of 36 hours after administration; wherein the Agent has a mean plasma terminal half-life of less than 9 hours.

[0016] In a further aspect of the present invention, the modified release pharmaceutical composition releases at least 70%, 80%, 90% or 100% by weight of the total amount of the Agent contained within the modified release pharmaceutical composition within a period of 36 hours after administration.

[0017] In another aspect of the present invention, the modified release pharmaceutical composition can maintain a geometric mean plasma concentration of the Agent of at least 3 pg/mL and preferably at least 4 pg/mL throughout at least a 20 hour period (preferably at least a 22 or 24 hour period). The composition can also provide a geometric mean plasma concentration of the Agent of at least 3 pg/mL, preferably 5 pg/mL and more preferably at least 7 pg/mL for at least the first 3 hours after administration. Particular compositions of the invention also produce a geometric mean concentration of the Agent at 20 hours after administration (C20) of at least 5 pg/mL, conveniently 6 pg/mL and more conveniently at least 7 pg/mL.

[0018] In yet a further aspect, certain compositions also produce a geometric mean plasma concentration (Cmax) of the Agent of between 80 pg/mL and 280 pg/mL and optionally a ratio of Cmax/AUCo-24 between 0.04 and 0.14, conveniently between 0.07 and 0.14.

[0019] In a further aspect, the compositions of the invention provide a dose of the Agent in a range of 10-100 pg, preferably 15-55 pg, more preferably 15-40 pg and yet more preferably 20-35 pg.

[0020] In a further aspect, the modified release pharmaceutical composition of the present invention is an aqueous based depot, an in-situ gelling system, an oil-based depot, a protein-binding based depot, a viscous depot or an emulsion based pharmaceutical composition suitable for subcutaneous administration.

[0021] In a further aspect, the modified release pharmaceutical composition of the present invention is an aqueous based depot, an in-situ gelling system, an oil-based depot, a protein-binding based depot, a viscous depot or an emulsion based pharmaceutical composition suitable for subcutaneous administration; wherein the Agent has a mean plasma terminal half-life of less than 9 hours.

[0022] Conveniently, the modified release pharmaceutical composition is an oil-based depot composition suitable for subcutaneous administration. Conveniently, the modified release pharmaceutical composition is an emulsion based (such as a water in oil-based) composition suitable for subcutaneous administration.

[0023] In a further aspect, the present invention provides a modified release pharmaceutical composition as described herein for use in therapy. In particular, the present invention provides a modified release pharmaceutical composition as described herein for use in a method of reducing elevated ICP or a method of treating a disorder associated with elevated ICP. The disorder associated with elevated ICP can be idiopathic intracranial hypertension (IIH) and its various subtypes (e.g. idiopathic intracranial hypertension without papilloedema (IIHWOP), fulminant IIH, typical IIH, atypical IIH and IIH in ocular remission), secondary pseudo-tumour cerebri, hydrocephalus, normal pressure hydrocephalus, raised intracranial pressure secondary to a brain tumour or meningitis, raised intracranial pressure associated with primary mild traumatic brain injury, primary moderate traumatic brain injury or primary severe traumatic brain injury, venous sinus thrombosis, headache associated with raised intracranial pressure, raised intracranial pressure associated with primary intracerebral hemorrhage, ischemic or hemorrhagic stroke or raised intracranial pressure associated with subarachnoid hemorrhage.

[0024] In yet a further aspect, the modified release pharmaceutical composition as described herein for use in treating a disorder associated with elevated intracranial pressure is administered once daily, optionally just prior to the onset of sleep and optionally after a meal.

[0025] In a further aspect, the present invention provides a pharmaceutical composition as described herein, further comprising a second active agent.

[0026] In yet a further aspect, the present invention provides a process for the preparation of a modified release pharmaceutical composition as described herein.

BRIEF DESCRIPTION OF FIGURES

[0027] Figure 1 shows an in vitro test setup for oil-based, viscous and emulsion formulations.

[0028] Figure 2 shows the in vitro release profiles of the lead Exenatide formulations of Example 8.

[0029] Figure 3 shows the in vivo release profiles in mice of Exenatide following subcutaneous administration of formulations according to Example 9, which were formulated with (A) saline; (B) chitosan; (C) safflower oil; (D) soybean oil; (E) castor oil emulsion; (F) castor oil; (G) albumin; and (H) SAIB.

[0030] Figure 4 shows deconvoluted mouse PK profiles following subcutaneous administration of exenatide in (A) albumin; (B) castor oil; (C) castor oil emulsion; (D) chitosan; (E) safflower oil; (F) saline; and (G) soybean oil compositions. The numerically deconvoluted absorption profiles were set relative to the saline absorption.

[0031] Figure 5 shows simulated human PK profiles of Exenatide following subcutaneous administration of formulations according to Example 9, formulated with (A) albumin; (B) castor oil emulsion; (C) castor oil; (D) chitosan; (E) safflower oil; (F) saline; and (G) soybean oil. The release profiles of SC formulations from Example 9 were imputed into the updated human PK model for a range of doses (10, 15 and 20 pg).

[0032] Figure 6 shows an overview of the design of the IIH pressure trial according to Example 12.

[0033] Figure 7 shows baseline visit scheme from the IIH pressure trial of Example 12.

[0034] Figure 8 shows the week 12 scheme from the IIH pressure trial of Example 12.

[0035] Figure 9 shows ICP recording over 24 hour period in the IIH study of Example 11.

[0036] Figure 10 shows the change in ICP from baseline over the first 150 minutes after dosing either subcutaneous placebo or exenatide according to the Example 12 trial (* indicates p<0.05).

[0037] Figure 11 shows ICP from midnight (0:00) until 6 am (6:00) while continuously lying supine after administration of subcutaneous placebo (saline) or exenatide (20 pg) according to the Example 12 trial (* indicates p<0.05).

[0038] Figure 12 shows the mean change in ICP from baseline at (A) 2.5 hr; (B) 24 hr; and (C) 12 weeks; after dosing either subcutaneous placebo (saline) or exenatide according to the Example 12 trial.

[0039] Figure 13 shows the mean change from baseline to 12 weeks after dosing either subcutaneous placebo (saline) or exenatide according to the Example 12 trial, in terms of (A) monthly headache days; and (B) monthly analgesia days.

[0040] Figure 14 shows the change in the Logarithm of the Minimum Angle of Resolution (logMAR) from baseline to 12 weeks after dosing either subcutaneous placebo (saline) or exenatide according to the Example 12 trial, in terms of (A) mean change for each cohort; and (B) individual subject changes.

[0041] Figure 15 shows the in vitro release profiles of the oil-based Exenatide formulations of Example 13.

[0042] Figure 16 shows the log-linear geometric mean plasma concentration time profiles in rats of Exenatide following administration of formulations according to Example 16A, which were formulated with (a) saline (IV administration); (b) saline (SC administration); (c) 85% castor oil/15% benzyl benzoate; (d) 70% castor oil/30% benzyl benzoate; (e) 78% castor oil/15% benzyl benzoate/5% sorbitan monooleate/2% pH 4.5 NaOAc buffer; (f) 75% castor oil/15% benzyl benzoate/5% sorbitan monooleate/5% pH 4.5 NaOAc buffer.

[0043] Figure 17 shows the in vivo release profiles in rats of Exenatide following subcutaneous administration of formulations according to Example 16B, which were formulated with saline (SC exenatide); albumin; castor oil (oil); and castor oil emulsion (emulsion); (A) log-linear plot (LCMS/MS) of formulations according to Example 16B [concentrations below LLOQ (0.1 ng/mL have not been plotted); (B) plot (ELISA) of formulations according to Example 16B [inset showing expanded section at 0-5 ng/ml concentration]

DETAILED DESCRIPTION

[0044] The disclosed compositions, processes of manufacture and methods may be understood more readily by reference to the following detailed description which form a part of this disclosure. It is to be understood that the disclosed compositions, processes of manufacture and methods are not limited to the specific compositions, processes of manufacture and methods described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed compositions, processes of manufacture and methods.

[0045] Reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. When a range of values is expressed, another embodiment includes from the one particular value and/or to the other particular value. Further, reference to values stated in ranges include each and every value within that range. All ranges are inclusive and combinable.

[0046] When values are expressed as approximations, by use of the antecedent “about”, it will be understood that the particular value forms another embodiment. As used herein and unless stated otherwise, it is to be understood that the term “about” is used synonymously with the term “approximately”. Illustratively and unless stated otherwise, the use of the term “about” indicates values slightly outside the cited criteria values, namely, ± 10% (conveniently ± 2%). Such values are thus encompassed by the scope of the claims reciting the terms “about” or approximately”.

[0047] It is to be appreciated that certain features of the disclosed compositions, processes of manufacture and methods which are for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions, processes of manufacture and methods that are, for brevity, described in the context of a single embodiments, may also be provided separately or in any sub-combination.

[0048] As used herein, the singular forms “a”, “an”, and “the” include the plural.

[0049] The following abbreviations are used herein: glucagon-like peptide 1 (GLP-1 ), cerebrospinal fluid (CSF), intracranial pressure (ICP), idiopathic intracranial hypertension (IIH), idiopathic intracranial hypertension without papilloedema (IIHWOP), body mass index (BMI), geometric mean maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time zero up to 24 hours post-dose (AUCo-24), overall mean area under the curve (AUCo-inf), geometric mean plasma concentration at 24 hours after administration (C24), geometric mean plasma concentration at 20 hours after administration (C20), time at which Cmax is observed (Tmax), immediate release (IR), modified release (MR), pharmacokinetic (PK), intravenous (IV), subcutaneous (SC), optical coherence tomography (OCT), polyethylene glycol 300 (PEG300), polyethylene glycol 400 (PEG400), high performance liquid chromatography (HPLC), 2-hydroxypropyl- b-cyclodextrin (HPpCD), carboxymethylcellulose sodium, low viscosity (CMCS), dimethyl sulfoxide (DMSO), hydroxypropyl methylcellulose (HPMC), povidone (PVP), sulfobutylether-p-cyclodextrin (SBEpCD), sucrose acetate isobutyrate (SAIB), phosphate-buffered saline (PBS), ultra-high performance liquid chromatography (UHPLC), limit of quantification (LOQ), lower limit of quantification (LLOQ), extended- release (ER), central nervous system (CNS) and quality of life (QoL), magnetic resonance imaging (MRI), computerised tomography (CT), Dual-energy X-ray absorptiometry (DEXA), Central Corneal Thickness (CCT), human chorionic gonadotropin (HCG), polytetrafluoroethylene (PTFE), minimum angle of resolution (MAR), Humphrey Visual Field (HVF), retinal nerve fibre layer (RNFL).

[0050] As used herein, “treating” and like terms refer to reducing the severity and/or frequency of symptoms, eliminating symptoms and/or the underlying cause of said symptoms, reducing the frequency or likelihood of symptoms and/or their underlying cause, delaying, preventing and/or slowing the progression of diseases and/or disorders, and improving or remediating damage caused, directly or indirectly, by the diseases and/or disorders.

[0051] As used herein, the phrase “therapeutically effective dose” refers to an amount of a composition comprising at least one active pharmaceutical ingredient, as described herein, effective to achieve a particular biological or therapeutic result such as, but not limited to, biological or therapeutic results disclosed, described, or exemplified herein. The therapeutically effective dose may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to cause a desired response in a subject.

[0052] As used herein, “subject” includes a vertebrate, mammal, domestic animal or preferably a human being.

[0053] As used herein, the phrasing “pharmaceutically acceptable salt” refers to those salts of compounds (for example GLP-1 receptor agonist described herein) which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem of complication, commensurate with a reasonable benefit/risk ratio.

[0054] As used herein, the phrasing “plasma terminal half-life” refers to the time required for the plasma concentration to decrease by 50% after pseudo-equilibrium of distribution has been reached.

Modified Release Pharmaceutical Compositions

[0055] The pharmaceutical compositions of the present invention are modified release pharmaceutical compositions and provide certain drug release profiles and pharmacokinetics when administered to a subject.

[0056] As used herein, the term “immediate release” or “IR” is used in its conventional sense to refer to a dosage form that provides for release of a drug from a composition immediately after administration. Upon administration, immediate release formulations of GLP-1 receptor agonists exhibit a rapid increase in drug plasma concentration followed typically by rapid clearance and elimination of the drug from the body. For example, Byetta, which is an immediate release formulation of exenatide (a synthetic version of the GLP-1 receptor agonist, exendin-4) is approved for the treatment of type 2 diabetes and requires twice daily administration. Following subcutaneous administration of a 10 pg dose to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in about 2.1 hours. The mean peak exenatide concentration (Cmax) is about 211 pg/mL and the overall mean area under the curve (AUCo-inf) is 1036 pg*h/ml_. The mean apparent clearance of exenatide in humans is 9.1 L/h and the mean plasma terminal half-life is only 2.4 hours (Byetta product label, U.S. Food and Drug Administration, Issued 28 April 2005).

[0057] As used herein, the term "modified release" or "MR" means that the release of a drug, such as the Agent, from the dosage form (e.g. oral tablet, capsule, pellet, granule, injectable composition, intranasal formulation etc.) has been modified so that the release rate is either slower than that from an unmodified or immediate release dosage form or begins at a later time point.

[0058] It is to be understood that “Modified Release” encompasses delayed release (release at a time other than immediately after administration), extended release (release over a prolonged time period), sustained release (rate of drug release is sustained over a period of time), and controlled release (rate of drug release is controlled to get a particular drug concentration profile in the body). As used herein, a slower dissolution profile is one in which the release of a drug from the dosage form is slower, i.e. it takes more time for the drug to be released in a slower dissolution profile than a faster dissolution profile.

[0059] Conveniently, the modified release is extended release, sustained release or controlled release. More conveniently, the modified release is extended release (such as extended release over a period of at least 12 hours, at least 16 hours, at least 20 hours, or at least 24 hours). In an embodiment, the modified release composition is an extended release composition, wherein the Agent is released from the composition over a period of at least 12 hours, at least 16 hours, at least 20 hours, or at least 24 hours. Conveniently, the modified release composition is an extended release composition, wherein the Agent is released from the composition over a period of at least 24 hours. Conveniently, the modified release composition is an extended release composition, wherein the Agent is released from the composition over a period of between 18 hours and 48 hours, conveniently between 18 hours and 36 hours. [0060] In one embodiment, the composition continually releases the Agent throughout a prolonged period when compared to an immediate release composition of the Agent. In an embodiment, the composition continually releases exenatide, or a pharmaceutically acceptable salt thereof, throughout a prolonged period when compared to an immediate release composition of the Agent (such as Byetta).

[0061] In a first aspect, the present invention provides a modified release pharmaceutical composition comprising the Agent, wherein said composition, after administration to a subject in need of treatment thereof: a) maintains in the subject a geometric mean plasma concentration of the Agent of at least 2 pg/mL throughout at least a 20 hour period; and b) releases at least 50% by weight of the total amount of the Agent contained within the modified release pharmaceutical composition within a period of 36 hours after administration.

[0062] The modified release pharmaceutical composition according to the first aspect of the invention can be administered by various means, including oral, sublingual, buccal, nasal, intra-arterial, intra-articular, intracardiac, intradermal, intramuscular, intraocular, intrathecal, intravenous, intravitreal, intraventricular or subcutaneous administration.

[0063] Conveniently, the modified release pharmaceutical composition according to the first aspect of the invention is administered by means of parenteral administration, most conveniently by means of subcutaneous administration.

[0064] In a second aspect of the present invention, there is provided a modified release pharmaceutical composition comprising the Agent, wherein said composition, after subcutaneous administration to a human subject in need of treatment thereof: a) maintains in the subject a geometric mean plasma concentration of the Agent of at least 2 pg/mL throughout at least a 20 hour period; and b) releases at least 50% by weight of the total amount of the Agent contained within the modified release pharmaceutical composition within a period of 36 hours after administration; wherein the Agent has a mean plasma terminal half-life of less than 9 hours.

[0065] In an embodiment, the modified release composition according to the first or second aspects of the invention, is administered to the subject in a dose of about 5 pg to about 40 pg (such as about 5 pg, 10 pg, 15 pg, 20 pg, 25 pg, 30 pg, 35 pg or 40 pg).

[0066] The modified release compositions described herein can provide a reduced geometric mean maximum plasma concentration (Cmax) of the Agent compared to analogous immediate release formulations. Therefore, in an embodiment, the modified release composition according to the first or second aspects of the invention, after administration to a human subject in need of treatment thereof, produces in the subject a geometric mean maximum plasma concentration (Cmax) of the Agent of less than 200 pg/mL, such as less than 150 pg/mL, less than 100 pg/mL, or less than 50 pg/mL.

[0067] In an embodiment, the modified release composition according to the second aspect of the invention, after subcutaneous administration in a dose of about 10 to 40 pg (such as about 10 pg, or about 20 pg) to a human subject in need of treatment thereof, produces in the subject a geometric mean maximum plasma concentration (Cmax) of the Agent of less than 200 pg/mL, such as less than 150 pg/mL, less than 100 pg/mL, or less than 50 pg/mL.

[0068] The modified release compositions described herein also provide a geometric mean maximum plasma concentration (Cmax) of the Agent which occurs later after administration compared to analogous immediate release formulations. Therefore, in an embodiment, the modified release composition according to the first or second aspects of the invention, after administration to a human subject in need of treatment thereof, produces in the subject a geometric mean maximum plasma concentration (Cmax) of the Agent at a time (Tmax) more than 2.1 hours after administration, such as more than 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4.0 hours after administration.

[0069] In an embodiment, the modified release composition according to the second aspect of the invention, after subcutaneous administration in a dose of about 10 to 40 pg (such as about 10 pg, or about 20 pg) to a human subject in need of treatment thereof, produces in the subject a geometric mean maximum plasma concentration (Cmax) of the Agent at a time (Tmax) more than 2.1 hours after administration, such as more than 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4.0 hours after administration.

[0070] In an embodiment, the modified release composition according to the first or second aspects of the invention, after administration to a human subject in need of treatment thereof, produces in the subject a geometric mean maximum plasma concentration (Cmax) of the Agent (i) of less than 200 pg/mL, such as less than 150 pg/mL, less than 100 pg/mL, or less than 50 pg/mL; and (ii) at a time (Tmax) more than 2.1 hours after administration, such as more than 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4.0 hours after administration.

[0071] In an embodiment, the modified release composition according to the second aspect of the invention, after subcutaneous administration in a dose of about 10 to 40 pg (such as about 10 pg, or about 20 pg) to a human subject in need of treatment thereof, produces in the subject a geometric mean maximum plasma concentration (Cmax) of the Agent (i) of less than 200 pg/mL, such as less than 150 pg/mL, less than 100 pg/mL, or less than 50 pg/mL; and (ii) at a time (Tmax) more than 2.1 hours after administration, such as more than 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4.0 hours after administration.

[0072] For the modified release compositions according to the first or second aspects of the invention, after administration to a subject in need of treatment thereof, at least 50% by weight (conveniently at least 70%, 75%, 80%, 85%, 90%, 95% and 100% by weight) of the total amount of the Agent contained within the modified release pharmaceutical composition is released within a period of 36 hours (conveniently 24 hours or 18 hours) after administration.

[0073] Suitably the modified release compositions of the invention are designed for once- daily administration.

[0074] Conveniently, at least 90% of the total amount of the Agent contained within the modified release pharmaceutical composition is released within a period of 24 hours after administration.

[0075] Release of the Agent from the modified release compositions of the invention can be determined by methods known in the art. For example, release rates can be determined using in-vitro dissolution tests, which mimic an aqueous physiological-type environment. The term "aqueous physiological environment" as used herein refers to the body of a warm blooded animal, particularly human. In particular embodiments, the modified release compositions of the invention are designed for subcutaneous administration and the term "aqueous physiological environment" for such compositions refers to the subcutaneous environment of such a body. These conditions may be simulated in vitro by placing a modified release composition in an aqueous dissolution medium, optionally buffered to a physiological pH, at a temperature of from 35 to 40°C. A suitable dissolution medium comprises a saline solution buffered to a pH of approximately 7.4 using a phosphate buffer, for example phosphate buffered saline or Mcllvaines citric acid phosphate. In a preferred embodiment, the dissolution medium is pH 7.4 phosphate-buffered saline. Preferably, the aqueous dissolution medium is maintained at a temperature of 37°C ± 2°C. The amount of Agent released over a given time period may be determined by sampling the dissolution medium and measuring the concentration of the Agent using a suitable analytical method, for example HPLC.

[0076] In a convenient embodiment, the release of the Agent from an injectable composition is determined by:

(a) adding 1 ml_ of pH 7.4 phosphate-buffered saline to 1 ml_ of the composition in a suitable vial;

(b) placing the vial in a water bath at about 37 °C; and

(c) analysing the buffer layer to determine at a given time point, the amount of Agent released from the composition.

[0077] In a yet more convenient embodiment, the modified release pharmaceutical composition comprising the Agent is water-immiscible and the release of the Agent from the injectable composition is determined by:

(a) adding 1 ml_ of pH 7.4 phosphate-buffered saline to 1 ml_ of the composition in a suitable vial;

(b) placing the vial in a water bath at about 37 °C; and

(c) analysing the buffer layer to determine at a given time point, the amount of Agent released from the composition.

[0078] Release of the Agent from the modified release compositions of the invention can also be determined by in-vivo methods known in the art. For example, release in vivo can be tested by measuring plasma concentrations at predetermined time periods and thereby obtaining a plasma concentration versus time profile for the Agent.

[0079] Other tests may also be used to determine the amount of release of the Agent in vivo. Animals (e.g. mice, rats, dogs etc.) may be used as models to investigate release characteristics. For example, for a subcutaneous modified release composition, animals can receive the composition under investigation and after specified periods of time, the animals can be sacrificed and the subcutaneous modified release composition can be extracted/retrieved and analysed. By determining the content of the Agent remaining in the modified release composition at specified periods of time, the amount and extent of release can be calculated.

[0080] The modified release pharmaceutical compositions according to the first or second aspects of the invention, after administration to a subject in need of treatment thereof, maintain in the subject a geometric mean plasma concentration of the Agent of at least 2 pg/mL throughout at least a 20 hour period (conveniently at least a 22 or 24 hour period), preferably at least 3 pg/mL and more preferably at least 4 pg/mL throughout at least a 20 hour period (conveniently at least a 22 or 24 hour period).

[0081] As used in this context, ‘maintain’ or ‘maintains’ means that the composition delivers plasma levels of the Agent which may vary but are always at, or above, a defined minimum threshold level for a defined period of time after administration of the composition. For example, a short while (e.g. 5 minutes) after administration mean plasma levels of the Agent in excess of 2 pg/mL are obtained and they are then at the 2 pg/mL threshold or above for the remainder of the defined period (such as 20 hours) after administration.

[0082] In an embodiment, the modified release pharmaceutical composition according to the first or second aspect of the invention, after subcutaneous administration of the composition comprising the Agent in a dose of about 10 to 30 pg (such as about 20 pg) to a human subject in need of treatment thereof, maintains in the subject a geometric mean plasma concentration of the Agent of at least 2 pg/mL throughout at least a 20 hour period (conveniently at least a 22 or 24 hour period), preferably at least 3 pg/mL and more preferably at least 4 pg/mL throughout at least a 20 hour period (conveniently at least a 22 or 24 hour period).

[0083] In an embodiment, the modified release pharmaceutical composition according to the first or second aspect of the invention, after a single subcutaneous administration of the composition comprising the Agent in a dose of about 10 pg, about 20 pg, or about 30 pg to a human subject in need of treatment thereof, maintains in the subject a geometric mean plasma concentration of the Agent of at least 2 pg/mL throughout at least a 20 hour period after administration (conveniently at least a 22 or 24 hour period), preferably at least 3 pg/mL and more preferably at least 4 pg/mL throughout at least a 20 hour period after administration (conveniently at least a 22 or 24 hour period). [0084] Advantageously compositions of the invention are able to maintain a therapeutically effective plasma concentration of the drug throughout this period.

[0085] In an embodiment, the modified release pharmaceutical composition according to the first or second aspect, after administration to a subject in need of treatment thereof maintains a geometric mean plasma concentration of the Agent of at least 3 pg/mL, preferably 5 pg/mL and more preferably at least 7 pg/mL for at least 3 hours, conveniently 5 hours or 7 hours. In an embodiment, the modified release pharmaceutical composition according to the first or second aspect, after administration to a subject in need of treatment thereof maintains a geometric mean plasma concentration of the Agent of at least 20 pg/mL, such as at least 30, 40, 50 or 75 pg/mL for at least 3 hours, conveniently 5 hours or 7 hours, more conveniently at least 12 hours, 18 hours or 24 hours. Providing such levels over the initial period post-administration can provide rapid control of elevated ICP levels.

[0086] In an embodiment, the modified release pharmaceutical composition according to the first or second aspect of the invention, after subcutaneous administration of the composition comprising the Agent in a dose of about 5 to 40 pg (such as about 20 pg) to a human subject in need of treatment thereof, maintains in the subject a geometric mean plasma concentration of the Agent of at least 3 pg/mL, such as at least 5, 7, 20, 30, 40, 50 or 75 pg/mL for at least 3 hours, conveniently 5 hours or 7 hours after administration. In an embodiment, the modified release pharmaceutical composition according to the first or second aspect, after administration to a subject in need of treatment thereof produces in the subject a geometric mean concentration of the Agent at 20 hours after administration (C20) of at least 5 pg/mL, preferably 6 pg/mL and more preferably at least 7 pg/mL. In an embodiment, the modified release pharmaceutical composition according to the first or second aspect, after administration to a subject in need of treatment thereof maintains a geometric mean plasma concentration of the Agent at 20 hours after administration (C20) of at least 20 pg/mL, such as at least 30, 40 or 50 pg/mL. Maintaining such plasma levels at 20 hours after administration helps ensure sustained and controlled lowering of elevated ICP.

[0087] In an embodiment, the modified release pharmaceutical composition according to the first or second aspect of the invention, after subcutaneous administration of the composition comprising the Agent in a dose of about 10 to 40 pg (such as about 20 pg) to a human subject in need of treatment thereof, produces in the subject a geometric mean concentration of the Agent at 20 hours after administration (C20) of at least at least 3 pg/mL, such as at least 5, 7, 20, 30, 40, 50 or 75 pg/mL.

[0088] In an embodiment, the modified release pharmaceutical composition according to the first or second aspect, after administration to a subject in need of treatment thereof, produces in the subject a geometric mean maximum plasma concentration (Cmax) of the GLP-1 receptor agonist or the pharmaceutically acceptable salt thereof between 80 pg/mL and 280 pg/mL, conveniently between 80 pg/mL and 230 pg/mL, more conveniently between 150 pg/mL and 230 pg/mL. In an embodiment, the modified release pharmaceutical composition according to the first or second aspect, after administration to a subject in need of treatment thereof, produces in the subject a geometric mean maximum plasma concentration (Cmax) of the GLP-1 receptor agonist or the pharmaceutically acceptable salt thereof of between 10 pg/mL and 200 pg/mL, conveniently between 10 pg/mL and 150 pg/mL, more conveniently between 10 pg/mL and 100 pg/mL, such as between 10 pg/mL and 50 pg/mL.

[0089] In an embodiment, the modified release pharmaceutical composition according to the first or second aspect of the invention, after subcutaneous administration of the composition comprising the Agent in a dose of about 10 to 40 pg (such as about 20 pg) to a human subject in need of treatment thereof, produces in the subject a geometric mean maximum plasma concentration (Cmax) of the Agent of between 80 pg/mL and 280 pg/mL, conveniently between 80 pg/mL and 230 pg/mL, more conveniently between 150 pg/mL and 230 pg/mL. In an embodiment, the modified release pharmaceutical composition according to the first or second aspect of the invention, after subcutaneous administration of the composition comprising the Agent in a dose of about 10 to 40 pg (such as about 20 pg) to a human subject in need of treatment thereof, produces in the subject a geometric mean maximum plasma concentration (Cmax) of the Agent of between 10 pg/mL and 200 pg/mL, conveniently between 10 pg/mL and 150 pg/mL, more conveniently between 10 pg/mL and 100 pg/mL, such as between 10 pg/mL and 50 pg/mL

[0090] In an embodiment, the modified release pharmaceutical composition according to the first or second aspect, after administration to a subject in need of treatment thereof produces an AUCo-24 of between about 500 pg.hr/mL and 1500 pg.hr/mL, conveniently between about 700 pg.hr/mL and 1200 pg/mL. In an embodiment, the modified release pharmaceutical composition according to the first or second aspect, after administration to a subject in need of treatment thereof produces an AUCo-24 of between about 100 pg.hr/ml_ and 2000 pg.hr/ml_, conveniently between about 100 pg.hr/ml_ and 1000 pg/mL, such as conveniently between about 100 pg.hr/ml_ and 500 pg/mL, such as conveniently between about 100 pg.hr/ml_ and 300 pg/mL.

[0091] In an embodiment, the modified release pharmaceutical composition according to the first or second aspect of the invention, after subcutaneous administration of the composition comprising the Agent in a dose of about 10 to 40 pg (such as about 20 pg) to a human subject in need of treatment thereof, produces an AUCo-24 of between about 500 pg.hr/ml_ and 1500 pg.hr/ml_, conveniently between about 700 pg.hr/ml_ and 1200 pg/mL. In an embodiment, the modified release pharmaceutical composition according to the first or second aspect, after subcutaneous administration of the composition comprising the Agent in a dose of about 10 to 40 pg (such as about 20 pg) to a human subject produces an AUCO-24 of between about 100 pg.hr/ml_ and 2000 pg.hr/ml_, such as between about 100 pg.hr/ml_ and 1000 pg.hr/ml_, conveniently between about 100 pg.hr/ml_ and 500 pg/mL, such as conveniently between about 100 pg.hr/ml_ and 300 pg/mL.

[0092] In an embodiment, the modified release pharmaceutical composition according to the first or second aspect, after administration to a subject in need of treatment thereof, also produces in a subject a geometric mean maximum plasma concentration (Cmax) of the Agent of between 80 pg/mL and 280 pg/mL (conveniently 80 pg/mL and 230 pg/mL) and an AUCo-24 of between about 500 pg.hr/ml_ and 1500 pg.hr/ml_ (conveniently between about 700 pg.hr/ml_ and 1200 pg.hr/ml_). In an embodiment, the modified release pharmaceutical composition according to the first or second aspect, after administration to a subject in need of treatment thereof, also produces in a subject a geometric mean maximum plasma concentration (Cmax) of the Agent of between 10 pg/mL and 200 pg/mL (conveniently 10 pg/mL and 150 pg/mL) and an AUCO-24 of between about 100 pg.hr/ml_ and 2000 pg.hr/ml_ (conveniently between about 100 pg.hr/ml_ and 1000 pg.hr/ml_). In an embodiment, the modified release pharmaceutical composition according to the first or second aspect of the invention, after subcutaneous administration of the composition comprising the Agent in a dose of about 10 to 40 pg (such as about 20 pg) to a human subject in need of treatment thereof, produces in the subject a geometric mean maximum plasma concentration (Cmax) of the Agent of between 80 pg/mL and 280 pg/mL (conveniently 80 pg/mL and 230 pg/mL) and an AUCo-24 of between about 500 pg.hr/mL and 1500 pg.hr/mL (conveniently between about 700 pg.hr/mL and 1200 pg.hr/mL). In an embodiment, the modified release pharmaceutical composition according to the first or second aspect of the invention, after subcutaneous administration of the composition comprising the Agent in a dose of about 10 to 40 pg (such as about 20 pg) to a human subject in need of treatment thereof, produces in the subject a geometric mean maximum plasma concentration (Cmax) of the Agent of between 10 pg/mL and 200 pg/mL (conveniently 10 pg/mL and 150 pg/mL) and an AUCO-24 of between about 100 pg.hr/mL and 2000 pg.hr/mL (conveniently between about 100 pg.hr/mL and 1000 pg.hr/mL).

[0093] In an embodiment, the modified release pharmaceutical composition according to the first or second aspect, after administration to a subject in need thereof produces a ratio of Cmax/AUCo-24 between 0.04 and 0.14 hr 1 , preferably between 0.06 and 0.14 hr 1 , such as between 0.06 and 0.12 hr 1 , or between 0.06 and 0.10 hr 1 .

[0094] In an embodiment, the modified release pharmaceutical composition according to the first or second aspect is administered to the subject to provide a dose of the Agent in a range of 5-100 pg, preferably 10-55 pg, more preferably 10-40 pg and yet more preferably 10-35 pg.

[0095] In an embodiment, the modified release pharmaceutical composition according to the first or second aspect contains 10-100 pg, preferably 10-55 pg, more preferably IQ- 40 pg and yet more preferably 10-35 pg of the Agent. In an embodiment, the modified release pharmaceutical composition according to the first or second aspect contains 10, 20 or 30 pg of the Agent (such as about 20 pg of the Agent).

[0096] In an embodiment, the modified release pharmaceutical composition according to the first or second aspect, after subcutaneous administration to a subject in need of treatment thereof produces a geometric mean plasma concentration of the Agent at 1 hour after administration of at least 20 pg/mL, preferably at least 30 pg/mL, more preferably at least 40 pg/mL and even more preferably at least 50 pg/mL.

[0097] In an embodiment, the modified release pharmaceutical composition according to the first or second aspect, after subcutaneous administration at a dose of about 20 pg to a subject in need thereof produces a geometric maximum plasma concentration (Cmax) of the Agent of between 80 pg/mL and 230 pg/mL and an AUCo-24 of between about 700 pg.hr/mL and 1200 pg.hr/mL. In an embodiment, the modified release pharmaceutical composition according to the first or second aspect, after subcutaneous administration at a dose of about 20 pg to a human subject in need thereof produces a geometric maximum plasma concentration (Cmax) of the Agent of between 10 pg/mL and 100 pg/mL and an AUCO-24 of between about 100 pg.hr/ml_ and 1000 pg.hr/ml_.

[0098] In an embodiment, the modified release pharmaceutical composition according to the first or second aspect, after administration to a subject in need of treatment thereof produces a geometric mean maximum plasma concentration (Cmax) at a time (Tmax) no later than 7 hours after administration, preferably no later than 6 hours after administration and more preferably no later than 5 hours after administration. Providing such levels over the initial period post-administration allows rapid control of symptoms associated with elevated ICP levels.

Particular Modified Release Compositions

[0099] The benefits of the present invention are not limited to a particular type of dosage form having a particular mechanism of drug release. Indeed, modified release of the Agent may be accomplished by a range of compositions. However, certain compositions provide particular benefits.

[00100] Conveniently, the modified release pharmaceutical composition as described herein is a subcutaneous composition.

[00101] Suitable subcutaneous modified release pharmaceutical composition include aqueous-based depots, in-situ gelling systems, oil-based depots, protein-binding based depots, viscous depots and emulsion-based pharmaceutical compositions.

[00102] As herein used in relation to the compositions, the term ‘based’ refers to the primary characteristic of the composition that is responsible for the modified release provided by the composition, but without excluding the presence of other characteristics. For example, it will be the “oil” component of an “oil-based depot” that will act as the primary release rate modifying agent to provide the modified release. Conveniently, the primary characteristic of the composition will be the only characteristic of the composition that is responsible for providing the modified release.

[00103] Therefore, in a third aspect of the present invention there is provided a modified release pharmaceutical composition comprising the Agent, wherein said composition is an aqueous-based depot, an in-situ gelling system, an oil-based depot, a protein-binding based depot, a viscous depot or an emulsion-based pharmaceutical composition suitable for subcutaneous administration.

[00104] In a fourth aspect of the present invention there is provided a modified release pharmaceutical composition comprising the Agent, wherein said composition is an aqueous-based depot, an in-situ gelling system, an oil-based depot, a protein-binding based depot, a viscous depot or an emulsion based pharmaceutical composition suitable for subcutaneous administration; wherein the Agent has a mean plasma terminal half-life of less than 9 hours.

[00105] The Applicant has surprisingly found that certain types of subcutaneous modified release dosage forms, e.g. subcutaneous oil-based depots are particularly well suited to providing the required release characteristics.

[00106] Furthermore, particular compositions of the invention have also been found to offer additional benefits in respect to formulation preparation and manufacture and/or stability, tolerability and/or biopharmaceutical properties.

[00107] In a particular embodiment, the modified release pharmaceutical composition comprising the Agent is an oil-based depot or an emulsion-based pharmaceutical composition suitable for subcutaneous administration.

[00108] It will be appreciated that the modified release compositions of the third and fourth aspects of the invention may possess the drug release profiles and pharmacokinetics described for the first and second aspects of the invention. Therefore, any of the embodiments described in relation to the compositions according to the first or second aspects of the invention may also apply to the compositions according to the third and fourth aspects of the invention.

[00109] Accordingly, there is provided a modified release pharmaceutical composition comprising the Agent, wherein said composition, after administration to a subject in need of treatment thereof: a) maintains in the subject a geometric mean plasma concentration of the Agent of at least 2 pg/mL throughout at least a 20 hour period; and b) releases at least 50% by weight of the total amount of the Agent contained within the modified release pharmaceutical composition within a period of 36 hours after administration; wherein said composition is an aqueous based depot, an in-situ gelling system, an oil- based depot, a protein-binding based depot, a viscous depot or an emulsion based pharmaceutical composition suitable for subcutaneous administration (preferably an oil- based composition).

[00110] Furthermore, there is provided a modified release pharmaceutical composition comprising the Agent, wherein said composition, after subcutaneous administration to a human subject in need of treatment thereof: a) maintains in the subject a geometric mean plasma concentration of the Agent of at least 2 pg/mL throughout at least a 20 hour period; and b) releases at least 50% by weight of the total amount of the Agent contained within the modified release pharmaceutical composition within a period of 36 hours after administration; wherein the Agent has a mean plasma terminal half-life of less than 9 hours; and wherein said composition is an aqueous based depot, an in-situ gelling system, an oil-based depot, a protein-binding based depot, a viscous depot or an emulsion based pharmaceutical composition suitable for subcutaneous administration (preferably an oil- based composition).

Oil-based pharmaceutical compositions

[00111] Conveniently, the modified release pharmaceutical composition according to the third or fourth aspects of the invention is an oil-based pharmaceutical composition suitable for subcutaneous administration. Without wishing to be bound to any particular theory, the Agent from the oil-based composition partitions from the oil phase to an aqueous phase by way of diffusion. The rate and extent of this diffusion-mediated partitioning and release can be viscosity dependent.

[00112] Conveniently, the modified release pharmaceutical composition as described herein is a single phase oil-based pharmaceutical composition suitable for subcutaneous administration. By “single-phase” it is meant that the Agent is dissolved or dispersed in an oil-based homogenous mixture rather than a multi-phase system such as an emulsion.

[00113] In an embodiment, the oil-based pharmaceutical composition comprises the Agent in an amount of 10-100 pg, preferably 10-55 pg, more preferably 10-40 pg and yet more preferably 10-35 pg.

[00114] More conveniently, the oil-based pharmaceutical composition comprises one or more pharmaceutically acceptable oils. In one embodiment, the one or more pharmaceutically acceptable oils are selected from castor oil, sesame seed oil, safflower oil, cottonseed oil, soybean oil, peanut oil, corn oil, medium chain triglycerides and long chain triglycerides. In one embodiment, the oil-based pharmaceutical composition comprises one or more oils selected from castor oil, sesame seed oil, safflower oil, cottonseed oil and soybean oil.

[00115] The term “medium chain triglycerides” refers to triglycerides with two or three fatty acids having a saturated aliphatic tail of 6-12 carbons atoms. Examples of fatty acids having an aliphatic tail of 6-12 carbon atoms include caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid and lauric acid. In an embodiment, the medium chain triglyceride is Miglyol, preferably Miglyol 812.

[00116] The term “long chain triglycerides” refers to triglycerides with two or three fatty acids having a saturated or unsaturated aliphatic tail of 13-21 carbon atoms. Examples of fatty acids having an saturated or unsaturated aliphatic tail of 13-21 carbon atoms include tridecylicacid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, arachidic acid, heneicosylic acid, a-linolenic acid, stearidonic acid, eicosapentaenoic acid, linoleic acid, linolelaidic acid, g-linolenic acid, dihomo-y-linolenic acid, arachidonic acid, palmitoleic acid, vaccenic acid, paullinic acid, oleic acid, elaidic acid, gondoic acid and mead acid.

[00117] Suitably, the oil-based pharmaceutical composition comprises a single oil. Suitably, the oil-based pharmaceutical composition comprises a single oil selected from castor oil, sesame seed oil, safflower oil, cottonseed oil and soybean oil, preferably castor oil.

[00118] Suitably, the total amount of oil present is at a level of between about 51 % and about 99% by weight of the final composition, preferably about 60-99%, 65-95%, 65- 90%, 70-90%, 75-90%, 70-85%, or 75-85% by weight of the final composition.

[00119] In an embodiment, the oil-based modified release pharmaceutical composition suitable for subcutaneous administration according to the third or fourth aspect further comprises one or more cosolvents selected from benzyl alcohol, ethanol, polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), propylene glycol, benzyl benzoate and water. In an embodiment, the one or more cosolvents are selected from benzyl alcohol, ethanol, polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), propylene glycol and benzyl benzoate. Conveniently, the cosolvent is benzyl alcohol, benzyl benzoate or propylene glycol, more conveniently benzyl alcohol or benzyl benzoate, most conveniently benzyl benzoate. Suitably, the total amount of cosolvent present is at a level of between about 1 and about 50% by weight of the final composition, preferably about 5-40%, 10-35%, 15-30%, 10-30%, 15-25%, or 20-25% by weight of the final composition.

[00120] In an embodiment, the oil-based modified release pharmaceutical composition suitable for subcutaneous administration as described herein further comprises additional excipients such as preservatives and/or surfactants and/or other processing aids.

[00121] In an embodiment, the modified release pharmaceutical composition according to the third or fourth aspect is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) the Agent in an amount of 10-100 pg, preferably 10-55 pg, more preferably 10-40 pg and yet more preferably 10-35 pg; b) one or more oils selected from castor oil, sesame seed oil, safflower oil, cottonseed oil, soybean oil, peanut oil, medium chain triglycerides or long chain triglycerides wherein the total amount of oil present is at a level of between about 50 to about 99% (conveniently about 70% to about 90%) by weight of the final composition; and c) one or more cosolvents selected from benzyl alcohol, ethanol, polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), propylene glycol and benzyl benzoate wherein the total amount of cosolvent present is at a level of between about 1 to about 50% (conveniently about 10% to about 30%) by weight of the final composition.

[00122] In an embodiment, the modified release pharmaceutical composition according to the third or fourth aspect is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) the Agent at a level of between about 0.001 % and about 0.025% (conveniently about 0.005% to about 0.02%) by weight of the final composition; b) one or more oils selected from castor oil, sesame seed oil, safflower oil, cottonseed oil, soybean oil, peanut oil, medium chain triglycerides or long chain triglycerides wherein the total amount of oil present is at a level of between about 50 to about 99% (conveniently about 70% to about 90%) by weight of the final composition; and c) one or more cosolvents selected from benzyl alcohol, ethanol, polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), propylene glycol and benzyl benzoate wherein the total amount of cosolvent present is at a level of between about 1 to about 50% (conveniently about 10% to about 30%) by weight of the final composition.

[00123] In a preferred embodiment, the modified release pharmaceutical composition according to the third or fourth aspect is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) the Agent (such as exenatide or a pharmaceutically acceptable salt thereof) at a level of between about 0.001 % and about 0.025% by weight of the final composition; b) an oil selected from castor oil, cottonseed oil, safflower oil, sesame oil and soybean oil at a level of between about 50% and about 90% by weight of the final composition; and c) one or more cosolvents selected from benzyl alcohol, ethanol, propylene glycol, PEG 400 and benzyl benzoate wherein the total amount of cosolvent present is at a level of between about 10% and about 50% (conveniently about 15% to about 40%) by weight of the final composition.

[00124] In a preferred embodiment, the modified release pharmaceutical composition according to the third or fourth aspect is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) Exenatide or a pharmaceutically acceptable salt thereof at a level of between about 0.001% and about 0.025% by weight of the final composition; b) an oil selected from castor oil, cottonseed oil, safflower oil, sesame oil and soybean oil at a level of about 70 to 90% by weight of the final composition; and c) one or more cosolvents selected from benzyl alcohol, ethanol, propylene glycol, PEG 400 and benzyl benzoate wherein the total amount of cosolvent present is at a level of about 10 to 30% by weight of the final composition.

[00125] In a preferred embodiment, the modified release pharmaceutical composition according to the third or fourth aspect is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) Exenatide or a pharmaceutically acceptable salt thereof at a level of between about 0.005% and about 0.015% (such as about 0.008% or about 0.012%) by weight of the final composition; b) an oil selected from castor oil, cottonseed oil, safflower oil, sesame oil and soybean oil at a level of about 75 to 85% by weight of the final composition; and c) a cosolvent selected from benzyl alcohol and benzyl benzoate at a level of about 10 to 30% by weight of the final composition.

[00126] In a preferred embodiment, the modified release pharmaceutical composition according to the third or fourth aspect is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) exenatide at a concentration of about 20 pg/mL; b) an oil selected from castor oil, cottonseed oil, safflower oil, sesame oil and soybean oil at a level of about 95 to 98% by weight of the final composition; and c) a cosolvent selected from benzyl alcohol and propylene glycol.

[00127] In a preferred embodiment, the modified release pharmaceutical composition according to the third or fourth aspect is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) The Agent (such as exenatide or a pharmaceutically acceptable salt thereof) at a concentration of between about 20 to 150 pg/mL (conveniently about 80 pg/mL or 120 pg/mL); b) an oil selected from castor oil, cottonseed oil, safflower oil, sesame oil and soybean oil at a level of between about 50% to about 90% by weight of the final composition; and c) one or more cosolvents selected from benzyl alcohol, ethanol, propylene glycol, PEG 400 and benzyl benzoate wherein the total amount of cosolvent present is at a level of between about 10% to about 50% (conveniently about 20% to about 40%) by weight of the final composition.

[00128] In a preferred embodiment, the modified release pharmaceutical composition according to the third or fourth aspect is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) Exenatide or a pharmaceutically acceptable salt thereof at a concentration of about 40 to 150 pg/mL, such as about 80 pg/mL or 120 pg/mL; b) an oil selected from castor oil, cottonseed oil, safflower oil, sesame oil and soybean oil at a level of about 70 to 90% by weight of the final composition; and c) a cosolvent selected from benzyl alcohol and benzyl benzoate at a level of about 10 to 30% by weight of the final composition.

[00129] In a preferred embodiment, the modified release pharmaceutical composition according to the third or fourth aspect is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) exenatide or a pharmaceutically acceptable salt thereof at a concentration of between about 60 to 140 pg/mL (conveniently about 80 pg/mL or 120 pg/mL); b) castor oil at a level of between about 70% and about 90% by weight of the final composition; and c) a cosolvent selected from benzyl alcohol, ethanol, propylene glycol, PEG 400 and benzyl benzoate at a level of between about 10% and about 30% by weight of the final composition.

[00130] In a preferred embodiment, the modified release pharmaceutical composition according to the third or fourth aspect is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) exenatide or a pharmaceutically acceptable salt thereof at a concentration of between about 40 to 140 pg/mL (conveniently about 80 pg/mL or 120 pg/mL); b) castor oil at a level of between about 70% and about 85% by weight of the final composition; and c) benzyl benzoate at a level of between about 15% and about 30% by weight of the final composition.

[00131] In a preferred embodiment, the modified release pharmaceutical composition according to the third or fourth aspect is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) exenatide or a pharmaceutically acceptable salt thereof at a concentration of between about 60 to 100 pg/mL (conveniently about 80 pg/mL); b) castor oil at a level of between about 75% and about 85% by weight of the final composition; and c) benzyl benzoate at a level of between about 15% and about 25% by weight of the final composition.

[00132] In a preferred embodiment, the total volume of the oil-based subcutaneous modified release pharmaceutical composition is between about 100 pL to about 1500 pL, conveniently about 100 pL to about 1000 pL, more conveniently about 100 pL to about 500 pL, yet more conveniently about 250 pL.

[00133] Preferred oil-based modified release pharmaceutical compositions completely solubilize the Agent (e.g. exenatide) and are visually stable for at least 7 days with no signs of precipitation. Furthermore, particular oil-based modified release pharmaceutical compositions of the invention are chemically stable and free from microbial contamination.

[00134] Particular castor oil-based compositions give an advantageous initial burst of exenatide after administration to a subject, followed by a sustained and continual release of exenatide over at least 24 hours. The initial burst may be beneficial to achieve a rapid onset of therapeutic effect (reduction in ICP), while the sustained release over 24 hours is important for maintaining control of elevated ICP following a once daily administration.

[00135] Particular castor oil-based compositions give a reduced Cmax of exenatide compared to analogous immediate release formulations. Furthermore, particular castor oil-based compositions give a delayed Cmax (i.e. a prolonged Tmax) of exenatide after administration compared to analogous immediate release formulations. By reducing and delaying the peak plasma concentrations of exenatide, whilst still providing a beneficial initial burst of the Agent, the compositions may provide effective ICP control, however, with reduced risk of orthostatic headaches or nausea associated with very high plasma drug levels.

[00136] Particular castor oil-based compositions according to the present invention accordingly have advantages related to their controlled release of Agent (e.g. 24 hour coverage), tolerability, stability and injectability for subcutaneous administration.

Protein-binding based pharmaceutical compositions

[00137] In an embodiment, the modified release pharmaceutical composition according to the third or fourth aspect of the invention is a protein-binding based pharmaceutical composition suitable for subcutaneous administration.

[00138] The term “protein-binding” refers to the binding of a drug to a protein(s) resulting in a protein-drug complex. The bound portion may act as a reservoir or depot from which the drug is slowly released as the unbound form. The extent and efficiency of release may be effected by the degree to which it binds to the protein. Furthermore, the bound protein can also transport the drug into the systemic circulation and provide a diffusion gradient allowing the drug to be released slowly.

[00139] In an embodiment, the modified release pharmaceutical composition as described herein is a protein-binding based pharmaceutical composition suitable for subcutaneous administration comprising one or more plasma proteins. In a particular embodiment, the one or more plasma proteins is selected from a, b, g globulins, glycoprotein, lipoprotein and albumin. In an embodiment, the plasma protein is albumin.

[00140] In an embodiment, the protein-binding based modified release pharmaceutical composition suitable for subcutaneous administration as described herein further comprises one or more cosolvents selected from benzyl alcohol, ethanol, polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), propylene glycol and water.

[00141] In an embodiment, the modified release pharmaceutical composition as described herein is a protein-binding based pharmaceutical composition suitable for subcutaneous administration comprising: a) the Agent in an amount of 10-100 pg, preferably 10-55 pg, more preferably 10-40 pg and yet more preferably 10-35 pg; b) one or more plasma proteins selected from a, b, g globulins, glycoprotein, lipoprotein and albumin at a level of between about 0.001-1 % by weight of the final composition; and c) one or more cosolvents selected benzyl alcohol, ethanol, polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), propylene glycol and water.

[00142] In a preferred embodiment, the modified release pharmaceutical composition as described herein is a protein-binding based pharmaceutical composition suitable for subcutaneous administration comprising: a) exenatide at a concentration of about 120 pg/mL; b) albumin; c) a cosolvent selected from benzyl alcohol and propylene glycol; and d) (optionally) a tonicity modifying agent.

[00143] Examples of suitable tonicity modifying agents include sodium chloride, potassium chloride, dextrose, lactose, sucrose, trehalose, glycerin, mannitol and glycine.

[00144] Particular protein-binding based modified release pharmaceutical compositions are stable for at least 7 days with no visible signs of precipitation.

Emulsion based pharmaceutical compositions

[00145] In an embodiment, the modified release pharmaceutical composition according to the third or fourth aspect of the invention is an emulsion based pharmaceutical composition suitable for subcutaneous administration. The emulsion based pharmaceutical composition is a multi-phase system and can have various oil and water based configurations. Conveniently, the modified release pharmaceutical composition comprising the Agent as described herein is a water-in-oil emulsion, oil-in- water emulsion, oil-in-water-in-oil emulsion or a water-in-oil-in-water emulsion based pharmaceutical composition suitable for subcutaneous administration.

[00146] Conveniently, the modified release pharmaceutical composition is a water- in-oil-based emulsion.

[00147] In an embodiment, the Agent is dissolved or dispersed in the emulsion, preferably dissolved.

[00148] In an embodiment, the Agent is dissolved in the emulsion and the concentration of the Agent in the final composition is at least 10 pg/mL, preferably at least 20 pg/mL, more preferably at least 50 pg/mL, more preferably 100 pg/mL and yet more preferably about 120 pg/mL. In an embodiment, the emulsion-based modified release pharmaceutical composition comprises the Agent at a level of between 0.001 % to 0.02% (such as about 0.012%) by weight of the final composition.

[00149] In an embodiment, the modified release pharmaceutical composition according to the third or fourth aspect is a water-in-oil-based emulsion comprising: a) a water dispersed phase; b) an oil continuous phase; and c) at least one emulsifying agent.

[00150] In an embodiment, the water dispersed phase may be water, or it may comprise water and one or more aqueous-soluble components, such as inorganic salts. In an embodiment, the water dispersed phase may be water, saline or buffer (such as pH 4.5 sodium acetate buffer). Conveniently the water dispersed phase comprises buffer, such as pH 4.5 sodium acetate buffer.

[00151] In an embodiment, the oil used to from the continuous phase comprises an oil selected from castor oil, sesame oil, safflower oil, cottonseed oil, soybean oil, peanut oil, corn oil, medium chain triglycerides and long chain triglycerides, preferably castor oil. The terms “medium chain triglycerides” and “long chain triglycerides” are defined as above.

[00152] In an embodiment, the at least one emulsifying agent is a surfactant selected from sorbitan esters, ethoxylated sorbitan esters, poloxamers, lecithins, organosulfate salts and bile salts or a combination thereof.

[00153] In an embodiment, the at least one emulsifying agent is a surfactant selected from sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, sorbitan monopalmitate, sorbitan monooleate, sorbitan trioleate, polysorbate 20, polysorbate 21 , polysorbate 40, polysorbate 60, polysorbate 61 , polysorbate 65, polysorbate 80, polysorbate 81 , polysorbate 85, lecithin, poloxamer 407, poloxamer 401 , poloxamer 237, poloxamer 338, poloxamer 231 , poloxamer 188, poloxamer 124, sodium dodecyl sulfate and bile salts or a combination thereof. Conveniently, the at least one emulsifying agent is sorbitan monooleate.

[00154] In an embodiment, the at least one emulsifying agent is present at between about 1 % to 15% by weight of the final composition, preferably about 3% or 5% by weight of the final composition.

[00155] In an embodiment, the at least one emulsifying agent is a surfactant and is present at between about 1 % to 15% by weight of the final composition, preferably between about 3% to 10% by weight of the final composition and more preferably about 3% or 5% by weight of the final composition.

[00156] In a particular embodiment, the continuous phase of the water-in-oil emulsion based modified release pharmaceutical composition comprises an oil and further comprises a cosolvent selected from benzyl alcohol, ethanol, polyethylene glycol (e.g. PEG300 and PEG400), benzyl benzoate and propylene glycol. Conveniently, the cosolvent is miscible with the oil and has minimal miscibility with the water dispersed phase. Conveniently, the cosolvent is selected from benzyl alcohol, ethanol, PEG400, benzyl benzoate and propylene glycol, more conveniently benzyl benzoate.

[00157] In an embodiment, the modified release pharmaceutical composition according to the third or fourth aspect comprises: a) exenatide or a pharmaceutically acceptable salt at a level of between about 0.001 % to 0.02% by weight of the final composition; and b) an emulsion comprising: i. a water dispersed phase at a level of between 1-15% (such as 5- 15%) by weight of the final composition; ii. a continuous phase comprising castor oil at a level of between 40- 90% by weight of the final composition and optionally one or more cosolvents selected from benzyl alcohol, ethanol, polyethylene glycols (e.g. PEG300 and PEG400), benzyl benzoate and propylene glycol wherein the total amount of cosolvent present is at a level of between 5-50% by weight of the final composition; and iii. at least one surfactant at a level of between 1-15% by weight of the final composition.

[00158] In an embodiment, the modified release pharmaceutical composition according to the third or fourth aspect comprises: a) exenatide at a concentration of between about 10 and 150 pg/mL, such as about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 or 120 pg/mL; and b) an emulsion comprising: i. a water dispersed phase at a level of about 10% by weight of the final composition; ii. a castor oil continuous phase at a level of about 85% by weight of the final composition; and iii. at least one surfactant.

[00159] Particular castor oil emulsions are stable for up to 24 hours and give an advantageous initial burst of exenatide followed by a sustained and continual release of exenatide over at least 24 hours.

[00160] In an embodiment, a process for the preparation of the water-in-oil emulsion based modified release pharmaceutical composition comprises the steps of: a) incorporating (e.g. by mixing) the Agent in a water dispersed phase; and b) combining (e.g. by mixing) the dispersed phase with the oil continuous phase (optionally containing the solvent) and the at least one emulsifying agent to provide an emulsion based modified release composition.

The Agent

[00161] The Agent is a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof. Glucagon-like peptide-1 (GLP-1 ) is an incretin hormone derived from the post-translational modification of proglucagon and secreted by gut endocrine cells. GLP- 1 mediates its actions through a specific G protein-coupled receptor, namely GLP-1 R. GLP-1 is characterized as a hormone that regulates glucose homeostasis.

[00162] As used herein, the term “GLP-1 receptor agonist”, also known as incretin mimetic, refers to compounds having glucagon-like peptide-1 (GLP-1 ) receptor agonist activity. It is to be understood that this includes the natural GLP-1 peptide (or either of the forms it is primarily secreted as, namely GLP-1 (7-37) and GLP-1 (7-36)amide) and any analogues or derivatives thereof, which also have GLP-1 receptor agonist activity. The term “agonist”, as used herein, shall mean an agent (e.g. ligand, or compound) that by virtue of binding to a GLP-1 receptor activates the receptor so as to elicit an intracellular response mediated by the receptor.

[00163] The term "analogue" includes a modified peptide wherein one or more amino acid residues of the peptide have been substituted by other amino acid residues and/or wherein one or more amino acid residues have been deleted from the peptide and/or wherein one or more amino acid residues have been added to the peptide. Such addition or deletion of amino acid residues can take place at the N-terminal of the peptide and/or at the C-terminal of the peptide. In one embodiment an analogue exhibits at least 40% (conveniently at least 50%, 60%, 70%, 80% and 90%) homology to the amino acid sequence of the native peptide. In one embodiment an analogue comprises less than 10 modifications (substitutions, deletions, additions). In another embodiment an analogue comprises less than 6 modifications (substitutions, deletions, additions) relative to the native peptide. In another embodiment an analogue comprises less than 5 modifications (substitutions, deletions, additions) relative to the native peptide. In another embodiment an analogue comprises less than 4 modifications (substitutions, deletions, additions) relative to the native peptide. In another embodiment an analogue comprises less than 3 modifications (substitutions, deletions, additions) relative to the native peptide. In another embodiment an analogue comprises less than 2 modifications (substitutions, deletions, additions) relative to the native peptide. In another embodiment an analogue comprises only a single modification (substitutions, deletions, additions) relative to the native peptide.

[00164] The term "derivative" as used herein in relation to a parent peptide/protein or analogue means a chemically modified parent peptide/protein or analogue thereof, wherein at least one substituent is not present in the parent peptide/protein or an analogue thereof. For example, a derivative would include a parent peptide/protein or an analogue thereof which has been covalently modified. Typical modifications include amides, carbohydrates, alkyl groups, acyl groups, esters, PEGylations, immunoglobulins (such as lgG4), plasma proteins (such as a, b, g globulins, glycoprotein, lipoprotein and albumin, conveniently albumin) and the like. Such entities can be directly conjugated to the parent peptide/protein or analogue thereof or be conjugated via a suitable linker. [00165] Exemplary types of GLP-1 receptor agonists include exendins, exendin analogs, GLP-1 (7-36)amide, GLP-1 (7-36)amide analogs, GLP-1 (7-37), GLP-1 (7-37) analogs, and the like.

[00166] The term “exendin” includes naturally occurring (or synthetic versions of naturally occurring) exendin peptides that are found in the salivary secretions of some beaded lizards (Heloderma). Exendins of particular interest include exendin-3, exendin-4 and exenatide, especially exendin-4 and exenatide. Exendin-4 is a 39 amino acid peptide secreted by the salivary glands of the desert Gila monster (Heloderma suspectum). Exendin-4 is a potent agonist of mammalian GLP-1 R and shares around 50% sequence homology with human GLP-1 . Exendin-3 is a peptide found in the saliva of the Mexican beaded lizard (Heloderma horridum) and differs from exendin-4 by two amino acid substitutions, Gly2-Glu3 in place of Ser2-Asp3, but is otherwise identical. Exenatide is a synthetic version of exendin-4.

[00167] The term “exendin analog” refers to peptides or other compounds which elicit a biological activity of an exendin reference peptide, preferably having a potency equal to or better than the exendin reference peptide (e.g. exendin-4), or within five orders or magnitude (plus or minus) of potency compared to the exendin reference peptide, when evaluated by art-known measures such as receptor binding and/or competition studies (Hargrove DM, Kendall ES, Reynolds JM et al. , Biological activity of AC3174, a peptide analog of exendin-4, Regulatory Pept. 2007; 141 : 113-119). In one embodiment, the term “exendin analog” refers to a peptide having at least 75% sequence identity to exendin-4. Exendin analogs include lixisenatide (Sanofi-Aventis) and albenatide (ConjuChem, Inc.). Lixisenatide is a 44-amino acid peptide based on the structure of exendin-4, with modifications consisting of a deletion of a proline residue and addition of six lysine residues at the C-terminal. Albenatide is a 40-amino acid peptide based on the structure of exendin-4, with modifications consisting of an additional lysine residue conjugated to recombinant human albumin.

[00168] As mentioned above, GLP-1 is secreted primarily in two forms, GLP-1 (7- 37) and GLP-1 (7-36)amide. The intracellular precursor to GLP-1 , GLP-1 (1 -37), is cleaved from proglucagon, and the first six amino acids are subsequently removed from the N- terminus to form bioactive peptides. About 80% of truncated GLP-1 is amidated to form GLP-1 (7-36)amide, the predominant secreted form of GLP-1 , whereas the remainder is released as GLP-1 (7-37). GLP-1 (7-37) and GLP-1 (7-36)amide have a very short physiological half-life of less than 2 minutes. This is due to the rapid cleavage of the amide bond of alanine in position 8 at the N-terminal by dipeptidyl peptidase-4 (DPP-IV), resulting in two truncated inactive forms, GLP-1 (9-36) and GLP-1 (9-37).

[00169] The term “GLP-1 (7-36) analogs” refers to peptides or other compounds which elicit an enhanced DPP-IV enzymatic stability compared to native GLP-1 (7- 36)amide and/or which elicit a biological activity of GLP-1 (7-36)amide, preferably a potency equal to or better than GLP-1 (7-36)amide, or within five orders of magnitude (plus or minus) of potency compared to GLP-1 (7-36)amide. GLP-1 (7-36) analogs of particular interest include albiglutide (GlaxoSmithKline). Albiglutide consists of two modified GLP-1 (7-36) fused in tandem to human serum albumin. The peptide sequence has a glycine to alanine replacement at position 8.

[00170] The term "GLP-1 (7-37) analogs” refers to peptides or other compounds which elicit an enhanced DPP-IV enzymatic stability compared to native GLP-1 (7-37) and/or which elicit a biological activity of GLP-1 (7-37), preferably a potency equal to or better than GLP-1 (7-37), or within five orders of magnitude (plus or minus) of potency compared to GLP-1 (7-37)amide. GLP-1 (7-37) analogs include liraglutide (Novo Nordisk), dulaglutide (Eli Lilly and Co.) and semaglutide (Novo Nordisk). Liraglutide is 97% homologous to native human GLP-1 (7-37) and contains a substitution of arginine for lysine at position 34. Liraglutide is made by attaching a C-16 fatty acid (palmitic acid) with a glutamic spacer on the remaining lysine residue at position 26 of the peptide precursor. Dulaglutide consists of a modified human GLP-1 analog sequence covalently attached to each of the two chains of a modified human immunoglobulin G4 (lgG4) heavy chain fragment (Fc) via a flexible 16 amino acid peptide with three Gly-Gly-Gly-Ser repeat sequences and an Ala residue. The GLP-1 analog is approximately 90% homologous to native GLP-1 (7-37) with amino acid substitutions at position 8, 22 and 36by a small peptide linker. The GLP-1 analog portion of dulaglutide is approximately 90% homologous to native human GLP-1 (7-37) by substituting alanine for glycine at position 8, glycine for glutamic acid at position 22 and alanine for glycine at position 36. Semaglutide is chemically similar to liraglutide, with the inclusion of two structural modifications. The first is replacement of glycine with the non-proteinogenic amino acid 2-aminoisobutyric acid (Aib) at position 2. The second is the attachment of octadecanoic diacid to the side chain of lysine at position 26 through a short polyethylene glycol (PEG) spacer and a g-glutamic acid linker. [00171] It is understood that the biological half-life of GLP-1 receptor agonists or pharmaceutically acceptable salts thereof vary. For example, according to the relevant European Summary of Product Characteristics (SmPC) or FDA product label publications, the reported mean plasma terminal half-lives for a range of marketed GLP- 1 receptor agonists are as follows:

[00172] In an embodiment, the Agent is selected from exendin-4, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide or a combination thereof.

[00173] Preferably, the Agent is a short-acting GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof. Short-acting GLP-1 receptor agonists typically have a mean plasma terminal half-life of less than approximately 12 hours, such as 2-5 hours. In a particular embodiment of the present invention, the Agent has a mean plasma terminal half-life of less than 3, 5 7 9 13 or 15 hours.

[00174] Conveniently the Agent has a mean plasma terminal half-life of less than 13 hours. More conveniently, the Agent has a mean plasma terminal half-life of less than 9 hours. Advantageously, the Agent has a mean plasma terminal half-life of less than 5 hours.

[00175] It is also to be understood that the extent to which the Agent is able to penetrate the brain will also vary. For example, different GLP-1 receptor agonists or pharmaceutically acceptable salts thereof will exhibit different levels of permeability across the blood-brain-barrier. In one particular embodiment, the Agent has a high level of brain penetration and/or high permeability across the blood-brain-barrier.

[00176] In a particular embodiment, the Agent is selected from exendin-4, exenatide and lixisenatide or a pharmaceutically acceptable salt thereof.

[00177] In a more preferred embodiment, the Agent is exendin-4 or exenatide or a pharmaceutically acceptable salt thereof.

[00178] In a preferred embodiment, the Agent is exenatide,

[00179] The Agent may be used in various solid state forms, all of which are included within the scope of the invention. These include amorphous or crystalline forms, and anhydrous forms as well as solvates of hydrates.

[00180] The GLP-1 receptor agonist may be used as a pharmaceutically acceptable salt, such as a pharmaceutically acceptable acid addition salt formed through reaction with a suitable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Q-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2- naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1 -carboxylic acid, glucoheptonic acid, 4, 4’-methylenebis-(3-hydroxy-2-ene-1 -carboxylic acid), 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid.

[00181] In a preferred embodiment, the Agent is a pharmaceutically acceptable salt of exenatide, such as exenatide acetate.

Particular compositions

[00182] In an embodiment, the modified release pharmaceutical composition is an oil-based composition as described herein and consists of: exenatide or a pharmaceutically acceptable salt thereof; one or more oils selected from castor oil, sesame seed oil, safflower oil, cottonseed oil, soybean oil, peanut oil, corn oil, medium chain triglycerides and long chain triglycerides; and optionally one or more cosolvents selected from benzyl alcohol, ethanol, polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), propylene glycol and benzyl benzoate.

[00183] In an embodiment, the modified release pharmaceutical composition is an oil-based composition as described herein and consists of: exenatide or a pharmaceutically acceptable salt thereof; one or more oils selected from castor oil, sesame seed oil, safflower oil, cottonseed oil, soybean oil, peanut oil, corn oil, medium chain triglycerides and long chain triglycerides; and one or more cosolvents selected from benzyl alcohol and benzyl benzoate.

[00184] In an embodiment, the modified release pharmaceutical composition is an oil-based composition as described herein and consists of: exenatide or a pharmaceutically acceptable salt thereof; an oil selected from castor oil, sesame seed oil, safflower oil, cottonseed oil and soybean oil; and one or more cosolvents selected from benzyl alcohol and benzyl benzoate.

[00185] In an embodiment, the modified release pharmaceutical composition is an oil-based composition as described herein and consists of: exenatide or a pharmaceutically acceptable salt thereof; castor oil; and benzyl benzoate.

[00186] In an embodiment, the modified release pharmaceutical composition is an oil-based composition as described herein and comprises: a) about 20 pg of exenatide or a pharmaceutically acceptable salt thereof; b) castor oil at a level of about 98% by weight of the final composition; and c) benzyl alcohol. [00187] In an embodiment, the modified release pharmaceutical composition as described herein comprises: a) about 20 pg of exenatide or a pharmaceutically acceptable salt thereof; b) castor oil at a level of about 98% by weight of the final composition; and c) propylene glycol.

[00188] In a preferred embodiment, the modified release pharmaceutical composition as described herein is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) exenatide or a pharmaceutically acceptable salt thereof at a concentration of between about 60 to 150 pg/mL (conveniently about 100 or 120 pg/mL); b) castor oil at a level of between about 50% to about 90% by weight of the final composition; and c) one or more cosolvents selected from benzyl alcohol, ethanol, propylene glycol, PEG 400 and benzyl benzoate wherein the total amount of cosolvent present is at a level of between about 10% to about 50% (conveniently about 20% to about 40%) by weight of the final composition.

[00189] In a preferred embodiment, the modified release pharmaceutical composition as described herein is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) exenatide or a pharmaceutically acceptable salt thereof at a concentration of between about 80 to 130 pg/mL (conveniently about 100 or 120 pg/mL); b) castor oil at a level of between about 50% to about 90% by weight of the final composition; and c) one or more cosolvents selected from benzyl alcohol, ethanol, propylene glycol, PEG 400 and benzyl benzoate wherein the total amount of cosolvent present is at a level of between about 10% to about 50% (conveniently about 20% to about 40%) by weight of the final composition; and wherein the total volume of the oil-based modified release pharmaceutical composition is between about 100 pL to about 500 pL, suitably about 250 pL. [00190] In a preferred embodiment, the modified release pharmaceutical composition as described herein is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) exenatide or a pharmaceutically acceptable salt thereof at a concentration of between about 70 to 90 pg/mL (conveniently about 80 pg/mL); b) castor oil at a level of between about 50% to about 90% by weight of the final composition; and c) one or more cosolvents selected from benzyl alcohol, ethanol, propylene glycol, PEG 400 and benzyl benzoate wherein the total amount of cosolvent present is at a level of between about 10% to about 50% (conveniently about 20% to about 40%) by weight of the final composition; and wherein the total volume of the oil-based modified release pharmaceutical composition is between about 100 pL to about 500 pL, suitably about 250 pL.

[00191] In a preferred embodiment, the modified release pharmaceutical composition as described herein is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) Exenatide or a pharmaceutically acceptable salt thereof; b) 50% to 90% w/w castor oil; and c) 10% to 50% w/w cosolvent (conveniently benzyl benzoate).

[00192] In a preferred embodiment, the modified release pharmaceutical composition as described herein is an oil-based pharmaceutical composition suitable for subcutaneous administration consisting of: a) Exenatide or a pharmaceutically acceptable salt thereof; b) 50% to 90% w/w castor oil; and c) 10% to 50% w/w cosolvent (conveniently benzyl benzoate).

[00193] In a preferred embodiment, the modified release pharmaceutical composition as described herein is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) 0.001 % to 0.02% w/w (conveniently about 0.012% w/w) exenatide or a pharmaceutically acceptable salt thereof; b) 70% to 85% w/w (such as 77% to 83% w/w) castor oil; and c) 15% to 30% w/w (such as 17% to 23% w/w) benzyl benzoate.

[00194] In a preferred embodiment, the modified release pharmaceutical composition as described herein is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) 0.001 % to 0.02% w/v (conveniently about 0.012% w/v) exenatide or a pharmaceutically acceptable salt thereof; b) 50% to 90% w/v (such as 70% to 85% w/v) castor oil; and c) 10% to 50% w/v (such as 15% to 30% w/v) benzyl benzoate.

[00195] In a preferred embodiment, the modified release pharmaceutical composition as described herein is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising: a) Exenatide or a pharmaceutically acceptable salt thereof; b) 50% to 90% v/v (such as 70% to 85% v/v) castor oil; and c) 10% to 50% v/v (such as 15% to 30% v/v) benzyl benzoate.

[00196] In a preferred embodiment, the modified release pharmaceutical composition as described herein is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising exenatide or a pharmaceutically acceptable salt thereof and 10% to 50% w/v (such as 15% to 30% w/v) benzyl benzoate; wherein the composition is made up to 100% volume with castor oil.

[00197] In a preferred embodiment, the modified release pharmaceutical composition as described herein is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising exenatide or a pharmaceutically acceptable salt thereof at a concentration of between about 70 to 130 pg/mL (conveniently about 80 pg/mL or about 120 pg/mL) and 10% to 50% w/v (such as 15% to 30% w/v) benzyl benzoate; wherein the composition is made up to 100% volume with castor oil.

[00198] In a preferred embodiment, the modified release pharmaceutical composition as described herein is an oil-based pharmaceutical composition suitable for subcutaneous administration comprising exenatide at a concentration of between about 70 to 130 pg/mL (conveniently about 120 pg/mL) and 10% to 50% w/v (conveniently about 20% w/v) benzyl benzoate; wherein the composition is made up to 100% volume with castor oil. Conveniently, the volume of this formulation that is administered to a patient is about 250 pi. [00199] In an embodiment, the modified release pharmaceutical composition as described herein is an emulsion based pharmaceutical composition and contains: a) about 20 pg of exenatide acetate; b) water at a level of about 10% by weight of the final composition; c) castor oil at a level of about 87% by weight of the final composition; and d) sorbitan monooleate.

[00200] In an embodiment, the modified release pharmaceutical composition as described herein is an emulsion based pharmaceutical composition and contains: a) about 20 pg of exenatide acetate; b) water at a level of about 10% by weight of the final composition; c) sesame oil at a level of about 87% by weight of the final composition; and d) sorbitan monooleate.

[00201] In an embodiment, the modified release pharmaceutical composition as described herein is an emulsion based pharmaceutical composition and comprises: a) about 20 pg of exenatide; b) water at a level of about 10% by weight of the final composition; c) castor oil or soybean oil at a level of about 87% by weight of the final composition; and d) sorbitan monooleate.

[00202] In an embodiment, the modified release pharmaceutical composition as described herein is an emulsion based pharmaceutical composition and comprises: a) about 20 pg of exenatide; b) water at a level of about 10% by weight of the final composition; c) castor oil; and d) sorbitan monooleate at a level of about 5% by weight of the final composition.

[00203] In a particular embodiment, the modified release pharmaceutical composition as described herein is an emulsion based pharmaceutical composition and comprises: a) exenatide at a level of between about 0.001 % to 0.02% (conveniently about 0.012%) by weight of the final composition; and b) an emulsion comprising: i. a water dispersed phase at a level of between 1-15% by weight of the final composition (conveniently about 5-15%, or about 10% by weight of the final composition); ii. a continuous phase comprising castor oil at a level of between 40- 90% by weight of the final composition and optionally one or more cosolvents selected from benzyl alcohol, ethanol, polyethylene glycols (e.g. PEG300 and PEG400), benzyl benzoate and propylene glycol wherein the total amount of cosolvent present is at a level of between 5-50% by weight of the final composition; and iii. at least one surfactant at a level of between 1-15% (conveniently about 5%) by weight of the final composition.

[00204] In a further embodiment, the modified release pharmaceutical composition as described herein is an emulsion based pharmaceutical composition and comprises: a) about 20 pg or about 35 pg of exenatide; b) an emulsion comprising: i. a water dispersed phase at a level of between 1-15% by weight of the final composition (conveniently about 5-15%, or about 10% by weight of the final composition); ii. a continuous phase comprising castor oil at a level of between 40- 90% by weight of the final composition and optionally one or more cosolvents selected from benzyl alcohol, ethanol, polyethylene glycols (e.g. PEG300 and PEG400), benzyl benzoate and propylene glycol wherein the total amount of cosolvent present is at a level of between 5-50% by weight of the final composition; and iii. at least one surfactant at a level of between 1-15% (conveniently about 5%) by weight of the final composition.

[00205] In a further embodiment, the modified release pharmaceutical composition as described herein is an emulsion based pharmaceutical composition and comprises: a) about 20 pg or about 35 pg of exenatide; b) an emulsion comprising: i. a water dispersed phase at a level of between about 1 -15% by weight of the final composition (conveniently about 5-15%, or about 10% by weight of the final composition); ii. a continuous phase at a level of between about 40-90% by weight of the final composition comprising castor oil at a level of about 50% by weight of the continuous phase, benzyl alcohol at a level of about 10% by weight of the continuous phase, ethanol at a level of about 10% by weight of the continuous phase and propylene glycol at a level of about 30% by weight of the continuous phase; and iii. at least one surfactant at a level of between 1-15% (conveniently about 5%) by weight of the final composition.

[00206] In a further embodiment, the modified release pharmaceutical composition as described herein is an emulsion based pharmaceutical composition and comprises: a) about 20 pg or about 35 pg of exenatide; b) an emulsion comprising: i. a water dispersed phase at a level of between 1-15% by weight of the final composition (conveniently about 5-15%, or about 10% by weight of the final composition); ii. a continuous phase at a level of between about 40-90% by weight of the final composition comprising castor oil at a level of about 60% by weight of the continuous phase, benzyl alcohol at a level of about 10% by weight of the continuous phase, ethanol at a level of about 10% by weight of the continuous phase and PEG 400 at a level of about 20% by weight of the continuous phase; and iii. at least one surfactant at a level of between 1-15% (conveniently about 5%) by weight of the final composition. [00207] In a preferred embodiment, the modified release pharmaceutical composition as described herein is an emulsion based pharmaceutical composition suitable for subcutaneous administration comprising: a) Exenatide or a pharmaceutically acceptable salt thereof; b) 50% to 90% w/w castor oil; c) 10% to 50% w/w cosolvent (conveniently benzyl benzoate); d) 2% to 8% w/w emulsifying agent (conveniently sorbitan monooleate); and e) 2% to 10% w/w water, saline or buffer (conveniently pH 4.5 sodium acetate buffer).

[00208] In a preferred embodiment, the modified release pharmaceutical composition as described herein is an emulsion based pharmaceutical composition suitable for subcutaneous administration consisting of: a) Exenatide or a pharmaceutically acceptable salt thereof; b) 50% to 90% w/w castor oil; c) 10% to 50% w/w cosolvent (conveniently benzyl benzoate); d) 2% to 8% w/w emulsifying agent (conveniently sorbitan monooleate); and e) 2% to 10% w/w water, saline or buffer (conveniently pH 4.5 sodium acetate buffer).

[00209] In a preferred embodiment, the modified release pharmaceutical composition as described herein is an emulsion based pharmaceutical composition suitable for subcutaneous administration comprising: a) 0.001% to 0.02% w/w (conveniently about 0.012% w/w) exenatide or a pharmaceutically acceptable salt thereof; b) 65% to 80% w/w (such as 70% to 75% w/w) castor oil; c) 15% to 30% w/w (such as 17% to 23% w/w) benzyl benzoate; d) 3% to 7% w/w sorbitan monooleate; and e) 2% to 6% w/w pH 4.5 sodium acetate buffer.

[00210] In a preferred embodiment, the modified release pharmaceutical composition as described herein is an emulsion based pharmaceutical composition suitable for subcutaneous administration comprising: a) 0.001% to 0.02% w/v (conveniently about 0.012% w/v) exenatide or a pharmaceutically acceptable salt thereof; b) 65% to 80% w/v (such as 70% to 75% w/v) castor oil; c) 15% to 30% w/v (such as 17% to 23% w/v) benzyl benzoate; d) 3% to 7% w/v sorbitan monooleate; and e) 2% to 6% w/v pH 4.5 sodium acetate buffer.

[00211] In a preferred embodiment, the modified release pharmaceutical composition as described herein is an emulsion based pharmaceutical composition suitable for subcutaneous administration comprising: a) Exenatide or a pharmaceutically acceptable salt thereof; b) 65% to 80% v/v (such as 70% to 75% v/v) castor oil; c) 15% to 30% v/v (such as 17% to 23% v/v) benzyl benzoate; d) 3% to 7% v/v sorbitan monooleate; and e) 2% to 6% v/v pH 4.5 sodium acetate buffer. Dosing

[00212] The amount of the Agent required in the modified release composition of the invention for the therapeutic or prophylactic treatment of a particular disease or medical condition will necessarily be varied depending on for example, the host being treated and the severity of the illness being treated. Indeed, the amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.00005 to about 2 mg per kg body weight per day, preferably about 0.0001 to about 0.002 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.007 to 0.14 mg/day (i.e. 7 to 140 pg/day), preferably about 0.01 to about 0.10 mg/day (i.e. 10 to 100 pg/day). In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.

[00213] A unit dose of the composition will usually contain, for example 5-150 pg of active ingredient, and preferably 10-100 pg of active ingredient. Preferably a daily dose selected from any of the following is envisaged, 5pg, 10pg, 20pg, 30pg, 35pg, 50pg, 75pg, 100pg, 125pg and 150pg. In a particular embodiment, the daily dose is 20pg or 35pg. In a particular embodiment, the daily dose is 10pg, 20pg or 30pg. In a particular embodiment, the Agent is exenatide and the daily dose is 10pg, 20pg or 30pg. It will be understood that a broad range of doses is considered to account for the diverse needs of the clinical population which may show differences in exposure as well as differences in exposure from different formulations.

[00214] Typically the Agent will be present in the composition of the invention in an amount within the range of from 0.001 to 0.02% weight per weight, suitably from about 0.002 to 0.015% weight per weight and especially from about 0.008 to 0.013% weight per weight of the composition. In a particular embodiment, the Agent will be present in the composition of the invention in an amount of about 0.012% weight per volume of the composition (i.e. about 120 pg/mL). It is to be understood that the term ‘about’ when relating to the proportion of Agent present in the composition refers to ± 2% by weight of the total composition.

[00215] In an embodiment, the modified release pharmaceutical composition as described herein is administered once daily at any time during the day. For example, administration may be upon waking or prior to sleep onset.

[00216] As shown by the data described herein, the Applicant has discovered that in IIH patients ICP levels increase overnight during sleep (see Example 11 and Figure 9). It has also been demonstrated that the treatment of IIH patients with subcutaneous exenatide can prevent the overnight ICP increases from occurring (see Example 12 and Figure 11 ). It is therefore postulated that once daily dosing of exenatide might be most efficacious at managing elevated ICP in IIH patients, when administered within a short period prior to sleep onset. [00217] In an embodiment, a composition comprising the Agent is administered once daily within two hours prior to sleep onset. Conveniently, the composition comprising the Agent is administered once daily as a 10 pg or 20 pg dose within two hours prior to sleep onset, such as within one hour of sleep onset and yet more conveniently within 30 minutes of sleep onset. More conveniently, there is provided a composition comprising exenatide or a pharmaceutically acceptable salt thereof, wherein the composition is administered subcutaneously once daily as a 10 pg or 20 pg dose within two hours prior to sleep onset, such as within one hour of sleep onset and yet more conveniently within 30 minutes of sleep onset. In an embodiment, the composition comprising the Agent is a modified release composition as described herein. Therefore, conveniently, the modified release pharmaceutical composition as described herein is administered once daily within two hours prior to sleep onset, more conveniently within one hour prior to sleep onset and yet more conveniently within 30 minutes prior to sleep onset. More conveniently, the modified release composition comprises exenatide or a pharmaceutically acceptable salt thereof and is administered subcutaneously once daily as a 10 pg, 20 pg, or 30 pg dose within two hours prior to sleep onset, such as within one hour of sleep onset and yet more conveniently within 30 minutes of sleep onset.

[00218] Administration may be before or after a meal. Specifically, administration may be less than 1 hour before a meal or more than one hour before a meal. Administration may be less than one hour after a meal or more than one hour after a meal. Conveniently, administration is at the same time or about the same time each day.

[00219] In a particular embodiment, the modified release pharmaceutical composition as described herein is administered once daily prior to sleep onset.

[00220] In a more preferred embodiment, the modified release pharmaceutical composition as described herein is administered once daily prior to sleep onset and after a meal.

Medical Uses

[00221] In an aspect of the present invention, there is provided a modified release pharmaceutical compositions as described herein for use in therapy.

[00222] There is also provided a method for treating a warm blooded animal, preferably a human suffering from a condition treatable by the Agent comprising administered thereto a modified release pharmaceutical composition as described herein. [00223] In further aspect of the present invention, there is provided a modified release pharmaceutical composition as described herein for use in a method of reducing elevated intracranial pressure (ICP). In a further aspect of the present invention, there is provided a modified release pharmaceutical composition as described herein for use in a method of treating a disorder associated with elevated intracranial pressure (ICP).

[00224] In a further aspect of the present invention, there is provided a method of reducing elevated intracranial pressure (ICP) in a warm blooded animal, preferably a human suffering from elevated ICP, the method comprising administering to said warm blooded animal a modified release pharmaceutical composition as described herein. In a further aspect of the present invention, there is provided a method of treating a disorder associated with elevated intracranial pressure (ICP) in a warm blooded animal, preferably a human suffering from a disorder associated with elevated intracranial pressure (ICP), the method comprising administering to said warm blooded animal a modified release pharmaceutical composition as described herein.

[00225] In a further aspect of the present invention, there is provided use of a modified release pharmaceutical composition as described herein for the manufacture of a medicament for reducing elevated intracranial pressure (ICP). In a further aspect of the present invention, there is provided use of a modified release pharmaceutical composition as described herein for the manufacture of a medicament for treating a disorder associated with elevated intracranial pressure.

[00226] In a further aspect of the present invention, there is provided use of a modified release pharmaceutical composition as described herein for reducing elevated intracranial pressure (ICP). In a further aspect of the present invention, there is provided use of a modified release pharmaceutical composition as described herein for treating a disorder associated with elevated intracranial pressure (ICP).

Elevated ICP

[00227] Elevated ICP is typically characterized by intracranial pressure of greater than 20-25 mmHg for more than 5 minutes (Roytowski et al. Raised intracranial pressure: What it is and how to recognize it, Continuing Medical Education, 2013; 31 (3): 85-90). Headache, vomiting and visual disturbances are common symptoms associated with elevated ICP. Multiple techniques for monitoring ICP exist: invasive as well as noninvasive. Noninvasive monitoring techniques include transcranial doppler, tympanic membrane displacement optic nerve sheath diameter, CT scan/MRI and fundoscopy. Several different invasive methods of measuring ICP exist. Depending on the technique, ICP measuring can be undertaken in different intracranial anatomical locations: intraventricular, intraparaenchymal, epidural, subdural and subarachnoidal. Additionally, in patients with communicating CSF pathways, ICP may under certain circumstances be assessed by lumbar puncture (Raboel et al. Intracranial Pressure Monitoring: Invasive versus Non-lnvasive Methods - A Review, Volume 2012, Article ID 950393, 14 pages).

[00228] The Applicants have performed a pressure physiology study to investigate diurnal ICP changes in IIH patients with monitoring achieved by use surgically implanted telemetric ICP devices inserted under general anesthesia to the right frontal lobe. The Applicant has surprisingly found that in female IIH patients, diagnosed according to the modified Dandy criteria who had active disease (papilloedema [Frisen grade ^ 1], significantly raised ICP > 25cmH20) and no evidence of venous sinus thrombosis (magnetic resonance imaging (MRI) or computerised tomography (CT) imaging and venography as noted at diagnosis), ICP fell abruptly when participants fell asleep but then began to rise. Indeed, it was found that ICP was markedly higher whilst asleep than when awake (7.2 +/- 0.72 mmHg) despite the variability in sleeping position. Further details of the study are described in Example 11 and results are also shown in Figure 9.

[00229] The Applicant has also surprisingly found that particular modified release pharmaceutical compositions as described herein are able to reduce the elevated ICP by at least 20%, preferably by at least 25% and more preferably by at least 30% for continued periods of time (such as over a period of 12 weeks of daily dosing of the composition).

[00230] In a particular aspect of the present invention, the disorder associated with elevated intracranial pressure is selected from idiopathic intracranial hypertension (IIH) and its various subtypes (e.g. idiopathic intracranial hypertension without papilloedema (IIHWOP), fulminant IIH, typical IIH, atypical IIH and IIH in ocular remission), secondary pseudo-tumour cerebri, hydrocephalus, normal pressure hydrocephalus, raised intracranial pressure secondary to a brain tumour or meningitis, raised intracranial pressure associated with primary mild traumatic brain injury, primary moderate traumatic brain injury or primary severe traumatic brain injury, venous sinus thrombosis, headache associated with raised intracranial pressure, raised intracranial pressure associated with primary intracerebral hemorrhage, ischemic or hemorrhagic stroke and raised intracranial pressure associated with subarachnoid hemorrhage. [00231] In a particular preferred embodiment, the disorder associated with elevated ICP is selected from idiopathic intracranial hypertension (IIH) or raised intracranial pressure associated with primary mild traumatic brain injury, primary moderate traumatic brain injury or primary severe traumatic brain injury.

[00232] In a particular more preferred embodiment, the disorder associated with elevated intracranial pressure is idiopathic intracranial hypertension (IIH).

[00233] Idiopathic intracranial hypertension is characterised by signs and symptoms of raised intracranial pressure with no established pathogenesis. The disorder is strongly associated with obesity, and patients are mostly female and typically of reproductive age. Common symptoms of idiopathic intracranial hypertension include headaches, visual loss, pulsatile tinnitus, and back and neck pain, but the clinical presentation is highly variable, which can lead to delays in diagnosis. If left untreated, the disorder can lead to substantial visual morbidity (Markey et al. , Understanding idiopathic intracranial hypertension: mechanisms, management, and future directions, The Lancet, 2016, 15: 78-91 ). Weight loss is the most effective treatment. Other pharmaceutical based treatments commonly prescribed for IIH, such as Acetazolamide or Topiramate, are unapproved for use in IIH and have little evidence to support their use and are broadly considered by neurologists as ineffective. A lack of effective drugs means that some IIH patients currently undergo neurosurgery to reduce brain pressure and prevent blindness, resulting in a three-fold increase in such procedures in the United States (US) between 1988-2002.

[00234] Papilloedema is a serious consequence of IIH and refers to swelling of the intraocular (prelaminar) portion of the optic nerve head, and in IIH, takes place as a result of elevated ICP. If severe papilloedema is not recognized and treated early, extended ischaemia from failed perfusion of the optic nerve head could result in optic atrophy, leading to permanent visual loss. The extent of papilloedema can be monitored by optical coherence tomography (OCT), a non-invasive imaging method that uses reflected infrared light to obtain high-resolution, cross-sectional images of subsurface structures (Markey et al., Understanding idiopathic intracranial hypertension: mechanisms, management, and future directions, The Lancet, 2016, 15: 78-91 ).

[00235] By providing a modified release pharmaceutical composition as described herein that maintains therapeutic plasma concentrations of the Agent throughout at least a 20 hour period and provides a drug release profile that is tailored to address natural variations in ICP it may be possible to prevent or treat papilloedema (by reducing elevated ICP) thereby preventing or treating visual impairment and/or visual loss associated with papilloedema.

[00236] Visual acuity is acuteness or clearness of vision, especially form vision, which is dependent on the sharpness of the retinal focus within the eye, the sensitivity of the nervous elements, and the interpretative faculty of the brain. It can be measured by using a LogMAR chart (Logarithm of the Minimum Angle of Resolution), also called a Bailey-Lovie chart or an ETDRS chart (Early Treatment Diabetic Retinopathy Study). This chart consists of rows of letters and is used by ophthalmologists, orthoptists, optometrists, and vision scientists to estimate visual acuity. The LogMAR units can be used as a measure to monitor improvement and visual acuity gain.

[00237] In an embodiment, a composition comprising the Agent improves the visual acuity of a patient. In an embodiment, a composition comprising the Agent improves the visual acuity of a patient suffering from IIH. In an embodiment, a composition comprising the Agent improves the logMAR by at least one line in a patient suffering from IIH.

[00238] In an embodiment, a modified release pharmaceutical composition as described herein improves the visual acuity of a patient. In an embodiment, a modified release pharmaceutical composition as described herein improves the visual acuity of a patient suffering from IIH. In an embodiment, a modified release pharmaceutical composition as described herein improves the logMAR by at least one line in a patient suffering from IIH.

Combination Therapies

[00239] Pharmaceutical compositions of the present invention may be administered alone as a sole therapy or can be administered in addition with one or more other substances and or treatments. Such conjoint treatment may be achieved by way of simultaneous, sequential or separate administration of the individual components of the treatment.

[00240] For example, therapeutic effectiveness may be enhanced by administration of an adjuvant (i.e. , by itself the adjuvant may only have minimal therapeutic benefit, but the combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Or, by way of example only, the benefit experienced by an individual may be increased by administering the Agent with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. By way of example only, in a treatment for IIH, increase therapeutic benefit may result by also providing the individual with another therapeutic agent for IIH. Or, the additional therapy or therapies may include, but are not limited to general and physiologic management such as cerebrospinal fluid removal, fluid restriction, controlled hyperventilation, sedation, and elevating the patients head; pharmacologic management such as osmotic diuretics, loop diuretics, corticosteroids and barbiturates; and the like.

[00241] In the instances where the Agent is administered in combination with other therapeutic agents, the Agent need not be administered via the same route as other therapeutic agents, and may, because of different physical and chemical characteristics be administered by a different route. For example, the Agent may be subcutaneous to generate and maintain good blood levels thereof, while the other therapeutic agent may be administered orally. The initial administration may be made according to established protocols known the art and/or described herein, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[00242] The particular choice of other therapeutic will depend upon the diagnosis of the attending physicians and their judgement of the condition of the individual and the appropriate treatment protocol. In some embodiments, the additional agent is for the treatment of idiopathic intracranial hypertension (IIH).

[00243] In some embodiments, the additional agent is a carbonic anhydrase inhibitor. Examples of carbonic anhydrase inhibitors include but are not limited to acetazolamide, furosemide or topiramate. In some embodiments, the additional agent is a DPP-IV inhibitor. Examples of DPP-IV inhibitors include but are not limited to vildagliptin, saxagliptin, azetidine, sitagliptin, omarigliptin, alogliptin and linagliptin.

[00244] In an embodiment, a modified release pharmaceutical composition as described herein, further comprises a second active agent selected from a carbonic anhydrase inhibitor (such as acetazolamide, furosemide or topiramate), a DPP-IV inhibitor (such as vildagliptin, saxagliptin, azetidine, sitagliptin, omarigliptin, alogliptin and linagliptin), and a long acting GLP-1 receptor agonist (such as liraglutide, albiglutide, dulaglutide and semaglutide).

Kits [00245] In one embodiment, the modified release pharmaceutical compositions and methods described herein provide kits for the treatment of disorders, such as the one described herein. These kits comprise a modified release pharmaceutical composition described herein in a container and, optionally, instructions teaching the use of the kit according to the various methods and approaches described herein. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. Kits described herein can be provided, marketed and/or promoted to health provides, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer.

[00246] The modified release pharmaceutical compositions of the invention may be utilized for diagnostics and as research tools. For example, the modified release pharmaceutical compositions containing the Agent, either alone or in combination with other compounds, can be used as tools in differential and/or combinatorial analyses to elucidate expression patterns of genes expressed within cells and tissues.

[00247] Besides being useful for human treatment, modified release pharmaceutical compositions of the invention, may be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. Conveniently, such animals include horses, dogs and cats.

[00248] The following numbered statements are not claims, but refer to certain aspects and embodiments of the invention:

1 . A modified release pharmaceutical composition comprising the Agent, wherein said composition, after administration to a subject in need of treatment thereof: a. maintains in the subject a geometric mean plasma concentration of the Agent of at least 2 pg/mL throughout at least a 20 hour period; and b. releases at least 50% by weight of the total amount of the Agent contained within the modified release pharmaceutical composition within a period of 36 hours after administration. A modified release pharmaceutical composition according to statement 1, wherein said administration is by means of subcutaneous administration. A modified release pharmaceutical composition according to statement 1 or 2, wherein said composition, after administration to a subject in need of treatment thereof maintains in the subject a geometric mean plasma concentration of the Agent of at least 3 pg/mL throughout at least a 20 hour period (conveniently a 24 hour period) and more preferably at least 4 pg/mL throughout at least a 20 hour period (conveniently a 24 hour period). A modified release pharmaceutical composition according to any one of statements 1 to 3, wherein said composition, after administration to a subject in need of treatment thereof, releases at least 70%, 80%, 90% or 100% by weight of the total amount of the Agent contained within the modified release pharmaceutical composition within a period of 36 hours after administration. A modified release pharmaceutical composition according to any one of statements 1 to 4, wherein said composition, after administration to a subject in need of treatment thereof produces for at least the first 3 hours after administration a geometric mean plasma concentration of the Agent of at least 3 pg/mL, preferably at least 5 pg/mL and more preferably at least 7 pg/mL. A modified release pharmaceutical composition according to any one of statements 1 to 5, wherein said composition, after administration to a subject in need of treatment thereof produces in the subject a geometric mean concentration of the Agent at 20 hours after administration (C20) of at least 5 pg/mL, preferably at least 6 pg/mL and more preferably at least 7 pg/mL. A modified release pharmaceutical composition according to any one of statements 1 to 6, wherein said composition, after administration to a subject in need thereof produces in the subject a geometric mean maximum plasma concentration (Cmax) of the Agent of between 80 pg/mL and 280 pg/mL. A modified release pharmaceutical composition according to any one of statements 1 to 7, wherein said composition, after administration to a subject in need thereof produces a ratio of Cmax/AUCo-24 between 0.04 and 0.14 hr 1 , preferably between 0.07 and 0.14 hr 1 . 9. A modified release pharmaceutical composition according to any one of statements 1 to 8, wherein said composition is administered to the subject to provide a dose of the Agent in a range of 10-100 pg, preferably 15-55 pg, more preferably 15-40 pg and yet more preferably 20-35 pg.

10. A modified release pharmaceutical composition according to any one of statements

1 to 9, wherein said composition contains 10-100 pg, preferably 15-55 pg, more preferably 15-40 pg and yet more preferably 20-35 pg of the Agent.

11. A modified release pharmaceutical composition according to any one of statements

2 to 10, wherein said composition, after subcutaneous administration to a subject in need of treatment thereof produces a geometric mean plasma concentration of the Agent at 1 hour after administration of at least 20 pg/mL.

12. A modified release pharmaceutical composition according to any one of statements 2 to 10, wherein after subcutaneous administration at a dose of about 20 pg to a subject in need of treatment thereof the composition produces a geometric maximum plasma concentration (Cmax) of the Agent of between 80 pg/mL and 230 pg/mL and an AUCo-24 of between about 700 pg.hr/ml_ and 1200 pg.hr/ml_.

13. A modified release pharmaceutical composition according to any one of the preceding statements, wherein after administration to a subject in need of treatment thereof the composition produces a mean maximum plasma concentration (Cmax) at a time (Tmax) no later than 5 hours after administration.

14. A modified release pharmaceutical composition according to any one of the preceding statements, wherein the subject in need of treatment thereof is a human subject.

15. A modified release pharmaceutical composition comprising the Agent, wherein said composition is an aqueous based, an in-situ gelling system based, an oil-based, a protein-binding based, a viscous depot based or an emulsion based pharmaceutical composition suitable for subcutaneous administration, preferably an oil-based or emulsion based pharmaceutical composition for subcutaneous administration.

16. A modified release pharmaceutical composition according to statement 15, wherein the composition is an oil-based pharmaceutical composition for subcutaneous administration. 17. A modified release pharmaceutical composition according to statement 16 comprising: a) the Agent in an amount of 10-100 pg, preferably 15-55 pg, more preferably 15-40 pg and yet more preferably 20-35 pg; b) one or more oils selected from castor oil, sesame seed oil, safflower oil, cottonseed oil, soybean oil, peanut oil, corn oil, medium chain triglycerides and long chain triglycerides wherein the total amount of oil present is at a level of between about 60 to about 99% (conveniently about 70% to about 90%) by weight of the final composition; and c) one or more cosolvents selected from benzyl alcohol, ethanol, polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), propylene glycol and benzyl benzoate wherein the total amount of cosolvent present is at a level of between about 1 to about 50% (conveniently about 10% to about 30%) by weight of the final composition.

18. A modified release composition according to statement 16 comprising: a) The Agent at a concentration of between about 80 to 150 pg/mL (conveniently about 120 pg/mL); b) an oil selected from castor oil, cottonseed oil, safflower oil, sesame oil and soybean oil at a level of between about 50% to about 90% by weight of the final composition; and c) one or more cosolvents selected from benzyl alcohol, ethanol, propylene glycol and PEG 400 wherein the total amount of cosolvent present is at a level of between about 10% to about 50% (conveniently about 20% to about 40%) by weight of the final composition.

19. A modified release pharmaceutical composition according to statement 15, wherein the composition is a water in oil-based emulsion.

20. A modified release pharmaceutical composition according to statement 19, wherein the Agent is dissolved in the emulsion and the concentration of the Agent in the final composition is at least 10 pg/mL, preferably at least 15 pg/mL, more preferably at least 20 pg/mL, more preferably at least 100 pg/mL and yet more preferably about 120 pg/mL.

21. A modified release pharmaceutical composition according to any one of statements 19 or 20, wherein the emulsion comprises: a) a water dispersed phase; b) an oil continuous phase; and c) at least one emulsifying agent. A modified release pharmaceutical composition according to statement 21 , wherein the oil used to form the continuous phase is an oil selected from castor oil, sesame oil, safflower oil, cottonseed oil, soybean oil, peanut oil, corn oil, medium chain triglyceride and long chain triglycerides, conveniently castor oil. A modified release pharmaceutical composition according to statement 21 or 22, wherein the emulsifying agent is a surfactant selected from sorbitan esters, ethoxylated sorbitan esters, poloxamers, lecithins, organosulfate salts and bile salts or a combination thereof, conveniently sorbitan esters. A modified release pharmaceutical composition according to statement 23, wherein the emulsifying agent is a sorbitan ester selected from sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, sorbitan monopalm itate, sorbitan monooleate or sorbitan trioleate, conveniently sorbitan monooleate. A modified release pharmaceutical composition according to statements 23 or 24, wherein the surfactant is present at between 1 to 15% by weight of the final composition, preferably about 3% or about 5% by weight of the final composition. A modified release pharmaceutical composition according to any one of statements 23 to 25, wherein the composition further comprises a cosolvent selected from benzyl alcohol, ethanol, PEG300, PEG400 and propylene glycol, conveniently benzyl alcohol. A modified release pharmaceutical composition according to any one of the preceding statements, wherein the Agent is selected from exendin-4, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide and semaglutide, preferably exendin- 4, exenatide or lixisenatide, A modified release pharmaceutical composition according to any one of the preceding statements, wherein the Agent is exendin-4 or exenatide. A modified release pharmaceutical composition according to any one of statements 19 to 26, wherein the composition comprises: a) exenatide at a level of between 0.001% to 0.02% by weight of the final composition; and b) an emulsion comprising: i. a water dispersed phase at a level of between 5-15% by weight of the final composition; ii. a continuous phase comprising castor oil at a level of between 40- 90% by weight of the final composition and optionally one or more cosolvents selected from benzyl alcohol, ethanol, polyethylene glycol, benzyl benzoate and propylene glycol wherein the total amount of cosolvent present is at a level of between 5-50% by weight of the final composition; and iii. at least one surfactant at a level of between 1-15% by weight of the final composition. A modified release pharmaceutical composition according to any one of statements 19 to 26, wherein the composition comprises: a) exenatide at concentration of about 20 pg/mL of the final composition; and b) an emulsion comprising: i. a water dispersed phase at a level of about 10% by weight of the final composition; ii. a castor oil continuous phase at a level of between 85% by weight of the final composition; and iii. at least one surfactant at a level of between 5% by weight of the final composition. A modified release pharmaceutical composition according to any one of statements 16 to 30, wherein the modified release pharmaceutical composition is a subcutaneous composition and the total volume of the modified release pharmaceutical composition is between about 100 pl_ to about 1500 mI_, conveniently about 100 mI_ to about 1000 mI_, more conveniently about 100 mI_ to about 500 mI_, yet more conveniently about 250 mI_. A modified release pharmaceutical composition according to any one of statements 1 to 31 for use in therapy. 33. A modified release pharmaceutical composition according to any one of statements 1 to 31 for use in a method of reducing elevated intracranial pressure (ICP) or a method of treating a disorder associated with elevated intracranial pressure.

34. A modified release pharmaceutical composition for use according to statement 33, wherein the disorder associated with elevated intracranial pressure is selected from idiopathic intracranial hypertension (IIH) and its various subtypes (e.g. idiopathic intracranial hypertension without papilloedema (IIHWOP), fulminant IIH, typical IIH, atypical IIH and IIH in ocular remission), secondary pseudo-tumour cerebri, hydrocephalus, normal pressure hydrocephalus, raised intracranial pressure secondary to a brain tumour or meningitis, raised intracranial pressure associated with primary mild traumatic brain injury, primary moderate traumatic brain injury or primary severe traumatic brain injury, venous sinus thrombosis, headache associated with raised intracranial pressure, raised intracranial pressure associated with primary intracerebral haemorrhage, ischemic or haemorrhagic stroke and raised intracranial pressure associated with subarachnoid haemorrhage.

35. A modified release pharmaceutical composition for use according to statement 33, wherein the disorder associated with elevated intracranial pressure is idiopathic intracranial pressure (IIH).

36. A modified release pharmaceutical composition for use according to any one of statements 32 to 35, wherein the composition is administered once daily.

37. A modified release pharmaceutical composition for use according to statement 36, wherein the composition is administered once daily within two hours prior to sleep onset.

38. A modified release pharmaceutical composition for use according to statement 37, wherein the composition is administered once daily after a meal and within two hours prior to sleep onset.

39. A method for treating a warm blooded animal, preferably a human suffering from a condition treatable by the Agent comprising administering thereto a pharmaceutical composition according to any one of statements 1 to 31.

40. A pharmaceutical composition according to any one of statements 1 to 31 , further comprising a second active agent selected from a carbonic anhydrase inhibitor (such as acetazolamide, furosemide or topiramate) or a DPP-IV inhibitor (such as vildagliptin, saxagliptin, azetidine, sitagliptin, omarigliptin, alogliptin and linagliptin).

41. A process for the preparation of a modified release pharmaceutical composition according to any one of statements 21 to 31 , the process comprising the steps of: a) incorporating (e.g. by mixing) the Agent in a water dispersed phase; b) combining (e.g. by mixing) the dispersed phase with the oil continuous phase (optionally containing a cosolvent) and the at least one emulsifying agent to provide an emulsion based modified release composition.

[00249] The invention is illustrated below by the following non-limiting examples. EXAMPLES

Excipients and chemicals

[00250] The excipients and chemicals referred to in the Examples were obtained from the sources indicated in Table 1.

Table 1. EXAMPLE 1: Exenatide acetate solubility in a range of solvents and oils

Methodology

[00251] Aliquots (~1 mg) of exenatide acetate were added to 1 mL of solvents or oils and the mixture shaken, vortexed or sonicated at ambient room temperature. If the aliquot of compound fully dissolved a further aliquot was added. This process was repeated until the compound no longer fully dissolved. The maximum solubility is reported as greater than the final concentration of compound that fully dissolved and less than the concentration of the next aliquot. Experiments were designed to investigate whether a target solubility of at least 20 pg/mL could be achieved.

Results

[00252] Solubility of exenatide acetate in solvents (benzyl alcohol, ethanol, PEG300, PEG400 and propylene glycol) and oils (castor oil, cottonseed oil, safflower oil, sesame oil and soybean oil) are shown in Table 2. [00253] Exenatide acetate was found to be soluble in all solvents at the target concentration of 20 pg/mL. The solvents in which solubility was highest were benzyl alcohol, propylene glycol and PEG 400. Benzyl alcohol and propylene glycol stock formulations remained stable for >14 days, whereas the PEG 400 precipitated after 5 days. Table 2. Exenatide acetate solubility in solvents and oils EXAMPLE 2: Determination of compound solubility in aqueous-based systems

Methodology

[00254] Exenatide acetate dissolved in the best solvents identified in the experiments described in Example 1 (i.e. benzyl alcohol, PEG400 and propylene glycol) were added to 1 mL of aqueous vehicle containing viscosity enhancing agents, stability enhancing agents and/or pH controlling agents to give a target concentration of 20 pg/mL. If precipitation occurred, small amounts of co-solvents were added, and different combinations of excipients were investigated to ensure drug was solubilized. The resulting mixtures prepared were stored at ambient conditions with a view of determining the physical stability of the formulations (i.e. occurrence of precipitation). If precipitation was observed, reformulation took place aiming to find a formulation that did not precipitate.

Results

[00255] The highest concentrations observed for the compound exenatide acetate in the aqueous-based formulations are shown in Table 3. All aqueous formulations were visually stable for at least 7 days with no signs of precipitation.

Table 3. Exenatide acetate solubility in aqueous-based systems EXAMPLE 3: Development of in-situ gelling systems

Methodology

[00256] Experiments were undertaken to determine whether exenatide acetate could be formulated with agents known to form gels or liquid crystalline phases at physiological conditions. If drug precipitation occurred, the vehicle was reformulated to identify an alternative composition, whereby the drug was solubilized and remained in solution. The pH and/or temperature (dependent on the gelling trigger for the agent being investigated) was measured and recorded. Results

The highest concentrations observed for the compound exenatide acetate in the in-situ gelling systems is shown in Table 4.

Table 4. Exenatide acetate solubility in in-situ gelling systems EXAMPLE 4: Development of oil-based depot systems

Methodology

[00257] Exenatide acetate was investigated for its use in an oil-based system. Numerous oils were tested for their ability to solubilize exenatide acetate. Different oils were tested as their differing properties meant that they would retain the drug for different periods of time.

[00258] An exenatide acetate in solvent (water, benzyl alcohol or propylene glycol) solution was made at a stock concentration of 1 mg/mL. 2 mg of exenatide was weighed into a clean vial, and 2 mL of solvent was added. This was then vortexed for ~30 seconds. 9.8 g of oil was accurately weighed into a vial. 200 mI_ of the exenatide solvent stock was then added and the mixture was vortexed for ~2 minutes. The resulting formulation was at a concentration of 20 pg/mL.

Results [00259] The highest concentrations observed for compound exenatide acetate in the oil-based depot formulations are shown in Table 5. All oil-based formulations where exenatide acetate was completely solubilised were visually stable for at least 7 days with no signs of precipitation.

Table 5. Exenatide acetate solubility in oil-based systems Exenatide 2% w/v propylene glycol, 20 pg/mL A clear formulation was produced after - -2

Acetate 98% w/v soybean oil minutes of vortexing.

All oil-based formulations where exenatide was completely solubilised were visually stable for at least 7 days with no signs of precipitation.

EXAMPLE 5: Development of protein-binding systems

Methodology

[00260] Experimental studies were undertaken to investigate whether a protein- binding system could solubilize the drug. Protein-binding molecules were used, and if precipitation occurred, some solubility enhancing agents were added with the aim of formulating a protein-binding system that allowed sufficient solubility of exenatide acetate.

Results

[00261] The highest concentrations observed for compound exenatide in the protein-based depot formulations are shown in Table 6.

Table 6. Exenatide acetate solubility in protein-binding systems

EXAMPLE 6: Development of viscous depot systems

Methodology [00262] Exenatide acetate was investigated for its use in a viscous system, sucrose acetate isobutyrate (SAIB). SAIB is a clear liquid with very high viscosity which is soluble in organic solvents. SAIB is combined with a solvent to reduce viscosity and increase injectability. Once injected, the solvent disperses and leaves the viscous depot which slowly erodes to produce a slow release of drug. Investigations were carried out to investigate whether exenatide acetate could be pre-dissolved in benzyl alcohol and then combined with ethanol and SAIB.

Results

Table 7. Exenatide acetate solubility in viscous depot system EXAMPLE 7: Development of an emulsion-based depot system

Methodology

[00263] Experimental investigations were undertaken to see if a stable water in oil emulsion could be formulated with exenatide acetate.

[00264] An exenatide acetate in water stock solution was made at a concentration of 1 mg/mL. 2 mg of exenatide acetate was weighed into a clean vial, and 2 mL of water was added. This was then vortexed for ~30 seconds.

[00265] An amount of oil (e.g. 8.5, 8.7, 8.8 or 8.9 g) was weighed into a vial. Am amount of sorbitan monooleate (e.g. 0.1 , 0.2, 0.3 or 0.5 g), was added and the mixture was vortexed.

[00266] 1 mL of the exenatide water stock was diluted 1 :5 to achieve a stock concentration of 200 pg/mL. 1 mL of this was then added to the oil and surfactant mix and homogenized using an IKA® UltraTurrax® for 5 minutes. The resulting formulation was at a concentration of 20 pg/mL.

Results

[00267] The highest concentrations observed for compound exenatide acetate in the putative preclinical formulations are shown in Table 8.

Table 8. Exenatide acetate solubility in modified release-based systems EXAMPLE 8: In-vitro release testing of lead formulations

Methodology

[00268] The lead formulations from each system were tested in vitro to assess their ability to control the release of drug over a 24-hour period. For the oil-based formulations, viscous systems and water in oil emulsion formulations, a simple test could be performed as addition of buffer produced 2 layers - a receptor (formulation) and receiver (buffer). 1 mL of pH 7.4 phosphate-buffered saline (PBS) buffer was placed on top of 1 mL of formulation in 4 mL vials and were placed in a water bath at 37 °C for 24 hours (Figure 1 ).

[00269] Samples were taken from the buffer at 1 , 2, 3, 4, 5, 6 and 24 hours, and analysis was performed with HPLC using the method conditions and gradient described in Tables 9 and 10 respectively. Samples were taken from the buffer and analyzed neat (i.e. no dilution) due to the low concentration of exenatide acetate present in the formulations. Standards were prepared by dissolving an accurate amount of drug substance batch to a volumetric flask and making up to volume with 50:50 acetonitrile:water - a calibration curve was then made by diluting the top standard.

Table 9. HPLC conditions

Table 10. HPLC gradient [00270] This produced a release profile of exenatide from the formulations which could be compared to each other, and against the control (exenatide in water).

[00271] In vitro release testing could not be performed in this way on the aqueous, albumin-based or chitosan formulations as the buffer diluted the sample and did not provide distinct donor and receptor layers as seen above. Results

[00272] The formulations chosen for in vitro release tests were formulations that gave suitable solubility of exenatide at the required concentration (20 pg/mL). Oils of varying viscosities were chosen to see which ones gave a good release profile, with castor, sesame and soybean oil being picked. Both castor oil and soybean oil emulsions were stable for 24 hours and were therefore tested for their exenatide release, and varying surfactant (sorbitan monooleate) levels were tested in each to determine if this provided adequate stability of the emulsion for the duration of the in vivo study. SAIB was tested as it had an alternative mechanism of delaying the release of exenatide, by creating a depot upon injection.

[00273] The in vitro release profiles of the formulations (nominal concentration 20 pg/mL) were assessed using the HPLC method described in Tables 9 and 10 above. Samples were taken hourly for the first 6 hours, followed by a 24-hour time point. Exenatide acetate was used for the in vitro tests. Results are shown in Figure 2.

[00274] Figure 2 demonstrates a range of in vitro release profiles from the formulations tested. The data is presented as the cumulative concentration of exenatide in the receptor layer. Safflower oil, sesame oil and both soybean oil emulsions gave a high initial burst of exenatide, suggesting equilibrium was reached within 6 hours. Soybean oil, SAIB and the castor oil emulsions gave a lower initial burst followed by a slower release of exenatide which was still increasing at 24 hours. Castor and cottonseed oil did not produce an initial burst of exenatide and gave a slower, more sustained in vitro release.

[00275] At least one formulation from each different system was selected to be investigated in vivo. For the formulations that could be tested in vitro, formulations were selected for in vivo assessment that gave a range of release profiles - castor oil, castor oil emulsion, soybean oil, safflower oil, SAIB. As well as these formulations, the albumin- based protein binding and chitosan-based in-situ gelling formulations were chosen for investigation in vivo, as despite not having in vitro release data, their mechanisms provide a sustained release of exenatide.

EXAMPLE 9: In vivo performance of lead formulations in mice

Methodology

[00276] A total of 8 formulations were selected to be tested in initial in vivo studies in mice. Male CD1 mice were used and injected at the scruff of the neck. Plasma samples were taken at 0.25, 0.5, 1 , 2, 4, 6, 8 and 24 hours, n =3 for each. Samples were stored at -20 °C and then subsequently analyzed by UFIPLC tandem mass spectrometry using electrospray ionization.

[00277] The lead formulations, their compositions and any observations made during manufacture of formulations are outlined in Table 11 . Exenatide was used for the manufacture of formulation dosed into the in vivo mouse study. [00278] The formulations were prepared as follows:

[00279] Benzyl alcohol stock: An exenatide in benzyl alcohol was made at a concentration of 1 mg/ml_. 2 mg of exenatide was weighed into a clean vial, and 2 ml_ of benzyl alcohol was added. This was then vortexed for ~30 seconds.

[00280] Water stock: An exenatide in water stock was made at a concentration of 1 mg/mL. 2 mg of exenatide was weighed into a clean vial, and 2 ml_ of water was added. This was then vortexed for ~30 seconds.

[00281] Aqueous formulation: 200 pL of exenatide water stock was added to 9.8 mL of saline and the mixture vortexed.

[00282] Albumin formulation: 0.01 g of albumin was added to 9.8 ml_ of saline and this was vortexed. 200 pl_ of exenatide benzyl alcohol stock was then added and the mixture vortexed.

[00283] Chitosan formulation: 200 mI_ of exenatide benzyl alcohol stock was added to 9 mL of saline. 200 mI_ of acetic acid was then added. 200 mg of chitosan was then added. The pH was then adjusted to pH 4 using 1 M NaOH. The mixture was then made up to volume using saline.

[00284] Castor oil formulation: 200 mI_ of exenatide benzyl alcohol stock was added to 9.8 g of castor oil and the mixture vortexed.

[00285] Soybean oil formulation: 200 mI_ of exenatide benzyl alcohol stock was added to 9.8 g of soybean oil and the mixture vortexed.

[00286] Castor oil emulsion: 8.5 g of oil was weighed into a vial. 0.5 g of sorbitan monooleate was added and the mixture was vortexed. 1 mL of the exenatide water stock was diluted 1 :5 to achieve a stock concentration of 200 pg/mL. 1 mL of this was then added to the oil and surfactant mix and homogenized using an IKA® UltraTurrax® for 5 minutes.

[00287] SAIB formulation: 8.5 g of SAIB was weighed into a vial. 1 .3 mL of ethanol was added, and the mixture heated to 50 °C and vortexed until the mixture was no longer viscous. It was then left to cool to room temperature. 200 pL of benzyl alcohol stock was then added and the mixture vortexed.

Table 11. Formulation information and observations

Results

[00288] The results from the in vivo investigation of the 8 formulations are shown as individual PK profiles in Figure 3. The PK profiles of Figure 3 show that exenatide in saline provides the fastest release of exenatide amongst all formulations, which was expected for an immediate-release formulation. A high initial burst is observed followed by reduced level of release up to 4 hours, after which the samples were below the limit of quantification (LOQ). The chitosan formulation released exenatide very slowly and did not produce a burst, with samples were below LOQ after 6 hours. Safflower oil gave an initial burst followed by a steady release for up to 8 hours. The albumin formulation gave a high initial burst of exenatide, and then a steady release up to 4 hours. The castor oil formulation gave a profile consisting of a burst, but release was then sustained over 24 hours. The castor oil emulsion also gave a high initial burst followed by a sustained release over 24 hours. The soybean oil gave a similar profile to the castor oil, but the concentrations were lower. SAIB had the lowest release of exenatide, with the highest level only reaching 1.5 ng/mL, and samples were below LOQ after 0.5 hours. [00289] All formulations provided slower release of exenatide compared to saline alone. Some formulations such as the albumin and castor oil emulsion formulation (and safflower oil to some extent) gave an initial burst of exenatide release, followed by a more sustained release. Other formulations such as the castor oil and soybean oil provided a low concentration sustained release of exenatide, whereas the SAIB and chitosan formulations provided very low release of exenatide and had most of the samples taken below the LOQ.

EXAMPLE 10: Modelling to predict release of exenatide from formulations in man

Deconvolution of subcutaneous absorption profiles of exenatide in mice and translation into humans

Method of deconvolution

[00290] The mouse pharmacokinetic data from Example 9 was numerically deconvoluted. To numerically deconvolute the PK profiles, an intravenous PK profile was stimulated using the IV PK model derived by Chen et al. (Chen T, Magger DE, Kagan L, Interspecies modeling and prediction of human exenatide pharmacokinetics, Pharm. Res. 2013; 30(3): 751-760). Effectively the IV profile is subtracted from the PK profile to deconvolute the absorption profile. As the IV PK model was from a different study, the numerically deconvoluted absorption profiles were set relative to the saline absorption. Finally, the deconvoluted release profiles were modelled kinetically using zero and first order rate equations in order to input them into a human PK model.

Numerical deconvolution

[00291] The deconvoluted mouse PK profiles following subcutaneous administration of exenatide in chitosan, safflower, albumin, castor oil, castor oil emulsion and soybean oil are plotted in Figure 4.

[00292] For the chitosan formulation (Fig. 4D), the release relative to saline (Fig. 4F) is approximately 14% after 6 hours and after 6 hours plasma concentration is less than the LLOQ. For the safflower oil (Fig. 4E) formulation, there is a sharp initial burst followed by gradual release, the release relative to saline is approximately 12.8% after 8 hours and after 8 hours plasma concentration is less than the LLOQ. For the albumin formulation (Fig. 4A), the release relative to saline is approximately 55.6% after 4 hours and after four hours the plasma concentration is less than the LLOQ. For the castor oil formulation (Fig. 4B), the release is sustained for 24 hours and the release relative to saline is approximately 22.4% after 24 hours. For the castor oil emulsion formulation (Fig. 4C), the release is sustained for 24 hours and the release relative to saline is approximately 77.0% after 24 hours. For the soybean oil formulation (Fig. 4G), the release is sustained for 24 hours and the release relative to saline is approximately 12.5% after 24 hours.

Translating the absorption profiles from mice to humans

[00293] To understand the interspecies differences in exenatide kinetics, interspecies PK models for formulations of exenatide from the literature were recreated. All models demonstrated that mouse absorption is much faster than human absorption of exenatide.

[00294] The release profiles of SC formulations from Example 9 were inputted into the human PK model and simulated PK profiles for a range of doses (10, 15 and 20 pg) are reported in Figure 5.

[00295] Figure 5B shows that exenatide with castor oil emulsion gives an initial burst before a slow, long acting release. Administration of castor oil and castor emulsion results in relatively high concentrations of exenatide even at 24 hours. Exenatide in castor oil gives the flattest human PK profile.

Simulating human PK parameters for example 3 formulations

[00296] Table 12 shows the simulated maximum plasma concentration (Cmax), plasma concentration at 24 hours (C24) and area under the curve at 24 hours (AUC24) for each formulation if a 20 pg dose is administered.

Table 12. Simulated Cmax, C24 and AUC24 for 20 pg exenatide formulations [00297] The albumin and castor oil emulsion modified-release formulations result in the highest Cmax. The castor oil and castor oil emulsion modified-release formulations maintain above 7 pg/ml at 24 hours, but C24 is lower for other formulations.

[00298] The castor oil emulsion modified-release formulation has an AUC of approximately 70% of the IR (saline) formulation and all other formulations have a lower percent of exenatide absorbed.

EXAMPLE 11: Pressure Physiology study of Diurnal ICP in IIH patients

Recruitment

[00299] Female IIH patients aged between 18 and 60 years, diagnosed according to the modified Dandy criteria who had active disease (papilloedema [Frisen grade ^ 1], significantly raised ICP > 25cmH20) and no evidence of venous sinus thrombosis (magnetic resonance imaging (MRI) or computerised tomography (CT) imaging and venography as noted at diagnosis).

Surgery

[00300] Following eligibility visit and 1 -month headache diary participants underwent implantation of Raumedic P Tel telemetric ICP devices (Raumedic, Germany) inserted under general anaesthesia to the right frontal lobe.

Visit

[00301] 1 week after surgery participants attended a baseline visit. ICP was recorded continuously. At regular timepoints participants adopted standard postures for the purpose of standardised recording, these included: 5 and then 30 minutes fully supine (no pillow) then 5 minutes standing. Timepoints (+/- 1 hr) 0900, 1200, 1800, 2300. In between these time periods participants were fully ambulant. Overnight recording was also performed continuously from the time of sleep onset (midnight +/- 1 hour) and documented hourly. Participants were not instructed regarding sleeping position and used pillows/inclination as was their usual practice.

Analysis

[00302] ICP recordings were analysed using Dataview 3.0 software (Raumedic, Germany). Recordings were inspected and mean values taken over the fullest period available for daytime recordings. For the diurnal traces fully supine (30 min), standing (5 min) and continuous overnight recordings (hourly means after midnight (0000 - 0700) were analysed.

Results - ICP Recording over 24 hour period

[00303] The change in ICP observed in the study is shown in Figure 9. No significant change in ICP was observed whilst awake and standing (p=0.07) or whilst awake and intermittently adopting a supine position (p=0.07). Flowever, during sleep ICP increased ( ** 5.22 +/- 0.89 mmFIg, p=0.0051 ). ICP fell abruptly when participants fell asleep and ICP was markedly higher whilst asleep than when awake (7.2 +/- 0.72 mmFIg) despite the variability in sleeping position.

EXAMPLE 12: IIH pressure trial: the acute and chronic effect of gut neuropeptides on intracranial pressure regulation

Trial Design

[00304] The trial was a prospective, randomized, parallel group, placebo controlled, exploratory trial in 16 female patients with idiopathic intracranial hypertension. 16 Patients with a diagnosis of IIFH were identified and recruited to the main trial, up to 8 additional participants recruited to participate in sub-studies only. Participants have a telemetric ICP monitor implanted. In the first part participants are randomized to exenatide or a control group; allocation is 1 :1.

Background and Rationale

[00305] In this study the aim is to evaluate the effects of GLP-1 agonists on CNS fluid secretion in humans. The effects of exenatide in patients with idiopathic intracranial hypertension (IIFH) are investigated.

[00306] Patients with IIFH are an ideal population in which to study the CNS effects of gut neuropeptides as patients are typically obese with evidence of central adipokine dysregulation (Ball AK, Sinclair AJ, Curnow SJ, Tomlinson JW, Burdon MA, Walker EA, et al. Elevated cerebrospinal fluid (CSF) leptin in idiopathic intracranial hypertension (IIH): evidence for hypothalamic leptin resistance? Clin Endocrinol. 2009; 70(6): 863-869). Patients also have elevated ICP (Friedman Dl, McDermott MP, Kieburtz K, Kupersmith M, Stoutenburg A, Keltner JL, et al. The idiopathic intracranial hypertension treatment trial: design considerations and methods. J Neuroophthalmol. 2014; 34(2): 107-117). Effects of GLP-1 on fluid secretion at the choroid plexus are reflected in alterations in ICP which can be evaluated though telemetric intracranial pressure monitoring.

[00307] Telemetric intracranial pressure monitors are increasingly being used clinically and for research (Lilja A, Andresen M, Hadi A, Christoffersen D, Juhler M. Clinical experience with telemetric intracranial pressure monitoring in a Danish neurosurgical center. Clin Neurol Neurosurg. 2014; 120: 36-40). They provide many advantages particularly allowing frequent and accurate monitoring of pressure; which is non-invasive following initial implantation. The telemetric probes are inserted surgically under local or general anesthesia via a burr-hole with placement of the probe into the brain parenchyma of the right frontal lobe. The safety profile has been established (Lilja A, Andresen M, Hadi A, Christoffersen D, Juhler M. Clinical experience with telemetric intracranial pressure monitoring in a Danish neurosurgical center. Clin Neurol Neurosurg. 2014; 120: 36-40; Antes S, Tschan CA, Heckelmann M, Breuskin D, Oertel J. Telemetric Intracranial Pressure Monitoring with the Raumedic Neurovent P-tel. World Neurosurgery. Elsevier Inc; 2016; 91 (C): 133-148). The risks are minimal and relate to the surgical procedure itself; of note however is driving status. Currently patients need to desist from driving and inform the DVLA once a monitor is placed and request permission to resume driving, a process that can take some weeks. Rarely telemeters can fail in use, in this instance replacement would be necessary involving a further surgical procedure if the participant agreed.

Primary Aims

[00308] The trial assesses the biological role of acute administration of exenatide on intracerebral pressure (ICP). The trial also assesses the biological role of chronic administration of exenatide on ICP.

Secondary Aims

[00309] Evaluate the acute and chronic effects on the biological role of exenatide on CNS and systemic adipokines, inflammatory cytokines, biomarkers, headache and quality of life.

Primary Endpoints

[00310] Change in ICP between baseline and 24hrs post drug administration. Change in ICP between baseline and end of trial visit. Change in ICP baseline vs 2.5 hours post administration. Secondary Endpoints

[00311] The trial evaluates the biological effects of exenatide on modulation of serum and cerebrospinal fluid (CSF) adipokines, gut neuropeptides, biomarkers, fat distribution, serum and CSF Exenatide levels, headache measures and quality of life (QoL) measures after acute and chronic administration.

Participant Population and Sample Size

[00312] The trial is conducted in a population of women diagnosed with active Idiopathic Intracranial Flypertension (IIH). Sample size is 8 participants per arm, total 16 participants in the main trial.

Eligibility

Inclusion Criteria

[00313] 1 ) Female IIH patients aged between 18 and 60 years, diagnosed according to the modified Dandy criteria who have active disease (papilloedema [Frisen grade > 1], significantly raised ICP > 25cmH20) and no evidence of venous sinus thrombosis (magnetic resonance imaging (MRI) or computerised tomography (CT) imaging and venography as noted at diagnosis); and 2) able to give informed consent.

Exclusion Criteria

[00314] 1 ) Age less than 18 or older than 60 years; 2) pregnant or trying to conceive;

3) significant co-morbidity; such that in the opinion of the investigator it would not be in the participant’s best interest to participate in the trial; 4) Addison’s or Cushing’s disease; 5) functioning CSF shunt/stent or optic nerve sheath fenestration; 6) currently using GLP- 1 agonist or DPP-4 inhibitor; 7) surgical contra-indication; 8) concomitant therapy with acetazolamide, topiramate or diuretics (this can be discontinued 1 month prior to enrolment); and 9) inability to give informed consent e.g. due to cognitive impairment.

Intervention

[00315] Participants in the active arm are treated with the GLP-1 agonist drug Exenatide (250 pg/mL exenatide in pH 4.5 acetate buffer). Initial dose is a single bolus of 20pg s/c at visit 1 . The control arm receive normal saline s/c placebo for the first 24 hours. For the 3 month continuation study phase patients are dosed with Exenatide 10pg BD s/c and the control group receive normal saline placebo s/c. [00316] Patients on drugs such as acetazolamide or other ICP manipulating drugs are required to discontinue these for 1 month prior to enrolment.

[00317] Following enrolment, there is a 1 -month run-in period prior to implantation of the ICP monitor to allow the recording of a headache diary (headache days, migraine days, headache severity 0-10 VRS, days of analgesic use).

[00318] Surgical implantation of ICP monitor is conducted under local or general anesthesia - decision making is by the surgical team in consultation with the participant. Implantation can occur immediately prior to baseline if agreed with the participant. Rarely telemeters can fail in use. If this were to occur we offer to replace with a new monitor, requiring a further surgical procedure, if the participant agrees.

[00319] Patients attend baseline fasted. At the baseline visit patients are randomised to either Exenatide or a control arm. Initially a Dual-energy X-ray absorptiometry (DEXA) scan (fat distribution), visual testing, headache scores and questionnaires are conducted. Then continuous telemetric ICP monitoring commences. Sleep monitoring occurs overnight.

[00320] Following a 1 hour baseline recording of ICP, participants receive active treatment with subcutaneous dosing of 20mcg of Exenatide or placebo treatment with a subcutaneous saline injection. Continuous ICP monitoring continues for 24hours post first dose. A second dose is administered on day 2 (10pg Exenatide or saline placebo and ICP monitored for a further 3 hours). Treatment allocation is blinded to patient and investigators. Serum samples are collected at 0, 2.5, 6, 11 and 24 hours.

[00321] CSF sampling is undertaken in patients as an optional procedure - the rationale and procedure is explained below. Following the baseline visit the groups proceed for a further 3 months receiving either twice daily Exenatide 10pg or placebo as per initial randomization. During the 3 month phase both groups monitor body weight weekly with supplied scales.

[00322] Participants return for a brief visit at 2 weeks to record ICP over a 3 hour period, with visual testing and cognition as below.

[00323] At the end of the 3 month phase patients attend for the 12 week visit. Patients attend fasted from midnight. This visit consists of a DEXA scan, visual testing, questionnaires, headache scoring and blood sampling. Then continuous telemetric ICP monitoring commences for 3 hours. [00324] Participants have the option of additional home intermittent ICP monitoring before and during the 3 month dosing phase.

Overview of Trial design

[00325] Figure 6 shows an overview of the trial design.

Schedule of Assessments - Trial Part 1 - Exenatide Enrolment visit

[00326] Urine HCG test is performed. Following screening participants complete a headache diary for 1 month prior to surgical implantation.

Surgery visit

[00327] All participants attend for insertion of a telemetric ICP monitor under local or general anaesthesia. Anaesthetic decisions are undertaken by the anaesthetic team in consultation with the participant. Telemetric monitor is inserted via a scalp incision and burr-hole with the catheter inserted into the brain parenchyma of the right frontal lobe. Fleadache scores are recorded.

Baseline visit

[00328] Participants attend the clinical research facility, fasted, after a minimum 1 month headache diary period and surgery. Consent is re-affirmed verbally and noted. Basic medical history, examination and clinical measurements are recorded, urine HCG test, visual assessments, including LogMAR (log of minimum angle of resolution), HVF automated perimetry (Humphrey 24-2 central threshold), OCT (Optic Coherence Tomography) and questionnaires and cognitive testing is completed. DEXA is completed on the day (or at the surgical visit). Participants go on to have a cannula placed to allow blood sampling. A minimum 1 hour telemetric baseline pressure is recorded and baseline blood samples are collected.

[00329] Participants are randomised and are then administered Exenatide or normal saline according to allocation with investigator and patient blinded. Medication is administered by an unblinded nurse.

[00330] ICP is recorded continuously. Recordings are taken in a recumbent position for a minimum of 5 minutes every hour. Headache score are recorded with each defined ICP measure. [00331] OCT and cognitive testing are repeated at 6 hours after drug administration. Central Corneal Thickness (CCT) are recorded at baseline.

[00332] See Figure 7 for Baseline visit scheme.

ICP Monitoring Week 2

[00333] Participants attend the clinical research facility after 2 weeks treatment (+/- 7 days). They undergo 2.5 hours of ICP monitoring and complete a headache severity score, OCT, blood samples and cognitive testing.

Week 8 [00334] Participants are asked to complete a further 1 month headache diary prior to the end of the trial period.

Week 12

[00335] Participants attend the clinical research facility after 3 months treatment (+/- 7days if required). They undergo ICP recording and blood sampling. Visual testing is completed and repeated clinical measurements, headache scores, HIT-6 and SF-36 questionnaires are completed, DEXA and cognitive testing. IIH symptoms are recorded. Headache scores are completed alongside ICP measures. Clinical data is recorded on the Visit 2 CRF. IIH Pressure Med PIS, IIH Pressure Head PIS and IIH Pressure Fit PIS is offered. Figure 8 shows the week 12 scheme. Statistical considerations

Planned Randomisation Methodology

[00336] Participants are randomized by a paper randomization system administered by the Birmingham Clinical Trials Unit. Allocation will be 1:1.

Planned Interim Analysis [00337] Interim analysis is optionally performed after the first 6-10 patients. The

Investigators do not partake in this analysis to maintain allocation concealment.

Planned Final Analyses

[00338] The main trial analysis is conducted after the final visit of the final patient of the main trial. A number of sub-studies are performed after the main trial. Power Calculations

[00339] The study proposes to investigate the effect of GLP-1R agonist on the continuous variable, intracranial pressure (ICP) via a two-arm, randomised, study. The primary outcome is change in ICP. In a study of 25 patients, Sinclair et al (Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension: prospective cohort study, BMJ. 2010 Jul 7;341) showed that the cross-sectional sample standard deviation of ICP is 4.9 - 5.1 cm H2O, measured at baseline and immediately before and after a longitudinal intervention (low energy diet). There are very few trials in IIH and the minimal clinically important change (MCIC) for LP pressure is not established and may vary with individual patients.

[00340] For this trial a reduction in ICP of 6.5 cm H2O is clinically meaningful, however a smaller or greater change is also likely to be clinically meaningful. Seeking significance at least alpha < 0.1 and power at least 80% using equal group sizes, a total sample size of 14 patients is required, i.e. 7 patients are randomised to receive active treatment and a further 7 to receive control. This calculation assumes that the standard deviation of ICP is 5.1, the upper end of the range observed previously. Allowing for 10% drop-put, the recruitment is 8 patients per arm, and 16 patients in total.

[00341] Table 13 shows the patient baseline characteristics of the participants in the Example 12 IIH trial. Table 13. Patient Baseline Characteristics

*significant difference at 5% level

[00342] As can be seen from Table 13, the patients were well balanced at baseline with the only significant difference at baseline between the groups being monthly headache days, where the difference was skewed by two patients in the placebo group with very low monthly headache days at baseline.

IIH Trial Results

Intracranial Pressure

[00343] The Example 12 IIH patients receiving exenatide via subcutaneous injection were found to have improved (reduced) ICP compared to equivalent patients receiving placebo at 2.5 hours after visit 1 administration (Figure 10; mean change in ICP from baseline at 150 mins was -0.5 mmHg (exenatide) and +1.4 mmHg (placebo)).

[00344] Figure 12 further demonstrates that exenatide reduced ICP in a statistically significant manner at all three key time points during the trial; 2.5 hours, 24 hours and 12 weeks (mean change in ICP from baseline at 24 hours was -3.4 mmFIg (exenatide) and - 1.1 mmFIg (placebo); mean change in ICP from baseline at 12 weeks was -0.9 mmFIg (exenatide) and +1.4 mmFIg (placebo)). Exenatide use reduced ICP in a rapid and sustained manner by 4.1 - 4.6 mmFIg (5.7 -6.4 cm FI2O) or 18.1-20.8% compared to placebo. [00345] After the visit 1 dosing of either 20pg s/c exenatide or s/c saline injection in the morning, and within the 24 hour period of continuous ICP monitoring, Table 14 and Figure 11 show the variations in ICP for both cohorts while continuously lying supine overnight.

Table 14. Overnight ICP data

[00346] It can be seen that, in accordance with the data shown in Figure 9, ICP rises overnight whilst a subject is supine as noted in the placebo arm in Figure 11. The overnight rise in ICP does not occur, however, in those subjects treated with Exenatide. Higher ICP overnight is clinically relevant and can lead to an exacerbation of IIH with increased morning headaches and potential impact on the degree of papilloedema and subsequent risk of visual loss. Patients with IIH often report needing to sleep overnight ‘sat up’ to help mitigate the exacerbation of their IIH symptoms which they note if they lie supine all night, with resulting elevation of ICP. Therapeutic strategies to prevent the overnight rise in ICP in IIH would consequently be clinically advantageous.

[00347] The current dosing of exenatide in this study is, however, suboptimal, as the effect to reduce overnight ICP has been lost by approximately 9 am (Table 14); at 09:00 the mean ICP in the exenatide group is 20.0 mmFIg (compared with 16.1 mmFIg at midnight and 22.3 mmFIg at baseline pre-dosing), whereas at 09:00 the mean ICP in the placebo group is 22.8 mmFIg (compared with 18.2 mmFIg at midnight and 24.6 mmFIg at baseline pre-dosing). This loss of ICP control, by the end of the 24 hour period following dosing of an immediate release formulation, suggests that the patients were likely experiencing sub-therapeutic levels of Exenatide at this stage.

[00348] By comparison, it is expected, based on the in vitro and in vivo pharmacokinetic release data described herein, that modified release formulations of the present invention will deliver a sustained, therapeutically-effective dose of exenatide over a 24 hour period following once daily administration, thereby potentially providing superior ICP control compared to once daily dosing of an equivalent amount of an immediate release exenatide formulation. Furthermore, once daily night-time dosing of a modified release formulation (e.g. just prior to onset of sleep) should provide further advantages in terms of managing the overnight rises in ICP typically seen in IIH patients.

Headaches/Analgesia usage

[00349] As described in the Example 12 protocol above, various headache measures were assessed at baseline and at 12 weeks using standardized tests.

[00350] The changes in the headache frequency (as measured by the number of monthly headache days) are shown in Figure 13A. In the exenatide cohort of IIH patients there was a mean reduction of 7.7 monthly headache days, whereas in the placebo cohort the mean reduction was only 1 .5 monthly headache days. Similarly, there was a trend to reduction in the use of pain medication by IIH patients receiving exenatide as compared to placebo over the 12 week period of the study, as shown in Figure 13B; in the exenatide cohort of IIH patients there was a mean reduction of 0.9 monthly analgesia days, whereas in the placebo cohort there was a mean increase of 2.4 monthly analgesia days.

[00351] Group sizes were too small to enable a meaningful comparison between the two patient cohorts for headache related quality of life (as measure by the Fleadache Impact Test (HIT)-6 and SP-36 questionnaires), or headache severity (11 -point Verbal rating Scale) and no meaningful difference between the two groups was observed. It is predicted that modified release formulations of the present invention by maintaining a constantly lowered ICP (with the reduced risk of triggering orthostatic headaches associated with over-treatment) may produce additional benefits in terms of these headache measures.

Vision

[00352] As part of the Example 12 IIH trial, vision assessments were made at baseline and 12 weeks using standard tests.

[00353] Visual acuity was assessed using a LogMAR Chart assessment (Figure 14A and Table 15) and demonstrated a statistically significant improvement (measured as a reduction in LogMAR) in the exenatide treated patient cohort. Although there has been no determination of a minimal clinically important improvement in LogMAR in IIH, an improvement equivalent to a whole line (-0.1 ) on the acuity chart is a significant change for an IIH patient and could, for example, mean the difference between being able to drive or not.

[00354] Furthermore, LogMAR improved in all but one of the exenatide treated patients, whereas in the placebo group only one patient experienced an improvement in LogMAR visual acuity (Figure 14B).

Table 15. Vision Results

[00355] As seen in Table 15, Optical Coherence Tomography (OCT) and Humphrey Visual Field (HVF) measurements did not show any significant difference between the two patient groups at 12 weeks. It is predicted that modified release formulations of the present invention, by maintaining a constantly lowered ICP, may produce additional benefits in terms of OCT and HVF.

Body Mass Index

[00356] Mean patient BMI did not change significantly during the 12 week study confirming that the reduction in ICP and clinical benefit seen through the use of exenatide was not a result of weight loss in the treatment arm.

Safety

[00357] No serious adverse events were observed relating to the use of exenatide in this cohort of IIH patients. Overall, adverse events were relatively low; 38% of patients treated with Exenatide experienced nausea (4 adverse events of mild transient nausea and 3 adverse events of nausea requiring treatment). Nausea is a known and most frequent adverse event associated with the sub-cutaneous administration of this immediate release formulation of Exenatide (Byetta®).

[00358] Currently the most widely used drug in IIH, acetazolamide, is discontinued in approximately 48% of patients (Ball A. K. et al., J. Neurol. (2011 ); 258(5), 874-881 ) due to intolerable side effects, whereas no patients withdrew from the current study due to side effects from exenatide use. Acetazolamide is not approved in any market for the treatment of IIH.

Summary

[00359] The treatment of IIH patients with an immediate release formulation of Exenatide (dosed as an initial 20 pg bolus on day 1 , followed by 10 pg twice daily dosing from day 2 onwards) provided a statistically significant reduction in ICP over the 12 week duration of the trial. In terms of secondary endpoints, there were statistically significant improvements in monthly headache days and visual acuity (LogMAR) at 12 weeks for patients receiving Exenatide.

[00360] In order to effectively manage IIH with once daily dosing of Exenatide, formulations are required that are capable of providing Exenatide release over a 24 hour period at therapeutically-effective levels. It would not be desirable to increase the Cmax and AUC levels to those associated with 20 pg of exenatide in an immediate release formulation, as nausea was seen in a number of patients, presumably linked to high peak levels of Exenatide. It is therefore expected that an improved balance between efficacy and tolerability may be achieved with the modified release formulations of the present invention, which are capable of delivering Exenatide at a sustained level throughout at least a 20 hour period post administration, without reaching the peak Exenatide concentrations (Cmax) associated with the immediate release formulation. Further Formulation Development

EXAMPLE 13: Stability of Exenatide in binary excipient mixtures

[00361] To identify specific excipient incompatibilities, the stability of exenatide acetate was investigated in binary excipient mixtures. Exenatide acetate (120 pg/mL) was combined in binary mixtures (n = 2) with a variety of solvents (100% v/v), and surfactants (5% w/v surfactant, 95% v/v water) and monitored for stability at ambient temperature (22-25 °C) out of direct sunlight for up to 12 days. Placebo mixtures were also analysed, which were prepared in the same way as the exenatide-containing mixtures but did not have exenatide added. Qualitative analysis was performed by HPLC, whereby reduction in parent peak or appearance of additional peaks attributable to degradant products was interpreted as instability. The data is shown in Table 16.

[00362] Prior to analysis by HPLC, some of the binary mixtures required liquid-liquid extraction (LLE). LLE was performed as follows for the benzyl alcohol, benzyl benzoate and Miglyol 812 mixtures:

• Step 1 - extraction solvent (deionised water adjusted to pH 5) was added to the binary mixture in a 1 :1 ratio.

• Step 2 - the sample was vortexed for 2 minutes to allow the layers to interact and for the exenatide acetate to partition into the extraction solvent.

• Step 3 - After a suitable equilibration time, the sample was centrifuged for 5 minutes to separate the immiscible extraction solvent from the formulation components.

• Step 4 - as much of the supernatant (formulation component) as possible was removed with a pipette and discarded. The sample was centrifuged for a further 5 minutes.

• Step 5 - the subnatant (extraction solvent containing extracted exenatide acetate) was then sampled with a pipette, taking care not to disturb any remaining immiscible formulation in the top layer.

• Step 6 - the extraction solvent was then analysed by HPLC.

[00363] Liquid: liquid extraction was required for benzyl alcohol, benzyl benzoate and Miglyol 812.

Table 16. Stability of exenatide acetate at room temperature with excipients- % peak area attributed to the parent peak

* data could not be obtained due to sample preparation difficulties or difficulties with data interpretation due to multiple unresolved excipient peaks

[00364] The data in Table 16 suggest that exenatide has reasonable stability in aqueous solution, with 93% of exenatide still present on day 12. The stability in a pH 4.5 sodium acetate (Na-Ac) buffer appeared better than in water alone, with >99% of exenatide still present on day 12. Based on this, a pH 4.5 Na-Ac buffer was taken forward and used as the aqueous phase in the emulsion formulations.

[00365] In terms of solvents, benzyl alcohol showed a reduction in main peak area from 95% on day 0, to 69% on day 5 (a 26% reduction). Benzyl benzoate performed better, changing from 82% on day 0 to 72% on day 5 (a 10% reduction).

[00366] In terms of the surfactants, polysorbate 20 and polysorbate 80 showed spilt peaks on day 0. Poloxamers are not considered optimal in terms of hydrophilic-lipophilic balance (HLB) for a water-in-oil emulsion. For sorbitan monooleate, % peak area only reduced from 96% to 83% over 12 days. Sorbitan monooleate was therefore taken forward as a preferred surfactant.

[00367] In the Miglyol 812 sample, % peak area showed no change between day 0 and day 5 and was also taken forward as a preferred excipient.

EXAMPLE 14: Syringeability, injectability, filtration and physical stability of oil- based and emulsion-based formulations

[00368] A sample of each oil-based or emulsion-based formulation was aspirated through a blunt fill needle into a 1 mL syringe and dispensed through a variety of needles from 27G (narrowest bore) to 21 G (widest bore). The ease of aspiration and dispensing was assessed by the analyst, and the most suitable needle was recorded (Error! Reference source not found, and Error! Reference source not found.). Ability to pass 1 ml_ of formulation through a 0.22 pm PTFE syringe filter (ThermoFisher, product code: 15151499), plus physical stability observations are additionally reported in Error!

Reference source not found. andError! Reference source not found.. For the emulsions (Table 18) the formulations were centrifuged at various speeds to determine at which point they split in order to compare physical stability of the mixtures.

Table 17. Injectability, syringeability, filtration and physical stability of the oil formulations

Table 18. Injectability, syringeability, filtration and physical stability of the emulsion formulations

[00369] For the oil-based formulations tested in Table 17, the 85% castor oil/15% benzyl benzoate formulation demonstrated good physical stability over 7 days and was syringe-able, and injectable through a 23G needle. Filtration through a 0.22 pm syringe filter did however prove challenging owing to solution viscosity. Increasing the benzyl benzoate content successfully reduced the formulation viscosity (80% castor oil; 20% benzyl benzoate was injectable through a narrower bore 25G needle).

[00370] Of the emulsion-based formulations tested in Table 18, three were still physically stable on day 7: (i) 93% castor oil; 5% sorbitan monooleate; 2% water; 70% castor oil; (ii) 5% sorbitan monooleate; 15% benzyl benzoate, 10% water; and (iii) 75% castor oil; 5% sorbitan monooleate; 15% benzyl benzoate; 10% water. Of these emulsions, those containing benzyl benzoate ((ii) and (iii)) had lower viscosity and hence were easier to filter through a 0.22 pm syringe filter. Variants of these castor oil/sorbitan monooleate/benzyl benzoate/water emulsion formulation were further investigated via in vivo testing.

EXAMPLE 15: In vitro release testing of exenatide acetate from selected oil-based and emulsion-based formulations

[00371] Certain preferred formulations were selected for in vitro assessment of release rate over a 24-hour period. For the oil-based formulations, 1 mL of pH 7.4 buffer was added to 1 mL of formulation in 4 mL vials. Samples were prepared in quadruplicate to provide a separate sample for each of the four sampling timepoints (1 , 2, 4 and 22 hours). Since pH 7.4 buffer is immiscible with the formulation, a two-phase system was produced comprising donor phase (oil-based formulation) and receiver phase (buffer). Samples were stored at room temperature out of direct sunlight and without agitation. 500 pL of the receiver phase was sampled from the buffer by inserting a pipette through the surface oil layer at the predetermined time point. Analysis of the aqueous receiver phase samples was performed by HPLC.

[00372] This two-phase partition method was not successful for the emulsion formulations. Exenatide was undetectable in the aqueous receiver phase. It is postulated that the surfactant present in the emulsions created a barrier at the water-oil interface and prevented partitioning of the exenatide acetate. Vials were instead placed in a dry bath at 37 °C and were shaken at 200 rpm with the aim of agitating the barrier and facilitating exenatide partitioning. Exenatide was detected, but recovery was incomplete. Increasing shaking speed to 400 rpm failed to improve recovery.

[00373] Figure 15 shows the cumulative amount of exenatide detected in the receiver layer (buffer) over a 24-hour period. 120 pg exenatide represents complete release. The 98% castor oil/ 2% benzyl alcohol formulation appeared to give the slowest release initially, with no burst observed, however levels reached ~50 pg by 24 hours. The 75% castor oil/ 25% benzyl benzoate formulation released slightly faster than the 98% castor oil, however only reached ~25 pg and appeared to have reached a plateau at 4 hours. The 85% castor oil/ 15% benzyl benzoate formulation (two repeats were carried out) had released 40-50 pg in the first 4 hours, reaching ~70 pg (rep 2) and 90 pg (rep 1 ) by 24 hours. The 70% castor oil/ 30% Miglyol formulation and the 70% castor oil/ 15% Miglyol/ 15% benzyl benzoate formulation seemed to perform similarly, reaching 70-80 pg in the first 4 hours followed by further release to ~100-110 pg by 24 hours. The 50% castor oil/ 50% Miglyol formulation demonstrated rapid release to 55 pg in the first hour and demonstrated complete release with a cumulative release of 120 pg at 24 hours. The 100% Miglyol formulation provided the fastest initial burst reaching nearly 80 pg in the first hour. Complete release was not observed since release appeared to plateau at ~85 pg after 2 hours. The oil solution having the most promising release profile based on the in vitro data described above was the 85% castor oil/15% benzyl benzoate formulation.

EXAMPLE 16: In vivo performance of lead formulations in rats

Example 16A: Rat PK Study 1 Methodology

[00374] Based on in vitro release, injectability and physical stability, 4 formulations were selected for dosing in a rat PK study - two castor oil solutions (formulations 1 and 2) and two w/o emulsions (formulations 3 and 4). Intravenous and subcutaneous saline formulations (formulations 5 and 6 respectively) were dosed as controls: Formulation 1 = 85% castor oil / 15% benzyl benzoate,

Formulation 2 = 70% castor oil / 30% benzyl benzoate,

Formulation 3 = 78% castor oil / 15% benzyl benzoate / 5% sorbitan monooleate / 2% pH 4.5 Na-Ac buffer, Formulation 4 = 75% castor oil / 15% benzyl benzoate / 5% sorbitan monooleate / 5% pH 4.5 Na-Ac buffer,

Formulation 5 = 100% saline (IV),

Formulation 6 = 98% saline, 2% pH 4.5 Na-Ac buffer (SC).

[00375] Formulations were manufactured on a 10 mL scale at a concentration of 120 pg/mL (except formulation 5, IV saline, at 150 pg/mL), using exenatide supplied by

Alta Biosciences. The formulations, their compositions and any observations are outlined in Table 19.

Table 19. Formulation manufacture for rat PK study 1

[00376] The formulations were dosed at 1.25 mL/kg, equating to an exenatide dose of 0.15 mg/kg. Results

[00377] The log-linear plot of the geometric mean plasma concentrations of exenatide in the rats at various time points post dosing with the above formulations are shown in Figure 16. Although there were some difficulties with the analysis of the rat plasma samples obtained from this study, it can be seen that the oil formulations, in particular Formulation 1 (plot (c) in Figure 16), gave sustained levels of exenatide in excess of 2 ng/ml for at least 6 hours post dosing.

Example 16B: Rat PK Study 2

Methodology

[00378] In rat PK study 2 the following exenatide formulations were dosed: Formulation A = 80% castor oil / 20% benzyl benzoate,

Formulation B = 72.8% castor oil / 18.2% benzyl benzoate / 5% sorbitan monooleate / 4% pH 4.5 Na-Ac buffer

Formulation C = 96% saline (containing 2% albumin), 4% pH 4.5 Na-Ac buffer, Formulation D = 96% saline, 4% pH 4.5 Na-Ac buffer (SC control).

[00379] Formulations were manufactured on a 5 ml_ scale at a concentration of 30 pg/mL, using exenatide acetate sourced from Bachem. The concentration was reduced 4-fold from 120 pg/mL to 30 pg/mL compared to Example 16A. Formulations were prepared and stored overnight at ambient temperature prior to dosing. Formulation preparation methods are detailed in Table 20.

[00380] There were 8 animals in each of the four formulation groups (32 animals in total). Plasma samples were taken at the following time points; 30 mins, 1 hour, 2, 4, 6, 12, 16 & 24 hours post dose (350 mI_ whole blood collected in individual Lith/Hep tubes, stored on ice, spun in centrifuge at 13,000 rpm at 4°C for 3 mins. Supernatant was removed to individual 2 ml safe lock Eppendorf tubes and stored at -80°C). Equal volumes of plasma from up to four animals (where blood volume was sufficient) in each formulation group was pooled to make one composite sample per timepoint.

[00381] Plasma samples from the remaining four animals at each timepoint were subject to ELISA analysis to determine exenatide concentrations. The samples were diluted in assay buffer until they were in the linear part of the standard curve, otherwise the assay was performed as per the manufacturer’s instructions (Exendin-4 Fluorescent Enzyme Immunoassay Protocol; Phoenix Pharmaceuticals Inc; https://www.phoenixpeptide.com/doc/protocol/FEK-070-94.pdf). All samples from the same animal were assayed on the same ELISA plate (using Exendin-4 (Heloderma suspectum) - Fluorescent EIA Kit; catalog number FEK-070-94; Phoenix Pharmaceuticals Inc.) and were carried out in triplicate. Serum blank samples and assay background were deducted from each sample reading to give a final Exenatide concentration.

Table 20. Formulation manufacture for rat PK study 2

[00382] The formulations were dosed at 1 .25 mL/kg, equating to an exenatide dose of 0.0375 mg/kg. All animals were very subdued post dosing but recovered quickly and all animals maintained normal bowel movements throughout this study. All animals were much slower to bleed around 4-6hrs post dose and some samples were unattainable at these timepoints but other than that the animals bled well and nothing abnormal was been observed at necropsy.

Results [00383] The log-linear plot of the pooled plasma concentration of exenatide in the rats up to 12 hours post dosing with the above formulations (as analysed by LCMS/MS) are shown in Figure 17A. Results indicate that peak plasma concentration (Cmax) is approximately halved for all three formulations relative to the saline formulation. In addition, plasma concentrations for the control formulation (saline) are below the lower limit of quantification from 6 hours onwards, but detectable levels were present for all 3 prototype formulations at 6 hours, and also at 12 hours for the castor oil formulation (formulation A).

Figure 17B shows the linear plot of the plasma concentrations for the four formulations out to 24 hours post dosing, as analysed by the ELISA assay. These data show that, compared to the immediate release saline control (labelled SC Exenatide), the time to achieve peak plasma concentration (Tmax) post-administration is delayed for the three modified release formulations (Tmax 60 mins for oil, emulsion and albumin compositions c.f. 30 mins for saline control). For the oil-based composition (formulation A) the exenatide release is significantly extended over the period studied.

EXAMPLE 17: Preparation of lead castor oil/benzyl benzoate formulations

Example 17A: 77.34% w/w castor oil, 22.66% w/w benzyl benzoate

15.0 mg Exenatide was pre-dissolved in 100 mL benzyl benzoate to provide a stock solution. 2.2255 g of this stock solution was then added to 7.5944 g castor oil.

Example 17B: Exenatide 30 uo in 250 uL solution for subcutaneous injection comprising: 20% w/v Benzyl Benzoate (co-solvent) qs Castor oil, Refined.

24 mg of exenatide is weighed into an appropriate volumetric vessel, and 40.0 g of benzyl benzoate is added. This is then mixed until dissolved. The exenatide benzyl benzoate solution is then made up to 200 mL with castor oil and the mixture vortexed to obtain a clear, pale yellow solution.

EXAMPLE 18: Preparation of a lead castor oil/benzyl benzoate/sorbitan monooleate emulsion formulation

A 70.19% w/w castor oil, 20.66% w/w benzyl benzoate, 5.11 % w/w sorbitan monooleate, 4.05% w/w pH 4.5 Na-Ac buffer composition was prepared as follows.

The oil phase was prepared by combining 6.9377 g castor oil with 2.0417 g benzyl benzoate. 0.5047 g Sorbitan monooleate was added to the oil phase. 14.8 mg Exenatide acetate was pre-dissolved in 20 mL pH 4.5 Na-Ac buffer, of which 0.4 mL was added to the oil phase, and homogenised for 5 minutes to form an emulsion.