D E S C R I P T I O N

SOLID ORAL DOSAGE FORM COMPRISING POMALIDOMIDE

TECHNICAL FIELD

[0001] The present disclosure relates to the field of pharmaceutical technology, in particular to the formulation of new pharmaceutical dosage forms of pomalidomide for therapeutic use.

BACKGROUND

[0002] Pomalidomide is the international non-proprietary name (INN) of 4- amino-2-(2,6- dioxopiperidine-3-yl)isoindoline-l,3-dione with the following structure:

[0003] Pomalidomide is currently registered and marketed in many countries under the brand names IMNOVID ^* and POMALYST ^* . Pomalidomide is used in monotherapy or in combination with dexamethasone for the treatment of multiple myeloma.

[0004] Document WO 9803502 discloses a method of synthesizing pomalidomide.

[0005] The prosecution history of EP 2 391 355 (Celgene) discloses that pharmaceutical compositions of pomalidomide comprising several excipients such as anhydrous dibasic calcium phosphate, starch (corn starch and pregelatinized), lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, starch glycolate and/or sodium stearyl fumarate or magnesium stearate presented compatibility problems, i.e. were unstable after two weeks. Compositions of pomalidomide comprising anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate were initially deemed to be suitable for the production of pharmaceutical products but later evidenced unsatisfactory storage stability.

[0006] Furthermore, the European Public Assessment report (EPAR) for IMNOVID ^* discloses that the initial attempt to formulate IMNOVID oral composition contained pomalidomide, anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate. However, this initial composition was deemed unsuitable due to processing issues and during the development of the formulation, a number of qualitative alterations were implemented with the purpose of overcoming the limitations. The removal of anhydrous lactose and its direct substitution by dibasic calcium phosphate is singled out.

[0007] Pomalidomide is a Class IV compound according to the Biopharmaceutics Classification System (BCS Class IV) meaning that it is characterized as a low aqueous solubility and low permeability active compound. Class IV compounds ^' poor bioavailability makes it challenging for pharmaceutical formulators to develop compositions comprising these compounds. Absorption is characteristically poor and an increased plasmatic variability is expected across the pH range (1.2 to 6.8).

[0008] Systemic absorption of most drug products consists of a succession of rate processes. These processes include: (i) disintegration of the drug product and subsequent release of the drug; (ii) dissolution of the drug in an aqueous environment; and (iii) absorption across cell membrane into the systemic circulation. During the process of drug disintegration, dissolution and absorption, the rate at which the drug reaches the circulatory system is determined by the slowest step in the sequence. The slowest step in a series of kinetic process is called the rate-limiting step, except for sustained release or prolonged-action products, disintegration of a solid drug product is usually more rapid than dissolution and drug absorption. For drugs that have very poor aqueous solubility, for example pomalidomide, the rate at which the drug dissolves (dissolution) is often the slowest step and therefore exerts a rate-limiting effect on drug bioavailability.

[0009] In biologic systems, drug dissolution in an aqueous medium is an important condition for systemic absorption and subsequent bioavailability. The rate at which drug with poor aqueous solubility dissolve from an intact or disintegrated solid dosage form into the gastro intestinal tract often controls the rate of systemic absorption of the drug.

[0010] Pomalidomide is an immunomodulatory drug which is used for the treatment of multiple myleoma.

[0011] Taking into consideration the abovementioned, it is expected that pomalidomide ^' s solubility may limit its dissolution rate and dissolution extension. For a drug substance that has a poor aqueous solubility, the rate at which it dissolves in the gastrointestinal fluids is often the slowest step, and therefore the bioavailability of that drug is said to be dissolution-rate limited. [0012] According to the results obtained during the pharmaceutical development, for immediate release drug products that present low aqueous solubility which impacts the dissolution rate, time points of 60-minutes are considered the most suitable indicators of complete drug release.

[0013] The main goal of performing a 60-minutes time point dissolution test is to ensure that a complete release of the drug is achieved. Complete drug release is deemed to have occurred if, after 60 minutes, at least 90% of the pomalidomide is dissolved. Achieving this result means the drug dissolution profile is consistent with in vivo dissolution performance and hence implies in vivo drug efficacy and safety. This tight specification for a highly discriminating in vitro test is to ensure that the desired therapeutic or pharmacological effect is achieved. The therapeutic or pharmacological effect is measured in vivo through the pharmacokinetic parameters AUC and

Cmax·

[0014] Plasma concentration time curve is generally used to assess the rate and extent of drug absorption. AUC, the area under the concentration time curve, reflects the extent of drug exposure and is related to the extent of drug dissolution. C _max , the maximum plasma concentration of peak exposure, and the time to maximum plasma concentration, t _max , are parameters that are influenced by absorption rate and are related to the dissolution rate.

[0015]

GENERAL DESCRIPTION

[0016] The present disclosure relates to new pharmaceutical dosage forms of pomalidomide for therapeutic use.

[0017] In an embodiment, the present disclosure relates to an immediate release pharmaceutical composition comprising

0.10 % to 3.00 % (wt/wt) of pomalidomide;

40.00 % to 93.00 % (wt/wt) of anhydrous lactose as a diluent;

6.00 % to 25.00 % (wt/wt) of hypromellose as a binder.

[0018] In an embodiment, the pharmaceutical composition further comprises 5% to 20% (wt/wt) of at least a further diluent.

[0019] In an embodiment, the pharmaceutical composition further comprises 2% to 10% (wt /wt) of disintegrant.

[0020] In an embodiment, the pharmaceutical composition further comprises 0.2% to 2% (wt/wt) of lubricant.

[0021] In an embodiment, the further diluent ranges from 10% to 20% (wt/wt), preferably from 10% to 15% (wt/wt).

[0022] In an embodiment, the pharmaceutical composition comprises 1 mg to 4 mg of pomalidomide.

[0023] In an embodiment, the amount of pomalidomide is from 0.2% to 2% (wt/wt), preferably from 0.3% to 1.5% (wt/wt).

[0024] In an embodiment, the amount of anhydrous lactose ranges from 50% to 90% (wt/wt). [0025] In an embodiment, the amount of hypromellose ranges from 8 % to 22 % (wt/wt). [0026] In an embodiment, the lubricant is selected from: magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, stearic acid, glyceryl behenate, hexanedioic acid, hydrogenated vegetable oil, glycerine fumarate, or mixtures thereof.

[0027] In an embodiment, the disintegrant(s) is selected from: sodium croscarmellose, sodium carboxymethyl cellulose, sodium starch glycolate, crospovidone, or mixtures thereof.

[0028] In an embodiment, the further diluent is microcrystalline cellulose.

[0029] In an embodiment, the pharmaceutical composition comprises: 1.43% (wt/wt) pomalidomide, 75.57% (wt/wt) anhydrous lactose, 12.5 % (wt/wt) microcrystalline cellulose, 10% (wt/wt) hypromellose, and 0.5% (wt/wt) magnesium stearate.

[0030] In an embodiment, the pharmaceutical composition comprises: 0.36% (wt/wt) pomalidomide, 76.64% (wt/wt) anhydrous lactose, 12.5% (wt/wt) microcrystalline cellulose, 10% (wt/wt) Hypromellose, and 0.5% (wt/wt) magnesium stearate.

[0031] In an embodiment, the pharmaceutical composition comprises: 1.43% (wt/wt) pomalidomide, 83.07% (wt/wt) anhydrous lactose, 5 % (wt/wt) sodium croscarmellose, 10%

(wt/wt) Hypromellose, and 0.5% (wt/wt) magnesium stearate.

[0032] In an embodiment, the pomalidomide has a particle size characterized by a D50 ranging from 3pm to 20pm, preferably ranging from 5pm to 10pm.

[0033] In an embodiment, the pharmaceutical is a capsule, preferably a hard shell capsule. [0034] In an embodiment, the pharmaceutical ingredient percentage is not more than 5 wt.% of total capsule content.

[0035] In an embodiment, the pharmaceutical composition is for use in the treatment of cancer, preferably multiple myeloma.

[0036] In an embodiment, the present disclosure relates to a solid pharmaceutical dosage form comprising the composition of the present disclosure in the form of a capsule, preferably a hard shell capsule.

[0037] In an embodiment, the pharmaceutical composition of the present disclosure comprises hydroxypropyl methylcellulose (hypromellose).

[0038] In an embodiment, the pharmaceutical compounds of the present disclosure has stability profile, dissolution profile, immediate release profile despite containing anhydrous lactose and Hypromellose, in particular, its dissolution profile at 60-minutes time point.

BRIEF DESCRIPTION OF THE DRAWINGS

[0039] The following figures provide preferred embodiments for illustrating the disclosure and should not be seen as limiting the scope of invention. [0040] Figure 1 shows a manufacturing process flowchart of pharmaceutical compositions according to table 4.

[0041] Figure 2 shows a manufacturing process flowchart of pharmaceutical compositions 2c and 2d.

DETAILED DESCRIPTION OF THE INVENTION

[0042] The present disclosure relates to new pharmaceutical dosage forms of pomalidomide for therapeutic use.

[0043] In an embodiment, the pharmaceutical composition of the present disclosure comprises hydroxypropyl methylcellulose (hypromellose).

[0044] In an embodiment, the amount of hypromellose ranges from 6% to 25% (wt /wt), preferably from 7% to 23% (wt /wt), more preferably from 8% to 22% (wt /wt).

[0045] Hypromellose is well known in the art and its use as a binder usually corresponds to a total % by weight of a composition ranging from 2% to 5%. When present in larger amounts, 10% to 80% by weight of a composition, it is known to form a matrix resulting in the delayed release of active substances. In the present disclosure, hypromellose is used in an amount that is expected to contribute to a slower drug release, however, it acts as a fundamental component of immediate release compositions of poorly soluble active ingredients. Despite comprising an active ingredient with documented low solubility, the compositions described in the present disclosure possess an advantageous immediate release profile with high dose dissolution at the 60 minutes time point. [0046] In an embodiment, the pharmaceutical compositions of the present disclosure also includes anhydrous lactose as diluent.

[0047] In an embodiment, the amount of diluents range from 40% to 93% (wt/wt), preferably from 50% to 92%, more preferably from 60% to 90% (wt/wt). The compositions obtained are stable and with no detectable adverse effect (with regard to either its stability or industrial processing) attributable to the presence of anhydrous lactose .

[0048] In an embodiment, the pharmaceutical composition further comprises additional pharmaceutical excipients namely, at least a further diluent(s), lubricant(s) and disintegrant(s). In the context of the present disclosure, the inclusion of each of these excipients shall be understood as including a single compound as well as mixtures of two or more compounds of that class. [0049] In an embodiment, the pharmaceutically acceptable further diluent(s) according to the present disclosure include microcrystalline cellulose, kaolin, magnesium oxide, calcium sulfate, citric acid, tartaric acid, fumaric acid, co-polymers of vinyl pyrrolidone and vinyl acetate, co polymers of polyethylene glycol, and mixtures thereof. [0050] In an embodiment, the further diluent(s) make up from 5% to 20% (wt/wt), preferably from 10% to 20% (wt/wt) and, more preferably from 10% to 15% (wt/wt).

[0051] In an embodiment, the preferred further diluent is microcrystalline cellulose.

[0052] In an embodiment, pharmaceutically acceptable lubricant(s) according to the present disclosure includes magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, stearic acid, glyceryl behenate, hexane dioic acid, hydrogenated vegetable oil, glycerin fumarate and mixtures thereof.

[0053] In an embodiment, the amount of lubricant(s) ranges from 0.2% to 2% (wt/wt), preferably from 0.3% to 1% (wt /wt).

[0054] In an embodiment, the preferred lubricant is sodium magnesium stearate.

[0055] In an embodiment, pharmaceutically acceptable disintegrant(s) according to the present disclosure includes croscarmellose, sodium carboxymethyl cellulose, sodium starch glycolate, crospovidone and mixtures thereof.

[0056] In an embodiment, the amount of disintegrant(s) ranges from 2% to 10% (wt/wt), preferably from 3% to 8% (wt /wt).

[0057] In an embodiment, the preferred disintegrant is croscarmellose sodium.

[0058] In an embodiment, the pomalidomide is micronized prior to the formulation.

[0059] In an embodiment, the pharmaceutical composition comprises pomalidomide with a particle size characterized by a D ₅ o ranging from 3pm to 20pm, preferably ranging from 5pm to 10pm.

[0060] In an embodiment, the oral dosage form of the pharmaceutical composition is a capsule, preferably a hard shell capsule.

[0061] In an embodiment, the oral pharmaceutical compositions comprise from lmg to 4mg of pomalidomide.

[0062] In an embodiment, the active pharmaceutical ingredient (API) percentage is preferably not more than 5wt.% of the capsule content.

[0063] In an embodiment, the method for manufacturing the oral pharmaceutical compositions comprising pomalidomide comprises the following steps:

(a) calibrating, blending and mixing the drug substance, diluents(s), binder(s) and, where applicable, disintegrant(s),

(b) calibrating the lubricant and adding it to the mixture,

(c) lubricating the mixture,

(d) filling the final blend into capsules,

(e) packaging. [0064] In an embodiment, as an example (Example 1 - Pharmaceutical compositions), tables 1 to 4 show the formulations of the pomalidomide pharmaceutical compositions described in the present disclosure.

Table 1 - Qualitative and quantitative composition data

* Each ingredient is expressed as a percentage (wt/wt) of the total mixture

Table 2 - Qualitative and quantitative composition data

* Each ingredient is expressed as a percentage (wt/wt) of the total mixture Table 3 - Qualitative and quantitative composition data

* Each ingredient is expressed as a percentage (wt/wt) of the total mixture

Table 4 - Qualitative and quantitative composition data

* Each ingredient is expressed as a percentage (wt/wt) of the total mixture

[0065] In an embodiment, according to Table 4, the powder mixture mass (280 mg) is the same for compositions 4a, 4b, 4c and 2a. The qualitative composition is the same for 1 mg, 2mg, 3mg and 4 mg compositions. The API percentage ranges from 0.1% to 3% by weight (wt/wt), preferably range from 0.2% to 2% by weight (wt/wt), more preferably range from 0.3% to 1.5% by weight (wt/wt).

[0066] In an embodiment, as an example (Example 2 - Dissolution profiles), the dissolution profiles of the example compositions are listed in Table 5. Table 5 - Dissolution profiles of compositions

[0067] Tables 5 discloses the dissolution profiles of example Composition la, Composition lb, Composition 2a, Composition 2b, Composition 2c, Composition 2d, Composition 3a, Composition 3b, Composition 4a. The example compositions of the present disclosure showed an advantageous immediate release profile with high dose dissolution at the 60 minutes time point. All example compositions comprising pomalidomide, anhydrous lactose and hypromellose have an advantageous immediate release profile with high dose dissolution at the 60 minutes time point. [0068] In an embodiment, as an example (Example 3 - Comparative pharmaceutical formulations), Tables 6 to 8 show the composition data of comparative formulations. These comparative formulations are to be compared against the example compositions of the present disclosure.

Table 6 - Qualitative and quantitative comparative compositions

* Each ingredient is expressed as a percentage (wt/wt) of the total mixture

Table 7 - Qualitative and quantitative comparative compositions

* Each ingredient is expressed as a percentage (wt/wt) of the total mixture

Table 8 - Qualitative and quantitative comparative compositions

* Each ingredient is expressed as a percentage (wt/wt) of the total mixture [0069] In an embodiment, as an example (Example 4 - Dissolution profiles of comparative compositions), the dissolutions profiles of the comparative compositions are listed in Table 9.

Table 9- Dissolution profiles of comparative compositions

[0070] Tables 9 discloses the dissolution profiles of Comparative Composition 5a, Comparative Composition 5b, Comparative Composition 6a, Comparative Composition 6b, Comparative Composition 6c, Comparative Composition 6d, Comparative Composition 7a and Comparative Composition 7b. As compared to the example compositions, the comparative compositions do not have an advantageous immediate release profile with high dose dissolution at the 60 minutes time point.

[0071] In an embodiment, as an example (Example 5 - Stability testing of the formulations), the stability of the example compositions was analyzed.

[0072] Example Composition la, Composition 2a, Composition 2c, Composition 2d, Composition 3b and Composition 4a were submitted to stability studies at several standard conditions. The results obtained are presented in Tables 10 to 18.

Table 10 - Assay and related compounds stability results - Composition la

Table 11 - Assay and related compounds stability results - Composition 2a

Table 12 - Assay and related compounds stability results - Composition 2a (continued)

Table 13 - Assay and related compounds stability results - Composition 2c

Table 14 - Assay and related compounds stability results - Composition 2d Table 15 - Assay and related compounds stability results - Composition 2d (continued)

Table 16 - Assay and related compounds stability results - Composition 3b

Table 17 - Assay and related compounds stability results - Composition 3b (continued)

Table 18 - Assay and related compounds stability results - Composition 4a

[0073] The controlled related compounds referred to in Tables 10 to 18 are: POMA03 (Nitropomalidomide) CAS 19171-18-7; Thalidomide CAS 50-35-1; POMA4-isomer CAS 191732-76- 0; POMA-OH CAS 1547162-41-3 and S.L.U. Impurity refers to the Single Largest Unknown Impurity detected.

[0074] The assay and related compounds tests results in Tables 10 to 18 show that example Composition la. Composition 2a, Composition 2c, Composition 2d, Composition 3b and Composition 4a are stable despite being submitted to various standard conditions (accelerated and long term conditions). The example compositions comprising pomalidomide, anhydrous lactose and hypromellose are stable despite being submitted to various standard conditions (accelerated and long term conditions). [0075] In an embodiment, the formulation according to the disclosure meet the specifications for all the packaging materials that were investigated, in particular OPA blisters.

[0076] In an embodiment, as an example (Example 6 - In-vitro dissolution testing of stability batches), the dissolution profiles of several example compositions.

[0077] (Composition 2c, Composition 2d, Composition 3b and Composition 4a) were analysed after the example compositions were subjected to stability studies. The results obtained are shown in Tables 19 to 22.

Table 19 - In-vitro dissolution data of stability batches - Composition 2c

Table 20 - In-vitro dissolution data of stability batches - Composition 2d Table 21 - In-vitro dissolution data of stability batches - Composition 3b

Table 22- In-vitro dissolution data of stability batches- Composition 4a

[0078] The dissolution profiles disclosed in Tables 19 to 22 show that the example compositions maintained their advantageous immediate release profile with high dose dissolution at the 60 minutes time point even after being submitted to stability conditions (accelerated and long term conditions).

[0079] In an embodiment, in vitro dissolution data (table 5, table 9 and tables 19 to 22) was obtained according to the settings as set out in Table 23. Table 23 - in-vitro dissolution settings

[0080] The term "comprising" whenever used in this document is intended to indicate the presence of stated features, integers, steps, components, but not to preclude the presence oraddition of one or more otherfeatures, integers, steps, components orgroups thereof.

[0081] It will be appreciated by those of ordinary skill in the art that unless otherwise indicated herein, the particular sequence of steps described is illustrative only and can be varied without departing from the disclosure. Thus, unless otherwise stated the steps described are so unordered meaning that, when possible, the steps can be performed in any convenient or desirable order.

[0082] The disclosure should not be seen in any way restricted to the embodiments described and a person with ordinary skill in the art will foresee many possibilities to modifications thereof. The above described embodiments are combinable.