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Title:
PHARMACEUTICAL COMPOSITIONS COMPRISING AZITHROMYCIN
Document Type and Number:
WIPO Patent Application WO/2018/215638
Kind Code:
A1
Abstract:
The present invention provides a pharmaceutical composition in the form of a suspension comprising: (a) particles of azithromycin and/or a hydrate thereof, and (b) a liquid vehicle comprising a semifluorinated alkane of the formula (I), CF3(CF2)n(CH2)mCH3 (I), wherein n is an integer from 3 to 5, and m is an integer from 4 to 7.

Inventors:
GÜNTHER, Bernhard (Schriesheimerstrasse 19, Dossenheim, 69221, DE)
LÖSCHER, Frank (Burgweg 31, Schriesheim, 69198, DE)
EICKHOFF, Kirsten (Vangerowstrasse 43, Heidelberg, 69115, DE)
KRÖSSER, Sonja (Brennerweg 2/2, Heidelberg, 69124, DE)
GRILLENBERGER, Ralf (Alte Schulstr. 10, Ilvesheim, 68549, DE)
Application Number:
EP2018/063749
Publication Date:
November 29, 2018
Filing Date:
May 25, 2018
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
NOVALIQ GMBH (Im Neuenheimer Feld 515, Heidelberg, 69120, DE)
International Classes:
A61K9/10; A61K31/7052; A61K47/24
Domestic Patent References:
WO2012062834A12012-05-18
WO2012160179A22012-11-29
Foreign References:
EP2462921A12012-06-13
US6458376B12002-10-01
US6569443B12003-05-27
US6861411B12005-03-01
US7056893B22006-06-06
Other References:
"PHARMAZEUTISCHE TECHNOLOGIE : FüR STUDIUM UND BERUF", 1 January 1995, ULLSTEIN MOSBY, ISBN: 978-3-86126-108-7, article RUDOLF VOIGT: "Pharmazeutische Technologie", pages: 508, XP055486823
"Pharmazeutische Technologie, 5. Auflage", 1 January 1997, ISBN: 978-3-7741-0638-3, article KURT H. BAUER: "Pharmazeutische Technologie", pages: 251 - 252, XP055486834
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 83905- 01-5
T. AMAR ET AL., CURRENT EYE RESEARCH, vol. 33, no. 2, 2008, pages 149 - 158
Attorney, Agent or Firm:
PHARMA CONCEPTS GMBH (Unterer Rheinweg 50, 4057 Basel, 4057, CH)
Download PDF:
Claims:
Patent Claims

A pharmaceutical composition in the form of a suspension comprising:

(a) particles of azithromycin and/or a hydrate thereof, and

(b) a liquid vehicle comprising a semifluorinated alkane of the formula (I)

CF3(CF2)n(CH2)mCH3 (I), wherein n is an integer from 3 to 5, and m is an integer from 4 to 7; wherein at least about 90 % of the suspended particles have a size of not more than about 15 μιη.

The composition of any preceding claim, wherein at least about 90 % of the suspended particles of azithromycin have a size in the range from about 2 μιη to about 15 μιη.

The composition of any preceding claim, wherein at least about 90% of the suspended particles of azithromycin have a size in the range from about 2 μιη to about 10 μιη.

The composition of any preceding claim, wherein the semifluorinated alkane of formula (I) is perfluorohexyl-octane (CF3(CF2)s(CH2)7CH3, F6H8).

The composition of any preceding claim, wherein the concentration of azithromycin in the composition is in the range from 0.5 to 5% (w/v).

The composition of any preceding claim, wherein the concentration of azithromycin in the composition is in the range of from 1.5 to 3% (w/v).

The composition of any preceding claim, wherein azithromycin is azithromycin-dihydrate.

The composition of any preceding claim, wherein the composition substantially consists of perfluorohexyl-octane (F6H8) and azithromycin- dihydrate.

9. The composition of any preceding claim, wherein the composition is free of water.

10. The composition of any preceding claim, wherein the composition is free of a preservative.

11. The composition of any preceding claim, wherein the composition is free of a surfactant.

12. The composition of any preceding claim for use as a medicament.

13. The composition of any of claims 1 to 11 for use as a medicament for

topical administration to the eye of a patient.

14. The composition of any of claims 1 to 11 for use in the treatment of an infective ocular disease.

15. The composition for use according to claim 14, wherein the infective

ocular disease is caused by gram-positive and/or gram-negative bacteria.

16. The composition of any of claims 1 to 11 for use in the treatment of an inflammatory ocular disease.

17. The composition for use according to any of claims 13 to 16, wherein the infective and/or inflammatory ocular disease is selected from the group consisting of bacterial conjunctivitis, blepharitis, trachoma and neonatal conjunctivitis.

18. The composition for use according to any of claims 13 to 17, wherein the infective and/or inflammatory ocular disease affects an ophthalmic tissue selected from the group consisting of eyelid, cornea, and (bulbar) conjunctiva; or wherein the infective and/or inflammatory ocular disease affects an ophthalmic fluid selected from the group consisting of tears and aqueous humor.

19. The composition for use according to claim 16 for use in the treatment of an inflammatory ocular disease affecting tissues of the anterior segment of the eye.

20. The composition for use according to claim 19, wherein the inflammatory ocular diseases affecting tissues of the anterior segment of the eye are selected from blepharitis, dry eye disease (DED), uveitis and keratitis.

21. The composition for use according to claim 19 or 20, wherein the tissue of the anterior sector of the eye are selected from cornea, conjunctiva, eye lids, lacrimal glands, meibomian glands and/or anterior chamber.

22. The composition for use according to any of claims 13 to 21 for use in the treatment of an infective and inflammatory ocular disease simultaneously affecting the anterior segment of the eye of a patient. 23. The composition for use according to claim 22, wherein the infective and inflammatory ocular disease of the anterior segment of the eye is selected from the group consisting of bacterial conjunctivitis, blepharitis, trachoma and neonatal conjunctivitis.

24. The composition for use according to any of claims 13 to 23, wherein the composition is administered topically to the eye of a patient.

25. The composition for use according to any of claims 13 to 24, wherein the composition is administered dropwise, preferably at a single drop volume of about 8 to 12 μΐ, preferably at a single drop volume of about 10 to 11 μΐ.

26. A kit comprising the composition of any of claims 1 to 11 and a container for holding the composition, said container comprising dispensing means for dropwise topical administration to a surface of the eye of a patient, said dispensing means preferably being adapted to dispense the composition dropwise in volumes of less than about 15 μΐ.

Description:
TITLE: PHARMACEUTICAL COMPOSITIONS COMPRISING AZITHROMYCIN

Description BACKGROUND

The present invention relates to pharmaceutical compositions in form of a suspension which are suitable for the delivery of azithromycin by topical

administration to the surface of an eye of a patient.

Pharmaceutical compositions in liquid form represent one of the preferred types of drug formulations. Certain topical routes of topical administration, such as ophthalmic administration, typically require the liquid form in order to provide for an efficient delivery of the active ingredient and a patient-friendly mode of use.

The simplest type of liquid formulation is a solution, such as an aqueous solution of the active pharmaceutical ingredient. In certain cases, however, the development of a more complex formulation such as a suspension may be considered. For example, if a drug substance is very poorly soluble in aqueous or other

biocompatible solvent systems, or if it is hydrolytically labile, a simple solution may not be feasible or represent the best choice. Another occasional motivation to formulate a drug suspension is in order to achieve a prolonged pharmacological effect by slow dissolution and uptake of the active ingredient.

An ophthalmic suspension that has reached the market stage is, for example, Livocab ® (active ingredient: levocabastine). Common problems associated with pharmaceutical suspensions are usually related to physical stability issues, potential irritability, and/or manufacturing challenges. Obviously, suspensions are prone to physical changes of various types, all of which may have impact on drug product quality and performance.

For example, suspended particles may flotate or sediment, depending on their density relative to that of the liquid phase in which they are dispersed. Along with flotation or sedimentation, the suspended particles may aggregate, and depending on the forces by which the particles attract each other, the aggregates thus formed may be rather difficult to resuspend. A further problem is that in suspensions having nonuniform particle sizes there is a tendency for smaller particles to gradually dissolve, whereas larger particles grow through the deposition of dissolved material onto their surfaces (Ostwald ripening). In result, the particle size distribution of a suspension may become broader over time. Particles which grow beyond a certain size may be unsuitable for the intended use; for example, they may occlude an injection cannula or, in case of ophthalmic administration, irritate or even damage the ocular surface.

Neither is it straightforward to manufacture a pharmaceutical suspension in a highly reproducible manner as is required in particular for non-oral products. If the particle size and the distribution thereof is critical, which is likely in the case of a parenteral suspension, but to some degree also for an ophthalmic suspension, significant process engineering efforts may be required in order to ensure the reproducibility of the physical properties of the formulation. Moreover, if the product is required to be sterile, which is always the case for an injectable or ophthalmic product, heat sterilisation will normally be extremely difficult in view of the major physical changes which the product undergoes during heating, and sterile filtration which is typically performed with products that cannot be heat sterilised will be generally unfeasible. The remaining options include aseptic processing, which is technically complex and challenging, and gamma sterilisation, which may be feasible depending on the chemical stability of the drug substance and of the excipients.

Nevertheless, topical ophthalmic delivery, while not highly efficient in absolute terms, is still relatively effective for many small molecular drugs, and acceptable to patients in terms of convenience.

As an alternative to aqueous preparations, oily eye drops may be formulated if the respective drug substance is poorly water-soluble or prone to hydrolytic degradation. However, one of the major disadvantages of all oil-based formulations for ophthalmic administration is that they inherently have a negative impact on vision. Whether used as oily solutions or oil-in-water emulsions, they exhibit a refractive index which differs substantially from that of physiological tear fluid, which leads to visual disturbances and blurring.

Moreover, oil-based formulations do not readily mix with tear fluid to form a homogenous liquid phase. Oily solutions are altogether immiscible with the aqueous tear fluid, and the exact fate of an emulsion mixed with tear fluid in a physiological setting is not completely predictable. Further, oily carrier such as medium chain triglycerides (MCT) are known to cause a strong burning sensation upon instillation to the eye. Oil-in-water emulsions of poorly water-soluble drugs like ciclosporin further exhibit the disadvantage that they have a limited drug load capacity. While the active ingredient may have some solubility in the oil phase, this phase is only dispersed in the coherent aqueous phase of the emulsion so that the maximum overall drug concentration in the formulation is very limited. In contrast to single phase systems such as aqueous or oily solutions, oil-in- water emulsions are also more complex and difficult to manufacture, especially in sterile form. Frequently, emulsions are not readily sterilisable by thermal treatment without negative impact on the physical properties of the emulsion. On the other hand, aseptic processing is complex, costly, and is associated with higher risks of failure, i.e. microbial contamination of the product.

Furthermore, oil-in-water emulsions are like aqueous solutions prone to microbial contamination during use. If they were to be presented in multi-dose containers which are in principle more cost-efficient and convenient for patients than single-use vials, they would have to be preserved in order to ensure their

microbiological quality. At the same time, preservatives which can be used in ophthalmic formulations are potentially damaging to the eye, in particular to the ocular surface, and should be avoided whenever possible.

As another alternative to aqueous liquid carriers which are problematic for water-sensitive drug substances, US 6,458,376 proposes eye drops on the basis of non-aqueous liquid perfluorocarbons. At least some of the preferred

perfluorocarbons are presented as biocompatible and non-irritating to the eye. The compositions are formulated as suspensions, in particular of polymeric carrier particles which include the drug substance and which are capable of releasing the drug slowly over an extended period of time. Moreover, the compositions may comprise a surfactant such as a non-ionic ethoxylated alcohol or sorbitan. The surfactant functions as a suspension stabiliser and prevents aggregation. However, it has been found that these drug suspensions in perfluorocarbons suffer from various disadvantages. If formulated without surfactant, they tend to separate (by flotation, or sometimes by sedimentation) very rapidly, and lead to substantial particle aggregation. At the same time, the settled suspensions are very difficult to redisperse by shaking alone. These poor physical suspension properties would seriously impact their usefulness as eye drops. Not only is vigorous shaking and the need for rapid administration before the suspension separates again very inconvenient to patients; poor suspension properties are also associated with the risk of substantial dosing errors. On the other hand, surfactants, which are potentially irritating to the eye and whose use in ophthalmic preparations should be avoided or limited to a low level, are not very effective in stabilising perfluorocarbon

suspensions. The incorporation of high amounts of surfactant which may achieve a better stabilisation of the suspension system is physiologically undesirable.

WO 2012/062834 Al discloses liquid pharmaceutical compositions for the treatment of conditions affecting the posterior segment of an eye. The liquid carriers have a density of at least 1.2 g/ml and may be selected from non-aqueous vehicles such as perfluorocarbons, semifluorinated alkanes, polysiloxanes and mixtures thereof. The compositions may be administered topically into the eye or in a minimally invasive manner by periocular injection and may or may not comprise a large variety of suitable active ingredients in dissolved or dispersed form.

WO 2012/160179 A2 discloses topical pharmaceutical compositions for use in the treatment of a disease affecting the skin or a skin appendage comprising an active ingredient and a semifluorinated alkane for the treatment of acne. Antiinfective agents such as azithromycin, erythromycin, clindamycin and minocycline are proposed as active ingredients.

US 6,569,443 Bl refers to a process for treating an eye, comprising topically applying an azalide antibiotic to an eye in an amount effective to treat infection in a tissue of the eye, wherein said topically applying comprises supplying a depot of a composition containing said azalide antibiotic on the eye. As a preferred azalide azithromycin is mentioned. Furthermore, said depot preferably is an aqueous polymeric suspension of said azalide antibiotic. US 6,861,411 Bl discloses a method of treating an ocular infection, comprising topically administering to an eye of an animal in need of such treatment an ocular infection-treating amount of azithromycin.

US 7,056,893 B2 discloses a composition, preferably an ophthalmic

composition comprising water, a polymeric suspending agent and an azalide antibiotic, wherein said composition has a pH of about 6.0 to 6.6. As preferred polymeric suspending agents water-swellable, water-insoluble crosslinked carboxy- vinyl polymers are disclosed.

Unfortunately, is has been observed, that especially in cases in which azithromycin is provided in form of non-aqueous solutions, topical administration to the eye of a patient is often accompanied by a high level of discomfort, due to undesirable and unpleasant perceptions such as scratching, burning, pain or foreign body sensations in the eye of the user. This unfortunately, may lead to reduced compliance of the user with regard to the prescribed administration scheme, which is especially important when using an antibiotic for the treatment of an ocular infection.

Furthermore, as mentioned above, especially in cases where pharmaceutical compositions for ophthalmic use have to be administered repeatedly, the sterility of the composition is essential, especially in case in which infective ocular disease are treated to avoid multiple infections. Therefore, especially in cases in which multiple doses are provided the use of preservative is necessary. Preservatives, however, may lead to further irritations, especially when used in the eye of a patient.

Accordingly, there is still a need for further improvements in the formulation of azithromycin for the treatment of ophthalmic disease or conditions, especially for topical administration to the eye of a patient. It is therefore an object of the present invention to provide a novel pharmaceutical composition which is useful for the delivery of azithromycin. Another object is to provide improved formulations of azithromycin for topical ophthalmic delivery which overcome one or more

disadvantages of known formulations. A further object is to provide improved nonaqueous liquid formulations of azithromycin which overcome the limitations of presently known formulations. Further objects of the invention will become clear on the basis of the following description, examples, and patent claims. SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a pharmaceutical composition in the form of a suspension comprising:

(a) particles of azithromycin and/or a hydrate thereof, and

(b) a liquid vehicle comprising a semifluorinated alkane of the formula (I)

CF3(CF 2 )n(CH 2 )mCH3 (I), wherein n is an integer from 3 to 5, and m is an integer from 4 to 7.

In a specific embodiment of the first aspect, the present invention provides a pharmaceutical composition in the form of a suspension comprising:

(a) particles of azithromycin and/or a hydrate thereof, and

(b) a liquid vehicle comprising a semifluorinated alkane of the formula (I)

CF 3 (CF 2 ) n (CH 2 ) m CH3 (I), wherein n is an integer from 3 to 5, and m is an integer from 4 to 7; wherein at least about 90% of the suspended particles have a size of not more than about 15 μιη.

In a second aspect, the present invention provides the compositions of the first aspect of the invention for use as medicament.

In a further aspect, the present invention provides the compositions of the first aspect of the invention for use in the treatment of an infective and/or inflammatory ocular disease, such as for example bacterial conjunctivitis, blepharitis and others.

In yet a further aspect, the present invention provides a kit comprising the composition of the first aspect of the invention and a container for holding the composition. Said container comprises dispensing means for dropwise topical administration to a surface of the eye of a patient, wherein said dispensing means are preferably adapted to dispense the composition dropwise in volumes of less than about 15 μΐ.

In a further aspect, the present invention provides a method for the treatment of an ocular disease of the eye of a patent, wherein the ocular disease is an

inflammatory and/or infective disease, comprising

- providing a composition according to the first aspect of the invention, and

- topically administering said composition to a surface of the eye of the patient.

In yet a further aspect, the present invention provides a method for transporting azithromycin to an ophthalmic tissue selected from the group consisting of eyelid, cornea, and (bulbar) conjunctiva; or a method for transporting

azithromycin to an ophthalmic fluid selected from the group consisting of tears and aqueous humor.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows the ocular distribution of a suspension of 1.5 % and 3.0 % (w/v) azithromycin-dihydrate suspended in l-perfluorohexyl-octane (F6H8) in tears (T);

Fig. 2 shows the ocular distribution of a suspension of 1.5 % and 3.0 % (w/v) azithromycin-dihydrate suspended in l-perfluorohexyl-octane (F6H8) in eyelids (EL);

Fig. 3 shows the ocular distribution of a suspension of 1.5 % and 3.0 % (w/v) azithromycin-dihydrate suspended in l-perfluorohexyl-octane (F6H8) in cornea (C);

Fig. 4 shows the ocular distribution of a suspension of 1.5 % and 3.0 % (w/v) azithromycin-dihydrate suspended in l-perfluorohexyl-octane (F6H8) in bulbar conjunctiva (BCJ);

Fig. 5 shows the ocular distribution of a suspension of 1.5 % and 3.0 % (w/v) azithromycin-dihydrate suspended in l-perfluorohexyl-octane (F6H8) in aqueous humor (AH). DETAILED DESCRIPTION OF THE INVENTION

It has been found by the inventors that the composition of the invention surprisingly overcomes several drawbacks of previously known aqueous and nonaqueous formulations of azithromycin. In particular, the compositions of the present invention allow for fast delivery of azithromycin to affected tissues or liquids of the eye of a patient in combination with a sustained pharmaceutically relevant level of azithromycin in such tissues or liquids.

In a first aspect, the present invention provides a pharmaceutical composition in the form of a suspension comprising:

(a) particles of azithromycin and/or a hydrate thereof, and

(b) a liquid vehicle comprising a semifluorinated alkane of the formula (I)

CF3(CF 2 )n(CH 2 )mCH3 (I),

wherein n is an integer from 3 to 5, and m is an integer from 4 to 7.

Furthermore, the present invention provides a pharmaceutical composition in the form of a suspension comprising:

(a) particles of azithromycin and/or a hydrate thereof, and

(b) a liquid vehicle comprising a semifluorinated alkane of the formula (I)

CF 3 (CF 2 ) n (CH 2 ) m CH3 (I), wherein n is an integer from 3 to 5, and m is an integer from 4 to 7; wherein at least about 90% of the suspended particles have a size of not more than about 15 μιη.

The pharmaceutical compositions according to the present invention comprise particles of azithromycin and/or a salt or a hydrate of azithromycin. The compound azithromycin as used herein is an antibiotic macrolide with CAS Registry No. 83905- 01-5 also known as 9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A, which has the molecular formula C38H72N2O12 and a molar mass of 748.984 g/mol. It is commercially available in form of its monohydrate as well as in form of its dihydrate. Azithromycin-dihydrate, is a white crystalline powder with a molecular formula of C38H72N2O12 x 2H2O and a molecular weight of 785.0. In a preferred embodiment of the present invention, azithromycin is used in form of the monohydrate or in form of the dihydrate as described above.

Preferably, the azithromycin as defined above is present in the pharmaceutical compositions according to present invention in a therapeutically effective amount. The term "a therapeutically effective amount" as used herein refers to a dose, concentration or strength which is useful for producing a desired pharmacological effect.

The pharmaceutical compositions of the present invention are provided in form of a suspension. A suspension may be defined as a type of a dispersion, a dispersion being a system having at least one continuous (or coherent) phase and at least one discontinuous (or inner) phase which is dispersed in the continuous phase. In a suspension, the dispersed phase is in the solid state. The suspensions useful for practising the present invention are liquids, at least at physiological temperature, which means that the continuous phase is a liquid. Typically, the suspensions are also liquid at room temperature.

Accordingly, the present invention provides pharmaceutical compositions, in which particles of azithromycin or a hydrate thereof as the dispersed phase are suspended in a liquid vehicle comprising a semifluorinated alkane of the formula (I) as defined above as the continuous phase. In a preferred embodiment, the particles of azithromycin or a hydrate thereof are solid particles. In a further preferred

embodiment, the particles, preferably the solid particles of azithromycin substantially consist of azithromycin or a hydrate thereof, namely azithromycin monohydrate or azithromycin dihydrate, preferably azithromycin dihydrate.

Some of the key advantages of the present invention are brought about by the presence of a semifluorinated alkane in the composition, functioning as a liquid suspension vehicle. The semifluorinated alkanes according to the present invention are those of the general formula (I) CF 3 (CF 2 ) n (CH 2 ) m CH 3 (I), wherein the index n is an integer selected from 3 to 5, and m is an integer selected from 4 to 7.

An alternative nomenclature for the specified semifluorinated alkanes as noted in parentheses below and as may be further used herein, is based on the general formula FnHm, wherein F means the linear perfluorinated hydrocarbon segment, H means the linear non-fluorinated hydrocarbon segment and n, m is the number of carbon atoms of the respective segment. For example, F4H5 may be used to denote 1-perfluorobutyl-pentane or CF 3 (CF 2 ) 3 -(CH 2 )4CH 3 (which may be also, alternatively expressed as formula F(CF 2 )4(CH 2 )sH), which has a linear perfluorinated segment F with four carbons (n = 4) and a linear non-fluorinated hydrocarbon segment with five carbons (m = 5). Furthermore, F6H8 may be used to denote 1- perfluorohexyl-octane or CF 3 (CF 2 )5-(CH 2 ) 7 CH 3 (which may be also, alternatively expressed as formula F(CF 2 )6(CH 2 )sH), which has a linear perfluorinated segment F with six carbons (n = 6) and a linear non-fluorinated hydrocarbon segment with 8 carbons (m = 8).

Accordingly, said semifluorinated alkane as used in the compositions of the present invention may be selected from CF 3 (CF 2 ) 3 -(CH 2 )4CH 3 (F4H5), CF 3 (CF 2 ) 3 - (CH 2 ) 5 CH 3 (F4H6), CF 3 (CF 2 ) 3 -(CH 2 ) 6 CH 3 (F4H7), CF 3 (CF 2 ) 3 -(CH 2 ) 7 CH 3 (F4H8), CF 3 (CF 2 ) 4 -(CH 2 ) 4 CH 3 (F5H5), CF 3 (CF 2 ) 4 -(CH 2 )5CH 3 (F5H6), CF 3 (CF 2 ) 4 -(CH 2 ) 6 CH 3 (F5H7), CF 3 (CF 2 ) 4 -(CH 2 ) 7 CH 3 (F5H8), CF 3 (CF 2 ) 5 -(CH 2 ) 4 CH 3 (F6H5), CF 3 (CF 2 ) 5 - (CH 2 ) 5 CH 3 (F6H6), CF 3 (CF 2 ) 5 -(CH 2 ) 6 CH 3 (F6H7) and CF 3 (CF 2 ) 5 -(CH 2 ) 7 CH 3 (F6H8). More preferably, said semifluorinated alkane may be selected from CF3(CF 2 )3- (CH 2 ) 4 CH 3 (F4H5) and CF 3 (CF 2 ) 5 -(CH 2 ) 7 CH 3 (F6H8). In a preferred embodiment, the pharmaceutical composition according to the present invention comprise a semifluorinated alkane of formula (I) which is selected from 1-perfluorohexyl-octane (CF 3 (CF 2 )5-(CH 2 ) 7 CH 3 (F6H8)) and 1-perfluorobutyl- pentane (CF 3 (CF 2 ) 3 -(CH 2 )4CH 3 (F4H5)). In a particular preferred embodiment of the present invention, the semifluorinated alkane of formula (I) is perfluorohexyl-octane (CF 3 (CF 2 ) 5 (CH 2 ) 7 CH 3 , F6H8).

The pharmaceutical compositions of the invention comprising of "a" semifluorinated alkane is to be understood herein, as comprising at least one semifluorinated alkane of Formula (I) as described above. Optionally, however, the composition may comprise of more than one, for example, a mixture of two or more semifluorinated alkanes of Formula (I), i.e. of any one of the semifluorinated alkane species as described above.

In yet further embodiments, the liquid continuous phase of the pharmaceutical suspension composition of the present invention may consist of a semifluorinated alkane of Formula (I) as specified above. In this context, the term "a" semifluorinated alkane is to be understood as at least one semifluorinated alkane but may also include the option of more than one, or a plurality of semifluorinated alkane compounds. Accordingly, in one embodiment, the composition may consist of more than one semifluorinated alkane of Formula (I) as specified above.

In yet further embodiments, the pharmaceutical composition in the form of a suspension according to the present invention essentially consists of:

(a) particles of azithromycin and/or a hydrate thereof, and

(b) a liquid vehicle comprising a semifluorinated alkane of the formula (I)

CF3(CF 2 )n(CH 2 )mCH3 (I), wherein n is an integer from 3 to 5, and m is an integer from 4 to 7.

In further embodiments, in the pharmaceutical composition in the form of a suspension according to the present invention essentially consisting of particles of azithromycin and/or a hydrate thereof, and a liquid vehicle comprising a

semifluorinated alkane of the formula (I) as described above, at least about 90% of the suspended particles have a size of not more than about 15 μιτι, preferably at least about 90% of the suspended particles of azithromycin have a size in the range from about 2 μιη to about 15 μιη or more preferably in the range from about 2 μιη to about 10 μιη.

As used herein, the term "consists" and related terms "consisting" or "consist" is to be understood as meaning that no other features, other than those prefaced by the term are present. In the context of compositions, if any other constituent or component is present in the composition other than those prefaced by such term, then it is present only in trace or residual amounts such as to confer no technical advantage or relevance in respect of the object of the invention, such as may be further understood by the term 'essentially" or "substantially" used in conjunction with these terms (e.g. 'essentially consisting of"). It is to be understood that isomeric or olefinic impurities that originate from synthesis of semifluorinated alkanes and that are present in only trace or residual amounts as these cannot be quantitatively removed upon purification and that do not confer any technical advantage or relevance in respect of the object of the present invention, do fall under the above definition of such other constituent or component. In contrast, the term 'comprising" or related terms "comprises" or "comprise" in the context of the present

compositions, is to be understood as meaning that other features, other than those prefaced by the term may be present in the composition.

In a further embodiment, the liquid vehicle of the present pharmaceutical compositions as defined in any of the previous embodiments described above, preferably comprises a semifluorinated alkane or optionally, a mixture of

semifluorinated alkanes in an amount of at least 70% (w/w), 75 % (w/w), 85 % (w/w), 90 % (w/w), 95 % (w/w), 98% (w/w), 98.5% (w/w), 99%(w/w), 99.5% (w/w), 99.8% (w/w) or at least 99.9 % (w/w) of a semifluorinated alkane or a mixture of semifluorinated alkanes as described above, with respect to the total weight of the liquid vehicle. In one preferred embodiment, the liquid vehicle of the present invention consists of 100% (w/w) of a semifluorinated alkane or mixture of semifluorinated alkanes.

The term "% (w/w)" as used herein and unless indicated otherwise refers to the amount of a component of a composition as a weight percentage in relation to the total weight of the liquid vehicle of the present pharmaceutical composition (with 'w' denoting weight).

Unless otherwise indicated, the term "% (w/v)" as used throughout herein in connection with the present pharmaceutical composition denotes the amount of a component of a composition (such as azithromycin or a hydrate thereof) as a weight percentage in relation to the total volume of the composition (with 'w' denoting the weight and V denoting volume). For example, 1.5 % (w/v) may be understood as relating to 15 mg of a component in 1 mL of the composition, and 3.0 % (w/v) would correspond to 30.0 mg of a component in 1 mL of the composition.

In a particularly preferred embodiment, the liquid vehicle of the

pharmaceutical composition for according to the present invention comprises 1- perfluorohexyl-octane (CF3(CF2)s-(CH2)7CH3 (F6H8)), preferably as the only semifluorinated alkane present in the pharmaceutical composition. In a further preferred embodiment, the liquid vehicle of the pharmaceutical composition of the present invention essentially consists of 1-perfluorohexyl-octane (F6H8). It is understood that a liquid vehicle essentially consisting of l-perfluorohexyl-octane may comprise in trace or residual amounts isomeric or olefinic impurities (such as 2- perfluorohexyl-octane or 1-perfluorohexyl-octene) originating from synthesis of F6H8 which cannot be quantitatively removed upon purification.

In a further particularly preferred embodiment, the liquid vehicle of the pharmaceutical composition for according to the present invention comprises 1- perfluorobutyl-pentane (CF3(CF2)3-(CH2)4CH3 (F4H5)), preferably as the only semifluorinated alkane present in the pharmaceutical composition. In a further preferred embodiment, the liquid vehicle of the pharmaceutical composition of the present invention essentially consists of 1-perfluorobutyl-pentane (F4H5). It is understood that a liquid vehicle essentially consisting of l-perfluorobutyl-pentane may comprise in trace or residual amounts isomeric or olefinic impurities (such as 2- perfluorobutyl-pentane or 1-perfluorobutyl-pentene) originating from synthesis of F4H5 which cannot be quantitatively removed upon purification.

The liquid SFA's as described above are chemically and physiologically inert, colourless and stable. Their typical densities range from 1.1 to 1.7 g/cm 3 , and their surface tension may be as low as 19 mN/m. SFA's of the RFRH type are insoluble in water but also somewhat amphiphilic, with increasing lipophilicity correlating with an increasing size of the non-fluorinated segment.

It has been found by the inventors that SFA's are particularly suitable as carriers or vehicles in ophthalmic compositions for topical administration. This is based on the fact that SFA's are unexpectedly well-tolerated by the eye, as shown in preclinical testing. This is very surprising as organic or non-aqueous solvents, perhaps with the exception of oily compounds, are typically very irritating or even highly damaging when administered topically to an eye.

Compared to oily carriers or vehicles in ophthalmic compositions for topical use, the SFA's as described above exhibit a refractive index which is much better compatible with the aim of a minimally affected vision: While oily preparation lead to a blurry vision and can therefore not be administered in any situation in which the patient needs a clear vision, SFA's cause little or no blurring. Furthermore,

azithromycin dihydrate formulated as a solution in an oily carrier such as medium chain triglycerides (MCT) causes a strong burning sensation when administered to the eye, while SFAs effect a silky feeling and may lead to higher patient compliance.

As outlined above, azithromycin as the active ingredient of the present pharmaceutical compositions is incorporated in the form of suspended solid particles. In a particular embodiment, the suspended particles largely or exclusively consist of the active ingredient. The particle size of the suspended azithromycin is preferably below about 300 μιτι, which means that most of the particles, e.g. at least about 90% thereof, have a size in this range. Which type of particle diameter is considered as particle size will depend on the method use for particle size distribution, which in turn is selected to be appropriate for the type of solid material and the approximate size range. For example, laser diffraction or dynamic light scattering (also known as photon correlation spectroscopy or quasi-elastic light scattering) are appropriate methods for determining particle sizes in the colloidal and low micron range, whereas sedimentation analysis, sieve analysis or photoanalysis may be selected for larger particle sizes. In a further embodiment, at least about 90% of the suspended particles have a size of not more than about 200 μιτι, in particular from about 0.2 μιη to about 200 μιτι, or from about 0.5 μιη to about 150 μιτι, or from about 1 μιη to about 100 μιη.

Especially for ophthalmic administration, it may also be useful to select micronised azithromycin material with at least about 90% of the suspended particles having a size in the range from about 1 μιη to about 20 μιτι, preferably with at least about 90% of the suspended particles having a size of not more than about 15 μιτι, e.g. in the range from about 2 μιη to about 15 μιτι, as measured by state-of-the-art particle size distribution techniques (e.g. laser diffraction, dynamic light scattering), and in particular from about 2 μιη to about 10 μιτι, as measured by state-of-the-art particle size distribution techniques (e.g. laser diffraction, dynamic light scattering).

Accordingly, in specific embodiments the particle size distribution of the particles of azithromycin and/or a hydrate thereof as comprised by the compositions of the present invention are measured by laser diffraction or dynamic light scattering.

In a preferred embodiment, the pharmaceutical composition of the present invention consists of from about 90 to about 99.999% wt.-%, more preferably from about 95 to about 99.99% wt.-%, more preferably from 97 to 99.99% wt.-% even more preferably from 98 to 99.99% wt.-% of the liquid vehicle comprising a semifluorinated alkane as described above, preferably F6H8, based on the weight of the final composition.

In some preferred embodiments, the pharmaceutical composition according to the present invention comprises up to 100 mg/mL azithromycin based on the amount of azithromycin suspended, preferably up to 50 mg/mL azithromycin and more preferably up 30 mg/mL azithromycin (all based on the volume of the final

composition (final dosage form).

Accordingly, preferred embodiments of the pharmaceutical composition for use according to the present invention comprise about 0.1% (w/v) to about 10% (w/v) (corresponding to 1.0 to 100 mg/mL respectively) of azithromycin based on the total volume of the composition. In a preferred embodiment, however, the present pharmaceutical composition comprises azithromycin in range of from about 0.5% to about 5 % (w/v) (corresponding to 5.0 to 50 mg/mL) and even more preferably, from about 1.5 % to about 3% (w/v) (corresponding to 15 to 30 mg/mL) and most preferred in a concentration of 1.5% (w/v) (all based on the amount of azithromycin- dihydrate and F6H8 as the liquid vehicle in the final dosage form).

In contrast to some other suspensions known in prior art, the formulations of the present invention require no surfactant, or, if at all, only small amounts of surfactant, for their physical stabilisation. This is a significant advantage as surfactants have a substantial potential for irritation and local toxicity, especially when administered to the eye or by injection. According to one of the preferred embodiments, the compositions of the invention are substantially free of surfactant. In a further embodiment, the total amount of surfactant or surfactants, if more than one surfactant is incorporated, is not more than about 5 wt.-%, in particular not more than about 3 wt.-%, or preferably not more than about 1 wt.-%, respectively. In further preferred embodiments, the amount is not more than about 0.5 wt.-%, or not more than about 0.25 wt.-%, respectively.

In this context, the SFA's as described herein, although they possess some amphiphilic properties due to their chemical structure which includes fluorinated and non-fluorinated alkyl (or alkylene) groups characterised by different degrees of lipophilicity, are not understood as being within the scope of surfactants. The surfactants which are absent or only present in small amounts include non-ionic, cationic, anionic, and zwitterionic surfactants as commonly used as excipients in various types of pharmaceutical compositions, e.g. as wetting agents, emulsifiers, dispersing agents, solubilisers and the like. Examples of surfactants which are considered potentially useful include tyloxapol, poloxamers such as Pluronic F68LF or Lutrol F68, Pluronic L-G2LF and Pluronic L62D, polysorbates such as polysorbate 20 and polysorbate 80, polyoxyethylene castor oil derivatives, sorbitan esters, polyoxyl stearates, lecithins, purified or synthetic phospholipids, and mixtures of two or more thereof.

The compositions of the invention may further comprise excipients in range of up to about 10% (w/v), more preferably up to about 5% (w/v), even more preferably up to about 2% (w/v) such as, for example, non-fluorinated organic liquids, for example in order to modify the properties of the liquid vehicle, such as the viscosity. Such other liquid may be an oil selected from glyceride oils, liquid waxes, and liquid paraffin, or an organic solvent exhibiting a high degree of biocompatibility, or a mixture of more than one liquid excipients.

Examples of potentially useful oily excipients which may be used in

combination with one or more SFA's as described above may include triglyceride oils (i.e. soybean oil, olive oil, sesame oil, cotton seed oil, castor oil, sweet almond oil), mineral oil (i.e. petrolatum and liquid paraffin), medium chain triglycerides (MCT), oily fatty acids, isopropyl myristate, oily fatty alcohols, esters of sorbitol and fatty acids, oily sucrose esters, or any other oily substance which is physiologically tolerated by the eye. Examples of potentially useful organic solvents include glycerol, propylene glycol, polyethylene glycol, and ethanol. However, the concentration of the cosolvent should preferably be low relative to that of the SFA or SFA mixture. If an organic solvent such as ethanol is used, it is recommendable to keep it below a level of approx. 5 wt.-%. More preferably, the content of ethanol is from about 0.1 to about 2 wt.-%, and most preferably not more than about 1 wt.-%. In one preferred

embodiment, the suspension compositions according to the invention are free of an organic liquid or solvent. In a particularly preferred embodiment, the suspensions are free of ethanol. The compositions of the present invention may, of course, comprise further pharmaceutical excipients as required or useful. Potentially useful excipients include acids, bases, antioxidants, stabilisers, synergists, coloring agents and thickening agents. In a preferred embodiment, however, the liquid vehicle of the pharmaceutical composition according to the present invention is free of any (further) excipients. Furthermore, the invention provides a means of formulating non-aqueous ophthalmic compositions comprising azithromycin, which are microbiologically stable. This is due to the fact that SFA's as described above are not normally prone to microbial contamination. Hence, it is possible to formulate preservative-free ophthalmic compositions which are better tolerable for many patients, in particular patients suffering from an ophthalmic disease or condition. The preservative-free ophthalmic composition may be provided both in multi-dose or single-dose format.

Accordingly, although the pharmaceutical compositions of the present invention may comprise a pharmaceutically acceptable preservative, in a preferred embodiment, the pharmaceutical compositions of the present embodiment are free of a preservative. This is especially useful when the compositions of the present invention are provided not only in dosage forms for single use (single dosage forms), but especially in multiple dosage forms with a plurality of doses.

In a further embodiment, water can also be present in the pharmaceutical composition of the present invention, however, preferably in small amounts of up 1.0 wt.-% or even up to 0.1 wt.-% or less, based on the final composition (final dosage form). In a preferred embodiment, the pharmaceutical composition, preferably the liquid vehicle of the pharmaceutical composition of the present invention is essentially free of water, whereas the residual water may be attributed to the potential residual water content of azithromycin mono- or dihydrate. The term 'essentially' as used herein means if present then in trace or residual amounts such as to confer no technical advantage or relevance in respect of the object of the invention. For example, l-perfluorohexyl-octane (F6H8) or l-perfluorobutyl-pentane

(F4H5) as preferred semifluorinated alkanes in some embodiments of the present invention do not comprise any water, or have a water content of no more than the maximal solubility of water in l-perfluorohexyl-octane or in l-perfluorobutyl-pentane; for example-perfluorobutyl-pentane has a water-content of less than 1.6 x 1CH mg/ml as determined by methods known in the art for moisture analysis, such as Karl-Fischer titration methods.

In a particularly preferred embodiment, the pharmaceutical compositions of the present invention substantially consist of l-perfluorohexyl-octane (F6H8) and azithromycin-dihydrate. The liquid suspensions of the invention may be prepared by conventional methods. In principle, the solid azithromycin particles may be suspended in the liquid vehicle comprising the SFA. Alternatively, the particles may be precipitated in situ by adding a - typically organic - solution of the active ingredient (and, optionally, one or more solid excipients) under controlled conditions to the SFA-based vehicle. The particle size of the suspended phase may be adjusted before or after the particles are combined with the liquid vehicle. In one of the preferred embodiments, azithromycin particles are provided which already have the appropriately selected particle size. Powders having such selected particle size may be obtained directly from the synthesis of the respective compound by crystal engineering, or after synthesis by conventional grinding or milling methods using standard equipment such as a ball mill, hammer mill, roller mill, colloidal mill, jet mill, or the like. If the particle size is to be reduced after preparation of a suspension, ultrasonication as well as various types of homogenisers may be used, such as colloid mills or high pressure homogenisers. In a preferred embodiment, the particle sizes of the azithromycin in the composition according to the invention are adjusted by first combining the drug particles with a liquid vehicle comprising or consisting of a semifluorinated alkane such as described in any one of the above embodiments, followed by a step of milling or grinding according to any of the above methods.

The pharmaceutical compositions comprising azithromycin in suspended form in a liquid vehicle comprising a semifluorinated alkane provide several advantageous properties over conventional, aqueous or not SFA-based formulations, especially with respect to topical administration for ophthalmic use. For example, when conventional perfluorinated compounds are used as liquid vehicles, the suspensions tend to separate very rapidly by flotation of the dispersed phase, or by its sedimentation, depending on the relative densities of the dispersed phase and of the continuous phase. This is accompanied by a rapid formation of particle aggregates which may be dense and poorly redispersible. Rapid flotation or sedimentation makes precise and reproducible dosing very challenging, if not impossible. For example, if an ophthalmic suspension settles very rapidly after shaking, the first dosing from a full container, if not withdrawn immediately upon shaking, will contain a lower-than-intended number of drug particles, unless the container is held upside down, in which case more than the intended quantity of drug particles will be dispensed. When the same container is nearly empty and the last doses are dispensed, the drug dose withdrawn per volume will be too high if it was low in the beginning, and vice versa.

Moreover, aggregates may easily obstruct the dispensing channels or openings of containers and thereby lead to erroneous dosings. If dispensed from the container, they may cause irritation of the conjunctiva or of the cornea, depending on their size, shape and hardness.

In contrast, the SFA-based suspensions comprising azithromycin according to the invention remain finely dispersed and homogeneous. If flotation or sedimentation takes place, it occurs slowly, leaving sufficient time for the patient to withdraw a dose after shaking the container. The formation of large aggregates is not observed. After flotation or sedimentation, the drug particles are easily redispersed by gentle shaking, and appear to largely retain their original particle size distribution.

These properties of SFA-based suspensions of azithromycin result in superior pharmaceutical quality and performance characteristics for the use of azithromycin in the treatment of ocular diseases such as infections. The level of convenience to the patient and/or health care provider is greatly increased. More importantly, the dosing accuracy, i.e. precision and reproducibility of dosing, is greatly improved over other types of pharmaceutical suspensions. This will bring about a more reliable therapeutic effect and a reduced risk of adverse effects which result from overdosing.

A further advantage of the present SFA-comprising azithromycin suspensions - in contrast to available solutions of azithromycin in medium-chain triglycerides - is that no burning sensation is caused upon administration to the eye. Instead a pleasant silky feeling is triggered that may lead to higher patient compliance, especially important in a pediatric population.

A further surprising advantage of the present SFA-comprising azithromycin suspensions is that they appear to form very small droplets when dispensed from a dropper such as an eye dropper. Without wishing to be bound by theory, it is believed that the small droplet size is a result of an interplay of the SFA's unique properties in terms of their density, viscosity, and surface tension. In any case, it is believed that for topical administration into an eye a small drop or volume of administration is highly advantageous as the capability of the lacrimal sac to accept and hold fluid is extremely limited. In fact, it is very common that the administration of a conventional eye drop formulation based on water or oil immediately leads to a discharge of a substantial fraction of the administered medicine as well as some tear fluid. At the same time, there is a risk that some of the administered dose will be taken up systemically via the nasolacrimal duct. Hence, if an effective dose of an active ingredient can be incorporated in a small volume of liquid which can be dispensed as a very small droplet, this should also contribute to a substantially increased dosing reliability and reproducibility, thus enhancing the safety and effectiveness of the therapy. A yet further advantage of the invention which is based on the use of SFA's is that they can be designed or mixed for an optimally adjusted evaporation behaviour after administration. Thus, it is possible to formulate an ophthalmic composition which delivers an azithromycin efficiently to the eye in such a way that the liquid vehicle is subsequently eliminated via evaporation. This is in sharp contrast to oily or perfluorinated eye drop vehicles which do easily not evaporate and thus form non- physiological residues at the site of administration, e.g. in the lacrimal sac. In a second aspect, the present invention provides the pharmaceutical compositions according to the first aspect of the invention, namely a pharmaceutical composition in the form of a suspension comprising:

(a) particles of azithromycin and/or a hydrate thereof, and

(b) a liquid vehicle comprising a semifluorinated alkane of the formula (I)

CF3(CF 2 )n(CH 2 )mCH3 (I), wherein n is an integer from 3 to 5, and m is an integer from 4 to 7, for use as a medicament.

Furthermore, the present invention provides a pharmaceutical composition in the form of a suspension comprising:

(a) particles of azithromycin and/or a hydrate thereof, and

(b) a liquid vehicle comprising a semifluorinated alkane of the formula (I)

CF 3 (CF 2 ) n (CH 2 ) m CH3 (I), wherein n is an integer from 3 to 5, and m is an integer from 4 to 7; wherein at least about 90% of the suspended particles have a size of not more than about 15 μιη for use as a medicament.

The pharmaceutical compositions including all embodiments thereof as described above for the first aspect of the invention are especially useful for the therapy or prevention of diseases or conditions or any symptoms associated therewith related to an eye of a subject, preferably to an eye of a human subject.

The pharmaceutical compositions of the present invention are especially useful as an ophthalmic composition, and may preferably be administered topically to the eye, eye lid, eye sac, eye surface and/or to an ophthalmic tissue of a patient. Preferably, the pharmaceutical composition of the present invention may be topically administered to an outer surface of an eye of a patient or to an ophthalmic tissue which is readily accessible by the patient or by another person administering the pharmaceutical composition to the eye of the patient in need thereof.

The present pharmaceutical composition, especially when used as liquid of either low or higher viscosity (usually in the range of 1 to 3.5 mPa s) may

advantageously be administered in form of drops or by spraying or by injection. Most preferably, however, the liquid pharmaceutical composition of the present invention may be administered as drops, more specifically as eyedrops to be administered topically to the eye.

Depending on the extent of the disease, or whether or not both eyes of the patient to be treated are affected, the drops or eyedrops of the present ophthalmic pharmaceutical compositions may be administered to only one eye or to both eyes of the patient. The present pharmaceutical composition, provides droplet sizes when administered from conventional droppers, with a volume usually in the range from about 5 to about 15 μΐ. This small droplet size usually facilitates the dropwise administration and, moreover, facilitates precise dosage of the pharmaceutical composition of the present invention. Accordingly, the ophthalmic pharmaceutical composition of the present invention is administered as single drops with a volume of about 5 to 15 μΐ per dose per eye, preferably with a volume of about 8 to 13 μΐ per dose per eye, more preferably with a volume of about 9 to 12 μΐ per dose per eye and most preferably with a volume of about 10 to 11 μΐ per dose per eye.

The pharmaceutical composition of the present invention may be administered one time per day or several times per day, usually up to 8 times or up to 5 times per day, preferably in more or less equal intervals. In an acute setting (e.g. treatment of bacterial conjunctivitis) the pharmaceutical composition of the present invention may be administered several times per day, such as up to 8 times per day or up to 4 times per day for, preferably over a short treatment period, such as up to 7 days or up to 4 days. Alternatively, in a chronic setting (e.g. treatment of blepharitis), the

pharmaceutical composition of the present invention may be administered at less frequent intervals, such as only one or twice per day, but over a longer treatment period, such as for at least 1 week, or for at least 1 month or for at least 6 months or even for continuous treatment. In a preferred embodiment, however, the composition of the present invention is administered up to three times per day. The pharmaceutical compositions according to the present invention are especially useful in the treatment of an infective disease, which may be caused by bacteria, especially selected from any one or a combination of bacteria from the genus staphylococcus, pseudomonas, streptococcus, haemophilus, chlamydia moraxella, neisseria, bordetella, legionella, peptostreptococcus, prevotella, mycoplasma and ureaplasma. In a preferred embodiment, the present pharmaceutical compositions are useful in the treatment of an infective disease, wherein the infective disease is caused by gram-positive and/or gram-negative bacteria. Such bacteria may include either gram-positive or gram-negative bacteria, such as, for example, Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumonia, Haemophilus influenzae, Streptococcus mitis, Chlamydia trachomatis, Streptococcus agalactiae, Streptococcus pyogenes, Haemophilus ducreyi, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Bordetella pertussis, Legionella pneumophila, Peptostreptococcus species, Prevotella bivia, Chlamydia pneumoniae, Mycoplasma genitalium, Mycoplasma pneumoniae, Ureaplasma urealyticum.

The pharmaceutical compositions according to the present invention are especially useful in the treatment of an infective ocular disease. Such an infective ocular disease or infection of the eye of a patient or one or more segments or tissues thereof may be caused by bacteria, especially selected from any one or combination of bacteria from the genus streptococcus, staphylococcus, chlamydia, neisseria, enterococcus, peptostreptococcus, pseudomonas, mycobacteria, haemophilius, Clostridium, corynebacterium, escherichia, and klebsiella. In a preferred embodiment, the present pharmaceutical compositions are useful in the treatment of an infective ocular disease, wherein the infective ocular disease is caused by gram-positive and/or gram-negative bacteria. Such bacteria may include either gram-positive or gram- negative bacteria or by gram-positve or gram-negative bacteria, such as, for example, Staphylococcus epidermidis, Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumonia, Haemophilus influenzae, Streptococcus mitis, Chlamydia trachomatis, Moraxella lacunata, Streptococcus viridans, Neisseria gonorrhoeae, Neisseria meningitidis and Proteus mirabilis. Typical infective ocular diseases caused by a bacterial infection comprise, but are not limited to, for example, acute bacterial conjunctivitis, hyperacute bacterial conjunctivitis, chronic bacterial conjunctivitis, trachoma, blepharitis, neonatal conjunctivitis, follicular conjunctivitis, giant papillary conjunctivitis, corneal ulcer and keratitis.

Furthermore, in other embodiments, the present pharmaceutical compositions are useful in the treatment of an inflammatory ocular disease, preferably the present pharmaceutical compositions are useful in the treatment of inflammation affecting the cornea, conjunctiva, eye lids, lacrimal glands, meibomian glands and/or anterior chamber. Typical inflammatory ocular diseases comprise, but are not limited to, for example, blepharitis, dry eye disease (DED), uveitis and keratitis.

Furthermore, in other embodiments, the present pharmaceutical compositions are useful in the treatment of an inflammatory ocular disease of the anterior segment of the eye. Preferably the present pharmaceutical compositions are useful in the treatment of an inflammation or an inflammatory ocular disease affecting tissues of the anterior segment of the eye, such as cornea, conjunctiva, eye lids, lacrimal glands, meibomian glands and/or anterior chamber. Typical inflammatory ocular diseases affecting the anterior segment of the eye or, more specifically tissues of the anterior segment of the eye comprise, but are not limited to, for example, blepharitis, dry eye disease (DED), uveitis and keratitis.

Furthermore, in other embodiments, the present pharmaceutical compositions are useful in the treatment of a combination of an infective ocular disease as described above and an inflammatory ocular disease. Accordingly, in a preferred embodiment, the present pharmaceutical compositions are useful for the treatment of an infective and/or inflammatory ocular disease simultaneously affecting an eye of a patient. In a further preferred embodiment, the infective and/or inflammatory ocular disease is selected from the group consisting of bacterial conjunctivitis, blepharitis, trachoma and neonatal conjunctivitis.

Furthermore, in other embodiments, the present pharmaceutical compositions are useful in the treatment of a combination of an infective ocular disease as described above and an inflammatory ocular disease of the anterior segment of the eye.

Accordingly, in a preferred embodiment, the present pharmaceutical compositions are useful for the treatment of an infective and inflammatory ocular disease simultaneously affecting the anterior segment of the eye of a patient. Preferably, the present pharmaceutical compositions are useful for the treatment of an infective and inflammatory ocular disease simultaneously affecting the tissues of the anterior segment of the eye, such as cornea, conjunctiva, eye lids, lacrimal glands, meibomian glands and/or anterior chamber. In a further preferred embodiment, the infective and inflammatory ocular disease of the anterior segment of the eye is selected from the group consisting of bacterial conjunctivitis, blepharitis, trachoma and neonatal conjunctivitis. The infective and/or inflammatory ocular diseases as outlined above typically affect either the whole eye or one or more separate structures, liquids or tissues of an eye of a patient or subject. In preferred embodiments of the present invention, the infective and/or inflammatory ocular disease affects ophthalmic tissues selected from the group consisting of eyelids, cornea, (bulbar) conjunctiva and the infective and/or inflammatory ocular disease affects an ophthalmic fluid selected from the group consisting of tears, aqueous humor.

In a further aspect, the present invention provides a method for the treatment of an ocular disease of an eye of a patent, comprising

- providing a composition in the form of a suspension comprising:

(a) particles of azithromycin and/or a hydrate thereof being present in a therapeutically effective amount, and

(b) a liquid vehicle comprising a semifluorinated alkane of the formula (I)

CF3(CF 2 )n(CH 2 )mCH3 (I), wherein n is an integer from 3 to 5, and m is an integer from 4 to 7; preferably wherein at least about 90% of the suspended particles have a size of not more than about 15 μιτι, and

- topically administering said composition to a surface of the eye of the patient. It should be noted that for the method according to this aspect of the invention all embodiments and preferred embodiments as described above in connection with the other aspects of the invention apply respectively. Accordingly, in a preferred embodiment, the ocular disease according to the method of the present invention is an inflammatory and/or an infective ocular disease. In some embodiments, however, the ocular disease of the method of the present invention is either an inflammatory disease as described above or an infective disease as described above. In further embodiments, the method according to this aspect of the invention is useful for the simultaneous treatment of an inflammatory and an infective ocular disease. The pharmaceutical compositions according to the present invention offer the possibility to administer and deliver or transport the antibiotic macrolide compound azithromycin in form of particles to tissues or liquids of an eye of a subject or patient. As the compound azithromycin is administered in form of particles, suspended in a liquid vehicle comprising a semifluorinated alkane as described above, high concentrations of the antibiotic compound can be delivered in relatively small volumes of the composition.

Accordingly, relatively high doses of azithromycin can be administered to the eye of a subject by administration of relatively small volumes of the present pharmaceutical compositions. Furthermore, high levels of the antibiotic azithromycin can be achieved in affected ocular tissues or liquids in a short period of time, often within minutes. As a further advantage, the high levels or concentrations of azithromycin may be kept at a therapeutically relevant range for prolonged periods of time, such as up to several hours, for example up to 6, 12 or even 24 h, concentrations which are also usually decreasing slowly afterwards. Without wishing to be bound by theory, this may be attributed to the fact, that azithromycin is administered in form of particles, preferably in form of solid particles, which dissolve at a certain rate after administration, thereby forming a depot of azithromycin.

Therefore, in yet a further aspect, the present invention provides a method for delivering azithromycin to an ophthalmic tissue or an ophthalmic fluid or liquid selected from the group consisting of tears, eyelids, cornea, bulbar conjunctiva and aqueous humor, preferably for a prolonged period of time as described above. In yet a further aspect, the present invention provides a pharmaceutical kit comprising the composition as described above in connection with the first aspect of the invention and a container for holding the composition. Preferably, the container which contains the composition has a dispensing means such as a dropping device adapted for topically administering the composition to the eye of a patient. In one of the preferred embodiments, the dispensing means is adapted to dispense the composition dropwise in volumes of less than about 15 μΐ per drop. In further embodiments, the dispensing means is adapted to dispense drops having a volume of less than about 13 μΐ, 12 μΐ, or 11 μΐ, respectively. In particular, drop volumes of less than 12 μΐ are presently considered very useful in view of the limited holding capacity of one of the preferred sites of administration, the front of the eye. For the avoidance of doubt, such small droplet sizes are primarily enabled by the incorporation of the SFA (or SFA's) according to the invention, and common droppers for eye drops which normally deliver aqueous drops of about 30 to 60 μΐ are capable of dispensing much smaller drops of SFA-based formulations.

In a preferred embodiment of this aspect of the invention, accordingly, the present invention provides a kit comprising the composition of the first aspect of the invention and a container for holding the composition, said container comprising dispensing means for dropwise topical administration to a surface of the eye of a patient, said dispensing means preferably being adapted to dispense the composition dropwise in volumes of less than about 15 μΐ.

In the kit according to this aspect of the invention, the container may hold a single dose or a plurality of doses of the present pharmaceutical composition comprising particles of azithromycin suspended in a liquid vehicle comprising a semifluorinated alkane as described above.

Furthermore, the kit according to this aspect of the invention may further comprise instructions for use of the container for dropwise topical administration of the composition to a surface of the eye of a patient. The instructions or directions for use preferably comprised by the kit according to this aspect of the invention may be in in any form suited to instruct the user how to perform the topical administration to the affected eye of the patient or subject. It may be in any readable or tangible form, preferably in printed form or in any machine- or computer-readable form preferably in form of a machine-readable optical label such as, for example, a barcode or a QR- code. In a particularly preferred embodiment the directions for use are provided in form of an instruction leaflet, product or package insert or as an enclosed label.

DESCRIPTION OF THE DRAWINGS

Fig. 1 shows the ocular distribution of a suspension of 1.5 % and 3.0 % (w/v) azithromycin-dihydrate suspended in l-perfluorohexyl-octane (F6H8) in tears (T)

Fig. 2 shows the ocular distribution of a suspension of 1.5 % and 3.0 % (w/v) azithromycin-dihydrate suspended in l-perfluorohexyl-octane (F6H8) in eyelids (EL)

Fig. 3 shows the ocular distribution of a suspension of 1.5 % and 3.0 % (w/v) azithromycin-dihydrate suspended in l-perfluorohexyl-octane (F6H8) in cornea (C)

Fig. 4 shows the ocular distribution of a suspension of 1.5 % and 3.0 % (w/v) azithromycin-dihydrate suspended in l-perfluorohexyl-octane (F6H8) in bulbar conjunctiva (BCJ)

Fig. 5 shows the ocular distribution of a suspension of 1.5 % and 3.0 % (w/v) azithromycin-dihydrate suspended in l-perfluorohexyl-octane (F6H8) in aqueous humor (AH)

Fig. 1 to Fig. 5 are graphical representations of the results of the

pharmacokinetic study according to Example 2 below with the numerical data summarized in Table 1 and Table 2, respectively.

The following are numbered items comprised by the present invention:

1. A pharmaceutical composition in the form of a suspension comprising:

(a) particles of azithromycin and/or a hydrate thereof, and

(b) a liquid vehicle comprising a semifluorinated alkane of the formula (I)

CF3(CF 2 )n(CH 2 )mCH3 (I),

wherein n is an integer from 3 to 5, and m is an integer from 4 to 7.

2. The composition of item 1, wherein the particles of azithromycin are solid particles.

3. The composition of item 1 or 2, wherein the particles consist of azithromycin.

4. The composition of any preceding item, wherein the semifluorinated alkane of formula (I) is perfluorohexyl-octane (CF3(CF2)s(CH2)7CH3, F6H8).

5. The composition of any preceding item, wherein the liquid vehicle substantially consists of perfluorohexyl-octane. 6. The composition of any preceding item, wherein azithromycin is selected from the group consisting of azithromycin, azithromycin-monohydrate, and azithromycin-dihydrate.

7. The composition of any preceding item, wherein azithromycin is azithromycin-dihydrate. 8. The composition of any preceding item, wherein the concentration of azithromycin in the composition is in the range from 0.5 to 5% (w/v).

9. The composition of any preceding item, wherein the concentration of azithromycin in the composition is in the range from 1.5 to 3% (w/v).

10. The composition of any preceding item, wherein the concentration of azithromycin in the composition is 1.5% (w/v).

11. The composition of any preceding item, wherein the composition is free of a surfactant.

12. The composition of any preceding item, wherein the composition is free of a preservative. 13. The composition of any preceding item, wherein the composition is free of water.

14. The composition of any preceding item, wherein the composition is free of further excipients. 15. The composition of any preceding item, wherein the composition substantially consists of perfluorohexyl-octane (F6H8) and azithromycin- dihydrate.

16. The composition of any preceding item, wherein at least about 90% of the suspended particles of azithromycin have a size which is predominantly in the range from about 0.2 μιη to about 200 μιη.

17. The composition of any preceding item, wherein the particles of azithromycin have a size of not more than about 15 μιτι, or have a size of not more than 10 μιη. 18. The composition of any preceding item for use as a medicament.

19. The composition of any of items 1 to 17 for use as a medicament for topical administration to the eye of a patient.

20. The composition of any of items 1 to 17 for use in the treatment of an infective ocular disease. 21. The composition of item 20, wherein the infective ocular disease is caused by gram-positive and/or gram-negative bacteria.

22. The composition of any of items 1 to 17 for use in the treatment of an inflammatory ocular disease.

23. The composition for use of any of items 18 to 22, wherein the infective and/or inflammatory ocular disease is selected from the group consisting of bacterial conjunctivitis, blepharitis, trachoma and neonatal conjunctivitis.

24. The composition for use of any of items 18 to 23, wherein the infective and/or inflammatory ocular disease affects an ophthalmic tissue selected from the group consisting of eyelid, cornea, and (bulbar) conjunctiva; or wherein the infective and/or inflammatory ocular disease affects an ophthalmic fluid selected from the group consisting of tears and aqueous humor.

25. The composition for use of any of items 18 to 24, wherein the composition is administered topically to the eye of a patient. 26. The composition for use of any of items 18 to 25, wherein the composition is administered dropwise, preferably at a single drop volume of about 8 to 12 μΐ, preferably at a single drop volume of about 10-11 μΐ.

27. The composition for use of any of items 18 to 26, wherein the composition is administered up to three times per day.

28. A kit comprising the composition of any of items 1 to 17 and a container for holding the composition, said container comprising dispensing means for dropwise topical administration to a surface of the eye of a patient, said dispensing means preferably being adapted to dispense the composition dropwise in volumes of less than about 15 μΐ.

29. The kit of item 28, wherein the container holds a single dose or a plurality of doses of the composition of any of claims 1 to 17.

30. The kit of item 28 or 29, further comprising instructions for use of the container for dropwise topical administration of the composition to a surface of the eye of a patient.

The following examples serve to illustrate the invention; however, these are not to be understood as restricting the scope of the invention.

EXAMPLES

Example 1: Preparation of Azithromycin suspensions

120 mg of azithromycin-dihydrate (Chemos GmbH, Regenstauf Germany) were introduced to a 15 ml milling pot, filled with stainless steel balls, diameter 2 mm. Afterwards, 8 ml of F6H8 were added, the milling pot was closed and the milling was performed with a planetary ball mill (PM 100, Retsch GmbH Germany) for 3 hours at 150 rpm with an interval of 10 minutes (with change of direction). After the milling, the thereby formed suspension was transferred into a glass vial and sealed. Hereby, a 1.5 % (w/v) azithromycin suspension (15 mg/ml) in F6H8 was obtained.

Following the same procedure, a 1.5 % (w/v) azithromycin suspension in F4H5 as well as azithromycin suspensions with a concentration of 0.75 % (w/v) and 3 % (w/v) in F4H5 and F6H8 were prepared. Other suspensions of azithromycin in other SFAs can be prepared by suspension of azithromycin-monohydrate (HEC PHARM CO., LTD, China) or dehydrated azithromycin forms following the same procedure.

The 1.5 % (w/v) azithromycin suspension in F6H8 or in F4H5 were

characterized by light microscopy at 4-, 10- and 40-time magnification. Hereby, an even distribution of the particles in the liquid vehicle was observed, with the particles characterized by a uniform shape, with a particle size of below 10 μιη.

Example 2: Pharmacokinetic Study 2.1 Setup an Implementation

The aim of this pharmacokinetic study was to investigate the ocular distribution of two different F6H8-based ophthalmic azithromycin formulations in tears (T, measured using Schirmer strips), aqueous humor (AH), cornea (C), bulbar conjunctiva (BCJ) and eyelids (EL) after a single topical instillation of 11 μΐ of the respective formulation in both eyes of albino rabbits using an RRLC-MS/MS (rapid resolution liquid chromatography/tandem mass spectrometry) method for quantitative analysis.

120 albino rabbits, which were selected based on good health and

homogeneous body weight, were involved in this study and randomly distributed into 2 treatment groups corresponding to the two suspensions tested (1.5 % (w/v) and 3.0 % (w/v) azithromycin-dihydrate suspended in F6H8). Only animals with no ocular signs of irritation (evaluated after Draize test performed at baseline, before randomization) were included. 11 μΐ of the test items were instilled in the superior bulbar conjunctiva of both eyes of the albino rabbits, correlating to the intended way of human exposure to the tested azithromycin suspension. Due to the fact that the test formulations represent suspensions, the bottles comprising the azithromycin suspensions in F6H8 were shaken for a few seconds (10-20 seconds) before each application. Animals were observed daily and general clinical signs and appearance were observed and recorded. At the respective time-points (0.08, 0.25, 0,5, 1, 2, 4, 8, 12, 24, 36, 48, 72, 96, 120, 144 hours after application) the animals were anesthetized by an intramuscular injection of a mixed solution of xylazine and ketamine. Tears (T) were collected from both eyes with a Schirmer strip 1 min before euthanasia, weighed and stored at -80°C ± 15°C. Then, animals were euthanized by cardiac injection of overdosed pentobarbital, as recommended methods for euthanasia by the European authorities. Immediately after euthanasia, tears (T), aqueous humor (AH), cornea (C), bulbar conjunctiva (BCJ) and eyelids (EL) from individual eyes were quickly and carefully sampled in separate classical tube uniquely identified, weighed and stored at -80°C ± 15°C until assayed. The content of azithromycin was

quantitatively determined in tears (T), aqueous humor (AH), cornea (C), bulbar conjunctiva (BCJ) and eyelids (EL) from each eye utilizing a RRLC-MS/MS method (rapid resolution liquid chromatography /tandem mass spectrometry).

Under the experimental conditions, following a single instillation of 11 μΐ of 1.5 % or 3 % (w/v) azithromycin-dihydrate in F6H8 in both eyes of albino rabbits, it was found that both formulations (1.5 % and 3 % (w/v) azithromycin-dihydrate suspended in F6H8) were macroscopically well tolerated by the animals. No ocular effects were observed in both eyes after a single administration of the above- mentioned suspensions, except for slight conjunctival redness observed before euthanasia for 4 rabbits.

2.2 Results:

Tears: It was observed that the level of azithromycin in tears (T) peaked at 5 min after instillation at 347 μg/g and 992 μg/g for both 1.5 % and 3 % (w/v) azithromycin-dihydrate suspended in F6H8 and decreased rapidly afterwards until 4 h (240 min) post dose and then slower until 144 h (8640 min) post dose.

Bulbar Conjunctiva: It was found that the level of azithromycin in bulbar conjunctiva (BCJ) peaked at 30 min after instillation at 13 μg/g of for 1.5 % (w/v) azithromycin-dihydrate suspended in F6H8, being stable from 5 min to 2 h post dose and rapidly decreased until 144 h post dose. For 3 % (w/v) azithromycin-dihydrate suspended in F6H8 the level of azithromycin in bulbar conjunctiva (BCJ) peaked 5 min after instillation at 40 μg/g of being stable from 15 min to 2 h post dose and rapidly decreased until 144 h post dose. Eyelids: The level of azithromycin in eyelids (EL) peaked at 1 hour after instillation at 26 μg/g for 1.5 % and 3 % (w/v) azithromycin-dihydrate suspended in F6H8, and slowly decreased until 144 h post dose. Cornea: Further, the level of azithromycin in the cornea (C) peaked at 5 min after instillation at 13 μg/g and 22 μg/g for 1.5 % and 3 % (w/v) azithromycin- dihydrate suspended in F6H8, respectively, and decreased rapidly until 8 h post dose and then slowly decreased from 8 h to 144 h post dose. Aqueous humor: The levels of azithromycin in aqueous humor (AH) peaked at

5 min after instillation at 13 ng/g and 36 ng/g for 1.5 % and 3 % (w/v) azithromycin- dihydrate suspended in F6H8, respectively, were found to be stable until 144 h post dose.

Table 1 summarizes the data as observed after application of 1.5 % (w/v) azithromycin dihydrate suspended in F6H8.

Table 1:

"mean": mean value; "sd": standard deviation Table 2 summarizes the data as observed after application of 3.0% (w/v) azithromycin-dihydrate suspended in F6H8.

Table 2:

Example 3: Agar Diffusion Test (Hemmhof-Test)

The antibacterial activity of the two test formulations (1.5 % (w/v) and 3.0 % (w/v) azithromycin-dihydrate suspended in F6H8) in comparison to a negative control (vehicle, F6H8) and a reference substance (1.5 % (w/v) azithromycin- dihydrate suspended in medium-chain triglycerides; Azyter®, LABORATOIRES THEA) was tested according to DIN 58940-3:1989-06 for the following bacteria:

- Staphylococcus epidermidis (DSM 18857)

- Staphylococcus aureus (DSM 799) - Pseudomonas aeruginosa (DSM 939)

- Streptococcus pneumoniae

- Haemophilus influenzae (DSM 24049)

- Streptococcus mitis (DSM 12643) Herein, freshly prepared bacterial suspensions of 1 x 10 6 CFU/ml to 5 x 10 6

CFU/ml (inoculum) were evenly spread over an agar plate. The agar plate was incubated for 5 to 15 minutes. Then the test formulations (as described above) were placed onto the inoculated surface of the agar plate. Afterwards, the agar plate including the test formulations were incubated at 37°C for 18 ± 2 hours. Afterwards the agar plates were visually inspected and the diameter of the inhibition zones were determined and recorded.

It was found that all suspensions of azithromycin-dihydrate in F6H8 did resulted in formation of inhibition zones for the tested bacteria. The vehicle (F6H8) did not inhibit the growth of the tested bacteria. When comparing to the

commercially available suspension of 1.5 % (w/v) azithromycin-dihydrate in medium-chain triglycerides (Azyter®, LABORATOIRES THEA), the 1.5 % (w/v) azithromycin suspended in F6H8 showed comparable inhibition results, while the 3.0 % (w/v) azithromycin suspended in F6H8 resulted in a slightly improved inhibition profile. Table 3 below summarizes the results of the Agar diffusion test (Hemmhof- Test).

For bacteria most commonly involved in bacterial conjunctivitis, MIC90 (90 % minimal inhibitory concentration) ranges reported in the literature are usually between 0.5 μg/mL and 4 μg/mL. Based on these range, the MIC 0.5 μg/mL (assuming that for tissues, lg was equivalent to 1ml) was used to interpret the ocular

pharmacokinetic results in the above-mentioned study. Azithromycin concentrations for both tested formulations (1.5 % (w/v) and 3.0 % (w/v)) remained well above the MIC breakpoint of 0.5 μg/g for susceptible germs for up to 144 h in tears, cornea and eyelids, and up to 36 h for bulbar conjunctiva.

When comparing the pharmacokinetic values obtained with 1,5 % (w/v) azithromycin-dihydrate suspension in F6H8 and a published pharmacokinetic study with Miglyol® (see T. Amar et al. (2008) Current Eye Research, 33:2, 149-158) (1,50 % azithromycin dihydrate solution in medium-chain triglycerides) it was found that even with a lower target dose due to a lower drop volume(ll μΐ) of the F6H8 based azithromycin suspension, comparable azithromycin levels in the examined eye tissues (tears, cornea, eyelids, bulbar conjunctiva, aqueous humor) could be achieved. Thus, the overall exposure of the subject to the azithromycin was effectively reduced, which in turn contributed to an improved adverse effect profile.

Table 3: