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Dispersible concentrate for the delivery of cyclosprin Number:7,026,290 from the United States Patent and Trademark Office (PTO) owispatent

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Title: Dispersible concentrate for the delivery of cyclosprin

Abstract: A formulation for the administration of a cyclosporin. This formulation features a hydrophilic solvent which is characterized by being a lower alkyl ester of hydroxyalkanoic acid; and a surfactant, preferably a combination of a surfactant with a high HLB (hydrophilic/lipophilic balance) of at least about 8 and a surfactant with a low HLB of less than about 5. Other ingredients are optional, such as a fatty acid ester such as tricaprin, a phospholipid, and an ethoxylated fat such as Cremophor or another similar substance. Optionally, the ethoxylated fat is substituted for the surfactant. The preferred particle size of the resultant formulation is less than about 100 nm, more preferably less than about 60 nm, and most preferably from about 5 nm to about 50 nm. The formulation of the present invention is characterized by having high bioavailability.

Patent Number: 7,026,290 Issued on 04/11/2006 to Domb

Inventors: Domb; Abraham J. (Efrat, IL)
Assignee: Dexcel Ltd. (Hadera, IL)
Appl. No.: 869519
Filed: December 30, 1999
PCT Filed: December 30, 1999
PCT NO: PCT/IL99/00710
371 Date: September 17, 2001
102(e) Date: September 17, 2001
PCT PUB.NO.: WO00/40219
PCT PUB. Date: July 13, 2000

Current U.S. Class: 514/11; 514/9
Current Intern'l Class: A61K 38/13    (20060101)
Field of Search: 514/9,11

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Primary Examiner: Wax; Robert A.
Parent Case Text


This application is a national stage entry under 35 USC 371 of PCT/IL99/00710, filed Dec. 30, 1999, which is a continuation-in-part of Ser. No. 09/223,378, filed Dec. 30, 1998, now abandoned.
Claims


What is claimed is:

1. A composition for administering a cyclosporin compound, the composition comprising:

(a) a dispersible concentrate characterized by being capable of forming, upon contact with an aqueous solution, particles of a size of less than about 100 nm, said dispersible concentrate comprising:

(i) at least one surfactant; and

(ii) an amphiphilic solvent comprising a lower alkyl hydroxy alkanoic acid ester or a lower alkyl ester of N-alkyl pyrrolidone; and

(b) a pharmaceutically effective amount of the cyclosporin compound.

2. The composition of claim 1, wherein said lower alkyl hydroxy alkanoic acid ester includes ethyl lactate.

3. The composition of claim 1, wherein said amphiphilic solvent includes N-methyl pyrrolidone.

4. The composition of claim 1, wherein said amphiphilic solvent includes a combination of a lower alkyl ester of N-alkyl pyrrolidone an a lower alkyl hydroxy alkanoic acid ester.

5. The composition of claim 1, wherein said at least one surfactant is a combination of at least two surfactants, at least one surfactant of said combination being a hydrophilic surfactant and at least one surfactant of said combination being a hydrophobic surfactant.

6. The composition of claim 5, wherein said combination is a combination of polyoxyethylene(20)sorbitan monolaurate and sorbitan monooleate.

7. The composition of claim 5, further comprising:

(c) an ethoxylated fat.

8. The composition of claim 7, wherein said ethoxylated fat is selected from the group consisting of polyethyleneglycol-hydrogenated castor oils.

9. The composition of claim 8, wherein said polyethyleneglycol-hydrogenated caster oil is selected from the group consisting of polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, and polyoxyl 60 hydrogenated castor oil.

10. The composition of claim 7, further comprising:

(d) a phospholipid.

11. The composition of claim 10, wherein said phospholipid is selected from the group consisting of egg phospholipid, bovine heart phospholipid, and soy phospholipid.

12. The composition of claim 10, further comprising:

(e) a fatty acid ester.

13. The composition of claim 12, wherein said fatty acid ester is a solid fat at room temperature.

14. The composition of claim 13, wherein said fatty acid ester is tricaprin.

15. The composition of claim 1, wherein said particles size is less than about 60 nm.

16. The composition of claim 15, wherein said particle size is in a range of from about 5 nm to about 50 nm.

17. The composition of claim 1, wherein the cyclosporin compound is Ciclosporin.

18. A composition for administering a cyclosporin compound, the composition comprising a pharmaceutically effective amount of the composition of claim 1.

19. A composition for administering a cyclosporin compound, the composition comprising a lyophilized composition, said lyophilized composition being formed from a pharmaceutically effective amount of the composition of claim 1 to form a diluted solution, said diluted solution being lyophilized to form said lyophilized composition.

20. A method for administering a cyclosporin compound to a subject in need of treatment thereof, the method comprising the step of administering a pharmaceutically effective amount of the composition of claim 1 to the subject.

21. The method of claim 1 is administered to the subject through oral administration.

22. The method of claim 1 is administered as a dispersion with an aqueous solution as a diluent.

23. A method for determining storage stability of a formulation containing a cyclosporin compound, the method comprising the step of analyzing the composition of claim 1 for particle size, such that if said particle size is less than about 100 nm, the formulation is determined to be stable.

24. A composition for administering a cyclosporin compound, the composition comprising:

(a) a dispersible concentrate characterized by being capable of forming, upon contact with an aqueous solution, particles of a size of less than about 100 nm, said dispersible concentrate comprising:

(i) an ethoxylated fat; and

(ii) an solvent comprising a lower alkyl hydroxy alkanoic acid ester or a lower alkyl ester of N-alkyl pyrrolidone; and

(b) a pharmaceutically effective amount of the cyclosporin compound.

25. The composition of claim 24, wherein said ethoxylated fat is selected from the group consisting of polyethyleneglycol-hydrogenated castor oils.

26. The composition of claim 25, wherein said ethoxylated fat is selected from the group consisting of polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, and polyoxyl 60 hydrogenated castor oil.

27. The composition of claim 24, wherein said amphiphilic solvent includes a lower alkyl hydroxy alkanoic acid ester.

28. The composition of claim 24, wherein said amphiphilic solvent includes ethyl lactate.

29. The composition of claim 24, wherein said amphiphilic solvent includes a lower alkyl ester of N-alkyl pyrrolidone.

30. The composition of claim 29, wherein said lower alkyl ester of N-alkyl pyrrolidone includes N-methyl pyrrolidone.

31. The composition of claim 24, wherein said amphiphilic solvent includes a combination of a lower alkyl ester of N-alkyl pyrrolidone and a lower alkyl hydroxy alkanoic acid ester.

32. The composition of claim 5, wherein said hydrophilic surfactant has an HLB (hydrophilic/lipophilic balance) of at least 8.

33. The composition of claim 5, wherein said hydrophobic surfactant has an HLB of less than 5.

34. The composition of claim 5, wherein said hydrophobic surfactant comprises a sorbitan fatty acid ester.

35. The composition of claim 5, wherein said hydrophobic surfactant comprises PEG-6 glyceryl monooleate.

36. The composition of claim 5, wherein said hydrophobic surfactant comprises propylene glycol laurate.

37. The composition of claim 5, wherein said hydrophilic surfactant comprises polyoxyethylene-sorbitan-fatty acid ester.

38. The composition of claim 5, wherein said hydrophilic surfactant comprises sucrose fatty acid ester.

39. The composition of claim 10, wherein said phospholipid comprises lecithin.

40. The composition of claim 1, further comprising amphiphilic solvent selected from the group consisting of ethylene glycol, glycofurol and PEG 400.

41. The method of claim 20, wherein said subject is in need of treatment of a condition selected from the group consisting of autoimmune disease and inflammatory conditions.

42. The method of claim 20, wherein said subject is in need of treatment of organ or tissue transplant rejection.

43. The method of claim 1 is administered to the subject through administration.

44. The method of claim 1 is administered to the subject through parenteral administration.

45. The method of claim 1 is administered as a capsule.

46. The method of claim 1 is administered as a tablet.

47. The method of claim 1 is administered as a powder.

48. A method for administering a cyclosporin compound to a subject in need thereof, the method comprising the step of administering a pharmaceutically effective amount of a composition, said composition comprising a dispersible concentrate characterized by being capable of forming, upon contact with an aqueous solution, particles of a size of less than about 100 nm, said dispersible concentrate comprising at least one surfactant and an amphiphilic solvent comprising a lower alkyl hydroxy alkanoic acid ester or a lower alkyl ester of N-alkyl pyrrolidone.

49. A composition for administering a cyclosporin compound, the composition comprising:

(a) a dispersible concentrate characterized by being capable of forming, upon contact with an aqueous solution, a solid particulate suspension containing the cyclosporin compound, said particulate suspension containing particles of a size of less than about 100 nm, said dispersible concentrate comprising:

(i) at least one surfactant; and

(ii) an amphiphilic solvent comprising a lower alkyl hydroxy alkanoic acid ester or a lower alkyl ester of N-alkyl pyrrolidone; and

(b) a pharmaceutically effective amount of the cyclosporin compound.
Description


FIELD AND BACKGROUND OF THE INVENTION

The present invention is of a dispersible concentrate preparation for the delivery of cyclosporin, and in particular, of a dispersible concentrate preparation which provides a delivery system with high bioavailability of cyclosporin and related substances.

Many dispersion systems are currently in use as, or being explored for use as, carriers of substances, particularly biologically active compounds. These systems are designed to protect the substance from the environment during delivery and to provide a controlled release of the substance to a targeted area. In some cases, the goal is to target specific sites in the body using the dispersion. In other cases, the goal is to prepare a drug carrier system that acts as a reservoir at the site of injection.

Dispersion systems used for pharmaceutical and cosmetic formulations can be categorized as either suspensions or emulsions. Suspensions are defined as solid particles ranging in size from a few nanometers up to hundreds of microns, dispersed in an aqueous or nonaqueous medium using suspending agents. Solid particles include microspheres, microcapsules, and nanospheres.

Emulsions can be defined as dispersions of one liquid in another, stabilized by an interfacial film of emulsifiers such as surfactants and lipids. Despite their long history, emulsions are used less often today than many other dosage forms due to the inherent instability. Emulsion formulations include water in oil and oil in water emulsions, multiple water/oil/water emulsions, microemulsions, microdroplets, and liposomes.

A microemulsion is a transparent or substantially transparent emulsion which is formed spontaneously or substantially spontaneously when its components are brought into contact. Microemulsions are thermodynamically stable and contain dispersed particles or droplets of a size less than about 200 nm. Generally microemulsions feature droplets or particles having a mean diameter of less than about 150 nm. These particles may be spherical, although other structures are feasible, such as liquid crystals with lamellar, hexagonal or isotropic symmetries. Microemulsions are usually stable over periods in excess of 24 hours.

Microemulsions can also be used as a "microemulsion preconcentrate", defined herein as a composition which spontaneously forms a microemulsion in an aqueous medium, for example in water, upon dilution, or in the gastric juices after oral application. Dilution of the microemulsion in water can be for example from about 1:1 fold to about 1:10 fold dilution.

As noted above, while emulsion based delivery systems are useful for certain applications, the delivering vesicles are subject to physical rupture because of the delicate nature of the liquid/membrane/liquid structure. Emulsion based delivery systems also have relatively short release times. Further, it is difficult to isolate emulsion based vesicles from the aqueous media used for storage for subsequent reconstitution.

In spite of these difficulties, microemulsions have been the only successful delivery systems for certain types of pharmaceutical compounds, particularly compounds such as members of the cyclosporin class, which are cyclic oligopeptides. The cyclosporin class includes substances having pharmaceutical utility, for example as immunosuppressive agents, anti-parasitic agents and agents for the reversal of multi-drug resistance, as known and described in the art. Examples of such cyclosporins include, but are not limited to, Cyclosporin A (also known as and referred to herein as "Ciclosporin"), Cyclosporin G, [0-(2-hydroxyethyl)-(D)Ser]2-Ciclosporin and [3′-deshydroxy-3′-ket-MeBmt]1-[Val)]2-Ciclosporin.

The first of the cyclosporins to be isolated was the naturally occurring fungal metabolite Ciclosporin (Cyclosporine). Ciclosporin is the cyclosporin of formula (I): ##STR1##
wherein —MeBmt— represents the N-methyl-(4R)-4-but-2E-en-1-yl-4-methyl-(L)threonyl residue of formula (II): ##STR2##
in which —x-y— is —CH═CH— (trans). Ciclosporin is well known as an immunosupressive agent. In addition, Ciclosporin is being examined for the treatment of autoimmune and inflammatory diseases.

Since the original discovery of Ciclosporin, a wide variety of naturally occurring cyclosporins have been isolated and identified, and many further non-natural cyclosporins have been prepared by total- or semi-synthetic means or by the application of modified culture techniques. The class comprised by the cyclosporins now includes, for example, the naturally occurring cyclosporins A through Z [c.f. Traber et al., Helv. Chim. Acta. 60: 1247-1255, 1977; Traber et al.. Helv. Chim. Acta. 65: 1655-1667, 1982; Kobel el al., Europ. J. App. Microbio. and Biotech., 14: 273-240 (1982); and von Wartburg el al., Progress in Allergy, 38: 28-45 (1986)], as well as various non-natural cyclosporin derivatives and artificial or synthetic cyclosporins including: the so-called dihydro-cyclosporins, in which the moiety —x-y— of the —MeBmt— residue in Formula (II) above is saturated to give —x-y— of —CH2—CH2—; derivatized cyclosporins (e.g. in which a further substituent is introduced at the α-carbon atom of the sarcosyl residue at the 3-position of the cyclosporin molecule); cyclosporins in which the —MeBmt— residue is present in isomeric form (e.g. in which the configuration across positions 6′ and 7′ of the —MeBmt— residue is cis rather than trans); and cyclosporins in which variant amino acids are incorporated at specific positions within the peptide sequence. Many of these members of the cyclosporin class exhibit pharmaceutical utility which may be comparable to that of Ciclosporin.

Unfortunately, many difficulties have been encountered in the effective administration of Ciclosporin, difficulties which appear to be inherent in the nature of the members of the cyclosporin class. Cyclosporins are characteristically highly hydrophobic, and thus require a lipophilic carrier. The selection of a suitable carrier is particularly critical for the administration of cyclosporins, as the bioavailability of these compounds is known in the art to be highly variable, depending upon the properties of the carrier. Furthermore, these compounds are known to have bioavailability which may vary significantly between individuals. Such variation is particularly dangerous given the side effects of cyclosporins, such as nephrotoxicity. Thus, the suitable carrier must provide good bioavailability of cyclosporins which is substantially consistent between individuals.

As noted previously, cyclosporins may be administered with a microemulsion carrier. This carrier generally contains a hydrophilic solvent, such as liquid PEG200-600, ethylene or propylene glycol, ethanol or propanol, glycerin, water soluble fatty acid C6-C18 esters of sucrose, dimethylisosorbide, ethyl-acetate, glycofurol (fatty acid derivative of a cyclic polyol), PEG derivatives of tocopherol, or PEG-fatty acid esters; a surfactant, such as Tween 20, various PEG (polyethylene glycol) derivatives or phospholipids; a water insoluble oil such as corn oil and other oils from plants and mixtures of oils; and Cremophor™ and similar PEG derivatives of castor oil or other fats which are used as an amphiphilic solvent, emulsifier, surfactant and so forth. Unfortunately, none of these background art formulations provides high bioavailability for cyclosporin.

The currently commercially available formulation is disclosed in U.S. Pat. No. 5,342,625 to Sandoz A.G. This formulation includes a hydrophilic phase, a lipophilic phase and a surfactant. The hydrophilic phase could be a C1-5 alkyl di-or partial-ether of a mono- or poly-oxy-C1-12alkanediol, for example.

PCT Application No. WO 96/13273 to Sandoz describes compositions for cyclosporin and other macrolide drugs such as Rapamycin, containing a hydrophilic phase which includes dimethylisosorbide and/or a lower alkyl alkanoic ester, a lipophilic phase and a surfactant. The particle size after dispersion can be 200 nm but is preferably 100 nm or less. The hydrophilic phase is PEG, propylene glycol and glycofurol or dimethylisosorbide (a bicyclic ether). The bioavailability of a composition containing cyclosporin and the carrier is not disclosed.

PCT Application No. WO 97/19692, also to Sandoz, describes compositions which are based on PEG-derivatives of saturated hydroxy fatty acids such as PEG-hydroxystearate and a low alcohol such as ethanol or propylene glycol. Again, the bioavailability of such a composition is not disclosed.

PCT Application No. WO 98/33512 to Novartis describes compositions for oral administration of cyclosporin which do not contain oil. Instead, these compositions contain a surfactant with HLB 10 or higher and a hydrophilic phase which is polyethylene glycol and/or a lower alcohol (not more than 12%). The formulations are preconcentrates which provide a particle size of 10 to 150 nm upon dispersion. The disclosed advantage of these compositions is their ability to be stably contained within a hard capsule. However, no specific data is disclosed related to the bioavailability of cyclosporin with this composition. As noted above, the bioavailability of cyclosporin is known to be highly variable, depending upon the carrier.

PCT Application No. WO 97/04795 to POLI Industria describes compositions that must contain one polymer, linear or crosslinked PEG and poly (acrylic) or mixtures thereof and monoesters of fatty acids with a short alcohol. Again, the bioavailability of such a composition is not disclosed.

U.S. Pat. No. 5,756,450 to Novartis describes solid formulations for cyclosporin composed of a water soluble monoester of a fatty acid C6-C18 with a polyol, for example a saccharide such as Saccharose monolaurate or raffinose monolaurate. This solvent can be used in combination with other water soluble solvents including PEG, ethanol, ethylene glycol and glycerin. The examples describe solid solutions (powder) of Cyclosporin in saccharose monooleate which is completely soluble in water. Again, the bioavailability of such a composition is not disclosed.

U.S. Pat. Nos. 5,603,951 and 5,639,474 to Hanmi Pham. describe compositions of dimethylisosorbide as a cosurfactant and a primary alcohol, medium chain triglycerides and a surfactant having a HLB value of 10 to 17 such as Tween 20, formulated in soft gelatin capsule. The particle size is about 100 nm. Again, the bioavailability of such a composition is not disclosed.

U.S. Pat. No. 5,583,105 to Biogel describes cyclosporin formulations composed of PEG esters of tocopherol and a lipophilic solvent, an amphiphilic solvent and ethanol. Again, the bioavailability of such a composition is not disclosed.

U.S. Pat. No. 5,614,491 to Dr. Rentschler GmbH, describes formulations of PEG fatty acid monoesters as emulsifying agent and a polyol as solvent. U.S. Pat. No. 5,798,333 to Sherman describes formulations composed of Tocophersolan and a polyhydric alcohol. Tocophersolan is a water soluble surfactant which dissolves cyclosporin only at a 7:1 ratio.

U.S. Pat. No. 5,827,822 to Sangstat describes formulations of alcohol and a PEG surfactant forming particle size between 200 and 400 nm.

European Patent Application No. EP 0760237 A1 to Cipla describes a composition containing: vegetable oil triglycerides (castor, peanut, or coconut oil), phospholipid, a surfactant (Tween 20, polyoxyl-40-hydrogenated castor oil), and a hydrophilic solvent, propylene glycol. Again, the bioavailability of cyclosporin administered with such a composition is not disclosed.

None of these disclosed background art carrier formulations features a hydrophilic solvent which is a lower alkyl ester of hydroxyalkanoic acid, such as ethyl lactate or N-methyl pyrrolidone. Moreover, none of these disclosed background art carrier formulations features a combination of a surfactant with high HLB and a surfactant with low HLB. Furthermore, none of these background art carrier formulations is disclosed as having high bioavailability. Thus, the background art carrier formulations do not appear to possess the advantageous high bioavailability of the present invention, as described in greater detail below.

There is thus an unmet need for, and it would be useful to have, a composition for the administration of cyclosporins, particularly for oral administration, which would provide a high bioavailability, and which would preferably contain a hydrophilic solvent which is a lower alkyl ester of hydroxyalkanoic acid, and a surfactant which is preferably a combination of a surfactant with high HLB and a surfactant with low HLB.

SUMMARY OF THE INVENTION

The present invention is of a novel formulation for the administration of a cyclosporin. This formulation features a hydrophilic solvent which is characterized by being a lower alkyl ester of hydroxyalkanoic acid; and a surfactant, preferably a combination of a surfactant with a high HLB (hydrophilic/lipophilic balance) of at least about 8 and a surfactant with a low HLB of less than about 5.

Other ingredients are optional, such as a fatty acid ester such as tricaprin, a phospholipid, and an ethoxylated fat such as Cremophor™ or another similar substance.

The preferred mean diameter of the particle of the resultant formulation is less than about 100 nm, more preferably less than about 60 nm, and most preferably from about 5 nm to about 50 nm.

Hereinafter, the term "dispersible concentrate" includes those compositions featuring droplets or particles having a mean diameter of less than about 150 nm. Hereinafter, the term "nanodispersion preconcentrate" refers to a composition which spontaneously forms a nanodispersion in an aqueous medium, for example in water upon dilution, or in the gastric juices after oral application. Dilution of the nanodispersion preconcentrate in water can be for example from about 1:1 fold to about 1:10 fold dilution.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, with reference to the accompanying drawings, wherein:

FIG. 1 is a graph of cyclosporin blood concentration after oral administration


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