JP2002531412A - Pharmaceutical composition comprising cyclosporin in a lipid carrier - Google Patents

Abstract

  (57) [Summary] A pharmaceutical composition comprising cyclosporine as an active substance in a lipid carrier, said carrier comprising membrane lipids in combination with monoglycerides and optionally non-polar lipids, said composition being liquid at room temperature, It is characterized by containing 0.5-25% of crosporin, 10-45% of membrane lipid, 10-55% of monoglyceride and 0-45% of non-polar lipid. The compositions of the present invention are bioequivalent to commercially available agents that include toxic emulsifiers and ethanol in addition to cyclosporin and additives.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a new formulation of cyclosporine for oral administration with improved uptake.

[0002]

BACKGROUND OF THE INVENTION

Cyclosporins are a group of biologically active metabolites produced by different species of funghi imperfecti. Main components cyclosporin A and C
Is a non-polar, cyclic oligopeptide with immunosuppressive, antifungal and anti-inflammatory activity. Today, a number of minor metabolites have been identified, all of which are very hydrophobic oligopeptides. The main use of cyclosporin is to prevent organ rejection after transplantation.

[0003] Cyclosporin A, cyclosporine
Or cyclosporin is a cyclic oligopeptide consisting of 11 amino acids. Although the exact mechanism of action of cyclosporine is unknown, its effects are thought to be due to specific and reversible inhibition of immunoreactive lymphocytes. Cyclosporin is a registered trademark of Sandimmun Neoral ^(R) , Neoral ^(R) or
Under the Sandimmune ^(R), soft gelatin capsules, is commercially available as an oral solution or injectable concentrate. Each of these formulations contains more than 10% ethanol. However, from the gastrointestinal tract, Sandimmun Neoral ^(R) , Neoral ^(R)
Or the absorption of cyclosporine administered as Sandimmune ^(R) is incomplete and variable, and transplant patients taking soft gelatin capsules or oral solutions for a period of time will show higher levels of toxicity and lower absorption, respectively. It is recommended that blood levels of cyclosporin be monitored repeatedly at intervals to avoid organ rejection that may occur due to the disease.

[0004]

[Prior art]

US 4,388,307 relates to a pharmaceutical composition comprising a pharmacologically effective amount of cyclosporin and a carrier, wherein the carrier consists of a) a transesterification product of a natural vegetable oil, b) a vegetable oil and c) ethanol. The composition can be formulated as a beverage solution or as a capsule for oral administration. However, the use of ethanol is undesirable and can cause problems when the composition is presented in soft gelatin encapsulated form.

In GB 2 228 198 B, b) fatty acid triglycerides, c) full or partial esters of glycerol fatty acid partial esters or propylene glycol or sorbitol, and d) a hydrophilic-lipophilic balance (H) of at least 10
It has been proposed to use a carrier medium for cyclosporin consisting of a tenside with LB). This makes it possible to obtain an oil-based composition of cyclosporin that does not require the presence of solvents or solubilizers, for example ethanol. Surfactants used in the examples are other ethoxylation reaction products, such as Cremophor RH 40, Tween and Pluronic. The resulting composition is said to reduce the variability of cyclosporin blood levels. However, ethoxylated surfactants can cause allergic reactions, partly because they oxidize when exposed to air, so it is important to avoid them in medicine. This is a well-known fact.

[0006] Lipophilic carrier systems have also been described, for example WO 95/20945 discloses the production of lipophilic carriers having a continuous lipid phase consisting of polar lipid substances in combination with non-polar lipids. . The polar lipid substance must be a galactolipid substance consisting of at least 50% digalactosyldiacylglycerol and the rest of the other polar lipids. Example 2 of the publication discloses the preparation of a lipophilic carrier comprising 5% cyclosporin A in combination with a galactolipid substance and primrose oil. Said galactolipid material was obtained from plants, preferably cereals, by extraction and chromatographic separation, by an industrially applicable method for producing glycosylglycerides.

[0007] WO 92/05771 describes a lipid particle-forming matrix of at least two lipid components, one being non-polar and the other being amphiphilic and polar. The particle-forming matrix can include a bioactive agent and forms spontaneously discrete lipid particles when interacting with aqueous systems. The amphiphilic and polar lipid components are said to form a bilayer and are selected from phospholipids such as phosphatidylcholine; non-polar lipids are mono-, di- or triglycerides.

[0008]

DETAILED DESCRIPTION OF THE INVENTION

Here, the formulation of the lipid carrier cyclosporin, which surprisingly combines fractionated vegetable oils with monoglycerides and non-polar lipids, also contains toxic emulsifiers and ethanol in addition to cyclosporin and additives It has been found to exhibit cyclosporine uptake in blood that is bioequivalent to cyclosporine uptake from commercial drugs.

According to the FDA, the bioequivalence of a standard can be defined as a range of 80% to 120% of the average value of the product for a wide range of drugs (USP 24 NF
19 2058).

[0010] The present invention relates to a new pharmaceutical composition comprising cyclosporin as active substance in a lipid carrier, said carrier comprising membrane lipids in combination with monoglycerides and optionally non-polar lipids, wherein said composition is at room temperature. It is a liquid, characterized by the following: in weight percent of the total composition: cyclosporin 0.5-25% membrane lipid 10-45% monoglyceride 10-55% non-polar lipid 0-45%.

[0011] The present invention relates to a method for preparing a lipid carrier, wherein the lipid carrier is preferably 15 to 20% of a membrane lipid,
A pharmaceutical composition comprising 50% and 5-30% of a non-polar lipid. In another aspect of the invention, the lipid carrier of the pharmaceutical composition comprises 15-45% membrane lipid
And 25 to 50% of monoglycerides. Membrane lipids, preferably naturally occurring membrane lipids for biocompatibility and safety reasons, are all polar lipids and should be broadly defined as belonging to any type of phospholipids, glycolipids and sphingolipids Can be.

[0012] The phospholipids, mainly soybean and egg lecithin derived from soybean and egg, ie, produced by a synthetic route, are either bipolar, such as the phosphatidylcholine and phosphatidylethanolamine species, or phosphatidylinositol or It includes other phospholipids that can be negatively charged, such as phosphatidyl glycerol species.

Glycolipids from plants include glycolipids having predominantly galactose carbohydrate units bound to glycerol. Glycosyl glyceride is a kind of glycolipid,
It is a well-known component of plant cell membranes. The most important of these include 1-4 sugars linked to diacylglycerol via glycosides. The two most abundant types contain one and two galactose units, respectively, and are generally mono- and digalactosyldiacyl-glycerol, MGDG and DGDG.
And represents up to 40% of the dry weight of the thylakoid membrane. Galactolipids, mainly DGDG and DGDG-rich materials, have been investigated for industrial applications,
For example, it has been found to be an interesting surfactant in food, cosmetic and pharmaceutical applications.

Galactose or any other monosaccharide unit, for example, a synthetic diglycosyldiacylglycerol based on glucose, and carbohydrate units separate from galactose, for example, isolated from any source based on glucose Natural glycosyl glycerides can be used according to the present invention.

A unique beneficial feature of galactolipids is a galactose unit that contains a polar head group in each lipid molecule, which can sterically stabilize the emulsion droplets of the emulsion. Also, galactose groups can interact strongly with water and other polar substances, such as water-soluble drugs or excipients added to the emulsion. The interaction of glycosyl glycerides with non-polar or slightly polar lipids, such as mono-, di- and triglycerides, fatty alcohols and acids, sterols and sterol esters, optionally with other polar lipids such as phospholipids and sphingo When investigated in combination with lipids, without water or with only a small amount of water, we have found properties that make such formulations suitable as lipophilic carriers.

According to a preferred embodiment of the present invention, the membrane lipid of the pharmaceutical composition comprises a phospholipid and galactolipid. In particular, the membrane lipid of the pharmaceutical composition comprises DGDG in a mixture with phosphatidylcholine. Galactolipids can also be produced from almost all plant materials by extracting lipids with ethanol, for example according to WO 95/20945, followed by purification on a chromatographic column. Preferred plant materials are seeds and kernels from grains and grains, such as wheat, rye, oats and barley. Groat oat has a high lipid concentration, similar to wheat gluten,
Therefore, it is convenient for use in a manufacturing process. Digalactosylated - galactolipid consisting 50% to 70% diacyl glycerol and 30-50% other polar lipids substance, Scotia LipidTeknik AB, CPL by Stockholm ^(R) -Galactolip
Manufactured as id (registered trademark owned by Scotia Holdings PLC). Another polar lipid that is part of the galactolipid material is a mixture of different sugar- and phospholipids, such as MGDG and phosphatidylcholine.

WO 97/11141 describes a process for producing a fractionated vegetable oil, characterized in that it comprises 10 to 90% by weight of polar lipids, preferably 20 to 75% and the balance nonpolar lipids. ing. The fractionated vegetable oil contains galactolipid,
It can also be used to obtain the membrane lipids of the invention. The fractionated vegetable oil preferably comprises more than 5% by weight, preferably more than 20%, of glycolipids, and preferably more than 3% by weight, preferably more than 15% of DGDG. According to a preferred embodiment of the present invention, the fractionated oil is oat oil consisting of 40-60% polar lipids and the balance nonpolar lipids. The composition will depend on the starting materials and the method used to produce the galactolipids. The fractionated oat oil of this composition, consisting of a wide range of polar and amphiphilic lipids in a continuous triglyceride phase,
Manufactured as Galactolec ^™ by Scotia LipidTeknik AB (Stockholm) and also referred to as galactolecithin.

Sphingolipids can be obtained from milk raw materials by extraction and purification, for example by chromatography, and include sphingomyelin in combination with, for example, phosphatidylcholine, mono- and dihexosylceramides and triglycerides. Sphingolipids are a family of sphingosine-based lipids, whereas those previously described are glycerol-based. Examples of sphingolipids are sphingomyelin, mono- and dihexosylceramides and gangliosides. According to a preferred embodiment of the present invention, the membrane lipid should comprise DGDG in an amount of 0.1-90% by weight, preferably 10-70%, based on the membrane lipid.

Monoglycerides or monoacylglycerols are slightly polar in nature and have some surface activity. They can be obtained by fractionation of vegetable or animal oils. Preferred monoglycerides of the invention have a fatty acid chain of medium chain length, i.e., 8 to 12 carbon atoms, especially 8 to 10 carbon atoms, and can be obtained from coconut and palm kernel oil. Combining monoglycerides with membrane lipids facilitates the formation of lipid particles of the pharmaceutical composition in the gastrointestinal tract.

Non-polar lipids are, for example, such as natural or synthetic di- or triacylglycerols, or vegetable oils, animal oils, synthetic glycerides, fatty acids, fatty alcohols, sterols, such as cholesterol and their esters with fatty acids. Derived from The chain length and degree of saturation of the glycerides must be selected to obtain a liquid composition. Preferably, the non-polar lipid of the pharmaceutical composition consists mainly of triacylglycerol.

[0021] The present invention relates to a pharmaceutical composition of cyclosporin in a lipid carrier, especially comprising a mixture of fractionated vegetable oils and monoglycerides. Preferred compositions of the invention comprise cyclosporin 8 to 8% by weight of the total composition.
Contains 12%, galactolecithin 40-50% and MCM, ie C8-C10 monoacyl-glycerol 40-50%. The pharmaceutical composition of the present invention preferably comprises cyclosporin A, ie cyclosporin.

In general, the pharmaceutical compositions of the present invention may comprise non-polar lipids such as triglycerides and monoglycerides in glass bottles, optionally with cyclosporine and membrane lipids.
It can be produced by melting after melting in an open water bath at a temperature range of 0 to 70 ° C. The mixture is then brought to about 1000 using a high shear mixer.
Disperse at rpm and a temperature range of 40-70 ° C for 2-4 minutes. The mixture can optionally include an increased content of water or aqueous solution, which can form reverse vesicles, reverse micelles, or water-in-oil emulsions. If the lipid mixture is difficult to dissolve or if the content of cyclosporin is high, it may be necessary to first dissolve the mixture in ethanol and subsequently evaporate it.

The pharmaceutical compositions are intended primarily for oral administration, but are used for enteral, rectal, vaginal, topical, ocular, nasal or otic administration to animals, particularly mammals, including humans. You can also. In addition to the essential components, the pharmaceutical compositions of the present invention can also contain conventional additives and excipients, for example, preservatives, preservatives, thickeners, pigments, flavors, and the like, in the required combinations. Oral unit dosage forms, such as soft or hard gelatin capsules, can contain 5-200 mg, preferably 20-100 mg, of the active substance, ie, cyclosporine, for administration 1-5 times daily.

Examples of Cyclosporin Formulations The membrane lipid material used in the following examples is a galactolipid material, Galactolec ^™ (Scotia Lipid) manufactured from oats according to the method described in WO 97/11141.
idTeknik AB, Sweden) and is cited as galactolecithin. The galactolecithin consists of about 60% non-polar lipids and about 40% polar lipids. DGDG makes up about 20% by weight of the total mixture. The cyclosporin used in the below formulation was cyclosporin (ie, cyclosporin A (USP XXIII, Medial AG, Switzerland).

Embodiment 1Component weight%  Galactolecithin 67.5 Akoline MCM 20 Cyclosporin 12.5
Mono- (60%), di- (32%) and tri- (8%) acyl groups of C8-C10
Mixture of lyserol (Karlshamns AB, Sweden) and cyclospor
Weighed together with 6.245 g of the solution into a 100 ml beaker. Mix for about 36 hours
And homogenized with a magnetic stirrer. Yellow / brown cloudy high viscous liquid
The body is obtained.

Embodiment 2Component weight%  Galactolecithin 30 MCM 60 Cyclosporin 10 3.00 g of galactolecithin is added to 18.01 g of MCM, ie C8-C10
Noacylglycerol (99% pure by Scotia LipidTeknik AB)
25) with 9.00 g of cyclosporin
Weighed into a 0 ml round bottom flask. The mixture is homogenized by a spatula,
The mixture was heated to 60 ° C. under magnetic stirring until the active substance and lipids were dissolved. Get
The final product obtained was a tan clear solution.

Embodiment 3Component weight%  Galactolecithin 87.5 Cyclosporin 12.5 The same method as in Example 2 was used, and galactolecithin was replaced with cyclosporin 3
0.01 g by mixing with the final product of Example 2
The product was obtained.

Embodiment 4Component weight%  Galactolecithin 45 Akoline MCM 45 Cyclosporin 10 Using the same method as in Example 2, 13.50 g of galactolecithin, Akoline MCM
 Example by mixing 13.00 g and 3.01 g cyclosporin
A final product having the same appearance as the final product of No. 2 was obtained.

Embodiment 5Component weight%  Galactolecithin 45 MCM 45 Cyclosporin 10 Galactolecithin 13.50 g, MCM 13.
By mixing 51 g and 3.00 g of cyclosporin, the mixture of
A final product having the same appearance as the final product was obtained.

Embodiment 6Component weight%  Galactolecithin 30 Akoline MCM 60 Cyclosporin 10 Using the same method as in Example 2, 9.01 g of galactolecithin, Akoline MCM
Example 2 by mixing 18.01 g and 3.00 g of cyclosporin
A final product having the same appearance as the final product was obtained.

Comparative Example 1 A formulation according to WO 95/20945 was produced by mixing the following components:
Was.Component weight%  GL 20.0 EPO 67.5 AP 0.02 Cyclosporin 12.50 GL was produced from oats according to the method described in WO 95/20945.
Galactolipid substance containing about 60% DGDG, CPL^(R)-Galactolipid (Sco
tia from LipidTeknik AB, Sweden). EPO is primrose oil
(From Scotia Pharmaceuticals Ltd, UK) and the AP
Corville palmitate.

Producing additional formulations of cyclosporin having the composition described in Table 1 below
In the table, CS = cyclosporin G-lec = galactolecithin, Galactolec^TM  GL = galactolipid substance, CPL^(R)-Galactolipid h-GL = hydrogenated galactolipid material SL = sphingolipid material h-PE = hydrogenated phosphatidylethanolamine MCT = medium chain triacylglycerol, from Karlshamns AB A MCM = Akoline MCM Palm = palm The oil, Soy from Karlshamns AB Soy = soybean oil CH = cholesterol, Apoteksbolaget AB from PC = phosphatidylcholine, Lucas Meyer from SL, h-GL and h-PE were from Scotia LipidTeknik AB. Big
Soybean oil is a long chain C16-C20 triglyceride, CPL^(R)-Soybean oil (Scotia LipidT
eknik AB).

The formulations described in Examples 7-9, 11, 13 and 14 were prepared using ethanol as described in the following method referring to the formulation of Example 13. 13.123 g of the hydrogenated galactolipid are mixed with 2.627 g of Akoline MCM, C
PL ^(R) -2 with 10.513 g of soybean oil and 3.753 g of cyclosporin
Weighed into a 50 ml round bottom flask. Then, 40 ml of 95% ethanol was added to the flask. Pour flask into Rotavapor (Buechi, Switzerland) and add 70
C. and stirred for 10 minutes until the material and lipids dissolved. Then
The drying was completed by evaporating the product at a temperature of 70 ° C. during a drying time of 80 minutes. 30.02 g of the final product were obtained.

[0034]

[Table 1]

Biological Testing of Cyclosporin Formulations Efficacy of Oral Administration of Different Cyclosporine Formulations in Soft Gelatin Capsules
Commercially available drug Sandimmun Neoral as reference composition for studying fruit^(R)(Neoral ^(R) Known in most countries), 100 mg cyclo in ethanol
Compared to soft gelatin capsules containing sporin A, a cyclosporin
To perform an absorption test. Sandimmun Neoral per capsule^(R)The composition of rhinoceros
In addition to 100 mg of crosporin and 100 mg of ethanol, DL-α-tokofero
l, propylene glycol, corn oil, Polyoxyl 40 hydrogenated castor oil (Cre
mophor RH 40) and coloring agents.

[0036] Biological absorption studies were performed in healthy male volunteers. Exclusion criteria were known intolerance to cyclosporine, deviation from clinical adequacy, blood donation during the last two months, medical treatment that could interfere with the study, and smoking. The lab was designed to be open and portable, with the majority of subjects receiving two treatments after one reference treatment, ie, each subject was their own control. Each formulation was tested on three subjects, and three subjects also received only the reference composition in all cases to estimate inter-individual variability. The amount of cyclosporin was the same for all treatments. Inter-individual variation in three subjects in based Sandimmun Neoral ^(R) at three different observations was 15%. Inter-individual variability, ie Sandimmun Neo after a single dose to 18 different subjects
The variability in the uptake of ral ^(R) was 21%.

At the time of the first visit, informed consent and medical history were obtained from the subjects.
Hematology and clinical chemistry analyzes were performed. In the following three visits, subjects fasted from 22.00 the previous evening and arrived at 7.00 in the morning. About 7.30, about 15 tap water
The drug was taken with 0 ml. A catheter connected intravenously in the upper limb vein was used to obtain a blood sample. A series of blood samples for cyclosporin analysis were obtained according to the following schedule: pre-dose, 30, 60, 90 minutes post-dose,
And after taking 2,2.5,3,3.5,4,5.5,7.5,10,12,24,3
0 and 48 hours. Lunch was served 4 hours after drug ingestion and subjects were given tea, coffee and water. The total amount of blood drawn during the study was less than 400 ml.

The concentration of the active substance cyclosporin in the blood is determined by
Evaluated by a specific method at University Hospital, Lund. Cyclosporin analysis was performed using EMIT (Enzyme Multiple Immunoassay Tec) from DADE Behring.
hnique) kit using Hitachi 917.

The formulation of Example 1 (repeated) and Example 3 according to the present invention were tested in the same way as the formulation of Comparative Example 1 and the formulations of Examples 7-14. Relative following absorption values compared Sandimmun Neoral ^(R) and representing the area under the curve, AUC was obtained.

[0040]

[Table 2]

These results indicate that varying and sometimes surprisingly improved uptake can be obtained by varying the amount of the lipid component of the carrier pharmaceutical composition. Was repeated absorption test described in order to test the composition according to Example 2 and 4-6 with respect to uptake in comparison to Sandimmun Neoral ^(R). The mean value of uptake and the standard deviation of all test compositions, along with inter-individual variability,
It is described in Table 3 below.

[0042]

[Table 3]

[0043] Conclusion above test, the compositions of Examples 1, 4 and 5, because it has a relative uptake of ≧ 80%, considered a commercial drug Sandimmun Neoral ^(R) and to be bioequivalent You can conclude that you can. It should be noted that the composition according to the invention described above contains no harmful additives and only non-toxic lipids. It seems important that the final pharmaceutical composition be liquid at room temperature; see Examples 7, 11, 13 and 14, which are all solid at room temperature. It can be concluded that the physical state of the pharmaceutical composition is important for active substance uptake in the gastrointestinal tract. Also, too high a content of cyclosporin affects uptake. This is evident from Example 9.

[0044] Monoglycerides are important for uptake. From Examples 3, 8, 10, and 9 it can be concluded that if the monoglyceride content is lower than 10%, too low a monoglyceride content adversely affects the uptake. This is also true if the monoglyceride content is too high. Example 2 has a monoglyceride content of 60%, a high viscosity and poor uptake.

From the results, it can be concluded that the content of non-polar lipids must not be too high. In both Example 12 and Comparative Example 1, sufficient uptake was not possible because they contained too much triglyceride. It is believed that the improved variant of the composition of Example 5 compared to the composition of Example 4 was derived from the monoglyceride fraction used and defined in Example 5 instead of the lower content of diglycerides. However, the number of trials is not sufficient for its statistical confirmation.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/44 A61P 29/00 A61P 29/00 31/10 31/10 37/06 37/06 A61K 37 / 02 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, C , CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE , SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Karl-Gunnar Kruen S-126, Sweden 34 Hegesten. Tegelburg Swegen 40 F term (reference) 4C076 AA11 CC04 CC07 CC31 DD46 DD63 EE53 FF34 4C084 AA03 BA01 BA08 BA18 BA24 CA62 MA16 NA11 ZB08 ZB11 ZB32

Claims (10)

[Claims] 1. A pharmaceutical composition comprising cyclosporin as an active substance in a lipid carrier, said carrier comprising a membrane lipid in combination with a monoglyceride and optionally a non-polar lipid, wherein the composition is at room temperature. Pharmaceutical composition characterized in that it is liquid and comprises the following in weight% of the total composition: cyclosporin 0.5-25% membrane lipid 10-45% monoglyceride 10-55% non-polar lipid 0-45% object. 2. The method according to claim 1, wherein the lipid carrier comprises 15% of membrane lipids by weight of the total composition.
The pharmaceutical composition according to claim 1, comprising 20%, 25-50% monoglycerides and 5-30% non-polar lipids. 3. The pharmaceutical composition according to claim 1, wherein the lipid carrier comprises 15-45% of membrane lipid and 25-50% of monoglyceride. 4. The pharmaceutical composition according to claim 1, wherein the membrane lipid comprises DGDG in an amount of 0.1-90% by weight, preferably 10-70%. 5. The membrane lipid according to claim 1, wherein the membrane lipid comprises a phospholipid and galactolipid.
The pharmaceutical composition according to any one of claims 4 to 7. 6. The pharmaceutical composition according to claim 1, wherein the membrane lipid comprises DGDG in a mixture with phosphatidylcholine. 7. The pharmaceutical composition according to claim 1, wherein the non-polar lipid mainly comprises triacylglycerol. 8. The pharmaceutical composition according to claim 1, wherein the lipid carrier comprises a mixture of fractionated vegetable oil and monoglyceride. 9. The pharmaceutical composition according to claim 8, comprising cyclosporin 8-12% galactolecithin 40-50% MCM 40-50%, by weight of the total composition. 10. The method according to claim 1, wherein the cyclosporin is cyclosporin A.
The pharmaceutical composition according to any one of claims 9 to 9.