SA89100046B1 - Pharmaceutical compositions containing cyclosporins - Google Patents

Abstract

Abstract: This invention relates to new pharmaceutical formulations of cyclosporin in the form of a pre-concentrated microemulsion and/or based on the use of special solvent media which helps to counteract or significantly reduce the difficulties of treatment with cyclosporin (for example &"cyclosporin&") existing At the moment in (medical) practice. In particular, the invention permits the preparation of solid, semi-solid and liquid formulations containing cyclosporin of sufficiently high concentration to permit proper oral administration with improved efficacy.,

Description

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Pharmaceutical compositions containing cyclosporins Full description Background of the invention A new pharmacy that includes cyclosporine formulations This invention deals with formulations of active ingredient cyclosporin eleven peptides from a class of peptides cyclosporins Cyclosporins consist of multiple cyclic methyl groups linked to nitrogen with a distinctive structure, which are oo-cyclic compounds, and have a joint effect, especially in the field of immunosuppression and anti-inflammatory, and / or is the natural product of isolated and then isolated cyclosporin w0 against parasites. The first known cyclosporin was a fungal metabolite cyclosporin called 'cyclosporin 01010800110' or cyclosporine commercially available under the brand name Sandimmune* cyclosporin A | also known as 'ciclosporin' and 'SANDIMMUNER' or Sanadimion* 5220170011777 0

A of formula cyclosporin cyclosporine MeBmt-oAbu-Sar-Meleu-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal EERSTE methyl-(418)-?-but-25-yen -1- yl-?- methyl-(1) threonyl -N -MeBmt- where: B is represented as a part of the formula N-methyl-(4R)-4-but-2E-en-1-yl- 4-methyl-(L)threonyl y >”

CH,

HO (R) CH -N-CH-CO- d CH 3 : ‘eo (trans) -CH=CH- HO -X-y- Cua

Yan

. As the first in its group, cyclosporin has received the most attention so far. The first field of clinical investigation of 'cyclosporine 01010800110' was an immunosuppressive agent: particularly in its field of application for patients to whom organs such as heart, lung, heart and lung, liver, kidney, pancreas, bone marrow, skin or cornea are transplanted. In particular, 0 In the case of transplanting organs transferred from others different in genotype, ciclosporin has achieved remarkable success and a good reputation in this regard. At the same time, ciclosporin was used extensively for various autoimmune diseases and inflammatory conditions, especially those whose causes include an autoimmune component Je i, arthritis (such as rheumatoid arthritis, progressive chronic arthritis, and rheumatoid arthritis). deforming joints), rheumatic diseases, and reports and results from in vitro (ex vivo), animal, and clinical trials are scattered throughout the references. The list of autoimmune diseases for which ciclosporin therapy is indicated or applied includes: autoimmune blood diseases (including hemolytic anemia, aplastic anemia, solitary erythrocyte anemia, and unknown thrombocytopenia v.o.). (cause), systemic lupus erythematosus, polychondritis, scleroderma, chronic inflammatory Wegener's tumors, dermatomyositis, chronic active hepatitis, severe muscular weakness, psoriasis, Stevens-Johnson syndrome, swelling of unknown cause, autoimmune inflammatory bowel disease (including ulcerative colitis and Crohn's disease) Proposed eye disease with endocrine disorder and hyperthyroidism (Grave's disease), sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes mellitus (dis)type 1 diabetes, uveitis (anterior and posterior), keratoconjunctivitis sicca, and Keratoconjunctivitis vernal, interstitial fibrosis of the lung, osteoarthritis with psoriasis, glomerulonephritis (with or without transurethral proteinuria syndrome including transrenal protein loss syndrome of unknown etiology or definite renal disease changes). Yo, further research has shown that the drug can be useful in the treatment of parasites, particularly as an antiparasitic protozoan, with possible uses suggested for the treatment of malaria.

¢, coccidiomycosis, and schistosomiasis, but it has recently been proposed to be used to reverse or reverse Jalal anticancer resistance in tumours; etc. Since the original discovery of 'ciclosporin', a wide range of natural cyclosporins has been isolated and identified, and cyclosporins other than those naturally present have been prepared by synthetic methods, in whole or in part, by applying modified culture methods. Now they are large in number and include, for example, 0 cyclosporins A to Z found in nature, see: [c.f.

Traber et al. 1, Helv.

Chim.

Acta. 60, 1247-1255 (1977); Traber et al. 2, Helv Chim.

Acta. 65 no. 162, 1655-1667 (1982); Kobel et al., Europe.

J.

Applied 7 Microbiology and Biotechnology 14, 273-240 (1982); and von Wartburg et al., 01 Progress in Allergy, 38, 28-45 (1986)], as well as many cyclosporin derivatives not found in nature and synthetic or synthetic cyclosporins (Ley at that). labeled dihydro-cyclosporin [in which the x-y- part of -MeBmt- 1 (formula 3 above) is saturated so that it becomes -CH-CHp- = -X-y- and the cyclosporins Derived cyclosporins (in which a substituent is inserted at the carbon atom - the a-carbon atom of the sarcosyl 71 moiety at position -? of the cyclosporin molecule) and cyclosporins: in which the moiety is -MeBtm- In isomeric form (i.e., in which the shape is in relation to positions 1 and 7 "of the segment 'trans us cis -MeBtm- 0' and cyclosporins in which amino acids have been introduced at specific positions in the peptide chain using - for example - the total synthetic method for the production of 0a cyclosporins developed by - ~Wenger See 1 Traber 25 Traber Kobel Previous references and US patent numbers EY AGA 47191 770141 and International Published Patent Nos. 86/02080 1170; Wenger 1, Transp.

Proc. 15, suppl. 1:2230 (1983); Wenger 2, Angew.

Chem.

Int.

Yo Ed., 24, 77 (1985); and Wenger 3, Progress in the Chemistry of Organic Natural Products 50, 123 (1986). A 17.

0 The cyclosporins are now a very large class and include for example [Thr]?-[Nva]® 5 -[Nva}' 5 -[Nva]® [Val]? cyclosporin (also known as D©cyclosporins© and 14 respectively); ]¥= zero = ~[MeBmt-ds—ul [3-0-acyl-MeBmt]'-Ciclosporin (also known as ciclosporin A acetate [dihydro] Val]-'[MeBmt-cyclosporine [Dihydro-MeBtm]'-[Val]'-Ciclosporin (also known as dihydrocyclosporin ¢(dihydro-cyclosporin D[(d)fluoromethylsarcosine]”-cyclosporine [(D)Ser]® [(D)Fluoromethyl-Sar]'-ciyclosporin ciclosporin [(D]Ser]®-ciclosporin -[Melle]"! 0 cyclosporin -[(D)MeVal]' !([Melle]''-ciyclosporin -ciclosporin 00 11 [H00(11617)] (also known as cyclosporin H a ' -[MeAla]® ciclosporin «[MeAla]'- ciclosporin *[0(7:0]- cyclosporine [(D)Pro}*-ciclosporin etc. [According to the now-accepted nomenclature of cyclosporins, cyclosporins are known by reference to the structure of ciclosporin (i.e., ciclosporin) (cyclosporin) This is done first 1 by clarifying the existing amino acid moieties that differ from those found in Ms cyclosporin "for [Masram]" to clarify that the cyclosporin in question contains -0 (2:0 - instead of -Sar- in the position * and then using the flat 'ciclosporin' 7 to describe all other moieties identical to those in ciclosporin. The individual moieties are numbered starting with -MeBmt- or -dihydro ~ MeBmt -dihydroMeBmt- 0 in terms of position 1.) Many of these cyclosporins 070108001108 are of comparable pharmacological benefit to ciclosporin or even more than it in specificity; For example, in reversing tumor resistance to cytostatic therapy, there are many suggestions in reference materials for their use as therapeutics. Despite the very great contribution made by ciclosporin, especially in the field of organ transplantation and the treatment of autoimmune diseases, one of the obstacles to its widespread use was the difficulties in providing more effective and appropriate ways of administering it, as well as the occurrence of some undesirable side effects, in particular the effect Toxic to the kidneys. Cyclosporins are characterized by Yan

eyclosporins are highly hydrophobic. Until now, the proposed liquid formulations - for giving cyclosporing by mouth, for example - were based mainly on the use of ethanol, oils, coils, etc. from excipients as carrier media. Therefore, the commercially available ciclosporin solution drink is used Ethanol and olive M0 olive oil as Jala medium in combination with Lapravel 1801851 as a surfactant reducer. See, for example, US Patent No. 4,788,707. However, the use of syrup solutions and similar formulations presents many difficulties in practice. First, the need to use oils or oil-based carriers may impart an unpleasant taste to the preparations or reduce their taste quality, especially for long-term treatment purposes. This effect can be masked by providing the drug in the form of softgel capsules. However, to keep cyclosporin in solution form, the ethanol content must remain high. evaporation of cethanol e.g. from capsules or other forms; For example, when opened, it leads to the formation of a precipitate of cyclosporin. If such compositions are presented, for example, in the form of soft gelatin capsules; This difficulty necessitates packing the preparation 1, which will be placed inside a capsule inside an airtight container, cel gel, for example, inside an airtight vial or an aluminum foil vial 21010101000-1011. This, in turn, makes the preparation larger in volume and more expensive to produce. The storage properties of such formulations are also far from ideal. Bioavailability levels achieved with current oral cyclosporin 0a YS dosing regimens are also low and show significant variability between individuals, disease types and even for an individual patient at different times in the course of treatment. The reference reports indicate that the currently available treatment with commercially available ciclosporin provides: an average absolute bioavailability of about 770 with notable variation between patient groups; For example, bioavailability is relatively low for liver transplant patients and relatively high for ye bone marrow transplant patients. The reported variance in bioavailability among individuals ranged from 1 or a few percent for some to 7960 or more for others. As previously noted.; A significant change in the bioavailability of individuals is often observed over time.

To achieve an effective immunosuppressive treatment; The concentration of cyclosporine in blood or serum should be maintained within a specified range. The extent required may vary depending on the condition to be treated, for example, whether the treatment is to prevent expulsion of a transplanted organ or to control the course of an autoimmune disease. It also varies according to the use or not of using an alternative immunosuppressive therapy 6 at the same time as cyclosporin treatment. Due to the wide variation in bioavailability levels achieved by the known dosage forms (dade), the daily doses required to reach the required blood serum levels will also vary greatly from the AY individual and even from the same individual. For this reason, it is necessary to follow up the blood/serum concentration of patients who receive cyclosporin treatment at frequent and regular intervals. Monitoring of 0 drug concentration in blood or serum that is usually done by radioimmunoassay or equivalent immunoassay such as monoclonal antibody-based techniques should be done on a regular basis. This thus consumes time, causes discomfort and greatly increases the cost of treatment. In addition to all these very obvious practical difficulties, there is also the occurrence of unwanted side effects, which were previously mentioned, and which are seen when using the dosage forms of the drug, which are: ae taken by mouth. Specialists presented many suggestions to address these problems, including both solid and liquid forms for oral use. However, the abstaining difficulty that remained constant is the inability of: cyclosporins – cyclosporins, for example "cyclosporine 01010800110" to dissolve in aqueous media and therefore the inability to provide JSS a drug containing cyclosporin 0 at a concentration le sufficient to allow use a Dal that simultaneously satisfies the required requirements for bioavailability; i.e. allows effective absorption from the stomach or intestines; With achieving a stable and elevated concentration in an appropriate manner, pally or blood serum. The particular difficulties encountered in association with oral cyclosporins have inevitably limited the use of cyclosporin for the treatment of relatively less severe or less severe disease states. One of the difficulties in this field is the use of cyclosporin to treat autoimmune diseases and other skin conditions Jie Yan dermatitis:

A

Allergies and psoriasis, as well as - as suggested in scientific articles to stimulate hair growth - for example, to treat hair loss due to age or disease. Side effects on the effect of oral therapy may be possible for the treatment of psoriasis patients, thus preventing its widespread use. Many specialists have suggested the use of cyclosporins: 'Cyclosporin 0101080010' topically; many Jie-cyclosporin systems have described topical use, and despite that, cases of topical application failed to show tangible therapeutic efficacy. And the availability of a method for topical use of effective packaging inside The skin is suitable for the treatment of psoriasis, for example, available to a large number of patients who need it. cyclosporin will make treatment with cyclosporine General description of the invention 0 This invention provides new pharmaceutical formulations of cyclosporine 010160800110 in the form of preconcentrated microemulsion oli and/or as a founder On the use of certain solvent media as specified - for example - cyclosporin so that it confronts or greatly reduces the difficulties of using cyclosporine in treatment, those difficulties that practice currently faces.In particular, it was found that the formulations of this invention allow the preparation of formulations Solid, semi-solid and liquid containing cyclosporine ve appropriate oral administration; with Mia Lay achieving a sufficiently high concentration of cyclosporin allows an improvement in efficacy at the same time, eg in the area of bioavailability properties. This invention allows the administration of cyclosporins, lida, in particular. It was found that the formulations, in effective doses, with an accompanying activation of the levels of absorption / bioavailability, as well as 610901108 0 reduce the variation in the levels of absorption / bioavailability achieved both for the individual patient and between individuals - and by applying What is recommended by Led or cyclosporin who is being treated with cyclosporine leads to cyclosporin of the present invention Dosage forms of cyclosporine can be obtained: blood/serum achieved between cyclosporin to reduce the variation in cyclosporine concentration Dosing for individual patients as well as between individuals and groups of patients. Thus, the invention allows the necessary vo to obtain an effective treatment. In addition, Cyclosporin reduces the dose of cyclosporine, so it allows for better calibration as well as optimal adjustment of the continuous daily dose requirements for individuals q as well as for groups of patients receiving cyclosporin who receive treatment with cyclosporine: similar treatment. And with more accurate calibration of dose rates. For the individual patient and for the blood and/or serum concentration response as well as dose-response indicators in patient groups, follow-up requirements are reduced, effectively reducing the cost of treatment. It reduces dose adjustment/titration requirements for bioavailability profiles achieved; The present invention provides a means to reduce the incidence of unwanted side effects, especially cyclosporin, especially the toxic effect on the kidneys in patients receiving treatment with alkanolic cyclosporine. In addition, the invention allows the preparation of non-alkanolic formulations such as These ethanol formulations, that is, they may be free or almost free of ethanol 0, allow avoiding stability problems and the associated processing difficulties, previously referred to and known accompanying. Thus, the invention provides - among other things - usually alkanolic for alkanolic formulations better adaptability such as presentation in the form of capsules - such as hard or soft gelatin capsules and / or eliminates or significantly reduces packaging difficulties such as those previously mentioned, such as 1 With regard to topical use, the present invention allows the preparation of pharmaceutical preparations as an active ingredient “ciclosporin” such as new “cyclosporin” containing cyclosporine, which allows for better treatment of diseases Autoimmune diseases that affect the skin, especially diseases: the skin that is characterized by cell division and / or the formation of keratin in a pathological manner in the epithelial epithelial layer of the skin, especially psoriasis diseases and allergic skin disease and formulations subject to “topical use” according to the invention useful Also for the treatment of alopecia, that is, to prepare hair growth. microemulsion pre-concentrate

SAG wg Eel ad jadi wdalh adi; “ve” as used herein means a system that can “oil-in-water microemulsion pre-concentrate” in contact with water, for example, when water is added to it, to be a micro-oil-in-water emulsion and the term “ve” as used herein is used In the conventional sense, 'microemulsion' is a slimy, non-opaque or essentially opaque dispersion comprising water and organic constituents including microemulsions including hydrophobic (lipophilic) organic constituents and identifiable microemulsions They are those that are characterized by one or more of the following characteristics: they are formed spontaneously or spontaneously to a large extent when allowing the opportunity for their components to come into contact; That is, without an essential supply of energy; That is, without heating and without the use of high shear devices or any significant stirring. It is also thermodynamically stable; It is monophasic. It is also not opaque in the first place, that is: it is transparent or shimmering when viewed by optical microscopic means. In its undisturbed state, it is optically isotropic, although non-isotropic structures may be observed, for example, with the use of X-ray methods. 0 is in a dispersed or particle (droplet) phase; microemulsions microemulsions include angstroms; This is the interpretation of its optical transparency;. The particles of the microemulsion 00060 its particles from aan may be spherical although other shapes are possible such as liquid crystals with lamellar, hexagonal or symmetrical microemulsion - and in general emulsions include droplets or particles of their maximum dimensions (for their diameter ) less than vo microemulsions of angstroms [for further discussion of the properties of 0001 and 001 angstroms; They are usually between 0: Rosoff 620801 Advances in the Sciences of Jil See, for example, microemulsions and PLE technology and beyond Academic Press (9751); Freiberg; 405 VY Surfaces and Membranes; (7) 80; Müller 140116 et al.; The Pharmacist Scout (1985) and its sequels © 1017 oF) 1 cal .](1F) No and its sequels YL

SA It is clear from the foregoing that "an oil-in-water microemulsion pre-concentrate" to which the invention relates is an oil-in-water microemulsion pre-concentrate pharmacy systems as an active ingredient that can automatically form a cyclosporin oil-in-water microemulsion comprising cyclosporine or semi-automatically as soon as it comes into contact with water.

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111 As Active Ingredient - New Formulations. Accordingly, the present invention in one of its aspects —cyclosporines provides the following: as an active ingredient. and sh -" ° surfactant; -Y

SA This composition is an "oil-in-water microemulsion pre-concentrate" as used herein and in a "pharmaceutical composition" (the term 'pharmaceutical composition': the accompanying items to be protected should be understood as Determines the combinations of its components or individual elements 0 that are pharmaceutically acceptable by themselves, that is, when they are intended for oral use, they are acceptable for oral use, and when they are intended for topical use, they are acceptable for topical use). Suitable, both cyclosporin and cyclosporine, the hydrophobic and lipophilic phases, can play the role of the carrier medium. With the invention, it is “microemulsion 276-00660088” defined as “a pre-concentrated microemulsion vo of a type that provides hydro-oil micro-emulsions (also Oil / water). The characteristic microemulsion of microemulsions and the term oil-in-water microemulsion water-in-oil in el' oil or "in-water as used here must be understood" oil-in-water microemulsion pre- The pre-concentrated concentrate © accordingly includes those possibilities, which are obtained by contacting the compositions of the “microemulsions” and microemulsions derived from the invention with water or with a medium of “microemulsion pre-concentrate” aqueous another is thermodynamically stable; That is, it remains stable at normal temperatures, meaning that it does not darken or form emulsified droplets of apparent size or sedimentation over a long period of time. It is understood, of course, that to obtain a micro-emulsion, an appropriate amount of water must be added. Although the upper limit of mitigation is not an essential determining factor,

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VY

or higher) 001) for example from the previous micro-emulsion. A 0:1 dilution will usually be appropriate. And in the cases (water to water) microemulsion pre-concentrate

favourite; The formulations of the invention “pre-concentrate microemulsions,” upon contact with water, can form microemulsions that keep the “microemulsions pre-concentrate” stable at room temperature, meaning that it does not appear darkening or sedimentation that can be seen with the eye over a range of 0 m.

VY at least 2 hours; In the best cases for at least hours, and in the best cases for the duration obtained from microemulsions of at least an hour. and microemulsions YE to the invention”; For example, "microemulsions pre-concentrate" led in favorable cases at the degrees of dilution indicated above; The average particle size (JB A | angstroms down to 0101 or 0001 ang and in the best cases is less than 0 less than about 0.001 angstroms or 101 to about In particular, according to this invention, it is preferable to formulations as known under ( ) in which the alpha phase of water includes: Pharmacologically acceptable tetrahydrofurfuryl di- Crsalkyl Crs Alkyl: 1-1 for mono or poly. oxy-alkanediol partial-ether or partial-ether tetrahydrofurfuryl di-low molecular weight; or poly-oxy-alkanediol .1,2-propyleneglycol propylene glycol —=Ye) 1-7: spartial di spartial (Jad is for example (1-1) and the appropriate components are mono, especially poly, or poly- mono, for mono ethers, and in particular; partial- Ethers, especially OF, containing a number of ?to oxy-alkanediols, oxy-alkanediols “di” or “di-©”. It is preferable that the moiety be mono- or poly-oxy-carbon atoms; of carbon atoms Particularly suitable for straight-chain lS jal. Of the poly-oxy-alkanediol alkanediol (I) ethers of the formula for use according to the present invention, by themselves - or in part - are ethers of BZ -[0 -(CHz)2]x-0R; 0) ctetrahydrofurfuryl or tetrahydrofurfuryl Crsalkyl Cis is an alkyl Ry Cus Yo or tetrahydrofurfuryl Crsalkyl Crs alkyl chydrogen is hydrogen Ry and “tetrahydrofurfuryl yan

X is an integer from 1 to 1 especially from 1 to ;; Particularly about 1. Particularly preferred for use according to this invention are partial ethers as specified above; Any product of formula Ry Cus (I) is hydrogen and the alkyl moiety Csalkyl Crs in the ethers specified above may be branched or © straight chain; i.e. include emethyl -n ethyl propyl groups «n-propyl -i propyl -n i-propyl n-butyl and t-butyl +- butyl groups for example example. Such ethers are known compounds that are commercially available or can be produced by the Ales method of known products. Particularly preferred compounds of Formula 1 for use in conjunction with the present invention are those known and commercially available under the trade names Transcutol 0 and Glycofurol. Transcutol is the compound diethyleneglycol monoethyl ether. of formula (I) where b = Wh = R; 11 and R = .1 and Glycofurol also known as tetrahydrofurfuryl alcohol polyethylene glycol ether Lf or alpha- (tetrahydrofuranyl)-omega-polyhydroxy YO — Sf) o~(tetrahydrofuranyl)-o-hydroxypoly(oxy-1,2-ethanediyl) of formula (1) where Ry = << OCH — ; H=R, for its average value from 1 to ?. The average molecular weight is about 0'. The boiling point is about 0 (La ooh) at £0 N/oie, the density is about -01.17 4 g/cm" (at 50) and the hydroxy value is 400-701” and a refractive index of about 6080 V (1 084 mm sodium line) (Asif die) and a viscosity of about 8-18 ms/m’ (at 107'C). ), p. 577.] 127 Yo The exact properties of glycofurol vary according to its relative purity The lower quality grades contain significant amounts of tetrahydrofurfuryl alcohol and other impurities For the purposes of this invention glycofurol Vo is preferred Yat:

cglycofurol 5 which means a product that meets the physical data referred to above and in which the fraction arrives whose formula is the formula (I) shown above in which x = 1-7 and to a minimum of AY and has It was found that the use of the components known under (Y =) 5 (1-1) above provides, in particular, combinations identical to (1) in which the hydrophilic phase is particularly suitable as a carrier medium for cyclosporin, meaning that the hydrophilic phase in it makes The cyclosporin loaded in the formulation is suitable for therapeutic doses appropriate for oral administration, for example, and formulations according to (a) comprising components as known under (1-1) and/or (Y=): as phase Hydrophilic may of course include one or more components of those described as hydrophobic shall components However, it is preferable that any additional components include substances The active ingredient of cyclosporin can dissolve Led Sufficient so as not to significantly affect the efficiency of the alpha phase of water as Jala medium for cyclosporine 10 800 110 N. Possible examples of additional components of the alpha phase of water are lower alkanols (eg Cys and in particular ethanol Vo. although the use of alkanols calkanols such as ethanol “ethanol as a component of the hydrophilic phase is foreseen in this invention; It is for reasons previously discussed; That would generally be less favorable. It is preferable that the compositions specified under (a) not be based on alkanol, that is, they do not include alkanol as a basic component of the alpha phase of water. It is appropriate for the alpha phase of water to include a ratio of cannoline components less than 7090 by weight, and better than that less than AYO x, and preferably less than 7900. It is more appropriate that the alpha phase is devoid of water or almost devoid of calkanolic components. That is, it contains less than 75, and the best is less than AY, i.e. from zero to 71 of the calkanolic components, and by the word “alkanol” we mean in the capacity of Gals, the alkanols are Cis #Amosol.:; Lau ethanol .ethanol and in a particularly preferred form; the alpha phase of water of the compositions known under vo ( ) will consist or will consist mainly of components as defined under (1-10) or (1-7) above; in particular ctranscutol glycofurol and/or -710 propylene yan e:

Ve and more appropriate to consist or consist principally of any of the constituents 1, 2-propylene glycol glycol (YY) or constituent (1-10) thereof cglycofurol and compositions according to (a) comprising Component (1-1), particularly glycofurol, is particularly important in that it is well suited to be supplied in the form of soft gelatin capsules.Though these formulations have surprisingly excellent stability;for example as appears from the aay of the invention; Long-term stability tests at normal and elevated temperatures.Thus, these formulations are particularly suitable for overcoming the difficulties that usually occur in the transportation and storage of pharmaceutical preparations, including long-term storage in the consumer, i.e. in hospitals, clinics, and the like. Aspects.: (7) and the compositions known under (a) include in addition to the lipophilic phase ve and the components suitable for use as the lipophilic phase include any pharmaceutically acceptable solvent other than (YY) or (VY) miscible with the oleophobic phase of the water chosen, i.e., as is known under, and such solvents are preferably devoid or nearly devoid of surface tension-reducing property. The oleophobic of fats (7) for example shall be particularly suitable ingredients for use as components

Ja 10 The best of them are (fatty acid triglycerides) Triglycerides of medium-chain fatty acids. What is particularly suitable are neutral oils. For example, neutral vegetable oils, especially fractionated coconut oils such as Those known and commercially available under the trade name include the following products: <Miglyol (c.f. Fiedler, loc. cit. pp. 808-809) 00 Fractionated Coconut Oil Contains Triglycerides tMiglyol 810 4801 Miglyol OY The weight of the jizzichi is about caprylic-capric acid triglycerides © 778-716 Mga Cg «LY Max Cg = fatty acid Composition of fatty acids

FUE Acid Number - about 1.0; Saponification No. - approx. AY max ©, Yo-Yo; 1; Iodine No. -< max Fractionated Coconut Oil Contains Miiglyol Triglycerides 812 AVY Migliol OV Molecular Weight Approximately Caprylic -capric acid triglycerides Caprylic and capric yan

Composition of fatty acids Cg = fatty acid Max. Approx. 77 Cg Approx. 16-06 Cio Approx. 45-7 © max. Acid No. - Approx. 0) Saponification No. - Approx. 5-7 Iodine No. = max 1; Migliol: Miiglyol 818 AYA triglycerides of capric acids; caprylic-capric-linoleic acid triglyceride m caprylic-capric-linoleic acid triglyceride wt. - approx. 001 fatty acid composition Cg = fatty acid max Cg oF max 45 -07; 0,0 about *?- of © about 9-7 Cig about 1-4; Acid No. = max 0.7 Saponification No. = approx. 275-715 Iodine No. = max 10; and Captex Yoo 355 “016H0(') caprylic-capric acid triglyceride 0 Fatty acid content = caproic approximately 7 caprylic approximately foo capric capric approximately JY Acid number = max 1.1 Saponification number approximately 740-778 Iodine number - Maximum 010 It is also appropriate for triglycerides of caprylic-capric acid: caprylic-capric acid triglycerides such as those known and available commercially under the trade name (c.f.

Fiedler loc. cit., p. 834) Myritol 0 and includes the product Myritol 813 MY which has an acid number = max 1; The saponification number is about Fotis and the iodine number is about 00. Other suitable products in this group include: Captex (MCT(') Captex 3000) and Captex 800 () 800(1) Newby () 145 Neobee M5 () & Mazol + 1400 () (V€+) Capital City Products, PO.

Box 569, Columbus, OH, USA. (2) = Stepan, Y. = )1([ PVO Dept., 100 West Hunter Ave., Maywood, NJ 07607, USA. (3) = Mazer Chemicals, 3938 Porett Drive, Gurnee, IL, USA .]: The compositions according to the invention and defined under (a) also include a pharmaceutically acceptable surfactant (7). The surfactant component may include aide (=F) ve hydrophilic surfactant, (YF) lipophilic surfactant, or a mixture of both. Non-ionic, hydrophobic and non-ionic, lipophilic surfactants are particularly preferred. Examples are Ya

For suitable hydrophilic surfactants for use as components of surfactants, the following are: 1-1-* _ Reaction products of vegetable or hydrogenated oils with ethylene glycol i.e. polyoxyethylene glycols of natural or hydrogenated vegetable oils ; For example, polyoxyethylene glycols of natural or hydrogenated castor oils, and such preparations can be obtained in a well-known way, such as the interaction of natural or hydrogenated castor oil or sections thereof with ethylene oxide, for example, in molecular proportions ranging from 5:1 to about 1:10, with the possibility of eliminating the free polyethylene glycol Ve components from the product, for example, according to the methods indicated in the two German patents: A particularly suitable formulation is Cremophor RH 40, which has a saponification number of about 0-10, an acid JH number of 1, an iodine number of less than 1091, and a water content (Fischer Vo less than ZY). And the optical refractive index at oo about 80% for the water/fat affinity balance order = about Cremophor RH 60 V1=1¢ and the saponification number for it = about 6;-90 and the acid number is less than 1 and the iodine number is less than: from 1, water content (Fischer = about ©.79.9-4), optical refractive index at 95 - about 0.467-1.557, affinity balance for water and fat - about 9-2a1a, and Cremophor .51. Its molecular weight (in vapor osmotic measure) = about VIF, the saponification number - about 0-75, and the acid number = about ? And the iodine number - about 748-?? And that "and - about VEVY" (C.F.

Fiedler loc. cit. pp. 326-327) Also suitable for use in this group are the various interpretations available under the trade name Nikko! vo eg 1100-60 Nikko! This compound 1100-60 is the product of the reaction of hydrogenated castor oil with ethylene oxide Ethylene oxide has the following properties: acid number = about oF saponification number - about 47.4 defy hydroxy = Yan |

: approx. c£Y.0 pH pH (70) = approx. 6.1 color = APHA approx. cto Melting Point = approx. “#”*C;; Freezing Point = approx. 77, 4"C; content (KF) J = about 0.07 *-1-?: _polyoxyethylene-sorbitan-fatty acid esters ° e.g. mono- and tri-laurel esters <mono- and trilauryl (¢palmityl stearyl) and oleyl 016(1). For example, the kind known and commercially available under the trade name Twain (c.f.

Fiedler, loc. cit. pp. 1300-1304) Tween including preparations Tween (pg yo 1 [polyoxyethylene (Y +) polyoxyethylene sorbitan monolaurate [sorbitanmonolaurate 0] polyoxyethylene cul (+ ¥) Sorbitan monopalmitate “[sorbitanmonopalmitate 0 [polyoxyethylene (Y +) polyoxyethylene sorbitan monostearate [sorbitanmonostearate vo Ae [polyoxyethylene (Y +) polyoxyethylene sorbitan monooleate]] sorbitanmonooleate ' [polyoxyethylene (01) polyoxyethylene sorbitan tristearate “[sorbitantristearate] , ©” [polyoxyethylene (Y +) polyoxyethylene sorbitan trioleate “[sorbitantrioleate YY | [poly] polyoxyethylene (£) sorbitan monolaurate “[sorbitanmonolaurate] [polyoxyethylene (£) [sorbitanmonostearate Yo A] [polyoxyethylene] 2) Sorbitan monooleate SA “[sorbitanmonooleate A 151

Particularly preferred products of this group for use in the compounds of the invention are the above mentioned preparations Tween 500 and Tween Av : “-1-# polyoxyethylene fatty acid esters e.g. Polyoxyethylene stearic acid esters of the known type and available commercially under the trade name Myrj (834 m) (c.f.

Fiedler, loc. cit., as well as the well-known polyoxyethylene fatty acuid esters that are available commercially under the trade name ¢ (c.f.

Fiedler, loc. cit., p. 284) Cetiol HE. One of the preparations 1 particularly preferred for use in the formulations of the present invention is the preparation 52 Myr with an optical refractive index of =D? about 1.1 and a melting point of -about =r 4C; And the balance of affinity for water and fat is about 16.5, the acid number is about zero-1, and the saponification number is about Yo-Yo. For example, Gil is well known and commercially available under the brand names Pluronic and Emkalyx Fiedler, loc. cit., pp. 956-958).1.). Particularly preferred preparations from this group for use in formulations of the invention are Pluronic 768 8 #-1-e:_polyoxyethylene-polyoxypropylene confluent copolymers -0017076171606; For example, the well-known and commercially available type called .(c.f.

Fiedler, lore. cit., pp. 959) Poloxamer is a particularly suitable compound of this group for use in the compositions of the invention. binary-[7- Jf hexyl]- 17

di-[2-ethylhexyl]-succinate or tsodium lauryl sulfate :v—Y-¥ Phospholipids (phospholipids); Especially lecithins (c.f.

Fiedler, loc. cit., pp. 731-733) The lecithins suitable for use in the compositions of the invention include in particular soybean lecithins; A=) —Y esters propylene glycol mono- and di-fatty acids Jie propylene glycol dicaprylate “propylene glycol dicaprylate propylene glycol dilaurate propylene glycol hydroxystearate” propylene glycol hydroxystearate Ve propylene glycol isostearate propylene glycol isostearate propylene glycol laurate propylene glycol ricinoleate propylene glycol ricinoleate 0021006 glycol stearate <ul Ji uw Ma YW That's J aie. (cf.

Fiedler, loc. cit, pp. (c.f.

Fiedler, loc. cit., has fatty acid content = Cg max. Hawalli Cg oY Hawalli Mtnahnmak Cio | approx. 770-11©, max LY acid number - max 0/1; Y. saponification number = about 340-7760 iodine number = maximum 1; For example; Alkaline mineral salts, Jie, sodium taurocholate. Examples of familiar lipid surfactants suitable for use as a surfactant component are: vo #-1-71;: _esterification compounds of the type trans of the triglycerides of natural vegetable oils, polyalkylene polyalkylene. These trans ester compounds are technically known and can be obtained, for example, 1911

According to the general method described in US Patent No. ; drink,. Comprising type 0808 esterification preparations of various natural (ie, non-hydrogenated) vegetable oils such as corn oil; kernel oil; Almond oil; Peanut oil, olive oil, palm oil and their mixtures with polyethylene glycols °, especially polyethylene glycols of medium molecular weight from 000 to Ave | Preparations obtained by trans esterification of two molecular parts of a triglyceride of natural vegetable oil with one molecular part of polyethylene glycol (such as those with an average molecular weight of ve | vary from 00010 to (Ave) There are various forms of esterification preparations of a kind from the well-known group and are commercially available under the trade name Fiedler, loc. cit., 707] Labrafil 866. Particularly useful preparations as components of the compositions of the invention: M1944 CS 1.801851 It is a trans esterification of polyethylene glycol kernel oil with an acid number of vo = about 175-158 and a saponification number of about 175-158 and an iodine number of about “tr cLabrafil M2130 CS 0 It is an esterification of the trans glyceride type -d:© to -©_ and polyethylene glycol, the degree of: melting for it = about git To, the acid number = less than ?, and the saponification number = about Law mono-, di- and mono/di-glycerides esterification products of caprylic or capric acid Capric with glycerol Preferred preparations from this class are those that include or consist mainly or mainly of mono- and diglycerides of caprylic/capric acid Jia caprylic/capric acid, those available commercially Yo under the trade name (c.f. loc. cit., pp. 645) Imwitor and one of the preparations of this class that is particularly suitable for use in the compositions of the invention is the preparation dmwitor 2, which is the product of the esterification of a mixture of about 10 percent by weight of acid

: YY and about % by weight of caprylic acid. Caprylic acid is typically a yellow crystalline mass; Imwitor with glycerol 8170©:01. and 742 capric acid all iodine number = limit oF liquid at about 77"C; acid number = maximum 7# saponification number - approximately 775-778; 7 monoglycerides 1 approximately 1;-0 5 glycerol heat - max 77° = monoglycerides ° tonal melting - approx. 7-7*C; Unsaponifiable fraction = 75.7 max; It is commercially available under the trade name Span “sorbitan-monolauryl” for example on sorbitan monolauryl esters Ve “monostearyl monostearyl”-monopalmityl monopalmityl-trioleyl and monooleyl ctristearyl ¢ (c.f. Fiedler, loc. cit., pp. 1139-1140) pentaerythritol fatty acid esters pentaerythritol 3a pad a esters: ;-7-0 eg epolyalkylene glycol ethers and polyethers alkylene glycol vo distearate c-dioleate dioleate cpentaerythrite pentaerythrite polyglycol ether polyglycol ether <-monolaurate 19676; Monolaurate: as well as pentaerythrite-fatty acid esters -monostearate and monostearate ¢ (c.f. Fiedler, loc. cit. pp. 923-924) pentaerythrite-fatty acid esters e.g. monoglycerides monoglycerides Glycerides _. :»-”-#© v. glycerol monopalmitate glycerol monooleate (Example Jy of ¢glycerol monostearate and glycerol monostearate “Myvatex” is known and commercially available under the trade names 6.1); And he wasn't treated Fiedler, loc. cit, pp. 836) Myverol 3 Myvaplex mono- and di-acetylated monoglycerides, including acetylated Yo, for example what is known cmono-and di-acetylated monoglycerides : ¢ (c.f. Fiedler, loc. cit., pp. 835) Myvacet It is commercially available under the trade name

A

: 1-7-+ glycerol triacetate or (0701)- triacetin: (c.f.

Fiedler, loc. cit., pp. 952) (1,2,3)-triacetin and V-Y-¥ sterols and their derivatives. For example, cholesterols and their derivatives, especially phytosterols, such as compounds containing 0 csitosterol, campesterol, or cstigmasterol, and derivatives of ethylene oxide, such as soy sterols and their derivatives. Jie is known under the trade name (c.f.

Fiedler loc. cit., p.p. 554 and 555) Generol and in particular preparations 122 ES 5 “122 E10 122125 < Generol 122 0 and formulations as known under (1) above include systems including either a single surfactant or a combination of surfactants Surfactants; Jie those comprising a primary surfactant plus one or more auxiliary surfactants. Combinations of surfactants and surfactants may be selected from any of the types of surfactants as described under (7-1-1) ) to (V=Y=Y) above. vo and if the alpha phase of water includes a binary or partial ether as is known under (0-1) above and in particular transcutol or cglycofurol The use of a single surfactant will be LS although auxiliary surfactants can be added if desired, to further improve stability properties eg if Ye) propylene glycol 817001 1,2-propylene is used As the sole or main component of the phase '© alpha ell the use of at least two surfactants; Any reducer and auxiliary surfactant; It will generally be required - and the formulations as known under (1) comprise Ye = 1,2-propylene glycol as the hydrophilic phase and hereby comprise both a reducer and an adjuvant surfactant. Surfactants as known under (Y=1=1) 5 )1-(and (1)=F) (0-Y-F) 5 (Y-Y-Y) 5 vo above are particularly interesting for use in formulations as It is known under (a). Particularly suitable combinations of surfactants/Sil surfactant aids include hydrophilic/lipophilic surfactant combinations 15

For example, combinations of surfactants according to formula (1-1) with reducers according to formula (7-7-5). to (VF) surfactants or a combination thereof isd as eg for the above reducers; they may be incorporated into combinations as defined under (a) not only as (Y-Y-v)oo surfactant reducer but in quantity excess as an additional carrier phase or co-solvent, i.e., as part of the alpha phase of water or fat and compositions according to (a) above may also comprise: - a thickening agent. and used in technical application; 1 including, for example, pharmaceutically acceptable polymeric materials and inorganic thickeners; 7 for example, the following types: Polyacrylate resins and enacrylate copolymers: 1-4, for example, 0017801816 resins and polyacrylate co-polymer resins and poly-acrylic acid 585 vo such as those known and available “poly-acrylic acid/methacrylic acid” (c.f. Fiedler, loc. cit., pp. 254-256) Carbopol commercially under the trade name

Eudragit 5 «Carbopol 934, 940 and 941 and in particular preparations (c.f. Fiedler, loc. cit, pp. 486-487) and in particular preparations Budragit E, Ba S, RL and RS Y. ¢tBudragit E, L and S including: cellulose and cellulose derivatives celluloses celluloses 4-7 ethyl celluloses ethyl ethyl cmethyl Jie calkyl celluloses hydroxypropyl alkyl Hydroxypropyl-celluloses ¢propyl-celluloses and hydroxyalkyl-celluloses Hydroxypropyl-celluloses Jie Yo such as hydroxypropylalkyl-celluloses and chydroxypropyl-methyl-celluloses propyl-celluloses Methylcellulose

Yq

Yo «acetates-celluloses such as cacylated-celluloses celluloses acetate-z succinate ccellulose-acetatephthallates and acetate-phthalate-cellulose hydroxypropyl phthalate- Ji cellulose-acetatesuccinates cellulose Each of them is salts And salts of shydroxypropylmethyl-cellulose phthalates, sodium-carboxymethyl-celluloses, such as sodium-carboxymethyl-cellulose 0, and examples of those preparations suitable for use according to this invention are those

Methocel 3 Klucel known and commercially traded under trade names, especially formulations o (c.f. Fiedler, loc. cit., pp. 688 and 790) each SM each 100M each 15M «Methocel K 100 HF 5s GF «MF (LF Klucel; 100M E 15M ); 15 Ve comprising, for example, poly-7<- cpolyvinylpyrrolidones 6-?: polyvinylpyrrolidones and poly-N-vinylpyrrolidones Such as vinylpyrrolidone-vinyl acetate co-polymers, copolymers of vinylpyrrolidone, and examples of such compounds suitable for use according to .vinylpyrrolidone-vinylacetate (or Kollidon of the present invention) are those known and available commercially under the trade name and as (c.f. Fiedler, loc. cit., pp. 694-696) (Povidone in the United States; ¢Kollidon 30 and 90 especially formulations such as those containing alcohols and polyvinyl 001771031  Polyvinyl resins 4-6 Gum Jie as well as other resins polyvinylacetates and alcohols alginic acid acetate alginates tragacanth; catapulgite; Silicon A ald and as silica gels Yo colloidal silica as that known and available commercially under the empirical name silicon dioxide [c.f. Hand book of Pharmaceutical Excipients, loc. cit., p.p. 253-256] Aerosil

In particular, preparations 130 Lowe 200 300 380 0 « 50 0X » TT 600 80 Enemy 170 0 84 Aerosil R 9725 LK has a myelated group: in the case of formulations according to (1) intended for oral use; Such thickening agents 6 can be used to obtain an effect of gall release that lasts for a long time, but in cases where the drug is intended to be used by mouth, the use of the aforementioned thickening agents is usually not required, but it is usually not preferred, but on the other hand, the use of agents A thickener is required if the drug is intended for topical use, and formulations according to (a) above may also include one or more of the following ingredients, in particular diluents and antioxidants [(e.g., ascorbyl palmitate, butylated hydroxychloroquine) hydroxy anisole(BHA) J sus 7-butyl hydroxytoluene (BHT) and ctocopherols such as alpha-tocopherol (vitamin E)]; flavorings etc.; For oxidation, in particular tocopherol, is particularly beneficial.Vo Although it has been taken into account; Particularly where oral administration is to be considered that formulations according to this invention as known under (f) shall include final dosage forms for administration in this form; This invention provides Lad pharmaceutical formulations that include cyclosporin as an active ingredient and are themselves oil-in-water microemulsions. so that if it needs to be given by mouth; The microemulsions that will be obtained by diluting a 'microemulsion pre-concentrate' as defined under (AA) with water or other aqueous medium can be used as combinations for the use of the drug as a syrup. Also, if the topical use is a topic In contrast, formulations comprising a hydrocolloid thickening agent, such as those indicated under (?-7) or (;-;) above, will suitably incorporate water and thereby provide a matt micro-emulsion in the form of a gel, paste, cream, or the like This form of new Lay vo structures. According to this, the invention Mal provides, in a new field, the following: 1195

L (B) a drug combination that includes cyclosporin as an active ingredient (1) a hydrophilic case of a slurry; (1) a lipophilic case M: a 0m11; (Y) a surface-active substance Cua slay. The composition is a micro-emulsion of oil in water. The compositions as they are known under (B) may include any of the components (1) to (7) as: 6 previously described above in connection with the compounds known under (A) and water. Either composition (b) They are oily:aqueous micro-emulsions.It is preferable to have the stability characteristics previously described by Bi YU with the microemulsions obtained from the formulations known under (a).The formulations according to the present invention can be used for administration in any suitable form, for example, orally. or as a standardized dosage form; as hard or soft gelatin capsules; or for parenteral or topical use such as application to the skin or as a cream; paste; lotion; gel; ointment; poultice; plaster; skin patch; or the like or for ophthalmic use in the form of eye drops, lotions or gels (Ja) and easy-flowing forms, eg micro-emulsions, may also be used for example for injection into the same lesion to treat psoriasis or may be used rectally; For example by means of an enema to treat re inflammatory bowel disease or Crohn's disease. However, the formulations according to this invention are mainly intended for oral use or topical use, especially topical use on the skin. It is natural that the ratios between the amounts of ingredients in the formulations of the invention vary greatly according to the particular quality of the intended formulation; For example, if this composition was an “oil-in-water microemulsion pre-concentrate” or a “loil-in-water microemulsion,” the proportions between the ingredients will also vary. according to the specific function of each of the ingredients in the composition; For example, in Aa, the surfactant component of the oil-in-water microemulsion pre-concentrate, the proportions depend on whether it is used as a surfactant only or as a surfactant. surfactant and co-solvent at the same time. The relative amounts will also vary depending on the ingredients ve used and the desired natural properties in relation to the formulation of the preparation. For example, in the case of formulations for topical use, the matter differs if the formulation is for an easy-to-flow liquid than in the case of a paste. Determining practical proportions for any particular case is usually possible for person yan

Ya

skilled in this technical field. Thus, all areas of proportions and relative weights described below are to be understood as illustrative of personal preferences or efforts and not as limitations of the invention in its broadest sense. In the formulations of the invention; For example, cyclosporin, and of course the amount of cyclosporine will vary: to (£) as (Y) according to the intended method of administration and the degree of availability of other components, especially the 0 components. It is described above, in the amount of 778 by weight in relation to the total weight of the composition. Components weight relative to the total weight of the composition.In the case of formulations according to the invention containing 0, (1-10) “(Transcutol or Glycofurol Ds) (1-10) is a component ve to 79750 by weight attributable to 01 to 7450 by weight and usually of © or 1 whose percentage will generally be of (1-7) formulations according to (1) or (b) above comprising an AS component of the total weight of the formulation In the weight attributed to the total weight of the component, 780 will be generally proportioned from * to (1-7) each of these will be oF) or (1) and in the case of fixtures according to of the invention comprising a constituent to 798 by weight attributable to the total weight of the composition.In the form of #1 usually present in amounts ranging from 1 in particular preferred, the present invention relates to: (c) formulations as known under (1) above for oral administration, i.e. in a suitable or suitable form for oral use. For formulations as they are known under (a) to (c) intended for use other than topical use” and in particular. Dosage forms for oral use (C): © and preferably 7760 (BY) or 1 in general of cyclosporin. or from © to 716 by weight 7710 i.e. Yo from © to cyclosporin cyclosporine to total composition weight; to 01 and better from Ae to 15 the quality will range from Alla in (VY) component (9) ve or 7760 by weight 900 to 70 i.e. from 0 to Yo and better than cA based on total weight of the composition;

Ya

(c)_cyclosporin and component (VV) if present the ratio between them will range from 1.78: to 01 and more appropriately 1:1 to Vo and better 1:1 to © i.e. 1:1 or 1,5:11 to ; By weight ratios [Cyclosporine metdominated: (1-0)]; d component (1-7) in Ala quality will range from * to cto and better than Ho 270 by weight attributed to the total weight of the composition. ( e) _cyclosporin and component (Y=) in Alla their presence, the ratio between them will range from 11:1 to 01, and it is appropriate for it to be 17:1 to 01 by weight. be in a ratio of 17:1 to ; eg v0) to ? By weight [cyclosporin 1-1]: cyclosporin Ve, and component 1, if present, its quantity is up to e800, and it is appropriate to reach 74560 by weight based on the total weight of the composition. It is better that the component quantity be (7 ) from $0 to $7 and better between “©” to Fo and better than © or 01 to 700 by weight based on the total weight of the installation. (5) Components (V1) oY) if present It will usually be 9:1 to 560; The best would be 5:1 to 01 and the most appropriate would be 1,78:1 to 10, for example vert to ; by weight ratios. (YN (1)]. (H)- Components (YY) oY) If occurrences are in the ratio of YY every and preferably 1:1 to ve and the most 115:1 deed to 1 by weight For example ey to “* wt. 7 [(?): (YY) (i). Components (©) if present [including components of both types (“*-1) and (7-3)] are usually in proportions up to 0; For example, from Ye to Ze by weight based on the total installation weight. It is preferable that the components (©) be in an amount ranging from 01 or Yo to As or 796 by weight based on the total weight of the composition; For example from yo 7856 when using yo component (VY) or from 50 to ve when using component (YY) (z) cyclosporin and component (7) [including both components Of type (VF) and type [(Y-F), if they exist, the ratio between them is generally 15:1 to 01, and the best is to

© to 1:1 by weight eg 01 to 1:1 by weight. It is appropriate that the ratio be 1 {(¥) cyclosporin [cyclosporin] 1-7) by weight in the case of the presence of component (b) [oil-in-water microemulsions previously off) the formulations as they are known under Oil-in-water microemulsions pre-concentrates (1) Their relative amounts of components vary, including [oil-in-water microemulsions ° to water; (7) phase Aloes for lipids; (©) surfactant according to the concentration of cyclosporine: It will also vary according to the ratios between each other. (Y=1) or (1-1) example as defined under [J] phase of water (1) Ve above. (YY) or (VY) A lipophilic phase [eg as defined under (Y) above]; (Y=7) or (1-F) and a surfactant [eg as defined under oni are such that It is at (((1):(7) cyclosporin) and the proportions between cyclosporine are by weight or more 1:1 with water - for example; as indicated above in proportions consisting of an oil micro-emulsion in Water [7:1120] + (¥) + (1) + cyclosporin (usm slau] vo : example of oil-in-water microemulsion Je] oil-in-water microemulsion as well as formulations according to (b ) can be defined as including cyclosporine, as previously mentioned, with water in ratios - as previously indicated- (V) (Y); (1) with components, cyclosporin, for example, from [oil-in-water microemulsion It allows the formation of an oil-in-water micro-emulsion of the oil/water type

Yo Compositions according to () and (b) preferably include 7 to 0©; preferably from * to based on total cyclosporin to 716 by weight of cyclosporine 01 and more suitable than

AY) + (7) + (1) In addition to the constituents cyclosporin the weight of cyclosporine above - that is, it includes (1-1) of combinations (a) or (b) as defined under (1) and when The components A ~Glycofurol or Glycofurol Transcutol for example on transcutol Yo to Yo and preferably from JAS to 15 preferably in amounts of (YF) oY); (1-1) of 7710 and the best of “to © and the most preferred of” to ete and from * to (1-10) of 65

Ya i to 00 or 7760 from (¥) where all percentages are on Yo and the best is from Ao to Ve and from (7) Glycofurol of interest and use (¥) + (1) + (1-1) on a weight basis and based on a special total. 1,2-propylene glycol Propylene glycol-710 of combinations (a) or (b) is (1) and if

AYO Preferably in quantities of ? to (7) oY) (YY) above], the components (Yo) 0 of 771 are better to be from “ to 778 of (1-?); And from ? to 275 and better than * to to 746 for example from 55 to 74860 from 00 and from ©; to 790 and better than (Y) (7) + (7) + (YY) where all percentages are by weight and based on total oT) - then 1,2-propylene glycol (propylene glycol =e) It is, (1) already indicated; if the component LS (“)” will usually include a surfactant and an auxiliary surfactant. When using 0 auxiliary surfactant, the auxiliary reducer and the auxiliary reducer should preferably be the ratio of Example from Vive? It is more appropriate to have 0:01 and it is better to have 1:80 between them by weight (surfactant: auxiliary surfactant). Vite to (0-1) Attached is a three-lane chart of the relative concentrations of the components 1 and Fig

Cremophore RH40 RH40 (eg); (¥) (Cremophor (Miglyol 812) (Y) for example); (eg) weight. The relative concentration of the component ciclosporin at the lower right corner, as shown by the arrow 7001 left edge of the diagram increases to 79000 at the right edge of the diagram, from zero at the right edge of the diagram to (Y) and the concentration of the component increases NY (1-1); at the peak; as shown 7001 from zero at the baseline of the diagram to (7) 7100 at each edge to ia of 7010 by the arrow *?”. The lines within the graph represent increments of at the peak (1-1) For the combinations as defined under (a) and (b), the ratios between the components vo and the most appropriate would be (1). Within the area (1) delineated by line (C) in the form if oY) within the space B delineated by line B in the figure (¥) oY); (1-1) the ratios between the components 1 º

YY

It has been found that the microemulsions formed based on these ratios have a higher degree of stability. For an example. Thus, 0001 hours and the average particle size is less than YE. Example for periods exceeding and (7) and (©) in the ratios specified above (1-1) then the compositions according to the invention that include the components with reference to a form representing Particularly preferred patterns. And (7) on (1-7) m and Fig. ? attached; represents a three-lane plot of the relative concentrations of components 701 ex. 812 14181701 and (©) in formulations according to (1) and included In this case (?) De ciclosporin (cyclosporin) includes an appropriate mixture of surfactants and co-surfactants, for example, and one part by weight Cremophor 183140 parts by weight of 11 weights e.g. 1:11 in ratio (Y=1) and relative amounts of ingredients. Glycerin monooleate .0 in stock (1-?); 1 (©) respectively. (1) (7); (©) are shown as for the figure from (oY) (YY) for the compositions as they are known under (a); (b) the proportions between the components and the best The proportions between the appropriate LY should be within the area (Y) delimited by the line (M) in the figure in the figure ?, and the most suitable (J) the area (Z) delimited by the line Jada (©) Components (1-7) ); (7); specified by line (1) that the proportions between the components be (1-?); (7); (©) within the space (x) in the form of ve (k); and in microemulsions formed on the basis of The ratios within the two spaces (Z); (X) are respectively 001 Angstroms and less than 10111 the average particle size in them within an hour. Their stability - for example - is greater than YE and compositions according to (c) above may additionally include a thickening agent, although as explained above this is less desirable. Suitable thickening agents include any of those described above under (4). The amount of thickening agent used may vary - For example depending on the degree of cohesion required in the final product - if what is required is a thick form that is able to flow into capsules or the like or a form that is flexible enough to be formed or combined for use, for example in the manufacture of tablets or the like. The amount will of course depend on the nature of the thickening agent chosen.As a proportion to the total weight of Us 7705 the components (4) if present are in a ratio of up to Ade vo or 11 or © to 1.5 to 770 weighs For example, in a proportion of 115 percent of the composition, and it is better if it is in proportion to the weight relative to the total weight of the installation. Z 0 17

Compositions under (C) may also include additives or ingredients eg as described above in connection with Compositions (A). and in particular may include antioxidants - for example, to an amount of up to 1.5 to 71 by weight by weight of the total composition and a sweetener or flavoring; For example, by an amount of up to Yio or 76 weights to the total weight of the installation.

° formulations (c) found to have some properties particularly advantageous for oral administration; For example in terms of consistency and the high degree of bioavailability achieved. In particular; In comparison with other pharmaceutical systems - as is known from technical references; It was found that these combinations are compatible with the surfactant regulating substances such as bile salts present in the gastrointestinal tract. that is, it is completely dispersible in aqueous systems containing mall 0 surfactants; They can therefore provide stable topical microemulsion systems; It does not show sedimentation or any other disturbance in the fine particle system. The performance of these systems upon oral administration remains independent and/or unaffected by the relative presence or absence of bile salts at a given time or for a given individual. Such compositions thus represent a form of special preference.

Compositions according to (C) above, it is preferable to synthesize them in the forms of “amy” doses, i.e., “Jay” covers

vo capsules for oral administration; capsule shells for oral administration; covers of soft or hard gelatin capsules; or by combination into tablets or other formulations; And if the formulations (LGB) are in the form of “unit doses”, then each dose unit is appropriate to contain from © or 01 to Yoo mg of coyclosporin, and the best is between 11 or Yo to 100 mg; that is, for example 00 Yo or 100 mg cyclosporin and accordingly the appropriate dosage unit forms according to the invention

© For administration once, twice, three times to five times daily (depending on the specific purpose of the treatment; referring to the treatment itself; etc.). It is appropriate to contain, for example, 50 mg or 100 mg of cyclosporin per dose unit.

Compositions according to (b) above may be prepared for oral administration; Add the fixtures as is

described in connection with (i) or (c) above to water or any other water system in relative amounts

vo (composition: water) as indicated above” e.g. a sweetener or flavored preparation for use as a drink. Such combinations may include any of the known systems

Yan

b above or as described in connection with Compositions (a) or (c) plus sufficient water to form a fine emulsion. Z. Compositions as defined under (d) above are specifically administered orally, but they also include use in a form suitable for topical use, whether for skin, eye, parenteral or rectal administration. The formulations as defined under (a) to (b) above are also of particular interest for topical use. Thus the present invention also addresses as a new aspect: (d) formulations as defined under any of (1) to (b) above for topical use and if topical use is intended; cyclosporine is appropriate to be in an amount of 0 © And the best is from 1.1 to 716 by weight attributed to the total weight of the composition. It is more preferable to have an amount from 1.1 to 701 by weight. In the case of formulations (D), the proportions between the components are (1). and (7) and () will be as described ole for these assemblies by way of example by reference to Figures (1) and (7). assemblies (d) may appropriately include one or more carriers, reducers and/or components Others vo supply Jie Dela system cadet agents Emulsifying agents Preservatives of gall Moisturizing pigments etc. And formulations (d) may be in any form suitable for topical use i.e. application on the surface of the skin They may be flowable - in liquid or semi-liquid form ie they may be in powder form or in the form of a spray solution for topical use Examples of suitable flowable forms are gels including emulsions or micro-emulsion for oil in water or for water in cy, creams, pastes, paints and the like, lotions and dyes; etc. These formulations also include patches and sprays as well as penetrating patch systems. And the choice of excipients for the preparation of such formulations will be determined, of course, by the type of formulation to be desired, as well as by the disease condition to be treated, the degree of assessment of the condition, the area to be ladle, the condition of the skin, and the desired effect. Thus, chronic psoriatic plaques are best treated with hydrophobic formulations; For example, oil-based formulations; Such as the compositions according to the invention comprising A 1

Yo on a petroleum jelly-based ointment or cream (such as Vaseline) as a carrier medium. On the other hand, “the formulations used in the treatment of pathological conditions involving inflammatory processes in their acute phase are better treated with formulations that are more affinity for water,” for example, formulations according to the invention in the form of an emulsion or gel (gel) of oil in water, although Formulas (d) may include:

Jie as a diluent or component of a diluent, for example; It is preferable to avoid ethanol ethanol jie e ethanol these short alcohols, for example when treating infected skin as in cases of psoriasis. The preferred formulations (d) are thus considered to be free or nearly free of alkanol, i.e. containing less than 75 and preferably less than 100% by weight of the alkanolic constituents; Particularly ethanol 71 for example from zero to oY -ethanol and of (3) particularly preferred formulations; formulations according to (1) or (b) comprising additionally: 0:1) an acceptable (additional) diluent Pharmaceutical or carrier medium immiscible with component (0) and compositions according to what is mentioned above preferably in the form of a water-free or almost water-free emulsion and the best is less than 78 and most 701 is water-free; That is, it contains less than (1-1) and such emulsions include emulsions containing component 71. preferably less than (e), as well as emulsions containing (*) in (171), and it is better to contain on an emulsion of (0e). paraffins 4d all and paraffins ceresin cvaseline® such as Vaseline as well as waxy substances such as animal, vegetable and synthetic waxes such as amber wax, 3-carnauba wax and beeswax; 027855058 liquid paraffins and liquid Jie esters; hydrocarbons Hydrocarbons: Y-o, such as isopropyl myristate, fatty acid esters, tcetyl palmitate, and cetyl palmitate, non-volatile isopropylmyristate containing oils and pastes.

Yan

pp. 1109 and 1110] silicone-polyalkyleneoxide [c.f.

Fiedler, loc., for example, is known and commercially available under the trade name Piroethicon. Components (0) are appropriate to be in formulations (d) in an amount up to 280 z for example from 0 to Ye and better than 15 to 770 by weight relative to the total weight of the 0 formulation. Using the single ingredients (0) or mixtures thereof, emulsions can be obtained in liquid or semi-liquid form depending, for example, on the desired requirements for topical use. And formulations (d) are appropriate It should also contain a surfactant and suitable surfactants that are lipophilic, including any of those mentioned under (11-7-©) 0 to (V-Y-Y) above, especially surfactants in which the equilibrium value between The affinity for water and the affinity for lipids are about V0. Examples of surfactants of particular benefit for formulations (d) are those described under (Y=) =F) and (3-?-"): above, as well as glycerol monostearate. monostearate propyleneglycol monostearate diethyleneglycol monostearate | Te for example who? to +75 and better than 01 ls i by weight attributable to the total formula weight. Compositions (3) may also include one or more binding agents. For example, microcrystalline waxes, vegetable oils, Jie olive oils, corn oils, kernel oils, and vegetable oil derivatives, including hydrogenated vegetable oils and vegetable oils partially combined with glycerides. For example, in quantities from 151 to 7701, the best formulations (d) are also appropriate to include: Antioxidant Jie any of the above-described antioxidants in association with formulations (a); Je ve eg JB from 1.01 to 750.6 by weight relative to the total weight of the formulation; antibacterial; e.g. methyl-benzyl alcohol or propyl-paraben benzalkonium chloride benzoic acid Yan rv

benzoic acid sorbic acid or chlorobutanol “for example” in an amount of 1.05 to ZY by weight attributed to the total weight of the formulation.

Stabilizer such as cmicrocrystalline starch Sodium ethylene tetraamine or Disodium EDTA or magnesium sulfate in an amount of 11 to

20 by weight attributed to the total weight of the formulation; and/or a stimulator of skin penetration. For example JO fatty acid Clogs mono- or poly-unsaturated fatty acid But unsaturated fatty acid or an alcohol (eg vaccenic acid 18©- <cis- vaccenic linoleic 11101616 linolenic celaidic oleic petroselinic erucic acid © 0016 or

oleic acid or any of its corresponding alcohols, especially oleic acid, nervonic acid 0 or “(oleyl alcohol) or oleyl alcohol

-1-dodecylazacycloheptan-7-one 1-dodecylazacycloheptan-2-one also known as Fiedler, loc. cit., 0.190) Azone 6.5); For example, by an amount from 1 to 01 and more: suitability from © to 216 by weight attributed to the total weight of the formulation.

Ve In addition to the foregoing, the present invention Lad provides a method for producing a placebo pharmaceutical composition defined above—that is, as defined under any of (1) to (d)—edelel. Airtight; and if necessary, the installation of what was obtained from it

| Formulation in unit dosage form - eg “Je mentioned formulation in gelatin”. for example

Hard or soft gelatin capsules.

Y. More specifically, the invention also provides a method for preparing a composition as defined under any of (1) to (2) above.” This method includes the controlled mixing of a cyclosporin, such as “cyclosporin 01010800110” for example, with component (1). -1) or (Y=1) as specified above: with component (?) and component (¥) as specified before; ratios between ingredients are chosen from (VY) or Jia (¥) 5 (Y) (YY) That combination as defined under (1) as needed;

Yo the contact of such a formulation (a) with water so that a formulation as defined under (b) may be obtained and if necessary the form obtained may be packaged (a) in unit-dose forms such as hard gelatin capsules or route.

1

Ya

In particular, the present invention provides a method for preparing a composition as defined (for example, ciclosporin). This method includes the controlled mixing of cyclosporine coded under (A), component (V) as defined above, and component (Y=) Or (1-1) with a component (ciclosporin SY) or (1-1) as previously defined with choosing the ratios between the amounts of the components (V) used so that it is possible to obtain cyclosporin or (©) for cyclosporine (Y) 0 'oil-in-water microemulsion pre-concentrate' any formulation capable of forming a system comprising a dispersed or particle phase; the particle size It has less angstroms at 0001 to about 001 angstroms; better than about 7000 of the addition of water. The application of this cyclosporins is one of the cyclosporins "ciclosporin also known as [Nva]*-ciclosporin cyclosporin -[Nva]' is the lle invention .cyclosporin G illustrates the preparation of Yo and the following examples illustrate the formulations according to the present invention. Examples The formulations are in unit dose forms for oral administration and are suitable for use eg to prevent 1 Jie from any immune disease or condition expulsion of transplanted organs or to treat autoimmune diseases 0 to © 0 units per day. Example 1 illustrates the administration of the endogenous sal described above, by preparing formulations for topical use, which are suitable, for example, for the treatment of allergic contact dermatitis or: contact dermatitis, psoriasis, or hair loss, and that is placed on the site to be treated, such as inflammatory reaction psoriasis of the scalp at regular intervals; For example, once, twice or thrice (ala) dermal or © daily. However, it is possible to obtain ciclosporin and examples are described with a special reference to 'cyclosporine': another suitable. In particular, cyclosporin on equivalent formulations with the use of any ciclosporin "[Nva]*-ciclosporin cyclosporine -[Nva]® Equivalent formulations can always be obtained by substituting 'Cyclosporin 1010800710' with the same amounts as shown for " Ciclosporin Jae Ye.”ciclosporin

Yan

Example 1 Preparation of dosage forms for oral administration of the type of “oil-in-water microemulsion pre-concentrate” 1-1 Ingredient Amount (mg/capsule) Cyclosporin (cyclosporin) ou ciclosporin "eg) (1-1) Glycofurol 75 Vo (VY) Miglyol 812 MY 4. (VY) Cremophor 40 YA.

Cremophor RH 40 RH Aggregate & Ou: cyclosporin was dissolved in (1-1) with stirring at room temperature and (VY) 0 and (©-1-0) were added to the solution prepared It is obtained by stirring again.The resulting mixture is filled into a size 1 hard gelatin capsule and closed using the Quali-Seal method.It is also possible to prepare analogue compositions of size 1 ml* or size ¥ of hard gelatin capsules: Y = Ingredient Amount (mg/capsule) cyclosporin (‘0 ciclosporin: ‘eg) (0-1) glycofurol YA.

Glycofurol 75 Vo : 10-1) Miglyol VA Miglyol 812 AYY (V-V-Y) Cremophor 40 ay Cremophor RH 40 RH GW 0.6 2-1 Ingredient Amount (mg/capsule) Cyclosporine cyclosporin (eg cyclosporin or (‘ciclosporin) (0-1) glycofurol Yoo Glycofurol 75 Vo (0-7) Miglyol Te Miglyol 812 AVY (1-1-’) _ Nikkol 010 HCO-40 HCO-40 Ethanol* Ethanol* 5 Ascorbyl Palmitate** Y Ascorbylpalmitate®* Total to. * Co-solvent (hydrophilic phase) ** Antioxidant: Ve Yau

Amount (mg/capsule) ssa -1 or (eg cyclosporin 'ciclosporin' Yoo Glycofurol 75 Yo Glycofurol (V) veo Miglyol 812 AVY Miglyol (7-10)

Yo Lecithin (v- 1 -¥)

Yoo Total : Ingredient Amount (mg/capsule) ey

Ver (for example 'cyclosporin' cyclosporin ('ciclosporin \

Yi. Glycofurol 75 Vo (1-0) ' ©. propyleneglycol Propylene glycol (1-0)

You Myritol 318 ¥YA

Vis Cremophor RH 40 RH 40 (V-)-Y) ° BHA*

AGO Total Antioxidant * Ingredient Amount (mg / capsule) _ 1-1 or (cyclosporin cyclosporin for example) "ciclosporin º TA 1,2-propyleneglycol propylene glycol = Ye ) (Y-Y)

TA Miglyol 812 AVY Miglyol (7-10)

You Cremophor RH 40 RH 40 (V-V-Y)

Yi glycerol monooleate" (0-Y-T):

Glycerol monooleate £7. Total Ingredient Amount (mg/capsule) 1-7 6 (cyclosporin, for example, ciclosporin)

TA 1,2-propyleneglycol Propylene glycol -00 (0-1)

Ye Miglyol 812 AVY

You Cremophor RH 40 RH 40 (V-V-Y)

TA primes”* el alls x (e-Y-v)

Glycerol monooleate £9. Total 5 1

1 Ingredient Amount (mg/capsule) A=

Yoo (eg cyclosporin (‘ciclosporin yo 1,2-propyleneglycol J Sila propylene —Yo) (-1)

Yo Miglyol 812 AVY

Vou Monoprim* Jy ls (e-Y-¥)

Glycerol monooleate” : Cun 2 mg 1 Ingredient Amount (mg/capsule) 1-5 : or (eg ‘cyclosporin’ ‘ciclosporin’;

Yoo 1,2-propyleneglycol Propylene glycol —Ye (Y-Y) 84 Miglyol 812 AVY Miglyol (10-7)

Vou Cremophor RH 40 RH 40 (V-V-Y)

So. Generol 122 E16* E16* 111 Generol (V-Y-Y)

Ou Total Ingredient Amount (mg/capsule) Ye) ©. Mia) cyclosporin (‘ciclosporin ‘cyclosporin’ vo b_ruellin glyc_sol -Ya (Y=) 1,2-propyleneglycol

Veo Miglyol 812 AVY

Yo. Cremophor RH 40 RH 40 (1-1-*)

Ss Generol 122 E25* E25% 111 Generol (V-V-Y)

Ose Total Auxiliary Surfactant. * Particularly preferred. Y=) 5 1-1 (YY AA-1 formulations by component substitution 1-1 to 1-1 and can be used in all Conditions Prepare equivalent formulations for formulations in the same quantity or in an equivalent amount. Transcutol Glycofurol Glycofurol © ov By replacing the amount of omy to 1-1, formulations equivalent to the formulations cyclosporin 0 mg FR can be prepared pa cyclosporin 1 mg of cyclosporine (for example, "Cyclosporin 1010800:8©"), with the quantities of all other ingredients for each formulation remaining the same 1. Shown 5

Example 0 Preparing dosage forms for oral administration: type of “oil-in-water microemulsion pre-concentrate” Thickening: Ny Ingredient Quantity (mg/capsule): Cyclosporin (eg "Cyclosporin or ('ciclosporin (YY) Glycofurol YAS Glycofurol 75 Vo Miglyol 812 AVY J glare (VY) .1 (10-1-') Cremophor 40 YA.

Cremophor RH 40 RH (Y-£) Methocel Yen Methocel K100 K100 Total Tq “Cyclosporin 1610800110” and (1-01) are combined into (1-1-”7) as In example 1, the mixture obtained is mixed homogeneously with (?-1).The resulting bags are in hard gelatin capsules of size 1. The following composition can also be obtained: Y-Y Component | Quantity (mg/capsule) cyclosporin (for example, ciclosporin 0-1) glycofurol YA.

Glycofurol 75 Yo (\-Y) Miglyol 812 AVY 4 (0-1-””) Cremophor 40 YA.

Cremophor RH 40 RH (?-1) Aerosil 200 001 4 (Y-¢£) Yeo Methocel K100 K100: Total. 1.9 "-© _ Ingredient Amount (mg/capsule) cyclosporin (eg cyclosporin Veo ('ciclosporin) (0-1) ARK Glycofurol Miglyol 813 MY Jalsa (VY) 5 We Nikkol HCO-60 HCO-60 Js (1-1-Y) (?-) Closel ve Kiucel EF EF Total Teo SIS compositions can be prepared for 1-1 to Y= ¥ By substituting the glycofurol component 0 with transketol 1780800101 with the same amount or an equivalent amount. yan

find an example Preparation of a form for topical use of the type of “oil-in-water microemulsion pre-concentrate” Ingredient Quantity (mg / capsule) cyclosporin SU) cyclosporin 01 (‘ciclosporin’) (0-1) On Glycofurol (0-7) Miglyol 812 AVY 711 (V-)-Y) Cremophor 40 yyy Cremophor RH 40 RH The above formula is prepared in a similar way For example 1. An equivalent formula for L can be obtained by replacing the glycofurol component with Transcutol and the formula can be made on the basis of a cream or gel or the like by combining with other additives; such as hydrocolloid thickeners; paraffins, etc., as described above. The usefulness of the formulations prepared according to the invention can be demonstrated in animal experiments or clinical trials, for example, as follows: Va study of the bioavailability of the formulations according to the invention & in the dog: (1) Combinations for testing combination 1 as in Example 1-1 combination Y as in Example 1-L combination 1 as in Example 1-9 combination ; as in Example 1-10 combination 0 As in Example 7-7(b) Test Method: Groups of A use beagle dogs (males about 10-10 kg) and the animals are withheld from food for YA 1 hour prior to administration of the formula that induces the test but is allowed to eat freely of water until Yo at the time of giving ef gall Test formulations are given by tube feeding followed by alle Ye from a solution of 70.9 of each Animals are allowed free intake of food and water three hours after administration of the test formulation Blood samples are taken ¼ milliliter (or ¾ milliliter of drug-free control) from the saphenous vein and collected in ¾ milliliter plastic tubes containing EDTA Yau

EDTA at 0 10 min (for drug-free control)” Ve min and 0 1.0 FY for YE (VY hr) after administration. Blood samples are kept at dyCY A= until calibration. A: Blood samples are analyzed by radioimmunoassay. The areas under the drug concentration curves in blood are calculated against time using the trapezoidal rule. A differential analysis is performed for the area m under the curve, the maximum concentration and the timing of the peak. (C) Results The following table shows the average values of the areas under the curve ( In nanograms h/mL') and the maximum concentration (ng/mL') from typical experiments. Also shown is the calculated response variation between tested animals that received the same formulation. (0-YE h) z Ct 1|WS 0 It is clear from the above table that the formulations according to the invention are characterized by high bioavailability (AUC and maximum concentration) coupled with a relatively low variability in a single response, both for the area inducting the curve and the maximum concentration. Excellent results can also be obtained by using the other formulations according to the examples. 700 above and in particular the formulations of example 1.ve. The excellent properties of the formulations of the invention for oral administration in clinical trials may also be demonstrated” eg; As follows: the subjects of the experiment are adult volunteers; For example, Liga educated males from *0 to 00 years old. It is appropriate that the experimental groups include 11 individuals. The following inclusion and exclusion criteria apply: 7 Inclusion: electrocardiogram (anh) blood pressure and heart rate within normal limits. body weight = 16-850 kg. exclusion: clinically significant medical conditions that may affect drug absorption, distribution, or its metabolism, excretion, or safety, as well as symptoms of any clinically significant disease in M | Ya1

l During the two-week period preceding the experiment, abnormal laboratory or electrocardiogram results of clinical significance and need; To use other drugs throughout the research period and to give any drug that is known to have a toxic effect on important parts of the body during the months: the three preceding the study; administering any elective aT drug during abd 1 prior to entry into the trial; a previous history of alcohol or drug addiction; loss of 0,000 milliliters of blood or more during the previous 3 months; hypersensitivity or adverse drug reactions; Previously had an allergy requiring Ladle 0 medication; Positive for hepatitis C virus [3] or HIV. A comprehensive medical examination and an electrocardiogram are conducted before and after the experiment. The following variables were evaluated at one-month intervals before and after the experiment. 0 blood: RBC count; hemoglobin; hematocrit; erythrocyte sedimentation; white blood cell count » smear for blood elements; pallet plate counting and fasting glucose measurement; Serum/Plasma - (Alea) Protein, Protein Electrophoresis, Cholesterol, Triglycerides, Sodium 118, Potassium K1, Iron Fe™, Calcium Ca™, Chloride 1©, Creatinine, Urea, Uric Acid, Enzyme ve Glutamic transaminase, glutamic transaminase, alkaline phosphate, total bilirubin, and alpha-amylase 0-80071886. urine: pH; microalbumin cmicroalbumin glucose cglucose red blood cells ketone bodies precipitate ketone bodies Creatinine clearance was also determined within a month prior to enrollment in the study. Each of the individuals receives experimental combinations in a random sequence. The formulations are given orally; once to a total dose of 1510 mg of cyclosporin eg ciclosporin and allow at least 16 days between each administration and the next. It is administered in the morning after fasting during the previous night for 10 hours, during which only water is allowed. Only decaffeinated beverages are allowed during the YE hour prior to administration. vo subjects are not allowed to smoke within the VY hour period after administration. Individuals receive a standard meal four hours after administration. Yan

£1 Blood samples (? milliliters) are taken one hour before administration and then after administration at 76 + 1 shelf – 1.0 qt read of 4 4 FY 18 74 VE VY hours. To determine creatinine, ¥ milliliters of blood were sampled immediately before administration, at YE VY, and 48 hours after administration. Samples for cyclosporin measurement are collected in two polystyrene tubes lined with ethylene 0 diamine tetraacetate (1 milliliter in JS) at each time point and deep frozen at - 0 after gently agitating. Cyclosporine is titrated cyclosporin in whole blood using radioimmunoassay with qualitative and/or non-specific MAB titration - detection was found in both cases - about 01 ng/mL. As 0 hard gelatin capsules) with formulation .01 formulation 01 [technical comparative formulation] unit dose form (soft gelatin capsule) comprising: Ciclosporin 6 mg Labrafil YOu Labrafil 1 mg Ethanol Ethanol 5 mg Maize oil 0 mg Total 7 mg/dose (= known oral Sandemmon syrup solution) In an experiment conducted in this way a bioavailability of 71449 (£) EA was recorded for Composition 1 A 1 compared to formulation 01 (for which bioavailability was considered to be 7000). and AUC values (0-7” hour; ng. h/mL) and peak concentration values (ng/mL) determined for Formula 1 are 7947 (+177) 5 (VA + (AAY) respectively compared to 717 (YAY ( Vo (Te)) for formulation 01. The attached Figures ET show the results, graphed and matched, from one such trial on the whole blood concentration of “Cyclosporine 01010800110” as recorded for VY subjects after a single oral dose of the formulation. 1 (fig. Time (in hours) horizontally. Yan

And . Comparison of the two figures (“) (£) clearly shows the significant decrease in the response variance between individuals with respect to bioavailability measures recorded when formula 1 was given in comparison with combination .01 and the specific coefficient of variation [[(standard deviation/mean) [V+eX] Gail for peak concentration is 0 for combination 10; compared to a value of just 7700 for combination 1.

° Similar or equivalent results have been obtained after oral administration of other formulations consistent with the invention; For example; As described above in the examples and in particular the example combinations 1. Examination of local forms in the uterine body

Allergic contact dermatitis test in guinea pigs. Hypersensitivity is created in guinea pigs (Hartley; males; 005;-00© mg) using 0 1 μL of 74.0 DNFB in acetone/olive oil and applied to the visible parts of the left and right flanks after shaving and exposure. This treatment (excitation treatment) for a second time leads to allergic inflammation causing redness and dermatosis (thickening) of the skin. Using a spoon, spread the mixture under test (for example according to example 9 above) in an amount of 701-750 mg on the parts treated with DNFB on the right flank. The left flank is treated with a placebo (placebo) 1 as well, to be used as a control. The tested formula/placebo© is applied twice at 71-minute intervals; A hours; YE hour; TY hour; fA an hour after the arousal treatment. The skin thickness is measured at the treatment site before each painting process and also hours after the last of these operations, by bending the skin and measuring the thickness of the fold. The degree of redness or inflammation is also estimated by looking at the scale from 0 to 4. The effectiveness of the product under test pied is determined by the occurrence of the inflammatory response by comparing the results recorded with those recorded for the loin treated with placebo. By applying the test described above, a significant decrease in skin thickness was achieved compared to placebo in the case of prior use of the tested formulation; For example, according to an example? This phenomenon continued throughout the treatment until the completion of the experiment. The following results are recorded for the example combination ?. 7 in reducing the increase in skin thickness compared with | 89 vo VU TA] to placebo as a control 7

Claims (1)

Protective_Agents cyclosporin on cyclosporine Jai Jy pharmacutical composition Pharmacist Bickert-1 1 as active ingredient “Y < hydrophilic hydrophilic phase (9 1) and “lipophilic [lipophilic phase]” $ “surfactant A surfactant reducer (V °) and the composition is an oil-in-water microemulsion pre-concentrate v hydrophilic a “oil-in-water microemulsion pre-concentrate v hydrophilic” Cus 1 according to the protection element “- Composition 1 !on: (V) Y mono- from pharmaceutically acceptable tetrahydrofurfuryl di or partial-ether or © alkyl ( 0-1 and 11 carbon atom includes from ? to or poly-oxy-alkanediol where: 1 according to the claim composition “‘-composition 1 tetrahydrofurfuryl alcohol df diethylene glycol monoethyl ether )1-1 Y .polyethylene glycol ether 3 hydrophilic hydrophilic phase comprises Cus 1 According to claim composition ;-00 on: (1) Y .1,2-propylene glycol (¥—?r : 1 *-composition according to which protection element? to; where the Y-phase of hydrophilic water (1) includes Cys alkanol as an additional hydrophilic phase component v. 1 “-composition according to the claim element © where the alkanol is .ethanol Y 1 7- Composition according to claim element © or 1 where the hydrophilic phase of water (1) comprises less than 0 75 of the weight of the aforementioned alkanol. 01 +- Wh composition of any protectant Y to where the hydrophilic phase is Wa (1) hydrophilic Y from Cys alkanol Ya. 01 4- Composition according to any claim 1 to 1, where the precursor phase of the lipid (1) lipophilic Y contains fatty acid triglyceride -01 1 composition according to the claim 4, where the mentioned fatty acid triglyceride is .caprylic-capric acid triglyceride Y -11 1 Composition according to any protection element 1 to 01 where the surfactant (Y) surfactant Y includes polyoxyethylene glycolated natural vegetable oil or hydrogenated. 1-1 lids composition of any protective element; to 01 where the (Y) surfactant Y comprises a surfactant and an auxiliary surfactant .co-surfactant 3 ° -1 “ 00 ih composition of protection element VY where the surfactant Y (0) includes polyoxyethylene glycolated natural or hydrogenated vegetable oil v as a reducer Monoglyceride surfactant as an auxiliary surfactant .co-surfactant ¢ —VE composition according to any Claim 1 to VY comprising from 1.1 to Ive by weight cyclosporin based on the total weight of the composition . -1#1 composition according to any claim 1 to VE for oral administration. -11 1 composition according to claim Vo comprising from © to 771 of weight Y: cyclosporin -117 1 composition according to claim 11 comprising © to 716 by weight Y cyclosporin -08 0 composition according to any claim 11 to 117 where the alpha phase of the lipophilic (Y) Y is present in an amount of ? to 7485 by weight based on the total weight of the installation. -V 1 composition according to Claim 18 where the quantity is from 01 to .7718 -01 1 composition according to any Claim 15 to Cua 19 There is a reducer Surface tension surfactant Y (©) in an amount from 01 to 7980 by weight based on the total weight of the composition. -71 1 Composition according to any claim 15 to Yo where the hydrophilic phase (1) includes the component (VY) as specified in the claim? or 7. yan on in an amount of (1-1) where the component is oF of the protective element Wh composition of the composition 77 - 10 by weight based on the total weight of the composition. TAS to 75860 of 71 Where the quantity is from YY according to claim composition 779-01 weight. Y to 77 where the thousands phase of the fat is 71 according to any claim composition 4?7-composition 1 part of weight. 01 to 178:1 in a ratio of (VY) and (Y) lipophilic component Y 0 to every part where the ratio is of YE according to the claim † —Yo 1 of weight. Y where the surfactant is located YO to YY of any protective lids composition - 1 71 to 780 of weight based on total weight of the composition. Ye in quantity of (YY) surfactant Y Joo according to claim 77 where the quantity is from © to composition YY 1 where the thousandth phase comprises water 01 to 115 according to any claim composition - “8* 1 .1,2-propylene glycol (1-1) on (1) hydrophilic Y ¥ in an amount of (YY) in which component YA is present according to claim composition 4?- Composition 1 to 746 by weight based on the total weight of the installation. 7 77.8 The quantity shall be from * to Cua YA according to the claim composition TY = F 1 where cyclosporine Vo to YA according to any claim composition TY is part of the weight 01 to 11:1 ratio of (YY) and component cyclosporin Y to the ?*ony fraction, wherein the ratio is VY according to the claim ‒ YY composition 1 by weight Y where the alpha phase of the lipid is YY to YA according to any protection composition FY composition 1 to > part by weight very in the ratio (1-1) and component (1) ( lipophilic Y to ? fraction 11:5 where the ratio is YY according to the claim ‒ VE composition 1 by weight. Y There is a surface tension reducer Cus YE to YA for any Protective element Wh composition —Ye 1 composition in an amount from 50 to 7975 by weight based on the total weight of the composition. (YY) surfactant Y 117 01 “2©#- Composition according to any protectant YA to Yo in which cyclosporin 1 and surfactant (Y) are present in a ratio of 7:1 to A part of the weight. -717 01 Composition according to any protection element YA to Yo where the Y surfactant (7) includes a surfactant and a co-surfactant 1 As stated in claim 11 or 11 and wherein the said surfactant ¢ and co-surfactant are present in a ratio of * to 0 9 parts by weight. : or ¥, where the relative amount of components 1 according to the claim ↓ TA composition (1). -1) Y—T4 0 composition according to the claim (FA) where the relative amount falls within region (B) .(1) delimited by line (d) of Figure Y 1 > 46- Composition according to the claim of where the relative amounts of the components Jala (F)i(Y):(Y-Y) 0 The area (r) marked by line (m) of the attached figure (7). From Figure (Y) 49- Composition according to claim 8) where the relative amount is located within the region: (Y) (X) defined by line (K) of Figure Y for enteral administration and in the form of £Y to 1 according to any claim of composition 9;- 1 composition Y unit dose. 1 ¢£— A composition according to claim 47 in the form of a soft or hard gelatin capsule. 01 ©*;- Composition according to the protection element ?; or ;; Contains from * to Yoo mg of cyclosporine [oyclosporin] as a unit dose. 1 46- The Wiha composition of claimant £0 comprises from 101 to 100 mg Y cyclosporin [eyclosporin] unit dose. 0 7;- Composition according to claim £1 comprising from Ye to 001 mg Y cyclosporin [oyclosporin] unit dose. A Yan : ox cyclosporin comprising cyclosporine Pharmaceutical composition 8; Emulsion surfactant surfactant (YY) phase v oil-in-water flour. (¥) and/r (1) (7) where the ingredients are £A according to the claimant. -49 AY AS SPECIFIED IN ANY CLAIMING COMPOSITION? TO 0 INCLUDING 06 TO £35 EA OF TO 1 ACCORDING TO ANY CAUTION COMPOSITION COMPOSITION - #01 0 BASED ON THE TOTAL WEIGHT OF THE COMPONENT IN FORM cyclosporin of 00#21 weight cyclosporin is suitable or suitable for topical application. Cyclosporine 7 is in a flowable form; in the form of ©1 or on the protective component lk composition -#7 1 or in the form of a topically applicable spray as a powder; in a topically applicable spray form ‎ Y .transdermal patch or patch for transdermal delivery poultice 434 « cataplasm adhesive ¥ in gel form; ointment; paste; Ointment OF protective ingredient Wh composition —oY 0 composition or tincture. Where cyclosporine is oF to 1 according to any protective ingredient composition -#©4 1 º .Ciclosporin is cyclosporin Y , where cyclosporine is OF to 1 according to any protective element composition -#* 0 . [Nva]*-Cyclosporin is cyclosporin Y Yan