HU212727B - Process for producing pharmaceutical compositions in form of microemulsion-prae-concentrate or microemulsion containing cyclosporin(s) as active component - Google Patents

Abstract

The present invention relates to a process for the preparation of a pharmaceutical composition in the form of a microemulsion pre-concentrate containing from 0.1 to 35% by weight of cyclosporin and 1 to 90% by weight of a 1-12 carbon mono- or polyoxyalkanediol as a hydrophilic component. C 5 -C 5 alkyl) or di (tetrahydrofurfuryl) ether or partial ether and / or 1,2-propylene glycol and optionally C 1-5 alkanol; 2) from 0.5 to 90% by weight of a lipophilic component and 3) from 1 to 90% by weight of a wetting agent and optionally a co-wetting agent, wherein the total amount of the components is 100% by weight. Microemulsion can be prepared from the pre-concentrates by the addition of water. The pharmaceutical compositions of the present invention are useful in the treatment of autoimmune and inflammatory diseases and pathological conditions. EN 212 727 B Description scope: 26 pages (including 5 sheets)

Description

1) as a hydrophilic component, 1 to 90% by weight of a pharmaceutically acceptable di (C 1 -C 5) alkyl or di (tetrahydrofurfuryl) ether or partial ether of a C 1 -C 12 mono- or polyoxyalkanediol and / or 1,2-propylene glycol and optionally C 1 -C 5 alkanol;

2) 0.5-90% by weight of a lipophilic component and

3) It contains from 1 to 90% by weight of a wetting agent and optionally a co-wetting agent, wherein the total amount of the components is 100% by weight. Microemulsion can be prepared from the preconcentrates by addition of water.

The pharmaceutical compositions of the present invention are useful in the treatment of autoimmune diseases and inflammatory diseases and conditions.

Description: 26 pages (including 5 pages)

HU 212 727 B

HU 212 727 Β

FIELD OF THE INVENTION The present invention relates to the preparation of pharmaceutical formulations containing cyclosporin (s), more particularly galenic compositions.

Cyclosporins are specific cyclic, multi-N-methylated undecapeptides which generally exhibit pharmacological, in particular immunosuppressive, anti-inflammatory and / or anti-parasitic effects. The first isolated ciclosporin, also a parent compound of this group, is a natural substance, metabolite of cyclosporin A, which is currently commercially known as Sandimmun ^R and Sandimmune ^R , respectively. In the formula (A), -MeBmt- represents the N-methyl- (4R) -4-but2E-en-1-yl-4-methyl- (L) -threonyl group represented by the formula (B), wherein -xy- is trans. a spaced -CH = CH- group.

So far, the parent compound of the compound group, cyclosporin A, has attracted the most interest. In clinical trials, ciclosporin as an immunosuppressive agent, in particular organ transplants such as lung, heart, combined lung-heart, liver, kidney, pancreas, bone marrow, skin and corneal transplantation, in particular allogeneic ) organs transplantation. Cyclosporin A has achieved remarkable success in this area.

At the same time, the potential for the use of cyclosporin A in various autoimmune diseases and inflammatory conditions, in particular in inflammatory diseases of autoimmune origin, has been extensively studied; such diseases include arthritis (such as rheumatoid arthritis, chronic, worsening and distorted arthritis), and rheumatic diseases. Many in vitro results have been achieved in these areas. as in animal models, and even in clinical trials. These results are reported in detail in the literature. Ciclosporin A treatment has been specifically recommended for the following autoimmune diseases: autoimmune haematological disorders (such as haemolytic anemia, aplastic anemia, anemia associated with red blood cells only, and idiopathic thrombocytopenia); systemic Lupus erythematodes, multiple cartilage. scleroderma, Wegener's granulomatosis, myocarditis, chronic, active liver inflammation, severe muscle weakness, psoriasis, Steven-Johnson syndrome, idiopathic fatty tissue, autoimmune, inflammatory bowel disease (such as ulcerative colitis); internal weaning ophthalmology, Graves disease, multiple sclerosis, sarcoidosis, primary biliary obstructive liver cirrhosis, primary juvenile diabetes mellitus, anterior and posterior uveitis, pulmonary conjunctivitis, pleurisy and renal glomerular inflammation (with or without nephrotic syndrome, such as idiopathic nephrotic syndrome and minor renal disorders).

Research has also focused on the potential of cyclosporin A for the treatment of parasitic infections, particularly protozoan infections such as malaria, coccidiomycosis and helminth; more recently, their use as an antitumor agent has been attempted to eliminate or reduce tumor resistance.

Since the discovery of cyclosporin A, many naturally occurring cyclosporins have been isolated and identified, and a large number of additional non-natural cyclosporins have been produced by total or semi-synthesis or by modified cultivation methods. As a consequence, the group of cyclosporins, for example, includes naturally occurring AZ products [Helv. Chim. Acta 60, 1247 (1977); 65: 1655 (1982); Europ. J. Appl. Microbiology and Biotechnology 14, 273 (1982); and Progress in Allergy 38, 28 (1986)], as well as various non-naturally occurring cyclosporin derivatives, as well as synthetic cyclosporins, such as dihydrocyclosporins (wherein the -xy group in formula (B) above is saturated, i.e., -CH ₂ -). -CH ₂ group]; derivatized cyclosporins (in which, for example, an additional substituent is attached to the carbon atom of the 3-position sarcose of the cyclosporin molecule); and cyclosporins in which the -MeBmt group is in isomeric form (e.g., where the configuration at the 6 'and 7' positions is cis rather than trans); and cyclosporins which have other amino acids at certain positions within the peptide sequence. The latter products were prepared, for example, by a synthetic method developed by R. Wenger for the preparation of cyclosporins [see the above cited citations and U.S. Patent Nos. 4,108,985, 4,210,581 and 4,220,641, and 0,034,567 and 0,056. European Publication No. 782; PCT Publication No. 86/02080; and Transp. Proc. 15, Suppl. 1: 2230 (1983); Angew. Chem. Int. Ed. 24, 77 (1985); Progress in Chemistry of Organic Natural Products 50, 123 (1986)].

It can be seen that the compound group of cyclosporins is indeed very large and includes, for example, [Thr] ² -, [Val] ² -, [Nva] ² - and [NVA] ² - [Nva] ⁵ -ciclosporin A (these are cyclosporin C, Also known as D, G, or M); and [3-O-Acyl-MeBmt] '- Ciclosporin A (also known as Ciclosporin A acetate); a [dihydro-MeBmt] '- [Val] ² -ciclosporin A (dihydrocyclosporin D); [(D) -fluoro-methyl-Sar] ³ cyclosporin A, [(D) Ser] ^{8-Ciclosporin} A, [Melle] cyclosporin A, [(D) MeVal] ¹ 'cyclosporin A (cyclosporin H); [MeAla] ^6- cyclosporin At [(D) Pro] ^3- cyclosporin At and so on.

[The nomenclature currently used to name cyclosporins in this patent refers to cyclosporin A. Based on this, we first provide amino acid residues that are different from the amino acid residues present in cyclosporin A (e.g., "[(D) Pro] ³ " means that in the given cyclosporin molecule, instead of -Sar at position 3), (D) There is a pro group), s

EN 212 727 Β hereinafter referred to as "cyclosporin A" means portions of the molecule which are identical to the corresponding portions of cyclosporin A molecule. Each group is numbered starting with the -MeBmt or -dihydroMeBmt group at position 1.]

Many of the cyclosporins listed above exhibit similar or more specific therapeutic potentials than the original cyclosporin A: some products, for example, are particularly effective in reversing tumor resistance for cytostatic therapy and have been suggested in the literature for their therapeutic use.

Despite significant advances in cyclosporin A therapy, particularly in the field of organ transplantation and autoimmune disease therapies, difficulties have arisen in developing more effective and expedient dosage forms and in advancing unwanted side effects, particularly kidney damage, which have been a serious obstacle to cyclosporin. expanding its therapeutic potential. Cyclosporins are typically very hydrophobic in nature. Liquid dosage forms used hitherto, for example for oral administration, have utilized mainly ethanol or oils or the like. For example, in commercially available drink, ethanol and olive oil are used as vehicle, and labrafil is used as surfactant (see, for example, U.S. Patent No. 4,388,307). However, the use of such drinkers and similar preparations presents various difficulties.

The use of oils or oil-based carriers may render the compositions unpalatable and, particularly during prolonged use, diminish the palatability of the composition. These effects can be eliminated by using a gelatin capsule. However, in order to keep cyclosporin in solution, the ethanol content must be high. When ethanol evaporates from the capsule or other dosage forms, for example upon opening, cyclosporine precipitates. When these compositions are encapsulated, for example, in soft gelatin, the difficulty is that the encapsulated product must be enclosed in an airtight container such as an airtight foil, such as an airtight aluminum blister. As a result, the product takes up more space and becomes more expensive. The storage conditions of the formulations are also far from ideal.

Current oral ciclosporin formulations have a low bioavailability and vary from patient to patient, according to disease, at different times of therapy for the same individual. According to the literature, the average absolute bioavailability of the currently available commercially available cyclosporine broth is only about 30% and varies significantly between patient groups, for example, when used in liver transplantation (when bioavailability is relatively low). and bone marrow transplants (when bioavailability is relatively high). The variability in bioavailability in different patients ranges from 1% or a few% in some patients to 90% or more in other patients. In addition, as noted above, a pronounced change in bioavailability is frequently observed in individuals over the course of treatment.

In order to achieve an immunosuppressive therapy, the concentration of ciclosporin in the blood or plasma should be kept within a certain range. The desired range may vary depending on the condition to be treated: for example, the purpose of the treatment is to prevent organ rejection or to combat an autoimmune disease; and whether other immunosuppressive therapies are used concomitantly with ciclosporin. Bioavailability achieved with current dosage forms! Due to significant fluctuations in values, the daily doses required to achieve the desired plasma concentrations vary significantly from patient to patient and even from single patient to individual. As a result, blood and plasma concentrations should be monitored at regular intervals in patients treated with ciclosporin. Blood and plasma concentrations are usually measured regularly by radioimmunoassay or an equivalent immunoassay, such as a monoclonal antibody, which is inevitably time consuming, inconvenient, and greatly increases the overall cost of treatment.

In addition to the obvious practical difficulties mentioned above, the currently available oral dosage forms may cause undesirable side effects.

Many suggestions have been made in the literature for solving both solid and liquid oral dosage forms. However, there has been a constant problem with the low solubility of cyclosporins, such as cyclosporin A, which is poorly soluble in aqueous media. It is necessary to develop a dosage form containing ciclosporin in a sufficiently high concentration for the intended application, while also meeting the criteria of bioavailability, i.e. effective absorption from the stomach or intestine, resulting in a constant and sufficiently high blood or plasma concentration. concentrations.

The particular difficulties associated with the oral administration of ciclosporin have inevitably led to the use of ciclosporin only for the treatment of relatively mild or serious conditions. In this regard, the introduction of cyclosporin therapy for autoimmune diseases and other skin-related diseases such as atopic dermatitis and psoriasis, and, as it has been widely suggested, to stimulate hair growth such as aging or disease, was particularly difficult. to treat baldness.

As a result of the above - though it was done orally

Treatment with ciclosporin resulted in a significant improvement in the condition of, for example, patients with psoriasis - the risk of side effects following oral treatment prevented its general use. Various proposals have been made for the topical use of cyclosporins, such as cyclosporin A, and several formulations suitable for the topical release of the active ingredient have been described. However, attempts at topical application have not yet led to demonstrably effective therapeutic results. A topical formulation for effective transdermal delivery, such as for the treatment of psoriasis, would allow cyclosporine treatment for a significant patient population.

The present invention makes it possible to prepare novel galenical formulations containing cyclosporin in the form of a microemulsion preconcentrate using specific solvent media, as defined below, which eliminate or substantially reduce the difficulties encountered so far with cyclosporins, such as cyclosporin A. In particular, it has been found that the process of the present invention provides solid, semi-solid, and liquid formulations containing ciclosporin in sufficiently high concentrations, for example for proper oral administration, while also improving the efficacy of the formulation, for example in terms of bioavailability.

More specifically, it has been found that the compositions of the present invention allow effective administration of cyclosporin, while simultaneously increasing absorption and bioavailability, and reducing absorption and bioavailability fluctuations, both in the type of cyclosporin-treated disease and in individual patients. Using the principles of the present invention, ciclosporin dosage forms can be prepared that will allow patients to reduce fluctuations in ciclosporin levels in their blood or plasma. and between different patient groups. As a result, the present invention makes it possible to reduce cyclosporin doses while achieving the desired therapeutic effect. In addition, the compositions of the present invention (hereinafter briefly, the compositions of the present invention) allow for a more accurate standardization and optimization of the daily dosage requirements of cyclosporin-treated individuals in groups of patients receiving equivalent therapy.

By tightening the standardization of individual dosing volumes and by stabilizing blood and plasma levels, and by more evenly matching dosing and evoked biological response parameters across different patient populations, the need for control, and thus treatment costs, can be significantly reduced.

By reducing the required doses of ciclosporin and by standardizing the bioavailability characteristics, the invention provides an opportunity to reduce the incidence of unwanted side effects, especially to avoid renal toxic reactions in patients treated with ciclosporin.

The invention furthermore provides non-alkanol based formulations which may be completely or substantially free of, for example, ethanol. Such formulations do not present stability and processing difficulties, which always occur with known alkanol formulations. Thus, the invention makes it possible, inter alia, to provide compositions which, for example, are more suitable for making hard or soft gelatine capsule formulations and which do not at all, or substantially do not cause any difficulty in packaging (as mentioned above for soft gelatine capsules).

For topical use, the present invention provides novel galenic formulations containing cyclosporin, such as cyclosporin A, as active ingredients, which are useful in treating autoimmune diseases of the skin, in particular skin disorders associated with the proliferation and / or cornea of the epidermis, particularly psoriasis and atopic dermatitis. . The topical compositions of the present invention may also be used to treat baldness, for example, to promote hair growth.

The process of the invention makes it possible to prepare pharmaceutical compositions containing the active ingredient cyclosporin in the form of a "microemulsion pre-concentrate".

As used herein, "microemulsion pre-concentrate" means a system which, when added to water, forms a microemulsion, for example by the addition of water. Microemulsion is generally understood to mean a non-opaque or substantially opaque colloidal dispersion consisting of water and organic components, including hydrophobic (lipophilic) organic components. The microemulsion property can be determined by one or more of the properties listed below. Microemulsions are formed voluntarily or substantially voluntarily when they are brought into contact, i.e. without contact with any significant energy transfer, for example without heating or a powerful agitator or other type of vigorous movement. Microemulsions are thermodynamically stable, single phase. They are essentially non-opaque, i.e., transparent or opalescent when viewed with an optical microscope. They are optically isotropes in the undisturbed state, although their anisotropic structure can be observed, for example, by X-ray examination.

Microemulsions contain a dispersed phase consisting of discrete particles (droplets) having a particle size of less than 2000 Å; as a result, they are optically transparent. The particles of the microemulsion may be spherical, although other structures may be realized, for example in the form of liquid crystals having a sheet, hexagonal or isotropic symmetry. The droplets or particles of microemulsions have a maximum size (e.g., diameter) of less than 1500 A, generally between 100 and 1000 Å.

[See, for example, Rosof, Progress in Surface and Membrane Science 12, p. 405, for a more detailed discussion of the characteristics of microemulsions. pages, Academic Press (1975); Friberg, Dispersion Science and Technology 6, 317 (1985); and Müller et al., Pharm. Ind. 50, 370 (1988).]

It will be understood from the foregoing that the "microemulsion preconcentrates" produced by the process of the present invention are galenic systems which contain a cyclosporin as an active ingredient and are capable of forming microemulsion voluntarily or substantially voluntarily in contact with water.

Accordingly, the present invention provides a process for preparing a pharmaceutical composition in the form of a microemulsion pre-concentrate. According to the invention, 0.1 to 35% by weight of cyclosporin is used

1) as a hydrophilic component, 5 to 70% by weight of a pharmaceutically acceptable di (C 1 -C 5) alkyl or di (tetrahydrofurfuryl) ether or partial ether of a C 1 -C 12 mono- or polyoxyalkanediol; -propylene glycol and optionally a C 1 -C 5 alkanol;

2) up to 2-45% by weight of a lipophilic component and

3) 20-90% by weight of a wetting agent and optionally a co-wetting agent and, if desired, other additives and excipients

wherein the total amount of the components is 100% by weight, and if desired, the resulting composition is formulated in a unit dose, preferably filled into soft or hard gelatin capsules.

Preferably, the hydrophilic component is 1,2-propylene glycol.

C 1-5 alkanol may also be used as an auxiliary component of the hydrophilic component.

Preferably, C 1-5 alkanol is ethanol, fatty acid triglyceride is used as the lipophilic component, and polyoxyethylene glycolated natural or hydrogenated vegetable oil is used as wetting agent. In addition to the wetting agent, a co-wetting agent may be used.

Polyoxyethylene glycolated natural or hydrogenated vegetable oil is a wetting agent and a monoglyceride is used as a co-wetting agent.

In a preferred embodiment of the process of the invention 3-45% by weight of 1,2-propylene glycol, 5-20% by weight of cyclosporine and 2-45% by weight of lipophilic component are used.

Pharmaceutical preparations containing the active ingredient cyclosporin in the form of a microemulsion and a "microemulsion pre-concentrate" are novel. The invention enables:

A) Preparation of a "microemulsion pre-concentrate" containing a cyclosporin as an active ingredient.

(A "pharmaceutical composition" as used herein refers to compositions whose components or active ingredients are pharmaceutically acceptable per se, for example, for oral administration when the composition is intended for oral administration, or for topical administration when the composition is intended for topical administration.)

In addition to the active ingredient ciclosporin, the "microemulsion pre-concentrate" formulations of the invention are as described above.

1) a hydrophilic phase;

2) a lipophilic phase; and

3) they contain a surfactant component (wetting agent) and, optionally, auxiliaries customary in the preparation of pharmaceuticals.

Cyclosporin is introduced with the lipophilic component. Preferably, both the hydrophilic and lipophilic components are present as carriers.

The "microemulsion pre-concentrates" of the present invention are oil / water (o / v) microemulsions.

However, it will be appreciated that the compositions of the present invention may contain minimal amounts of water and exhibit fine structure characteristic of o / v or v / o (water / oil) microemulsions. Accordingly, the term "microemulsion pre-concentrate" refers to each of the possible cases. Depending on the amount of water relative to the pre-concentrate, a microemulsion of the o / or v / o type is obtained.

The microemulsions obtained by contacting the "microemulsion pre-concentrate" compositions of the present invention with water or other aqueous media have thermodynamic stability, i.e., they remain stable at ambient temperatures, for example, do not turbid and do not form droplets or precipitates of regular size in the form of regular emulsions. [Obviously, a sufficient amount of water is required to produce a microemulsion. The upper limit of dilution is not critical, for example systems containing a "microemulsion pre-concentrate" in water in a ratio of 1: 1 by weight, for example 1: 5 or more are generally suitable.] In contact with water, the "microemulsion pre-concentrate" compositions of the invention which remain stable at ambient temperatures, as evidenced, for example, by the fact that turbidity or precipitation is not visually observed for at least 2 hours, more preferably at least 4 hours, most preferably at least 12-24 hours. For example, microemulsions obtained from "microemulsion preconcentrates" of the invention, for example by dilution, have an average particle size of about 1,500 µm, preferably less than about 1,000 or 1,100 µm, e.g.

Particularly preferred are compositions according to A) having a hydrophilic component

1.1. a di (C 1 -C 5 alkyl) or di (tetrahydrofurfuryl) ether or partial ether of a low molecular weight mono- or polyoxyalkanediol which is pharmaceutically acceptable; obsession

1.2. 1,2-propylene glycol.

Suitable for 1.1. components are, for example, dieters or partial esters of mono- or polyoxy-, especially mono- or dioxy-alkanediols having from 2 to 12 carbon atoms, in particular

Ethers, in particular partial ethers. The mono- or polyoxyalkanediol moiety is preferably straight-chain. Particularly preferred according to the invention is the use of di or partial ethers of formula I wherein

R 1 is C 1 -C 5 alkyl or tetrahydrofurfuryl;

R ₂ is hydrogen, C 1-5 alkyl, or tetrahydrofurfuryl; and x is an integer from 1 to 6, especially from 1 to 4, most preferably about 2. Particularly preferred compounds of the present invention are those compounds of formula I wherein R ₂ is hydrogen.

In the ethers as defined above, the C 1-5 alkyl groups may be straight or branched; such as methyl, ethyl, η-propyl, isopropyl, η-butyl and tert-butyl.

These ethers are known compounds and are commercially available or can be prepared similarly to known products. Particularly preferred are the known products available under the tradenames Transcutol and Glycofurol.

Transcutol is the dietilglikolmonoetil ether of formula (I) wherein R is ethyl, _R2 is hydrogen, and x is the second

Glucofural is also known as tetrahydrofurfuryl alcohol polyethylene glycol ether or α- (tetrahydrofuranyl) yl-hydroxy polyphoxy-1,2-ethanediyl), wherein R 1 is 2-tetrahydrofurfuryl, R _{2 is} hydrogen. , and the mean of x is 1-2. It has an average molecular weight of 190, boiling at 80-100 ° C / 40 Pa, a density at 20 ° C of about 1.070-1.090 g / ml, a hydroxy value of about 300-400, n _b of about 1.4545, and a viscosity at 20 ° C. about 8-18 s / m ² [see Handbook of Pharmaceutical Excipients (published by the American Pharmaceutical Society and the British Pharmaceutical Society), p. (1986); and Fiedler, "Lexicon Dairy Hilfsstoffe", 3rd edition, p. (1989)].

The properties of Glycofurol vary depending on its relative purity: the lower quality product contains significant amounts of tetrahydrofurfuryl alcohol and other impurities. Glycofurol 75, the physical properties of which are as defined above, of which at least 95% is a fraction of the formula (I) wherein x is 1 to 2 is preferred in the process of the invention.

The use of the components defined in sections 1.1 and 1.2 above has been found to be particularly advantageous for the preparation of compositions according to A), the hydrophilic phase of which is a particularly suitable carrier for cyclosporin, the hydrophilic phase of which enables the composition to be used therapeutically, e.g. contain a sufficient amount of eiclosporin.

Formulations according to A) containing the components defined as hydrophilic phase in the above 1.1 and / or 1.2 may, of course, additionally contain one or more additional components as the hydrophilic phase. Preferably, however, any further component is a substance in which the active ingredient cyclosporin is sufficiently soluble, so that the effectiveness of the hydrophilic phase used as the vehicle for cyclosporin is not impaired. Other hydrophilic phase components include lower alkanols, such as C1-C5 alkanols, especially ethanol.

Although the use of alkanols such as ethanol as a hydrophilic component may be contemplated in the present invention, it is generally of little advantage. The formulations defined in A) are preferably non-alkanol based, i.e. they do not contain an excess of alkanol as the hydrophilic phase component: preferably the hydrophilic component is less than 50% by weight, more preferably less than 25% by weight, and most preferably less than 10% by weight. contain. Most preferably, the hydrophilic component will be free from or substantially free of alkanols, i.e. less than 5%, preferably less than 2%, e.g. 0-1%. "Alkanol" in particular means C 1-5 alkanol, especially ethanol.

In a particularly preferred embodiment of the process according to the invention, the hydrophilic component of the compositions defined in A) is wholly or substantially the same as those defined in 1.1 or 1.2 above, in particular Transcutol, Glycofyrol and / or 1,2-propylene glycol. ; most preferably only or essentially the components defined in 1.1 or 1.2 are used.

Particularly noteworthy are the preparations according to A) which 1.1. Its component is primarily Glycofurol as they are advantageously used for the preparation of soft gelatine capsules. In accordance with the present invention, it has been found that such compositions have surprisingly advantageous stability, as demonstrated by long-term tests at ordinary or higher temperatures. These formulations are particularly well suited to the requirements generally encountered in the transportation and storage of pharmaceutical products, and are suitable for long-term storage by the user, for example, prior to use in hospitals, clinics and the like.

Compositions as defined in A) also contain a lipophilic component 2).

Lipophilic components are all pharmaceutically acceptable solvents which do not mix with the selected hydrophilic component, such as the hydrophilic components defined in 1.1 or 1.2 above. These solvents are preferably non-surfactant or non-surfactant. Particularly suitable lipophilic 2) components include:

fatty acid triglycerides, preferably medium chain fatty acid triglycerides; especially inert oils, such as inert vegetable oils, especially fractionated coconut oils, such as those known and commercially available under the name Miglyol

EN 212 727 Β (see Fiedler, cited above, pp. 808-809), in particular the following:

Miglyol 810: fractionated coconut oil containing caprylic and capric triglycerides having a molecular weight of about 520. Containing 2% or less of C 6, about 65 to 75% of C 8, about 25 to 35% of C 10 and up to 2% of C 12, an acid number of about 0.1, a saponification number of about 340-360, and an iodine number of up to 1;

Miglyol 812: fractionated coconut oil containing caprylic and capric triglycerides, molecular weight approximately 520. Containing 3% or less of C 6, about 50 to 65% of C 8, about 30 to 45% of C 10 and up to 5% of C 12 fatty acids. 0.1, saponification number about 330-345, iodine number up to 1;

Miglyol 818: Triglyceride of caprylic acid, capric acid and linoleic acid, molecular weight about 510. Not more than 3% of C 6, about 45-60% of C 8, about 25-40% of C 10, about 2-5% of C 12 and about 4 6% containing 18 carbon atoms, acid number up to 0.2, saponification number about 315-335, iodine number up to 10; and

Captex 355 ^(l) (Capital City Products, PO Box 569, Columbus, OH, USA) caprylic acid-capric acid triglyceride; about 2% capric acid, about 55% caprylic acid, and about 42% capric acid groups, acid number up to 0.1, saponification number about 325-340, iodine number up to 0.5.

Caprylic acid-capric acid triglyceride may also be used, such as the commercially available product known as Myritol (see Fiedler, cited above, p. 834), including Myritol 813 having an acid number of up to 1 and a saponification number of about 340-350. , iodine number about 0.5.

Suitable lipophilic components are Campul MCT (Capital City Products), Captex 300 (Capital City Products), Captex 800 (Capital City Products), Neobee M5 (Stepan, PVO Dep., 100 West Hunter Ave., Maywood, NJ 07607, USA). and Mazol 1400 (Mazer Chemicals, 3938 Porett Drive, Gurnee, IL, USA). As a lipophilic component, Miglyol 812 can be used with particular advantage.

The compositions of the invention as defined in A) further comprise 3) a pharmaceutically acceptable surfactant (wetting agent). The wetting agent, ie the surfactant component 3.1. hydrophilic; or 3.2. a lipophilic surfactant or mixtures thereof. Nonionic hydrophilic and nonionic lipophilic wetting agents are particularly preferred. For example, the following hydrophilic wetting agents are useful as wetting agents:

3.1.1. Reaction products of naturally occurring or hydrogenated vegetable oils and ethylene glycol, i.e., polyoxyethylated, naturally occurring or hydrogenated vegetable oils, such as polyoxyethylene, natural and hydrogenated castor oils. These products are known in the art, for example by reaction of natural or hydrogenated castor oil or its fractions with ethylene oxide, for example by taking ethylene oxide in a molar ratio of about 35 to about 60 times and optionally removing free polyethylene glycol components from the product (e.g. using the methods described in German Patent Publication Nos. 1,182,388 and 1,518,819). Of particular advantage are the various commercially available surfactants known as Cremophor. Of these, particularly useful are: Cremophor RH 40 having a saponification number of about 50-60, an acid number of less than 1, an iodine number of less than 1, a water content of less than 2%, n of about 1.453-1.457, and an HLB of about 14-16. ; Cremophor RH 60, saponification number about 40-50, acid number less than 1, iodine number less than 1, water content about 4.55.5%, n _b about 1.453-1.457, HLB about 15-17; and Cremophor EL having a molecular weight (measured by steam osmometry) of about 1630, a saponification number of about 65-70, an acid number of about 2, an iodine number of about 28 to 32, n _b is about 1.471 (refer to. Fiedler, supra, pp 326-327 .). Various commercially available surfactants known as Nikkol, such as Nikkol HCO 60, which is a reaction product of hydrogenated castor oil and ethylene oxide, has an acid number of about 0.3, a saponification number of about 47.5, and a hydroxyl number of about 42.5. %) is about 4.6; Color APHA has a hydroxyl number of about 40, melts at about 36.0 ° C, freezes at about 32.4 ° C, and has a water content of about 0.03%.

3.1.2. Polyoxyoxyethylene sorbitan fatty acid esters such as mono- and trilauryl, palmityl, stearyl and oleyl esters such as the commercially available Tween (see Fiedler, 1300-1304). Tween 20: Polyoxyethylene 20-sorbitan monolaurate;

Tween 40: polyoxyethylene 20 sorbitan monopalmitate;

Tween 60: polyoxyethylene 20 sorbitan monostearate;

Tween 80: polyoxyethylene 20 sorbitan monooleate; Tween 65: polyoxyethylene 20 sorbitan tristearate; Tween 85: polyoxyethylene 20 sorbitan trioleate; Tween 21: polyoxyethylene 4-sorbitan monolaurate; Tween 61: Polyoxyethylene 4-sorbitan monostearate; and

Tween 81: Polyoxyethylene 5-sorbitan monooleate.

Of this group, a

Tween 40 and Tween 80.

3.1.3. Polyoxyethylene fatty acid esters, such as the polyoxyethylene stearic acid esters of known type and commercially available as Myrj (see Fiedler, p. 834); and the polyoxyethylene fatty acid ester known and commercially available as Cetiol HE7

EN 212,727 (see Fiedler, p. 284); Mytj 52, D ²⁵ about 1.1, m.p. about 4044 ° C, HLB about 16.9, acid number about 0-1, saponification number about 2535 are particularly useful.

3.1.4. Polyoxyethylene-poly (oxypropylene) copolymers, such as those of the known type commercially available as Pluronic and Emkalyx (see Fiedler, cited above, pp. 956-958). Of this group, Pluronic F68 can be used with particular advantage in the present invention.

3.1.5. Polyoxyethylene-poly (oxypropylene) block copolymers, such as the known type commercially available as Poloxamer (see Fiedler, p. 959). Of this group, the product Poloxamer 188 is useful in the compositions of the invention.

3.1.6. Dioctyl succinate, dioctyl sodium sulfosuccinate. di (2-ethylhexyl) succinate and sodium lauryl sulfate.

3.1.7. Phospholipids, especially lecithins (see Fiedler, cited, pp. 731-733). For example, lecithins derived from soybeans are useful in the present invention.

3.1.8. Mono- and di-esters of propylene glycol with fatty acids such as propylene glycol dicaprilat, propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol, propylene glycol, pages). Particularly preferred is the known propylene glycol caprylic acid caprylic acid diester commercially available as Miglyol 840 (see Fiedler, p. 809). Miglyol 840 contains up to about 3% C 6, about 65-80% C 8, about 15-30% C 10 and up to 3% C 12 fatty acid groups, has an acid number of up to 0.1, a saponification number of about 320-340, and an iodine number of up to 1 .

3.1.9. Salts of bile acids, such as alkali metal salts of bile acids, such as n-titrate.

For example, the following lipophilic surfactants may be used as wetting agents:

3.2.1. The products of the transesterification reaction of natural vegetable oil triglycerides with polyalkylene polyols are known and can be prepared, for example, by the general methods described in U.S. Patent 3,288,824. These products include transesterification products of various natural oils (e.g., non-hydrogenated), such as corn oil, wheat germ oil, almond oil, peanut oil, olive oil, palm oil, and polyethylene glycols with polyethylene glycols, in particular 200 to 800 average molecular weight. Of these, products which are prepared by the transesterification reaction of 2 moles of natural vegetable oil triglyceride and 1 mole (e.g. 200 to 800 average molecular weight) of polyethylene glycol are preferred. Transesterification products of this group of compounds are known and are commercially available as Labrafil (see Fiedler, cited, p. 707). Labrafil M 1944 CS, which is a transesterification product of wheat germ oil and polyethylene glycol, has an acid number of about 2, a saponification number of about 145-147, and an iodine number of about 60-90; and Labrafil M 2130 CS, a product of transesterification of C12-C18 glycerides with polyethylene glycol, op. about 35-40 ° C, an acid number of less than 2, a saponification number of about 185-200, and an iodine number of less than 3.

3.2.2. Products of the glycerol esterification reaction of mono-, di- and mono-diglycerides, in particular caprylic acid or capric acid. Preferred products of this group include, for example, predominantly or substantially mono- and diglycerides of caprylic acid and capric acid, commercially available as Imwitor (Fiedler, p. 645). Imwitor 742, which is a product of the esterification reaction of about 60 parts by weight of caprylic acid with about 40 parts by weight of capric acid with glycerol, is a particularly useful compound in this invention, a yellowish crystalline mass which liquefies at about 26 ° C and has an acid number of 2 or less. not more than 1, having a saponification number of about 235 to 275, containing from about 40 to 50% of monoglycerides, not more than 2% of free glycerol, melting at about 24 to 26 ° C, having a non - saponifiable moiety of not more than 0.3% and of not more than 1.

3.2.3. Sorbitan fatty acid esters are known and commercially available, for example, as Span; such as sorbitan monolauryl, monopalmityl, monostearyl, tristearyl, monooleil and trioleyl esters (see Fiedler, p. 1139-1140).

3.2.4. Fatty acid esters of pentaerythritol and ethers with polyalkylene glycols, such as pentarithritol dioleate, distearate, monolaurate, polyglycol ether and monostearate; and fatty acid esters of pentaerythritol (see Fiedler, cited above, pp. 923-924).

3.2.5. Monoglycerides such as glycerol monooleate, glycerol monopalmitate and glycerol monostearate; such as the known and commercially available products of Myvatex, Myvaplex and Myverol (see Fiedler, p. 836) and their acetylated derivatives such as mono- and diacetylated monoglycerides, such as the known and commercially available product Myvacet (see Fiedler, cited, page 835).

3.2.6. Glycerol triacetate, i.e., 1,2,3-triacetin (see Fiedler, p. 952).

3.2.7. Sterols and their derivatives, such as cholesterol and their derivatives, especially phytosterols, ex

For example, products containing sitosterol, campesterol or stigmasterol and their ethylene oxide adducts, such as soyesterol and their derivatives, such as those known and commercially available under the name Gene (see Fiedler, cited above, pages 554 and 555). ), in particular products A, 122, 122 E5, 122 E10 and 122 E25 from gene A.

Compositions as defined in A) above include systems containing a single wetting agent or a mixture of wetting agents, for example, systems comprising a main wetting agent and one or more co-wetting agents. The combination of wetting agent and co-wetting agent may be selected, for example, from any of the components mentioned in points 3.1.1 to 3.2.7 above.

When the hydrophilic component contains a diethyl ether or a partial ether as defined in 1.1 above, in particular Transcutol or Glycofural, a single surfactant is usually sufficient although co-wetting agents may be added, if desired, for example to improve stability. When 1,2-propylene glycol, alone or as a hydrophilic principal component, is used, it is desirable to use at least two wetting agents, i.e. a wetting agent and a co-wetting agent. The compositions comprising the hydrophilic component 1,2-propylene glycol as defined in (A) above, therefore, preferably contain both a wetting agent and a co-wetting agent.

See sections 3.1.1, 3.1.3, 3.1.7, 3.2.2 above. and 3.2.5 are particularly noteworthy for use in the compositions defined in A). Preferably, a humectant / co-humidifier combination comprising a hydrophilic and a lipophilic humectant is used, e.g. wetting agents according to

3.2.5. combinations with wetting agents according to.

If the wetting agent is a good solvent for cyclosporin as an active ingredient, for example, the above-mentioned 3.1.1 to 3.2.7. In the case of the wetting agents and mixtures thereof listed below, they may not only play the role of a wetting agent in the formulations defined in A), but may also, in excess, serve as additional excipients or co-solvents, i.e. part of the hydrophilic or lipophilic component.

The formulas defined in A) may also contain the following components:

4. Thickeners

Known and commonly used thickeners, for example, pharmaceutically acceptable polymeric materials, and inorganic thickeners, for example of the following types, may be used:

4.1. Polyacrylate and polyacrylate copolymer resins: for example, polyacrylic acid and polyacrylic acid / polymethacrylic acid resins, such as the known and commercially available Carbopol products (see Fiedler, cited, pp. 254-256), in particular Carbopol 934, 940 and 941. products; and Eudragit (see Fiedler, cited above, pages 486-487), in particular Eudragit products E, L, S, RL and RS, in particular Eudragit E, L and S.

4.2. Celluloses and cellulose derivatives such as: alkylcelluloses such as methyl, ethyl and propyl celluloses; hydroxyalkyl celluloses such as hydroxypropyl celluloses and hydroxypropyl alkyl celluloses such as hydroxypropyl methylcelluloses; acylated celluloses such as target cellulose acetates, cellulose acetate phthalates, cellulose acetate succinate and hydroxypropyl methylcellulose phthalates; and salts thereof, such as sodium salts of carboxymethylcelluloses. Known and commercially available products such as Klucel and Methocel (see Fiedler, p. 688 and 790), in particular Klucel LF, MF, GF and HF, and Methocel K 100, K 15M, K 100M, E 5M, E 15, E 15M and E 100M.

4.3. Polyvinylpyrrolidones, such as poly (N-vinylpyrrolidone) and copolymers thereof such as vinylpyrrolidone and vinyl acetate. Of this group of compounds known in the process of the invention and commercially known, for example, as Kollidon (Povidone in the United States) (see Fiedler, cited above, pages 694-696), in particular Kollidon 30 and 90 can be used.

4.4. Polyvinyl resins such as polyvinyl acetate and polyvinyl alcohols as well as other polymeric products such as gum tragacanth, gum arabic, alginates such as alginic acid and salts such as sodium alginates.

4.5. Inorganic thickeners such as attapulgite, bentonite and silicates such as hydrophilic silica derivatives such as alkylated (e.g. methylated) silica gels, in particular colloidal silica products such as the known and commercially available Aerosil (see Handbook of Pharmaceutical Excipients, loc. Cit., Pp. 253-256), in particular Aerosil 130, 200, 300, 380, O, OX 50, TT 600, MOX 80, MOX 170, LK 84, and Methylated Aerosil R 972.

The above thickeners can be added, for example, above

Formulations mentioned in A) for oral administration, for example, to provide delayed release (retardation effect). In general, however, it is not necessary and less advantageous to use the above thickeners in compositions for oral administration. However, it is appropriate to use these thickeners, for example, in topical formulations.

Compositions as defined in A) may further comprise one or more components, for example: diluents; antioxidants (e.g. ascorbyl palmitate, butylhydroxyanisole), butylhydroxytoluene and tocopherol derivatives such as α-tocopherol (vitamin E); as well as flavoring agents and additional ingredients. The use of an antioxidant, especially tocopherol, is particularly preferred.

Although it is foreseeable - especially when targeting oral administration - that it is defined in A)

The formulations of the present invention represent the final dosage form, the invention also makes it possible to formulate pharmaceutical compositions containing cyclosporin as the active ingredient and microemulsions per se. Thus, for oral administration, the microemulsions obtained, for example, by diluting the "microemulsion preconcentrate" as defined in A) with water or other aqueous media, can be used as oral preparation. Similarly, if the target is a topical application, compositions containing the hydrocolloid thickener (see, e.g., 4.2 and above).

4.4), preferably containing water to form an aqueous microemulsion in the form of a gel, paste or cream. These formulations are also new. Accordingly, the present invention provides the following capability:

B) Preparation of a microemulsion pharmaceutical composition containing cyclosporin as an active ingredient

The compositions of B) may contain any of the components listed above in (1) to (3) mentioned above in connection with the compositions of A) and the use of water. The compositions of B) are microemulsions of the o / v type, which preferably have the same stability characteristics of the microemulsions obtainable from the compositions defined in A) above.

The processes described in C) -F) below are further embodiments which, although not always within the scope of the invention, are not always microemulsions or microemulsion preconcentrates, but are always close to the embodiments of the invention.

It has further been found that the use of the diethers and partial ethers as defined in 1.1 as carriers for the preparation of pharmaceutical compositions containing cyclosporins in general, and not only the "microemulsion pre-concentrates" and microemulsion formulations described above. It has now been found that the use of such ethers as components in systems for oral and especially topical application surprisingly overcomes the difficulties described above and to date. Such formulations are also novel. Accordingly, the present invention also provides:

C) Preparation of a pharmaceutical composition comprising cyclosporine as an active ingredient and a pharmaceutically acceptable C 1 -C 5 alkyl or tetrahydrofurfuryl diethyl ether or partial ether thereof as a lower molecular weight mono- or polyoxyalkanediol.

The process according to C) can advantageously employ the ethers described in 1.1 above, in particular the Transcutol and Glycofurol products. One or more additional components in the compositions of Formula C include, for example, wetting agents, co-solvents, and thickening agents.

A pharmaceutically acceptable hydrophilic wetting agent, in particular a nonionic hydrophilic wetting agent, is suitably used in the formulations of C). Preferably, the products described in 3.1.1 to 3.1.9 above may be used for this purpose.

A pharmaceutically acceptable lipophilic wetting agent, which may play a role as either a wetting agent or a co-solvent, is preferably used in the compositions of Formula C; or a pharmaceutically acceptable cosolvent. Suitable cosolvents / lipophilic wetting agents are preferably those described in (2) above and 3.2.1 to 3.2.7.

Formulations according to C) may also be in forms other than A) and B), such as solutions, suspensions, dispersions, regular emulsions, in particular formulations containing a wetting agent or both a wetting agent and a co-solvent, e.g. (i.e., formulations which when in contact with water form regular emulsions of the o / v or v / o type) or may form regular emulsions of the hydrophilic / lipophilic or lipophilic / hydrophilic type. For example, in the case of ointments or topical formulations, aqueous emulsions of the o / v or v / o type are prepared. Particularly for oral administration, it is generally preferable to formulate pre-concentrates of o / v emulsions and o / v emulsions.

Pharmaceutically acceptable thickeners may also be used in the formulations of C); for this purpose, it is preferable to use the products described in 4.1 to 4.5 above.

The formulations of C) may also contain further excipients. Such are, for example, the preservatives and flavoring agents described above for the compositions of A). These compositions preferably also include an antioxidant; specific antioxidants mentioned in connection with the compositions of A) may be used for this purpose.

Particularly noteworthy are the following compositions of the present invention:

D) Preparations as defined in C) above containing additional fatty acid saccharide monoester as component 5)

Formulations prepared according to Method D generally contain cyclosporin in a vehicle such as that described in 1.1. component such as Glycofurol or Transcutol and component 5). Cyclosporin and component 5) are generally present in the formulations of D) as a molecular dispersion or solution, optionally in the form of a solid solution. Component 5 generally acts as a solubilizing component of cyclosporin in the compositions of D). The formulations according to D) are particularly advantageous, on the one hand, in terms of stability and, on the other hand, in eliminating difficulties arising from the highly hygroscopic properties of component 5).

Water-soluble fatty acid saccharide monoesters, such as esters having a solubility at ambient temperature, for example 20 'Con of at least 3.3%, are preferably used as component 5) in the compositions of D); that is, fatty acid saccharide monoesters having a mass of at least 1 g are soluble in 30 ml of water at ambient temperature.

The fatty acid moiety of component 5) may be derived from saturated or unsaturated fatty acids or mixtures thereof.

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5) The saccharide monoesters of C 6-18 fatty acids, especially the water soluble saccharide monoesters of C 6-18 fatty acids, are particularly preferred as components. Particularly suitable as component 5) are C 6 capric acid, C 8 caprylic acid, C 10 capric acid, C 12 lauric acid, C 14 myristic acid, C 16 palmitic acid, C 18 oleic acid, C 18 ricinoleic acid and C 18 saccharide monoesters of hydroxystearic acid, in particular saccharide monoesters of lauric acid.

The saccharide moiety of component 5) may be any suitable sugar moiety, such as a mono-, di- or trisaccharide moiety. The saccharide moiety is preferably a di- or trisaccharide moiety. As component 5), it is preferred to use disaccharide monoesters of C 6 -C 14 fatty acids and trisaccharide monoesters of C 8 -C 18 fatty acids. Preferably the saccharide moiety is the sucrose or raffinose moiety.

Particularly preferred components 5) are: sucrose monocaproate, sucrose monolaurate, sucrose monomyristate, sucrose monooleate, sucrose monoricinoelate, raffinose monocaproate, raffinose monolaurate, raffinose mono-myristine. The most preferred component 5) is raffinose monolaurate, especially sucrose monolaurate.

Preferably component 5) is a product. having a hydrophilic-lipophilic balance (HLB) of at least 10.

The purity of the component (5) relative to the ester group is at least 80%, more preferably at least 90%, most preferably at least 95%. Components 5) preferably have a melting point of from about 15 ° C to about 60 ° C, more preferably from 25 ° C to about 50 ° C.

The formulations prepared according to D) may also contain additional components, such as those described for C): for example, a component that modifies the release of cyclosporin from the formulation; such as the thickening agents described in Sections 4.1 to 4.5 above.

The compositions of D) preferably contain one or more antioxidants; for example, antioxidants useful in the compositions of A) may be used.

The formulations prepared according to D) preferably contain one or more preservative or buffering agents, in particular to prevent the hydrolysis of component 5) during processing or storage. These preservatives may be acidic in nature, such as citric acid, acetic acid, tartaric acid and fumaric acid; or basic in nature such as potassium hydrogen phosphate.

Preservatives and buffering agents are suitably added to the composition in an amount sufficient to achieve or maintain a pH of from about 3 to about 8, more preferably from about 5 to about 6 (since the compositions of (D) preferably have a pH within this range).

The compositions of D) preferably also contain a polyoxyalkylene-free hydrophilic wetting agent; the products listed in 3.1.6-3.1.7 above may be used for this purpose.

The compositions of the invention may be administered by any suitable route, for example orally, for example, in the form of a dosage unit such as hard gelatine or soft gelatine capsules; and parenterally or topically, such as in the form of a cream, paste, lotion, gel, ointment, lotion, lotion, patch, flastrom; for ophthalmic use, for example in the form of eye drops, lotions or gels. Flowable formulations such as solutions and microemulsions may be used to treat psoriasis directly by injection at the site of injury; or rectally, for example to treat inflammatory bowel disease or Crohn's disease. However, the compositions of the invention are formulated primarily for oral or topical application, particularly for dermal application.

Of course, the proportion of the components in the formulations will depend to a large extent on the type of formulation itself, e.g., whether it is a "microemulsion pre-concentrate", a microemulsion, a regular emulsion or a solution. The relative proportions also depend on the role of the components in the formulation, for example, whether the surfactant component of a "microemulsion pre-concentrate" is used only as a wetting agent or as a wetting agent and co-solvent. The relative proportions also depend on the components used and the physical characteristics required of the composition, for example, for topical application, whether the purpose is to form a fluid or paste. The determination of the applicable ratios in each case is within the skill of the skilled artisan. Accordingly, the recommended ratios and relative weight ranges described herein are for reference only and are for the purpose of illustrating the preferred embodiment, but are not intended to limit the invention.

The amount of cyclosporin in the compositions of the present invention will, of course, depend, for example, on the mode of administration and the amount of other components, particularly those described in (2) to (5); however, in general, cyclosporin is present in an amount of 0.05% by weight, in particular about 0.1% to about 35% by weight, of the total composition.

In the compositions of the present invention, the components of (1) are suitably from about 0.5% by weight of the total composition. up to about 90% by weight. In formulations of the invention wherein the component described in 1.1 is used, this component, such as Glycofurol or Transcutol, will generally be from about 1% to about 90% by weight of the total composition, generally from about 5% to about 70% by weight. , ll

More preferably, it is present in an amount of 10-70% by weight. If in the preparation according to A) or B) 1.2. If the component is used, the latter is generally present in an amount of from about 2% to about 50% by weight of the total composition. Component 2) or 3) generally comprises from about 0.5% to about 90% by weight of the total composition. A particularly advantageous feature of the invention is the following:

E) Preparation of the formulations defined in A) or C) above for oral administration, for example in a convenient or convenient form for oral administration.

For non-topical dosage forms as defined above in A) -C), particularly for oral dosage forms E):

a) Cyclosporin is generally employed in an amount of from about 1% to about 30% or about 2% to about 30% by weight of the total composition, preferably from about 4% to about 25% by weight; more preferably, the cyclosporin is present in an amount of from about 5% to about 25% by weight of the total composition, in particular from about 20% to about 5%, for example about 5% to about 15% by weight.

b) If 1.1. component, it is conveniently from about 15% to about 85% by weight based on the total weight of the composition, preferably from about 20% to about 80%, more preferably from about 25% to about 70% by weight of the composition. up to about 50%, e.g. about 30% to about 50% or about 60%.

(c) If, in addition to ciclosporin, 1.1. component is present in the composition, their ratio (in the above order) is generally from about 1: 0.75 to 1:20, preferably from about 1: 1 to 1:15, more preferably from about 1: 1 1 to 5, for example about 1: 1 or 1: 1.5 to 1: 4 (these ratios are by weight).

(d) If the preparation 1.2. is used, it is generally present in an amount of from about 3% to about 45% by weight of the total composition, preferably from about 5% to about 30% by weight.

(e) If the preparation, in addition to ciclosporin 1.2. component, then cyclosporin 1.2. the weight ratio to component is generally from about 1: 0.1 to about 1:20, preferably from about 1: 0.2 to about 1:10, more preferably from about 1: 0.3 to about 1: 6 , e.g., about 1: 0.5 to 1: 3.

f) If the composition comprises component 2), the latter will generally be present in an amount of about 45% by weight, preferably about 40% by weight, of the total composition; more preferably, the composition of component 2) is from about 2% to about 45% by weight, more preferably from about 3% to about 35% by weight, most preferably from about 5% or about 10% to about 30% by weight, up to.

g) If the preparation is in addition to component 2)

1.1. the weight ratio of these components is generally about 1: 0.5 to 1:40, preferably about 1: 0.5 to 1:20, more preferably about 1: 0.75 to 1 in the above order. : 10 to about 10, for example about 1: 0.75 to 1: 4.

(h) If the preparation is subject to both (2) and (1.2). preferably containing from about 1: 0.0075 to 1: 22, preferably from about 1: 0.1 to 1: 15, most preferably from about 1: 0.15 to about 1: 1, by weight. Up to 6, for example, about 1: 0.5 to 1: 3.

(i) If the preparation contains component (3) (both

3.1 and 3.2. generally present in an amount of up to about 90% by weight of the total composition, for example from about 20% to about 90% by weight. Components 3) are more preferably present in an amount of from about 20 or 25% to about 80 or 90% by weight of the total composition; for example, from about 25% to about 55% by weight if 1.1. component 40 and about 40-75% by weight if 1.2. component.

j) If the composition comprises component 3 in addition to cyclosporin (including both components 3.1 and 3.2), the weight ratio of cyclosporin to component 3 is generally from about 1: 0.5 to about 1:20, more preferably 1: 0.5 to 1: 12. More preferably, the ratio is from about 1: 1 to 1:10, for example from about 1: 1 to 1:10 if 1.1. component is used and ranges from about 1: 3 to 1: 8 if 1.2. component.

For formulations A) and B) ("microemulsion preconcentrates" and microemulsions), the ratio of 1) hydrophilic components, 2) lipophilic component and 3) wetting agent varies depending on the concentration of cyclosporin and varies with each other. too.

Accordingly, the formulations of A) contain a cyclosporin 1) with a hydrophilic component (e.g., hydrophilic component 1.1 or 1.2), 2) with a lipophilic component (e.g.

2.1. or 2.2. 3) together with a wetting agent (e.g. wetting agent 3.1 or 3.2) and the composition has a weight ratio of cyclosporin / l) / 2) / 3) such that when in contact with water, for example 1: 1 or more in greater proportions [expressed in parts by weight ((cyclosporin + 1) + 2) + 3)): H ₂ O] microemulsion (e.g., o / v microemulsion).

Similarly, the formulations according to B) contain a cyclosporin compound of Compounds 1), 2) and 3).

With water and water, for example in the proportions necessary to form a microemulsion (e.g., o / v microemulsion).

The compositions of A) and B) preferably contain from about 2% to about 30% by weight of the total amount of cyclosporin and components 1) + 2) + 3), more preferably from about 5% to about 20% by weight. up to about 10% by weight, most preferably from about 10% to about 15% by weight of cyclosporin.

If, in the preparations according to A) or B), the content of component 1) 1.1. , such as Transcutol or Glycofurol; component is preferably about 15 to 85% by weight, more preferably about 25 to 65% by weight, a

Component 2) is present in an amount of about 2-40% by weight, more preferably about 3-35% by weight, most preferably about 3-30% by weight, and component 3) is present in an amount of about 15-85% by weight, more preferably about 25-55 or 25-60% by weight is present in section 1.1. + 2) + 3) based on the total weight of the components. Particular attention should be paid to the use of Glycofurol.

If component 1) of formulations A) or B) is 1,2-propylene glycol (see 1.2 above), then component 1.2, 2) and 3) is a compound of formula 1.2. component 3 is preferably present in an amount of about 3-35% by weight, more preferably about 3-25% by weight; component 2) is present in an amount of from about 2% to about 35% by weight, more preferably from about 3% to about 30% by weight; and the

Component 3) is present in an amount of about 45-90% by weight, more preferably about 50-90% by weight, for example about 55-80% by weight of component 1.2. + 2) + 3) based on the total weight of the components. As indicated above, when component 1) is 1,2-propylene glycol, component 3) generally functions as both a wetting agent and a co-wetting agent. If a co-wetting agent is used, the weight ratio of the wetting agent to the co-wetting agent is preferably about 50: 1, preferably 20: 1, more preferably 15: 1, e.g. 2: 1 to 15: 1.

The attached Figure 1 is a triangular graph showing

1.1. (e.g. Glycofurol), relative concentrations of components 2) (e.g. Miglyol 812) and 3) (e.g. Cremophore RH40) in formulations A) containing about 10% by weight of cyclosporin (e.g. cyclosporin A). 1.1. The relative concentration of the component increases from the lower left vertex of the triangle (0%) to the lower right of the triangle (100%). The concentration of component 2) increases from the lower right peak (0%) of the triangle to the lower left peak (100%). Thus, a composition which is only 50% 1.1. and 50% component 2), indicated by the midpoint of the triangle baseline. The relative concentration of component 3) increases from the base line of the triangle (0%) to the top of the triangle (100%). The dividing lines within the triangle represent a 10% increase, meaning values increasing from 0% to 100% from the line to the opposite vertex.

For formulations A) and B), the relative proportions of components 1.1, 2 and 3 are preferably in the "A" area enclosed by the "a" in Figure 1. More preferably, it is

The relative proportions of components 1.1, 2 and 3 are within area "B" enclosed by the "b" line in Figure 1; microemulsions based on these ratios were found to be most stable, which means, for example, that they have an average particle size of less than 1000 Å for more than 24 hours. Accordingly, the compositions of the invention containing the components 1.1, 2 and 3 in a weight ratio as defined in Figure I represent particularly preferred embodiments of the process of the invention.

The attached Annex II. Figure 3A is a triangular graph showing the relative concentrations of Components 1.2, 2) (e.g. Miglyol 812) and 3) in formulations A) containing about 10% by weight of cyclosporin (e.g. cyclosporin A). In this case, component 3) is a suitable mixture of a wetting agent and a co-wetting agent, wherein the weight ratio of the wetting agent to the co-wetting agent is, for example, 11: 1; For example, it contains 11 parts by weight of Cremophor RH40 product and 1 part by weight of glycerol monooleate. The relative amounts of components 1.2, 2 and 3 are indicated by arrows "1.2", "2" and "3" as in Figure I.

For the formulations defined in A) and B), the relative ratios of components 1.2, 2 and 3) are preferably as shown in Table II. are in the "X" area enclosed by the "x" shown in FIG. more preferably, it is

The relative proportions of components 1.2, 2 and 3 are shown in Table II. is in the "Y" area enclosed by the "y" line shown in FIG. Most preferably, the proportions of components 1.2, 2) and 3) are as shown in Table II. Figure 5a is within the "Z" area enclosed by the line "z"; microemulsions based on ratios within the 'Y' and 'Z' ranges have an average particle size of less than 1100 Å and 200 Å and are stable for more than 24 hours.

The compositions of E) may also contain a thickening agent, although, as noted above, it is generally of little advantage. Suitable thickeners as described in (4) above are suitable. The amount of thickener may vary, for example, depending on the desired consistency of the final product, for example, whether it is in a compact, easy-to-flow form, e.g. The amount of thickener will, of course, also depend on the nature of the agent. Generally, when component 4) is used, it will be present in an amount of about 25% by weight, more preferably about 15 or 20% by weight, based on the total weight of the composition, for example 0.5-15 or 5-20% by weight. composition.

The formulations of E) may contain additional excipients and components, such as those described for formulations A) and C). Thus, the compositions of E) are based on the total weight of the compositions

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They may contain up to 0.5% to about 1% by weight of antioxidants and, for example, up to about 2.5% or 5% by weight of sweetening or flavoring agents.

The formulations according to E) have been shown to exhibit particularly advantageous properties when administered orally: for example, their consistency and high bioavailability are favorable. In contrast to other galenic systems, which are known in the art, these compositions have been found to be compatible with surfactant-like substances, such as bile salts, which are present in the gastrointestinal tract. This means that these formulations are perfectly dispersible in aqueous systems containing this type of surfactant of natural origin and, as a result, are capable of forming in situ microemulsion systems which are stable and do not precipitate, thus not having a fine particle structure. When administered orally, the functionality of such systems is independent of the presence or absence of bile salts at any time in any individual. Such compositions therefore represent a particularly preferred embodiment of the process of the invention.

The compositions of E) are preferably formulated in a unit dosage form, for example, by pouring into a capsule for oral administration, such as a soft or hard gelatine capsule, or tableting it or otherwise forming it. When the composition of Formula E is formulated in a unit dosage form, the latter is conveniently present in an amount of about 5 or 10 mg to about 200 mg, more preferably 15 or 25 mg to about 150 mg, e.g. It contains 50 or 100 mg of ciclosporin as active substance. Each unit dosage form according to the invention will contain, for example, about 50 mg or about 100 mg ciclosporin, depending on the purpose of the therapy or the phase of the healing process, and such unit dosage will be administered 1, 2, 3, 4 or 5 times daily.

Compositions as defined in B) above for oral administration may be prepared by adding a composition of A) or E) above to water or other aqueous system, for example, such that the ratio of the composition to water is as defined above. For example, a sweetened or flavored preparation suitable for drinking is obtained. Accordingly, these formulations may be prepared from any of formulations A) or E) by adding sufficient water to form a microemulsion.

The compositions of D) are formulated for oral administration, although they can be used, for example, for topical (dermal or ocular), parenteral or rectal administration, and can be injected directly into the site of injury.

The formulations according to D) are cyclosporin and the desired compound 1.1. the component may be present in a weight ratio of from about 1: 0.5 to 1: 200, preferably from about 1: 0.5 to 1: 100, more preferably from 1: 0.5 to 1:50; more preferably, the weight ratio of cyclosporin to component 1.1 is from about 1: 1 to 1:10, more preferably from 1: 1 to 1: 5, most preferably from about 1: 1.5 to 1: 2.5 for example about 1: 1.6 or 1: 2. The weight ratio of cyclosporin to the desired component 5) is preferably from about 1: 3 to 1: 200, preferably from about 1: 3 to 1: 100, more preferably from 1: 3 to 1:50; more preferably, the weight ratio of cyclosporin to component 5) is from about 1: 5 to about 1:20, preferably from about 1: 5 to about 1:10, most preferably from about 1: 6.0 to about 1: 6.5- to about 1: 6.25, for example.

The compositions of D) are conveniently formulated in a dosage unit for oral or other administration.

The amount of cyclosporin present in such a unit dosage form will, of course, vary, for example, with the condition being treated, the mode of administration and the effect desired. In general, however, the compositions of D) will contain from about 2 mg to about 200 mg of ciclosporin per dosage unit.

Suitable dosage forms for oral administration include, for example, liquids and granules. However, the dosage unit is generally selected from the unit dosage form, for example in the form of tablets or capsules, especially hard or soft gelatine capsules.

Dosage unit dosage forms for oral administration according to AD) preferably contain from about 5 or 10 mg to about 200 mg of cyclosporin, more preferably from about 15 or 20 mg to about 100 mg, e.g. mg.

A further advantage of the formulations according to D) is the possibility of modifying the release properties of the active ingredient: for example, they allow delayed or prolonged release of cyclosporin, for example, after oral administration. Such formulations also contain a component that is capable of modifying the release of cyclosporin from the formulation. Examples of such components are thickeners, such as

Components listed in 4.1 to 4.5.

When used in the compositions of D), component 4) is preferably present in an amount of from about 0.5% to about 50% by weight, more preferably from about 120% by weight, most preferably from about 2% to about 10% by weight of cyclosporin A + 1.1. + 4) + 5) based on the total weight of the components.

As mentioned above, the compositions of D) preferably contain one or more preservatives or buffering agents or a polyoxyalkylene-free surfactant. Such preservatives and / or buffering agents are preferably contained in cyclosporin + 1.1. + 5) up to 5% by weight based on the total weight of the components or up to 10% by weight if citric acid or acetic acid is used. If present, the amount of wetting agent is preferably about 14% by weight of component 5).

5 to 50% by weight, more preferably about 10 to 25% by weight.

The compositions of D) also suitably contain additional excipients, in particular flavoring agents and antioxidants. These compositions may conveniently employ the same antioxidants in the same amounts as described for the compositions of E).

The compositions according to AD) are preferably also free or substantially free of free alkanols, especially ethanol, e.g. less than 5% by weight, more preferably less than 2% by weight of the total composition, for example only 0-1% by weight of lower alkanol components. They contain. The formulations A) -C) deserve special attention also for topical administration. Accordingly, the invention enables:

F) Preparation of the compositions of A) -C) for topical application, i.e. application in a form suitable for topical use, in particular on the skin.

When the composition is formulated for topical application, the composition will comprise from about 0.05% to about 15% by weight of cyclosporin, more preferably from about 0.1% to about 15% by weight of the total composition; more preferably, the cyclosporin is present in an amount of from about 0.1% to about 10% by weight.

In formulations F) based on formulations A) or B), the proportions of components 1), 2) and 3) are similar to those described for such formulations, for example as in Figures I and 11. we presented.

On the other hand, formulations F) according to C) may be in any convenient form, for example solutions, suspensions, dispersions and regular emulsions. In these preparations, the substances listed in 1.1. component is suitably in an amount of from about 1% to about 70% by weight of the total composition, preferably from about 5% to about 50% by weight, more preferably from about 7% to about 25% by weight can be present.

The formulations of Formula F may conveniently contain one or more carriers or diluents and / or other components, such as thickeners, emulsifiers and preservatives, wetting agents, coloring agents, to form a carrier system.

The compositions of Formula F may be in any form suitable for topical application, for example, in the form of a fluid, semi-liquid or liquid, or in the form of a powder or topically applied spray, for example, for topical application. Examples of easy-flowing forms are gels such as o / v or v / o emulsions or microemulsions, creams, pastes and ointments, as well as lotions and tinctures. Such formulations include, for example, lotions and lotions, as well as patches for penetration through the skin.

For the preparation of these compositions, excipients will be determined by the type of formulation desired, the condition to be treated, the progression of the pathological condition, the area to be treated, the condition of the skin and the effect desired. For example, chronic psoriatic scales may conveniently be treated with hydrophobic, e.g., fat-based, formulations in which a petroleum-based ointment or cream may be used as a vehicle. In contrast, more hydrophilic formulations, such as o / v emulsions or gels, are preferred for the treatment of conditions associated with acute inflammatory processes. Although the compositions of Formula F may contain, for example, lower alkanols such as ethanol, for example, as a diluent or as a component of a diluent, their use is advantageously avoided, for example, when treating a damaged skin, such as psoriasis. Thus, the compositions according to F) are preferably alkanol-free or substantially alkanol-free, i.e. they contain less than 5% by weight, preferably less than 2% by weight, for example only 0-1% by weight of the alkanol component, especially when the alkanol component is ethanol.

Particularly preferred are formulations F) which are pharmaceutically acceptable, e.g.

1.1. Formulations according to A), B) or C) with a further diluent or carrier which are immiscible with component 6). Such formulations preferably contain anhydrous or substantially anhydrous emulsions, i.e. less than 10% by weight, preferably less than 5% by weight, most preferably less than 1% by weight of water. These emulsions may also be emulsions having the characteristics set out in 1.1. containing component 6) divided into component 6) or emulsions containing component 6) according to 1.1. divided into component; these emulsions are preferably as described in section 1.1. containing the component emulsified in component 6).

6) preferred components include:

6.1. Solid hydrocarbons such as petroleum-based gels such as white petrolatum, cerezine, solid paraffins and waxes such as animal, vegetable and synthetic waxes such as spermaceti, camauba and beeswax.

6.2. Liquid hydrocarbons such as liquid paraffins and fatty acid esters such as isopropyl myristate and cetyl palmitate.

6.3. Non-volatile silicones such as silicone oils and pastes and copolymers of silicone and poly (alkylene oxide) (see Fiedler, cited, pp. 1109-1110), for example, are known and commercially available as Piroethicon.

In compositions F), components 6) are preferably present in an amount of about 80% by weight, based on the total weight of the composition, for example from about 5% to about 70% by weight, preferably from about 25% to about 60% by weight. are present in amounts up to.

By using the individual components or mixtures thereof according to 6), for example, a topical application is desired

Depending on the requirements, liquid or semi-solid emulsions may be prepared.

The compositions of Formula F preferably also contain a wetting agent. Suitable wetting agents are lipophilic surfactants such as a

The products listed in 3.2.1 to 3.2.7, in particular wetting agents having an HLB of about 5-7. Particularly useful as wetting agents in the formulations of F) are, for example, those described in 3.1.2. and 3.2.3. and glycerol monostearate, propylene glycol monostearate, diethylene glycol monostearate and glycerol ricinoleate.

In compositions F), these wetting agents are suitably present in an amount of up to 60% by weight, based on the total weight of the composition, for example from about 2% to about 50% by weight, preferably from about 10% to about 40% by weight. in an amount ranging from.

The compositions of F) may further comprise one or more consistency enhancing agents, such as microcrystalline waxes, vegetable oils (such as olive oil), corn and wheat germ oils, and derivatives of vegetable oils such as hydrogenated vegetable oils and partial glycerides of vegetable oils. in an amount of from about 0.1% to about 10% by weight, preferably from about 1% to about 5% by weight, of the total weight.

The compositions of F) further suitably comprise:

an antioxidant such as the antioxidant described for the compositions of A), for example from about 0.01% to about 0.5% by weight of the total composition;

an antibacterial agent such as benzyl alcohol, methyl or propylparaben, benzalkonium chloride, benzoic acid, sorbic acid or chlorobutanol, for example in an amount of from about 0.05% to about 2% by weight of the total composition;

a preservative such as microcrystalline starch, EDTA sodium salt or magnesium sulfate, for example in an amount of from about 0.1% to about 10% by weight of the total composition; and or

a skin permeation enhancer, such as a C 12 -C 24 mono- or poly-unsaturated fatty acid or fatty alcohol (e.g. oleyl alcohol) or l-dodecyl azacycloheptan-2-one known as Azone (see Fiedler, cited above, p. 190), for example from about 1% to about 20% by weight of the total composition, up to about 15% by weight.

Accordingly, the present invention also relates to the preparation of a pharmaceutical composition, such as the pharmaceutical composition according to A) to F) above. This involves mixing the components internally and, if desired, converting the resulting product into dosage units, for example filled into gelatin capsules, such as soft or hard gelatine capsules.

In a preferred embodiment of the process of the invention, the compositions defined in A) -D) above are prepared by cyclosporin A, e.g. mixing the component internally to form a composition as defined in C); and optionally adding a component as defined in (5) above to form a composition as defined in D); or, where appropriate, 1.2. mixed with the component and, where appropriate, 1.1. using a component or, where appropriate, 1.2. component is used, the above components are also combined with a component as defined in (2) and (3) above, in which the compound of formula 1.1. or the relative proportions of components 1.2, 2) and 3) are obtained such that a composition according to A) is obtained; and, if desired, contacting the resulting composition of A) with water to form a composition of B); and, if desired, forming the resulting composition of A), C) or D) into a dosage unit, for example, in the form of a hard or soft gelatin capsule.

In a particular embodiment of the process according to the invention, a composition according to the above A) is prepared by cyclosporin A, e.g. or 1.2. with component 2) and component 2) and component 3), during which step 1.1. or 1.2, and 2) and 3), relative to the amount of cyclosporin, to form a "microemulsion preconcentrate", e.g., a formulation which is added to water, e.g., at least 1: 1 composition / water in a dispersed, i.e. particulate, phase. comprising a system having a particle size of less than 2000 Å, preferably between about 100 Å and about 1000 Å.

The cyclosporin active ingredient of the compositions of the present invention is preferably cyclosporin A; cyclosporin is also preferred, and [Nva] ^2- cyclosporin, also known as cyclosporin G.

The invention is illustrated by the following non-limiting examples. Examples 1 and 2 illustrate the preparation of a unit dosage form for oral administration, for example, to prevent rejection of a transplanted organ or to treat autoimmune diseases, such as the autoimmune diseases or conditions described above, by using 1 to 5 dosage units per day. Example 3 describes the preparation of topical formulations which are, for example, atopic

Or contact dermatitis, psoriasis, or hair loss at a site in need of the desired therapy, for example, at regular intervals, such as once, twice or three times daily, at the site of an inflammatory reaction or psoriatic lesion, or on the scalp.

In the examples, cyclosporin A is mainly used; however, equivalent formulations may be prepared using any other suitable cyclosporin active ingredient. In particular, equivalent formulations are obtained when the cyclosporin A is replaced by the same amount of [Nva] ² -ciclosporin.

Example 1 Preparation of an oral dosage form of the microemulsion pre-concentrate type

1.1. Components Quantity (mg per capsule)

Cyclosporin (e.g. Ciclosporin A) 50.0 (1.1) Glycofurol 75 180.0 (2.1) Miglyol 812 90.0 (3.1.1) Cremophor RH 40 180.0

Total: 500.0

Ciclosporin is as described in section 1.1. Compound II is dissolved at room temperature with stirring, and stirring is continued by adding 2.1. and 3.1.1. component. The mixture thus obtained is filled into a "size 1 hard gelatin capsule and sealed by the" Quali-Seal "technique.

In a similar manner, the following formulations are prepared and filled into "1" or "2" hard gelatin capsules.

1.2. Components Quantity (mg per capsule)

Cyclosporin (e.g. Ciclosporin A) (1.1) Gly cofurol 75 (2.1) Miglyol 812 (3.1.1) Cremophor RH 40 Altogether: 50.0 180.0 78.0 192.0 500.0 1.3. components Quantity (mg per capsule) Ciclosporin (e.g. Ciclosporin A) 50.0 (1.1.) Glycofurol 75 200.0 (2.1.) Miglyol 812 60.0 (3.1.1.) Nikkol HCO-40 120.0 * ethanol 19.0 Ascorbyl palmitate ** 1.0 Altogether: 450.0 Co-solvent (hydrophilic phase) Anlioxidáns 1.4. components Quantity (mg per capsule) Ciclosporin (e.g. Ciclosporin A) 50.0 (1.1.) Glycofurol 75 100.0 (2.1.) Miglyol 812 75.0 (3.1.7.) Lecitin 75.0 Altogether: 300.0

1.5. Components Quantity (mg per capsule)

Ciclosporin (e.g. Ciclosporin A) 100.0 (1.1.) Glycofurol 75 260.0 (1.2) Propylene glycol 50.0 (2.1.) Myritol 318 100.0 (3.1.1) Cremophor RH 40 340.0 BHA * 5.0 Altogether: 855.0 Anlioxidáns 1.6. components Quantity (mg per capsule) Ciclosporin (e.g. Ciclosporin A) 50.0 (1.2) 1,2-Propylene glycol 68.0 (2.1.) Miglyol 812 68.0 (3.1.1.) Cremophor RH 40 250.0 (3.2.5.) Glycerol monooleate * 24.0 Altogether: 460.0 1.7. components Quantity (mg per capsule) Ciclosporin (e.g. Ciclosporin A) 50.0 (1.2) 1,2-propylene glycol 68.0 (2.1.) Miglyol 812 24.0 (3.1.1.) Cremophor RH 40 250.0 (3.2.5.) Glycerol monooleate ' 68.0 Altogether: 460.0 1.8. components Quantity

(mg per capsule)

Cyclosporin (eg Ciclosporin A) (1.2) 1,2-Propylene glycol (2.1) Miglyol 812 (3.1.1) Cremophor RH 40 (3.2.5) Glycerol monooleate * Total: 100.0 75.0 25.0 150.0 150.0 500 1.9. components Quantity (mg per capsule) Ciclosporin (e.g. Ciclosporin A) 50.0 (1.2) 1,2-Propylene glycol 200.0 (2.1.) Miglyol 812 50.0 (3.1.1.) Cremophor RH 40 150.0 (3.2.7.) About the gene 122 El 6 * 50.0 Altogether: 500.0 1:10. components Quantity (mg per capsule) Ciclosporin (e.g. Ciclosporin A) 50.0 (1.2) 1,2-Propylene glycol 75.0 (2.1.) Miglyol 812 75.0 (3.1.1.) Cremophor RH 40 250.0 (3.2.7.) General 122 E25 * 50.0 Altogether: 500.0 Co-wetting

HU 212 727 Β

1.1, 1.2, 1.6. and 1.7. compositions are particularly preferred. In each case the equivalent of 1.1 to 1.5 is equivalent. Formulations may be prepared by replacing the Glycofurol component with an equal or equivalent amount of Transcutol.

1.1.-1.5. Formulations equivalent to those of Formulations 2 may be prepared by replacing 50 mg of cyclosporin A with 15, 20 or 100 mg of other cyclosporin or cyclosporin A and maintaining the amounts of each of the other components in each formulation.

The microemulsion pre-concentrate type pharmaceutical composition of Example 1 can be mixed with an equal volume of water to form a microemulsion type pharmaceutical composition for similar purposes.

Example 2

Preparation of an oral dosage form of a concentrated "microemulsion pre-concentrate" type

2.1. Components Quantity (mg per capsule)

Ciclosporin (e.g. Ciclosporin A) 50.0 (1.1.) Glycofurol 75 180.0 (2.1.) Miglyol 812 90.0 (3.1.1.) Cremophor RH 40 180.0 (4.2.) Methocel K100 100.0 Altogether: 600.0 Ciclosporin and Sections 1.1 to 3.1.1. components

The mixture was mixed as described in Example 1 and the resulting mixture was mixed according to Example 4.2. The product thus obtained is filled into size 2 hard gelatin capsules.

The following preparations may be prepared in a similar manner:

2.2. Components Quantity (mg per capsule)

Ciclosporin (e.g. Ciclosporin A) 50.0 (1.1) Glycofurol 75 180.0 (2.1) Miglyol 812 90.0 (3.1.1) Cremophor RH 40 180.0 (4.6) Aerosil 200 9.0 (4.2) .) Methocel K100 100.0

Total: 609.0

2.3. Components Quantity (mg per capsule)

Cyclosporin (e.g. Ciclosporin ΑΡΟ, Ο (1.1.) Glycofurol 210.0 (2.1.) Myritol 318 90.0 (3.1.1.) Nikkol HCO-60 170.0 (4.2.) Klucel EF 30.0

Total: 600.0

In Figures 2.1 to 2.3. Formulations equivalent to those of Formula I may be prepared by replacing the glycofurol component with an equal or equivalent amount of Transcutol.

Example 3 Preparation of a topical formulation of the microemulsion pre-concentrate type

Components Tomeg%

Ciclosporin (e.g. Ciclosporin A) 0.1 (1.1) Glycofurol 50.0 (2.1) Miglyol 812 16.6 (3.1.1) Cremophor RH 40 33.3

The above composition was prepared in a similar manner to that described in Example 1. An equivalent formulation is obtained even when the Glycofurol component is replaced by Transcutol. The above formulation may be based, for example, on a cream, gel or similar formulation combined with additional additives, such as hydrocolloid thickeners, paraffins, as described below.

Investigation of the bioavailability of the compositions of the present invention in dogs

(a) Test preparations

Formulation I: such as 1.1.

II. preparation: such as 1.2.

III. preparation: such as 1.6.

ARC. preparation: such as 2.1.

Formulation V: such as 2.2.

b) The test method used male hunts of approximately 11-13 kg body weight. The animals were deprived of food for 18 hours prior to the administration of the test preparation, but were allowed to drink water freely until the time of administration. The test formulations were administered by gavage, followed by the addition of 20 ml of 0.9% saline. Three hours after administration of the test preparation, animals were allowed to feed and breathe freely.

Blood samples of 2 ml (5 ml for the "blind" test) were taken from the animal's leg vein and the samples were collected in 5 ml plastic test tubes containing EDTA. Sampling is shown in -15. minutes (in the "blind" test), 30 minutes after dosing, and 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours. Blood samples were stored at -18 ° C until measurement.

Blood samples were analyzed by radioimmunoassay (RIA). Areas under the curve plotting the blood concentration of the drug over time were calculated using the trapezoid rule. Analysis of variance was performed for area under the curve (AUC), C max (peak concentration) and T _max (peak time).

c) Results

The following table summarizes the calculated mean area under the curve (in ngxh / ml) and the C _max values (in ng / ml) obtained in our typical experiments; we also provided a calculated variation of the response in experimental animals treated with the same formulation.

HU 212 727 Β

The preparation AUC 0-24 hours Calculated Variation% G '-'max Calculated Variation% First 2969 46.1 655 42.4 11th 3315 35.9 606 29.0 Hl. 3392 33.0 623 25.0 ARC. 4010 35.1 756 30.0 V 2769 27.8 469 21.7

The table shows that the formulations of the present invention have a high degree of bioavailability (AUC and Cmax) and, in addition, the fluctuation of the individual response is low in both AUC and values.

Similarly favorable results were obtained with other formulations described in Examples 1 and 2 above, in particular with the formulations described in Example 1.

Advantageous properties of the compositions of the invention after oral administration have also been demonstrated in clinical trials, for example as follows.

The subjects studied were adult volunteers, such as 30-55 year old medical professionals. Study groups generally consisted of 12 subjects.

The following selection and exclusion criteria were used in the tests:

Recording Requirements: Normal ECG; normal blood pressure and heart rate; 50-95 kg body weight.

Exclusion Criteria: A condition of clinical significance, which may interfere with the absorption, distribution, metabolism, excretion or safety of the active substance; significant clinically abnormal condition within 2 weeks prior to study; clinically relevant abnormal laboratory values or ECG; the need for concurrent treatment throughout the study; administration of any drug known to be toxic to the larger organ system during the previous 3 months; dosing of any drug in the research phase during the 6 weeks prior to the study; drug or alcohol abuse; Blood loss of 500 ml or more in the last 3 months; adverse reaction or hypersensitivity to the active substance; allergy requiring medication in the individual's history; Hep.-B / HIV-positive controversy.

Before and after our experiment, we performed a complete physical and ECG examination. During the 1-month period before and after the experiment, the following parameters were evaluated:

Blood tests: determination of red blood cell count, hemoglobin, hematocrit, blood cell count, white blood cell count, smear, platelet count (platelet count) and fasting blood glucose (glucose concentration).

Blood serum / plasma: total protein, electrophoresis; cholesterol, triglyceride, sodium, potassium, iron **, Ca **, Cl, creatinine, urea, uric acid; SDOT, SGPT values; Determination of -GT, alkaline phosphatase, total bilirubin, α-amylase.

Urine test: determination of pH, microalbumin, glucose, erythrocytes, ketone bodies, sediment.

The creatinine clearance of the test subjects was determined 1 month prior to enrollment.

Test formulations were administered to all test subjects in random order. The formulations were administered once daily up to a total dose of 150 mg cyclosporin, e.g. cyclosporin A, and were omitted for at least 14 days between each administration.

Dosing was done so that patients could only drink water for at least 10 hours before breakfast, but no food. For the 24 hours following dosing, only decaffeinated soft drinks were allowed. Subjects were not allowed to smoke for 12 hours after dosing. Each subject had a standardized lunch after 4 hours post-dose.

One hour before dosing, and one hour after dosing, one hour, half an hour, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 9, 12, 14, At 24, 28 and 32 hours, 2 ml blood samples were taken. Blood samples of 2 ml were taken immediately prior to dosing, and 12, 24 and 48 hours after dosing to determine creatinine. For the determination of cyclosporin, blood samples were placed in two EDTA polystyrene tubes (1 ml each) at each indicated time point and frozen at -20 ° C with gentle agitation. Ciclosporin was determined in whole blood by radioimmunoassay (RIA) for specific and / or non-specific monoclonal antibody measurements; the limit of detection in both cases was about 10 ng / ml.

In one experiment, Formulation 1 (i.e., hard gelatin capsule formulation) prepared by the process of the invention was compared with Formulation X below.

Composition of Formulation X (Known for Comparison)

The dosage unit (soft gelatin capsule) of this preparation contained the following components:

Ciclosporin 50 mg

Labrafil 150 mg

Ethanol 50 mg

Corn oil 213 mg

Total unit dose: 463 mg (This product is a commercially available oral Sandimmun drink.)

A study with Formula I and Formula X above showed that the rate of bioavailability of Formula I was 149.0% (+ 48%) compared to Formula X, which has a bioavailability! was taken as 100%. For formulation I, the AUC (0-32 hours, hours xng / ml) and C50 (ng / ml) were 2992 (± 627) and 882 (± 18), while those for formulation X these values are 2137 (± 606) and 515 (± 180).

In III. and IV. Figures 3A to 5B show superimposed graphs obtained from such an assay

Cyclosporin A concentrations were determined in all 12 test subjects following single oral administration of formulation I (Figure III) and single oral administration of formulation X (Figure IV). In each case, 150 mg of ciclosporin A was added and ciclosporin A was measured by a specific monoclonal RIA assay. Blood concentration (blood level, ng / ml) was plotted on the ordinate and elapsed time (in hours) was plotted against the abscissa.

In III. and IV. Comparison of Figures 1 to 5 clearly shows that, unlike Preparation X, the variation in bioavailability parameters in the biological response of individual test subjects was significantly reduced during the administration of Formulation I. The coefficient of variation (standard deviation multiplied by 100) was determined to be 35% for Formula X and only 20% for Formula I.

Similar or equivalent results may be obtained using other formulations of the present invention, such as those described in the Examples, especially those described in Example I.

In vivo testing of topical dosage forms

Investigation of allergic contact dermatitis in guinea pigs

Male Hartley guinea-pigs (400-500 g) were sensitized with 50 μΐ of 0.5% DNFB in 4: 1 acetone / olive oil by applying the solution to the epilated areas of the left and right flanks of the animals. The second application of the sensitizing solution caused allergic inflammation, which was accompanied by reddening and cellular infiltration (thickening) of the skin. The test composition (e.g., Example 3, 6.1 or 3.2) was applied at 200-250 mg with a spatula in the area of the right flank treated with DNFB. The left flap was treated with placebo as control. The test preparation was applied 5 times after sensitization, ie 20 minutes, and then 8, 24, 32 and 48 hours after sensitization. The skin thickness at the site of sensitization was determined before each application and 8 hours after the last application by lifting the skin in a single fold and measuring the thickness. The degree of redness or inflammation was evaluated by eye scale, ranging from 0 to 4. The anti-inflammatory response of the test preparation was determined by comparing it with placebo-treated flanks.

When using the above assay method, a significant reduction in skin thickness was observed compared to placebo, e.g. or 6.2. from the first application of the composition of Example 1 to the final treatment in the experiment.

The following table summarizes the results obtained with the composition of Example 3.

Time elapsed after sensitization (hours) 8 24 32 48 56 % Inhibition of skin thickening compared to placebo as control 56 68 76 75 73

PATENT CLAIMS

Claims (3)

PATENT CLAIMS 1) as a hydrophilic component, 1 to 90% by weight of a pharmaceutically acceptable di (C 1 -C 5) alkyl or di (tetrahydrofurfuryl) ether or partial ether of a C 1 -C 12 mono- or polyoxyalkanediol and / or 1,2-propylene glycol and optionally a C 1 -C 5 alkanol, 1) as a hydrophilic component, 1 to 90% by weight of a pharmaceutically acceptable di (C 1 -C 5) alkyl or di (tetrahydrofurfuryl) ether or partial ether of a C 1 -C 12 mono- or polyoxyalkanediol and / or 1,2-propylene glycol and optionally C 1 -C 5 alkanol; 1) as a hydrophilic component, 5 to 70% by weight of a pharmaceutically acceptable di (C 1 -C 5) alkyl or di (tetrahydrofurfuryl) ether or partial ether of a C 1 -C 12 mono- or polyoxyalkanediol and / or 1,2 -propylene glycol and optionally a C 1 -C 5 alkanol; HU 212 727 Β 1) as a hydrophilic component, a pharmaceutically acceptable di (C 1 -C 5) alkyl or di (tetrahydrofurfuryl) ether or partial ether of a C 1 -C 12 mono- or polyoxyalkanediol, and / or -propylene glycol and optionally a C 1 -C 5 alkanol; 1) as a hydrophilic component in an amount of from 1 to 90% by weight of a pharmaceutically acceptable di (C 1 -C 5) alkyl or di (tetrahydrofurfuryl) ether or partial ether of a C 1 -C 12 mono- or polyoxyalkanediol; -propylene glycol and optionally a C 1 -C 5 alkanol; A process for the preparation of a pharmaceutical composition in the form of a microemulsion pre-concentrate comprising 0.1 to 35% by weight of cyclosporin, and 2) as a lipophilic component, 0.5-90% by weight of a fatty acid triglyceride and 2) 0.5-90% by weight of the lipophilic component, 3) 1-90% by weight of a wetting agent and at least an equal volume of water and optionally other additives and excipients, where the total amount of the components is 100% by weight, is intimately mixed into a microemulsion. (Priority: September 16, 1988) 16. The process according to claim 15, wherein the components 1), 2) and / or 3) are as defined in claims 1 or 4-13. The materials defined in claims 1 to 5 are used. (Priority: September 16, 1988) 17. The process according to any one of the preceding claims, wherein the cyclosporin is eiclosporin A or [Nva] ² -ciclosporin (Preferred September 16, 1988). 18. A pharmaceutical composition for oral administration A process for preparing a microemulsion preconcentrate form upon contact with water forms a smaller average particle size of the microemulsion than 1000 nm, wherein the active ingredient is 0.1 to 35% by weight eiklosporin A or [Nva] ² -Ciclosporin, furthermore 2) up to 2-45% by weight of a lipophilic component and 3) 20-90% by weight of a wetting agent and optionally a co-wetting agent and optionally other additives and excipients, wherein the total amount of the components is 100% by weight, and if desired, the resulting composition is formulated in a unit dose, preferably soft - or filled into hard gelatine capsules. (Priority: September 1, 1989) 4. A process according to claim 3 wherein the hydrophilic component is 1,2-propylene glycol. (Priority: 09.09.1989) The process according to claim 3 or 4, wherein the hydrophilic component is an additional component of a C 1 -C 5 alkanol. (Priority: 09.09.1989) 6. A process according to claim 5 wherein the C 1 -C 5 alkanol is ethanol. (Priority: 09/09/1989) 7. The process according to any one of claims 1 to 3, wherein the lipophilic component is a fatty acid triglyceride. (Priority: September 16, 1988) 8. A process according to any one of claims 1 to 3, characterized in that the wetting agent is a polyoxyethylene glycol naturalized or hydrogenated vegetable oil. (Priority: September 16, 1988) 9. A process according to any one of claims 1 to 3, characterized in that the wetting agent component is a wetting agent and a co-wetting agent. (Priority: 9/9/1988) 10. The process of claim 9, wherein the wetting agent is a polyoxyethylene glycolated natural or hydrogenated vegetable oil and the co-wetting agent is a monoglyceride. (Priority: 09.09.1989) 11. A 3-10. A process according to any one of claims 1 to 5, wherein 5-45% by weight of 1,2-propylene glycol is used. (Priority: 09.09.1989) A method according to any one of the preceding claims. characterized in that 5 to 20% by weight of cyclosporine is used. (Priority: 09.09.1989) The process according to any one of the preceding claims, wherein the lipophilic component is present in an amount of from 2% to 45% by weight. (Priority: 09.09.1989) 14. The process of claim 2, wherein the wetting agent is a fatty acid saccharide monoester. (Priority: 2/9/1989) 15. A process for the preparation of a pharmaceutical composition in the form of a microemulsion comprising 0.1 to 35% by weight of cyclosporin as an active ingredient. 2) 0.5-90% by weight of a lipophilic component and 3) 1 to 90% by weight of a wetting agent and optionally a co-wetting agent and, if desired, other additives and excipients wherein the total amount of the components is 100% by weight, and if desired, the resulting composition is formulated in a unit dosage form, preferably filled into soft or hard gelatin capsules. (Priority: 2/9/1989) 3. A process for the preparation of a pharmaceutical composition in the form of a microemulsion pre-concentrate comprising 1-30% by weight of cyclosporin, and 2. A process for the preparation of a pharmaceutical composition in the form of a microemulsion preconcentrate which, when contacted with water, is capable of forming a microemulsion having an average particle size of less than 100 nm, characterized in that 0.1 to 35% by weight of cyclosporin 2) 0.5-90% by weight of a lipophilic component and 3) 1 to 90% by weight of a wetting agent and optionally a co-wetting agent and, if desired, other additives and excipients wherein the total amount of the components is 100% by weight, and if desired, the resulting composition is formulated in a unit dose, preferably filled into soft or hard gelatin capsules. (Priority: September 16, 1988) 3) from 1% to 90% by weight of a natural or hydrogenated vegetable oil of polyoxyethylene glycol and a monoglyceride as a wetting agent and, if desired, other additives and excipients wherein the total amount of the components is 100% by weight - mixed internally. (Priority: 09.09.1989)