HU213394B - Process for producing pharmaceutical compositions containing cyclosporins as active components - Google Patents

Description

FIELD OF THE INVENTION The present invention relates to novel pharmaceutical compositions containing cyclosporins as active ingredient, preferably in galenic form, using 3 to 50 times the amount of fatty acid sucrose / fatty acid raffinose monoester and using a diluent or carrier.

Cyclosporins are specific cyclic, multi-N-methylated undecapeptides that generally exhibit pharmacological, in particular immunosuppressive, anti-inflammatory and / or anti-parasitic effects. The first 20 isolated ciclosporin, also a parent compound of this group, is a natural substance, a fungal metabolite of cyclosporin A of formula (A), which is currently marketed as Sandimmun ^R and Sandimmune ^R , respectively. In the formula (A), -MeBmt represents the N-methyl- (4R) -4-but-2E-en-1-yl-4-methyl- (L) threonyl group of the formula (B), wherein -xy- is trans -CH = CH-.

So far, the parent compound of the compound group, cyclosporin A, has attracted the most interest. In clinical trials, cyclosporine is used as an immunosuppressive agent, particularly in organ transplantations, such as lung, heart, combined lung-heart, liver, kidney, pancreas, bone marrow, skin and corneal transplantation. used in the transplantation of organs (from other individuals). Cyclosporin Aval has achieved remarkable success in this area.

At the same time, the potential for use of cyclosporin A in various autoimmune diseases and inflammatory conditions, in particular in 40 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. In these areas 45 numerous results have been achieved in both in vitro and 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 hemolytic anemia, aplastic anemia, anemia associated with red blood cells only, and ideopathic thrombocytopenia); systemic Lupus erythematodes, multiple cartilage, scleroderma, Wegener's granulomatosis, myocardial inflammation, chronic active liver inflammation, severe muscle weakness, psoriasis, Steven-Johnson syndrome, idiopathic fibrosis and autoimmune Crohn's disease); internal weaning ophthalmic diseases, Graves disease, multiple sclerosis, sarcoidosis, primary biliary obstructive hepatic cirrhosis, primary juvenile diabetes mellitus, anterior and uveal inflammation, pulmonary peritonitis, pleural effusion psoriatic arthritis and renal glomerular inflammation (nephrotic; with or without syndrome, such as idiopathic nephrotic syndrome and minor renal disorders).

Research has further explored the possibility of using cyclosporin A for the treatment of parasitic infections, particularly protozoan infections such as malaria, cocci cidomycosis and helminth; more recently, attempts have been made to use it as an anticancer agent in cancer therapy 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 cyclosporin group of compounds includes, for example, naturally occurring cyclosporin 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 the dihydro-cyclosporins (wherein the -xy- in formula (B) above is saturated, i.e., -CH ₂ - CH ₂ ]; derivatized cyclosporins (wherein, for example, an additional substituent is attached to the α-carbon of the 3-position sarcosyl 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, as well as U.S. Pat. and Nos. 4,220,641; U.S. Patent Nos. 0,034,567; and 0 056 782. European publication documents; No. 86/02080; PCT Application; and the following are 60: Transp. Proc. 15, Suppl. 1, 2230 (1983); Angew.

HU 213 394 Β

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 includes, for example, / Thr / ² -, / Val / ² -, / Nva / ² - and / NVA / ² - / Nva / ⁵ -ciclosporin A (these are cyclosporin C, D, G and Also known as M); and [3-0-acyl-MeBmtj'-cyclosporin A (also known as cyclosporin A acetate); a [dihydro-MeBmt] '- [Val] ² -ciclosporin A (dihydrocyclosporin D); [3'-deoxy-3'-oxo-MeBmt] '- [Val] ² - and - [Nva] ² -ciclosporin At, a [(D) -fluoromethyl-Sar] ^3- cyclosporin A, a [ (D) Ser] ^s -ciclosporin At, a / Melle / ¹ '-ciclosporin At, a [(D) MeVal] ¹¹ cyclosporin At (cyclosporin H); [MeAla] ^6- cyclosporin At and [(D) Pro] ^3- cyclosporin At.

The nomenclature currently used to designate cyclosporins in this patent application 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, at position 3, instead of -Sar-, - (D) There is a pro group) followed by the term "cyclosporin A" to identify those portions of the molecule which are identical to the corresponding portions of the cyclosporin A molecule. Each group is numbered starting with the -MeBmt or -dihydro-MeBmt group at position 1 or the corresponding 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 therapy, difficulties have arisen in developing more effective and expedient dosage forms, and due to the occurrence of undesirable side effects, particularly renal effects, which have caused severe 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, especially 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.

The bioavailability value of the oral ciclosporin formulations currently used is low and varies from patient to patient, from disease to disease, and even from time to time in the same individual. According to the literature, the average absolute bioavailability of the currently available commercially available ciclosporin broth is only about 30% and varies significantly between patient groups, such as its use in liver transplants, for which the 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.

For the purpose of immunosuppressive therapy, the concentration of ciclosporin in 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 concurrently with ciclosporin therapy. Due to the wide variation in bioavailability achieved with the currently conventional dosage forms, the daily doses required to achieve the desired plasma concentrations vary significantly from patient to patient and even from one patient to another. 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 inevitably is 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.

Various suggestions have been made to overcome the above difficulties, both for solid and liquid oral dosage forms. Thus, Japanese Patent Publication No. 71682/1985 to Takada et al., discloses methods for the release of cyclosporins in the lymph

EN 213 394 Β, specifically by co-administration with surfactants. Examples of surfactants (wetting agents) listed generally include: fatty acid esters of sucrose, such as oleate, palmitate and stearate of sucrose; and other fatty acid esters, in particular sorbitan fatty acid esters such as sorbitan oleate, palmitate or stearate. Although the use of both mono- and polyesters is suggested herein, it is preferred to use mono- or di-esters. Other surfactants include polyoxyethylated, hydrogenated vegetable oils, such as those known and commercially available under the tradenames Cremophore RH and Nikkol HCO 60; according to this disclosure, the latter products are obviously more advantageous than sucrose ester surfactants.

Example 3 of the above-cited Japanese Patent Application describes the preparation of an aqueous solution containing a sucrose fatty acid ester FI60 as a surfactant. This aqueous preparation contains 3.5 mg of cyclosporin A and 2 mg of sucrose ester in 1 ml of water. Ultrasound at 100 W for 5 minutes is required to disperse cyclosporin A. The resulting composition, described as a "clear solution", is used directly in animal models to test the relative absorption in the lymph. Since cyclosporin A is very insoluble in water and minimal amounts of wetting agent are used, it is obvious that the exemplary solution is the product of an ultrasound treatment. The concentration of ciclosporin A thus obtained is insufficiently low, for example, for oral administration, and the composition is by no means stable and can therefore be excluded in practice, for example as a commercially available galenic form. Essentially, it is an experimental system that can be used for laboratory research but is not suitable for any other purpose. The use of surfactants is described herein solely in connection with lymphatic release.

Japanese Patent Application Laid-Open No. 193129/1987, also published by Takada et al., Issued 038029/1989 and published on 08.08.1989, discloses powder formulations which are solid, non-wetting, such as sucrose, sorbitol. containing tartaric acid, urea, cellulose acetate phthalate, methacrylic acid / acrylic acid methyl ester or hydroxypropyl methylcellulose phthalate, in combination with a small amount of surfactant. Again, the surfactant is used for the purpose of enhancing lymphatic release, and in this respect, the disclosure is clearly intended to enable the practice of the above-mentioned Japanese Patent Application Laid-Open No. 71682/1985. Sucrose esters are not mentioned in this application as useful humectants. Sorbitan esters are still mentioned as useful humectant components. However, it is reiterated that Nikkol HCO 60 products are the preferred wetting agents and in the examples only Nikkol HCO 60 is used; they do not suggest that any increase in lymphatic release provides any practical benefit or that any difficulties previously encountered with cyclosporine therapy, such as any of the above-mentioned problems, can be overcome.

The present invention enables the preparation of novel Galenic cyclosporin formulations containing novel fatty acid saccharide monoesters as the primary excipient components that overcome or substantially reduce the difficulties encountered so far with cyclosporin therapy, such as cyclosporin Aval.

In particular, it has been found that the compositions of the invention (hereinafter briefly, the compositions of the invention) enable the preparation of solid, semi-solid and liquid dosage forms containing a sufficient concentration of at least 10% by weight of cyclosporin for oral administration, for example. and, at the same time, the efficacy of the composition is improved, which is reflected, for example, in the bioavailability characteristics.

It has thus been found that the compositions of the present invention allow effective administration of ciclosporin by simultaneously increasing absorption and bioavailability and reducing absorption and bioavailability variability in both the type of ciclosporin-treated disease and the individual patient. Using the principles of the invention, dosage forms of ciclosporin can be prepared that will reduce fluctuations in ciclosporin levels in blood or plasma between patients 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 allow for a more accurate standardization and optimization of the daily dose of cyclosporine-treated individuals in groups of patients receiving equivalent therapy.

Accordingly, the present invention provides a method for preventing the transplantation of a transplanted organ containing a cyclosporin active ingredient as component a), a monoester of sucrose monoester and / or raffinose monoester fatty acid as component b) and optionally your pharmaceutical excipient. and a pharmaceutical composition for treating autoimmune diseases. According to the invention, component (a) is used in a weight ratio of component (a) to component (b) of from 1: 3 to 1:50, and component (c) is optionally mixed with diluents or excipients to form a pharmaceutical composition. , where

(i) both active ingredient (a) and component (b) are independently soluble in component (c) at a concentration of at least 10% by weight at ambient temperature; or ii) the active ingredient a) relative to component c)

The weight ratio of the composition in the composition ranges from 1: 0.5 to 1:50; or iii) the composition is formulated in a solid dosage unit for oral administration; or (iv) component (c) is a poly (C 2 -C 4 alkylene) glycol having an average molecular weight of not more than 7,000 or a viscosity of not more than 15,000 mPa.s at 50 ° C; or component (c) is a (C 3 -C 5 alkylene) polyol; ether or ester; obsession

v) component c) is a solid polymer carrier, an organic silica polymer, or a dilute or viscous paraffin, and the active ingredient a) is in the form of a solid solution with component b).

The present invention preferably relates to a process for the preparation of a pharmaceutical composition which

(a) an active ingredient, ciclosporin, and

b) Contains a C18 -C8 sucrose monoester as component.

The process is characterized by:

(c) as a component, a substance in which:

The active ingredient a) and component b) are independently soluble at ambient temperature in a concentration of at least 10% by weight.

The invention further preferably relates to a process for the preparation of a pharmaceutical composition which

(a) an active ingredient, cyclosporin, and

(b) as a component, one C 0 -C contains sucrose monoester. The process is characterized in that the cyclosporin active ingredient is used as a solid solution in the form of a solid solution with fatty acid sucrose monoester in a carrier medium.

The invention further relates to a process for the preparation of a pharmaceutical composition which

(a) an active ingredient, ciclosporin, and

b) as a component containing a sucrose monoester of C ^ is C Cavav acid.

The process is characterized in that the cyclosporin active ingredient is used in the form of a solid solution with the fatty acid monoester, and component (c) is a solid carrier, preferably a solid polymer.

A preferred embodiment of the method of the invention relates to the preparation of a pharmaceutical composition for use as an active ingredient in the prevention of transplantation of a transplanted organ containing cyclosporin and in the treatment of autoimmune diseases, wherein:

(a) as an ingredient, a cyclosporin active substance,

(b) sucrose monoester as a component and

c) diluent component c ¹ ) ethanol, c ² ) C 2 -C 4 alkylene glycol, c ³ ) C 3 -C 5 alkylene polyol or c ⁴ ) poly (C 2 -C 4 alkylene) glycol optionally mixed with pharmaceutical excipients to form a pharmaceutical composition. wherein (ii) the weight ratio of component (a) to component (c) is from 1: 0.5 to 1:50; or iii) the composition is formulated in a solid dosage unit for oral administration; or iv) component c) comprises a component having an average molecular weight of less than 7,000 or a viscosity of at most 15,000 mPa.s. at 50 ° C.

In a further preferred embodiment of the present invention, pharmaceutical compositions for use as an active ingredient in the prevention of the transplantation of a transplanted organ containing cyclosporin and in the treatment of autoimmune diseases are prepared by:

(a) as an ingredient, a cyclosporin active substance,

(b) a sucrose monoester as a component and

c) optionally forming 1,2-propylene glycol as a component in admixture with excipients customary in the pharmaceutical formulation, wherein ii) the weight ratio of component a) to component c) ranges from 1: 0.5 to 1:50; or iii) the composition is formulated in a solid dosage unit for oral administration.

The present invention provides pharmaceutical compositions containing cyclosporin as an active ingredient for the prevention of transplantation and for the treatment of autoimmune diseases by:

a) an active ingredient of cyclosporin as component

(b) in the form of a solid solution with a sucrose monoester of a fatty acid; and

c) as component, polyvinylpyrrolidone as a solid polymeric carrier is optionally mixed with a pharmaceutical excipient to form a pharmaceutical composition. In this process, component (a) is preferably used in a weight ratio of from 1: 3 to 1: 20 relative to component (b), and component (c) is used in an amount of at least 10% by weight based on the total weight of the composition.

The composition is conveniently formulated in a dosage unit containing from 2 to 200 mg of component a) each.

According to the present invention, pharmaceutical compositions containing cyclosporin as an active ingredient for the prevention of transplantation and for the treatment of autoimmune diseases are preferably prepared by:

(a) as an ingredient, a cyclosporin active substance,

b) a sucrose fatty acid mono ester component and c) 1,2-propylene glycol component ² ) optionally in the conventional pharmaceutical formulation5

EN 213,394 Β to form component (a) in an amount of 20 mg to 100 mg, component (a) to component (b) in a weight ratio of 1: 3 to 1: 200, and Component a) is present in a weight ratio to component c) of from 1: 0.5 to 1:50.

In the process of the invention, component (a) is preferably cyclosporin A and component (b) is preferably raffomose monolaurate or sucrose monolaurate.

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 standardizing the bioavailability characteristics, the present invention provides an opportunity to reduce the incidence of undesirable side effects in patients treated with ciclosporin, particularly to avoid renal toxicity.

The invention also makes it possible to prepare non-alkanol based formulations which may be completely or substantially free of, for example, ethanol. The stability and processing problems associated with such formulations - which always occur with known alkanol formulations - do not occur. Thus, the invention makes it possible, inter alia, to provide compositions which, for example, are more suitable for the preparation of hard or soft gelatine capsule formulations and which do not at all, or substantially do not cause any difficulty in packaging such as those mentioned above for soft gelatine capsules.

In particular, the present invention makes it possible to prepare a pharmaceutical composition in which

(i) both active ingredient (a) and component (b) are independently soluble in component (c) at ambient temperature in a concentration of at least 10%; or ii) the weight ratio of active ingredient a) to component c) in the composition is from 1: 0.5 to 1:50; or iii) the composition is formulated in a solid dosage unit for oral administration; or (iv) component (c) is a poly (C 2 -C 4 alkylene) glycol having an average molecular weight of not more than 7,000 or a viscosity of not more than 150,000 mPa.s at 50 ° C; or component (c) is a (C 3 -C 5) alkylene a) polyol ether or ester; obsession

v) component c) is a solid polymer carrier, an organic silica polymer, or a dilute or viscous paraffin, and the active ingredient a) is in the form of a solid solution with component b).

The compositions defined above are new and a

Particularly advantageous versions of French Patent Application No. 8811953 and corresponding formulations which are widely claimed in other countries around the world.

(For example, U.S. Patent Application Serial No. 07 / 243,577, German Patent Publication No. 3,830,494, Japanese Patent Publication No. 231396/88, and British Patent Publication No. 88 21443.9; first published in France, March 1989 Published on the 17th under 2,620,336.)

The definitions in (i) to (v) above shall be understood as not mutually exclusive. Thus, the compositions of the present invention may meet any one of the above definitions, or multiple definitions at the same time. Preferred compositions according to the invention are, for example, those which meet two or more of the definitions enumerated in i) to v).

By "pharmaceutical composition", as used herein, is meant a composition whose individual components or active ingredients are pharmaceutically acceptable per se, for example, orally, when intended for oral administration; or, for example, for topical administration, when the composition is formulated for topical administration.

Preferably, the active ingredient a) is cyclosporin A. A preferred component a) is also cyclosporin G, also known as (Nva) ² -ciclosporin.

Water-soluble fatty acid saccharide monoesters, such as fatty acid saccharide monoesters, which are soluble in water at ambient temperature in a concentration of at least 3.3%, i.e. in which at least 1 g is soluble in 30 ml of water at ambient temperature, are preferably used as components b).

The fatty acid units of the products used as component b) may be saturated or unsaturated fatty acids or mixtures thereof. Thus, component (b) may be a monoester of C 6 -C 18 fatty acids with sucrose or raffinose, in particular a water-soluble (C 6 -C 18) sucrose monoester. Particularly preferred components (b) are C 6 -caproic acid, C 8 -caprylic acid, C 10 -capric acid, C 12 -carboxylic acid, C 14 -myristic acid, C 14-palmitic acid, C 18 oleic acid, C 18 ricinoleic acid and C 18 carboxylic acid. sucrose or raffinose monoesters of stearic acid, especially lauric sucrose or raffinose monoesters.

Particularly preferred components (b) are sucrose monocaproate, sucrose monolaurate, sucrose monomyristate, sucrose monoolicinoleate, sucrose monocaproate, raffinose monolaurate, raffinose monomiristate, raffinose monourate, raffinose mono-monopyrate, raffinose mono-monopyrate, raffinose Most preferred component b) is raffinose monolaurate; sucrose monolaurate is highly preferred.

The hydrophilic-lipophilic equilibrium (HLB) of the components b) is preferably at least 10.

The purity of the components b) for the ester group is vo6

Preferably, at least 80%, more preferably at least 90%, most preferably at least 95% are used. The melting point of component b) is preferably in the range of about 15 ° C to about 60 ° C, more preferably in the range of about 25 ° C to about 50 ° C.

Components (c), as defined in formulations (ii) and (iii) above for the compositions of the invention, are materials in which components (a) and (b) are substantially soluble at ambient temperatures, e.g. Preferred components c) are materials in which components a) and b) are independently soluble in at least 10% [as required by definition (i)], preferably at least 25%, most preferably at least 50% soluble [e.g. , in which each component (a) and (b) are independently soluble in an amount of at least 100 mg, preferably 250 mg, most preferably at least 500 mg, at ambient temperature]. Particularly preferred are materials in which component a) is soluble in a concentration of at least 10%, preferably at least 25%, most preferably at least 50%, and / or in which component b) is soluble in at least 100%, more preferably at least 200%, most preferably at least 300%. that is, in which component (b) has a solubility of at least 1000, more preferably 2000, most preferably at least 3000 mg / ml],

Examples of components c) used in the compositions of the invention include:

c ¹ ) ethanol:

c ² ) C 2 -C 4 alkylene glycols;

c ³ ) C 3 -C 5 alkylene polyols;

c ⁴ ) poly (C 2 -C 4 alkylene) glycols, and c ⁵ ) ethers or esters of C 3 -C 5 alkylene polyols.

According to the general object of the invention, the use of ethanol, either alone or in admixture with other component c), is generally less advantageous.

If component c) is a C ² -C 4 alkylene glycol according to c ² ), it is preferably propylene glycol, most preferably 1,2-propylene glycol. If component c) is a C ³ -C 5 alkylene polyol according to c ³ ), it is preferably a C 3 -C 5 alkylene triol, most preferably glycerol.

If component (c) is poly (C2-C4 alkylene) glycol, it is preferably polyethylene glycol. Preferably, such components are used in the compositions of the invention with an average molecular weight of up to 7000 (see definition (iv) above), for example up to 6600, more preferably up to about 2000, for example up to 1600, and most preferably not more than about 500. preferably having a viscosity of at most about 15,000 mPa.s, more preferably at most about 1000 mPa.s, most preferably at most about 200 mPa.s at 50 ° C or more preferably at ambient temperature (see definition (iv)); Polyethylene glycols described in Fiedler, "Lexikon hoar Hilfstoffe, 2nd Revised and Extended Edition, Vol. 2, 726-731. p. (1981); in particular PEG (polyethylene glycol) 200,300,400 and 600 and PEG 1000, 2000, 4000 and 6000, in particular PEG 200, 300 and 400, which have approximately the following physical characteristics:

PEG 200 PEG 300 PEG 400 PEG 600 Molecule- crowd approx. 190-210 approx. 285-215 approx. 380-420 approx. 570-63 Viscosity mPa.s. approx. 46-53 approx. 66-74 approx. 85-95 approx. 130-15 freezing point approx. -50 ° C approx. -16 ° C to -12 ° C approx. -3 ° C Up to 8 ° C approx. 15 ° C Up to 25 ° C n ²⁵ approx. 1459 approx. 1463 approx. 1465 b. 1467

If c) component comprises a C3-5 alkylene polyol ethers or esters ^[5 c) component], it is suitably C3-5 alkiléntriol, particularly ether or ester is glycerin. Suitable components c ³ ) are, for example, mixed ethers or esters of C 3 -C 5 alkylene triols, i.e. substances having different ether or ester groups, for example, esterified products of C 3 -C 5 alkylene triol esters with other mono- or di-polyols.

Particularly preferred components c ⁵ ) are the mixed fatty acid esters of C 3 -C 5 alkylene triol / poly (C 2 -C 4 alkylene) glycol, in particular glycerol / polyethylene glycol or glycerol / polypropylene glycol.

Particularly useful as components c ⁵ ) in the composition according to the invention are products which are obtained by transesterification of glycerides, such as triglycerides, with poly (C 2 -C 4) alkylene glycols, for example polyethylene glycols, optionally with glycerol. These transesterification products are generally obtained by alcoholysis of glycerides, such as triglycerides, in the presence of poly (C 2 -C 4 alkylene) glycol, e.g. ). Such a reaction is generally carried out by reacting said components (such as glyceride and polyalkylene glycol, optionally glycerol) at elevated temperature under continuous stirring in an inert gas space.

For this purpose, fatty acid triglycerides, such as triglycerides of C 10 -C 22 fatty acids, such as natural and hydrogenated oils, in particular vegetable oils, are preferably used. Suitable vegetable oils are, for example, olive oil, almond oil, peanut oil, coconut oil, palm oil, soybean oil and wheat germ oil, in particular vegetable or hydrogenated oils rich in ester groups with C12-C16 fatty acids.

Preferred polyalkylene glycols are polyethylene glycols, in particular polyethylene glycols having a molecular weight of from about 500 to about 4000, for example from about 1000 to 2000.

Thus, suitable components c ⁵ ) are mixtures of C 3 -C 5 alkylene triol esters, such as mixtures containing mono-, di- and triesters in varying proportions; and mono- and diesters of poly (C 2 -C 4 alkylene) glycols containing small amounts of free C 3 -C 5 alkylene triol and free poly (C 2 -C 5 alkylene) glycol. As stated above, the alkylene triol moiety is preferably glyceryl; preferred polyalkylene glycol units are in particular polyethylene glycol moieties having a molecular weight of about 500-4000; and preferred fatty acid groups are the C 10 -C 22 fatty acid ester groups, especially the C 10 -C 22 saturated fatty acid ester groups.

Particularly preferred C ⁵⁾ so as components can be defined as a natural or hydrogenated vegetable oils and polyethylene glycol, with glycerol transesterification products of optionally substituted; or mixtures of mono-, di- and triesters of C10-C22 fatty acids with glycerol and mono-diesters of C10-C22 fatty acids with polyethylene glycol, optionally with lower amounts of free glycerol or free polyethylene glycol.

Preferred vegetable oils, polyethylene glycols or polyethylene glycol units and fatty acid groups for the purposes of the above definition are those detailed above. Particularly preferred components c ⁵ ) in the compositions of the present invention are the known commercially available Gelucir products (manufactured by Gatteforse, France), in particular:

(i) Gelucir 33/01, m.p. about 33-38 ° C, saponification number about 240-260;

(ii) Gelucir 35/10, m.p. about 29-34 ° C, saponification number about 120-140;

(iii) Gelucir 37/02, m.p. about 34-40 ° C, saponification number about 200-220;

(iv) Gelucir 42/12, m.p. about 41-46 ° C, saponification number about 95-115;

(v) Gelucir 44/14, m.p. about 42-46 ° C, saponification number about 75-95;

(vi) Gelucir 46/07, m.p. about 47-52 ° C, saponification number about 125-145;

(vii) Gelucir 48/09, m.p. about 47-52 ° C, saponification number about 105-125;

(viii) Gelucir 50/02, m.p. about 48-52 ° C, saponification number about 180-200;

(ix) Gelucir 50/13, m.p. about 46-51 ° C, saponification number about 65-85;

(x) Gelucir 53/10, m.p. about 48-53 ° C, saponification number about 95-115; and (xi) Gelucir 62/05, m.p. about 60-65 ° C, saponification number about 70-90.

The acid number of the products (i) to (x) is less than 2. The acid number of product (xi) is less than 5. All products (ii), (iii) and (vi) - (x) have iodine numbers less than 3. Product (i) has an iodine number of 8 or less. The iodine number of products (iv) and (v) is less than 5. Product (xi) has an iodine number of less than 10. Preferred are components c ⁵ ) having an iodine number of less than 1. It will be appreciated that mixtures of components c ⁵ ) as defined above may also be used in the compositions of the present invention.

When a component c) (i.e. component i) -iv) defined above or component c ') to c ⁵ ) as specifically described above is used, the compositions of the invention will generally employ component a) b) and c). ) components in a carrier medium. Components a) and b) are generally present in the compositions of the invention in a dispersed state or in solution, i.e. in molecular distribution or in the form of a micellar dispersion (optionally as a solid solution). Thus, component (a) (the active ingredient) is generally present as a dispersion or solution in both components (b) and (c); and components b) are generally dissolved in component c). Component b) in the formulations of the invention is generally present as a carrier or solubilizer for component a), while component c) plays the role of a carrier or fluidizing agent. [The invention is obviously not limited to any of the functional relationships of components (a), (b) and (c) unless specifically noted.]

More preferably, when component (c) is used as described above, the composition of the invention is formulated in a solid dosage unit for oral administration, such as hard or soft gelatine capsules for oral administration (see definition iii). ]. Such dosage units, as described in detail below, conveniently contain, for example, 2 to 200 mg of component a).

When the aforementioned component c) is used, the weight ratio of component a) to component c) in the compositions of the invention is preferably from 1: 0.5 to 1:50 (see definition ii). The weight ratio of components a) to b) ranges from 1: 3 to 1:50.

When component c) is used as described above, the compositions of the invention are preferably non-aqueous or substantially non-aqueous compositions (see definition v), e.g., having a water content of 20 Zones, more preferably 10%, more preferably 5%, less than or equal to 1% of the total weight of the composition.

As stated above, specific embodiments of the invention provide the following:

HU 213 394 Β

- Preparation of a pharmaceutical composition comprising component a) and component b) as defined above and one of the components d) c) ¹ ) to c ⁴ ) as a diluent and meeting any of the definitions ii) -v) above;

^_ A pharmaceutical composition comprising a), b) and c ²⁾ as defined above, and satisfies the above ii), iii) or v) definition; as well as

- a pharmaceutical composition comprising a), b) and c ⁵⁾ component as defined above.

When a component c) (i.e. a component according to definitions i) to iv) or a component c ¹ ) to c ⁵ ) as specifically described above is used in the compositions of the invention, the weight ratio of component a) to component c) is preferably about 1: It's between 5 and 1:50. More preferably, the weight ratio of component a) to component c) is from about 1: 1 to about 1:10, more preferably from about 1: 1 to about 1: 5, most preferably from about 1: 1.5 to about 1: 2 To about 5, for example about 1: 1.6 or about 1: 2. The weight ratio of component a) to component b) in the compositions is from 1: 3 to 1: 200, preferably from about 1: 3 to 1: 1. Up to 100, more preferably from about 1: 3 to about 1:50. More preferably, component (a) relative to component (b) 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 by weight.

When the compositions of the invention contain sucrose monolaurate as component b) and 1,2-propylene glycol as component c), the weight ratio of component a) to component b) is preferably from about 1: 6 to about 1: 7, and component a) is ac ) is preferably present in a weight ratio of about 1: 1.5 to 1: 2.5, for example about 1: 2 by weight.

Compositions of the present invention comprising component c) as defined above in any suitable dosage form, for example, for oral, parenteral or topical application, such as on the skin or on the eye, such as for the treatment of ocular autoimmune conditions, or at the site of injury. injection, for example for the treatment of psoriasis.

These compositions are preferably formulated in a dosage unit for oral or other administration.

The amount of component (a) in the unit dosage form will, of course, depend on the condition to be treated, the mode of administration desired and the effect desired; however, in general, these dosage units will each conveniently contain from about 2 mg to about 200 mg of component a), such as cyclosporin A.

Suitable dosage forms for oral administration are, for example, liquids and granules. However, solid dosage unit forms, such as tablets or capsules, especially hard or soft gelatine capsules, are preferred. These oral dosage unit forms conveniently contain from about 5 to 200 mg, more preferably from about 10 to 100 mg, or from about 20 to 100 mg, such as 15, 20, 25, 50, 75 or 100 mg of component a), such as cyclosporin A, each.

A further advantage of the compositions of the invention containing component c) as defined above is that they provide the basis for formulating compositions which release the active ingredient at a modified rate, thereby allowing delayed release of component a) or sustained release of component a) e.g. after oral administration. Such formulations preferably contain a further pharmaceutical excipient, component d), which is capable of modifying the release characteristics of component a). Examples of such d) components are polymeric carriers, in particular thickeners such as polymeric or colloidal thickeners; and water-swellable materials such as water-swellable polymers and colloids.

Examples of well-known known components d) include:

d ¹ ) polyacrylate and polyacrylate copolymer resins, such as polyacrylic acid and polyacrylic acid polymethacrylic acid resins, such as known products commercially available as Carbopol (see Fiedler, Vol. 1, pp. 206-207), especially Carbopol 934, 940 and 941; and Eudragit (Fiedler, Vol. 1, pp. 372-373), in particular Eudragit E, L, S, RI and RS, in particular Eudragit E, L and S;

d ² ) Celluloses and cellulose derivatives such as alkyl celluloses such as methyl, ethyl and propyl celluloses; hydroxypropyl methylcellulose; acylated celluloses include cellulose acetates, cellulose acetate phthalates, cellulose acetate succinate and hydroxypropyl methylcellulose phthalates; and salts thereof, such as sodium salts of (carboxymethyl) celluloses. Suitable materials for use in the compositions of the invention include, for example, known products commercially available under the names Klucel and Methocel (see Fiedler, Vol. 1, pp. 521 and 2, p. 601), in particular Klucel products LF, MF, GF and HF and Methocel K100 KI 5M, K100M, E 5M, E 15, E 15M and E 100M.

d ³ ) Copolymers of polyvinylpyrrolidones, such as copolymers of poly (N-vinylpyrrolidone) and vinylpyrrolidone, such as vinylpyrrolidone and vinyl acetate. For example, commercially available products known as Kollidon (see Fiedler, Vol. 1, pp. 526-527), in particular Kollidon 30 and 90, may be used in the compositions of the invention.

d ⁴ ) Polyvinyl resins such as polyvinyl acetate and polyvinyl alcohol and other polymeric materials such as gum tragacanth, rubber 9

EN 213 394 Β arabic, and alginates such as alginic acid and its salts such as sodium alginates.

d ⁵ ) Silica-type materials such as hydrophilic silica products such as alkylated (such as methylated) silica gels, in particular colloidal silica products such as those known and commercially available under the trade name Aerosil (see Handbook of Pharmaceutical Excipients', published by the British Pharmaceutical Company, pp. 253-256), in particular Aerosil 130, 2 00, 300, 380, 0, OX 50, TT 600, MOX 80, MOX 170, LK 84, and Methylated Aerosil R 972.

If component (d) is used in the composition of the invention, it will be present in an amount of from about 0.5% to about 50% by weight, more preferably from 1% to 20% by weight, based on the total weight of the components (a) + b) + c) + d) from about 2% to about 10% by weight.

When component c) of the composition of the invention is a solid polymeric carrier c ⁶ ) of the type defined in vi) above, it is preferably a water-insoluble or substantially water-insoluble polymeric carrier.

Specifically preferred ⁶ c) are present in the poly (vinylpyrrolidone) s (see Fiedler, supra, concludes 2, pp 748-750), in particular the cross-linked poly (vinylpyrrolidone) s.... Among the substances of this type known in the art and commercially available under the tradename Kollidon (see Fiedler, Vol. 1, p. 527), such as Kollisept (Fiedler, cited in Vol. 719-720) and Povidone and Crospovidone (Fiedler, Vol. 2, p. 751).

Particularly suitable C ⁶⁾ components are poly (vinyl pyrrolidone) s having a molecular weight of at least about 10,000, at least 20,000, or about 25,000, e.g., greater than about 40,000, or more preferably. Particularly noteworthy in this respect are crosslinked polyvinylpyrrolidones. Plasdone XL, Plasdone XL 10 and Crospovidone can be used as components c ⁶ ) in the compositions of the invention.

If the compounds of the present invention uses ⁶ c) component, then preferably component d) is cellulose or cellulose derivative as a water-swellable or water-soluble components, such as any above, d) - is added.

In connection with the compounds of the invention are particularly remarkable c ⁶⁾ components are known, commercially available under the trade name Avicel products (Fiedler, supra, first, Vol. 160-161. P.), Elcema (Fiedler, supra, first binds 326) and Pharmacoat (Fiedler, Vol. 2, p. 707), such as Avicel PH 101 and PH 102, Elcema and Pharmacoat 603.

, Compositions of the invention comprising component c ^{6) of} the component a) is present in b) component in a solid solution form, for example in the form of solid micellar solution, completely or substantially completely molecular distribution or micellar dispersion form. [In practice, components (b) often exhibit high fluidity, for example at ambient or slightly elevated temperatures, and are therefore not considered "solid" in the strictest sense of the word. Accordingly, the term "solid solution" is used herein, for example, in viscous or highly viscous systems.] The solid solution referred to in (a) and (b) preferably comprises a dispersion, i.e., the c ⁶ ) particles are very finely divided . Consequently, the components c ⁶ ) in the compositions of the invention generally play the role of the non-dispersible matrix for the components [a) + b)]. Components d) generally play the role of disintegrants, for example when they come into contact with the contents of the gastrointestinal tract.

Compositions of the invention comprising component c ⁶⁾ preferably comprise an additional component e) which is a binder and / or lubricant. Suitable binders and lubricants are, in particular, salts of fatty acids and alkyl sulfonates, such as metal salts, such as those having more than 10 carbon atoms in the fatty acid or alkyl moiety; for example, salts of C 10 -C 22 fatty acids and C 10 -C 22 alkyl sulfonates with alkali metals or alkaline earth metals, such as sodium, calcium and magnesium. Sodium lauryl sulfate and magnesium stearate (Fiedler, Vol. 2, p. 584) are preferred for use in the compositions of the invention.

If the compositions of the invention are used c ⁶⁾ component in the ratio of component a) to component b) is preferably about 1: 2től 1: 20, preferably about 1: 2.5 to 1: 10, most preferably 1: 3 to 1: 8.

The compositions of the present invention c ⁶⁾ components of the total weight of the composition preferably at least 10 wt%, more preferably at least 15%, in a proportion of at least 20% more preferably. The components ⁶ c) are present in amounts% preferably 10-60% by weight, preferably 15-50% by weight, for example about 20 to 40 weight percent, from about 25 to 30 or 35% by weight relative to the total weight of the composition in the present invention.

If component (d) is used, the weight ratio of component (d) to component (c) ( ⁶ ) is preferably from about 1: 0.5 to about 1: 4, more preferably from about 1: 1 to about 1: 3, most preferably about 1: 1. , From 5 to 1: 2.5, for example about 1: 2 or about 1: 2.5.

If component (e) is used, the weight ratio of component (e) to component (c) ⁶ is preferably from about 1: 5 to about 1:25, more preferably from about 1: 5 to about 1:20, most preferably about 1: 7 from 1 to 15:15.

When the compositions of the present invention contain both components c ⁶ ), d) and e), the total amount thereof is based on the total weight of the composition 10.

And from about 25% to about 75%, more preferably from about 30% to about 65%, and most preferably from about 40% to about 65%. The weight ratio of [a) + b)]: [c) + d) + e)] is preferably from 1: 0.25 to 1: 7.5, more preferably from 1: 0.5 to 1: 5. most preferably from 1: 0.5 to 1: 2, for example about 1: 0.8, 1: 1.2 or 1: 1.3.

Compositions of the invention comprising ^six component c) may be obtained in any appropriate dosage form, for example orally, parenterally or topically administrable form. The compositions of the present invention are conveniently formulated in a unit dosage form, for example, for oral administration.

The amount of component (a) in these dosage units will, of course, depend, for example, on the condition to be treated, the particular mode of administration and the effect desired; however, these dosage units will generally contain from about 2 mg to about 200 mg each of component a), such as cyclosporin A.

For oral administration, for example, granular compositions are preferred. Solid dosage unit forms, such as tablets or capsules, are desirable. These unit dosage forms for oral administration preferably contain from about 10 to about 20 mg to about 100 mg of component a), such as cyclosporin A, for example 15,20.25, 50.75 or 100 mg.

When component c) in the composition of the invention is component c ⁷ ), such as a thin or dense fluid organic silica polymer or paraffin as defined in vi) above, it is component c ^{7 up to} 150 ° C, preferably It is easily fluid at temperatures up to 100 ° C, more preferably up to 50 ° C. Components c ⁷ ) preferably have a maximum viscosity of 15,000 mPa.s, more preferably 1000 mPa.sa, at the above temperatures.

⁷ c) may be used as components of paraffinic hydrocarbons in liquid and semi-solid paraffins and mixtures thereof, such as viscous and flowable paraffin (Fiedler, supra, 2nd vol., 690-691. p.). To facilitate the design of the composition is preferably substantially a liquid or semi-solid paraffins, e.g., thin or viscous paraffin or ⁷ paraffinkeverékeket c) component. However, if it is desired to provide a formulation which releases the active ingredient at a slow rate, this can be achieved by adding solid paraffin, such as hard paraffin ("paraffin durum").

If it contains only a liquid or semi-solid paraffins composition of the present invention as component c ^7), the liquid paraffin in the composition the weight ratio of semi-solid paraffin is about 1: 0.5 to 1: 1.0. In this case the components a) relative preferably about 1 c ⁷⁾ components: 6 to 1: 200, preferably 1: 6 to 1: 100, preferably 1: 6 to 1: 20 up to a weight ratio, for example, in a weight ratio of about 1: 8.

When the composition of the invention contains solid paraffin as component c ⁷ ), the weight ratio of [liquid + semi-solid paraffin] to [solid paraffin] is preferably from about 1: 0.06 to 1: 0.1. In this case, the weight ratio of component a) to component c ⁷ ) is preferably from 1: 6 to 1: 200, more preferably from 1: 6 to 1: 100, most preferably from 1: 8 to 1:20, e.g. 1:10.

Suitable organic silicon oxide polymers suitable as component ⁷ ) are, for example, mainly liquid and semisolid polymeric materials containing the -R ₂ Si-O- moiety, wherein R ₂ is a monovalent organic group, for example C 1-4 alkyl, in particular methyl or phenyl. Particular advantages can be used as organic siloxane polymers which value 0.65-10 about ⁵ cP or 50 cP to 500 cP or 1000 cP to about 10 cP, especially from the viscosity.

Liquid organic siloxane polymers, such as polymethylsiloxane polymers, are preferably used as component c ⁷ for ease of formulation. Such products include, for example, various known silicone oils, such as silicone oils 550, DC 200, SF-1066 and SF-1091 (Fiedler, cited in Vol. 2, p. 826). If the composition of the invention contains as component c ⁷ ) only a liquid organic siloxane polymer, the weight ratio of component a) to c ⁷ ) is preferably from about 1: 6 to 1: 200, more preferably from about 1: 6 to 1: 100 from about 1: 6 to about 1:20, for example about 1: 8.

For example, formulations which are suitable for slow release of the active ingredient may be prepared with semi-solid organic siloxane polymers. For example, various known silicone pastes, such as silicone paste "A" (Fiedler, Vol. 2, p. 826), or mixtures of this paste with other organic silica polymers, can be used. In the latter case, the weight ratio of liquid organic silicone polymer to semi-solid organic silicone polymer in the composition of the invention is preferably from about 1: 0.5 to about 1: 1. In this case, component (a) is preferably used in a weight ratio to component (c) ( ⁷ ) of from about 1: 6 to about 1: 100, preferably from about 1: 6 to about 1:20.

It will be appreciated that the compositions of the invention mixtures of ⁷⁾ ac components may be used.

Compared preferably about one component if the compositions of the invention, c ⁷⁾ component, the B component a)): 6 to 1: 20, preferably from about 1: 6 to 1: 10, most preferably about 1: It is used in a weight ratio of from 6.0 to 1: 6.5, for example about 1: 6.25.

, Compositions of the invention comprising component c ⁷⁾ of the component a) is present in component A) b completely or substantially completely molecular distribution or micellar dispersion form; for example, a solid solution or solid micellar dispersion form. [Here the term "solid solution" is the same

GB 213,394 Β used in a broad sense, as for compositions containing ⁶⁾ component c.] Solid solution comprising component a) and b) ⁷ c) are present in the form of very fine particles in its entirety.

Compositions of the invention comprising component c ⁷⁾ in an appropriate form any suitable dosage form such as oral, parenteral or topical administration - can be prepared by or injection into the damaged site, e.g., for the treatment of psoriasis forms - used, for example skin or eye shape. These compositions are conveniently formulated in a dosage unit for both oral and non-oral administration.

The amount of component (a) in such dosage unit form will, of course, depend upon the condition to be treated, the particular mode of administration and the effect desired; however, these dosage units will generally contain from about 2 mg to about 200 mg each of component a), such as cyclosporin A.

Forms suitable for oral administration include liquids and particulate preparations; however, solid dosage units such as tablets or capsules, especially hard or soft gelatine capsules, are preferably used. These oral dosage units include component (a), e.g. cyclosporin A, in an amount of about 5-200 mg each, more preferably about 10-100 mg or about 20-100 mg, for example 15, 20, 25, 50, 75 or 100 mg in quantities.

A further advantage of the compositions of the invention containing component c ⁷ ) is that they provide the possibility of a modified release of the active ingredient, for example, delayed release of component a) after oral administration or sustained release of component a). Such compositions may be prepared as described above with the solid or semi-solid, ⁷ c) suitable amounts of component applications. Alternatively, such compositions may be prepared by the use of an additional component d) suitable for the

a) modifying the release parameters of the component from the formulation. Such d) components may be, for example, polymeric fillers, in particular thickening agents such as polymeric or colloidal thickening agents, and materials which swell in water; water-swellable polymers and colloids, for example, as defined above under d ¹ ) to d ⁵ ).

If the composition of the invention is applied to component d), then the total weight of suitably from about 0.5 to 30 parts by weight ⁰ /), about 1-20% by weight, most preferably about 1 to 10 weight ⁰ /, quantities present in this component preferably.

It is especially appropriate to the application of compositions ⁵⁾ components of the invention which contain silica in an organic polymer, c ⁷⁾ component.

Compositions of the invention are substantially non-aqueous or contain the components ^{of 7} or c) component c ⁶⁾ non-aqueous, essentially non-aqueous compositions and preferably as described in relation to compositions containing other components c) are described.

The compositions of the invention, whether or not they contain component c) (e.g., whether or not they contain any of the components c ¹ ) to c ⁷ ) or other adjuvants, such as known and commonly used pharmaceutical excipients, e.g. They may contain antioxidants (such as ascorbyl palmitate, tocopherols, butylhydroxyanisole (BHA) or butylhydroxytoluene (BHT)) and flavoring agents.

In particular, the compositions of the invention preferably contain one or more stabilizers and buffering agents, in particular to prevent hydrolysis of component b) or degradation of component a) during processing or storage. Stabilizers include citric acid, acetic acid, tartaric acid or fumaric acid, and basic stabilizing agents such as potassium hydrogen phosphate, glycine, lysine, arginine or tris (hydroxymethyl) aminomethane.

These stabilizers or buffering agents are used in an amount suitable to achieve or maintain a pH of from about 3 to about 8, more preferably from about 5 to about 7, such as from 6 to 7. Stabilizers are generally used in amounts of up to 5% by weight of the total composition or up to 10% by weight, for example when using citric acid or acetic acid. In the case of the compositions of the present invention, especially those containing the active ingredient cyclosporin A, it is preferable to maintain the above pH range.

The compositions of the present invention are also preferably a polyoxyalkylene-free surfactant such as dioctylsuccinate, dioctylsulfosuccinate, di (2-ethylhexyl) succinate, sodium lauryl sulfate or a phospholipid, e.g. lecithin. If such a surfactant is used, it is preferably present in an amount of 5 to 50, more preferably 10 to 50, for example 10 to 25% by weight of component b).

For compositions comprising a component a) b) component in the form of solid solutions - for example, if the c) component can be defined by above c ⁶⁾ or c ⁷⁾ Component -, stabilizing agents, buffering agents and / or surfactants are preferably incorporated in the solid solution. Such materials may be incorporated, for example, into component c).

The compositions of the invention, irrespective of component c), are preferably ethanol-free or substantially ethanol-free, e.g. containing less than 5.0% ethanol, more preferably less than 2.5% ethanol, e.g. 0% by weight.

In addition to the above, the invention

It is possible to provide a process for the preparation of the pharmaceutical compositions defined above. This process consists of intimately mixing components a), b) and c) as hereinbefore defined, optionally with component d) and / or another component such as a stabilizer, buffer or surfactant as described above, and optionally the resulting composition is converted, for example, by tabletting or filling into gelatin capsules or in any other suitable dosage unit form suitable for oral administration.

If ac) component solvents or as defined above c ^l), c ²⁾ c ^3), c ⁴⁾ or c ⁵⁾ component, it is in the implementation of the method detailed above in a), b) the components a) and b) and components c) are conveniently combined by dissolving components a) and b) in component c), for example, by heating to a temperature of 50 ° C to 150 ° C, preferably up to 70-75 ° C. The resulting mixture is then blended intimately with d) and other components. The filling into capsules, such as hard gelatine or soft gelatine capsules, is suitably carried out at elevated temperatures, for example up to 50 ° C, so that the composition remains warm in liquid form.

In preparing the compositions of the present invention containing component (a) in the form of a solid solution in component (b), for example, compositions containing component (c) ( ⁶ ) or (c) ( ⁷ ) as described above, it is convenient to prepare component (a) first. solid solution in component b) and the resulting solid solution is intimately mixed with other components such as c) and optionally d). A solid solution of component (a) in component (b) can be prepared in a manner known per se, for example, by solidifying the melt containing component (a) in component (b) or by removing the solvent from solution (a) and (b). The latter method is generally preferred for the process of the invention.

Suitable solvents for components a) and b) are preferably lower alkanols, such as ethanol. The stabilizing agents, buffering agents and / or surfactants are suitably included in this solution state.

The resulting solid solution is suitably mixed in a finely divided form with component c) and optionally components d) and e), for example, by distributing it in component c).

Although ethanol may be used in the preparation of the compositions of the present invention, for example in the preparation of the solid solutions described above, this ethanol is preferably removed, for example by evaporation, to form an ethanol-free or substantially ethanol-free product.

The following non-limiting Examples illustrate the process of the present invention in more detail.

Note that it is used in the examples

Sucrose monolaurate L-1969 is commercially available from MitsubishiKasei Food Corp. (Tokyo 104, Japan); HLB (hydrophilic-lipophilic equilibrium) value of at least 12.3, purity of the lauryl ester group of at least 95%, melting at about 35 ° C, decomposing at about 235 ° C, and surface tension of 0.1% by weight - in aqueous solution at about 72.0 dynes / cm at 25 ° C.

EXAMPLES

Components Relative amount mg

1. (a) Ciclosporin (e.g., Ciclosporin A) 50.0

b) Sucrose monolaurate L-1695 312.5

c) 1,2-Propylene glycol 100.0

Total: 462.5

2. (a) Ciclosporin (e.g. Ciclosporin A) 50.0

b) Sucrose monolaurate L-1695 312.5

c) Glycerol 100.0

Total: 462.5

3. (a) Ciclosporin (e.g. Ciclosporin A) 50.0

b) Sucrose monolaurate L-1695 312.5

c) PEG 200 100.0

Total: 462.5

4. (a) Ciclosporin (e.g., Ciclosporin A) 50.0

b) Sucrose monolaurate L-1695 312.5

c) PEG 400 100.0

Total: 462.5

5. a) Cyclosporin (e.g., Ciclosporin A) 50.0

b) Sucrose monolaurate L-1695 350.0

c) 1,2-Propylene glycol 100.0

d) Eudragit E 50.0

Total: 550.0

6. a) Cyclosporin (e.g., Ciclosporin A) 50.0

b) Sucrose monolaurate L-1695 350.0

c) 1,2-Propylene glycol 100.0

d) Methocel K.100 110.0

Total: 610.0

7. (a) Ciclosporin (e.g., Ciclosporin A) 50.0

b) Sucrose monolaurate L-1695 350.0

c) 1,2-Propylene glycol 100.0

d) Aerosil200 15.0.0.0.0

Total: 515 0

HU 213 394 Β

8. a) Cyclosporin (e.g. cyclosporin A) 50.0 b) Sucrose monolaurate L-1695 350.0 c) PEG 400 200.0 d) Eudragit L 2.5 Altogether: 602.5 9. (a) Cyclosporin (e.g. cyclosporin A) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Gelucir (e.g. Gelucir 42 / 12,44 / 14 or 35/10) 100.0 Altogether: 462.5 10. a) Cyclosporin (e.g. cyclosporin A) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Gelucir 100.0 (d) Klucel LF 50.0 Altogether: 512.5

The composition of Example 1 is prepared by dissolving component a) and b) in component c) with stirring on an oil bath at 100 ° C. 2-10. The formulations of Examples 1 to 8 are prepared in a similar manner. In Examples 5 and 8, component d) is dissolved in a pre-prepared mixture of a), b) and c). In Examples 6, 7 and 10, component d) is suspended in a mixture of components a), b) and c).

The compositions thus obtained are filled with "1" size hard gelatin capsules (Examples 1-4 and 9) or "0" size size (Examples 5-7 and 10) during heating, so that An encapsulated end product is obtained wherein each capsule contains 50 mg cyclosporin (e.g. cyclosporin A) which can be used to prevent transplantation or to treat autoimmune diseases. 1-5 capsules are administered daily.

EXAMPLES

Components Relative amount mg

11. a) Cyclosporin (e.g., Ciclosporin A) 100.0

b) Sucrose monolaurate L-1695 300.0

c) Plasdone XL 350.0

d) Avicel PH 102 150.0

e) Sodium lauryl sulfate 25.0

Altogether: 925.0 a) Cyclosporin (e.g. cyclosporin A) 50.0 b ¹ ) Sucrose monolaurate L-1695 350.0 b ² ) Sucrose monostearate 50.0 (c) Crospovidone 250.0 d) Elcema 150.0 (e) Magnesium stearate 30.0 Altogether: 880.0

13. a) Cyclosporin (e.g., Ciclosporin A) 50.0

b) Sucrose monolaurate L-1695 160.0

c) Plasdone XL 10 200.0 d ¹ ) Pharmacoate 603 25.0 d ² ) Avicel PH 101 75.0

e) Magnesium stearate 20.0

Total: 530.0

Afenti 11-13. The formulations of Examples 1 to 4 preferably contain 25 mg of tartaric acid as component f) and / or 50 mg of dioctyl succinate as component g); preferably they contain both products so that the final weight of the composition is all. 1000 mg, Example a

1055 mg for Example 12 and 6180 mg for Example 13.

11-13. preparations are prepared as follows:

Components a) and b) are abs. dissolved in ethanol and the ethanol was completely evaporated in vacuo at 50 ° C. Components c) - e) are added (optionally also components f) and g) and mixed thoroughly by the usual mixing method. The solid solution containing components (a) and (b) is ground to a fine powder and homogeneously mixed with components (c) to (g), and the resulting homogeneous mass is individually compressed into tablets containing 100, 50 or 25 mg of active ingredient (a). for the treatment of autoimmune diseases. During this treatment, 1-5 tablets per day are administered.

EXAMPLES

Components Relative quantity

14. a) Ciclosporin (e.g. Ciclosporin A) 50.0 b) Sucrose Monolaurate L-1695 312.5 c) Liquid paraffin 397.5 Altogether: 15. (a) Ciclosporin (e.g. Ciclosporin A) 50.0 b) Sucrose Monolaurate L-1695 312.5 c) DC 200 silicone oil 397.5 Altogether: 760.0

Components a) and b) are abs. dissolved in ethanol and the ethanol was completely evaporated in vacuo at 50 ° C. The resulting solid solution is ground to a fine powder and suspended homogeneously in component c). The resulting liquid suspension is filled into size 0 hard gelatin capsules to provide capsules each containing 50 mg of cyclosporin (e.g., cyclosporin A) and can be used to prevent transplantation or to treat autoimmune diseases. During this treatment, 1-5 capsules are administered daily.

HU 213 394 Β

EXAMPLES (continued) Components Relative quantity mg 16. a) Cyclosporin (e.g. cyclosporin A) 50.0 b) Sucrose monolaurate L-1695 312.5 c) Dense liquid paraffin 372.5 (d) Hard paraffin 25.0 Altogether: 760.0 17. (a) Cyclosporin (e.g. cyclosporin A) 50.0 b) Sucrose monolaurate L-1695 312.5 (c) Liquid paraffin 397.5 d) Aerosil 10.0 Altogether: 770.0 18. a) Cyclosporin (e.g. cyclosporin A) 50.0 b) Sucrose monolaurate R-1695 312.5 c) Water 100.0 Altogether: 462.5 19. (a) Cyclosporin (e.g. cyclosporin A) 50.0 b) Raffinose monolaurate 400.0 (c) Liquid paraffin 310.0 Altogether: 760.0 20. a) Cyclosporin (e.g. cyclosporin A) 50.0 b) Raffinose monolaurate 312.5 c) Dense liquid paraffin 372.5 (d) Hard paraffin 25.0 Altogether: 760.0 21. (a) Cyclosporin (e.g. cyclosporin A) 50.0 b) Raffinose monolaurate 312.5 (c) Liquid paraffin 397.5 d) Aerosil 10.0 Altogether: 770.0

The formulations of Examples 16 and 17 were prepared in a manner similar to that described for Examples 14 and 15. In Example 16, components (c) and (d) are first mixed and internally mixed, and the solid solution containing components (a) and (b) is suspended in the mixture containing components (c) and (d). In Example 17, component (d) is suspended in component (c) together with components (a) and (b).

1-17. Formulations equivalent to those described in Examples 1 to 8 may be prepared by using another cyclosporin, such as [Nva] ² -ciclosporin, as component a) in place of cyclosporin A; or another fatty acid saccharide monoester (as detailed above), such as raffinose monolaurate as component b), in each case in the same or equivalent amounts or proportions.

The use of the compositions of the invention has been demonstrated in animal and clinical trials, for example as follows.

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

(a) Test preparations

Formulation I: Example 1

II. Preparation: Example 14

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

Blood samples of 2 ml (5 ml for the "blind" test) were collected from the animal's leg vein and 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 abbreviated). 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.

The preparation AUC 0-24 hours Calculated Variation% Cmax Calculated Variation% I 3058 19.9 583 30.9 II. 2894 14.91 544 19.7

The table shows that the level of the compositions of the present invention the bioavailability (AUC and Cmax) low high, moreover, the individual response to fluctuations in both the AUC and C _max values with respect.

Similarly favorable results were obtained with other methods described in Figures 1-17 above. in the use of the compositions described in Examples 1-10, in particular in Examples 1-10. with the compositions described in Examples.

The compositions of the invention are for oral administration

EN 213,394 Β 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 simultaneous 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.

A full physical and ECG examination was performed before and after our experiment. The following parameters were evaluated during the 1-month period before and after the experiment:

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 levels).

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 at least 14 days were discontinued 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 quarter hour, one half hour and one hour; 1.5; 2; 2.5; 3; 3.5; 4; 4.5; 5; 6; 9; 12; 14; 24; Blood volumes of 2 ml were collected at 28 and 32 hours. Blood samples of 2 ml were taken immediately prior to dosing and 12.24 and 48 hours post-dosing for creatinine determination. 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 (abbreviated as R1A) by measuring specific and / or non-specific monoclonal antibodies; the limit of detection in both cases was about 10 ng / ml.

In one of our experiments, the composition of Example 1 (i.e., hard gelatine capsule formulation) prepared by the process of the invention was compared with a commercially available ciclosporin A containing active ingredient. (The test preparation contained 50 mg of cyclosporin A, 150 mg of Labrafil, 50 mg of ethanol and 213 mg of corn oil in soft gelatine capsules; total weight per unit dose was 463 mg.) The test preparation (i.e., Example 1 formulation) contained significantly increased bioavailability; this is shown by both the area under the curve (0-32 hours) and the C _max . We also compared the change in blood concentration of cyclosporin A (as determined by a specific monoclonal RIA) over a single dose versus time, and compared with the change in blood concentration after administration of 150 mg cyclosporin A. It was shown that in all subjects treated with the composition of Example 1, response fluctuation was significantly reduced compared to subjects treated with the standard composition used for comparison.

Similar or equivalent results were obtained with other formulations of the present invention, such as those described in the examples.

Claims (12)

1. A method of preventing the transplantation of a transplanted organ containing a) a cyclosporin active ingredient, component b), a sucrose monoester C6-fatty acid monoester and / or a monoester of fatty acid and optionally a pharmaceutical excipient (s), and characterized in that component (a) is present in a weight ratio of component (a) to component (b) of from 1: 3 to 1:50, and component (c) is optionally mixed with a diluent or excipient in a pharmaceutical composition. we shape where (i) both active ingredient (a) and component (b) are independently soluble in component (c) at ambient temperature in a concentration of at least 10%; obsession (Ii) the weight ratio of active ingredient (a) to component (c) in the preparation is from 1: 0.5 to 1:50; or iii) the composition is formulated in a solid dosage unit for oral administration; or (iv) component (c) is a poly (C 2 -C 4 alkylene) glycol having an average molecular weight of not more than 7,000 or a viscosity of not more than 15,000 mPa.s at 50 ° C; or component (c) is a (C 3 -C 5 alkylene) polyol; ether or ester; obsession v) component c) is a solid polymer carrier, an organic silica polymer, or a dilute or viscous paraffin, and the active ingredient a) is in the form of a solid solution with component b). (Priority: 02.07.1990) Process according to claim 1, characterized in that component (c) is a substance in which the active ingredient (a) and component (b) are independently soluble at ambient temperature in a concentration of at least 10%. (Priority: 2/9/1989) 3. The process of claim 1, wherein component a) is used in the form of a solid solution with component b) in a carrier medium. (Priority: February 2, 1989) 4. The process of claim 1, wherein component a) is used in the form of a solid solution with component b) and component c) is a solid carrier, preferably a solid polymer. (Priority: February 2, 1989) The process of claim 1, wherein (b) as component C ₆ . ₁₈ sucrose monoester fatty acids and c) diluent component is c ¹ ) ethanol c ² ) C 2 -C 4 alkylene glycol, c ³ ) C 3 -C 5 alkylene polyol or c ⁴ ) poly (C 2 -C 4 alkylene) glycol, wherein i) the weight ratio of component a) to component c) is from 1: 0.5 to 1.50; or (ii) a solid dosage unit for oral administration; or (iii) component (c) is an ingredient having an average molecular weight of less than 7,000 or a viscosity of at most 15,000 mPa.s. at 50 ° C. (Priority: 02.02.1990) 6. The method of claim 1, wherein (a) as an ingredient, a cyclosporin active substance, (b) as a component a sucrose monoester of C6 is and c) 1,2-propylene glycol is used as component, wherein i) the weight ratio of component a) to component c) is from 1: 0.5 to 1.50; or ii) the composition is a solid dosage unit for oral administration. (Priority: 02.02.1990) 7. The process of claim 1 wherein component a) is used in the form of a solid solution with component b) and component c) is polyvinylpyrrolidone as a solid polymeric vehicle. (Priority: 02.02.1990) The process according to claim 7, wherein the cyclosporin active ingredient is present in a weight ratio of from 1: 3 to 1:20 relative to C 6 fatty acid sucrose monoester, and component c) is at least 10% by weight of the total composition. by weight. (Priority: 02.07.1990) 9. A process according to any one of claims 1 to 4, wherein the composition is prepared in a dosage unit containing from 2 to 200 mg each of component a). (Priority: 02.02.1990) 10. The method of claim 1, wherein (a) as an ingredient, a cyclosporin active substance, b) as a component, a C C ^. ₁₈ sucrose monoester fatty acids and Component c) is 1,2-propylene glycol, wherein component a) is present in an amount of from 20 mg to 100 mg, component a) is present in a weight ratio of 1: 3 to 1:50 relative to component b), and component a) is used. in a weight ratio to component ac) of from 1: 0.5 to 1:50. (Priority: 02.02.1990) 11. The method of claim 1 or 5-10. A process according to any one of claims 1 to 3, wherein component (a) is cyclosporin A. (Priority: February 7, 1990) 12. A process according to any one of claims 1 to 3, wherein component b) is raffinose monolaurate or sucrose monolaurate. (Priority: 02.02.1990)