KR100256007B1 - Pharmaceutical compositions comprising cyclosporins - Google Patents

Abstract

PURPOSE: Provided are novel galenic formulations comprising a cyclosporin as an active ingredient. The cyclosporins comprise a class of structurally distinctive, cyclic, poly-N-methylated endecapeptides, commonly possessing pharmacological, in particular immunosuppressive, anti-inflammatory and/or anti-parasitic activity. CONSTITUTION: A pharmaceutical composition is characterized by comprising a cyclosporin as an active ingredient, and (1) a hydrophilic phase; (2) a lipophilic phase, and (3) a surfactant, which composition is a 'microemulsion pre-concentrate'. Dosage forms include topical formulations and, in particular, oral dosage forms.

Description

Pharmaceutical composition containing cyclosporin {PHARMACEUTICAL COMPOSITIONS COMPRISING CYCLOSPORINS}

The present invention relates to a novel galenic preparation containing cyclosporin as an active ingredient.

Cyclosporines include a class of structurally unique cyclic poly-N-methylated endecapeptides which have in common pharmacological activity, in particular immunosuppressive, anti-inflammatory and / or antiparasitic activity. The first cyclosporine isolated is a naturally occurring fungal metabolite, Cyclosporin or Cyclosporine, also known as cyclosporin A and sold under the trade names SANDIMMUN ^R or SANDIMMUNE ^R.

Cyclosporin is the cyclosporin of Scheme 1 below.

In Scheme 1, -MeBmt- is the N-methyl- (4R) -4-but-2E-en-1-yl-4-methyl- (L) threonyl residue of Scheme 2 below.

In Scheme 2, -x-y- is -CH = CH- (trans).

As a parent compound of the above compounds, cyclosporine has attracted much attention so far. The first field of clinical research on cyclosporin is as an immunosuppressive agent, in particular organ transplants such as heart, lung, combined cardio-lung, liver, kidney, pancreas, bone marrow, skin and cornea and in particular, inertia (allogenic) long-term transplants, such as the application to the recipients. In this area, cyclosporine has received great results and good reviews.

At the same time, the applicability of cyclosporin to various autoimmune diseases and inflammatory conditions, particularly inflammatory conditions with etiology including autoimmune components such as arthritis (eg, rheumatoid arthritis, chronic progressive arthritis and modified arthritis) and rheumatoid diseases, was high. Reports and results from, in vitro, animal models and clinical trials are widely described in the literature. Specific autoimmune diseases for which cyclosporine treatment is proposed or applied include autoimmune blood diseases (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma, Wegener Wegener granulamatosis, dermatitis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine Systemic eye disease, Graves' disease (ophthalmic goiter), sarcoidosis, multiple sclerosis, primary biliary cirrhosis, acute diabetes mellitus (diabetes type I), uveitis (front and back), dry keratoconjunctivitis and spring keratoconjunctivitis, interstitial Pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephropathy, such as idiopathic nephropathy or microlesion nephropathy).

In other areas of research, as antiparasitic, in particular antigenic, agents, as well as possible uses, including the treatment of malaria, coccidiosis and schistosomiasis, and more recently as agents for extinction of anti-neoplastic drug resistance in tumors, etc. Found promising availability.

Since cyclosporin was first discovered, a variety of natural cyclosporins have been isolated and identified, and more non-natural cyclosporines have been prepared by pre-synthesis or semi-synthesis, or by modified cultures. That is, there are many compounds currently included in cyclosporins, for example, natural cyclosporins A to Z [Traber et al. 1, Helv, Chim, Acta, 60, 1247-1255 (1977); Traber et al. 2, Helv. Chim, Acta. 65 162, 1655-1667 (1982); Kobel et al., Europ. J. Applied Microbiology and Biotechnology 14, 273-240 (1982); And von Wartburg et al., Progress in Allergy, 38, 28-45 (1986)], as well as various non-natural cyclosporine derivatives and artificial or synthetic cyclosporines, such as the so-called dihydrocyclosporin (in Scheme 2, -MeBmt-residue Part of -xy- is saturated to produce -xy- = -CH ₂ -CH _2- ; Derivatized cyclosporin (eg, additional substituents are introduced at the α-carbon atom of the sarcosyl residue at position 3 of the cyclosporin molecule); Cyclosporines wherein the -MeBmt-residue is in isomeric form (eg, the conformation of positions 6 'and 7' of the -MeBmt-residue is in a cis form, not trans); And cyclosporines wherein the variant amino acid is incorporated at a specific position in the peptide sequence. These are for example by the use of pre-synthetic preparations of the cyclosporin of Benzer (see, eg, Traber 1, Traber 2 and Kobel; US Pat. Nos. 4 108 985, 4 210 581 and 4 220 641; European Patent Publications 0 034 567 and 0 056 782; International Patent Publication WO 86/02080; Wenger 1, Transp. Proc. 15, Suppl. 1: 2230 (1983); Wenger 2, Angew. Chem. Ed., 24, 77 (1985); See Wenger 3, Progeress in the Chemistry of Organic Natural Products 50, 123 (1986)).

That is, there are many compounds currently included in cyclosporin, such as [Thr] ² -cyclosporine, [Val] ² -cyclosporine, [Nva] ² -cyclosporine and [Nva] ^2- [Nva] ⁵ -cyclosporine ( Known as cyclosporin C, D, G and M, respectively, [3-0-acyl-MeBmt] ¹ -cyclosporin (also known as cyclosporin A acetate), [dihydro-MeBmt] ^1- [Val] ^2- Cyclosporin (also known as dihydrocyclosporin D), [(D) fluoromethyl-Sar] ³ -cyclosporin, [(D) Ser] ⁸ -cyclosporin, [MeIle] ¹¹ -cyclosporin, [(D) MeVal] ¹¹ -cyclosporin (known as cyclosporin H), [MeAla] ⁶ -cyclosporin, [(D) Pro] ³ -cyclosporin and the like.

[According to the conventional nomenclature for cyclosporine at present, they are defined by quoting the structure of cyclosporin (ie cyclosporin A). This initially marks amino acid residues other than those present in the cyclosporin (e.g., to indicate that the cyclosporin has-(D) Pro-, rather than -Sar-residue at position 3, "[(D ) Pro] ³ and named using the "use a), and the remaining residue is to indicate that it is the same as the ones in the cyclosporine" cyclosporin "refers to. Each residue is numbered beginning with residue -MeBmt- or -dihydro MeBmt- at position 1.]

Most of these additional cyclosporins exhibit comparable pharmaceutical or more specific utility to cyclosporin, such as, in particular, having the activity of extinguishing tumor resistance to cytostatic treatment and their application as therapeutics. Suggestion of gender.

Although cyclosporine has made many contributions, especially in the field of treatment of organ transplantation and autoimmune diseases, it is not only a problem in providing a more effective and convenient method of administration, but also in particular as a nephrotoxic response. Unfavorable side effects are very serious obstacles to widespread use or application. Cyclosporine is characterized by high hydrophobicity. Previously proposed liquid formulations, such as liquid formulations for oral administration of cyclosporin, mainly use ethanol and oil or similar excipients as carrier media. That is, the commercially available cyclosporin beverage-solution uses ethanol and olive oil as carrier media together with the surfactant labrafil (see US Pat. No. 4,388,307). However, the use of beverage-solutions and similar compositions proposed in the art involves many difficulties.

Firstly, oils or oily carriers should be used, which may result in the preparation of an unpleasant taste or in particular cause a taste loss in long-term treatment. This effect can be masked by formulating it in the form of a gelatin capsule. However, to maintain cyclosporin in solution, the ethanol content must be kept high. For example, when ethanol evaporates when opened, for example from capsules or other formulations, the result is cyclosporine precipitation. When such a composition is provided, for example, in a soft gelatin encapsulation formulation, the encapsulated product is encapsulated due to this particular disorder such as an air-tight compartment, for example an airtight blister or aluminum-foil-blister-package. Need to be packed with. This increases the volume of the product and increases the production cost. The storage properties of the formulations described above are far from ideal.

The bioavailability levels achieved using existing cyclosporine oral administration systems are low and show large rates of change between individuals, depending on the type of patient, and even at different times of treatment for one individual. Current commonly used treatments using commercially available cyclosporin beverage solutions exhibit an average absolute bioavailability of only about 30%, between each group, for example, between liver (relatively low bioavailability) and bone marrow (relatively high bioavailability) transplant recipients. It is reported in the literature that the rate of change is large. The reported rate of change in bioavailability among subjects varied from 1% or several% for some patients to 90% or more for others. And as is already known, it is frequently observed that the bioavailability for an individual changes significantly over time.

In order to achieve effective immunosuppressive treatment, cyclosporine blood or serum concentrations must be maintained within certain ranges. The range of needs depends on the specific symptoms to be treated, for example, whether it is for the prevention of transplant rejection or for the control of autoimmune diseases, and whether other immunosuppressive treatments are concurrent with cyclosporine treatment. . Because of the large rate of change in bioavailability obtained with conventional dosage forms, the daily dosage required to achieve the required serum concentrations varies significantly from individual to individual, even for one individual. For this reason it is necessary to monitor the blood / serum concentrations of patients undergoing cyclosporin treatment at regular and frequent intervals. Monitoring of blood / serum concentrations is generally carried out by RIA or equivalent immunoassay techniques, for example using techniques based on monoclonal antibodies, which should be done regularly. This inevitably is time consuming and inconvenient and significantly increases the total cost of treatment.

In addition to all these obvious practical difficulties, the use of commercially available oral dosage forms results in the undesirable side effects already mentioned.

Various methods have been proposed in the art to solve the various problems described above, including solid and liquid oral dosage forms. However, the biggest problem still remains is the insolubility of cyclosporin (e.g. cyclosporin) in aqueous media, thus meeting the required criteria for bioavailability (e.g., constant and reasonably high blood / serum concentrations). To provide a dosage form that can contain cyclosporin at a sufficiently high concentration so that it can be conveniently used to achieve and to achieve effective absorption from the stomach or intestinal lumen.

This specific problem associated with oral administration of cyclosporin inevitably limits the use of cyclosporin therapy for the treatment of relatively less severe or less dangerous diseases. In this respect, a particularly difficult area is for the treatment of autoimmune diseases and other conditions affecting the skin, for example for the treatment of atopic dermatitis and psoriasis, and for promoting hair growth, as is widely proposed in the art, for example It is the employment of cyclosporin therapy in the treatment of alopecia areata due to aging or disease.

Oral cyclosporine therapy has shown that this drug is quite beneficial for patients suffering from, for example, psoriasis, but is not generally available due to the risk of developing side effects after oral treatment. Various proposals have been made in the art for the application of cyclosporin, such as cyclosporin in topical form, and many topical delivery systems have been disclosed. However, to date, attempts at topical application have clearly not provided effective treatment. For example, if there is a topical application that is useful for treating psoriasis and provides effective skin delivery, then cyclosporine therapy will be available to the majority of patients in need thereof.

1 is a three-way plot of the relative concentrations of components (1.1), (2) and (3) in the composition according to (A).

2 is a three-way plot of the relative concentrations of components (1.2), (2) and (3) in the composition according to (A).

3 and 4 are graphs showing the concentration of cyclosporin in blood after oral administration of Composition I and Composition X, respectively.

The present invention provides novel cyclosporine galene formulations in the form of microemulsion preconcentrates and / or based on the use of certain solvent media as described below, and the present invention is directed to the treatment of cyclosporin, such as cyclosporin, which has been previously faced in the art. Solve or significantly reduce problems. In particular, the compositions of the present invention allow for the preparation of solid, semi-solid and liquid compositions containing cyclosporin at a concentration high enough to allow for convenient oral administration, for example, while enhancing efficacy in, for example, bioavailability properties. Turned out.

In particular, the composition according to the present invention simultaneously increases the absorption / bioavailability, as well as reducing the variability of the absorption / bioavailability obtained for each patient undergoing cyclosporin treatment and between individuals, It has been found herein to enable effective cyclosporin administration. Application of the teachings of the present invention can yield cyclosporin dosage formulations that reduce the rate of change in cyclosporin blood / serum concentrations obtained between the doses for each patient as well as between individual / individual patient groups. That is, the present invention can reduce the cyclosporin dosage level required for effective treatment. In addition, the present invention allows for more precise standardization and optimization of continued daily dosage requirements for each individual receiving cyclosporine treatment as well as for a group of patients receiving equivalent treatment.

By more precisely standardizing the dose and response parameters for each patient group as well as the dose rate and blood / serum concentration response of each patient, the need for monitoring can be reduced, thereby significantly reducing the cost of treatment.

By standardizing the bioavailability properties obtained / reducing the required cyclosporin dose, the present invention also provides a means by which to reduce the occurrence of undesirable side effects observed in cyclosporine treatment, in particular the nephrotoxic response. do.

The present invention also allows the preparation of non-alkanol-based compositions such as no or little ethanol. Such compositions can avoid the stability as described above and processing problems associated therewith inherent in known alkanol compositions. The invention is particularly well suited when formulated, for example in the form of capsules (e.g. hard or soft gelatin capsules) and / or for example packaging problems as described above, for example with respect to the soft gelatin encapsulated form. Provided are compositions that exclude or nearly reduce.

With regard to topical application, the present invention contains cyclosporin (such as cyclosporin) as an active ingredient and is an autoimmune disease affecting the skin, in particular pathological proliferation of the epidermis and / or keratinization of the epidermis, in particular psoriasis and atopic dermatitis, etc. It allows the preparation of new galen formulations that can improve the treatment of skin diseases, including. Topically applicable compositions according to the invention are also useful for treating alopecia areata, such as for promoting hair growth.

In a first aspect, the present invention particularly provides a pharmaceutical composition containing cyclosporin as an active ingredient, which composition is in the form of a "microemulsion preconcentrate".

As used herein, "microemulsion preconcentrate" means a system that can be contacted with water, such as added to water to provide a microemulsion. As used herein, the term microemulsion is used in the conventionally accepted sense as a non-opaque or almost transparent colloidal dispersion comprising water and organic components including hydrophobic (lipophilic) organic components. Microemulsions are identifiable as having one or more of the following features. Microemulsions are formed spontaneously or almost spontaneously when they are contacted, ie without a substantial supply of energy (eg without heating or high shear devices or other substantial agitation). Microemulsions exhibit thermodynamic stability. This is a monophase. They are almost transparent, i.e. they are transparent or whitish when viewed under an optical microscope. For example anisotropic structures can be observed when using X-ray techniques, but in the absence of disturbance the microemulsion is optically isotropic.

Microemulsions contain a dispersed phase or particulate (droplet) phase, the particles of which size is 2,000 mm 3 or less, and are optically transparent. Other structures such as, for example, lamellar, hexagonal or liquid crystals with isotropic symmetry are possible, but the particles of the microemulsion may be spherical. In general, microemulsions comprise particles or droplets having a maximum dimension (e.g., diameter) of 1,500 mm 3 or less, for example, usually from 100 to 1,000 mm 3 [more specifically for the properties of microemulsions, See Rosof, Progress in Surface and Membrane Science, 12, 405 or less, Academic Press (1975); Friberg, Dispersion Science and Technology, 6 (3), 317 or less (1985); And Muller et al., Pharm, Ind., 50 (3), 370 and below (1988).

As described above, the "microemulsion preconcentrate" of the present invention may form a microemulsion spontaneously or almost spontaneously in contact with water alone and is a galenic system containing cyclosporin as an active ingredient. Could be. The "microemulsion preconcentrate" pharmaceutical composition comprising cyclosporin as an active ingredient is novel. Thus, as one aspect, the present invention provides composition A) as follows.

A) A pharmaceutical composition which is a "microemulsion preconcentrate" comprising cyclosporin as an active ingredient (the term pharmaceutical composition as used herein and in the appended claims, wherein each component or element itself is pharmaceutically acceptable, For example, it is understood that it defines orally acceptable compositions for oral administration and locally acceptable compositions for topical administration).

In addition to the cyclosporin active ingredient, the "microemulsion preconcentrate" composition of the present invention

1) hydrophilic phase;

2) lipophilic phase; And

3) surfactant

Include ingredients as appropriate.

Cyclosporin is retained in the lipophilic phase. It is suitable that both the hydrophilic phase and the lipophilic phase act as carrier media.

The "microemulsion preconcentrate" of the present invention is a type that provides o / w (oil-in-water) microemulsions. Clearly, however, the composition according to (A) may contain a small amount of water or otherwise exhibit the microstructural properties of the microemulsion, for example in the form of o / w or w / o (water in water). Thus, the term "microemulsion preconcentrate" is understood herein to include this possibility.

The microemulsions obtained by contacting water or other aqueous media with the "microemulsion preconcentrate" compositions of the present invention exhibit thermodynamic stability, i.e., over a long period of time, such as clouding or regular emulsion size droplets. It will remain stable at ambient temperature without formation or precipitation [it is of course known that an appropriate amount of water is required to obtain the microemulsion. The upper limit of the dilution rate is not critical and generally a dilution rate of 1: 1, such as 1: 5 ppw ("microemulsion preconcentrate": H ₂ O) or higher, will be appropriate.] Preferably, the present The "microemulsion preconcentrate" composition of the invention can provide a microemulsion that is stable at ambient temperature when in contact with water, such stability being for at least 2 hours, more preferably at least 4 hours, most preferably at least It is demonstrated that there is no optically observable clouding or precipitation for 12 to 24 hours. For example, at the dilution rates given above, the microemulsions obtained from the "microemulsion preconcentrates" of the present invention preferably have an average particle size of about 1,500 kPa or less, more preferably about 1,000 kPa or 1,100 kPa or less, For example, it has an average particle size of about 150 GPa or 200 GPa or less.

Particularly preferred compositions according to the invention differ in hydrophilicity

1.1. Pharmaceutically acceptable C _1-5 alkyl or tetrahydrofurfuryl di-ethers or partial-ethers of low molecular weight mono-oxyalkanediols or poly-oxyalkanediols; or

1.2. 1,2-propylene glycol

It is a composition of (A) containing.

Suitable components (1.1.) Are, for example, diethers or partial ethers, in particular partial ethers of mono- or poly-oxyalkanediols, in particular mono- or di-oxyalkanediols, containing 2 to 12, in particular 4 carbon atoms. . The mono- or poly-oxyalkanediol moiety is preferably straight chain. Particularly suitable for use in the present invention are di- or partial-ethers of formula (1).

R _1- [O- (CH ₂ ) ₂ ] _x -OR ₂ (I)

In Formula 1, R ₁ is C _1-5 alkyl or tetrahydrofurfuryl,

R ₂ is hydrogen, C _1-5 alkyl or tetrahydrofurfuryl,

x is an integer from 1 to 6, in particular 1 to 4, most particularly about 2.

Especially preferred for use in the present invention are the products of formula 1 wherein the partial ethers as defined above, such as R _2, are hydrogen.

The C _1-5 alkyl moieties in the ethers defined above are branched or straight chains, such as methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl groups.

Such ethers are commercially available as known products or can be prepared analogously to known products. Particularly preferred products of formula 1 used in connection with the present invention are known and are sold under the trade names Transcutol and Glycofurol.

Transcutol is a diethylene glycol monoethyl ether compound of formula 1 wherein R ₁ = C ₂ H ₅ , R ₂ = H and x = 2.

Glycofurol is also known as tetrahydrofurfuryl alcohol polyethylene glycol ether or α- (tetrahydrofuranyl) -ω-hydroxypoly (oxy-1,2-ethanediyl), R ₂ = H and x is represented by Formula 1 having an average of 1 to 2. The average molecular weight is approximately 190; bp = about 80-100 ° C. (at 40 N / m ² ); Density = about 1.070-1.090 g / cm ³ (at 20 ° C.); Hydroxy-value = about 300-400; Refractive index = about 1.4545 (sodium D line, 589 mm) (at 40 ° C), and viscosity = about 8-18 mN s / m ² (at 20 ° C). (See Handbook of Pharmaceutical Excipients, published in American Pharmaceutical Association / The Pharmaceutical Society of Great Britain (1986), p. 127 and Fiedler, "Lexikon der Hilfstoffe", 3rd edition (1989), p. 577).

The exact nature of glycofurol varies with relative purity. In other words, the low quality grade contains a significant amount of tetrahydrofurfuryl alcohol and other impurities. In order to achieve the object of the present invention, as a product satisfying the physical data, Glycofurol 75 containing at least 95% of the fraction having the formula (1) in which x = 1 to 2 is preferable.

When the composition according to (A) is prepared, the hydrophilic phase is particularly suitable as a cyclosporin carrier medium, for example, such that the hydrophilic phase is sufficient for easy therapeutic administration, for example oral administration, of the composition. ) And (1.2) can be used.

The composition of (A) comprising a component defined as (1.1.) And / or (1.2.) As a hydrophilic phase may further comprise one or more additional components as hydrophilic phase components. However, it is preferred that any additional ingredient include a substance in which the cyclosporin active ingredient is sufficiently soluble so as not to significantly impair the efficacy of the hydrophilic phase as a cyclosporin carrier medium. Examples of possible additional hydrophilic phase components are lower (eg C _1-5 ) alkanols, in particular ethanol.

For the reasons mentioned above, the use of alkanols (eg ethanol) as hydrophilic phase components is suggested in the present invention, but this will generally be less preferred. It is preferred that the composition defined as (A) is non-alkanol-based, i.e. free of alkanol as the main hydrophilic phase component. The hydrophilic phase suitably comprises up to 50% by weight, more preferably up to 25% by weight and most preferably up to 10% by weight of alkanol components. It is most suitable that the hydrophilic phase contains no or almost no alkanol components, i.e. it comprises at most 5%, preferably at most 2%, such as 0-1% alkanol components. The term "alkanol" especially means C _1-5 alkanols, in particular ethanol.

In a particularly preferred embodiment, the hydrophilic phase of the composition as defined by (A) consists of or consists essentially of the component as defined in (1.1.) Or (1.2.) Above, which component is in particular transcutol, glyco Furol and / or 1,2-propylene glycol. The hydrophilic phase consists of, or consists of, component (1.1.) Or component (1.2.) As the main component.

Of particular interest is the composition (A) containing component (1.1), in particular glycofurol, which is very suitable for being formulated into soft gelatin encapsulated formulations. According to the present invention, such compositions have also been found to show unexpectedly good stability, which has been demonstrated, for example, by long-term stability tests at room temperature and high temperature. Such compositions are particularly well suited to overcome the difficulties typically encountered in the transportation and storage of medicaments, for example on the user's side, for example in long-term storage at hospitals, clinics, and similar facilities.

The composition defined by (A) further comprises a lipophilic phase (2).

Ingredients suitable for use as the lipophilic phase include any pharmaceutically acceptable solvent that cannot be miscible with the selected hydrophilic phase, such as the phase defined by (1.1.) Or (1.2.). Such solvents would be appropriate with little or no surfactant action. Examples of components particularly suitable for use as the lipophilic phase component (2) are as follows.

Fatty acid triglycerides, preferably intermediate chain fatty acid triglycerides. Particularly suitable are those known and sold under the trade names neutral oils such as neutral vegetable oils, specifically fractionated coconut oils such as Miglyol (see Fiedler, pp. 808-809, supra). The following products can be illustrated.

Miglyol 810: fractionated coconut oil comprising caprylic acid-capric acid triglycerides having a molecular weight of about 520. Fatty acid composition = C ₆ up to 2%, C ₈ about 65-75%, C ₁₀ about 25-35%, C ₁₂ up 2%; Acid value = about 0.1; Saponification index = about 340-360; Iodine no. = Maximum 1;

Miglyol 812: Fractionated coconut oil comprising caprylic-capric acid triglycerides and having a molecular weight of about 520. Fatty acid composition = C ₆ up to about 3%, C ₈ about 50-65%, C ₁₀ about 30-45%, C ₁₂ up to 5%; Acid value = about 0.1; Saponification index = about 330-345; Iodine = 1.

Miglyol 818: Caprylic acid-capric acid-linoleic acid triglycerides having a molecular weight of about 510. Fatty acid composition = C ₆ up to 3, C ₈ about 45-60, C ₁₀ about 25-40, C ₁₂ about 2-5, C _{18: 2} about 4-6; Acid value = 0.2 maximum; Saponification index = about 315-335, iodine number = maximum 10; And

Captex 355 ⁽¹⁾ caprylic acid-caprylic acid triglycerides. Fatty acid content = caproic acid about 2%, caprylic acid about 55%, capric acid about 42%, acid value = maximum; saponification index = about 325-340; Iodine = 0.5 max.

Also suitable are caprylic acid-capric acid triglycerides, such as, for example, those sold under the trade name Myritol (see Fiedler, P. 834, supra), examples of which are acid values = maximum 1, saponification index. = Myritol 813 = about 340-350 and iodine = about 0.5.

Other suitable products of this class include Capmul MCT ⁽¹⁾ , Captex 300 ⁽¹⁾ and Captex 800 ⁽¹⁾ , Neobee M5 ⁽²⁾ and Mazol 1400 ⁽³⁾ .

[(1) = Capital City Products, PO.Box 569, USA, Ohio, Columbus, (2) = Stepan, PVO Dept., USA, New Jersey 07607, Maywood, West Hunter Avenue 100, (3) = Mazer Chemicals, USA, Illinois, Gunni, Foret Drive 3938).]

Particularly preferred as lipophilic phase component is the Miglyol 812 product.

The composition of the present invention as defined in (A) further comprises a pharmaceutically acceptable surfactant (3). Surfactant components include (3.1.) Hydrophilic or (3.2) lipophilic surfactants or mixtures thereof. Especially preferred are nonionic hydrophilic and nonionic lipophilic surfactants. Examples of hydrophilic surfactants suitable for use as surfactant components are as follows:

3.1.1. Reaction products of natural or hydrogenated vegetable oils with ethylene glycol, ie polyoxyethylene glycolated natural or hydrogenated vegetable oils such as polyoxyethylene glycolated natural or hydrogenated castor oil. Such products are for example natural or hydrogenated castor oil or fractions thereof and ethylene oxide, for example according to known methods such as those described in German publications 1,182,388 and 1,518,819, for example from about 1:35 to about It can be obtained by reacting in a molar ratio of 1:60 and optionally removing the free polyethylene glycol component from the product. Especially suitable are various tensides sold under the trade name Cremophor. Particularly suitable products are: saponification index = about 50-60, acid value = 1 or less, iodine value = 1 or less, moisture content (Fischer) = 2% or less, n _D ⁶⁰ = about 1,453-1,457 and HLB = about 14 Cremophor RH40 which is -16; Cremophor RH60 with saponification index = about 40-50, acid value = 1 or less, iodine value = 1 or less, moisture content (Fischer) = about 4.5-5.5%, n _D ²⁵ = about 1.453-1,457 and HLB = about 15-17; And molecular weight = about 1630 (by steam osmotic analysis technique), saponification index = about 65-70, acid value = about 2, iodine number = about 28-32 and n _D ²⁵ = about 1.471 (see Fiedler, pp. 326-327).

Suitable for use in this category are various tensides sold under the trade name Nikkol, such as Nikkol HCO-60. The product Nikkol HCO-60 has the following characteristics as a reaction product of hydrogenated castor oil and ethylene oxide: acid value = about 0.3; Saponification index = about 47.4: hydroxy number = about 42.5; pH (5%) = about 4.6: chromaticity APHA = about 40; Melting point = about 36.0 ° C .; Freezing point = about 32.4 ° C .; H ₂ O content (%, KF) = about 0.03.

3.1.2. Polyoxyethylene-sorbitan-fatty acid esters, such as, for example, the trade name Tween (see Fiedler supra pp. 1300-1304) and known types of polyoxyethylene-sorbitan-fatty acid esters (eg mono- And tri-lauryl, palmityl, stearyl and oleyl esters). Examples include the following Tween products:

20 [polyoxyethylene (20) sorbitan monolaurate],

40 [polyoxyethylene (20) sorbitan monopalmitate],

60 [polyoxyethylene (20) sorbitan monostearate],

80 [polyoxyethylene (20) sorbitan monooleate],

65 [polyoxyethylene (20) sorbitan tristearate],

85 [polyoxyethylene (20) sorbitan trioleate],

21 [polyoxyethylene (4) sorbitan monolaurate],

61 [polyoxyethylene (4) sorbitan monostearate], and

81 [polyoxyethylene (5) sorbitan monooleate],

Particularly preferred products of this type used in the compositions of the invention are Tween 40 and Tween 80 in the above products.

3.1.3. Polyoxyethylene fatty acid esters, for example the trade name Cetiol HE (see Fiedler, supra, p. 284) as well as the commercially available polyoxyethylene fatty acid ester, under the trade name Myrj (see Fiedler, supra p.834) And commercially available types of polyoxyethylene fatty acid esters (eg, polyoxyethylene stearic acid esters). Particularly preferred products of this type for use in the compositions of the invention are those wherein D ²⁵ = about 1.1, melting point = about 40-44 ° C., HLB = about 16.9, acid value = about 0-1 and saponification index = about 25-35 Myrj 52.

3.1.4. A polyoxyethylene-polyoxypropylene copolymer of the type commercially known, for example, under the trade names Pluronic and Emkalyx (see Fiedler, supra, p. 956-958). A particularly preferred product of this type for use in the compositions of the present invention is Pluronic F68.

3.1.5. Polyoxyethylene-polyoxypropylene block copolymers of the type commercially available, for example known under the trade name Poloxamer (see Fiedler, supra, p959). Particularly suitable products of this type for use in the compositions of the present invention are Poloxamer 188.

3.1.6. Dioctylsuccinate, dioctylsodiumsulfosuccinate, di- [2-ethylhexyl] -succinate or sodium lauryl sulfate;

3.1.7. Phospholipids, in particular lecithin (see Fiedler, supra, p.731-733). Lecithin suitable for use in the compositions of the present invention is in particular soy bean lecithin.

3.1.8. Propylene glycol mono- and di-fatty acid esters such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinolate, propylene glycol Stearate et al. (See below, p. 1013, published by Fiedler). Especially preferred are propyleneglycol caprylic acid-capric acid diesters known under the trade name Miglyol 840 (see Fiedler, supra, p. 809). Miglyol 840 has a fatty acid content = C ₆ up to about 3%, C ₈ about 65-80%, C ₁₀ about 15-30%, C ₁₂ up to 3%, acid value = max. 0.1, saponification index = about 320-340, iodine = Has a maximum of 1.

3.1.9 bile salts such as alkali metal salts such as sodium taurocholate.

Examples of lipophilic surfactants suitable for use as surfactant components are as follows:

3.2.1. Trans esterification reaction products of natural vegetable oil triglycerides with polyalkylene polyols. Such transesterification reaction products are known in the art and can be obtained, for example, by the general methods described in US Pat. No. 3,288,824. Such reaction products include various natural (eg non-hydrogenated) vegetable oils such as corn oil, kernel oil, almond oil, ground nut oil, olive oil and palm oil and mixtures thereof and polyethylene glycol, in particular A transesterification reaction product with polyethylene glycol having an average molecular weight of 200 to 800. Preference is given to products obtained by transesterification of two mole parts of natural vegetable oil triglycerides with one mole part of polyethylene glycol (eg, an average molecular weight of 200 to 800). Various forms of transesterification reaction products of this class are known and are sold under the trade name Labrafil (see Fiedler, supra 707). Particularly useful as components of the compositions of the present invention are Labrafil M 1944 CS, a transesterification reaction product of polyethylene glycol with phosphorus oil having an acid value = about 2, a saponification index = about 145-175 and an iodine = about 60-90; And Labrafil M 2130 CS, a transesterification reaction product of polyethylene glycol with a melting point of about 35-40 ° C., an acid value of 2 or less, a saponification index of about 185-200 and an iodine value of 3 or less, and C ₁₂ to C ₁₈ -glycerides.

3.2.2. Esterification products of mono-, di- and mono / di-glycerides, in particular caprylic or capric acid with glycerol. Preferred products of this class are, for example, those based on caprylic / capric acid mono- and di-glycerides, such as those sold under the trade name Imwitor (see p. 645, supra). Particularly suitable products for use in the compositions of the present invention in this class are Imwitor 742, which is a product of an esterification reaction of glycerol with a mixture of about 60 p.p.w of caprylic acid and about 40 p.p.w of capric acid. Imwitor 742 is typically a yellow crystalline mass, liquid at about 26 ° C .; Acid value = up to 2; Iodine = 1 max; Saponification index = about 235-275:% monoglyceride = about 40-50%; Free glycerol = up to 2%; Melting point = about 24-26 ° C .; Non-saponifiable components = 0.3% maximum; Peroxide Index = 1 max.

3.2.3. Sorbitan fatty acid esters of the type commercially available, for example known under the trade name Span. For example, sorbitan-monolauryl, -monopalmityl, -monostearyl, -tristearyl, -monooleyl and -trioleyl esters (see Fiedler, supra, p. 1139-1140).

3.2.4. Pentaerythritol fatty acid esters as well as pentaerythritol fatty acid esters and polyalkylene glycol ethers, for example pentaerythritol dioleate, distearate, monolaurate, polyglycol ether and monostearate (Fiedler, supra, pp. 923-924).

3.2.5. Monoglycerides such as glycerol monooleate, glycerol monopalmitate and glycerol monostearate, for example the products known and commercially known under the trade names Myvatex, Myvaplex and Myverol (see Fiedler, supra p. 836), And acetylated, for example monoacetylated and diacetylated monoglycerides, for example products known and commercially available under the trade name Myvacet (see Fiedler, supra p 835).

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

3.2.7. Sterols and derivatives thereof, for example cholesterol and derivatives thereof, in particular products containing phytosterols such as cytosterol, campestrol or stigmasterol and its ethylene oxide adducts, for example soybean sterols and derivatives thereof, for example Trade names Generol (see Fiedler, supra, p. 554 and 555), in particular the products known as the products Generol 122, 122 E5, 122 E10 and 122 E25.

The composition as defined in (A) above comprises a system containing a single surfactant or a mixture of surfactants, such as a system containing a first surfactant and at least one co-surfactant. Combinations of surfactants and co-surfactants can be selected from, for example, any of the types of surfactants set forth in (3.1.1.) To (3.2.7) above.

If the hydrophilic phase comprises diethers or partial ethers as defined in (1.1) above, in particular transcutol or glycofurol, co-surfactants may be added, if desired, for example to improve stability properties, but in general The use of surfactants is sufficient. When 1,2-propylene glycol is used alone or as the main hydrophilic phase component, it is usually necessary to use at least two surfactants, namely surfactants and co-surfactants. The composition as defined in (A) comprising 1,2-propylene glycol as the hydrophilic phase is suitably comprised of both surfactants and co-surfactants.

The surfactants defined in (3.1.1), (3.1.3), (3.1.7), (3.2.2) and (3.2.5) above are of particular interest for use in the compositions defined in (A). . Particularly suitable combinations of surfactants / co-surfactants are hydrophilic / lipophilic surfactant combinations and are for example combinations of surfactants according to (3.1.1) and surfactants according to (3.2.5).

When the surfactant comprises an effective solvent for the cyclosporin active ingredient, for example, the surfactant as described in (3.1.1) to (3.2.7) above or a mixture of surfactants thereof, it is not only as a surfactant It may be incorporated into the composition of (A) in excess as an additional carrier or co-solvent phase, ie as a hydrophilic phase or as part of a lipophilic phase.

The composition of (A) may also comprise the following components:

4. Thickening Agent

Suitable thickening agents may be those known and used in the art and include, for example, the following types, including pharmaceutically acceptable polymeric materials and inorganic thickening agents.

4.1. Polyacrylate and polyacrylate copolymer resins such as polyacrylic acid and polyacrylic acid / methacrylic acid resins, for example the trade name Carbopol (see Fiedler, supra, pages 254-256), in particular the products Carbopol 934, 940 and 941, and the trade names Eudragit (see Fiedler, supra, pages 486-487), in particular the products Eudragit E, L, S, RL and RS, and most particularly of the products known and marketed as the products Eudragit E, L and S.

4.2. Cellulose and cellulose derivatives such as alkyl cellulose (eg, methyl-, ethyl- and propyl-cellulose); Hydroxyalkyl-celluloses (eg hydroxypropylalkyl-celluloses such as hydroxypropyl-cellulose and hydroxypropyl-methyl-cellulose); Acylated cellulose (eg, cellulose-acetate, cellulose-acetate phthalate, cellulose-acetate succinate and hydroxypropylmethyl-cellulose phthalate); And salts thereof (eg sodium carboxymethyl-cellulose). Examples of such products suitable for use in the present invention include, for example, products known and sold under the trade names Klucel and Methocel (see Fiedler, supra, pages 688 and 790), specifically the products Klucel LF, MF, GF and HF, and Methocel K100 , K15M, K100M, E5M, E15, E15M and E100M.

4.3. Polyvinylpyrrolidones such as poly-N-vinylpyrrolidone and vinylpyrrolidone copolymers (eg, vinylpyrrolidone-vinyl acetate copolymers). Examples of such compounds suitable for use in the present invention are, for example, products known and commercially available under the trade name Kollidon (or Povidone in the United States, see Fiedler, supra, pages 694-696), specifically the products Kollidon 30 and 90.

4.4. Polyvinyl resins (eg, including polyvinylacetate and alcohols) and other polymeric materials such as tragant gum, gum arabic, alginates (eg alginic acid) and salts thereof (eg sodium alginate).

4.5. Inorganic thickeners such as attapulgite, bentonite and silicates such as hydrophilic silicon dioxide products such as alkylated (eg methylated) silica gels, in particular the trade name Aerosil [Handbook of Pharmaceutical Excipients 253-256 supra Colloidal silicon dioxide products known and commercially available, specifically Aerosil 130, 200, 300, 380, O, OX50, TT600, MOX80, MOX170, LK84 and methylated Aerosil R 972.

In the case of the composition of (A) to be used for oral administration, the thickening agent may be added, for example, to provide a sustained release effect. However, for oral administration, the use of thickening agents as described above is generally unnecessary and less preferred. On the other hand, the use of thickening agents is indicated, for example when intended for topical application.

The composition according to (A) may comprise one or more additional ingredients, in particular diluents, antioxidants [e.g. ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT) and tocopherols, for example Α-tocopherol (vitamin E)], flavoring agents and the like. It is particularly advantageous to use antioxidants, in particular tocopherols.

It is anticipated that the composition of the invention as defined in (A) should include the final dosage form for administration, especially when intended for oral administration, but the present invention also includes cyclosporine as the active ingredient and is a microemulsion itself. To provide a composition. That is, for oral administration, the microemulsions obtained by, for example, diluting the "microemulsion preconcentrate" as defined in (A) with water or other aqueous media can be used as preparations for beverages. Similarly, for topical application, the composition comprising a hydrocolloid thickener, for example the hydrocolloid thickener of (4.2) or (4.4), suitably contains water, such as gels, pastes, creams and the like. It provides an aqueous microemulsion of the formulation. Such compositions are also novel. Accordingly, the present invention provides the following composition as a separate embodiment:

B) A pharmaceutical composition which is a microemulsion and contains cyclosporin as an active ingredient.

The composition defined in (B) may comprise water and any of the components (1) to (3) described above in connection with the composition defined in (A). The composition of (B) is an oil-in-water (O / W) microemulsion. The composition preferably exhibits the stability characteristics described above with respect to the microemulsion obtainable from the composition as defined in (A).

The use of di- or partial-ethers as defined in (1.1) above as carrier medium in accordance with the present invention includes cyclosporine as well as the preparation of the microemulsion and "microemulsion preconcentrate" formulations as described above. It has also been found to be generally advantageous for the preparation of pharmaceutical compositions. That is, the use of such ethers as components of other oral and in particular topical delivery systems has surprisingly been found to solve the problems encountered so far in the art as described above. Such compositions are also novel. Thus, as another embodiment, the present invention provides the following composition.

C) A pharmaceutical composition comprising cyclosporin as an active ingredient with a pharmaceutically acceptable C _1-5 alkyl or tetrahydrofurfuryl di- or partial-ether of low molecular weight mono- or poly-oxyalkanediols.

Preferred ether components for use in the composition as defined in (C) are described above in connection with (1.1), with transcutol and glycofurol products being particularly preferred. The composition of (C) suitably comprises one or more additional ingredients, for example surfactants, co-solvents or thickening agents.

Specifically, the composition as defined in (C) also suitably comprises pharmaceutically acceptable hydrophilic surfactants, in particular nonionic hydrophilic surfactants. Suitable hydrophilic surfactant components are ones defined in (3.1.1) to (3.1.9) above.

The composition defined by (C) preferably contains a pharmaceutically acceptable lipophilic surfactant as a surfactant or as a co-solvent, or a pharmaceutically acceptable co-solvent. Suitable co-solvent / lipophilic surfactant components are one of those described in (2) and (3.2.1) to (3.2.7) above.

The composition of (C) comprises other forms other than those described in (A) and (B), for example, solutions, suspensions, dispersions, regular emulsions and the like. Specifically, the composition of (C) additionally comprising a surfactant or both a surfactant and a co-solvent, for example, includes regular emulsions of hydrophilic / lipophilic and lipophilic / hydrophilic types, and emulsion preconcentrates ( Ie, a composition which provides a regular emulsion in the form of O / W or W / O when contacted with water-for a microemulsion). In the case of a preparation, for example a beverage or topical application preparation, the preparation will also specifically include an aqueous emulsion in the form of O / W or W / O. In general, emulsion preconcentrates which give O / W emulsions and (ii) O / W emulsions are particularly preferred when intended for oral administration.

The composition of (C) may further comprise a pharmaceutically acceptable thickening agent, a suitable thickening agent being one of those defined in (4.1) to (4.5) above.

The composition according to (C) may comprise additional additives, for example preservatives and flavoring agents and the like described above in connection with the composition (A). In particular, the composition (C) preferably comprises an antioxidant, for example any of the specific antioxidants described above in connection with the composition (A).

The present invention also provides the following compositions:

D) (5) A composition as defined in (C) further comprising a fatty acid saccharide monoester.

The composition as defined in (D) generally comprises cyclosporin and component (5) in a carrier medium containing component (1.1), for example glycofurol or transcutol. In the composition of (D) the cyclosporin and component (5) are each typically present in a molecular dispersion or solution containing a solid solution, as appropriate. Component (5) generally acts as a solubilizer for cyclosporin in the composition of (D). The composition of (D) has the special advantage of satisfying the problems and stability associated with component (5) having inherent strong hygroscopicity.

Preferred component (5) for use in the composition according to (D) is a water soluble fatty acid saccharide monoester, for example, having a water solubility of at least 3.3% at an ambient temperature such as about 20 ° C., ie water at ambient temperature. Fatty acid monoesters of saccharides which can be dissolved in water at a rate of at least 1 g of monoester amount per 30 ml.

The fatty acid portion of component (5) may comprise saturated fatty acids or unsaturated fatty acids or mixtures thereof. Particularly suitable components (5) are C _6-18 fatty acid saccharide monoesters, especially water-soluble C _6-18 fatty acid saccharide monoesters. Capric acid (C ₆ ), caprylic acid (C ₈ ), capric acid (C ₁₀ ), lauric acid (C ₁₂ ), myristic acid (C ₁₄ ), palmitic acid (C ₁₆ ), oleic acid (C ₁₈ ) , Ricinoleic acid (C ₁₈ ) and 12-hydroxystearic acid (C ₁₈ ) saccharide monoesters are particularly suitable components (5), among which lauric acid saccharide monoesters are particularly suitable.

The saccharide portion of component (5) may comprise any suitable sugar residue, eg, monosaccharide, disaccharide or trisaccharide residue. The saccharide moiety preferably comprises a disaccharide or trisaccharide residue. Preferred components (5) include C _{6-14 -fatty} acid disaccharide monoesters and C _{8-18 -fatty} acid trisaccharide monoesters. Particularly suitable saccharide moieties are saccharose and raffinose residues.

Examples of particularly suitable components (5) are as follows: saccharose monocaproate, saccharose monolaurate, saccharose monomyristate, saccharose monooleate, saccharose monolysinate, raffinose monocaproate, Raffinose monolaurate, raffinose monomyristate, raffinose monopalmitate and raffinose monooleate. Most preferred component (5) is raffinose monolaurate and in particular saccharose monolaurate.

Component 5 preferably has a hydrophilic-lipophilic equilibrium value (HLB) of at least 10.

Component (5) suitably has an ester residue purity of at least 80%, more preferably at least 90%, most preferably at least 95%. Component (5) suitably has a melting point of about 15 ° C to about 60 ° C, more preferably about 25 ° C to about 50 ° C.

The composition of (D) may further comprise further components, such as those described above in connection with the composition (C).

In particular, the composition of (D) may comprise components capable of modifying the release properties of the composition with respect to cyclosporin, for example thickening agents such as those described in (4.1) to (4.5).

In particular, the composition of (D) also preferably comprises one or more antioxidants, for example the antioxidants specifically described in connection with the composition of (A).

The composition of (D) suitably comprises at least one stabilizer or buffer to prevent hydrolysis of component (5), especially during processing or storage. Examples of such stabilizers include acidic stabilizers such as citric acid, acetic acid, tartaric acid or fumaric acid, as well as basic stabilizers such as potassium hydrogen phosphate.

The stabilizer or buffer is appropriately added in an amount sufficient to maintain or achieve a pH of the composition of (D) at about 3-8, more preferably at about 5-6, and having a pH in the ranges set forth above (D Composition is generally preferred.

Moreover, it is preferable that especially the composition of (D) contains a polyoxyalkylene-free hydrophilic surfactant, for example, said (3.1.6) or (3.1.7) surfactant.

The composition of the present invention may be administered in a suitable manner. For example, in unit dosage form (eg, hard or soft gelatin encapsulated formulations), for example orally; Parenteral or topically administered formulations, for example formulations administered to the skin (eg, in the form of creams, pastes, lotions, gels, ointments, compresses, cataplasmas, plasters, skin patches, etc.); Or in formulations that are administered to the eye (eg, eye drops, eye drops, eye gel preparations), and the like.

Weaning preparations such as solutions and microemulsions can be used, for example, for intralesional injection in the treatment of psoriasis or can be administered rectally, for example as an enema, in the treatment of inflammatory bowel disease or Crohn's disease. However, the compositions of the present invention are mainly used as oral or topical formulations, in particular for use on the skin.

The relative proportions of components present in the compositions of the present invention vary considerably depending on the specific type of composition (eg microemulsion preconcentrate, microemulsion, regular emulsion, solution, etc.). Relative proportions also vary with the specific action of the composition components, for example, for the surfactant component of the "microemulsion preconcentrate", whether it is used only as a surfactant or as both a surfactant and a co-solvent Depends on. The relative proportions also depend on the particular ingredients used and the desired physical properties of the resulting composition, for example in the case of topical use compositions depending on whether the composition is a wetting liquid or paste. In specific cases, the measurement of the operable ratio is generally within the capabilities of those skilled in the art. Thus, all indicated proportions and the following relative weight ranges merely indicate preferred or individual teachings of the invention and do not limit the scope of the invention in its broadest aspects.

The amount of cyclosporin in the composition of the invention depends, for example, on the intended route of administration and the amount of other components, in particular the amounts of the components (2) to (5). In general, however, cyclosporine is present in an amount ranging from 0.05, in particular from about 0.1% to about 35% by weight, based on the total weight of the composition.

Component (1) in the composition of the present invention is suitably present in an amount of about 0.5 to about 90 weight percent based on the total weight of the composition. For compositions of the present invention containing component (1.1) (eg, glycofurol or transcutol), component (1.1) is from about 1 to about 90 weight percent, more typically about 5, based on the total weight of the composition Or in an amount from 10 to about 70% by weight. For compositions (A) or (B) containing component (1.2), component (1.2) is generally present in an amount of about 2 to about 50 weight percent based on the total weight of the composition. In the case of compositions according to the invention comprising component (2) or component (3), these components are generally present in amounts of from about 0.5 to about 90% by weight, based on the total weight of the composition.

In a particularly preferred embodiment, the present invention provides the following composition (E).

E) Compositions of (A) or (C) for oral administration, for example compositions of (A) or (C) in a form suitable or convenient for oral administration.

For non-topical (A) to (C) compositions, and particularly for compositions (E) in oral dosage forms:

a) The cyclosporin is generally present in an amount of about 1 or 2 to about 30 weight percent, suitably about 4 to about 25 weight percent, based on the total weight of the composition. More suitably the cyclosporin is present in an amount of about 5 to about 25 weight percent, in particular about 5 to about 20 weight percent, for example about 5 to 15 weight percent, based on the total weight of the composition.

b) When present, component (1.1) is generally from about 15 to about 85 weight percent, suitably from about 20 to about 80 weight percent, more suitably from about 25 to about 70 weight percent based on the total weight of the composition %, For example about 30 to about 50 weight percent or about 30 to 60 weight percent.

c) cyclosporine to component (1.1), if present, is generally about 1: 0.75-20, suitably about 1: 1-15, more suitably about 1: 1-5, for example about 1: 1 Or 1: 1.5 to 4 ppw [cyclosporin: (1.1)].

d) When present, component (1.2) is generally present in an amount of about 3 to about 45 weight percent, suitably about 5 to about 30 weight percent, based on the total weight of the composition.

e) When present, cyclosporin and component (1.2) are generally present in a ratio of about 1: 0.1-20, suitably 1: 0.2-10 p.p.w. More suitably at a ratio of about 1: 0.3 to 6, for example about 1: 0.5 to 3 p.p. [cyclosporin: (1.2)].

f) Component (2), if present, is generally present in an amount of up to about 45% by weight, suitably up to about 40% by weight based on the total weight of the composition. More suitably, component (2) is about 2 to about 45 weight percent, even more suitably about 3 to about 35 weight percent, most suitably about 5 or 10 to about 30, based on the total weight of the composition Present in weight percent.

g) Component (2) to (1.1), if present, is generally about 1: 0.5 to 40, suitably about 1: 0.5 to 20, more suitably about 1: 0.75 to 10, for example about 1 : 0.75 to 4 ppw [(2) :( 1)].

h) Component (2) to (1.2), if present, suitably is about 1: 0.075-22, suitably about 1: 0.1-15, most suitably about 1: 0.15-6 ppw, for example about It exists in the ratio of 1: 0.5-3 ppw [(2) :( 1.2)].

i) When present, component (3) [including both components of type (3.1) and (3.2)] is generally up to about 90% by weight, for example from about 20 to about 90, based on the total weight of the composition Present in weight percent. More suitably component (3) is present in an amount of from about 20 or 25 to about 80 or 90 weight percent based on the total weight of the composition, for example from about 25 to about when using component (1.1) It is present in an amount of 55% or in an amount of about 40 to 75% when using component (1.2).

j) when present, cyclosporin to component (3) [including both components of type (3.1) and (3.2)] is generally in a ratio of about 1: 0.5 to 20, more suitably 1: 0.5 to 12 ppw. exist. About 1: 1 to 10 ppw when component (1.1) is present (eg about 1: 1 to 5 ppw) or about 1: 3 to 8 ppw when component (1.2) is present [cyclosporine: (3)] is appropriate.

In the case of the compositions as defined in (A) and (B) ["microemulsion preconcentrate" and microemulsions), The relative ratio will depend on the concentration of cyclosporine present. This will also vary in the ratio relative to each other.

That is, the composition of (A) comprises (1) a hydrophilic phase [eg (1.1) or (1: 2)], (2) a lipophilic phase [eg (2.1) or (2.2)], and a surfactant [example (3.1) or (3.2)] together with cyclosporin, wherein the relative ratio of cyclosporin: (1) :( 2) :( 3), for example, in contact with water, For example, a microemulsion upon contact with water at a relative ratio of 1: 1 ppw [cyclosporine + (1) + (2) + (3): H ₂ O) or higher, as described above, e.g. o / w Mold] can be obtained.

Similarly, the composition of (B) is combined with water and components (1), (2) and (3) in the relative proportions required to provide the microemulsion [e.g., o / w form], for example as indicated above. It can be defined to include cyclosporin.

The composition of (A) and (B) is preferably from about 2 to about 30% by weight, more preferably from about 5 to about 5% by weight, based on the total weight of the cyclosporin + component (1) + (2) + (3) 20 weight percent, most preferably about 10 to about 15 weight percent cyclosporin.

When component (1) of the composition of (A) or (B) is (1.1), for example when it contains transcutol or glycofurol, component (1.1) is preferably from about 15 to about 85%, More preferably in an amount of about 25 to about 65%, component (2) is preferably about 2 to about 40%, more preferably about 3 to about 35%, most preferably about 3 to about 30% Component (3) is preferably present in an amount from about 15 to about 85%, more preferably from about 25 to about 55 or 60%, wherein all% is (1.1) + (2) + ( % By weight based on total weight of 3). Of particular interest is the use of glycofurol.

When component (1) of the composition of (A) or (B) is 1,2-propylene glycol [above (1.2)], component (1.2) is suitably about 3 to about 35%, more preferably about In an amount of 3 to about 25%, component (2) is suitably in an amount of about 2 to about 35%, more preferably in an amount of about 3 to about 30%, and component (3) is suitably about 45 to about 90%, more preferably from about 50% to about 90%, such as from about 55% to about 80%, wherein all% is based on the total weight of (1.2) + (2) + (3) One weight percent. As mentioned above, when component (1) is 1,2-propylene glycol, component (3) generally comprises both surfactants and co-surfactants. When co-surfactants are used, the surfactant to co-surfactant is suitably about 50: 1 or less, preferably 20: 1 or less, more preferably 15: 1 or less, for example 2-15: 1. present in the ratio of ppw (surfactant: co-surfactant).

1 shows component (1.1) (e.g. glycofurol), component (2) (e.g. Miglyol 812) and component (a) in a composition of (A) containing about 10% by weight of cyclosporin (e.g. cyclosporin). 3) A three-way plot of relative concentrations of (eg Cremophore RH40) is shown. The relative concentration of component (1.1) increases from 0% along the left side of the plot to 100% of the bottom right corner, as indicated by arrow "1.1". The concentration of component 2 is increased from 0% of the right side of the plot to 100% of the lower left corner, as indicated by arrow "2". Therefore, a composition comprising only 50% of component (1.1) and 50% of component (2) is indicated at the baseline center point of this plot. The relative concentration of component (3) is increased from 0% of the baseline of the plot to 100% of the vertex, as indicated by arrow "3". The lines in the plot represent 10% increments from 0% of each side to 100% of the opposite vertex.

In the case of the compositions defined by (A) and (B), the relative proportions of components (1.1), (2) and (3) are preferably present in the region (A) partitioned by line (a) of FIG. The relative proportions of components (1.1), (2) and (3) are more suitably present in the area (B) partitioned by line (b) of FIG. 1, with microemulsions based on this ratio having the greatest stability, eg It has been found for example to have a stability of 24 hours or more and an average particle size of 1000 mm or less. Accordingly, the compositions of the present invention comprising components (1.1), (2) and (3) present in the relative proportions described above with reference to FIG. 1 represent particularly preferred embodiments.

FIG. 2 shows three directions of relative concentrations of components (1.2), (2) (eg, Megalyol 812) and (3) in the composition of (A) containing about 10% by weight of cyclosporine (eg, cyclosporine). Plots are shown. Component (3) in this case comprises a suitable surfactant / co-surfactant mixture, for example at a ratio of 11: 1 ppw, for example 11 ppw of Cremophor RH40 and 1 ppw of glycerin monooleate. . The relative amounts of components (1.2), (2) and (3) are indicated by arrows "1.2", "2" and "3" in the case of FIG. 1, respectively.

The relative proportions of components (1.2), (2) and (3) with respect to the compositions defined by (A) and (B) are preferably present in the area X partitioned by the line x in FIG. . The relative proportions of components (1.2), (2) and (3) are more suitably present in the region Y partitioned by the line y in FIG. The relative proportions of components (1.2), (2) and (3) are best suited to exist in the area Z defined by the line z, and the micros based on the proportions in the areas Y and Z. The emulsion has an average particle size and stability (eg, over 24 hours) on the order of 1100 kPa and <200 kPa, respectively.

The composition of (E) may further comprise a thickening agent, but as mentioned above such compositions are generally less preferred. Suitable thickening agents include those described in (4) above. The amount of thickening agent present varies, for example, depending on the consistency required by the final product, for example, whether it is in an enriched flowable form, for example for filling a capsule or the like, or for example used in the manufacture of tablets or the like. To have sufficient elasticity to enable casting or molding. The amount also depends on the nature of the thickening agent chosen. Generally, component (4), if present, is in an amount of about 25% by weight or less, more suitably about 15 or 20% by weight or less based on the total weight of the composition, for example 0.5 or 5% by weight or 15 or Present in an amount of 20% by weight.

The composition of (E) may also comprise separate components or additives, for example components as described in connection with the compositions of (A) and (C). In particular they may include, for example, antioxidants in an amount of up to about 0.5 or 1 weight percent based on the total weight of the composition, and sweeteners or flavoring agents in an amount of up to about 2.5 or 5 weight percent based on the total weight of the composition. Can be.

It has been found herein that the composition of (E) according to definition (A) exhibits particularly advantageous properties when administered orally, for example both in consistency and in achieving high levels of bioavailability. In particular, it has been found that such compositions are compatible with tenside materials (eg bile salts) present in the gastrointestinal tract, in contrast to other galen systems known in the art, for example. That is, the composition can be fully dispersed in an aqueous system comprising such natural tensides, providing a stable in situ microemulsion system that does not exhibit precipitation or other disruption of the particulate structure. In oral administration, the function of these systems is not impaired by the presence or absence of bile salts at any particular time point or within a given individual and / or is present irrespective of this. Such compositions thus represent particularly preferred embodiments of the invention.

The composition of (E) is preferably formulated in unit dosage form, for example, by filling into an orally administrable capsule shell, for example a soft or hard gelatin capsule shell, or by tableting or other shaping methods. . When the composition of (E) is in unit dosage form, each unit dose is suitably about 5 or 10 to about 200 mg of cyclosporine, more suitably about 15 or 25 to about 150 mg, for example 25, 50 or 100 mg. Cyclosporin. Therefore, a unit dosage form of the invention suitable for once, twice or three to five times daily administration (eg, depending on the specific therapeutic purpose and condition of treatment, etc.) may be, for example, about 50 mg or about 100 mg per unit dose. It is appropriate to include cyclosporin.

The composition of (B) for oral administration includes the composition described with respect to (A) or (E) above with respect to a drink preparation in which a sweetener or a flavoring agent is added to water or another aqueous system, for example, as described above. It can be prepared by adding in a relative ratio (composition: H ₂ O). Such a composition may comprise sufficient water to form a microemulsion and any system as defined or described above with respect to the composition of (A) or (E).

In particular, the compositions described in (D) are for oral administration, but include, for example, use in forms suitable for topical administration, including for intradermal injection as well as for skin and topical ophthalmic, parenteral or rectal administration.

In the case of the composition as defined in (D), the cyclosporin to the required component (1.1) is present in a ratio of about 1: 0.5 to 200, preferably about 1: 0.5 to 100, more preferably about 1: 0.5 to 50 ppw. Can be. However, they are more suitably about 1: 1 to 10, more preferably 1: 1 to 5, most preferably about 1: 1.5 to 2.5, for example about 1: 1.6 or 1: 2 ppw [cyclosporine: (1.1)]. Cyclosporin to the required ingredient (5) is suitably present in a ratio of about 1: 3 to 200, preferably about 1: 3 to 100, more preferably about 1: 3 to 50 p.p.w. They are more suitably in the ratio of about 1: 5-20, preferably about 1: 5-10, most preferably about 1: 6.0-6.5, for example about 1: 6.25 ppw [cyclosporin: (5)]. Exists as.

The composition according to (D) is suitably prepared in unit dosage form, whether for oral or other administration.

The amount of cyclosporin present in such unit dosage forms varies depending, for example, on the condition to be treated, the intended method of administration and the desired effect. Generally, however, the unit dosage form of (D) suitably comprises from about 2 to about 200 mg of cyclosporin per unit dose.

Dosage forms suitable for oral administration include, for example, liquids, granules, and the like. Preferred dosage forms, however, are unit dosage forms, for example in tablet or encapsulated form, especially hard or soft gelatin encapsulated formulations.

The unit dosage form for oral administration according to (D) suitably contains about 5 or 10 to about 200 mg, more suitably about 15 or 20 to about 100 mg, for example 25, 50 or 100 mg of cyclosporin per unit dose. Include.

The composition of (D) has the further advantage that it can provide a base for the composition which exhibits modified release properties, for example delayed release of cyclosporin or release of cyclosporin over a prolonged period after oral administration, for example. Such compositions additionally include ingredients that can modify the release properties of the composition with respect to cyclosporin. As an example of such a component, the thickening agent by (4) thickener, for example, any one of said (4.1)-(4.5) is mentioned.

When the composition of (D) comprises component (4), component (4) is suitably about 0.5 to 50% by weight, further based on the total weight of cyclosporine + (1.1) + (4) + (5) It is preferably present in an amount of about 1 to 20% by weight, most preferably about 2 to 10% by weight.

As mentioned above, the composition according to (D) advantageously comprises one or more stabilizers or buffers or polyoxyalkylene-free surfactants. Such stabilizers and / or buffers are suitably present in amounts of up to 5% by weight, based on the weight of cyclosporine + (1.1) + (5), or in amounts of 10% by weight or less when citric acid or acetic acid is used. do. As described above, when the surfactant is present, it is appropriate that the surfactant is present in an amount of about 5 to about 50 weight percent, more preferably about 10 to about 25 weight percent, based on the weight of component (5). .

The composition according to (D) also suitably comprises additives, in particular flavoring agents or in particular antioxidants. Suitable antioxidants and their amounts used are as described above with regard to the composition of (E).

The composition according to (D) also preferably contains little or no lower alkanols, in particular ethanol, for example up to 5% by weight, more preferably up to 2%, for example based on the total weight of the composition It contains a lower alkanol component of about 0 to 1%.

The compositions defined in (A) to (C) are of particular interest for topical administration. Thus, in a separate aspect, the present invention also provides the following composition.

F) The composition as defined in any one of (A) to (C) above for topical use, in particular for skin application, ie in a form suitable or easy for topical application.

If topical administration is proposed, the cyclosporin is suitably present in an amount from about 0.05, more preferably from about 0.1 to about 15 weight percent based on the total weight of the composition. More preferably cyclosporin is present in an amount from about 0.1 to about 10% by weight.

In the case of the composition of (F), which is the composition according to (A) or (B), the relative proportions of the components (1), (2) and (3) are, for example, referring to Figs. As described above.

On the other hand, the composition of (F) according to (C) may take any suitable form and may include, for example, solutions, suspensions, dispersions and regular emulsions. Component (1.1) is suitably about 1 to about 70 weight percent, preferably about 5 to about 50 weight percent, more preferably about 7 to about 25 weight, based on the total weight of the composition in such a composition. Present in an amount of%.

The composition of (F) suitably comprises one or more carriers or diluents and / or other ingredients that provide a carrier system such as thickening agents, emulsifiers, preservatives, humectants, colorants and the like.

The composition of (F) may be in any form suitable for topical application, for example to the skin surface, for example in a flowable form (eg liquid or semi-liquid form), in powder form or in a topically administrable spray form. . Examples of suitable flowable formulations include, for example, gels, creams, pastes and ointments, including oil-in-water and water-in-oil emulsions or microemulsions, as well as lotions and tinctures. Such compositions include, for example, cataplasm and poultice as well as transdermal patch systems.

Of course, the choice of excipients for preparing such formulations is determined not only by the type of formulation desired, but also by the specific symptoms to be treated, the extent of the symptoms, the area to be treated, the skin condition and the desired effect. That is, it is more suitable to treat chronic psoriasis plaques with a composition of the present invention comprising a hydrophobic, e.g., fatty based composition, e.g., petroleum-based ointment or cream as a carrier medium. In contrast, it is more suitable for the treatment of disease states related to an acute phase inflammatory response with a composition according to the invention in the form of a high hydrophilic, e.g. oil-in-water emulsion or gel.

The composition of (F) may include, for example, a lower alkanol (eg, ethanol) as a diluent or a diluent component, but, for example, in the case of psoriasis, etc. It is preferable not to use a component. That is, the composition of (F) preferably contains no or almost no alkanol, for example 5% by weight or less, more preferably 2% by weight or less, for example about 0 to 1% by weight of alkanol Preference is given to containing the components, in particular ethanol.

Particularly preferred compositions of (F) comprise a composition according to (A), (B) or (C) further comprising a (additional) pharmaceutically acceptable diluent or carrier (6) which is non-miscible with component (1.1). All. The composition preferably takes the form of an emulsion with little or no moisture, ie it contains up to 10%, preferably up to 5% and most preferably up to 1% water. This emulsion comprises both an emulsion comprising component (1.1) in component (6) and an emulsion comprising component (6) in component (1.1). These preferably comprise an emulsion containing component (1.1) in component (6).

Examples of suitable components (6) include the following:

6.1. Solid hydrocarbons such as petroleum jellys such as white petroleum or Vaseline ^R , ceresin and solid paraffins, as well as waxes including animal, vegetable and synthetic waxes such as sperm, carnauba and beeswax;

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

6.3. Non-volatile silicones, including silicone oils and pastes, and silicone-polyalkylene oxide copolymers [Fiedler, pp. 1109 and 1110], for example those known and sold under the trade name Piroethicon.

Component (6) is suitably in the composition of (F) based on the total weight of the composition, suitably up to about 80% by weight, for example from about 5 to about 70% by weight, preferably from about 25 to about 60% by weight Exists in the amount of.

By using each of the components 6 or mixtures thereof, the emulsion can be prepared in liquid or semisolid form, for example depending on the requirements desired for topical administration.

It is suitable that the composition of (F) also contains surfactant. Suitable surfactants include in particular lipophilic surfactants including any of the surfactants listed in (3.2.1) to (3.2.7) above, especially those having an HLB of about 5-7. Examples of particularly useful surfactants in connection with the composition of (F) include, for example, glycerol monostearate, propylene glycol monostearate, as well as surfactants as described in (3.1.2) and (3.2.3) above, Diethylene glycol monostearate and glycerol ricinolate.

The surfactant as described above is suitably up to about 60% by weight, for example from about 2 to about 50% by weight, preferably from about 10 to about 40, based on the total weight of the composition in the composition of (F) Present in weight percent.

The composition of (F) also contains one or more consistency enhancers, such as microcrystalline waxes, vegetable oils (eg olive oil, corn oil and phosphorus oil), and vegetable oil derivatives (eg hydrogenated vegetable oils and vegetable oil partial glycerides). May be contained, for example, in an amount of about 0.1 to about 10 weight percent, preferably about 1 to about 5 weight percent, based on the total weight of the composition.

It is preferable that the composition of (F) contains the following components:

Antioxidants, for example antioxidants present in an amount of from about 0.01 to about 0.5% by weight based on the total weight of the composition, for example one of the antioxidants described above in connection with the composition (A);

Antibacterial agents, for example antibacterial agents present in an amount of about 0.05 to about 2% by weight based on the total weight of the composition, for example benzyl alcohol, methylparaben, propylparaben, benzalkonium chloride, benzoic acid Sorbic acid or chlorobutanol;

Stabilizers, for example those present in an amount from about 0.1 to about 10% by weight based on the total weight of the composition, for example microcrystalline starch, sodium EDTA or magnesium sulfate; And / or

Skin permeation enhancers, for example skin permeation enhancers such as C _12-24 mono- or in an amount of about 1 to about 20% by weight, suitably about 3 to about 15% by weight, based on the total weight of the composition Poly-unsaturated fatty acids or alcohols (e.g. bacenic acid, cis-bacsenic acid, linoleic acid, linolenic acid, ellidic acid, oleic acid, petroleic acid, erucinic acid or nervonic acid or their corresponding alcohols, in particular oleic acid Oleyl alcohol), or 1-dodecylazacycloheptan-2-one known as Azone (see Fiedler, page 190, supra).

In addition, the present invention provides a method for preparing a pharmaceutical composition as described above, for example, a pharmaceutical composition as defined in the above (A) to (F), which method makes the individual components into an intimate mixture, Formulating the obtained composition as necessary in unit dosage form, for example, filling the composition into gelatin such as soft or hard gelatin capsules.

In a specific embodiment, the present invention provides a process for preparing the composition as defined in (A) to (D), wherein cyclosporine, such as cyclosporin, is sufficiently mixed with the component (1.1) to provide a composition as defined in (C). Obtained, optionally mixed with component (5) to obtain a composition as defined in (D), or optionally when using component (1.1) or essentially when using component (1.2). Are sufficiently mixed together, the components are further combined with the components (2) and (3), and the relative proportions of components (1.1) or (1.2), (2) and (3) are defined in (A). (A), (C) or (D) obtained, if necessary, to obtain the composition as defined in (B) by contacting water with the composition of (A) ) In a unit dosage form, e.g. Provides a method comprising formulating a hard gelatin capsule formulation.

In a specific embodiment, the present invention provides a process for the preparation of the composition of (A), wherein cyclosporine, for example cyclosporin, is sufficiently mixed with the above components (1.1) or (1.2), (2) and (3) It involves doing. Here, the relative proportions of component (1.1) or (1.2), (2) and (3) are selected relative to the amount of cyclosporine used, such as "microemulsion preconcentrate", for example to be added to water When, for example, when added in a ratio of at least 1: 1 ppw (composition: H ₂ O), the individual particles contain a particulate or dispersed phase having a size of 2000 GPa or less, preferably about 100 to about 1000 GPa. It provides a method comprising the one selected to obtain a composition that can provide.

Preferred cyclosporines in the context of the compositions of the invention are cyclosporines. A further preferred cyclosporine to which the teachings of the present invention can be applied is [Nva] ² -cyclosporin, also known as cyclosporin G.

The following examples illustrate the compositions according to the invention. Examples 1, 2, 4, 5 and 7 provide for the prevention of transplant rejection, for example, for the administration of 1 to 5 unit doses per day, or for treating autoimmune diseases, for example the autoimmune diseases or conditions described above. Illustrates the preparation of a composition of an oral unit dosage form suitable for use. Examples 3 and 6 may be applied at regular intervals, for example once, twice or three times a day, for example atopic or contact by application to the desired treatment site, such as a dermatitis response or psoriasis lesion or on the scalp. It illustrates the preparation of a topical composition suitable for treating dermatitis, psoriasis or hair loss.

Examples have been described in particular with regard to cyclosporin. However, any other suitable cyclosporine can be used to obtain an equivalent composition. A particularly uniform composition can be obtained by replacing cyclosporin with an equivalent amount of [Nva] ² -cyclosporin in all cases.

Example 1

Oral Dosage Forms: Preparation of the Type "Microemulsion Preconcentrate"

1.1 Ingredient amount (mg / capsule)

Cyclosporin (eg cyclosporin) 50.0

(1.1) Glycofurol 75 180.0

(2.1) Miglyol 812 90.0

(3.1.1) Cremophor RH 40 180.0

500.0 total

After cyclosporin was dissolved in (1.1) with stirring at room temperature, it was stirred again while adding (2.1) and (3.1.1) to the formed solution. The resulting mixture was filled into size 1 hard gelatin capsules and then sealed using the Quali-Seal technique.

The following compositions can be prepared in a similar manner by filling into hard gelatine capsules of size 1 or 2:

1.2 Ingredient Amount (mg / capsule)

Cyclosporin (eg cyclosporin) 50.0

(1.1) Glycofurol 75 180.0

(2.1) Miglyol 812 78.0

(3.1.1) Cremophor RH 40 192.0

500.0 total

1.3 Ingredient Amount (mg / capsule)

Cyclosporin (eg cyclosporin) 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

Ascorville Palmitate ** 1.0

Total 450.0

Co-solvent (hydrophilic phase)

** Antioxidant

1.4 Ingredient Amount (mg / capsule)

Cyclosporin (eg cyclosporin) 50.0

(1) Glycofurol 75 100.0

(2.1) Miglyol 812 75.0

(3.1.7) Lecithin 75.0

Total 300.0

1.5 ingredient amount (mg / capsule)

Cyclosporin (eg cyclosporin) 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

Total 855.0

* Antioxidant

1.6 Ingredient amount (mg / capsule)

Cyclosporin (eg cyclosporin) 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

Total 460.0

1.7 Ingredient Amount (mg / capsule)

Cyclosporin (eg cyclosporin) 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

Total 460.0

1.8 Ingredient Amount (mg / capsule)

Cyclosporin (eg cyclosporin) 100.0

(1.2) 1,2-propylene glycol 75.0

(2.1) Miglyol 812 25.0

(3.1.1) Cremophor RH 40 150.0

(3.2.5) Glycerol Monooleate * 150.0

500.0 total

1.9 Ingredient amount (mg / capsule)

Cyclosporin (eg cyclosporin) 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) Generol 122 E16 * 50.0

500.0 total

1.10 Ingredient Amount (mg / capsule)

Cyclosporin (eg cyclosporin) 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) Generol 122 E25 * 50.0

500.0 total

Co-surfactants

Particular preference is given to compositions 1.1, 1.2, 1.6 and 1.7.

In all cases Transcutol can be used in equivalent or equivalent amounts in place of the Glycofurol component to produce compositions equivalent to 1.1 to 1.5.

15, 20 or 100 mg of cyclosporin (eg cyclosporin) may be used instead of 50 mg of cyclosporin and the amount of the remaining components in each composition may be equivalent to 1.1 to 1.5, as described above.

Example 2

Oral Dosage Forms: Preparation of Enriched "Microemulsion Preconcentrate" Type

2.1 Ingredient amount (mg / capsule)

Cyclosporin (eg cyclosporin) 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

Total 600.0

Cyclosporin and (1.1) to (3.1.1) were mixed as in Example 1, and the obtained mixture was mixed uniformly with (4.2). The product was filled into size 2 hard gelatin capsules.

The following composition can be obtained in a similar manner:

2.2 Ingredient amount (mg / capsule)

Cyclosporin (eg cyclosporin) 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 Ingredient amount (mg / capsule)

Cyclosporin (eg cyclosporin) 100.0

(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

Compositions equivalent to 2.1 to 2.3 can be prepared by replacing the Glycofurol component with an equivalent or equivalent amount of Transcutol.

Example 3

Topically Applicable Formulations: Preparation of the Type "Microemulsion Preconcentrate"

Component weight%

Cyclosporin (eg cyclosporin) 0.1

(1.1) Glycofurol 50.0

(2.1) Miglyol 812 16.6

(3.1.1) Cremophor RH 40 33.3

The composition was prepared similar to Example 1. Equivalent composition was obtained using Transcutol instead of Glycofurol component. The composition may be combined with additional additives such as the hydrocolloid thickeners, paraffins, and the like described above, to prepare bases such as creams, gels, and the like.

Example 4

Oral Dosage Forms: Preparation of Regular Emulsion Preconcentrate Types

4.1 Ingredient amount (mg / capsule)

Cyclosporin (eg cyclosporin) 100.0

(1.1) Transcutol 154.0

(3.1.1) Cremophor RH 40 146.0

(3.2.1) Labrafil M 1944 CS 50.0

Total 450.0

The cyclosporin was dissolved in (1.1) under stirring at room temperature and stirred again while adding (3.1.1) and (3.2.1) to the solution obtained above. The resulting mixture was filled into size 1 hard gelatin capsules and sealed by the Chill-Seal technique.

The following compositions can be prepared in a similar manner and filled into hard gelatine capsules of size 1 or 2 as appropriate.

4.2 Ingredient amount (mg / capsule)

Cyclosporin (eg cyclosporin) 50.0

(1.1) Transcutol 80.0

(3.1.1) Cremophor RH 40 75.0

(3.2.1) Labrafil M 2130 CS 25.0

Total 230.0

4.3 Ingredient Amount (mg / capsule)

Cyclosporin (eg cyclosporin) 100.0

(1.1) Glycofurol 75 150.0

(3.1.1) Nikkol HCO-40 200.0

Total 450.0

4.4 Ingredient amount (mg / capsule)

Cyclosporin (eg cyclosporin) 50.0

(1.1) Transcutol 100.0

(3.1.1) Cremophor RH 40 94.0

(3.2.1) Labrafil M 1944 31.0

Total 275.0

Equivalent compositions may be prepared by using the same or equivalent amount of Glycofurol in place of Transcutol in 4.1, 4.2 or 4.4, or by using the same or equivalent amount of Transcutol in place of Glycofurol in 4.3.

Example 5

Oral Dosage Forms: Preparation of Enriched Emulsion Preconcentrate Type

5.1 Ingredient Amount (mg / capsule)

Cyclosporin (eg cyclosporin) 50.0

(1.1) Transcutol 80.0

(3.1.1) Cremophor RH 40 75.0

(3.2.1) Labrafil M 1944 CS 25.0

(4.1) Eudragit E 50.0

Total 280.0

(3.1.1), (3.2.1) and (4.1) were mixed and dissolved in (1.1) with mild warming with stirring. Cyclosporin was added to the solution with mild warming and then further stirred and the product was sealed by filling into size 2 hard gelatin capsules.

The following compositions can be prepared in a similar manner and filled into hard gelatine capsules of size 1 or 2 as appropriate.

5.2 Ingredient Amount (mg / capsule)

Cyclosporin (eg cyclosporin) 100.0

(1.1) Transcutol 180.0

(3.1.4) Pluronic F68 140.0

(3.1.6) Sodium Lauryl Sulfate 5.0

(4.2) Sodium Carboxymethylcellulose 25.0

Total 350.0

5.3 Ingredient amount (mg / capsule)

Cyclosporin (eg cyclosporin) 50.0

(1.1) Transcutol 163.0

(3.1.1) Cremophor RH 40 100.0

(3.2.1) Labrafil M 1944 CS 35.0

(4.3) Kollidon 30 72.0

Total 420.0

Equivalent compositions may be prepared by using equivalent or equivalent amounts of Glycofurol in place of the Transcutol component.

Example 6

Topical Dosage Forms: Preparation of Emulsion Types

In a similar manner to Examples 2 and 5 above, the following compositions were prepared intimately mixing the indicated ingredients to provide an ointment formulation suitable for topical administration.

6.1 Component Weight%

Cyclosporin (eg cyclosporin) 0.1

(1.1) Transcutol 15.0

(3.1.1) Cremophor RH 40 5.0

(3.2.1) Labrafil M 213 15.0

(3.2.5) Glycerol Monostearate 10.0

(6.2) White Petroleum 54.9

6.2 Ingredient weight%

Cyclosporin (eg cyclosporin) 0.1

(1) Glycofurol 15.0

(3.2.5) Glycerol Monostearate 8.0

(6.1) mineral oil 39.0

(6.1) white petroleum 37.9

Example 7

Oral Dosage Forms: Preparation of Sugar Ester Types

7.1 Ingredient amount (mg / capsule)

Cyclosporin (eg cyclosporin) 50.0

(1.1) Glycofurol 100.0

(5) Sacrose Monolaurate L-1695 * 312.5

Total 462.0

7.2 Ingredient amount (mg / capsule)

Cyclosporin (eg cyclosporin) 50.0

(1.1) Transcutol 80.0

(5) Sacrose Monolaurate L-1695 * 312.5

Total 442.5

7.3 Ingredient Amount (mg / Capsule)

Cyclosporin (eg cyclosporin) 50.0

(1.1) Glycofurol 100.0

(5) Sacrose Monolaurate L-1695 * 312.5

(4.2) Klucel LF 50.0

Total 512.5

(* Is commercially available from Mitsubishi-Kasei Food Corp., Tokyo 104, Japan: HLB = 12.3 or more: lauryl ester residue purity = 95% or more: melting point = about 35 ° C: decomposition at about 235 ° C: 25 Surface tension of an aqueous solution of 0.1% by weight at &lt; 0 &gt; C = 72.0 dyn / cm)

The composition of Example (7.1) was prepared by heating cyclosporin and (5) in an oil bath at 100 ° C. while dissolving in component (1.1) under stirring. The compositions of Examples 7.2 and 7.3 were prepared in a similar manner.

The resulting composition was filled into hard gelatin capsules of size 1 (compositions 7.1 and 7.2) or size 0 (composition 7.3) with warming.

The utility of the compositions according to the invention can be seen, for example, in animal or clinical trials carried out as follows.

Bioavailability Studies of the Compositions of the Invention in Dogs

a) test composition

Composition I Example 1.1

Composition II Example 1.2

Composition III Example 1.6

Composition IV Example 2.1

Composition V Example 2.2

Composition VI Example 4.4

Composition VII Example 5.3

b) test method

A group of eight beagle dogs (males, about 11-13 kg) were used. No food was given to the animals within 18 hours of administration of the test composition, but water was freely accessible until administration. 20 ml of NaCl 0.9% solution was administered after the test composition was administered in garbage. Three hours after administration of the test composition, animals were given free access to food and water.

15 ml before administration (blank), 30 ml, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after administration Blood samples (or 5 ml of blank) were taken from vena saphena and collected in 5 ml plastic tubes containing EDTA. Blood samples were stored at −18 ° C. to suit this experimental analysis.

Blood samples were analyzed by RIA. The area under the blood drug concentration curve over time was calculated according to the trapezoidal law. Variance analysis was performed on AUC (area curve), Cmax (maximum concentration) and Tmax (maximum time).

c) results

The mean AUC (ng hr./ml ^-1 ) and Cmax (ng / ml ^-1 ) values calculated from the formal experiment performance, along with the calculated rate of change (CV) in the response between test animals receiving the same composition It is shown in Table 1 below.

Composition AUC (0-24h) CV (%) Cmax CV% I 2969 46.1 655 42.4 II 3315 35.9 606 29.0 III 3392 33.0 623 25.0 IV 4010 35.1 756 30.0 V 2769 27.8 469 21.7 VI 2375 40.3 518 29.2 VII 2329 23.1 470 36.1

As can be seen from the table, the compositions according to the present invention exhibited high bioavailability (AUC and C _max ) and at the same time relatively low rates of change in the subject's response to AUC and C _max .

Other compositions of Examples 1, 2, 4, 5 and 7 herein, in particular the compositions of Example 1, can be used to obtain advantageous results comparable to the above.

Advantageous properties of the compositions of the present invention regarding oral administration can be demonstrated, for example, in clinical trials conducted as follows.

Subjects were adult volunteers, for example, men with 30 to 55 years of professional training. The experimental group suitably contains 12 subjects.

The following addition / exclusion criteria apply:

Inclusion requirements: normal screening ECG; Normal blood pressure and heart rate; Weight = 50-95 kg

Exclusion requirements: clinically significant intercurrent medical conditions that may interfere with the absorption, distribution, metabolism, excretion or safety of the drug; Signs of significant clinical illness seen during the two weeks prior to the study period; Clinically relevant abnormal laboratory values or electrocardiograms; The need for concurrent medications throughout the study; Administration of drugs known to have sufficient defined toxicity to the major organ systems within three months prior to the experiment; Administration of study drug within 6 weeks prior to testing; History of drug or alcoholism; Blood loss of 500 ml or more in the past 3 months; Drug side effects or hypersensitivity; History of allergies requiring drug therapy; Hep. -B / HIV- positive.

Complete physical examination and ECG were performed before and after the experiment. The following parameters were evaluated within one month period before and after the experiment.

Blood-erythrocyte count, hemoglobin, hematocrit, erythrocyte sedimentation, leukocyte count, smear, platelet count and fasting glucose;

Serum / plasma-total protein and electrophoresis, cholesterol, triglycerides, Na ⁺ , K ⁺ , Fe ⁺⁺ , Ca ⁺⁺ , Cl ^- creatinine, urea, uric acid, SGOT, SGPT, -GT, alkaline phosphatase, total bilirubin, α-amylase;

Urine-pH, microalbumin, glucose, erythrocytes, ketone bodies, precipitates.

Creatinine clearance was also measured one month before the start of the experiment.

Each subject was administered the experimental composition in random order. The composition was orally administered with a full dose of 150 mg of cyclosporin (eg cyclosporin) at one time, with at least 14 days between administrations.

After fasting overnight for 10 hours while allowing only water, the solution was administered in the morning. Only 24 hours after dosing allowed caffeine free beverages. Subjects were not allowed to smoke within 12 hours of dosing. A standardized lunch was provided 4 hours after administration to the subject.

Blood samples (2 ml) were taken 1 hour prior to dosing and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 9, 12, 14, 24, 28 and 32 At time, a blood sample (2 ml) was taken. To measure creatinine, 2 ml of blood samples were taken immediately before dosing and 12, 24 and 48 hours after dosing. Samples for measuring cyclosporin were collected in two EDTA-coated polystyrene tubes (1 ml each) at each time zone, shaken slightly and then rapidly frozen at -20 ° C. Cyclosporin was analyzed in total blood using RIA with specific and / or non-specific MAB assay (detection limit in both cases was about 10 ng / ml).

In this experiment, composition I (hard gelatin encapsulation formulation) according to the invention was compared with composition X.

Composition X [Comparative Composition (Prior Art)]

Unit dosage form (soft gelatin capsule) comprising the following ingredients:

50 mg of cyclosporin

Labrafil 150mg

Ethanol 50mg

Corn oil 213mg

463 mg / dose in total

(Oral beverage solution currently available as Sandimmun)

Composition I showed a bioavailability level of 149.0% (± 48) when compared to Composition X (fixed bioavailability obtained at 100%) in the tests conducted in this manner. AUC values (0-32 hours, ng.h / ml) and C _max values (ng / ml) were 2992 (± 627) and 882 (± 18) for Composition I, respectively, while 2137 for Composition X, respectively. (± 606) and 515 (± 180).

3 and 4 show the results of 12 trial participants after a single oral administration of Composition I (FIG. 3) and Composition X (FIG. 4) in amounts that provide a 150 mg cyclosporine dose, respectively, as measured by specific monoclonal RIA. The results of the above experiments on the concentration of whole blood cyclosporine shown are superimposed graphically. Blood concentration (ng / ml) is shown on the Y axis and time (hr) is shown on the X axis.

Comparing FIGS. 3 and 4 clearly demonstrates that the rate of change in inter-subject response is significantly reduced with respect to the bioavailability parameters recorded when administering Composition I compared to Composition X. The measured rate of change factor [(standard deviation / mean) × 100] for Cmax for composition X was 35%, compared to only 20% for composition I.

Similar or equivalent results can be obtained by oral administration of other compositions of the invention, for example the compositions described in the present examples, in particular the compositions of Example 1.

In vivo testing on topical formulations

Allergic Contact Dermatitis Test in Guinea Pigs

Guinea pigs were coated by applying 50 μl of 0.5% DNFB dissolved in acetone / olive oil (4: 1) to the marked areas of the epilated right and left flanks of guinea pigs (Hartley species, males, 400-500 g). Sensitized. Exposure to this second challenge causes allergic inflammation, causing redness of the skin and infiltration of cells (enrichment). Test compositions in amounts of 200-250 mg (eg Example 3, 6.1 or 6.2 above) were applied to the site treated with DNFB in the right flank using a weak spoon. The left flank was similarly treated with placebo as a control. The application of the test composition / placebo was performed five times at intervals of 20 minutes, 8 hours, 24 hours, 32 hours, and 48 hours after challenge. The skin thickness of the application site was subtracted by folding the skin before each application and 8 hours after the last application and measuring the thickness thereof. In addition, the degree of erythema or inflammation of the skin was visually evaluated on the basis of 0-4. The efficacy of the test formulation in preventing the inflammatory response was determined compared to the results of placebo-treated flanks.

In the test method, compared to the treatment with placebo, after the first application of the test composition (e.g., the composition of Example 3, 6.1 or 6.2) throughout the treatment, for example, until the experiment is complete, The thickness was significantly reduced.

The following result was obtained about the composition of Example 3.

Elapsed time after challenge (hr) 8 24 32 48 56 % Inhibition of skin thickness relative to placebo control 56 68 76 75 73

The composition of the present invention has a higher bioavailability than the conventional cyclosporin preparation, has a low rate of change of bioavailability at different times between subjects and in a single subject, and unlike the conventional galen preparation, It is not affected by substances such as bile salts present.

Claims (36)

Tetrahydrofur of about 5% to about 25% by weight of cyclosporin A and about 0.5% to about 90% by weight of low molecular weight mono-oxyalkanediol or poly-oxyalkanediol based on the total weight of the composition Hydrophilic component containing furyl di-ether or partial-ether, about 0.5% to about 90% by weight triglyceride lipophilic component and about 0.5% to about 90% by weight polyoxyethylene glycolated natural or hydrogenated ( hydrogenated) vegetable oil surfactant, wherein the surfactant and the hydrophilic component are not the same component, and the cyclosporin A, the hydrophilic component, the lipophilic component and the surfactant are 1/1 based on the weight of the composition / water. Spontaneously forming microemulsions in the form of oil-in-water (O / W) particles of up to 2,000 μs when diluted with water Present in a ratio against oral pharmaceutical composition for cyclosporine treatment. The method of claim 1, The maximum size (size) of the particles, characterized in that 1,500 Å or less. The method of claim 2, The particle size of the composition is characterized in that the 100 ~ 1,000Å. The method of claim 1, Dilution with water in the ratio of 1 part by weight of the composition to 1 part by weight of water. The method of claim 1, A composition comprising from about 2% to about 45% by weight lipophilic component based on the total weight of the composition. The method of claim 1, A composition comprising from about 20% to about 90% by weight surfactant based on the total weight of the composition. The method of claim 1, Hydrophilic component containing about 0.5% to about 90% by weight of the tetrahydrofurfuryl di-ether or partial-ether of low molecular weight mono-oxyalkanediol or poly-oxyalkanediol based on the total weight of the composition, about 2 A composition comprising from about 40 wt% to about 45 wt% lipophilic component and from about 20 wt% to about 90 wt% surfactant. Tetrahydrofurfuryl di- of about 5% to about 25% by weight of cyclosporin A and about 0.5% to about 90% by weight of low molecular weight mono-oxyalkanediol or poly-oxyalkanediol based on the total weight of the composition Hydrophilic component containing ether or partial-ether, about 0.5% to about 90% by weight triglyceride lipophilic component and about 0.5% to about 90% by weight polyoxyethylene glycolated natural or hydrogenated vegetable oil surfactant Wherein the surfactant and the hydrophilic component are not the same component, and the cyclosporin A, the hydrophilic component, the lipophilic component and the surfactant are diluted with water at a ratio of 1/1 of the composition / water by weight or less. Are present at a relative rate which spontaneously forms microemulsions in the form of oil-in-water (O / W) in which the average particle size is about 1,500 kPa or less. A pharmaceutical composition for oral use for the cyclosporin treatment. The method of claim 8, And wherein said average particle size is about 1,000 mm 3 or less. The method of claim 9, Wherein said average particle size is from about 150 kPa to about 1,000 kPa or less. The method of claim 8, Dilution with water in the ratio of 1 part by weight of the composition to 1 part by weight of water. The method of claim 8, A composition comprising from about 2% to about 45% by weight lipophilic component based on the total weight of the composition. The method of claim 8, A composition comprising from about 20% to about 90% by weight surfactant based on the total weight of the composition. The method of claim 8, Hydrophilic component containing about 0.5% to about 90% by weight of the tetrahydrofurfuryl di-ether or partial-ether of low molecular weight mono-oxyalkanediol or poly-oxyalkanediol based on the total weight of the composition, about 2 A composition comprising from about 40 wt% to about 45 wt% lipophilic component and from about 20 wt% to about 90 wt% surfactant. The method of claim 1, Wherein said surfactant is a polyoxyethylene glycolated natural vegetable oil. The method of claim 1, Wherein said surfactant is a polyoxyethylene glycolated hydrogenated vegetable oil. The method of claim 8, Wherein said surfactant is a polyoxyethylene glycolated natural vegetable oil. The method of claim 8, Wherein said surfactant is a polyoxyethylene glycolated hydrogenated vegetable oil. The method of claim 1, Wherein said hydrophilic component is tetrahydrofurfuryl alcohol polyethylene glycol ether. The method of claim 19, The maximum size (size) of the particles, characterized in that 1,500 Å or less. The method of claim 20, The particle size of the composition is characterized in that the 100 ~ 1,000Å. The method of claim 19, Dilution with water in the ratio of 1 part by weight of the composition to 1 part by weight of water. The method of claim 19, A composition comprising from about 2% to about 45% by weight lipophilic component based on the total weight of the composition. The method of claim 19, A composition comprising from about 20% to about 90% by weight surfactant based on the total weight of the composition. The method of claim 19, Hydrophilic component containing from about 0.5% to about 90% by weight of tetrahydrofurfuryl alcohol polyethyleneglycol ether, from about 2% to about 45% by weight of lipophilic component and from about 20% by weight, based on the total weight of the composition A composition comprising about 90% by weight surfactant. The method of claim 19, Wherein said surfactant is a polyoxyethylene glycolated natural vegetable oil. The method of claim 19, Wherein said surfactant is a polyoxyethylene glycolated hydrogenated vegetable oil. The method of claim 8, Wherein said hydrophilic component is tetrahydrofurfuryl alcohol polyethylene glycol ether. The method of claim 28, And wherein said average particle size is about 1,000 mm 3 or less. The method of claim 29, Wherein said average particle size is from about 150 kPa to about 1,000 kPa or less. The method of claim 28, Dilution with water in the ratio of 1 part by weight of the composition to 1 part by weight of water. The method of claim 28, A composition comprising from about 2% to about 45% by weight lipophilic component based on the total weight of the composition. The method of claim 28, A composition comprising from about 20% to about 90% by weight surfactant based on the total weight of the composition. The method of claim 28, Hydrophilic component containing from about 0.5% to about 90% by weight of tetrahydrofurfuryl alcohol polyethyleneglycol ether, from about 2% to about 45% by weight of lipophilic component and from about 20% by weight, based on the total weight of the composition A composition comprising about 90% by weight surfactant. The method of claim 28, Wherein said surfactant is a polyoxyethylene glycolated natural vegetable oil. The method of claim 28, Wherein said surfactant is a polyoxyethylene glycolated hydrogenated vegetable oil.