RU2292887C2 - Pharmaceutical composition, using carboxylic acid for stabilizing macrolide in this composition and method for stabilizing macrolide - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition, using a pharmaceutical composition, using carboxylic acid for stabilization of a macrolide in this composition and a method for stabilizing a macrolide. Invention proposes a pharmaceutical composition for enteral or parenteral administration that comprises macrolide and acid. Invention allows decision a problem concerning degradation of macrolides during storage.

EFFECT: improved and valuable properties of composition.

23 cl, 5 dwg, 32 ex

Description

The present invention relates to new galenic formulations, in particular, new galenic formulations in which the active ingredient is a sparingly soluble active agent, for example, macrolide, or, in particular, a cyclic poly-N-methylated undecapeptide or peptolid of the cyclosporin class (see, for example, UK Patent Publication Nos. 2222770 and 2257359A and analogues).

From these publications of British patents it is known that the use of cyclosporins causes highly specific difficulties with regard to their administration in general and galenic formulations, in particular, for example, problems of stability, drug bioavailability and inconsistency of the reaction to the administered dose in one or in different patients.

To overcome these and similar difficulties in the publications of British patents No. 2222770 and 2257359A a description of galenic compositions with cyclosporine as an active ingredient in the form of a microemulsion or microemulsion preconcentrate is proposed. Such formulations typically include 1) a hydrophilic phase, 2) a lipophilic phase, and 3) a surfactant.

In accordance with the present invention, it was unexpectedly discovered that a particularly stable microemulsion or microemulsion preconcentrate of galenic compositions with sparingly soluble active agents having the most interesting bioavailability characteristics and a reduced dispersion in bioavailability parameters in both one and different subjects can be obtained using a hydrophilic phase comprising dimethyl isosorbide.

The use of dimethyl isosorbide has been proposed (WO 94/05312) for the preparation of cyclosporin-containing formulations, but only in the form of complex formulations. The range of components of these considered formulations is precisely defined, therefore, it is obvious that the authors of WO 94/05312 believed that only a limited number of dimethyl isosorbide-based formulations would be active. So, in examples 1, 2 and 6, WO 94/05312 describes a composition containing dimethyl isosorbide with an emulsifier - anhydromannitol oleyl ether (Montanide 103), another emulsifier - citroglyceride (Axol C62), lipogel - aluminum-magnesium hydroxystearate (Gilugel MIG and short chain fatty acid glyceride (Miglyol 812) or milk thistle oil. Dimethyl isosorbide is described only as a solvent, and there is no indication that it can be used as a component of the hydrophilic phase of the microemulsion. The authors of WO 94/05312 have failed to reveal its capabilities in this regard.

In accordance with the present invention, it was unexpectedly found that such microemulsion formulations, contrary to the experience accumulated in this field, can actually be prepared in practice with the inclusion of dimethyl isosorbide as a component of the hydrophilic phase.

The present invention in one of its aspects encompasses a pharmaceutical composition comprising a microemulsion preconcentrate comprising a sparingly soluble active agent and a carrier comprising:

1) a hydrophilic phase, which includes dimethyl isosorbide and / or lower alkyl alkane ether;

2) lipophilic phase;

3) surfactant.

Preferred is a composition in the form of a “microemulsion preconcentrate” of the type that provides m / v (oil-in-water) type microemulsions. However, the composition may exist in the form of a microemulsion, which further comprises an aqueous phase, preferably water.

A “microemulsion preconcentrate,” as defined herein, is a composition that spontaneously forms a microemulsion in an aqueous medium, such as water, when diluted, for example, from 1: 1 to 1:10, or in gastric juice after oral administration.

A “microemulsion” is a transparent or substantially transparent colloidal dispersed system that forms spontaneously or mostly spontaneously when its components are brought into contact. The microemulsion is thermodynamically stable and contains dispersed particles less than approximately 2000 Å in size. Typically, microemulsions contain droplets or particles having an average diameter value of less than about 1500 Å, usually less than 10 nm, usually more than 10 nm, and are stable for more than 24 hours. Additional characteristics can be found in the aforementioned UK patent application No. 2222770.

The specified lipophilic phase may contain from 5 to 85 wt.% Media, for example, from 10 to 85%; preferably from 15 to 70 wt.%, more preferably from 20 to 60 wt.% and even more preferably about 25 wt.%.

The specified surfactant may contain from 5 to 80 wt.% Media; preferably from 10 to 70 wt.%, more preferably from 20 to 60 wt.%, and even more preferably about 40 wt.%.

The specified hydrophilic phase may contain from 5 to 50 wt.% Media, for example, from 10 to 50%; preferably from 15 to 40 wt.%, more preferably from 20 to 35 wt.%.

The specified active agent may be present in a weight amount of up to about 20% by weight of the composition. The specified active agent is preferably presented in an amount of from 1 to 15% by weight of the composition, for example, from about 2 to 10%.

Preferably, when said sparingly soluble active agent is a lipophilic drug, for example cyclosporine or macrolide. As used herein, the term “sparingly soluble” is understood in the sense that the solubility in water at 20 ° C. is less than 0.01 wt.% / Volume.

Cyclosporins to which the present invention is applicable have pharmaceutical uses, for example, as immunosuppressants, antiparasitic agents and multidrug resistance reversers, they are known in the art, in particular cyclosporin A (also known as Ciclosporin hereinafter) ; cyclosporin G, [O- (2-hydroxyethyl) - (D) Ser] ⁸ -Ciclosporin; and [3'-dehydroxy-3'-keto MeBmt] ¹ - [Val] ² -Ciclosporin. Ciclosporin is preferred.

As used herein, the term “macrolide” refers to a macrocyclic lactone, for example, a compound having a 12-membered or multi-member lactone ring. Of particular interest are “lactam macrolides,” that is, macrocyclic compounds having a lactam (amide) bond in the macrocycle in addition to the lactone (ether) bond, for example, lactam macrolides produced by microorganisms of the genus Streptomyces, namely rapamycin, ascomycin and FK506, as well as their numerous derivatives and analogues. It has been shown that such lactam macrolides have interesting pharmaceutical properties, in particular, immunosuppressive and anti-inflammatory.

Rapamycin is an immunosuppressive lactam macrolide that is produced by Streptomyces hygroscopicus. The structure of rapamycin is described [Kesseler H. et al., 1993; Helv. Chim. Acta, 76, 117]. The specified structure is described in formula A:

[see, for example, McAlpine J.B. et al., J. Antibiotics (1991) 44: 688; Schreiber S.L. et al., J. Am. Chem. Soc. (1991) 113: 7433; US patent No. 3929992]. (Various numbering schemes have been proposed for rapamycin. When specifying the names of specific rapamycin derivatives to avoid confusion, these names are given with reference to rapamycin using the numbering scheme of formula A). Rapamycin is a very strong immunosuppressant and has also been shown to have antitumor and antifungal activities. However, its use as a pharmaceutical is limited by its very low and variable bioavailability, as well as its high toxicity. In addition, rapamycin is very poorly soluble, which makes it difficult to prepare stable galenic formulations. Numerous rapamycin derivatives are known. Some 16-O-substituted rapamycins are known [WO 94/02136]. 40-O-substituted rapamycins are known [US 5258389 and WO 94/09010 (O-aryl- and O-alkylrapamycin); WO 92/05179 (carboxylic acid esters), US 5118677 (amide esters), US 5118678 (carbamates), US 5100883 (fluorinated esters), US 5151413 (acetals), US 5120842 (silyl ethers), WO 93/11130 (methylene rapamycin and derivatives), WO 94/02136 (methoxy derivatives), WO 94/02385 and WO 95/14023 (alkenyl derivatives)]. Known (US 5256790) 32-O-dihydrorapamycin or substituted rapamycin, for example, in US 5256790.

Rapamycin and its structurally similar analogues and derivatives are referred to by the generic term “rapamycins”.

Ascomycins, among which the best known are FK506 and ascomycin, constitute another class of lactam macrolides, many of which have strong immunosuppressive and anti-inflammatory activity. FK506 is a lactam macrolide immunosuppressant produced by Streptomyces tsukubaensis No. 9993. The structure of FK506 is given in the appendix to the 11th edition of the Merck Index (1989) in paragraph A5 (Merck Index). Ascomycin is described, for example, in US patent No. 3244592. A large number of derivatives of ascomycin and FK506 have been synthesized, including halogenated derivatives, such as, for example, 33-epichloro-33-deoxycoscomycin (EP 427680). Ascomycin, FK506 and their structurally similar analogues and derivatives are referred to by the general term ascomycins.

Thus, the macrolide can be rapamycin or its O-substituted derivative, in which the hydroxyl group of the cyclohexyl ring of rapamycin is replaced by —OR ₁ , where R ₁ is hydroxyalkyl, hydroalkoxyalkyl, acylaminoalkyl and aminoalkyl; e.g. 40-O- (2-hydroxy) -ethylrapamycin, 40-O- (3-hydroxy) propylrapamycin, 40-O- [2- (2-hydroxy) ethoxy] ethylrapamycin and 40-O- (2-acetaminoethyl ) rapamycin.

A preferred compound is 40-O- (2-hydroxy) ethylrapamycin (WO 94/09010).

Examples of compounds of class FK506 are the compounds mentioned above. These include, for example, FK506, ascomycin, and other naturally occurring compounds. In addition, they include synthetic analogues.

A preferred compound of class FK506 is described (EP 427680, for example, Example 66a), it is also known as 33-epichloro-33-deoxy-ascomycin. Other preferred compounds are also described (EP 465426 and EP 569337, for example, the compound of example 71 in EP 569337).

The hydrophilic phase component includes dimethyl isosorbide and / or lower alkyl alkane ether. The term lower alkyl is to be understood as encompassing alkyls containing a chain of C ₁ to C ₄ , for example ethyl. The term alkane ester should be understood as including acetate and propionate. Ethyl acetate is preferred. The solubility of ethyl acetate in water at room temperature is 8.5 g per 100 ml. Preferably, the solubility of the lower alkyl alkane esters in water at room temperature is from about 1 to 30 g / 100 ml.

The hydrophilic phase may also include an additional component that can be selected from Transcutol (having the formula C ₂ H ₅ - [O (CH ₂ ) ₂ ] ₂ -OH), Glycofurol (also known as tetrahydrofurfuryl alcohol and polyethylene glycol ether) and 1,2 propylene glycol. The hydrophilic phase may include other hydrophilic additional components, for example, lower alcohols such as ethanol. These additional components are usually introduced as partial substitutes for other components of the hydrophilic phase. Despite the fact that the use of ethanol in the compositions is not significant, it was found that it gives a particular advantage when it is necessary to prepare compositions in the form of capsules from soft gelatin. This is due to improved storage characteristics, in particular, reducing the risk of precipitation of the active agent after encapsulation. Thus, storage stability can be improved by using ethanol or some other additional component as an additional ingredient in the hydrophilic phase. Ethanol may comprise from 0 to 60% by weight of the hydrophilic phase, preferably from 20 to 55% by weight, and more preferably from about 50 to 50% by weight. Small amounts of liquid polyethylene glycols may also be introduced into the hydrophilic phase.

Dimethyl isosorbide is also known as 3,6-dianhydro-2,5-diO-methyl-D-glucite. It is manufactured by ICI American Inc. under the trade name Arlasolve DMI. It has the following physicochemical properties:

Boiling temperature approx. 234 ° C Density (25 ° C) 1,164 Refractive index 1,467 Viscosity (25 ° C) approx. 5 MPa · s Dielectric constant approx. 7

It is known (GB 2222770) a wide variety of components of the lipophilic phase, suitable for use in the present invention. Preferred components of the lipophilic phase are medium chain fatty acid triglycerides, mixed mono-, di-, triglycerides and transesterified ethoxylated vegetable oils.

The corresponding medium chain fatty acid triglycerides are known and are commercially available under the trade names Captex, Myritol, Capmul, Neobee and Mazol; most preferred is Miglyol 812. Miglyol 812 is a fractionated coconut oil containing capryl capric acid triglycerides with an approximate molecular weight of 520 daltons. Fatty acid composition: maximum C ₆ content of approximately 3%, C ₈ approximately 50 to 65%, C ₁₀ approximately 30 to 45%, maximum C ₁₂ content of 5%; the acid number is about 0.1; saponification number is approximately from 330 to 345; the maximum value of the iodine number is 1. Mygliol 812 is manufactured by Huels.

These triglycerides are described [Fielder H.P. "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete", Editio Cantor, D-7960 Aulendorf, 3rd edition, revised and supplemented (1989)].

Mixed mono-, di-, and triglycerides preferably include mixtures of mono-, di- and triglycerides of C _12-20 fatty acids, mainly mixed mono-, di- and triglycerides of C _16-18 fatty acids. Fatty acids contained in mixed mono-, di- and triglycerides may include residues of both saturated and unsaturated fatty acids. Preferred, however, is the predominance of residues of unsaturated fatty acids, in particular residues of C ₁₈ fatty acids. Suitably the mixed mono-, di- and triglycerides comprise at least 60%, preferably at least 75%, more preferably at least 85% by weight of mono-, di- and triglycerides of C ₁₈ unsaturated fatty acid (e.g., linolenic , linoleic and oleic acids). It is also acceptable that the mixed mono-, di- and triglycerides contain less than 20%, for example, from about 15% to 10% by weight or less, of mono-, di- and triglycerides of saturated fatty acids (for example, palmitic and stearic acids).

Preferred is the predominance of mixed mono-, di- and triglycerides of mono- and diglycerides, for example, when mono- and diglycerides comprise at least 50%, more preferably at least 70% of the total weight of the lipophilic phase. More preferred is a mono- and diglyceride content of at least 75% (e.g., approximately 80% or 85%) by weight of the lipophilic phase.

Preferably, the monoglycerides comprise from about 25 to 50%, based on the total weight of the lipophilic phase of all mixed mono-, di-, triglycerides. More preferred is a monoglyceride content of about 30 to 40% (e.g., 35 to 40%).

Preferably, the diglycerides comprise from about 30 to 60% (based on the total weight of the lipophilic phase) of all mixed mono-, di-, triglycerides. More preferred is a diglyceride content of about 40 to 55% (e.g., 48 to 50%).

Acceptable is the content of triglycerides in the composition of mixed mono-, di-, triglycerides, comprising at least 5%, but not more than approximately 25%, based on the total weight of the lipophilic phase. More preferred is a triglyceride content of about 7.5 to 15% (e.g., 9 to 12%).

Mixed mono-, di-, and triglycerides can be obtained by mixing individual mono-, di-, or triglycerides in a specific ratio. Usually, however, they contain transesterification products of vegetable oils, for example, almond, peanut, olive, peach, palm, or preferably corn oil, sunflower oil or safflower oil, and most preferably corn oil, with glycerin.

Such transesterification products can usually be obtained by known methods (GB 2257359 and / or WO 94/09211).

In the case of the manufacture of soft gelatin capsules, it is preferable to first remove glycerol residues to obtain a “substantially batch of product free of glycerin”.

From the purified transesterification products of corn oil and glycerol (GB 2257359 and / or WO 94/09211) the most suitable mixed mono-, di- and triglycerides are obtained, hereinafter referred to as "refined oil".

Alternatively, the lipophilic phase may contain, for example, a pharmaceutically acceptable oil, preferably with an unsaturated component, for example, vegetable oil or fish oil.

Alternatively, the lipophilic phase may contain suitably transesterified ethoxylated vegetable oils, obtained, for example, from the interaction of various natural vegetable oils (e.g., corn, stone, almond, peanut, olive, soybean, sunflower oil, safflower oil, palm oil or their mixtures) with polyethylene glycols with an average molecular weight of 200 to 800 in the presence of an appropriate catalyst. Such production methods are known in the art (see, for example, US Pat. No. 3,288,824). Most preferred is a transesterified ethoxylated corn oil.

Transesterified ethoxylated vegetable oils are known and are commercially available under the trade name LABRAFIL (H. Fiedler, loc cit, vol. 2, page 707). Examples include LABRAFIL M 2125 CS (obtained from corn oil and having an acid value of less than 2, saponification number from 155 to 175, HLB (hydrophilic-lipophilic balance) value from 3 to 4, and iodine number from 90 to 100) and LABRAFIL M 1994 CS (obtained from stone oil and having an acid value of about 2, saponification number from 145 to 175, iodine number from 60 to 90). LABRAFIL M 2130 CS can also be used (which is a transesterification product of C _12-18 glyceride and polyethylene glycol, the melting point of which is approximately 35 to 40 ° C, the acid number is less than 2, the saponification number is from 185 to 200, and the iodine number - less than 3). A preferred transesterified ethoxylated vegetable oil is LABRAFIL M2125 CS, which can be obtained, for example, from Gattefosse, Saint-Priest Cedex, France.

Examples of suitable surfactants for use in accordance with the present invention are:

i) reaction products of natural or hydrogenated castor oil and ethylene oxide. The reaction between natural or hydrogenated castor oil and ethylene oxide can be carried out with an approximate molar ratio of reactants from 1:35 to 1:60 and the possible removal of the polyethylene glycol component from the products. Similar diverse surfactants are commercially available. Polyethylene glycol hydrogenated castor oils commercially available under the trade name CREMOPHOR are particularly suitable. Most suitable are CREMOPHOR RH 40 having a saponification number of about 50 to 60, an acid number of less than 1, a water content (Fischer) of less than 2%, an n _D ^{60 of} about 1.453 to 1.457, and an HLB of about 14 to 16; and CREMOPHOR RH 60, having a saponification number of from about 40 to 50, an acid number of less than 1, an approximate value of the iodine number of less than 1, a water content (Fischer) of about 4.5 to 5.5%, n _D ²⁵ values of from about 1.453 up to 1.457 and HLB from about 15 to 17. A particularly preferred product of this class is CREMOPHOR RH 40. Polyethylene glycol castor oils are also acceptable, such as those sold under the trade name CREMOPHOR EL, having a molecular weight value (according to evaporative osmometry) of 1630, number about saponification from about 65 to 70, an acid number of about 2, an iodine number from about 28 to 32, and an n _D ²⁵ value of from about 1.471.

Similar or identical products that can also be used are commercially available under the trade names NIKKOL (e.g. NIKKOL NSO-40 and NSO-60), MAPEG (e.g. MAPEG CO-40h), INCROCAS (e.g. INCROCAS 40) and TAGAT ( for example, polyoxyethylene glycerol fatty acid esters, namely TAGAT RH 40; and TAGAT TO — polyoxyethylene glycerol trioleate having an HLB value of 11.3; TAGAT TO is preferred). A more detailed description of these surfactants can be found in Fiedler loc. cit.

ii) Esters of polyoxyethylene sorbitan and fatty acids, for example mono- and trilauryl, palmityl, stearyl and oleyl esters known (Fiedler, loc. cit., pp. 1300-1304) and commercially available under the trade name TWEEN, including TWEEN products:

20 [polyoxyethylene (20) sorbitan monolaurate],

21 [polyoxyethylene (4) sorbitan monolaurate],

40 [polyoxyethylene (20) sorbitan monopalmitate],

60 [polyoxyethylene (20) sorbitan monostearate],

65 [polyoxyethylene (20) sorbitan tristearate],

80 [polyoxyethylene (20) sorbitan monooleate],

81 [polyoxyethylene (5) sorbitan monooleate],

85 [polyoxyethylene (20) sorbitan trioleate].

Particularly preferred products of this class are TWEEN 40 and TWEEN 80.

iii) Fatty acid and polyoxyethylene esters, for example, stearic acid and polyoxyethylene esters, of the type known and commercially available under the trade name MYRJ (Fiedler, loc. cit. 2, pp. 834-835). A particularly preferred product of this class is MYRJ 52, having a D ²⁵ value of approximately 1.1, a melting point of approximately 40 to 44 ° C., an HLB value of approximately 16.9, an approximate acid value of 0 to 1, and a saponification number of 25 to 35.

iv) Polyoxyethylene-polyoxypropylene copolymers and block copolymers of the type known and commercially available under the trade names PLURONIC, EMKALYX and POLOXAMER (Fiedler, loc. cit., 2, p. 959). A particularly preferred product of this class is PLURONIC F68, having a melting point of about 52 ° C and a molecular weight of from about 6800 to 8975. Another preferred product of this class is POLOXAMER 188.

v) Dioctyl sulfosuccinate or di- (2-ethylhexyl) succinate (Fiedler, loc. cit., 1, pp. 107-108).

vi) Phospholipids, especially lecithins (Fiedler, loc. cit., 2, pp. 943-944). Suitable lecithins include, in particular, soya lecithins.

vii) Mono- and diesters of fatty acids and propylene glycol, for example propylene glycol dicaprylate (also known and commercially available under the trade name MIGLYOL 840), propylene glycol di-laurate, propylene glycol hydroxy stearate, propylene glycol isostearate, propylene glycol glycol urate, etc. (Fiedler, loc. Cit., 2, pp. 808-809).

Surfactants having a hydrophilic lipophilic balance (HLB) value of at least 10, for example Cremophor, are preferably selected.

Preferably, the relative ratio of the component (s) of the hydrophilic phase, the lipophilic phase and the surfactant lies within the “microemulsion” region in the standard ternary diagram. The compositions thus obtained are microemulsion preconcentrates of high stability, capable of forming microemulsions with an average particle size <1500 Å (150 nm) when added to water.

These compositions of microemulsion preconcentrates, for example, the compositions of the following examples, can show good stability indicators identified in standard stability tests, for example, storage stability for up to one, two or three years or even more. The microemulsion preconcentrate compositions of this invention form microemulsions that are stable, for example, up to one day or more.

The pharmaceutical composition may also include other additives or ingredients, for example, antioxidants (such as ascorbyl palmitate, butyl hydroxyanisole (BHA), butyl hydroxytoluene (BHT) and tocopherols) and / or preservatives. These additives or ingredients are present in an amount of about 0.05 to 1% by weight of the total weight of the composition. The pharmaceutical composition may also contain sweeteners or flavorings in an amount up to about 2.5 or 5% by weight, relative to the total weight of such a composition. A preferred antioxidant is α-tocopherol (vitamin E).

Pharmaceutical formulations exhibit particularly beneficial oral properties; Thus, the indicators of consistency and a high level of bioavailability obtained in standard bioavailability tests are, for example, 2-4 times higher than those for emulsions. These tests are performed on animals, for example rats or dogs, or on healthy volunteers using HPLC or a set of specific or non-specific monoclonal antibodies to determine the level of drug substance, for example, macrolide, in the blood. So, the composition indicated in example 1, administered orally to dogs, can give unexpectedly high C _max values determined by ELISA (enzyme-linked immunosorbent assay) using a monoclonal antibody.

Also high was the high predictability of pharmacokinetic parameters such as absorption and blood levels, which made it possible to eliminate or reduce problems with the introduction associated with migratory absorption. In addition, the pharmaceutical compositions effectively interact with tensid substances, for example, bile salts present in the gastrointestinal tract. This means that pharmaceutical formulations are completely dispersible in aqueous systems containing similar natural tensides, and are thus capable of forming in situ microemulsion systems that are stable and are not characterized by precipitation of the active agent or other destruction of the fine structure of the particles. The effect of the pharmaceutical compositions upon oral administration remains essentially independent and / or unaffected by the relative presence or absence of bile salts at any given time or in any given individual.

The compositions of this invention reduce the inconsistency of the reaction to the administered dose for both one and between different patients.

In a further aspect, the invention provides a process for the preparation of a pharmaceutical composition as defined above, comprising (1) hydrophilic phase; (2) lipophilic phase; and (3) a surfactant in a uniform mixture state and adding an active agent, for example, cyclosporin or a macrolide class compound. If necessary, the composition can be formed in the form of a single dose, for example, by packaging this composition in gelatin capsules.

Together with components (1), (2) and (3) or together or after adding the active agent, possible additional components or additives can be mixed, in particular, an additional component of the hydrophilic phase, for example ethanol.

In order to obtain a microemulsion, the composition can be mixed with water or a water-based solvent.

The authors of this application also consider the composition of microemulsion preconcentrates, which may not contain refined fish oil and / or ethanol, and / or transesterified ethoxylated vegetable oil.

The authors found that macrolides, in particular, 40-O- (2-hydroxy) ethylrapamycin, are unstable during storage and can be subjected to a number of different degradation reactions. For example, after several days of storage, one or more degradation products can be identified using, for example, HPLC. Although further study of the pathways of degradation is still necessary, the authors suggest that rupture of the lactone ring in the macrolide may occur.

The authors of this application have identified 40-O- (2-hydroxy) ethylrapamycin-2,3,4-secanoic acid as the main degradation product of 40-O- (2-hydroxy) ethylrapamycin. 40-O- (2-hydroxy) ethylrapamycin-2,34-seco-acid, hereinafter referred to as seco-acid, has the following structure:

It has now been established that stable formulations containing macrolides can be obtained by placing the macrolide in an acidic environment. It is understood that the formulations are stable if the substance of the drug-macrolide remains mostly intact born after several days or weeks of storage at room temperature (25 ° C).

In another aspect, the invention provides a pharmaceutical composition comprising macrolide and acid.

The term macrolide is used in the same meaning as previously described.

Preferred macrolides have at least one structure shown in the diagram:

As examples, the aforementioned and preferably rapamycin or 40-O- (2-hydroxy) ethylrapamycin can be mentioned.

Said acid may be soluble in lipids and / or ethanol. The acid may be, for example, a fatty acid, in particular oleic acid. Said acid may be a carboxylic acid, for example mono-, di- or tricarboxylic acid, and preferably mono- or dicarboxylic. The specified acid may contain one or more hydrophilic groups, for example, hydroxyl groups, and preferably one or two hydrophilic groups. Suitable acids for use in this invention include malonic, fumaric, maleic, D-malic, L-malic, citric, ascorbic, succinic, oxalic, benzoic or lactic acids, or an acid with a similar pKa value, for example, 2-7. Preferred are malonic, oxalic, citric and lactic acids. Malonic acid is most preferred.

The preferred amount of acid can be determined using conventional experiments. The weight ratio of macrolide to acid in the composition according to this invention can have a value of up to 20: 1, for example, from 1: 5 to 5: 1, in particular 1: 1. The specified acid may be present in an amount between 0.05% and 5% by weight of the composition.

Macrolide may be present in an amount of from 1 to 15% by weight of the composition.

The type of pharmaceutical composition is not critical. It may be a solid substance, but a liquid form is preferred. A macrolide, for example, can be incorporated into a microemulsion preconcentrate or emulsion preconcentrate as defined above and combined with a certain amount of acid. Such a stabilized acid composition can be administered enterally, for example orally, namely in the form of a capsule or solution for drinking, or parenterally, namely in the form of an infusion concentrate. Oral administration is preferred.

In a further aspect, the invention provides the use of an acid to stabilize a macrolide in a pharmaceutical composition.

In another aspect, the invention provides a method for stabilizing a macrolide in a pharmaceutical composition, comprising admixing an acid with a macrolide.

Thus, the invention contemplates obtaining stable formulations containing macrolides. Good bioavailability of the drug and reduction of variability in the response to the administered dose can be achieved both for one and between different patients.

The effectiveness of all pharmaceutical formulations of the present invention can be observed in standard clinical tests, for example, according to known indications of doses of the active agent giving equivalent levels in the blood; for example, when doses are administered in the range of 2.5 mg to 1000 mg of active agent per day per 75 kg of the weight of a mammal, namely an adult, and on standard model animals. The increased bioavailability of the active agent provided by these formulations can be observed in standard animal tests or in clinical trials, such as those described above.

The optimal dose of the active agent for administration to a particular patient should be carefully selected, since the susceptibility and metabolism of a macrolide compound, for example rapamycin, may vary between individuals. It may be appropriate to record the levels of the active agent in the blood plasma by radioimmunoassay, analysis using monoclonal antibodies, or other suitable conventional methods. The dose of macrolide typically ranges from 1 to 1000 mg per day, for example, from 2.5 mg to 1000 mg per day for an adult patient weighing 75 kg, preferably from 25 mg to 500 mg, with an optimal dose of from about 50 to 100 mg in a day. Successful results were obtained with the administration of approximately 75 mg per day, for example, in the form of two capsules, one containing 50 mg, and the other containing 25 mg; or three capsules, each 25 mg. Dosages of cyclosporin can be from 25 to 1000 mg per day (preferably from 50 mg to 500 mg), and a dose of FK506 from 2.5 mg to 1000 mg per day (preferably from 10 mg to 250 mg). For the administration of 40-O- (2-hydroxy) ethylrapamycin, a dose between 0.5 and 5 mg / kg body weight / day is recommended.

The pharmaceutical formulations are preferably combined in a single dose, for example, filling the capsule shells for oral administration. Capsule shells can be soft or hard gelatin capsule shells. If the pharmaceutical composition exists in unit dose form, then each unit dose will contain, respectively, from 10 to 100 mg of active agent, more preferably from 10 to 50 mg, for example, 15, 20, 25 or 50 mg. Such unit doses are suitable for administration from one to five times daily, depending on the specific goal of treatment, phase of treatment, and the like.

However, if necessary, the pharmaceutical compositions may be in the form of solutions for drinking and may include water or any other aqueous system to provide microemulsion systems suitable for drinking.

These pharmaceutical formulations are particularly useful for the treatment and prevention of the conditions described on pages 40 and 41 in EP 427680 and on pages 5 and 6 in PCT / EP93 / 02604.

These pharmaceutical formulations are particularly useful for:

a) the treatment and prevention of rejection of organ or tissue transplants, for example, for the treatment of recipients of the following transplants: heart, lung, heart and lung, liver, kidney, pancreatic gland, skin or cornea. These pharmaceutical formulations are also indicated to prevent a graft versus host reaction, which sometimes occurs in bone marrow transplantation;

b) treatment and prevention of autoimmune disease and inflammatory conditions, in particular, inflammatory conditions with an etiology, including an autoimmune component such as arthritis (for example, rheumatoid arthritis, chronic progressive arthritis and deforming arthritis) and rheumatic diseases; and

c) treatment of multidrug resistance (MDR).

In addition, these macrolide active agents exhibit antitumor and antifungal activity and, therefore, these pharmaceutical compositions can be used as antitumor and antifungal agents.

The contents of all the references mentioned above, especially regarding the compounds serving as an example (prototype), are given here as a reference, and each of the examples of compounds can be used as macrolide in the examples illustrated below.

Examples

The following is a description by way of example, referring only to the compositions of this invention. The content of the components, unless otherwise indicated, is presented in weight percent for each composition.

Examples 1-20

The following is a description by way of example, referring only to the microemulsion preconcentrate formulations of this invention in which the hydrophilic phase includes DMI or ethyl acetate.

Examples 1 and 2 illustrate unit dose formulations suitable for use, for example, for the prevention of transplant rejection or for the treatment of autoimmune diseases, and for administration in an amount of from 1 to 5 unit doses per day. Examples are described with specific reference to Ciclosporin, but equivalent formulations can be prepared using any macrolide or other active agent.

Example 1

Preparation of unit doses of oral dosage forms

Component Amount (mg / capsule) Cyclosporin e.g. ciclosporin one hundred 1) Dimethyl isosorbide 100-200, e.g. 150 2) Refined Corn Oil or Labrafil M2125CS 100-500, e.g. 320 3) Cremophor RH40 100-500, e.g. 380 4) Ethanol 10-100, e.g. 50 Total 1000 (by selecting the appropriate amount from the intervals)

A batch of 1000 capsules is being prepared.

Cyclosporin is dissolved with stirring at room temperature in (1), (2) and (3) are added to the resulting solution with stirring. Portions of the resulting 0.5 ml mixture are filled either with hard gelatin size 1 capsules, which are sealed using, for example, QualiSeal technique, or soft gelatin capsules.

Compositions containing 50 and 100 mg of Ciclosporin are prepared in a similar manner using the remaining specified ingredients in the indicated amounts.

In this example, refined oil is equivalent to “refined glycerol-transesterified corn oil” free of glycerol impurities (GB 2257359 and WO 94/09211).

Example 2

Preparation of oral solution for drinking

The composition is prepared analogously to example 1, based on a volume of 5 liters, ethanol, if desired, can be replaced by an equivalent amount of dimethyl isosorbide.

Examples 3-19

Compositions with cyclosporin A are prepared using as a lipophilic phase:

Miglyol 812 (from Huls) - in examples 3-9;

corn oil glyceride (mono-, di- and triglycerides from refined corn oil) - in examples 10-17; and

Labrafil 2125 CS (from Gattefosse) - in examples 18 and 19.

In the following examples, the abbreviation DMI is used to refer to dimethyl isosorbide.

A filler is prepared by mixing the components with each other. Then cyclosporin A is dissolved in the carrier with stirring.

Figure 1-5 presents triple diagrams of the relative concentrations of each of the hydrophilic, lipophilic and surface-active components. The relative concentration of DMI increases from 0% at the right edge of the diagram to 100% - in the lower left corner, as indicated by the arrow. The relative concentration of the surfactant indicated in FIGS. 1-5 by the abbreviation S increases from the baseline of the diagram to 100% at the apex, as indicated by the arrow. The relative concentration of the lipophilic phase increases from 0% along the left edge of the diagram to 100% in the lower right corner, as indicated by the arrow. The lines inside the diagram indicate a 10% increase from 0% in each corner to 100% in the corresponding upper position.

Thus, the theoretical composition, including 50% of the lipophilic phase and 50% DMI, is depicted in the diagram as a dot in the middle of the baseline.

The relative proportions of the main components of the filler for the preferred compositions of the present invention lie within the regions a and b, marked respectively by lines A and B in figure 1; areas c, d 'and d' 'marked respectively by lines C, D' and D '' in FIG. 2; area e, marked by line E in figure 3; region f marked with a line F in figure 4, and region g marked with a line G in figure 5.

In Figs. 1 and 2, Miglyol 812 is abbreviated with the letter M. In Figs. 3 and 4, the corn oil glyceride is abbreviated with the letter CG. 5, Labrafil 2125 CS is abbreviated as L.

Particle size measurements are carried out at 20 ° C. while diluting 60 μl of the composition in 1 ml of water by correlation photon spectroscopy using, for example, Malvern ZetaSizer No. 3 from Malvern Instruments.

Examples 3-9

Subsequent formulations containing cyclosporin A are prepared using Miglyol 812. Ethanol in the formulations of Examples 3 and 4 is present in an amount of 10% by weight.

Example 3 four Cremophor rh 40 48 40 Miglyol 812 24 32 Dmi 8 8 Ethanol abs. 10 10 Ciclosporin 10 10

For compositions 3 and 4, no phase separation is observed, the compositions are transparent. When diluted with water in a ratio of 1: 1 and 1:10 by volume, the composition from example 3 remains transparent. The composition of example 4 opalescent when diluted with water in the ratio of 1: 1 and 1:10 (1 volume part of the composition, 10 volume parts of water). Figure 1 shows ternary diagrams for compositions 3 (region a) and 4 (region b).

Example 5 6 7 8 9 Cremophor rh 40 36 36 45 54 54 Miglyol 812 27 eighteen eighteen eighteen 9 Dmi 27 36 27 eighteen 27 Ciclosporin 10 10 10 10 10

No phase separation is observed for any of compositions 5–9; the compositions are transparent. When diluted with water in the ratio of 1: 1 and 1:10 by volume, the compositions of examples 5-9 remain transparent. Figure 2 shows ternary diagrams for each of the compositions 5-9 (areas c, d 'and d' ').

Examples 10-17

Compositions containing cyclosporin A in examples 10-17 are prepared using corn oil glyceride. Ethanol in the compositions of examples 10 and 11 is present in an amount of 10% by weight.

Example 10 eleven Cremophor rh 40 40 32 Corn oil glyceride 32 40 Dmi 8 8 Ethanol abs. 10 10 Ciclosporin 10 10

For compositions 10 and 11, no phase separation is observed, the compositions are transparent. When diluted with water in a ratio of 1: 1 and 1:10 by volume, the compositions of examples 10 and 11 remain transparent (1 part of the composition, 10 parts of water). Figure 3 shows ternary diagrams for compositions 10 and 11 (region e).

Example 12 13 fourteen fifteen 16 17 Cremophor rh 40 27 45 36 45 45 36 Corn oil glyceride eighteen eighteen 27 27 36 36 Dmi 45 27 27 eighteen 9 eighteen Ciclosporin 10 10 10 10 10 10

For none of the compositions 12-17, no phase separation is observed, the compositions are transparent. When diluted with water in a ratio of 1:10 by volume (1 part of the composition, 10 parts of water) the compositions of examples 12-17 remain transparent. When diluted with water in a ratio of 1: 1, the compositions of examples 12-15 and 17 remain transparent, and opalescence appears in the composition of example 19.

Figure 4 shows the triple diagrams of compositions 12-17 (region f).

Examples 18 and 19

Compositions containing cyclosporin A in Examples 18 and 19 were prepared using Labrafil 2125 CS as the lipophilic phase.

Example eighteen 19 Cremophor rh 40 27 45 Labrafil 2125 CS eighteen eighteen Dmi 45 27 Ciclosporin 10 10

For compositions 18 and 19, no phase separation is observed, the compositions are transparent. When diluted with water in the ratios 1: 1 and 1:10 (1 part of the composition, 10 parts of water by volume), the composition of Example 19 remains transparent. When diluted with water in a ratio of 1: 1 and 1:10 of the composition of example 18, opalescence appears. Figure 5 shows a triple diagram for composition 19 (region g).

For compositions 3-19 carry out the measurement of the distribution of particle sizes. In all formulations, the maximum particle size is less than 70 nm. The Z-average value of the particle size lies in the range from 22.0 to 32.6 nm. The value of the polydispersity index lies in the range from 0.076 to 1.164.

Examples 20-24

Microemulsion preconcentrates are prepared using ethyl acetate as the hydrophilic phase. To form an emulsion, the compositions are diluted with water in a ratio of 1: 1, as well as adding 10 parts of water to 1 part of the composition.

Example twenty 21 22 23 24 Cremophor rh 40 40 45 45 54 48 Corn oil glyceride 24 27 Labrafil M2125 CS 27 Miglyol 812 eighteen 24 Ethyl acetate 16 eighteen eighteen eighteen eighteen Ethanol 10 10 Ciclosporin a 10 10 10 10 10 Water dilution 1: 1 epiphany epiphany epiphany epiphany epiphany 1:10 epiphany epiphany epiphany. epiphany epiphany Z-average droplet size 26.9 nm 23.7 nm 29.3 nm 27.1 nm 33.2 nm Polydispersity 0.08 0,089 0,110 0.152 0,111

According to visual observation, each of the compositions 21-24 after dilution forms a transparent and stable microemulsion.

Storage

The undiluted formulations of Examples 1-24 remain stable, that is, no precipitation or crystallization is observed for at least one month of storage at room temperature. After 2 months of storage at room temperature, the compositions of examples 5, 6, 7, 12 and 18 remain transparent.

Examples 25-27

Microemulsion preconcentrates are prepared and stored at room temperature for 12 months:

Example 25

Quantity in weight. % Cremophor rh 40 24 Corn oil glyceride 48 Dmi 8 Ethanol abs. 10 Cyclosporin A 10

After 12 months of storage, no precipitation or crystallization is observed.

Example 26

Quantity in weight. % Cremophor rh 40 27 Corn oil glyceride 54 Dmi 9 Cyclosporin A 10

After 12 months of storage, no precipitation or crystallization is observed.

Example 27

Quantity in weight. % Cremophor rh 40 27 Corn oil glyceride 45 Dmi eighteen Cyclosporin A 10

After 12 months of storage, no precipitation or crystallization is observed.

Cyclosporin A can be replaced in any of the formulations described in examples 1-27 by another cyclosporin or macrolide, for example, rapamycin, 40-O- (2-hydroxy) ethylrapamycin, 33-epichloro-33-deoxyamine and the compound of example 71 of EP 569337.

Examples 28-32

The following is a description in the examples of only acid stabilized macrolide compositions.

Example 28

An active agent of class FK 506 or class of rapamycin, for example, 40-O- (2-hydroxy) ethyl rapamycin, is introduced into the microemulsion preconcentrate of the following composition, expressed in weight percent: 2% active agent, 2% malonic, lactic or famonic acid, 44% Cremophor RH40, 26.4% mono-, di-, triglycerides of corn oil, 17.6% 1,2-propylene glycol and 10% ethanol.

Stability tests after 3 months showed that the composition with malonic acid contained by this time 98% of the active agent, and without malonic acid - only 73%.

Examples 29 and 30

Microemulsion preconcentrates are prepared using 40-O- (2-hydroxy) ethyl rapamipine in examples 29a and 29b and rapamycin in examples 30a and 30b as the active agent. In Example 29, the active agent 40-O- (2-hydroxy) ethyl rapamycin is abbreviated as “active agent R”.

The intact drug content and degradation product were determined by HPLC with a measurement error of ± 2%.

The content of the main degradation product is indicated in parentheses. The main degradation product of rapamycin is called secorapamycin.

The above examples demonstrate that malonic acid has a pronounced stabilizing effect on 40-O- (2-hydroxy) ethyl rapamycin and rapamycin.

Example 31

The composition of example 29a is mixed with malonic acid in concentrations lying between 0.05% and 5% by weight. A highly stabilizing effect is observed with malonic acid in the concentration range from 0.25 to 0.75% by weight of the composition.

Example 32

A concentrate for infusion is prepared using the following composition:

40-O- (2-hydroxy) ethylrapamycin 20 mg / ml Cremophor EL 600 mg / ml lemon acid 10 mg / ml ethanol up to 1 ml

After storage at 25 ° C. for 4 weeks, measuring the active ingredient content gives a value of 99.6%. This result demonstrates the stabilizing effect of citric acid on 40-O- (2-hydroxy) ethylrapamycin.

In the above Examples 28-32, the active agent may be replaced with 33-epichloro-33-deoxy-ascomycin or with compound 71 of EP 569337.

Claims (23)

1. A stable composition containing macrolide and acid, where the macrolide is introduced into the microemulsion preconcentrate or emulsion preconcentrate, characterized in that the macrolide is (i) rapamycin or a derivative thereof; (ii) 33-epichloro-33-deoxy-ascomycin or (iii) {[1E- (1R, 3R, 4R)] 1R, 4S, 5R, 6S, 9R, 10E, 13S, 15S, 16R, 17S, 19S, 20S} -9-ethyl-6,16,20- trihydroxy-4- [2- (4-hydroxy-3-methoxy-cyclohexyl) -1-methylvinyl] -15,17-dimethoxy-5,11,13,19-tetramethyl-3-oxa-22-azatricyclo [18.6. 1.0 (1.22)] heptacos-10-en-2,8,21,27-tetraone, and that the acid is monocarboxylic acid comprising one or more hydrophilic groups; dicarboxylic acid; or tricarboxylic acid, in which the acid is present in an amount of from 0.05 to 5% of the total weight of the composition and the weight ratio of macrolide to acid is up to 20: 1. 2. The composition according to claim 1, in which the acid is present in an amount of from 0.05 to 5% of the total weight of the composition. 3. The composition according to claim 1 or 2, in which the weight ratio of macrolide to acid is up to 20: 1. 4. The composition according to claim 3, in which the weight ratio of macrolide to acid is from 1: 5 to 5: 1. 5. The composition according to any one of the preceding paragraphs, in which the compound rapamycin or its derivative is 40-O- (2-hydroxy) ethylrapamycin. 6. The composition according to any one of the preceding paragraphs, in which the acid is selected from malonic, fumaric, maleic, D-malic, L-malic, citric, ascorbic, succinic, oxalic, benzoic and lactic acids. 7. The composition according to claim 6, in which the acid is malonic acid. 8. The composition according to any one of the preceding paragraphs, which is a pharmaceutical composition for use a) as an immunosuppressant; b) as an anti-inflammatory agent; c) as an antiproliferative agent. 9. The composition according to any one of the preceding paragraphs, which is a pharmaceutical composition and is intended for a) treatment and prevention of organ and tissue transplant rejection; b) to prevent the reaction "transplant against the owner"; c) for the treatment and prevention of autoimmune disease and inflammatory conditions; g) for the treatment of multidrug resistance (MDR); d) as an antitumor agent; e) as an antifungal agent. 10. The composition according to any one of claims 1 to 7, which is a pharmaceutical composition for use in the treatment and / or prevention a) recipients of the following transplants of the heart, lung, combined heart and lung, liver, kidney, pancreatic gland, skin or cornea; b) graft versus host reactions, which sometimes occurs during bone marrow transplantation; c) inflammatory conditions with etiology including an autoimmune component such as arthritis; d) arthritis, rheumatoid arthritis, chronic progressive arthritis, deforming arthritis; e) rheumatic diseases; e) autoimmune hematological disorders, hemophilic anemia, aplastic anemia, pure red cell anemia and idioplastic thrombocytopenia, systemic erythematous lupus; polychondria, scroderma, Wedgener's granulomatosis, dermatosis, chronic active hepatitis, severe myasthenia gravis, psoriasis, Steven-Jones syndrome, ideopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn’s disease, endocrine oculonopathy, Gravez’s disease, bilateral cirrhosis, juvenile diabetes (type I mellitus diabetes), uevit (anterior and posterior), dry keratoconjunctivitis and spring keratoconjunctivitis, interstitial pulmonary fibrosis, proriasis arthritis glomerulonephritis (with and without nephrotic syndrome, idiomatic nephrotic syndrome or minimal changes in nephropathy) and juvenile dermatomycosis; g) asthma; h) tumors, hyperproliferative skin disorder; i) inflammation caused by the action of steroids; j) infection; k) an overdose of FK-506, rapamycin, new immunosuppressive compounds and other macrophilin-binding immunosuppressants, or to increase the effectiveness of other chemotherapeutic agents in the treatment and control of multi-resistant conditions, multi-resistant cancer, multi-resistant AIDS. 11. The use of monocarboxylic acid comprising one or more hydrophilic groups; dicarboxylic acid or tricarboxylic acid to stabilize the lactam macrolide against degradation in a composition where the macrolide is: (i) rapamycin or a derivative thereof; (ii) 33-epichloro-33-deoxy-ascomycin or (iii) {[1E- (1R, 3R, 4R)] 1R, 4S, 5R, 6S, 9R, 10E, 13S, 15S, 16R, 17S, 19S, 20S} -9-ethyl-6,16,20- trihydroxy-4- [2- (4-hydroxy-3-methoxy-cyclohexyl) -1-methylvinyl] -15,17-dimethoxy-5,11,13,19-tetramethyl-3-oxa-22-azatricyclo [18.6. 1.0 (1.22)] heptacos-10-en-2,8,21,27-tetraone, comprising obtaining a composition by mixing macrolide and acid to obtain a composition where the acid is present in an amount of from 0.05 to 5% of the total weight of the composition and the weight ratio of macrolide to acid is up to 20: 1. 12. The use according to claim 11, in which the weight ratio of lactam macrolide to acid is from 1: 5 to 5: 1. 13. The use according to any one of claims 11-12, wherein the lactam macrolide is ascomycin, rapamycin or a derivative thereof. 14. The use according to any one of claims 11 to 13, wherein the acid is selected from malonic, fumaric, maleic, D-malic, L-malic, citric, ascorbic, succinic, oxalic, benzoic and lactic acids. 15. The use of claim 14, wherein the acid is malonic acid. 16. The method of stabilization of lactam macrolide against degradation in a pharmaceutical composition, characterized in that the macrolide is: (i) rapamycin or a derivative thereof; (ii) 33-epichloro-33-deoxy-ascomycin or (iii) {[1E- (1R, 3R, 4R)] 1R, 4S, 5R, 6S, 9R, 10E, 13S, 15S, 16R, 17S, 19S, 20S} -9-ethyl-6,16,20- trihydroxy-4- [2- (4-hydroxy-3-methoxy-cyclohexyl) -1-methylvinyl] -15,17-dimethoxy-5,11,13,19-tetramethyl-3-oxa-22-azatricyclo [18.6. 1.0 (1.22)] heptacos-10-en-2,8,21,27-tetraone, and comprising preparing a composition by mixing macrolide and monocarboxylic acid comprising one or more hydrophilic groups; dicarboxylic acid or tricarboxylic acid to obtain a composition where the acid is present in an amount of from 0.05 to 5% of the total weight of the composition and the weight ratio of macrolide to acid is up to 20: 1. 17. The method according to clause 16, in which the weight ratio of lactam macrolide to acid is from 1: 5 to 5: 1. 18. The method according to any one of p. 16 or 17, in which the lactam macrolide is ascomycin, rapamycin or its derivative. 19. The method according to any one of claims 16-18, wherein the acid is selected from malonic, fumaric, maleic, D-malic, L-malic, citric, ascorbic, succinic, oxalic, benzoic and lactic acids. 20. The method according to claim 19, in which the acid is malonic acid. 21. The use according to any one of claims 11-15, or the method according to any one of claims 16-20, wherein the composition is a pharmaceutical composition for use a) as an immunosuppressant, b) as an anti-inflammatory agent; c) as an antiproliferative agent. 22. The use according to any one of claims 11-15, or the method according to any one of claims 16-20, wherein the composition is a pharmaceutical composition and is intended for a) treatment and prevention of organ and tissue transplant rejection; b) to prevent the reaction "transplant against the owner"; c) for the treatment and prevention of autoimmune disease and inflammatory conditions; g) for the treatment of multidrug resistance (MDR); d) as an antitumor agent; e) as an antifungal agent. 23. The use according to any one of claims 11-15, or the method according to any one of claims 16-20, wherein the composition is a pharmaceutical composition for use in the treatment and / or prevention a) recipients of the following transplants of the heart, lung, combined heart and lung, liver, kidneys, pancreatic gland, skin or cornea; b) graft versus host reactions, which sometimes occurs during bone marrow transplantation; c) inflammatory conditions with etiology including an autoimmune component such as arthritis; d) arthritis, rheumatoid arthritis, chronic progressive arthritis. deforming arthritis; e) rheumatic diseases; e) autoimmune hematological disorders, hemophilic anemia, aplastic anemia, pure red cell anemia and idioplastic thrombocytopenia, systemic erythematous lupus; polychodia, scrorodoma, Wedgener's granulomatosis, dermatosis, chronic active hepatitis, severe myasthenia gravis, psoriasis, Steven-Jones syndrome, ideopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn’s disease, endocrine oculopathy, Grave’s disease, sarco bilateral cirrhosis, juvenile diabetes (type I mellitus diabetes), uvent (anterior and posterior), dry keratoconjunctivitis and spring keratoconjunctivitis, interstitial pulmonary fibrosis, proriasis arthritis, glo Merunephritis (with and without nephrotic syndrome, idiomatic nephrotic syndrome or minimal changes in nephropathy) and juvenile dermatomycosis; g) asthma; h) tumors, hyperproliferative skin disorder; i) inflammation caused by the action of steroids; j) infection; k) an overdose of FK-506, rapamycin, new immunosuppressive compounds and other macrophilin-binding immunosuppressants, or to increase the effectiveness of other chemotherapeutic agents in the treatment and control of multi-resistant conditions, multi-resistant cancer, multi-resistant AIDS.

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