The microemulsion preconcentrate

 

(57) Abstract:

The invention relates to medicine, in particular to the microemulsion preconcentrate, including soluble active agent and a carrier, comprising: 1) a hydrophilic phase, which includes dimetridazole and/or lower alkylalkoxy ether, 2) a lipophilic phase, and 3) a surfactant. The active agent may be cyclosporine or macrolide. Preconcentrate has the most interesting characteristics in terms of bioavailability and reduced variation in the characteristics of bioavailability of both the one and the various subdivisions. 4 C.p. f-crystals, 5 Il., 8 table.

The present invention relates to a new galenic formulations, in particular new galenic formulations in which the active ingredient is a soluble active agent, such as macrolides, or, in particular, cyclic poly-N-methylated undecapeptide or peptoid class cyclosporine - see, for example, publications, patents great Britain 2222770 and 2257359 a and analogues.

Of these publications, patents great Britain it is known that the use of cyclosporine causes specific difficulties in relation to their introduction in General, the TBA reaction to the administered dose as one, and the different patients.

To overcome these and similar difficulties in publications patents great Britain 2222770 and 2257359 And proposed description of herbal formulations of cyclosporine as an active ingredient in the form of a microemulsion or microemulsion preconcentrate. Such compositions typically include 1) a hydrophilic phase, 2) a lipophilic phase, and 3) a surfactant.

In accordance with the present invention it has been unexpectedly discovered that a particularly stable microemulsion or microemulsion preconcentrate galenical formulations with insoluble active agents, with the most interesting characteristics in terms of bioavailability and reduced variation in the characteristics of bioavailability of both the one and the different actors, can be obtained by applying the hydrophilic phase comprising dimetridazole.

It was suggested [WO 94/05312] the application of dimethylselenide to get ziklosporinami compositions, but only in the form of complex compounds. The range of considered components of these compositions precisely defined, it is therefore evident that the authors of WO 94/05312 believed that the active will be only a limited number of costed with emulsifier - aerowyn ether of anhydromannitol (Montanide 103), another emulsifier - nitroglicerina (Axol C62), lipocalin - aluminum-magnesium hydroxystearate (Gilugel MIG) and short-chain glycerides of fatty acids (Miglyol 812), or Thistle oil. Dimetridazole described only as a solvent, and there is no indication that it can be used as a component in the hydrophilic phase of the microemulsion. The authors WO 94/05312 failed to disclose its capabilities in this regard.

In accordance with the present invention it has been unexpectedly found that such microemulsion system contrary accumulated in this field experience really can be cooked in practice, with the inclusion of dimethylselenide as a component of the hydrophilic phase.

The present invention in one of its aspects, encompasses a pharmaceutical composition that represents the microemulsion preconcentrate, including soluble active agent and a carrier containing:

1) a hydrophilic phase, which includes dimetridazole and/or lower alkylalkoxy ether;

2) a lipophilic phase;

3) surface-active substance.

Preferred is a composition in the form of a "microemulsion PR the composition may exist in the form of a microemulsion, which further comprises an aqueous phase, preferably water.

"The microemulsion preconcentrate" according to the definition adopted herein, is a compound that spontaneously forms a microemulsion in an aqueous environment, such as water, when breeding for example from 1:1 to 1:10, or in the gastric juice after oral administration.

"Microemulsion" is a transparent or substantially transparent colloidal disperse system, which is formed spontaneously or substantially spontaneously when bringing the components into contact. The microemulsion is thermodynamically stable and contains dispersed particles of a size less than approximately 2000 typically, micro-emulsions containing droplets or particles having average diameter less than about 1500 typically less than 100 nm, typically more than 10 nm, and stable over 24 hours. Additional features can be found in the aforementioned patent application UK 2222770.

Specified lipophilic phase may contain from 5 to 85 percent by weight of the carrier, for example from 10 to 85%; preferably from 15 to 70 weight %, more preferably from 20 to 60 weight % and even more preferably about 25 weight %.

U weight %, more preferably from 20 to 60 weight % and even more preferably about 40 weight %.

The specified hydrophilic phase may contain from 5 to 50 percent by weight of the carrier, for example from 10 to 50%; preferably from 15 to 40 weight %, more preferably from 20 to 35 weight %.

The specified active agent can be represented in the weight amounts to approximately 20% by weight of the composition. The specified active agent is preferably present in an amount of from 1 to 15% by weight of the composition, for example from about 2 to 10%.

Preferably, when the specified soluble active agent is a lipophilic drug, such as cyclosporin or macrolide. Used herein, the term "sparingly soluble" is understood in the sense that the solubility in water at 20oWith less than 0.01% weight/volume.

Cyclosporine, which applies the present invention have pharmaceutical applications, for example as immunosuppressants, anti-parasitic and means of reversing multidrug resistance, they are known from the prior art, in particular cyclosporin a (also known as and referred to hereinafter as Ciclosporin; cyclosporine G, [O-(2-Ciclosporin.

Used herein, the term "macrolide" relates to macrocyclic lactone, for example, the connection having a 12-membered or consisting of more members lactoovo ring. Of particular interest are the "lactam macrolide antibiotics", i.e., macrocyclic compounds having the lactam (amide) bond in the macrocycle in addition to lactoovo (radio) communication, for example lactam macrolide antibiotics produced by microorganisms of the genus Streptomyces, it is a rapamycin, ascomycin and FK506, and their numerous derivatives and analogues. It was shown that such lactam macrolide antibiotics possess 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 described [Kesseler, H., et al.; 1993; Helv. Chim. Acta; 76; 117]. This structure is described in the formula:

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[Cm. for example, McAlpine, J. B., et al., J. Antibiotics (1991) 44: 688; Schreiber, S. L. , et al., J. Am. Chem. Soc. (1991) 113: 7433; U.S. patent 3929992] . (For rapamycin have been changed numbering schemes. When specifying the names of specific derivatives of rapamycin to avoid confusion, these names are given with reference to rapamycin using the ANO, it has antitumor and this makes it activities. However, its use as pharmaceutical agents is limited by its very low and variable bioavailability, as well as its high toxicity. In addition, rapamycin is very poorly soluble, which complicates the preparation of stable galenic formulations. Numerous derivatives of rapamycin. Known [WO 94/02136] some 16-O-substituted rapamycin. Famous 40-O-substituted rapamycin [US 5258389 and WO 94/09010 (O-aryl and O-alkylaromatic); WO 92/05179 (esters of carboxylic acids), US 5118677 (amide esters), US 5118678 (carbamates), US 5100883 (fluorinated ethers), US 5151413 (acetals), US 5120842 (Silovye esters), WO 93/11130 (methyltryptamine and derivatives), WO 94/02136 (methoxypropane), WO 94/02385 and WO 95/14023 (alkeneamine derivatives)]. Known [US 5256790] 32-dihydrocapsaicin or substituted rapamycin, for example in US 5256790.

Rapamycin and its structurally similar analogues and derivatives are called by the General term "rapamycin".

Ascomycin, among which the most well known FK506 and ascomycin, constitute another class of lactam, macrolides, many of which have strong immunosuppressive and anti-inflammatory activity. FK506 is a lactam is aniu Merck Index (1989) in paragraph A5 (Merck Index). Ascomycin described, for example, in U.S. patent 3244592. Synthesized a large number of derivatives of ascomycin and FK506, including halogenated derivatives, such as 33-epichloro-33-desoxycortisol [EP 427680]. Ascomycin, FK506 and their structurally similar analogues and derivatives are called by the General term "ascomycin".

Thus, the macrolide may be rapamycin or its O-substituted derivative in which the hydroxyl group tsiklogeksilnogo ring of rapamycin replaced by-OR1where R1is hydroxyalkyl, hydroalkoxylation, acylaminoalkyl and aminoalkyl; for example 40-O-(2-hydroxy)atrribution, 40-O(3-hydroxy)properposition, 40-O-[2-(2-hydroxy)ethoxy]-atrribution and 40-O-(2-acetamidomethyl)by rapamycin.

The preferred compound is 40-O-(2-hydroxy)tyramine [WO 94/09010].

Examples of compounds of the FK506 class are the compounds mentioned above. They include, for example, FK506, ascomycin and other existing in the nature of the connection. In addition, they include synthetic analogs.

The preferred compound of the FK506 class described [EP 427680, such as the Example 66A] , it is also known as 33-epichloro-33-desoxycortisol. Other preferred compounds phase includes dimetridazole and/or lower alkylalkoxy ether. The term lower alkyl is to be understood as covering alkali containing chain from C1to C4such as ethyl. The term alkanoyl ether should be understood as including acetate and propionate. Preferred is ethyl acetate. The solubility of ethyl acetate in water at room temperature is 8.5 grams per 100 ml. Preferably, the solubility of the lower alkyl-alkanovykh esters in water at room temperature was approximately from 1 to 30 g/100 ml

The hydrophilic phase may also include an additional component, which can be selected from Transcutol (having the formula C2H5-[O(CH2)2]2-OH), Glycofurol (also known as ether tetrahydrofurfuryl alcohol and polyethylene glycol and 1,2-propylene glycol. The hydrophilic phase may include other additional hydrophilic components, such as lower alcohols type of ethanol. These additional components are typically entered as partial substitutes for other components of the hydrophilic phase. Despite the fact that the use of ethanol in the composition is not significant, it was found that it gives a particular advantage when it is necessary to prepare the compositions in the form of capsules soft gelatin. This is due to lucchinelli. Thus, the stability during storage can be improved by the application of ethanol or any other additional component as an additional ingredient in a hydrophilic phase. Ethanol can be from 0 to 60% by weight of the hydrophilic phase, preferably from 20 to 55% by weight and more preferably from about 40 to 50% by weight. In the hydrophilic phase may also be introduced a small amount of liquid polyethylene glycols.

Dimetridazole also known as 3,6-dianhydro-2,5-dio-methyl-D-glucit. It is manufactured by the company ICI American Inc. under the commercial name Arlasolve DMI. Has the following physicochemical properties:

The boiling point of Approx. 234oWITH

Density (25oC) - 1,164

Refractive index - 1,467

Viscosity (25oC) approx. - 5 mPas

The dielectric constant of Approx. 7

It is known [GB 2222770] a wide variety of components lipophilic phase, suitable for use in the present invention. Preferred components of the lipophilic phase are triglycerides of medium chain fatty acids, mixed mono-, di-, triglycerides and transesterification ethoxylated vegetable oil.

Known ACC Myritol, Capmul, Neobee and Mazol; most preferred Miglyol 812. Miglyol 812 is a fractionated coconut oil containing triglycerides capryl-capric acid, with an approximate value of molecular weight component 520 daltons. Fatty acid composition: the maximum content6approximately 3%, WITH8approximately 50 to 65%, WITH10- approximately 30 to 45%, the maximum content125%; acid number is about 0.1; saponification number equal to from about 330 to 345; the maximum value the iodine value is 1. Miglyol 812 is firm Huels.

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

Mixed mono-, di-, triglycerides preferably include a mixture of mono-, di - and triglycerides of C12-20fatty acids, mainly mixed mono-, di - and triglycerides of C16-18fatty acid. Fatty acid included in the composition of the mixed mono-, di - and triglycerides, may include the remains of both saturated and unsaturated fatty acids. Preferred, however, is the prevalence of residues of unsaturated fatty acids, in particular OS is 0%, preferably at least 75%, more preferably at least 85% by weight of mono-, di - and triglycerides of C18unsaturated fatty acids such as linolenic, linoleic and oleic acids). Also acceptable to mixed mono-, di - and triglycerides contained less than 20%, for example approximately from 15% to 10% by weight or less of mono-, di - and triglycerides of saturated fatty acids (such as palmitic and stearic acids).

Preferred is the prevalence of mixed mono-, di - and triglycerides and 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 content of mono - and diglycerides, constituting at least 75% (for example about 80% or 85%) of the weight of the lipophilic phase.

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

Preferably the diglycerides comprise from about 30 to which is the content of diglycerides, approximately 40 to 55% (for example from 48 to 50%).

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

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

Similar products of transesterification can usually be obtained by known methods [GB 2257359 and/or WO 94/09211].

In the case of the manufacture of soft gelatin capsules is preferred prior removal of the residue of glycerol to produce essentially pure glycerol party product".

From refined products transesterification, called here in the future as "refined oil".

In the alternative case, the lipophilic phase may contain, for example, pharmaceutically acceptable oil, preferably unsaturated component, such as vegetable oil or fish oil.

In the alternative case, the lipophilic phase may contain appropriately transesterification ethoxylated vegetable oils, obtained, for example, as a result of interaction of various natural vegetable oils (e.g. corn, stone fruit, almond, peanut, olive, soy, sunflower oil, safflower oil, palm oil, or mixtures thereof) with polyethylene glycol with a mean molecular weight from 200 to 800 in the presence of an appropriate catalyst. Such methods of obtaining known from the prior art [see, for example, U.S. patent 3288824]. Most preferred is transetherification ethoxylated corn oil.

Transesterification ethoxylated vegetable oils are known and are commercially available under the trade name LABRAFIL (N. Fiedler, loc cit. vol 2, page 707). Examples include LABRAFIL M 2125 CS (derived from corn oil, which has a value to the a great number from 90 to 100) and LABRAFIL M 1994 CS (obtained from stone fruit oil with an acid number of about 2, a saponification number from 145 to 175, the iodine number of from 60 to 90). Can also be used LABRAFIL M 2130 CS (which is a product of transesterification WITH12-18glycerides and polyethylene glycol, melting point which is approximately 35 to 40oWith the value acid number less than 2, the number of saponification of from 185 to 200, and iodine value less than 3). Preferred transesterification ethoxylated vegetable oil is LABRAFIL M 2125 CS, which can be obtained, for example, Gattefosse, Saint-Priest Cedex, France.

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

i) the interaction products of natural or hydrogenated castor oil and ethylene oxide. The reaction of the interaction between natural or hydrogenated castor oil and ethylene oxide can be carried out at an approximate molar ratio of reagents from 1:35 to 1:60 and the possible destruction of the products poliatilenglikole component. Such a variety of surfactants are commercially available. The glycol guide is acceptable. The most appropriate are CREMOPHOR RH 40, having a saponification number from about 50 to 60, an acid number less than 1, a water content (Fischer) approximately less than 2%, the value of nD60approximately 1,453 up to 1,457 and HLB from about 14 to 16; and CREMOPHOR RH 60, having a saponification number from about 40 to 50, an acid number less than 1, the approximate value iodine value of less than 1, a water content (Fischer) from about 4.5 to 5.5%, the values of nD25approximately 1,453 up to 1,457 and HLB from about 15 to 17. Especially preferred product of this class is CREMOPHOR RH 40. Acceptable are also polietilenglikolya castor oil, such as commercially available under the trade name CREMOPHOR EL, having a value of molecular weight (according to the evaporative osmometry) equal to 1630, a saponification number from about 65 to 70, an acid number of about 2, the iodine number of from about 28 to 32 and the value of nD25approximately 1,471.

Similar or identical products that can be used are commercially available under the trade names NIKKOL (e.g. NIKKOL HCO-40 and HCO-60), MAPEG (for example MAPEG CO-40h), INCROCAS (for example INCROCAS 40) and TAGAT (for example esters polyoxyethyleneglycol,3; it is preferable TAGAT). A more detailed description of these surfactants can be found in Fiedler, loc. cit.

(ii) Esters of polyoxyethylenesorbitan and fatty acids, such as mono - and trilaurylamine, Piletilevi, stearyl and aerovee esters known [Fielder, loc. cit., C. 1300-1304] and commercially available under the trade name TWEEN, including the products TWEEN:

20 [polyoxyethylene(20)sorbitanoleat],

21 [polyoxyethylene(4)sorbitanoleat],

40 [polyoxyethylene(20)servicemanagement],

60 [polyoxyethylene(20)servicemonitor],

65 [polyoxyethylene(20)corbettreport],

80 [polyoxyethylene(20)servicemanual],

81 [polyoxyethylene(5)servicemanual],

85 [polyoxyethylene(20)sarbatorile].

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

iii) Esters of fatty acids and polyoxyethylene, for example esters of stearic acid and polyoxyethylene, of the type known and commercially available under the trade name MYRJ [Fiedler, loc. cit. 2. C. 834-835]. Especially preferred product of this class is MYRJ 52 having a value of25approximately equal to 1.1, a melting point from about 40 to 44oWith, were the.

(iv) Copolymers and block copolymers of polyoxyethylene-polyoxypropylene type known and commercially available under the trade names PLURONIC, EMKALYX and POLOXAMER (Fiedler, loc. cit., 2, S. 959). Especially preferred product of this class is PLURONIC F68, having a melting point of approximately 52oC and a molecular weight of from about 6800 to 8975). Another preferred product of this class is POLOXAMER 188.

v) Dioctylsulfosuccinate or di[2-ethylhexyl]-succinate [Fiedler, loc. cit., 1, S. 107-108].

vi) Phospholipids, in particular lecithins [Fiedler, loc. cit., 2, S. 943-944]. Acceptable lecithins include, in particular, soya lecithins.

vii) Mono - and diesters of fatty acids and propylene glycol, such as propilenglikolstearat (also known and commercially available under the trade name MIGLYOL 840), propilenglikolstearat, propilenglikolmonostearata, propilenglikolstearat, propilenglikolstearat, propilenglikolstearat, propilenglikolstearat etc. [Fiedler, loc. cit., 2, S. 808-809].

Preferably selected surfactants having the value hydrophilic-lipophilic balance (HLB) of at least 10, for example Cremophor.

Preferably, otnositel within the area of microemulsions on the standard ternary diagram. Thus obtained compounds are the microemulsion preconcentrate high stability, adding to the water capable of forming a microemulsion with an average particle size of < 1500 (150 nm).

These compositions microemulsion preconcentrates, for example compounds of the following examples may show good stability indicators identified in the standard tests for stability, such as stability during storage up to one, two, or three years or even more. The microemulsion compositions of preconcentration this invention to form micro-emulsions, stable, for example, up to one day or more.

The pharmaceutical composition may also include other additives or ingredients, such as antioxidants such as ascorbyl palmitate, butylhydroxyanisole (BHA) that is equivalent (BHT) and Tocopherols) and/or preservatives. These additives or ingredients are present in amounts of from about 0.05 to 1% by weight of the total weight of this composition. The pharmaceutical composition may also contain sweeteners or flavorings in the amount of approximately 2.5 or 5% by weight referred to the total weight of such composition. Preferred antiasthma oral application; so, consistency and high level of bioavailability obtained in standard tests for bioavailability, are, for example, 2-4 times higher than those for emulsions. These tests are conducted on animals such as rats or dogs, or in healthy volunteers using HPLC or set of specific or nonspecific monoclonal antibodies to determine the level of drug substance, for example of the macrolide in the blood. So specified in Example 1, a composition administered orally to dogs, can give unexpectedly high values of cmaxdetermined using ELISA (ELISA analysis) using monoclonal antibodies.

Also unexpected was the high predictability of such pharmacokinetic parameters, such as the absorption and blood levels, which made it possible to eliminate or reduce problems with the introduction associated with migratory absorption. In addition, pharmaceutical compositions effectively interact with ensename substances, such as bile salts present in the gastrointestinal tract. This means that the pharmaceutical composition is fully dispersible in aqueous systems containing natural surfactants are characterized by the deposition of an active agent or other destruction of the fine structure of the particles. The effect of pharmaceutical formulations for oral administration remains largely independent and/or unaffected by the relative presence or absence of bile salts at any particular time or any particular individual.

The compositions according to the present invention reduce the variability of response to administered dose as a single instance and between different patients.

In the following aspect, the invention provides a method of obtaining defined above pharmaceutical composition, which consists in bringing (1) a hydrophilic phase; (2) a lipophilic phase; and (3) surface-active substances in the state of a homogeneous mixture, and adding an active agent, such as cyclosporine or connection class macrolides. If necessary, the composition may be formed in the form of a unit dose, for example the packaging of this compound in gelatine capsules.

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

With the aim of obtaining a microemulsion the composition can be mixed with water is leonnig of preconcentration, which may not contain refined fish oil, and/or ethanol, and/or transesterification ethoxylated vegetable oil.

The authors found that macrolides, in particular 40-O-(2-hydroxy)tyramine unstable during storage and can be exposed to a variety of degradation reactions. For example, after several days of storage, you can identify one or more degradation products using, for example, HPLC. Although still a need to further explore ways of degradation, the authors suggest that it may rupture lactoovo ring macrolide.

The authors of this proposal, identified as 40-O-(2-hydroxy)tyramine-2,34-scaricato as the main product of degradation of 40-O-(2-hydroxy)tyramine. 40-O-(2-hydroxy)-tyramine-2,34-Sakakibara, referred to hereinafter as Sakakibara, has the following structure:

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To date, found that stable compositions containing macrolides, can be obtained by placing the macrolide in an acidic environment. This implies that the composition is stable, if the substance drugs of the macrolide remains largely intact, not damaged after a few days or netrivet pharmaceutical composition, containing macrolide and acid.

The term macrolide is used with the same meaning as described earlier.

Preferred macrolides have at least one structure:

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As examples, you can specify the above and preferably rapamycin and 40-O-(2-hydroxy)tyramine.

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

The preferred quantity is according to this invention can have a value up to 20:1, for example from 1:5 to 5:1, in particular 1:1. This acid may be present in amounts of 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. He can be a solid substance, but it is preferable for the liquid form. Macrolide, for example, can be entered in the microemulsion preconcentrate or emulsion preconcentrate defined above, and combined with a certain amount of acid. Such stable acid composition can be entered enterline, for example oral, namely in the form of capsules or solution for drinking or parenterally, namely in the form of an infusion concentrate. Oral administration is preferred.

In the following aspect, the invention provides for the use of acid for stabilization of the macrolide in the pharmaceutical composition.

In another aspect, the invention provides a method of stabilization of the macrolide pharmaceutical composition comprising mixing the acid with a macrolide.

Thus, the invention involves obtaining a stable compositions containing macrolides. Can the one, and between different patients.

The effectiveness of all the pharmaceutical compositions according to the present invention can be observed in standard clinical tests in, for example, known indications of the dose of active agent, giving him the equivalent levels in the blood; for example, at a dose in the range from 2.5 mg to 1000 mg of active agent per day for a 75 kg mammal, namely the adult, and in standard animal models. Enhanced bioavailability of the active agent, provided data structures, can be observed in standard animal tests or in clinical trials, such as described above.

The optimal dose of the active agent for administration to a particular patient should be carefully selected, since the sensitivity and metabolism macrolide compounds such as rapamycin, different individuals may vary. It may be appropriate to record the levels of the active agent in the blood plasma using radioimmunoassay, analysis using monoclonal antibodies or other acceptable traditional ways. Dose of the macrolide usually vary in the range from 1 to 1000 mg per day, for example from 2.5 mg to 1000 mg per day for adult is mg per day. Successful results have been obtained with the introduction of approximately 75 mg / day, for example in the form of two capsules, one containing 50 mg, and the other containing 25 mg; or three capsules, each with a 25 mg Dose of cyclosporine can be from 25 to 1000 mg per day (preferably from 50 mg to 500 mg) and the dose of FK506 - from 2.5 mg to 1000 mg per day (preferably from 10 mg to 250 mg). For the introduction of the 40-O-(2-hydroxy)tyramine recommended dose, lying between 0.5 and 5 mg/kg body weight/day.

The pharmaceutical compositions preferably are combined in a single dose, for example filling their shell capsules for oral administration. The capsule shell can be a capsule shell of soft or hard gelatin. If the pharmaceutical composition exists in the form of unit doses, 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 of Such unit doses acceptable for introduction from 1 to 5 times daily, depending on the specific treatment goals, phases of treatment, and the like.

However, if necessary, the pharmaceutical compositions can be in the form of solutions for drinking, and may include water or any other water with ticheskie compositions are particularly useful for the treatment and prevention of conditions described on pages 40 and 41 in EP 427680 and on pages 5 and 6 in PCT/EP 93/02604.

These pharmaceutical compositions are particularly useful for:

a) treatment and prevention of transplants of organs or tissues, for example for the treatment of recipients of the following transplants: heart, lung, combined heart and lung, liver, kidney, pancreatic, skin or corneal. Data pharmaceutical compositions are also shown to prevent graft versus host, which sometimes occurs when bone marrow transplantation;

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

C) treatment of multi-drug resistance (MDR).

In addition, the data macrolide active agents antineoplastic and anthropou activity, and therefore, these pharmaceutical compositions can be used as anticancer and antigenic agents.

The content of all with whom rivki, and each of example compounds may be used as the macrolide in the examples illustrated below.

Examples

The following presentation is a description by way of examples, related only to the compositions according to the present invention. The content of the components, unless otherwise indicated, are presented in weight percent for each composition.

Examples 1-20

The following presentation is a description by way of examples, apply only to compounds based microemulsion preconcentrate according to this invention, in which the hydrophilic phase comprises DMI or ethyl acetate.

Examples 1 and 2 illustrate compositions in the form of single dose suitable for use, for example for the prevention of transplant rejection or to treat autoimmune diseases, and intended for insertion in an amount of from 1 to 5 single doses per day. The examples described with particular reference to Ciclosporin, but equivalent formulations can be obtained using any of the macrolide or other active agent.

Example 1 (see table)

Preparing a batch of 1000 capsules.

Cyclosporine is dissolved under stirring at the room for the art volume 0.5 ml fill or capsules of size 1 from the solid gelatin, that sealed using, for example, the technique QualiSeal or soft gelatin capsules.

Formulations containing 50 and 100 mg Ciclosporin, prepared similarly, using the rest of the specified ingredients in the specified amounts.

In this Example, refined oil equivalent "rafinirovannom glycerin-transesterification corn oil, not containing impurities of glycerol [GB 2257359 and WO 94/09211].

Example 2

Preparation of oral solution for drinking

The composition is prepared analogously to Example 1 in the calculation of the volume of 5 liters, ethanol, if desired, can be replaced by an equivalent amount of dimethylselenide.

Examples 3-19

The compounds cyclosporin a is prepared using as the lipophilic phase:

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

the corn oil glycerides (mono-, di - and triglycerides of refined corn oil) in Examples 10-17;

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

In the following examples to refer to dimethylselenide is reduced DMI.

The filler is prepared by mixing the components with each other. Then, in the media, with stirring, dissolve the cyclosporin A.

Thus, theoretical composition comprising 50% lipophilic phase and 50% DMI, is depicted on the chart in the form of a point in the middle of the baseline.

The relative ratios of the main components of the filler for the preferred compositions of the present invention lie within areas a and b, marked respectively by the lines a and b in Fig.1; areas C, d' and d", are marked by lines C, D' and D" in Fig.2; region e, marked by the line E in Fig.3; f area, marked by the line F in Fig.4, and g-spot, marked by the line G in Fig.5.

In Fig. 1 and 2 Miglyol 812 marked abbreviated by the letter M In Fig.3 and 4 corn oil glycerides the particles is carried out at 20oWith breeding 60 μl of compound in 1 ml of water by the method of photon correlation spectroscopy, using, for example, Malvern ZetaSizer 3 (Malvern Instruments.

Examples 3-9 (Cm. table 2 and 3)

Subsequent compositions comprising cyclosporine a, are using Miglyol 812. The ethanol in the compositions of Examples 3 and 4 is present in the amount of 10% by weight.

For compounds 3 and 4 are not observed no phase separation, the composition is transparent. When diluted with water in ratio 1:1 and 1:10 by volume of the composition of Example 3 is transparent. The composition of Example 4 opalestiruet when diluted with water in ratio 1:1 and 1:10 (1 volume part of the composition, 10 parts by volume of water). In Fig.1 shows a ternary diagram for compositions 3 (region a) and 4 (area b).

None of the compounds 5-9 (see table 3) does not show any phase separation, the composition is transparent. When diluted with water in ratio 1:1 and 1: 10 by volume of the compositions of Examples 5-9 remain transparent. In Fig.2 shows a ternary diagram for each of the compositions 5-9 (areas C, d' and d").

Examples 10-17 (see table 4 and 5)

Compositions comprising cyclosporine a, in Examples 10-17 prepared using corn oil glycerides. Ethanol compositions of Examples 10 and 11 is present in the amount of 10% of the research Institute of water in ratio 1:1 and 1:10 by volume of the compositions of Examples 10 and 11 remain transparent (1 part composition, 10 parts of water). In Fig.3 depicts a ternary diagrams for compounds 10 and 11 (region e).

None of the compounds 12-17 no evidence of any phase separation, the composition is transparent. When diluted with water in ratio 1:10 by volume (1 part composition, 10 parts water) compositions of Examples 12-17 remain transparent. When diluted with water in ratio 1:1 compositions of Examples 12, 13, 14, 15 and 17 remain transparent, and in the composition of Example 19 appears opalescence.

In Fig.4 shows the ternary diagram compounds 12-17 (area f).

Examples 18 and 19 (see table 6)

Compositions comprising cyclosporine a, in Examples 18 and 19 are prepared, using as lipophilic phase Labrafil 2125 CS.

For compounds 18 and 19 with no evidence of any phase separation, the composition is transparent. When diluted with water in ratio 1:1 and 1:10 (1 part composition, 10 parts of water by volume) of the composition of Example 19 is transparent. When diluted with water in ratio 1:1 and 1:10 composition of Example 18 appears opalescence. In Fig.5 depicts a ternary diagram for composition 19 (region g).

For compositions 3-19 carry out the measurement of the distribution of particle sizes. In all compositions the maximum particle size is less than 70 nm. The Z - average value RS.

Examples 20-24 (see table 7)

The microemulsion preconcentrate prepared using ethyl acetate as the hydrophilic phase. For the formation of the emulsion composition is diluted with water in ratio 1:1, and adding 10 parts water to 1 part of composition.

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

Storage

Undiluted compositions of Examples 1-24 remain stable, i.e. no evidence of any precipitation or crystallization of at least one month storage at room temperature. After two months of storage at room temperature, the compositions of Examples 5, 6, 7, 12 and 18 remain transparent.

Examples 25-27

The microemulsion preconcentrate prepared and stored at room temperature for 12 months.

Example 25 - Number of in weight %

Cremophor RH 40 - 24

The corn oil glycerides - 48

DMI - 8

Ethanol abs. - 10

Cyclosporine A - 10

After 12 months of storage with no evidence of any precipitation or crystallization.

Example 26 - Number of in weight %

Cremophor RH 40 - 27

The corn oil glycerides - 54

DMI - 9

Example 27 - Quantity in weight %

Cremophor RH 40 - 27

The corn oil glycerides - 45

DMI - 18

Cyclosporine A - 10

After 12 months of storage with no evidence of any precipitation or crystallization.

Cyclosporine a may be substituted in any of the compositions described in Examples 1-27, other cyclosporin or a macrolide, e.g. rapamycin, 40-O-(2-hydroxy)atrribution, 33-epichloro-33-desoxycortisol or the compound of Example 71 from UR 569337.

Examples 28-32

Next follows the description in the examples only compounds on the basis of macrolides, stable acid.

Example 28

The active agent FK506 class or class of rapamycin, e.g. 40-O-(2-hydroxy)tyramine injected into the microemulsion preconcentrate the following composition, expressed in weight percent: 2% active agent, 2% malonic, lactic, or mamonovoj acid, 44% Cremophor RH40, 26.4% of mono-, di-, triglycerides, corn oil, 17.6% of 1,2-propylene glycol and 10% ethanol.

The 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 is only 73%.

Examples 29 and 30

The microemulsion perepelitsyn in the Examples 30A and 30B. In Example 29, the active agent 40-O-(2-hydroxy)tyramine abbreviated marked "active agent R".

The content of intact drug and product degradation was determined by HPLC with a measurement error of 2% (see table 8).

The content of the main product of degradation is indicated in brackets. The main product of degradation of rapamycin called scaramozzino.

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

Example 31

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

Example 32

Concentrate for infusion is prepared using the following ingredients:

40-O-(2-Hydroxy)tyramine 20 mg/ml

Cremophor EL - 600 mg/ml

Citric acid - 10 mg/ml

Ethanol To 1 ml

After storage at 25oC for 4 weeks measurement of content of active ingredient gives the value of 99.6 percent. This result demonstrates the stabilizing effect of citric acid is 33-epichloro-33-desoxycortisol or in connection 71 of the EP 569337.

1. The microemulsion preconcentrate, including soluble active agent and a carrier containing 1) a hydrophilic phase containing dimetridazole and/or lower alkylalkoxy ether, 2) a lipophilic phase, 3) the surface-active substance.

2. Preconcentrate under item 1, characterized in that the active agent is a cyclosporine or macrolide.

3. Preconcentrate under item 1 or 2, characterized in that the active agent is selected from cyclosporin a, rapamycin, 40-O-(2-hydroxy)tyramine, 33-epichloro-33-detoxicating, FK506 or ascomycin.

4. Preconcentrate according to any one of paragraphs.1-3, characterized in that the hydrophilic phase contains ethyl acetate as the lower alkylamino ether.

5. Preconcentrate on PP.1-4 for oral or parenteral administration.

Priority points:

02.11.1994 on PP.1-5, except p. 1 being the lowest alkalinity ether - 25.10.1995; p. 3 - 33-epichloro-33-desoxycortisol - 22.08.1995; p. 4 - ethyl - 15.12.1994; p. 5 - parenteral - 25.10.1995.

 

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