FI94837C - Water-soluble monoesters for use as carriers for pharmacologically active compounds and as solubilizers for pharmaceutical excipients - Google Patents

Description

, 94837

WATER-SOLUBLE MONOESTERS FOR USE AS CARRIERS OF PHARMACOLOGICALLY ACTIVE COMPOUNDS AND SOLUBILITIES OF PHARMACEUTICAL EXCIPIENTS

The invention relates to the use of water-soluble, saturated or unsaturated (C6-18) fatty acids and monoesters of polyols, preferably saccharides, as carriers and solubilizers for pharmaceutically active compounds or as a continuous phase former for the compound. The compounds may be aqueous solvents or water-miscible solvents such as polyethylene glycol, ethanol, glycerin or 1,2-propylene glycol.

[The term "water-soluble" -15 as used herein means: the solubility in water is at least 3.3% at room temperature. The water-soluble monoesters defined herein are thus monoesters having a solubility in water of at least 1 g of monoester per 30 ml of water at room temperature.

The term "aqueous solvent" refers to systems that contain a liquid phase consisting entirely or substantially entirely of water, as well as systems in which the liquid phase further comprises water-miscible solvents, e.g., the solvents described above. In preferred aqueous solvents, the liquid phase contains at least 75% by weight of water, suitably at least 90% by weight, preferably at least 95% by weight.]

It is an object of the invention to provide the use of such a monoester as a carrier for a substantially water-leachable pharmaceutically active polypeptide, preferably a cyclopeptide.

The term "substantially water-insoluble" means: water solubility is less than 1% at room temperature. Substantially water-insoluble polypeptides as defined above are thus polypeptides that require at least 100 ml of water at room temperature to dissolve 1 g. Preferably 2,94837 said term means substances, e.g. polypeptides, which have a solubility in water of less than 0.1%, preferably less than 0.01%, e.g. less than about 0.004%, at room temperature.] 5 Said monoesters are well known and known in the context of UK 1,134,878. water-soluble raffinose monoesters of the class of substances to stabilize specific non-polypeptide substances, e.g., 3-methoxy-4-hydroxycinnamic acid triterpene alcohol ester, in injectable solutions or oral solutions, however, it is typical that several other amounts are required. excipients (additional solubility enhancers (for stability in order to obtain a satisfactory solution) see page 5, lines 2-18). Thus, the monoesters used alone are not sufficient as satisfactory solubility enhancers. In addition, precipitate-rose monoesters are apparently not at all suitable for the solubility enhancers used (see p. 2, lines 70-73). The products obtained have been proposed for use, e.g., for subcutaneous injection, but have not been considered suitable for use in intravenous injection (p. 8, column 2, lines 3 25 - 4). The liquid preparations of the present invention are surprisingly suitable for intravenous injection.

Patent publication UK 2,126,588 relates to e.g.

stabilization of injectable solutions containing tumor necrosis factor (TNF) to prevent degradation of the active substance. A large number of nonionic solubility enhancers (esters and ethers) have been used in the publication. Examples of the publication show several polyoxyethylene derivatives, e.g. sorbitan monopal-35 mediate and sorbitan oleate. Most solubility enhancers are not water soluble per se and thus cannot be injected intravenously.

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In particular, sorbitan esters are not water soluble as defined above. Again, additional solubility enhancers must be used (see page 3, lines 16 - 22). The present invention does not require such excipients.

The publication (in the example section) mentions sucrose fatty acid esters, of which only monopalmitic and monostearic acid esters are mentioned in more detail (p. 4, line 11). These compounds do not meet the requirements of the present invention for water solubility. There is no mention of the use of water-soluble monoesters in improving the water solubility of pharmaceutically active polypeptides.

UK 1,601,613 discloses mixtures of 15 non-ionic solubility enhancers, e.g. in general sucrose monoesters (p. 2, line 53) and in particular sucrose monopalmitate (p. 2, line 53), and active ingredients, e.g. proteins and insulin (p. 2, line 24). The proposed solubilizers (sucrose monopalmitate is not water soluble) have been used to improve the absorption of active substances that are poorly absorbed after oral administration. The publication does not suggest that esters could be used as solubility enhancers in the preparation of aqueous solutions, as the substances already have a relatively good water solubility by nature (see p. 1, lines 17-21 and p. 2, lines 19-20).

The aqueous mixtures obtained are not solutions (p. 1, lines 33-39) but dispersions (p. 2, line 3 and p.

30 2, lines 63 - p. 3, line 4), and are recommended for rectal rather than intravenous use.

!: Patent application publication JA 86280435 relates to the preparation of aqueous dispersions of cyclosporins for oral use. The monoesters 35 used are mainly water-insoluble solubilizers, e.g. sucrose monopalmitate, sucrose monostearate or sorbitan fatty acid ester 4,94837. The use of sucrose monooleate has also been reported, but it does not appear that this ester produces a clear solution.

In one example of the publication, 5 dispersions of sucrose monofatty acid ester and cyclosporir are sonicated to obtain an oral liquid preparation. It does not appear from the publication that the resulting dispersion is used for intravenous administration. For a dispersion containing 0.35% ciclosporin in aqueous solution (3.5 to 10 mg / ml), a monoester concentration of 0.2% is used.

Solutions of the present invention containing 0.35 wt% cyclosporin can be obtained using a 2.3% aqueous solution of water-soluble sucrose monolaurate.

The invention further provides carrier compositions comprising sucrose monolaurate or raffinose monolaurate for use as carriers for polypeptides. Formulations of such carriers and active ingredients may optionally contain pharmaceutical excipients that are substantially insoluble in water. Such excipients are, for example, benzene derivatives, e.g. methyl ester of p-hydroxybenzoic acid.

The invention further provides solid solutions containing water-soluble monoesters for use as carriers for pharmaceutically active, especially substantially water-insoluble, pharmaceutically active compounds.

Pharmaceutically active, substantially water-insoluble compounds often have poor oral bioavailability. This is due to the fact that they do not dissolve sufficiently rapidly in the aqueous solution of the gastrointestinal tract, so that they are eliminated from the body in a considerably insoluble form.

It is difficult to find water-soluble excipients that dissolve pharmaceutically active compounds in an aqueous solvent to provide a solution that is stable and free of precipitate at all dilution steps, and that is further pharmaceutically acceptable. Studies have been carried out for a long time to find liquid galenic forms which are satisfactory from a pharmaceutical and medical point of view and which contain, in particular, substantially water-insoluble polypeptides, in particular cyclopeptides such as cyclos-10 porin. Excipients used in current commercial products have an unpleasant taste or are associated with a risk of hypersensitivity shock. Surfactants containing ethylene oxide units or having amine or amide structures are no longer pharmaceutically or medically acceptable.

It has surprisingly been found that water-soluble monoesters of saturated or unsaturated (C 6-18) fatty acids and polyols, in particular saccharides, which are acceptable in this respect, are very suitable solubilizers, especially for pharmaceutically active, substantially water-insoluble compounds. In addition, it has been found that said monoesters form solid solutions with pharmaceutically active compounds. These monoesters can dissolve the active compound sufficiently well. The addition of water or other aqueous solvents produces water-miscible solutions from which the bioavailability of the active compound is good. The active compound is completely soluble in the colloidal solution.

In particular, the invention comprises the use of solid solutions of monolesters of water-soluble saturated or unsaturated (C5ie) fatty acid polyols, in particular saccharides, as carriers for polypeptide substances, in particular substantially water-insoluble polypeptide substances. The fatty acid residues of said esters may be substituted e.g. by hydroxyl.

6,94837

Hydrotropic agents or additional solubility enhancers are not necessary for the solid solutions of the invention. The solubilizers used do not contain ethylene oxide, Amini-5 or amide moieties which are not pharmaceutically or medically acceptable.

A pharmaceutically active, e.g., substantially water-insoluble, pharmaceutically active agent, such as a polypeptide, e.g., cyclosporine, (i.e.,

Dissolved or dispersed phase) is in fully or substantially completely molecularly distributed form in the solid solution of the present invention, or a water-soluble fatty acid ester (i.e., solvent or continuous phase) and a water-insoluble pharmaceutically active agent are each in a fully or substantially completely amorphous state. in the solid solution according to the invention, which can be demonstrated, for example, by X-ray structural analysis. Solid solutions that meet the above criteria are preferred.

The water-soluble fatty acid esters used in the compositions of the carriers of the invention are themselves pharmaceutically acceptable. Preferred fatty acid esters for use in the invention are monoesters of disaccharides, e.g. maltose or, preferably, sucrose, and monoesters of trisaccharides, e.g. raffinose. Saccharides containing glucose, fructose and / or galactose units are preferred.

Preferred fatty acid poesters for use in the invention are caproic acid (Cg), caprylic acid (C8), capric acid (C10), lauric acid (C12), myristic acid (C14), palmitic acid (C16), oleic acid (C18) ), castor oil acid (C18) or 12-hydroxytearic acid (C18) esters.

In the fatty acid esters used in the invention, the lipophilicity of the acid unit is, depending on the choice of its length, in equilibrium with the hydrophilicity of the polyol, e.g. saccharide, unit. (C8-14) acid residues are preferably associated with disaccharides and (C8_18) acid residues are preferably associated with trisaccharides.

The fatty acid ester generally has a fatty acid ester value of at least 10. Particularly suitable fatty acid barrier esters are sucrose monocaproate, sucrose monolaurate, sucrose mononomyristate, sucrose mono-oleateate and raucinose monoseronate, raffinose monoate monooleate. Sucrose monolaurate and raffinose monolaurate are preferred.

The fatty acid esters used in the invention preferably have a monoester content of at least 80% by weight, preferably at least 90% by weight, i.e. said fatty acid esters preferably contain less than 20% by weight, preferably less than 10% by weight of di- or polyester impurities.

The esters can be prepared in a manner known per se, as described in Journal of the Society of Cosmetic Chemists (1956) 2 249-255, and are preferably purified by column chromatography to obtain the maximum monoester content.

The solid solutions of the invention can be used as carriers for pharmaceutically active compounds which are water-soluble or, preferably, substantially insoluble in water. These include, for example, Proquazone (= 1-isopropyl-7-methyl-4-phenyl-2 (1H) -quinazoline) having a water solubility of less than 0.1 g / 100 ml; xanthine derivatives, e.g. theophylline; HO tricyclic compounds, e.g. tricyclic antidepressants, or e.g. ketotifen; azulene derivatives, e.g. guaazulene, or steroids, e.g. prednisone.

The solid solutions of the invention can also be used as carriers for water-soluble pharmaceutically active compounds, as the combination of such substances and water-soluble monoesters is as advantageous as the combination of substantially water-insoluble substances and water-soluble monoesters due to their improved bioavailability.

The compositions and solid solutions of the invention may be used as carriers, preferably for pharmaceutically active compounds such as polypeptides, preferably substantially water-insoluble polypeptides having a molecular weight of 500 to 10,000, e.g. 500 to 1,500.

This class of compounds includes, in particular, cyclopeptides, e.g. cyclosporins, preferably cyclosporin with a water solubility of less than 0.004 g / 100 ml.

Cyclosporites belong to the class of structurally distinct cyclic, poly-N-methylated undeca-15 peptides. These have valuable pharmaceutical, in particular immunosuppressive, anti-inflammatory and antiparasitic activity, in particular antial cell activity. The first isolated cyclosporin and the "strain" compound of said class is the naturally occurring fungal metabolite cyclosporin, also known as cyclosporin A, the preparation and properties of which are described, e.g., in U.S. Pat. No. 4,117,118.

Since the first discovery of cyclosporine, a large number of naturally occurring cyclosporins have been isolated and identified. In addition, a large number of non-natural cyclosporins have been prepared by synthetic or semi-synthetic methods or by modified growth methods. The class of cyclosporins is thus considerable today and includes, for example, naturally occurring cyclosporins: (Thr2), (Vai2) and [(Nva2) -cyclosporin, (also known as cyclosporin C, D and G, respectively), as well as their various semi-synthetic derivatives such as their dihydro derivatives (e.g. as disclosed in U.S. Patent Nos. 4,108,985; No. 4,210,581 and No. 4,220,641), including e.g. (dihydro-MeBmt1) - (Val2) -cyclosporin 9,94837 (also known as as dihydrocyclosporin D), as well as other natural and artificial cyclosporins, e.g. in EP no. [(D) -Ser8] -cyclosporin shown in 0,058,134 B1; patent application publication UK 5 No.

[O-acetyl- (D) -Ser8] -cyclosporin shown in 2,115,936 A; and patent application EP No. [Val2 - [(D) -methylthio-Ser] 3- and [Dihydro-MeBmt] 1- [Val] 2 - [(D) -methylthio-Sar] 3-cyclosporin disclosed in 86810112.2.

10 [These compounds are defined herein

according to the current conventional nomenclature of cyclosporins with reference to the structure of cyclosporin (i.e. cyclosporin A). In this case, the residues of the molecule which differ from the residues in the cyclosporin are first mentioned and then the term "cyclosporin" is mentioned to characterize the remaining residues identical to the cyclosporin residues. Cyclosporine has the formula I.

20 -AB-Sar-MeLeu-Val-MeLeu-Ala- (D) Ala-MeLeu-MeLeu-MeVal —i 12 3 4 5 6 7 8 9 10 11 (I) 2b where A represents [N-methyl- (4R ) -4-but-2E-en-1-yl-4-methyl- (L) -threonyl] residue of formula II, CH3 x ch2 (Π) '*. ·

HO (R) ^ CH

CH <R \ CHj -N-CH-CO- (S) ch3, ο 94837 where -xy- is -CH = CH- (trans), and which residue is abbreviated -MeBmt-, and B represents an alpha-aminobutyric acid residue of which the abbreviation -aAbu- is used. Accordingly, (Thr2) -cyclosporin (cyclosporin 5 C) is a compound of formula I wherein A is as defined above and B is -Thr-, and (Dihydro-MeBmt1 (Val2) -cyclosporin (dihydrocyclosporin D) is a compound of formula I, wherein A represents a -dihydro-MeBmt residue of formula II above, wherein [xy- is -CH2-CH2, and B is -Or-].

Of the Mkanta "compounds, ciclosporin has received the most attention to date. The main area of clinical research in ciclosporin has been its use as an immunosuppressive agent. Research has specifically focused on its use in organ transplants, e.g., cardiac, pulmonary, Cyclosporine 20 has achieved considerable reputation and success in this area and is now commercially available and widely used in the field of heart, liver, kidney, pancreas, spinal cord, skin and cornea transplants and, in particular, allogeneic transplants. in clinical use.

Concomitant use of ciclosporin in various autoimmune diseases and inflammatory conditions, especially inflammatory conditions with an autoimmune component in their etiology, such as arthritis (e.g. rheumatoid arthritis, advanced chronic arthritis and osteoarthritis) and rheumatic diseases, has been intense. reports and results from in vitro animal experiments and clinical trials.

· Specific autoimmune diseases for which ciclosporin treatment has been proposed or applied include autoimmune haematological disorders (eg haemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus, erythematosus, erythematosus 94837 ma, Wegener's granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprueteal disease, autoimmune inflammatory bowel disease (eg ulcerative colitis, Crohn's disease of the eye, Crohn's disease) endocrine , multiple sclerosis, primary biliary cirrhosis, primary juvenile-onset diabetes mellitus (type I diabetes), otitis media (anterior and posterior), conjunctivitis 10 (e.g. corneal and conjunctivitis, such as vernal corneal and conjunctivitis, psoriatic arthritis and kidney disease co-inflammation (together and nephrotic syndrome, e.g., including idiopathic nephrotic syndrome or minimally altered kidney disease).

Another area of research has been the potential use of ciclosporin as antiparasitic agents, especially antisense agents. Cyclosporine has been proposed for use e.g. in the treatment of malaria, coccidio-20 mycosis and schistosomiasis.

Other cyclosporins have the same pharmacological utility as ciclosporin and various applications for the above indications have been reported in the literature.

25 The dose of ciclosporin (commercially available ciclosporin under the registered trademark SAN-DIMMUN) varies considerably depending on the subject and the condition being treated, as well as the method of treatment and the use of concomitant treatment. Dosage is usually monitored by HPLC, RIA, or equivalent blood level determination, and the dose administered to an individual subject is adjusted to maintain the desired serum levels. Oral doses usually start at 10 or 15-20 FIM / kg / day for initial treatment, decreasing by 3/5 to 10 mg / kg for 35 days. The intravenous infusion is about 3-5 mg / kg per day for initial treatment, decreasing by about 2-3 mg / kg per day for maintenance treatment (infusion if necessary 12 94837 eg in case of rejection crisis).

The solid solutions of the present invention are intended for use as a carrier for pharmaceutically active substances, preferably at least 7% by weight, preferably at least 10% by weight of a pharmaceutically active, substantially water-insoluble compound of the carrier and active substance composition.

The solid solution according to the invention as a carrier for cyclosporin and the composition containing cyclosporin as active ingredient preferably contain up to 30% by weight of cyclosporin based on the total weight of the ester and cyclosporin. The lowest concentration of cyclosprin is determined by treatment, but the concentration should not be less than 1% by weight.

Solid solutions of cyclosporin and sucrose monolaurate or raffinose monolaurate as carrier are preferred. In the first case, pure -20-monoester solid solutions containing up to 16% cyclosporin and in the second case monoester solutions containing up to 13.5% cyclosporin are preferred because they can be diluted with water without the formation of a cyclosporin precipitate. It is usually preferable to use as high a concentration as possible.

‘The solid solutions of the invention may be used as part of pharmaceutical formulations.

Such pharmaceutical formulations include dosage forms suitable for direct administration, e.g.

30 unit dosage forms for oral administration, e.g. tablets, capsules or the like, consisting of or containing a solid solution according to the invention. Such formulations may be prepared according to conventional methods, e.g. by suitably forming a solid solution or by grinding or grinding the solid solution and mixing the resulting powdered, e.g. finely divided, product optionally with other ingredients such as excipients, carriers, diluents, etc. for tableting or capsule shells. for filling.

The solid solutions of the invention may also be used in other conventional solid dosage forms, such as oral dosage forms, e.g. pellets and granules, topical dosage forms, e.g. fats, gels, creams or the like, for example for application to the skin or eye. and for the preparation of rectal dosage forms, e.g. suppositories.

The combination of carrier and active ingredient may contain cyclosporin, e.g. cyclosporin, as the active ingredient, the above unit dosage forms suitably containing from 20 to 250, preferably from 25 to 100, e.g. about 50 mg of cyclosporin per unit dose. In such formulations, the ratio of water-soluble fatty acid ester to cyclosporin is suitably in the range of 10: 0.5 to 10: 3.0, preferably 10: 1.0 to 10: 2.0, e.g.

20 about 10: 1: 2 to 10: 1.6 parts by weight.

Such pharmaceutical formulations also include dosage forms intended to be diluted in aqueous solvents prior to administration. Such substance combinations may be e.g.

25 infusion concentrates consisting of or containing said * solid solutions for dissolution in a suitable aqueous infusion solvent such as physiological saline i.v. for administration, JO, and preparations, e.g., beverage preparations and the like, for dissolution in an aqueous solvent before ingestion. Such formulations preferably contain a solid solution in powder form, especially a finely divided powder form, and in addition optionally contain other excipients or additives to improve solubility.

When such formulations contain 14,94837 losporin as the active ingredient, the ratio of ester to cyclosporin is as set forth above for oral unit dosage forms.

Compositions of this type of material are suitably in a suitable container, e.g. an ampoule, a vial or the like.

The solid solutions of the invention are readily soluble in aqueous solvents to form solutions that can be further diluted to any concentration without turbidity or precipitation of the solution. At high concentrations, an increase in viscosity is observed. Further dilution gives clear solution mixtures. Such solutions are also novel and form part of the invention.

In particular, the invention provides a solution obtained by dissolving a solid solution as described or defined above in an aqueous solvent or a water-miscible solvent; and a solution to which a substantially water-insoluble pharmaceutically active polypeptide can be added and the carrier is a monoester of a water-soluble saturated or unsaturated (C0-18) fatty acid and a polyol (a solvent for said peptide) in an aqueous solvent or a water-miscible solvent.

If such a liquid solution is formed * by simultaneously mixing the three components, the monoester, the active compound and water, then a liquid solution of the active compound, especially in the case of high concentrations, is obtained only by vigorous stirring. Therefore, the simplest method is one in which a solid solution of the active compound and the monoester is first prepared, after which dilution with water can be performed without any problems. Dissolution of the active compound in the liquefied monoester 35 and subsequent dilution of the resulting mixture with water, optionally with hot ethanol after intermediate treatment, is known from GB No. 1,134,878 (s.

, 5,94837 3, lines 22-32 and p. 6, lines 34-39). However, it is not clear from the publication how the cooling of the intermediate is carried out and whether a solid solution is formed.

Liquid solutions according to the invention are clear complete solutions or substantially clear or complete solutions. The pharmaceutically active compound, e.g. the substantially water-insoluble peptide component, is preferably completely or substantially completely in the actual solution. The solutions formed using the solutions of the invention as carriers are free or substantially free of the colloidal or otherwise compound or particulate form of the pharmaceutically active compound. The solutions are turbid or non-precipitating or substantially turbid or non-precipitating, as can be demonstrated by the absence of precipitation or precipitation during ultracentrifugation. The aqueous solutions according to the invention can, of course, consist of other components in addition to water, or they can contain other components in addition to water. They may also include, for example, water-miscible components. Such solutions include solutions as defined above with other non-water soluble, e.g. colloidal, components which may be in dispersion form, e.g., in the case of solutions for oral administration, flavoring agents, etc. i.v. In cases of administration, the solutions of the invention may be used as carriers, preferably for the active ingredients, and the solutions may contain a fatty acid component in an aqueous solvent for intravenous administration, such as iso-. in tonic saline, and the solutions are free of water-insoluble additives or substantially free of water-insoluble additives. The liquid solutions of the invention may also be used as ophthalmic formulations or may be components of ophthalmic formulations. Such formulations include, for example, eye drops.

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The present invention further provides a composition for carrier (e.g. for intravenous, oral or ocular administration) consisting of a solution in an aqueous solvent 5 as described or defined above.

The solid solutions of the invention as carriers for ciclosporin and aqueous solutions derived therefrom are useful for the exchange of alcoholic solutions of existing intravenous cyclosporin infusion concentrates containing Cremophor® EL, polyoxyethylated castor oil, or oral solutions containing olive oil containing olive oil.

A comparative test of cyclosporine aqueous solutions containing sucrose or raf-15 finose monolaurate as carrier and said cyclosporin infusion concentrate containing CremophorR EL in which these solutions were injected intravenously into dogs did not show different plasma concentrations of ciclosporin. This means that the distribution of the active compound in the body is similar. Figure 1 shows the concentrations in ng / ml and the time t in hours. Figure 1 shows a sucrose monolaurate solution, Figure 2 a raffinose monolaurate solution and Figure 3 shows a commercial solution.

A comparative experiment of a solution of cyclosporin containing sucrose monolaurate and a commercial solution in olive oil in which these solutions were administered orally to rats showed a 26% improvement in bioavailability with the solution according to the invention.

. The invention further comprises a solid solution of a monoester for use as a carrier for a water-soluble pharmaceutically active compound and for use according to the invention, since the improved bioavailability is also obtained with this type of substance.

The preparation of the solid solution is preferably carried out by dissolving the active substance and the sugar ester 17 94837 in a liquid solvent and evaporating the solvent from the resulting mixture.

Evaporation can be accomplished by steaming or freeze-drying. Water or, preferably, ethanol can be preferably used as a volatile solvent. If water is used, the evaporation is preferably carried out by freeze-drying. The invention further comprises a process for preparing a solid solution, which process comprises dissolving the active compound and the monoester in a volatile solvent, evaporating the solvent and recovering the solid solution thus obtained.

The invention further comprises a process in which the monoester is melted by heating, the active compound is dissolved in the melt, the mixture is solidified by cooling, and the resulting solid solution is recovered. Additional pharmaceutical excipients may be added to the solid solution, e.g., to improve the sliding properties of the solution, to thicken the solution, or to color the solution. Orally water-insoluble excipients can be solubilized with a monoester and can also be included in a solid solution.

In particular, in the first described solid solution preparation method, an antimicrobial treatment can be performed before the solid solution is formed and placed in ampoules. Antimicrobial treatment can be readily incorporated into the preparation process if a solid solution is formed according to the second method described by raising the liquefaction temperature.

The weight ratio of active compound to monoester can vary up to the capacity to increase the maximum solubility of the monoester.

Sucrose ester of lauric acid is a widely used excipient in the food industry and is readily biodegradable. The solubility-increasing capacity of a monoester with a monoester content of more than 80% in the case of cyclosporine, in aqueous solutions, at room temperature and at varying monoester concentrations is as follows: TABLE I 5

Sucrose monolaurate- The solubility-enhancing capas content in the water commissioned to cyclosporine contains 0.9 wt% NaCl. mg / ml at room temperature.

1 o _ 1% 1.5 mg / ml 3.5 5.5 5 8.0 6.5 10.0 15 8 13.0 10 16.0 20 35.0 20 Figure 2 shows the solubility-increasing capacity in mg / ml and the solubilizing solution. concentration, p% graph; a constant ratio can be observed. The solid solution of ciclosporin can thus be diluted with saline to any concentration without instability and precipitation of the drug compound or opalescence of the solution.

It can be seen from Table 1 that the maximum concentration of an aqueous solution of ciclosporin is obtained with a weight ratio of monoester to ciclosporin of 10:16.

The invention further comprises a solid solution or a solution in an aqueous solvent as defined or described above for use as a pharmaceutical carrier. The carrier of the invention may be used in a method of treatment to deliver a pharmaceutically active agent to a subject in need of treatment with said agent, the method comprising administering a solid solution or an aqueous solution as defined or described above. i m 19 94837 a solution in a second solvent containing said substance as an active ingredient in an amount sufficient to produce a therapeutic effect.

The solid solutions according to the invention and the solutions according to the invention in aqueous solvents which act as carriers for cyclosporin can be used: a) their use as immunosuppressive agents in the treatment of inflammatory conditions or parasitic diseases, e.g. their use in any of the cyclosporins described above, e.g. and b) immunosuppressive, anti-inflammatory or antiparasitic methods of treatment, e.g., methods of treatment with any of the cyclosporins, e.g., cyclosporine, described above, used in immunosuppressive, anti-inflammatory or antiparasitic effects.

Of course, all components of solid solutions and solutions in aqueous solvents intended for use as described above are themselves pharmaceutically acceptable, e.g., for intravenous administration, they are acceptable for intravenous administration.

25,

The following examples illustrate the invention: A) Preparation and use of a solid solution Example 1:

As a suitable sucrose monolaurate, commercially available product L-1695 from Mitsubishi-Kasei Food Corporation, Tokyo 104, Japan can be used due to its> 80% monoester weight content.

35 The HLM value of the product is at least 12.3. The purity of the lauryl ester residue is about 95%. The melting point is about 35 ° C, the decomposition temperature is about 235 ° C. The aqueous solution containing 20,94837 0.1 wt% monoester has a surface tension of about 72.0 dynes / cm, 25 ° C.

1000 mg of this sucrose monolaurate product and 160 mg of cyclosporin are dissolved in 20 ml of ethanol and the solvent is evaporated on a rotary evaporator to give the desired solid solution. The residue is ground in a mortar under dry conditions, as the monoester is hygroscopic.

10 Example 2: 1000 mg of the sucrose monolaurate of Example 1 and 160 mg of cyclosporine are mixed together and the mixture is heated to 150 ° C with stirring. The resulting clear solution is cooled to room temperature to give the desired solid solution, after which the solution is treated as described in Example 1.

Example 3: a) 1000 mg of the sucrose-20 monolaurate used in Example 1 and 30 mg of Proquazone (Biarison®) are dissolved in 20 ml of 100% ethanol and the solution is completely evaporated on a rotary evaporator to give the desired solid solution. The residue is ground in a mortar to a fine powder and mixed with 10 mg of magnesium stearate as a lubricant.

b) A similar solid solution is obtained by replacing the Proquazone component with 30 mg of Progesterone.

Example 4: 30 Solid solutions having the following formulations are prepared according to Example 1.

1 · SOLID SOLUTION CYCLOSPORINE-SUCCARSIM0NO- CONTENT ESTER CONTENT * A 120 mg 1000 mg sucrose monocaproate 35 21 94837 B 130 mg 1000 mg sucrose monomyristate 5 C 250 mg 1500 mg sucrose monoicoate oleate > 80%.

The solid solutions obtained are completely soluble in water.

Example 5: Solid solutions are prepared containing cyclosporin in 1000 mg raffinose monolaurate and 1000 mg raffinose monooleate (monoester content> 80%), respectively, using the evaporation method. 135 mg of cyclosporin could be dissolved in raffinose monolaurate and 200 mg of cyclosporin could be dissolved in raffinose monooleate. The solid solutions obtained are completely soluble in water.

Example 6: 2000 mg of sucrose monolaurate (monoester content> 80%) and 320 mg of cyclosporine are dissolved in 50 ml of an aqueous solution containing 10% by weight of ethanol and the liquid solution mixture is placed in ampoules for injection and lyophilized under sterile conditions. The solid solution thus obtained in the ampoule can be dissolved for 30 s by shaking in 0.9% aqueous NaCl to give a clear solution.

Example 7: 362 mg of a solid solution prepared according to the method of Example 1 and 375 mg of anhydrous citric acid and 150 mg of sodium bicarbonate are mixed together and the mixture is compressed. The effervescent tablet thus obtained contains 50 22 94837 mg of cyclosporine and dissolves in water over 2.5 minutes without leaving any residue. The resulting solution may be administered orally to effect effective cyclosporine therapy, e.g., in one or more doses of such a dose, e.g., 2-4 times per day.

Example 8: 181.25 mg of a solid solution prepared according to the method of Example 1 containing 25 mg of cyclosporin are mixed with 198.75 mg of viscous liquid paraffin and the resulting mixture is filled into hard gelatin capsules. The release rate of ciclosporin from the resulting oral unit dosage form is measured in water at 37 ° C: 15 Time dissolved ciclosporin mean deviation wt%, mean (n = 3) 5 3 2.2 10 14 3.5 20 15 29 6.8 30 65 7.0 60 98 0 Example 6: 1000 mg of sucrose monolaurate (monoester content> 80%) and 30 mg of Proquazone (Biarison®) are prepared according to the evaporation method to a solid solution. 1.0 g of Adeps Solidus Ph.

Eur. with suppositories to reduce hygroscopicity.

B) Preparation and use of a liquid solution mixture

The solid solution is preferably converted to a liquid (aqueous) solution mixture for human use.

The usual dose of the solution is 40 to 2000 mg of cyclosporine, orally or il; 19 1 am i I i at 23 94837 for intravenous administration. Higher doses are used for oral administration and lower doses are used for intravenous administration in the range indicated above.

5

Example 10.

16 mg of ciclosporin are dissolved in 1 ml of an isotonic aqueous solution consisting of 10% by weight of sucrose mono-laurate with a monoester content of> 80% by weight.

10 The solution is used to treat psoriasis as an internal injection into the lesion. Repeated injections are effective in treating psoriasis.

Example 11: 1000 mg of sucrose monolaurate with a monoester content of> 80% by weight and 160 mg of cyclosporin are dissolved in a mixture of 16 ml of 1,2-propylene glycol and 91 ml of distilled water, sterilized by filtration and placed in ampoules for injection. A dose of 1.5 mg cyclosporin per ml of reconstituted solution corresponds to the average dose and a dilution ratio of 50 mg / ml normal cyclosporin infusion concentrate 1:33.

Example 12: Clear solutions of P-hydroxybenzoic acid methyl ester, which is a substantially water-insoluble excipient, Proquazone (Biarison®) and Progesterone, which are substantially water-insoluble pharmaceutically active compounds, are prepared with 80% terose sucrose monolaurate: . 8 mg of p-hydroxybenzoic acid methyl ester, 3 mg of Proquazone and 3 mg of Progesterone per ml can be dissolved in an aqueous soluble solution (10% by weight). Dissolved solutions remain stable for long periods of time at room temperature. The solid solution is obtained by removing the water by freeze-drying.

Claims (9)

24 9 4 8 3 7 A water-soluble monoester 5 of a saturated or unsaturated C 8 -C 6 fatty acid and a saccharide for use as a carrier for a pharmaceutically active polypeptide, characterized in that it acts as a) a substance which increases the solubility of a substantially water-insoluble compound, and / or 10 b) a continuous phase Monoester according to Claim 1, characterized in that the monoester (b) is intended to form a solid solution. Monoester according to Claim 2, characterized in that the solid solution is intended to be dissolved in an aqueous medium or a water-miscible solvent to form a liquid solution. Monoester according to one of Claims 1 to 3, characterized in that it can optionally be used in combination with a substantially water-insoluble excipient. Monoester according to one of Claims 1 to 4, characterized in that the monoester is sucrose monolaurate or raffinose monolaurate. « Monoester according to Claim 2, characterized in that the solid phase in the solid solution is sucrose monolaurate or raffinose monolaurate. 7. Method of solid or liquid solution. characterized in that • a) the pharmaceutically active substance and the water-soluble monoester of saturated or unsaturated C8-C18 fatty acid and saccharide are dissolved in a volatile solvent 33 and the solvent is evaporated, or b) said monoester is liquefied by melting, the pharmaceutically active substance is dissolved in the resulting and solidifying the resulting solution by cooling; and recovering the solid solution thus obtained, which solid solution may, if desired, be dissolved in an aqueous medium or a water-miscible solvent to form a liquid solution. Process according to Claim 7, characterized in that the solid solution obtained is brought into a composition suitable for pharmaceutical administration. <«94837