DK175132B1 - Water-soluble monoesters - Google Patents

Description

in DK 175132 B1

The present invention relates to the use of water-soluble monoesters of saturated or unsaturated (Cg.j ^ g) fatty acids and polyols, preferably saccharides, as solvents for pharmaceutically active compounds in intravenously usable solutions in aqueous media or in water-miscible solvents. eg polyethylene glycol, ethanol, glycerine or 1,2-propylene glycol.

[By the term "water soluble" as used in this specification and claims is meant: having a solubility in water of at least 3.3Z at room temperature. Thus, water-soluble monoesters as defined herein describe monoesters which are soluble in water at room temperature in an amount of at least 1 g monoester per minute. 30 ml of water.

The term "aqueous medium" is to be understood to include systems containing a liquid phase consisting wholly or substantially entirely of water, as well as systems wherein the liquid phase further contains or comprises water-miscible solvents as described above. Preferred aqueous media are those in which the liquid phase comprises at least 75 weight Z, preferably at least 90 weight Z, especially at least 95 weight Z water.]

The invention provides a combination of such a monoester and a substantially water-insoluble pharmaceutically active polypeptide, especially a cyclopeptide, preferably a cyclosporin.

[The term "substantially water-insoluble" means: having a solubility in water not exceeding 1Z at room temperature. Thus, essentially water-insoluble polypeptides as defined above are polypeptides which require at least 100 ml of water to dissolve 1 g thereof at room temperature. The term is preferably used for substances, for example, poly peptides with a solubility in water of not more than 0.1Z, especially not more than 0.01Z, e.g. 0.004Z at room temperature.]

Said monoesters are generally known. From British Patent Specification no.

It is also known to use water-soluble raffinose monoesters of the same category as solvents to stabilize specific non-polypeptide agents, e.g., triterpene alcohol ester of 3-methoxy-4-hydroxycinnamic acid in solutions for injection or for oral application. . However, it is noteworthy that considerable amounts of several other excipients (co-solvents) were necessary to ensure a sufficiently stable solution (see page 5, lines 2-18). It follows that the monoesters used alone were not satisfactory solvents for the agent used. In addition, it was found that the sucrose monoesters were not at all suitable as solvents for the agent used (cf. page 2, line 70 * 73). The products obtained are indicated for eg Intradermal injection, but not as suitable for intravenous injection (page 8, column 2, lines 3-4).

10 Liquid compositions of the present invention have surprisingly proved suitable for intravenous injection.

British Patent No. 2,126,588 relates to the stabilization of, for example, injectable fluids containing tumor necrosis factor (TNF) against degradation of the active substance using a broad spectrum of 15 nonionic solvents (esters and ethers). The examples describe many polyoxyethylene derivatives, including, among others, sorbitan monopalmitate and sorbitanoleate. Most solvents are not water soluble per se and therefore cannot be injected intravenously.

In particular, the sorbitan esters are not water-soluble as defined herein. Co-solvents must also be used (cf. page 3, lines 16-22). According to the present invention, such excipients are not necessary.

Sucrose fatty acid esters are also occasionally mentioned in the specification (not in the Examples) and only monopalmin and monostearic acid esters 25 are specified (page 4, line 11). Also, these compounds do not meet the conditions of the present invention in terms of water solubility. There is no suggestion for the use of water-soluble monoesters to improve the water solubility of pharmaceutically active polypeptides. 1 2 3 4 5 6

British Patent Specification No. 1,601,613 discloses mixtures of non-ionic solvents, e.g. sucrose monoesters in general (page 3 2, line 53) and sucrose monopalmitate specifically (page 2, line 53), 4 and agents, e.g., proteins or insulin (page 2, line 24). The indicated 5 solvents (the sucrose monopalmitate is not water soluble) 6 are used to improve the resorption of the agents which are poorly resorbable after oral application. The use of the esters is not indicated as solvents for the preparation of aqueous solutions, since the agents already have relatively good water solubility per se (see page 1, lines 17-21, and page 2, lines 19-20). The aqueous 5 mixtures obtained are not solutions (page 1, lines 33-39) but dispersions (page 2, line 3, and page 2, line 63, to page 3, line 4), and they are recommended for rectal and not for intravenous application.

Japanese Patent Application No. 86 280 435 relates to the preparation of aqueous dispersions of cyclosporins for oral use. Mono esters used are mostly non-water-soluble solvents, e.g., sucrose monopalmitate, sucrose monostearate, or a sorbitan fatty acid ester. Sucrose monooleate was also used, but this ester was not shown to give a clear solution.

In one of the examples, a dispersion of a sucrose mono fatty acid ester and ciclosporin is sonicated to produce an oral wash preparation. There is no indication of the use of the dispersion obtained for intravenous administration. For a dispersion containing 0.35X ciclosporin in water (3.5 mg / ml), a concentration of 0.2X monoester is used. According to the present invention, solutions 20 comprising 0.35 wt.% Ciclosporin can be obtained using a 2.3 X solution of the water-soluble sucrose monolaurate in water.

The present invention also provides compositions, especially pharmaceutical compositions, comprising combinations of sucrose monolaurate or raffinose monolaurate with polypeptides. Such preparations may optionally contain pharmaceutical excipients which are substantially insoluble in water. Such excipients include, for example, benzene derivatives, e.g., p-hydroxybenzoic acid ethyl ester.

The invention also relates to solid solutions comprising pharmaceutically active, in particular substantially water-insoluble pharmaceutically active compounds in said water-soluble monoesters.

Pharmaceutically active, substantially water-insoluble compounds often suffer bioavailability losses if used orally. This occurs because they do not dissolve sufficiently quickly in the aqueous medium in the gastrointestinal tract and are eliminated from the body mainly in unresolved form.

It is difficult to find water-soluble excipients that dissolve the pharmaceutically active compounds in aqueous media to provide solutions that are stable in all reconstitution steps without forming a precipitate, and are additionally pharmaceutically acceptable. 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 the cyclosporins, have long been sought. Excipients used in commercially available forms are not tasty or are associated with the risk of anaphylactic shock. Surfactants containing ethylene oxide units or those with amine or amide structures are no longer acceptable from a pharmaceutical or medical point of view.

Surprisingly, it has now been found that in this respect, water-insoluble monoesters of saturated or unsaturated (Cg. G) fatty acids and polyols, especially saccharides, are highly suitable solvents, especially for pharmaceutically active, substantially water-insoluble compounds. Furthermore, it has been found that said monoesters form solid solutions with pharmaceutically active compounds.

These monoesters can dissolve the active compound sufficiently. By adding water or other aqueous media, aqueous micellar solutions are obtained from which the active compound is readily bioavailable. The active compound dissolves completely in the 25 colloidal solution.

In particular, the invention provides solid solutions comprising polypeptide agents, especially substantially water-insoluble polypeptide agents in water-soluble monoesters of saturated or unsaturated (Cg. G) fatty acids and polyols, especially saccharides. The fatty acid residues in said 30 esters can be substituted, for example, by hydroxyl.

Hydrotropic substances or co-solvents are not essential in the solid solutions of the invention. The solvents used do not contain ethylene oxide, amine or amide structural units which are not acceptable in pharmaceutical or medical terms.

In accordance with the present invention, solid solutions can be prepared in which the pharmaceutically active, e.g. substantially water-insoluble, pharmaceutically active agents, e.g., polypeptide such as cyclosporin (i.e., the dissolved or dispersed phase), are completely or substantially are present entirely in molecular distribution form, or in which the water-soluble fatty acid ester (i.e., the solvent or continuous phase) and the water-insoluble pharmaceutically active agent are each in completely or substantially completely amorphous form, as can be verified, for example, by X-ray structure analysis. Solid solutions meeting the above criteria are preferred.

The water-soluble fatty acid esters used in the compositions of the invention are themselves pharmaceutically acceptable.

Preferred fatty acid esters for use in the practice of the invention are monoesters of disaccharides, e.g., maltose, or especially sucrose, and of trisaccharides, e.g., raffinose. Saccharides containing glucose, fructose and / or galactose units are preferred.

The fatty acid esters for use in the practice of the invention are preferably capric acid (Cg) -, caprylic acid (Cg) -, capric acid (C ^ q) -. lauric acid (C myristic acid (C ^) ·, palmitic acid (C ^g), oleic acid (C ^g), castor oleic acid (C ^g) or 12-hydroxystearic acid (C ^g) esters.

In the fatty acid esters used in the practice of the invention, the lipophilicity of the acid moiety in choosing its length is in balance with the hydrophilicity of the polyol moiety, for example. (Cg.j ^ ^) - Acid residues are preferably associated with disaccharides and (Cg. ^ G) acid residues with trisaccharides.

In general, the HLB value of the fatty acid ester is preferably at least 10.

Suitable fatty acid esters are in particular sucrose monocaproate, sucrose mono laurate, sucrose monomyristate, sucrose mono oleate and sucrose monoquinoleate, raffinose serone ocaproate, raffinose monolaurate, raffinose sero monyristate, raffinose monopalmitate and raffinose monopalmitate. Sucrose monolaurate and raffinose monolaurate are particularly preferred.

6 DK 175132 B1

The monoester content of fatty acid esters used in the practice of the invention is preferably at least 80% by weight, especially at least 90% by weight, i.e. preferably said fatty acid esters contain less than 20 Z, preferably less than 10 Z di or polyester impurities. The esters 5 can be prepared in a manner known per se, for example, as described in Journal of the Society of Cosmetic Chemists (1956) 7, 249-255 and preferably purified by tough chromatography to obtain a maximum monoester content.

Pharmaceutically active compounds included in the solid solutions 10 of the invention are water-soluble or, preferably, substantially water-insoluble, e.g., Proquazon (- 1-isopropyl-7-methyl-4-phenyl-2 (1H) -quinazolinone) which has a solubility in water of less than 0.1 g / 100 ml; xanthan derivatives, e.g., theophylline; tricyclic compounds, e.g., tricyclic antidepressants or, e.g., ketotifen; azulender derivatives, e.g., guajazule, or steroids, e.g., prednisone.

Water-soluble pharmaceutically active compounds are included in the solid solutions of the invention, as such agents are as beneficial as substantially water-insoluble agents in combination with water-soluble monoesters as their bioavailability is improved.

Preferred pharmaceutically active compounds in the mixtures as well as in the solid solutions of the invention are polypeptides, especially substantially water-insoluble polypeptides having a molecular weight of from 500 to 10,000, for example from 500 to 1,500.

Particularly to this group of compounds are the cyclopeptides, eg cyclosporins, especially cyclosporin, which have a water solubility of less than 0.004 g / 100 ml.

The cyclosporins comprise a class of structurally distinct cyclic, poly-N-methylated undecapeptides with valuable pharmaceutical, particularly immunosuppressive, anti-inflammatory and anti-parasitic, especially anti-protozoal activity. The first of the cyclosporins to be isolated and the "parent" compound of the class is the naturally occurring fungal metabolite cyclosporin, also known as cyclosporin A, whose preparation and properties are described, for example, in U.S. Patent No. 4,117,118. .

Since the original discovery of cyclosporin, a large number of naturally occurring cyclosporins have been isolated and identified, and many other non-natural cyclosporins have been prepared in synthetic or semi-synthetic fashion or using modified cultivation techniques. Thus, the class comprising the cyclosporins is now of considerable scope and includes, for example, the naturally occurring cyclosporins (Thr2) ·, (Val2) and (Nva2) -cyclosporin 10 (also known as cyclosporin C, D and G, respectively). and various semi-synthetic derivatives thereof such as their dihydro derivatives (e.g., as disclosed in U.S. Patent Nos. 4,108,985; 4,210,581 and 4,220,641) including, for example (dihydro-MeBmt *) - (Val2) -ciclosporin D) and other natural and artificial cyclosporins such as those described in European Patent Publication No. 0.058,134 B1, e.g., [(D) -Ser®] -ciclosporin: British Patent Application No. 2,115,936 A, e.g. (D) -Ser®] -Ciclosporin; and European Patent Application No. 86810112.2, e.g., [Val] 2 - [(D) methylthio-Ser) and [dihydro-MeBmt] * - [Val] 2 - [(D) -methylthio-Sar] - cyclosporin.

[In accordance with the conventional nomenclature for cyclosporins, these are now defined in this specification from the structure of cyclosporin (i.e., cyclosporin A). This is done by first indicating the residues in the molecule that are different from those present in ciclosporin, and then adding the term "ciclosporin" to characterize the residual residues identical to those present. in ciclosporin. Ciclosporln has the formula I

Λ -A-B-Sar-MeLeu-Val-MeLeu-Ala- (D) Ala-MeLeu-MeLeu-MeVal — i 1 2 3 4 5 6 7 8 9 10 11 (I) 8 DK 175132 B1

where A represents the [N-methyl (4R) -4-but-2E-en-1-yl-4-methyl- (L) -threonyl] residue of formula II

CH 2 x (II)

HO (R) + CH

Nch <rX

ch 3 -N-CH-CO- (S) CH 2 where -x-y- is -CH-CH- (trans), which residue is abbreviated as -MeBmt-, 5 and B represents the α-amino butyric acid residue, abbreviated as -ocAbu-. Accordingly, (Thr 2) - cyclosporine (cyclosporin C) is the compound of formula 1 wherein A has the meaning given above and B represents -Thr-, and (dihydro-MeBmt *) - (Val 2) - cyclosporine (dihydrocyclosporin D) is the compound of formula I wherein A represents the -dihydro-MeBmt residue of the above formula II where (xy is -CH2-CH2- and B is -Val-].

As the "mother" compound to the class, ciclosporin has received the most attention so far. The primary area for clinical study of ciclosporin has been as an immunosuppressive agent, especially in relation to its use in recipients of organ transplants, e.g., cardiac, pulmonary, combined heart, lung, liver, kidney, pancreas, bone marrow, skin and corneal transplants, and especially allogeneic organ transplants, in this area, ciclosporin has achieved remarkable success and reputation and is now widely used in clinics and widely 1

Likewise, the use of ciclosporin for various autoimmune diseases and inflammatory disorders, particularly inflammatory disorders, with an aetiology comprising an autoimmune factor such as arthritis (e.g., rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases, and in vitro test results, from animal studies and from clinical trials are frequently described in the literature. Specific autoimmune diseases for which ciclosporin therapy has been proposed or used as a treatment include autoimmune hematologic disorders (including, for example, hemolytic anemia, aplastic anemia, blood cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma, sclerodomy hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic psilosis, autoimmune inflammatory bowel disease (including, for example, ulcerative bowel disease and Crohn's disease), endocrine ophthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis (diabetes mellitus type I), uveitis (pre and post), conjunctivitis (e.g., keratoconjunctivitis such as prenatal keratoconjunctivitis and keratoconjunctivitis sicca), interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic idiopathic syndrome, minimal change nephropathy).

Another area of research has been potential utility as an anti-parasite, especially anti-protozoan agent, with suggestions for possible uses, including treatment of malaria, coccidio * mycosis and schistosomiasis.

Other cyclosporins exhibit similar pharmacological utility as ciclosporin, and various application proposals, in the prescriptions as stated above are common in the literature.

Dosage of ciclosporin (which is commercially available under the registered trademark SANDIMMUN) varies greatly from person to person 30 and with the disease to be treated, as well as the course of therapy and the use of concomitant therapy. Generally, the dosage is controlled using HPLC, RIA or similar blood level testing, and individual dosage is adjusted so that the desired serum levels are maintained. Usually, the oral dosage starts at 10 or 15-20 35 mg / kg / day to start the treatment, after which it is reduced to 10 mg / kg / day. Intravenous infusion is approx. 3-5 ng / kg / day to start therapy, then reduced to approx. 2-3 mg / kg / day to maintain therapy (when infusion is required, eg in case of vomiting).

Preferably, solid solutions in accordance with the present invention comprise at least 7 weight Z, especially at least 10 weight X of the pharmaceutically active, substantially water-insoluble pharmaceutically active compound.

The solid solution of the invention comprising an cyclo-sporin as active ingredient preferably contains up to 30 wt

cyclosporin based on the total ester weight plus cyclosporin. The lowest concentration is determined only in relation to the therapy to be used, but should not be less than 1 wt.

Preferred solid solutions comprising a cyclosporin in sucrose monolaurate or in raffinose monolaurate. In the first - pure - monoester, solid solutions containing up to 16Z are preferred, in the second monoester, solutions with up to 13.5X cyclosporin are preferred as these can be diluted with water without forming a cyclosporin precipitate. It is generally recommended to use as high a concentration as possible.

The solid solutions of this invention may be used as, or as constituents of, pharmaceutical compositions. Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a solid solution as described or defined in the present disclosure.

Such pharmaceutical compositions include dosage forms suitable for direct administration, for example unit dosage forms for oral administration, eg tablets, capsules or the like comprising or containing a solid solution in accordance with the invention.

Such compositions may be prepared in accordance with conventional techniques, for example, by the appropriate preparation of the solid solution or by grinding or comminuting the solid solution and by composing the particles obtained, e.g., fine particles, product, optionally, 175132 B1.

LI

knead the sauna with other ingredients, such as fillers, emulsifiers, diluents, etc., for tablets or for filling in capsules.

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

Oral unit dosage forms as set forth above comprising a cyclosporin 10 as an active ingredient, e.g., cyclosporine, suitably comprise from 20 to 250, preferably 25-100, e.g. 50 mg cyclosporine per sis unit dose. The ratio of water-soluble fatty acid ester to cyclosporine in such compositions is suitably in the range of from 10: 0.5 to 10: 3.0, especially from 10: 1.0 to 10: 2.0, e.g. 10: 1.2 to 10: 1.6 15 parts by weight.

Such pharmaceutical compositions also comprise dosage forms intended for dilution in aqueous media prior to administration, e.g., infusion concentrates comprising or consisting of said solid solutions to be dissolved in a suitable aqueous infusion medium 20 such as physiological saline solution, for intravenous administration, and aqueous media, e.g., beverage preparations and the like, before ingestion. To promote dissolution, such compositions preferably comprise the solid solution in particulate form, especially fine particles, optionally together with other excipients or additives.

If such compositions comprise a cyclosporin as active ingredient, the ratio of ester to cyclosporin is convenient as described above in connection with the oral unit dosage forms.

Compositions of this type are conveniently present in a suitable container, e.g. ampoule, vial or the like. 1

The solid solutions herein are readily soluble in aqueous media to provide solutions which can be further diluted to any desired concentration without becoming cloudy or precipitated. At high concentrations, viscosity increase is observed.

12 DK 175132 B1

Upon further dilution, clear micellar solutions are formed. Such solutions are also novel and form part of the present invention.

More particularly, the invention provides: a solution obtained by dissolving a solid solution as described or defined herein in an aqueous medium or in a water miscible solvent; and: a solution comprising a substantially water-insoluble, pharmaceutically active polypeptide and a water-soluble monoester of a saturated or unsaturated (Cg. g) fatty acid and a polyol (as solvent for said peptide) in an aqueous medium or in an aqueous medium. solvent miscible with water.

If such a liquid solution is formed by the simultaneous mixing of the three constituents monoester, active compound and water, a liquid solution of the active compound, especially at higher concentration, is possible only after vigorous stirring. Therefore, the simplest method is first to prepare the solid active compound solution in the monoester, after which dilution with water can be carried out without any problems. Dissolution of the active compound in the liquefied monoester and subsequent dilution with water of the obtained mixture, after any intermediate hot ethanol treatment, is known from British Patent No. 1,134,878 (page 3, line 22 * 32 and page 6 , lines 34-39).

However, there is nowhere stated that an intermediate cooling is effected and that a solid solution should have been formed. 1 2 3 4 5 6

Liquid solutions according to the invention are clear or perfect or substantially clear or perfect. The pharmaceutically active constituent, e.g., the substantially water-insoluble peptide constituent, is preferably present in complete or substantially completely pure solution. Solutions of the invention exist without 6 or substantially without pharmaceutically active ingredients in colloidal or other associated or particulate form. They are not or essentially not obscure or cloudy, which can be demonstrated by the absence of precipitates or deposits by ultra-centrifugation.

13 DK 175132 B1

Of course, solutions of the invention in aqueous media may comprise or be present in conjunction with ingredients other than water.

For example, they can also incorporate water-miscible ingredients. Such solutions also include solutions as defined in which other water-insoluble, e.g., colloidal components are present, e.g., in dispersion, e.g., in the case of solutions for oral administration, flavoring, etc. For intravenous administration, solutions of the invention will preferably comprise the active constituent and the fatty acid component in an intravenously administerable aqueous medium such as isotonic saline and being free or substantially free of water-insoluble additives. Liquid solutions of the invention may also be used as or as constituents of ocular formulations, e.g., eye drops.

Therefore, the present invention also provides a pharmaceutical composition (e.g., for intravenous, oral or ocular administration) comprising a solution in an aqueous medium as described or defined herein.

The invention also relates to oral, buccal, lingual, ocular, cutaneous, intracutaneous, percutaneous, vaginal or rectal use of the solubilized liquid solution as well as the solid solution. The solubilized solution can also be used parenterally.

Solid solutions of ciclosporin of the present invention and aqueous solutions derived from their use can be used as alternatives to the existing intravenous ciclosporin infusion concentrate in alcohol in the presence of Cremophor® EL, a polyoxyethylated castor oil, or the oral solution in olive oil, which represents the prior art of ciclosporin.

A comparison between ciclosporin and sucrose or raffinose monolaurate containing aqueous solutions of the invention and said Cremophor® EL containing ciclosporin infusion concentrate in a test where dogs were injected intravenously with these solutions did not show different ciclosporin plasma concentrations. This means that the distribution of the active compound in the body is the same. In FIG. 1, the concentrations are given in ng / ml and the time t in 14 th 175132 B1 thins. Curve 1 represents the sucrose monolaurate solution, curve 2 the raffinose monolaurate solution and curve 3 the commercial solution.

A comparison between a sucrose monolaurate containing ciclo-sporin solution and the commercial solution in olive oil in a test in which these solutions were orally administered to rats resulted in a bioavailability improvement of 26Z of the solution of the invention.

The invention also relates to a solid solution of a water-soluble pharmaceutically active compound in a monoester used according to the invention, since an improvement in bioavailability is also achieved with this type of agent.

The solid solution preparation is preferably carried out in such a way that the agent and sugar ester are dissolved together in a liquid solvent and the solvent is volatilized from the mixture obtained.

The volatilization can be carried out by evaporation or by freeze-drying.

Water or preferably ethanol is used as a volatile solvent. If water is used, volatilization is preferably carried out by freeze-drying. The invention also relates to a process for preparing the solid solution which comprises dissolving the active compound and the monoester together in a volatile solvent, volatilizing the solvent and recovering the obtained solid solution.

The invention further relates to a process comprising melting the monoester by heating, dissolving the active compound in the melt, solidifying by cooling and recovering the obtained solid solution. Additional pharmaceutical excipients may be added to the solid solution, for example to lubricate, thicken or color it. Excipients which are substantially water-insoluble are dissolved under the influence of the monoester and may also be incorporated into the solid solution.

15 DK 175132 B1

Especially when the solid solution is phase by the first method described, an anti-microbiological treatment is possible before the solid solution is formed and filled into ampoules. The anti-microbiological treatment can be easily integrated into the process if the solid solution is formed according to the other method described, by increasing the melting temperature.

The weight ratios of the amount of active ingredient and the amount of monoester can be varied up to the maximum dissolution capacity of the monoester.

Lauric acid sucrose ester is an excipient that is widely used in the food industry and is readily biodegradable. The dissolution capacity of the monoester, with a monoester content of> 80%, for ciclosporin in aqueous solutions at room temperature and at different monoester concentrations is as follows:

Table I

15 Sucrose monolaurate concentration Solubilization capacity for in water containing 0.9 wt. * Cyclosporin in mg / ml at NaCl room temperature X mg / ml 20 - - 1.5 1.5 5.5 5 8.0 6.5 10.0 25 16.0 20 35.0

The dissolution capacity in mg / ml and the concentration of the solubilizer solution in wt% are depicted in FIG. 2; a constant relationship is shown.

Thus, the solid cyclosporin solution can be diluted with the saline solution to any desired extent, without destabilization and without precipitation of the drug compound or without the ac solution becoming opalescent.

Table 1 shows that a maximum concentrated aqueous solution of ciclosporin can be obtained if the weight ratio of mono-ester to ciclosporin is 100: 16.

The present invention further relates to a solid solution or solution in an aqueous medium as described above or defined for use as a pharmaceutical; and a method of performing therapy using a pharmaceutically active substance in a person subject to treatment with said substance, which is characterized by administering a solid solution or solution in an aqueous medium as described or defined, and which contains the substance as an active ingredient, in an amount sufficient to effect therapy.

With respect to the solid solutions of the invention and solutions of the invention in aqueous medium comprising an cyclosporin as active ingredient, the present invention provides: a) its use as immunosuppressive, for the treatment of inflammatory disorders or for the treatment of parasitic diseases, e.g. any of the diseases or disorders described herein in relation to cyclosporine, e.g., cyclosporine, therapy, and b) methods of immunosuppressive, anti-inflammatory or anti-parasite therapy, e.g., methods of treating any of the above-described specific diseases or disorders related to cyclosporin, e.g., cyclosporine, therapy, including its use in immunosuppressive, anti-inflammatory or anti-parasite-effective amounts. 1

It will be appreciated that all components of solid solutions and solutions in aqueous medium for use as defined above in themselves will be pharmaceutically acceptable, e.g., in relation to intravenous administration, and intravenously administrable.

17 DK 175132 B1

The invention is further illustrated by the following examples: A) Preparation of solid solutions and their use Example 1

A suitable sucrose monolaurate, since it has a monoester weight content of> 80X, is the commercially available product L-1695 by Mitsubishi-Kasei Food Corporation, Tokyo 104, Japan. The product has a HLB value of at least 12.3. The purity of the Laurylester remnant is ca. 95X. The melting point is approx. 35 ° C, the transmitter sharing temperature is approx. 235eC. The surface tension of an aqueous solution containing an amount of 0.1 10 wt x monoester is approx. 72.0 dynes / cm at 25 ° C.

1000 mg of this sucrose monolaurate product and 160 mg of ciclosporin were dissolved in 20 ml of ethanol and the solvent was evaporated in a rotavaporizer to give the desired solid solution. The residue was pulverized in a mortar under dry conditions as the monoester is hygroscopic.

Example 2 1000 mg of sucrose monolaurate according to Example 1 was mixed with 160 mg of cyclosporine and the mixture was heated to 150 ° C with stirring. The obtained clear solution was cooled to room temperature to give the desired solid solution and was then further processed as described in Example 1.

Example 3 a) 1000 mg of sucrose monolaurate used in Examples 1 and 30 mg of proquazone (Biarison®) were dissolved in 20 ml of 100X ethanol and the solvent was completely evaporated in a rotavaporizer to give the desired solid solution. The residue was reduced to a fine powder in a mortar and mixed with 10 mg of magnesium stearate as a lubricant.

b) A similar solid solution was prepared by replacing the proquazone component with 30 mg of progesterone.

EXAMPLE 4

Solid solutions of the following compositions can be prepared by analogy to Example 1.

SOLID SOLUTION CICLOSPORINE CONTENT SACCHAROSEMONOESTER CONTENT * 10 A 120 mg 1000 mg sucrose mono-caproate B 130 mg 1000 mg sucrose mono-myristate C 250 mg 1500 mg sucrose mono * 15 oleate * Monoester content for all esters is> 80X.

The solid solutions obtained are completely soluble in water.

EXAMPLE 5

Solid solutions containing ciclosporin in 1000 mg of raffinose monolaurate and 1000 mg of raffinose monoleate (monoester content> 80X, respectively) were prepared using the evaporation method. 135 mg of ciclosporin could be dissolved in the raffinose monolaurate and 200 mg of ciclosporin in the raffinose monoleate. The solid solutions obtained are completely soluble in water.

EXAMPLE 6 2000 mg of sucrose monolaurate (monoescer content> 80X) and 320 mg of ciclo-sporin were dissolved in 50 ml of an aqueous solution containing 10% by weight of ethanol and the liquid micellar solution was filled into 5 vials for injection and lyophilized under sterile conditions. conditions. The solid solution thus obtained in the vials could be dissolved within 30 seconds by shaking it in a 0.9X NaCl-containing aqueous solution to form a clear solution.

Example 7 10 362 mg of a solid solution prepared according to the method of Example 1 was mixed with 375 mg of anhydrous citric acid and 150 mg of sodium bicarbonate and the mixture was pressed. The effervescent tablet thus obtained contained 50 mg of ciclosporin and dissolved within 2.5 minutes in water without leaving residue. The solution obtained may be orally administered to provide an effective cyclosporin therapy, for example, by administering one or more such doses, e.g., 2 to U times daily.

EXAMPLE 8 181.25 mg of a solid solution prepared by the method of Example 1 containing 25 mg of ciclosporin was mixed with stirring with 198.75 mg of viscous liquid paraffin and filled into hard gelatin capsules. The rate of release of ciclosporin from the obtained oral unit dosage form was measured in water at 37 ° C: 20 Time 175 min X of dissolved ciclosporin Standard deviation average value (n-3) 5 3 2.2 10 14 3.5 5 15 29 6.8 30 65 7.0 60 98 0.6 120 98 0.6 180 98 0.6 Example 9 1000 mg sucrose monolaurate (monoester content> 80X) and 30 mg proquazone (Biarison®) were prepared according to the evaporation method for a solid solution. The powder is formed with 1.0 g Adeps solidus Ph. Eur. to a suppository, thereby reducing hygroscopicity.

15 B) Preparation of a liquid micellar solution and its use

For human use, the solid solution is preferably converted to a liquid (aqueous) micellar solution, of which a dose corresponding to a quantity of 40-2000 mg of cyclosporin is generally used for oral or intravenous use. For the oral use, the 20 larger dose is taken and for the intravenous use the smaller dose is taken within the indicated range.

EXAMPLE 10 16 mg of ciclosporin was dissolved in 1 ml of an isotonic aqueous solution of 10 weight Z sucrose monolaurate with a mono ester amount of> 80 weight X.

The solution was used to treat psoriasis by intralasional injection. Repeated injection is effective in the treatment of psoriasis.

EXAMPLE 11 1000 mg of sucrose monolaurate having a monoester content of> 80 wt. injection. A dose of 1.5 mg of ciclosporin per

. ml of solubilisate solution corresponded to the average dose range and a dilution to a ratio of 1:33 of the normal 50 mg / ml cyclosporin infusion concentrate.

EXAMPLE 12 With β-hydroxybenzoic acid methyl ester as a substantially water-insoluble excipient, proquazone (Biarison®) and progesterone as substantially water-insoluble pharmaceutically active compounds, clear solubilisate solutions with sucrose monolaurate having a monoester content of> 80 were prepared. In an aqueous solution of the solubilisate 15 (10 wt. X), 8 mg of p-hydroxybenzoic acid methyl ester, 3 mg of proquazone and 3 mg of progesterone can be dissolved per ml. ml. The solubilization solutions are stable over a long period of time at room temperature. A solid solution is obtained by removing the water by freeze-drying.

Claims (13)

A water-soluble monoester of a saturated or unsaturated (C C₂, 8) fatty acid and a polyol for use as a solvent of a substantially water-insoluble pharmaceutically active polypeptide in intravenously administrable clear solutions in an aqueous medium or in a solvent which is miscible with water. Mixture of a water-soluble monoester of a saturated or unsaturated (C6.18) fatty acid and a polyol and a substantially water-insoluble pharmaceutically active polypeptide, preferably a cyclosporin, characterized in that it comprises sucrose monolaurate or raffinose monolaurate as the monoester. Pharmaceutical composition, characterized in that it comprises sucrose monolaurate or raffinose monolaurate and a substantially water-insoluble pharmaceutically active polypeptide and optionally a substantially water-insoluble excipient. Solid solution, characterized in that it comprises (a) a pharmaceutically active compound and (b) a water-soluble monoester of a saturated or unsaturated (Cg. G) fatty acid, preferably capric acid (Cg), caprylic acid (Cg), capric acid (C ^ q), lauric acid (C ^), myristic acid (C ^^)), palmitic acid (C ^g), oleic acid (C ^g), castor oleic acid (C ^g) or 12-hydroxystearic acid (C C q) g) and a polyol, preferably a saccharide, especially a disaccharide such as sucrose, or a trisaccharide such as raffinose, or a saccharide containing a glucose unit, a fructose unit or a galactose unit. The solid solution according to claim 4, characterized in that (a) comprises a substantially water-insoluble pharmaceutically active compound, preferably a pharmaceutically active polypeptide, in particular a substantially water-insoluble pharmaceutically active polypeptide, more preferably with a molecular weight of from 500 to 1500, especially a cyclosporin such as cyclosporine. DK 175132 B1 A phase solution according to any one of claims 4 * 5, characterized in that (b) comprises sucrose monolaurate and (a) preferably comprises a cyclosporin in an amount up to 16% by weight based on the total weight of the compound (a) . Process for preparing a solid solution according to any one of claims 4-6, characterized in that the process comprises: a) dissolving the components (a) and (b) in a volatile solvent and volatilizing the solvent, or (B) liquefying component (b) by melting, dissolving component (a) in the obtained melt, and solidifying the obtained solution by cooling, and recovering the obtained solid solution. Pharmaceutical composition, preferably in the form of a capsule, pill, granule, tablet, ampoule, gel, suppository or small ball, characterized in that it contains a solid solution according to any one of claims 4-6. Liquid solution, characterized in that it is prepared by dissolving a solid solution according to any one of claims 4-6 in an aqueous medium or in a water-miscible solvent. Liquid solution, characterized in that it comprises a substantially water-insoluble pharmaceutically active polypeptide, preferably comprising at least 0.35 weight Z cyclosporin, in solution in an aqueous medium or in a water-miscible solvent, together with a water-soluble monoester of a saturated or unsaturated (Cg.13) fatty acid and a polyol. Solution according to claim 9 or 10, characterized in that it is used for oral, buccal, linguistic, percutaneous, intracutaneous, ocular, cuckane, vaginal, rectal or parenteral administration as well as for intravenous administration. Pharmaceutical composition, characterized in that it contains a liquid solution 5 according to claim 9 or 10. Pharmaceutical composition according to any one of claims 3 or 12, characterized in that it comprises a cyclosporin as active ingredient for use as an immunosuppressive, anti-inflammatory or anti-parasite agent.