NO179434B - Process for preparing a pharmaceutical composition and using a water-soluble monoester as a solubilizing agent - Google Patents

Description

The present invention relates to a method for producing a pharmaceutical preparation.

Furthermore, the present invention relates to the use of a water-soluble monoester as a solubilizing agent for a pharmaceutical active compound.

These and other features of the invention appear in the subsequent patent claims.

In the context of the invention, water-soluble monoesters are used as solubilizing agents for pharmacologically active compounds and pharmaceutical excipients.

In the context of the invention, water-soluble monoesters of saturated or unsaturated (C6 - C18) fatty acids and saccharides are used as solubilizing agents for pharmaceutically active compounds in solutions in aqueous media or in solvents that are miscible with water, e.g. polyethylene glycol, ethanol, glycerol or 1,2-propylene glycol, for intravenous administration.

The term "water-soluble" as used herein means solubility in water of at least 3.3% at room temperature. Water-soluble monoesters as defined herein are thus monoesters which are soluble in water at room temperature in an amount of at least 1 g of monoester per 30 ml of water.

The term "aqueous medium" shall include systems comprising a liquid phase consisting entirely or substantially entirely of water, as well as systems in which the liquid phase further includes or includes water-miscible solvents as indicated above. Preferred aqueous media are those in which the liquid phase comprises at least 75%, preferably at least 90%, and especially at least 95% by weight of water.

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

The term "mainly water insoluble" means a solubility in water of no more than 3% at room temperature. Mainly water-insoluble polypeptides as defined above are thus peptides which require at least 100 ml of water to effect dissolution of 1 g thereof at room temperature. The designation is preferably used for substances, e.g. polypeptides with a solubility in water of no more than 0.1%, in particular no more than 0.01%, e.g. not more than 0.004% at room temperature.

The mentioned monoesters are generally known. From UK patent 1,134,878, it is also known to use water-soluble raffinose monoesters of the same category as solubilizing agents for stabilizing specified non-polypeptide agents, e.g. the triterpene alcohol ester of 3-methoxy-4-hydroxycinnamic acid in solutions for injection or for oral administration. However, it is an important feature that considerable amounts of several other auxiliary substances (co-solubilizing agents) were necessary to guarantee a satisfactory stable solution (cf. page 5, line 2 -18). It therefore follows that for the agent used, the monoesters used alone were not satisfactory solubilizing agents. It was further shown that the sucrose monoesters were not suitable as solubilizing agents at all for the agent used (cf. page 2, lines 70 - 73). The obtained products are indicated for e.g. intradermal injection but not indicated as suitable for intravenous injection (page 8, column 2, lines 3 - 4). It is surprising that liquid preparations prepared in accordance with the present invention are suitable for intravenous injection.

UK patent 2.12 6.588 relates to stabilization of e.g. injectable liquids containing tumor necrosis factor (TNF) against cleavage of the active substance using a wide variety of different non-ionic solubilizing agents

(esters and ethers). The examples discuss many polyoxyethylene derivatives including, among others, sorbitan monopalmitin and sorbitan oleate. Most solubilizing agents are not water-soluble in themselves and are thus not intravenously injectable. In particular, the sorbitan esters are not water soluble as defined therein. Here too, co-solubilizing agents must be used (cf. page 3, lines 16 - 22). With regard to the present invention, no such auxiliaries are necessary.

Sucrose fatty acid esters are also mentioned in the description (not in the examples) completely at random and only the mono-palmitic acid and mono-stearic acid esters are indicated (page 4, line 11). These compounds also do not satisfy the requirement of the present invention that they should be water-soluble. There is no suggestion of the use of water-soluble monoesters for improving the water solubility of pharmaceutically active polypeptides.

UK Patent 1,601,613 teaches mixtures of non-ionic solubilizing agents, including sucrose monoesters in general (page 2, line 53) and sucrose monopalmitate specifically (page 2, line 53) and agents, e.g. proteins or insulin (page 2, line 24). The indicated solubilizing agents (sucrose monopalmitate is not water-soluble) are used to improve the resorption of agents that are poorly resorbable after oral administration. There is no teaching on the use of the esters as solubilizing agents for the production of aqueous solutions, as the agent already has relatively good water solubility in itself (cf. page 1, lines 17 - 21 and page 2, lines 19 -20). The obtained aqueous mixtures are not solutions (page 1, lines 33 - 39), but dispersions (page 2, line 3 and page 2, line 63 - page 3, line 4) and are recommended for rectal and not for intravenous administration.

Japanese patent application 86,280,435 relates to the preparation of aqueous dispersions containing cyclosporins for oral administration. The esters used were not water-soluble solubilizing agents, e.g. sucrose fatty acid esters such as sucrose palmitate, sucrose stearate or a sorbitan fatty acid ester. Sucrose oleate was also used, but this ester was not found to give a clear solution. Since the monoesters used in accordance with the present invention are water soluble, the aqueous dispersions obtained in accordance with the Japanese patent application must have been prepared using other esters, e.g. di- or triesters, which are not water-soluble.

In one of the examples, a dispersion of a sucrose fatty acid ester and "Ciclosporine" is sonicated to provide an oral liquid preparation. No indication of use of the obtained dispersion for intravenous administration can be seen. For a dispersion containing 0.35% "Ciclosporine" in water (3.5 mg/ml), a concentration of 0.2% monoester is used. With the present invention, solutions comprising 0.35% by weight of "Ciclosporine" can be obtained using a 2.3% solution of the water-soluble sucrose monolaurate in water.

The present invention thus relates to a method for the production of a pharmaceutical preparation, which is characterized in that a water-soluble monoester selected from raffinose and sucrose monolaurate, -monocaproate, -monomyristate and -monooleate is liquefied by melting or by dissolving this in an aqueous medium or in a solvent that is miscible with water, and a mainly water-insoluble pharmaceutically active polypeptide is dissolved in the obtained liquid mixture and the obtained solution is optionally solidified by cooling or by evaporation of the solvent, and if a solid solution is obtained, this is isolated , and the obtained solid solution is optionally dissolved in an aqueous medium or in a solvent which is miscible with water, the use of co-solubilizing agents not being necessary. Such preparations may optionally include pharmaceutical excipients which are mainly insoluble in water and such excipients include e.g. benzene derivatives, such as p-hydroxybenzoic acid methyl ester.

Furthermore, the present invention relates to the use of a water-soluble monoester selected from raffinose and sucrose monolaurate, -monocaproate, -monomyristate and -monooleate as a solubilizing agent for a mainly water-insoluble pharmaceutical active polypeptide, in intravenously administrable clear solutions in an aqueous medium or a solvent that is miscible with water.

Pharmaceutically active, mainly water-insoluble compounds often suffer from a loss of bioavailability if administered orally. This is due to that they are dissolved insufficiently quickly in the aqueous medium in the gastrointestinal tract and are eliminated from the body in significant quantities in undissolved form.

It is difficult to find water-soluble excipients which dissolve the pharmaceutically active compounds in aqueous media and give solutions which are stable at all dilution stages without forming a precipitate, and which are furthermore pharmaceutically tolerable. Liquid galenic forms which are satisfactory from a pharmaceutical and medical point of view and which contain in particular mainly water-insoluble polypeptides, especially cyclopeptides such as cyclosporins, have long been sought after. Excipients used in available commercial forms are not palatable and are associated with a risk of anaphylactic shock. Surfactants containing ethylene oxide units or surfactants with amine or amide structures are no longer acceptable from a pharmaceutical or medical point of view.

It has now been surprisingly found, to which no objections can be raised, that in this connection water-soluble monoesters of saturated or unsaturated (Cg - ^g) fatty acids and polyols, especially saccharides, are extremely suitable solubilizing agents, especially for pharmaceutical active, mainly water-insoluble compounds. It has further been observed that the mentioned monoesters form solid solutions with pharmaceutically active compounds. These monoesters can sufficiently dissolve the active compound. By adding water or other aqueous media, aqueous micellar solutions are obtained from which the active compound is easily bioavailable. The active compound is completely solubilized in the colloidal solution.

Particularly solid solutions can be provided comprising polypeptide agents, especially mainly water-soluble polypeptide agents in water-soluble monoesters of saturated or unsaturated (Cg - ^g) fatty acids and saccharides. The fatty acid residues in the mentioned esters can be substituted, e.g. with hydroxyl.

Hydrotropic substances or co-solubilizing agents are not necessary in solid solutions provided by the method according to the invention. The solubilizing agents used do not contain ethylene oxide, amine or amide structural units to which pharmaceutical or medical objections can be raised.

With the method according to the present invention, solid solutions can be obtained in which the mainly water-insoluble pharmaceutically active polypeptide, e.g. cyclosporine, (ie the dissolved or dispersed phase) is completely or almost completely present in molecular distribution, or in which the water-soluble fatty acid ester (ie the solvent or continuous phase) and the substantially water-insoluble pharmaceutically active polypeptide are each in complete or substantially complete amorphous state, e.g. which can be demonstrated using X-ray structural analysis. Solid solutions that satisfy the above criteria are preferred.

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

Fatty acid esters used in the practice of the invention are sucrose, which is a monoester of a disaccharide, and raffinose, which is a monoester of a trisaccharide. Preference is given to saccharides containing glucose, fructose and or galactose units.

The fatty acid esters for carrying out the invention are esters of caproic acid (C6), lauric acid (C12), myristic acid (C14) and oleic acid (C18).

In the fatty acid esters used in the practice of the invention, the lipophilic property of the acid part, by choosing its length, is in equilibrium with the hydrophilic property of the saccharide part. Preferred are (C6 - C14) acid residues associated with disaccharides and (C8 - C18) acid residues with trisaccharides.

In general, the HLB value (hydrophilic-lipophilic balance value) of the fatty acid ester is preferably at least 10. Suitable fatty acid esters are sucrose monocaproate, sucrose monolaurate, sucrose monomyristate and sucrose monooleate, raffinose monocaproate, raffinose monolaurate, raffinose monomyristate and raffinose -monooleate. Sucrose monolaurate and raffinose monolaurate are particularly preferred.

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

Pharmaceutically active compounds present in solid solutions are mainly water-insoluble, e.g. "Proquazone"

(= 1-isopropyl-7-methyl-4-phenyl-2-(1H)-quinazolinone) which has a water solubility of less than 0.1 g/100 ml, xanthine derivatives such as e.g. theophylline, tricyclic compounds such as tricycle

list of antidepressants or e.g. ketotifen, azulene derivatives such as guaiazulene or steroids such as "Prednisone".

Water-soluble pharmaceutically active compounds in solid solutions are as advantageous as mainly water-insoluble agents in combination with water-insoluble monoesters, as their bioavailability is also improved.

Pharmaceutically active compounds in the preparations which can be obtained by the method according to the invention are in particular predominantly water-insoluble polypeptides with a molecular weight of from 500 - 10,000, e.g. from 500 - 1500.

Cyclopeptides in particular belong to this class of compounds, e.g. the cyclosporins, especially "Ciclosporine", 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 a valuable pharmaceutical, particularly immunosuppressive, anti-inflammatory and anti-parasitic action, particularly anti-protozoal action. The first of the ciclosporins to be isolated and which is the "parent" compound of this class is the naturally occurring fungal metabolite "Ciclosporine", also known as "Ciclosporin A", the preparation and properties of which are described e.g. in US Patent 4,117,118.

Since the original discovery of "Ciclosporine", a large number of different naturally occurring cyclosporins have been isolated and identified and many additional non-natural cyclosporins have been produced by synthetic or semi-synthetic means or by the use of modified cultivation methods. The class covered by the cyclosporins is thus now extensive and includes e.g. naturally occurring cyclosporins (Thr<2>)-, (Val<2>)- and (Nva<2>)-"Ciclosporine" (also known as cyclosporins C, D and G respectively) as well as various semi-synthetic derivatives thereof, like for example. their dihydro derivatives (e.g. as disclosed in US Patents 4,108,985, 4,210,581 and 4,220,641) including e.g. (dihydro-MeBmt1) - (Val2) - "Ciclosporine" (also known as dihydro-cyclosporin D) and other natural and artificial cyclosporins such as e.g. those referred to in European patent publication 0.058.134 Bl, e.g.

[(D)-Ser<8>]-"Ciclosporine"; UK patent application 2,115,936 A, e.g.

[O-Acetyl-(D)-Ser<8>]-"Ciclosporine"; and European patent application 86810112.2, e.g. [Val]<2->[(D)-methylthio-Ser]<3-> and [dihydro-MeBmt] x-[Val]2-[(D)-methylthio-Sar]3-"Ciclosporine".

[In accordance with the currently used conventional nomenclature for the cyclosporins, these are defined herein by reference to the structure of "Ciclosporine" (ie, cyclosporine A). This is done by first indicating the residues in the molecule which are different from the residues present in "Ciclosporine" and then adding the term "Ciclosporine" to characterize the other residues which are identical to the residues present in "Ciclosporine". "Ciclosporine" has formula I

wherein A represents the [N-methyl-(4R)-4-but-2E-en-l-yl-4-methyl-(L)-threonyl] radical of formula II

in which -x-y- is -CH=CH- (trans), this residue being abbreviated as

-MeBmt-, and

B is the alpha-aminobutyric acid residue, abbreviated as -a-Abu-. Accordingly, (Thr<2>)-"Ciclosporine" (cyclosporine C) is the compound of formula I wherein A has the above meaning and B is -Thr-, and (dihydro-MeBmt<1>)-(Val<2>)- "Ciclosporine" (dihydro-cyclosporine D) is the residue of formula I, wherein A stands for the dihydro-MeBmt residue of formula II above wherein [x-y- is

-CH2-CH2, and B is -Val-].

As the "parent" compound of this class, "Ciclosporine" has so far received the greatest attention. The primary area of clinical investigation for "Ciclosporine" has been as an immunosuppressant, particularly in relation to its use in organ transplant recipients, e.g. heart, lung, combined heart-lung, liver, kidney, pancreas, bone marrow, skin and corneal transplants and especially allogeneic organ transplants. In this field "Ciclosporine" has achieved remarkable success and reputation and is now commercially available and has wide clinical application.

At the same time, the applicability of "Ciclosporine" in various autoimmune diseases and inflammatory conditions, especially inflammatory conditions with an etiology including an autoimmune component such as e.g. arthritis (e.g. rheumatoid arthritis, arthritis chronica progrediente and arthritis defor-mans) and rheumatic diseases, have been intensively investigated and reports and results in vitro, in animal experiments and in clinical trials have been widely disseminated in the literature. Specific autoimmune diseases for which "Ciclosporine" therapy has been proposed or used include autoimmune hematologic disorders (including, for example, hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic psilosis, autoimmune inflammatory bowel disease (including e.g. ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, primary juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), conjunctivitis (e.g. keratoconjunctivitis such as vernal keratoconjunctivitis and keratoconjunctivitis sicca) interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. eg inclusive idiopathic nephrotic syndrome or minimal change nephropathy ).

A further area of investigation has been possible applicability as an anti-parasitic agent, particularly anti-protozoal agent, with possible applications suggested including the treatment of malaria, coccidiomycosis and schizotsomiasis.

Other cyclosporins exhibit equivalent pharmacological utility as "Ciclosporine" and various suggestions for indicated uses as indicated above are generally prevalent in the literature.

Dosage for "Ciclosporine" (which is commercially available under the trade name "SANDIMMUN") varies considerably from person to person and with the condition being treated, as well as with the course of therapy and the use of concomitant therapy. In general, dosage is monitored by means of HPLC, RIA or equivalent analysis of blood levels and individual person dosage is adjusted to maintain desired serum levels. Oral dosing usually begins at 10 or 15 - 20 mg/kg day for initiation of therapy which is reduced to 3.5 - 10 mg/kg day. Intravenous infusion takes place at approx. 3 - 5 mg/kg day for initiating therapy which is reduced to approx. 2 - 3 mg/kg day for maintenance therapy (where infusion is required, e.g. in the case of rejection crisis).

Solid solutions obtained by the method in accordance with the invention preferably comprise at least 7% by weight and in particular at least 10% by weight of mainly water-insoluble pharmaceutical active compound.

Solid solutions obtained by the method according to the invention comprising a cyclosporin as active ingredient preferably comprise up to 30% by weight cyclosporin based on the total weight of ester plus cyclosporin. The lowest concentration is only determined in relation to the therapy being carried out, but should not be below 1% by weight.

Solid solutions comprising a cyclosporine in sucrose monolaurate or in raffinose monolaurate are preferred. In the first pure monoester solid solution a content of up to 16% cyclosporine is preferred and in the second monoester solution up to 13.5% cyclosporine is preferred as they can be diluted with water without forming a cyclosporine precipitate. It is generally preferred to use as high a concentration as possible.

The solid solutions that are obtained can be used as pharmaceutical preparations or as components of pharmaceutical preparations.

Such pharmaceutical preparations include dosage forms suitable for direct administration, e.g. unit dosage forms for oral administration, e.g. tablets, capsules or the like, comprising or containing a solid solution obtained in accordance with the invention. Such preparations can be prepared in accordance with usual techniques, e.g. by suitable preparation of the solid solution or by grinding or pulverizing the solid solution and mixing the resulting particulate, e.g. fine particulate product, possibly together with other components, e.g. fillers, carriers, diluents, etc., for tableting or filling into capsules.

The solid solutions that can be prepared by the invention can also be used in the production of other conventional solid dosage forms, e.g. oral dosage forms such as pellets and granules, topical dosage forms such as creams, gels, ointments and the like, e.g. for application to the skin or eyes, or rectal dosage forms such as suppositories.

Oral dosage forms as mentioned above comprising a cyclosporine as active ingredient, e.g. "Ciclosporine", suitably comprises from 20 - 250, preferably 25 - 100, e.g. 50 mg cyclosporine per unit dosage. Suitably, the ratio between water-soluble fatty acid ester and cyclosporine in these preparations is approximately from 10:0.5 - 10:3.0, in particular from 10:1 - 10:2.0, e.g. 10:1.2 - 10:1.6 parts by weight.

Such pharmaceutical preparations also include dosage forms intended for dilution in aqueous media prior to administration, e.g. infusion concentrates comprising or consisting of the aforementioned solid solutions, for dissolution in a suitable aqueous infusion medium such as e.g. physiological saline solution for i.v. supply, as well as preparations for dissolution in aqueous media, e.g. drink preparations and the like, before ingestion. In order to promote the dissolution, such preparations will preferably comprise the solid solution in particulate form, particularly fine particulate form, possibly together with other excipients or additives. When such preparations comprise a cyclosporine as active ingredient, the ratio between ester and cyclosporine will suitably be as described earlier in connection with oral unit dosage forms.

Preparations of this type will be suitably arranged in a suitable container, e.g. an ampoule, vial or similar.

The solid solutions that can be prepared by the invention are easily soluble in aqueous media and give solutions that can be further diluted to any desired concentration without cloudiness or precipitation. At high concentrations, an increase in viscosity is observed. Upon further dilution, clear micellar solutions are formed. These solutions will also be a new product.

More particularly, there may be provided a solution obtained by dissolving a solid solution as herein described or defined in an aqueous medium or a solvent miscible with water,

as well as a solution comprising a substantially water-insoluble pharmaceutically active polypeptide and a water-soluble monoester of saturated or unsaturated (Cg - 1g) fatty acid and a saccharide (as a solubilizing agent for said peptide) in an aqueous medium or in a solvent which is miscible with water.

If such a liquid solution is formed by simultaneous mixing of the three components monoester, active compound and water, a liquid solution of active compound, especially in higher concentration, is only possible after vigorous stirring. For this reason, the simplest method is first of all to prepare the solid solution of active compound in the monoester after which dilution with water can be carried out without problems. The dissolution of the active compound in the liquefied monoester and subsequent dilution of the resulting mixture with water, after any intermediate treatment with hot ethanol, is known from GB patent document 1,134,878 (page 3, lines 22-32 and page 6, line 34-39). However, there is no teaching that an intermediate cooling is carried out and that a solid solution would have been formed.

Liquid solutions obtained by the method according to the invention are clear or perfect or mainly clear or perfect. Solutions obtained by the method in accordance with the invention are free or mainly free of pharmaceutical active component in colloidal or other associated or particulate form. They are free or substantially free from turbidity or clouding as evidenced by freedom from sediment formation or sedimentation by ultracentrifugation. Solutions obtained by the method according to the invention in aqueous media can of course include or be present together with components other than water. They can e.g. also incorporate water-miscible components. Such solutions also include solutions as defined in which other non-water soluble, e.g. colloidal components, are present, e.g. in dispersion, e.g. in the case of solutions for oral administration, flavoring agents, etc. For i.v. administration, solutions obtained by the method in accordance with the invention will preferably comprise the active ingredient and the fatty acid component in an intravenously administrable aqueous medium such as e.g. isotonic saline and be free or substantially free of water-insoluble additives. Liquid solutions obtained in accordance with the invention can also be used as or as components in ocular preparations, e.g. eye drops.

With the method according to the invention, a pharmaceutical preparation (e.g. for intravenous, oral or ocular administration) comprising a solution in an aqueous medium as described or defined herein can be obtained.

The invention also enables the use of the liquid solubilized solution as well as the solid solution either orally, in the mouth, on the tongue, in the eyes, cutaneously, intracutaneously, percutaneously, vaginally or rectally. The solubilized solution can further be administered parenterally.

Solid solutions of "Ciclosporine" and aqueous solutions derived from its use are usable as an alternative to the hitherto available intravenous "Ciclosporine" infusion concentrate in alcohol in the presence of "Cremophor" EL which is a polyoxyethylated castor oil, or the oral solution in olive oil, all of which are forms of the state of the art for "Ciclosporine".

A comparison of "Ciclosporine"- and sucrose- or raffinose-monolaurate-containing aqueous solutions obtained by the method according to the invention with the aforementioned "Cremophor" EL containing "Ciclosporine" infusion concentrate in a test where dogs were injected intravenously with these solutions, showed not different "Ciclosporine" plasma concentrations. This means that the distribution of the active compound in the body is the same. In fig. 1, the concentration deposited is in ng/ml and the time t in hours. Curve 1 shows the sucrose monolaurate solution, curve 2 the raffinose monolaurate solution and curve 3 the commercial solution.

A comparison of a sucrose-monolaurate-containing "Ciclosporine" solution with the commercial solution in olive oil in a test in which these solutions were administered orally to rats resulted in a bioavailability improvement of 26% for the solution obtained by the method according to the invention.

The method according to the invention makes it possible to obtain a solid solution of a water-soluble pharmaceutical active compound in a monoester, and when used, an improvement in bioavailability is also achieved with this type of agent.

The preparation of the solid solution is preferably carried out in such a way that the agent and the sugar ester are dissolved together in a liquid solvent and the solvent is driven off from the resulting mixture. The removal can be carried out by evaporation or freeze-drying. Water or preferably ethanol is used as a volatile solvent. If water is used, the removal is preferably carried out by freeze drying. The method in accordance with the invention enables the preparation of the solid solution, comprising the active compound and the monoester being dissolved together in a volatile solvent, this is evaporated and the solid solution obtained is isolated.

The method in accordance with the invention enables a method which involves melting the monoester by heating, the active compound is dissolved in the melt, solidification is carried out by cooling and the obtained solid solution is isolated. Additional pharmaceutical excipients may be added to the solid solution. E.g. to smear the solution, thicken it or color it. Excipients which are mainly water insoluble are solubilized under the action of the monoester and can also be incorporated into the solid solution.

Especially when the solid solution is obtained according to the method first described, it is possible to have an anti-microbiological treatment before the formation of the solid solution and filling in ampoules. The anti-microbiological treatment can be easily integrated into the manufacturing process if the solid solution is formed according to the second described method by raising the temperature of the melting.

The weight ratio between the amount of active compound and the amount of monoester can be varied up to the maximum solubilizing capacity of the monoester.

The sucrose ester of lauric acid is an auxiliary substance that is frequently used in the food industry and is easily biodegradable. The solubilization capacity of the monoester, with a monoester content of more than 80%, for "Ciclosporine" in aqueous solutions at room temperature and at different monoester concentrations was as follows:

The solubilizing capacity in mg/ml and the concentration of the solubilizer solution in % by weight are set out in fig. 2. A constant ratio appears. The solid "Ciclosporine" solution can thus be diluted with saline to any desired extent, without destabilization and precipitation of the medically active compound or the solution becoming opalescent.

It is seen from Table 1 that a maximum concentrated aqueous solution of "Ciclosporine" can be obtained if the weight ratio between monoester and "Ciclosporine" is 100:16.

The solid solution or solution in an aqueous medium that can be prepared by the method according to the invention as previously defined or described can be used as a pharmaceutical preparation, as well as in a method for carrying out therapy using a pharmaceutical active substance in a person in need of treatment with the said substance, the method comprising the supply of a solid solution or a solution in an aqueous medium as herein defined or described and comprising the said substance as an active ingredient, in an amount sufficient to carry out therapy.

The solid solutions and solutions in aqueous media which can be prepared by the method in accordance with the invention, comprising a cyclosporin as active ingredient, can be used as follows: a) as immunosuppressive agents, for the treatment of inflammatory conditions or for the treatment of parasitic disease, e.g. for any of the diseases or conditions described above in connection with cyclosporine, e.g. "Ciclosporine", therapy,

as well as

b) for immunosuppressive, anti-inflammatory anti-parasitic treatment, e.g. for treatment of which

preferably that the specific diseases or conditions described above in connection with ciclosporin, e.g. "Ciclosporine", therapy, extensive use thereof in

immunosuppressive, anti-inflammatory or anti-parasitic effective amounts.

It will be clear that all components in solid solutions and solutions in aqueous media for use as defined above must themselves be pharmaceutically acceptable, e.g. that they must be intravenously usable by intravenous administration.

The following examples illustrate the invention:

A) Preparation of solid solution and use thereof

Example 1

A suitable sucrose monolaurate is the commercially available product "L-1695" from Mitsubishi-Kasei Food Corporation, Tokyo 104, Japan, as this product has a monoester weight content of more than 80%. The product has an HLB value of at least 12.3. The purity of the lauryl ester residues is approximately 95%. The melting point is approximately 35°C and the decomposition temperature is approximately 235°C. The surface tension of an aqueous solution containing an amount of 0.1% by weight of the monoester is approximately 72.0 dyne/cm at 25°C.

1000 mg of this sucrose monolaurate product and 16 mg of "Ciclosporine" are dissolved in 20 ml of ethanol and the solvent is evaporated in a rotary evaporator to give the desired solid solution. The residue is pulverized in a mortar under dry conditions as the monoester is hygroscopic.

Example 2

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

Example 3

a) 1000 mg of the sucrose monolaurate used in example 1 and 30 mg of "Proquazone" ("Biarison") are dissolved in 20 ml of 100% ethanol and the solvent is completely evaporated in a rotary evaporator to give the desired solid solution. The residue is reduced to a fine powder in a mortar and mixed with 10 mg of magnesium stearate as a lubricant. b) A similar solid solution is obtained by replacing the "Proquazone" ingredient with 30 mg of "Progesterone".

Example 4

Solid solutions with the following compositions can be obtained analogously to Example 1.

The solid solutions obtained are completely soluble in water.

Example 5

Solid solutions containing "Cyclosporine" in respectively 1000 mg of raffinose monolaurate and in 1000 mg of raffinose monooleate (monoester content more than 80%) are prepared using the evaporation method. In the raffinose monolaurate 135 mg of "Ciclosporine" could be dissolved and in the raffinose monooleate 200 mg of "Ciclosporine" could be dissolved. The solid solutions obtained are completely soluble in water.

Example 6

2,000 mg sucrose monolaurate (monoester content more than 80%) and 320 mg "Ciclosporine" are dissolved in 50 ml of an aqueous solution containing 10% by weight ethanol and the liquid micellar solution is filled into ampoules for injection and freeze-dried under sterile conditions. The thus obtained solid solution in the ampoule can be dissolved within 30 seconds by shaking in an aqueous solution containing 0.9% NaCl and gives a clear solution as product.

Example 7

3 62 mg of a solid solution prepared according to the method in Example 1 is mixed with 375 mg of anhydrous citric acid and 150 mg of sodium bicarbonate and the mixture is pressed. The effervescent tablet thus obtained contains 50 mg "Ciclosporine" and dissolves in water within 2.5 minutes without leaving any residue. The obtained solution is administered orally and provides effective "Ciclosporine" therapy, e.g. by administering one or more such doses, e.g. 2-4 times daily.

Example 8

181.25 mg of a solid solution, prepared according to the method in Example 1, containing 25 mg of "Ciclosporine" is mixed with stirring with 198.75 mg of viscous liquid paraffin and filled into hard gelatin capsules. The release rate of "Ciclosporine" from the obtained oral unit dosage form is measured in water at 37°C:

Example 9

1000 mg sucrose monolaurate (monoester content more than 80%) and 30 mg "Proquazone" ("Biarison") are processed by the evaporation method into a solid solution. The powder is cast with 1.0 g of Adeps solidus Ph. Eur. to a suppository so that the hygroscopicity is reduced.

B) preparation of a liquid micellar solution and its use

For human administration, the solid solution is preferably converted into a liquid (aqueous) micellar solution, of which a dose corresponding to an amount of 40 - 2000 mg "Ciclosporine" is generally used for oral or intravenous administration. For oral administration, the higher dosage is taken and for intravenous administration, the lower dosage within the specified range.

Example 10

16 mg of "Ciclosporine" is dissolved in 1 ml of an isotonic aqueous solution of 10% by weight sucrose monolaurate with a monoester amount of more than 80% by weight. The solution is used for the treatment of Psoriasis by intralesional injection. Repeated injection is effective for treating Psoriasis.

Example 11

1000 mg of sucrose monolaurate with a monoester content of more than 80% by weight and 160 mg of "Ciclosporine" are dissolved in a liquid mixture of 16 ml of 1,2-propylene glycol and 91 ml of distilled water, sterilized by filtration and filled into an ampoule for injection. Dosage of 1.5 mg "Ciclosporine" per ml of solubilizate solution corresponds to the average dosage range and a dilution to a ratio of 1:33 of the normal "Ciclosporine" infusion concentrate of 50 mg/ml.

Example 12

With p-hydroxybenzoic acid methyl ester as mainly water-insoluble excipient, "Proquazone" ("Biarison") and "Progesterone" as insoluble pharmaceutically active compounds, clear solubilizate solutions are prepared with sucrose monolaurate with a monoester content of more than 80% . In an aqueous solution of solubilizate (10% by weight), 8 mg p-hydroxybenzoic acid methyl ester, 3 mg "Proquazone" and 3 mg "Progesterone" can be solubilized per milliliters. The solubilizate 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 (3)

1. Procedure for the production of a pharmaceutical preparation, characterized in that a water-soluble monoester selected from raffinose and sucrose monolaurate, -monocaproate, -monomyristate and -monooleate is liquefied by melting or by dissolving this in an aqueous medium or in a solvent that is miscible with water, and a mainly water-insoluble pharmaceutical active polypeptide is dissolved in the obtained liquid mixture and the obtained solution is optionally solidified by cooling or by evaporation of the solvent, and if a solid solution is obtained this is isolated, and the obtained solid solution is optionally dissolved in an aqueous medium or in a solvent which is miscible with water, since the use of co-solubilizing agents is not necessary. 2. Method as stated in claim 1, characterized in that the mainly water-insoluble pharmaceutically active polypeptide is a cyclosporin. 3. Use of a water-soluble monoester selected from raffinose and sucrose monolaurate, -monocaproate, -monomyristate and -monooleate as a solubilizing agent for a substantially water-insoluble pharmaceutically active polypeptide, in intravenously administrable clear solutions in an aqueous medium or a solvent which is miscible with water.