IE882772L

IE882772L - Watersoluble monoesters as solubilisers

Info

Publication number: IE882772L
Application number: IE882772A
Authority: IE
Inventors: Lorenz Hahn
Original assignee: Sandoz Ltd
Priority date: 1987-09-15
Filing date: 1988-09-13
Publication date: 1989-03-15
Also published as: KR890004694A; GR880100602A; IL87746A; DK511188D0; ES2012118A6; SE503279C2; ATA224988A; IE61195B1; DK175132B1; IT1224886B; BE1001204A5; DK511188A; JPH01151526A; FI94837B; GB2209671B; FI884192L; AU628787B2; LU87335A1; GB2209671A; NL8802275A

Abstract

A combination of a pharmacologically active compound and a water soluble monoester of a saturated or unsaturated (C6-18) fatty acid and a polyol, especially a saccharide, particularly as a solid solution of the active compound in the monoester. The solid solution is especially suitable for substantially water insoluble active compounds, particularly such polypeptides, e.g. ciclosporins and is in all desirable weight ratios miscible with water. [CA1338775C]

Description

c L * i r\ I" S s-> Th® invention relates to pharmaceutical compositions lassad on the use of water soluble monoesters of saturated or unsaturated (Cs_i8) fatty acids and polyols, preferably saccharides, as solubilisers of ^ pharmaceutically active compounds in aqueous media or in solvents which are miscible with water, e.g. polyethylene glycol, ethanol, glycerin or 1,,2-propylena glycol.

[By the term "water soluble" as used herein is meant: having a 20 solubility in water of at least 3.3 % at room temperature. Water soluble monoesters as herein defined are thus monoesters dissolvable in water at room temperature in an amount of at least I g monoester per 30 ml water.

The term "aqueous medium" is to be understood to include systems comprising a liquid phase comprised entirely or substantially entirely of water, as well as systems in which the liquid phase additionally includes or comprises water miscible solvents such as hereinabove set forth. Preferred aqueous media are such, in which the liquid phase 30 comprises at least 75 Z, preferably at least 90 X, most especially at least 95 % water by weight.] More particularly the present invention provides™ in a first aspect: A) a pharmaceutical composition comprising a) a substantially water insoluble pharmaceutically active polypeptide and b) saccharose monolaurata or raffinose monolaurate.

In a further aspect the present invention slso provides; B) a pharmaceutical composition comprising a solid solution of a) a pharmaceutical^ active compound in b) a water soluble monoester of a saturated or unsaturated (Cg-i8) fatty acid and a polyol, especially a saccharide.

In a yet further aspect the present invention also provides: C) a pharmaceutical composition comprising a) a substantially water insoluble pharmaceutically active polypeptide and b) a water soluble monoester of a saturated or unsaturated (Cs„i8) fatty acid and a polyol in solution in an aqueous medium or in a solvent which is miscible with water.

{By the term -substantially water insoluble" is meant: having a solubility in water of not saore than 1 1 at room temperature. Substantially water insoluble polypeptides as defined above are thus polypeptides requiring at least 100 sal water to effect dissolution of 1 g thereof at room temperature. Preferably the term is applied to substances„ e.g. polypeptides having a solubility in water of not more than 0.1 X, in particular not more than 0.01 X, e.g. not more than ca. 0.004 X at room temperature.] The mentioned monoesters are generally known. From UK-Patent 1.134.878 it is also known, to us© water soluble raffinose monoesters-of the same category as solubilisers to stabilise specified non polypeptide agents, e.g. the triterpenealcoholester of 3-methoxy-4-hydroxycinnamic acid in solutions for injection or for oral application. However, and this is an important feature, considerable amounts of several other excipients (cosolubilisers) were necessary to guarantee a satisfactory stable solution (cf. page 5, lines 2-18)» Hence, it follows, that for the used agent the applied monoesters alone were not satisfactory solubilisers. Additionally it appeared that the saccharose monoesters were not suitable as solubilisers at all for the used agent (cf„ page 2, lines 70-73). The products obtained are indicated for e.g. intradermal injection but not as suitable for intravenous injection (page 8. column 2, lines 3-4). Surprisingly liquid preparations ^ according to the present invention are suitable for intravenous injection.

UK-Patent 2.126.588 relates to the stabilisation of* e.g. injectable? liquids containing tumor necrosis factor (TNF) against decomposition 10 of the active substance employing a wide variety of non-ionic solubilisers (esters and ethers)™ In the examples many polyoxye thylene derivatives are discussed including inter al. sorbitan monopalmitate and sorbitan olaate. Most solubilisers are not water soluble themselves and thus not intravenously injectable. In particular the 15 sorbitan esters are not water soluble as herein defined. Again co-solubilisers must be used (cf. page 3, lines 16-22). According to the instant invention no such excipients are neccessary.

Saccharose fatty acid esters ar® also mentioned in the description 20 (not in the examples) incidentally and only the aonopalmitic and the monostearic acid asters are specified (page 4. line 11). These compounds too do not meet the requirement of the instant invention, that should they be water soluble. Ho suggestion can be found to use water soluble monoesters for the improvement of the water solubility 25 of pharmaceut ically active polypeptides.

UK-Patent 1.601.613 discloses mixtures of non-ionic solubilisers. among others saccharose monoesters generally (page 2, line 53) and saccharose monopalmitate specifically (page 29 line 33)., and agents. 30 e.g. proteins or insulin (page 2, line 24). The indicated solubilisers (the saccharose monopalmitate is not water soluble) are used for the improvement of the resorption of agents, which are badly resorbable after oral application. There is no teaching to use the esters as solubilisers for the production of aqueous solutions, since the agents 35 already have relatively good water solubility by nature (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. lines 63-page 3- line 4) and 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. Monoesters which are applied are mostly not water soluble solubilisers, e.g. saccharose monopalmitate. saccharose monostearate or a sorbitan fatty acid ester. Saccharose monooleate was also used, but it was not found that this ester gives a clear solution- In one of the examples a dispersion of a saccharose mono fatty acid ester and Ciclosporine is sonicated, to provide an oral liquid preparation. Mo indication can be found to use the obtained dispersion for intraveneous administration. For a dispersion containing 0.35% of Ciclosporine in water (3*5 mg/ml) a concentration of 0.2Z nsonoester is employed. According to the instant invention solutions comprising 0.35% of Ciclosporine by weight are obtainable using a 2.3Z solution of the water soluble saccharose nonolaurate in water.

Pharmaceutically active, substantially water insoluble compounds often suffer from a loss of bioavailability if applied orally. This is because they are insufficiently rapidly dissolved in the aqueous medium of the gastro-intestinal tract and are eliminated from the body, in substantial amount in undissolved form.

It is difficult to find water soluble excipients, which solubilise the pharmaceutical^ active compounds in aqueous media to provide solutions which are stable at all dilution stages without forming a precipitate, and which are additionally pharmaceutical^ acceptable. Liquid galenical forms, which are satisfactory from a pharmaceutical and medical viewpoint and which contain, in particular, substantially water insoluble polypeptides, especially cydopeptides such as the cyclosporins, have long been sought. Excipients used in available commercial forms possess poor palatability or are associated with a risk of anaphylactic shock. Tensides containing ethylene oxide units " or such having amine or amida structures era no longer acceptable from a pharmaceutical or medical viewpoint.

Surprisingly, it has now been found that in this respect unobjectionable water soluble monoescers of saturated or unsaturated (Cg-ia) fatty acids and poly©lss especially saccharides, are extremely well suited solubilisers. especially for pharmaceutically active, substantially water insoluble compounds- It has further been observed. that the said monoesters form solid solutions with pharmaceutical^ active compounds- These monoesters can dissolve the active compound sufficiently. By addition of water or other aqueous media, aqueous micellar solutions are obtained fro® which the active compound is \ readily bioavailable. The active compound is completely solubilized in the colloidal solution.

Hydrotropic substances or cosolubilisers are not essential in the compositions of the invention as defined under (B) above. The used solubilisers do not contain ethylene oxide, amine or amide structural .units, which are pharmaceutically or medically objectionable.

In accordance with the present invention compositions as defined under (B) comprising solid solutions are obtainable in which the pharmaceutically active, e.g. substantially water insoluble. phar~ maceutically active agent, e.g. polypeptide., for example cyclosporin (i.e. the dissolved or disperse phase) is entirely or substantially entirely present in molecular distribution, 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 entirely or substantially entirely amorphous state, e.g. as verifiable by X-ray structure analysis. Solid solutions meeting the above criteria are preferred.

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

Preferred fatty acid esters for use in the compositions of the _ 6 - invention are monoesters of dis&ccharidas. e.g. maltose, or.. especially, saccharose, as well as of trisaccharides. e.g. raffinosa. Preferred ara saccharides which contain glucose, fructose and/or galactose units.

The fatty acid esters for use^in the compositions of the invention, are preferably caproic acid (C3), eaprylic acid (C@). capric acid (Cjo)p lauric acid (C12), myristic acid (Ci«), palmitic acid (Ci«), * oleic acid (Cig)® ricinoleic acid (Cj,8) or 12-hydroxystearic acid (Cx e) esters.

In the tatty acid esters used in the compositions of the invention, the lipophilic!ty of the acid moiety is, by the choice of its length, in balance with the hydrophilicity of the polyol. e.g. saccharide, moiety. Preferably (Cs-i4) acid residues are connected with disaccharides and (C8-xe) acid residues with trisaccharides.

In general the HLB-value of the fatty acid aster is preferably at least 10. Suitable fatty acid esters are in particular saccharose monocaproate, saccharose monolaurate, saccharose monomyristate, saccharose monooleate and saccharose monoricinoleate, raffinose monocaproate5, raffinose monolaurate, raffinose monomyristate, raffinose monopalmitate and raffinose monooleate. Saccharose monolaurate and raffinose monolaurate are especially preferred.

Pharmaceutical compositions comprising a substantially water insoluble pharmaceutically active polypeptide as hereinafter described in more detail and saccharose monolaurate or raffinose monolaurate are in themselves novel and form part of the present invention as such, i.e. as defined under (A) above- Such compositions may optionally include pharmaceutical excipients which are substantially insoluble in water. Such excipients include, e.g. benzene derivatives, e.g. p-hydroxy benzoic acid methyl ester.

The monoester content of fatty acid esters used in compositions of the invention is preferably at least 80 X, more preferably at least 90 Z by weight, i.e. the said fatty acid esters preferably contain less than 20 Z, more preferably less than 10 Z of di= or poly-ester impurities. The esters can be produced in a manner known per se, e.g. as described in the Journal of the Society of Cosmetic Chemists (1956) 7 249-255 and are preferably purified by column chromatography in order to obtain a maximal monoester content. s.

Pharmaceutically active compounds comprised in th® compositions of the invention as defined under (B) above are water soluble or, preferably, substantially water insoluble* e.g. Proquazone («l-isopropyl-7-methyl= 4-phenyl-2(lH)-quinazolinone) which has a water solubility of below 0.1 g/100 ml? xanthine derivatives, e.g. theophylline tricyclic compounds, for example tricyclic antidepressiva or e.g. ketotifen; azulene derivatives? e.g. guajazulene, or steroids? e.g. Prednisone.

Water soluble pharmaceutical^ active compounds are included in relation to the invention as defined under (B). since such agents are as advantageous as substantially water insoluble agents in combination with water soluble monoesters, since their bioavailability becomes improved.

Preferred pharmaceutical^ active compounds in compositions of the invention as defined und«r (B) are polypeptides, especially substantially water insoluble polypeptides having a molecular weight 25 of from 500 to 10'000, e.g. of from 500 to 1'500.

To this class of compounds especially belong the cyclopeptides, e.g. the cyclosporins., particularly Ciclosporine, which has a water solubility of below 0.004 g/100 ml.

The cyclosporins comprise a class of structurally distinct cyclic, poly-N-methylated undecapeptides having valuable pharmaceutical, in particular immunosuppressive, anti-inflammatory and. anti-parasitic, in particular anti-protosoal activity. The first of the cyclosporins to 35 be isolated and the "parent" compound of the class, is th® naturally occurring fungal metabolite Ciclosporine, also known as Cyclosporin A. the production and properties of which are described e.g. in US Patent No. 4,117,118.

Since the original discovery of Ciclosporine a wide variety of naturally occurring cyclosporins have been isolated and identified s:ad many further non-natural cyclosporins have been prepared by synthetic or semi-synthetic means or by the application of modified culture techniques. The class comprised by the cyclosporins is thus now substantial and includes, for example, the naturally occurring cyclosporins (Thr2)-. (val2)- and (Nva2)- Ciclosporine (also known as cyclosporins C, D and G respectively), as well as various semi-synthetic derivatives thereof, such as their dihydro derivatives (e.g. as disclosed in US Patents Nos. 4,108,985; 4,210,581 and 4,220,641) including e.g. (Dihydro-MeBmt1)-(Val2)-Ciclosporine (also known as dihydrocyclosporin D) and other natural and artificial cyclosporins such as those disclosed in European Patent Publication Mo. 0,058.134 Bl, for example [(D)»Ser®]-Ciclosporine; UK Patent Application Mo. 2,115,936 A, for example [O-Aeetyl-(D)-Ser8]-Ciclosporine; and European Patent Application No. 86810112.2, for example [Val]2-[(D)Methylthio-Ser)3- and [Dihydro-MeBmtJ1-[Val]2-[(D)-Hethylthio-Sar]3-Ciclosporine.

[In accordance with now conventional nomenclature for the cyclosporins, these are definded herein by reference to the structure of Ciclosporine (i.e. Cyclosporin A). This is done by first indicating those residues in the molecule which differ fro® those present in Ciclosporine and then Applying the term "Ciclosporine65' to characterise the remaining residues which are identical to those present in Ciclosporine. Ciclosporine has the formula I •A-B-Sar-MeLeu-Val-MeLeu~Ala-(D)Ala-MeLeu-MeLeu-HeVal— • * • 1 2 3 4 5 6 7 8 9 10 • 11 (I) wherein A represents the [N-methyl-(4R)-4-but-2E-en~l~yl-4-methyl-(L)-chreonyl) residue of formula II ch3 I x v\ ch, ho (r) ch ^Ch/(R)\ ch3 II -n-ch-co-(s) ch3 in which -x-y- is -CH«CH- (trans), which residue is abbreviated as -MeBmt-, and on B is the alpha-aminobutyric acid residue., abbreviated as -aibu-. Accordingly (Thr2)-Ciclosporine (cyclosporin C) is the compound of formula I, wherein A has the meaning given above and B is -Thr-, and (Dihydro-HeBmt1 >-(Val3)-Ciclosporine'(dihydrocydosporin D) is the compound of formula I. wherein A represents the -dihydro~He3mt~ 25 residue of formula II above in which [x-y- is -CH2-CH2-, and B is -val-].

As the "parent" compound of the class. Ciclosporine has so tar received the most attention. The primary area of clinical 30 investigation lor Ciclosporine has been a® an immunosuppressive agent, in particular in relation to its application to recipients of organ transplants, e.g. heart, lung, combined heart-lung, liver, kidney, pancreatic™ bone marrow, skin and corneal transplants and. in particular, allogenic organ transplants. In this field Ciclosporine 35 has achieved a remarkable success and reputation and is now commercially available and widely employed in clinic.

At the same time, applicability of Ciclosporine to various autoimmune diseases and to inflcimmatory conditions, in particular inflammatory conditions with an aetiology including an autoimmune component such as arthritis (for estample rheumatoid arthritis, arthritis chronica pro-gradients and arthritis deformans) and rheumatic diseases, has been intensive and reports and results in vitro, in animal models and in clinical trials are vdde-spread in the literature. Specific autoimmune diseases for which Ciclosporine therapy has been proposed or applied include autoimmune hematological disorders (including, e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopaenia), systemic lupus erythematosus, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis. chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflcimmatory bowel disease (including e.g. ulcerative colitis and Crohn's disease) endocrine opthalmopathy, Graves disease, sarcoidosis., multiple sclerosis, primary billiary cirrhosis, primary juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), conjunctivitis (e.g. keratoconjunctivitis for example, vernal keratoconjunctivitis and keratoconjunctivitis sicca), interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy).

A further area of investigation has been potential applicability as an anti-parasitic, in particular anti-protozoal agent, vith possible uses suggested including treatment of malaria, coceidiomycosis and schistosomiasis.

Other cyclosporins exhibit equivalent pharmacological utility as Ciclosporine and various proposals for application, in indications, as set forth above are prevelant in the literature.

Dosaging for Ciclosporine (which is commerciable available under the Registered Trade mark SANDIHHUN) varies considerably from subject to subject: and with condition to be treated, as well as with the course of therapy and use of concommitant therapy. In general,, dosaging is monitored by HPL.C, RIA or equivalent assay of blood levels and individual subject dosaging is adjusted to maintain desired serum levels. Commonly. oral dosaging starts at 10 or 15-20 nig/kg day for initating therapy, reducing to 3/5 - 10 rag/kg day. Intravenous infusion is at ca. 3-5 mg/kg day for initiating therapy reducing to ce. 2~3 mg/kg day for maintenance therapy (where infusion is required, e.g. in the case of rejection crisis).

Compositions in accordance with the present invention as defined under (B) preferably comprise at least 11, particularly at least 10% by weight of pharmaceutically active, substantially water insoluble pharmaceutical^ active, compound.

Compositions in accordance with the invention as defined under (B) comprising a cyclosporin as -active ingredient preferably comprise up to 30% of weight of cyclosporin based on the total weight of ester plus cyclosporin. Lowest concentration is only determined in relation to the therapy to be applied but should not be below IX by veight.

Compositions as defined under (B) comprising a cyclosporin in saccharose monolaurate or in raffinose monolaurate are preferred. Irs the first - pure - monoester solid solutions containing up to 16Z, in the second monoester solutions up to 13.5% cyclosporin are preferred since they can be diluted with water without forming a cyclosporin precipitate. It is generally preferred to use as high a concentration as possible.

Pharmaceutical compositions as defined under (B) above, include dosage forms suitable for direct administration, for example unit dosage forms for oral administration* for example tablets, capsules or the like comprising or containing a solid solution. Such compositions can be prepared in accordance with conventional techniques., e.g. by appropriate forming of the solid solution or by grinding or milling of the solid solution and compounding of the obtained particulate, e.g. fine particulate., product, optionally together with other ingredients, e.g. fillers, carriers, diluents and so forth, for tabletting or for filling into capsule shells.

The compositions of the invention as defined under (B) above may equally be employed in the manufacture of other conventional solid dosage forms, e.g. oral dosage forms such as pellets and granulates, topical dosage forms such as creams,, gels, ointments and the like,* e.g. for application to the skin or eye; and rectal dosage forms such as suppositories.

Oral unit dosage forms as aforesaid comprising a cyclosporin as active ingredient, for example Ciclosporine. suitably comprise from 20 to 250. preferably 25 to 100, e.g. about 50 ®g cyclosporin per unit dosage. Suitably the ratio of water soluble fatty acid aster to cyclosporin in such compositions is of the order of from 10:0.5 to 10:3-0, especially from 10:1.0 to 10:2.0, e.g. about 10:1.2 to 10:1,6 parts by weight.

Such pharmaceutical compositions also include dosage forms intended for dilution in aqueous media prior to administration, for example infusion concentrates comprising or consisting of said solid solutions, to be dissolved in an appropriate aqueous infusion medium such as physiological saline., tor administration i.v., as well as preparations for dissolution in aqueous media, e.g. drink preparations and the like, prior to ingestion. To aid dissolution, such compositions will preferably comprise the solid solution in particulate, especially fine particulate, form, optionally together with other excipents or additives. Vhere such compositions comprise a cyclosporin as active ingredient the ratio of ester to ciclosporin will appropriately be as described above in relation to unit oral dosage forms.

Compositions of this type will conveniently be presented in an appropriate container e.g. ampoule, phial, bottle or the like.

Solid solutions comprising the compositions of the invention are readily soluble in aqueous media to provide solutions which may be further diluted to any desired concentration without clouding or precipitation. At high concentrations increase in viscosity is observed. On further dilution clear micellar solutions are formed. Pharmaceutical compositions comprising such solutions are also novel and form part of the invention. More particularly tiia invention provides pharmaceutical compositions comprising solutions as defined under (C) above, per se. (The defined polyol acting in said compositions as solubiliser for the defined peptide).

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 agitation. For this reason., the most simple method is, firstly preparing the solid active compound solution in the monoester. after which diluting with water can be carried out without problems. Dissolving the aetive compound in the liquified monoester and subsequently diluting the obtained mixture, after an optional intermediate treatment with hot ethanol* with watet is known from the GB-Patent 1.134.878 (page 3* lines 22-32 and page 6* lines 34-39). However, there is no teaching* that an intermediate cooling is practised and that a solid solution would have been formed.

Compositions of the invention comprising liquid solutions are clear or perfect or substantially clear or perfect. The substantially water insoluble peptide component is preferably present entirely or substantially entirely in true solution. Said compositions of the invention are free or substantially free of pharmaceutically active component in colloidal or other associated or particulate form. They are free or substantially free of turbidity or clouding as may be evidenced by freedom from formation of precipitate or deposit on ultracentrifugation.

Compositions in accordance with the invention comprising solutions in aqueous media may of course comprise or be present together with further components other than water. They may for example also incorporate water miscible components. Such compositions equally include solutions as defined in which other non water solubles e.g. colloidal components are present, e.g. in dispersion, for example, in the case of compositions for oral administration, flavouring agents and so forth. For the purpose^. of i.v. administration compositions in accordance with the invention comprising liquid solutions will preferably comprise the active ingredient and the fatty acid component in an intravenously administrable aqueous medium such as isotonic saline and be free or substantially free of water insoluble additives. Compositions comprising liquid solutions in accordance with the invention may also ba employed as or as components of occular formulations, e.g. eye drops.

The present invention accordingly also provides: a pharmaceutical composition as defined under (C) above for intravenous, oral or occular administration.

The invention also provides compositions as defined under (B) and (C) above for oral, buccal, lingual, occular„ cutaneous, intracutaneous, percutaneous, vaginal or rectal administration. The compositions defined under (C) can additionally be applied, parenterally.

Compositions in accordance with the present invention comprising solid solutions of Ciclosporine and aqueous solutions derived therefrom are usable as alternative for the existing intravenous Ciclosporine infusion concentrate in alcohol in the presence of Cremophor® EL, a polyoxyethylated castor oil, or the oral solution in olive oil, which are the state of the art for Ciclosporine.

A comparison of Ciclosporine and saccharose or raffinose monolaurate containing aqueous solutions of the invention with the mentioned Cremophor* EL containing Ciclosporine infusion concentrate in a test in which dogs were injected intravenously with these solutions, did not show different Ciclosporine plasma concentrations. This means that the distribution of th® active compound in th« body is the same. In Figure 1 the concentrations are plotted in rig/ml and tha time t in hours. Curve 1 presents the saccharose monolaurate solution, curve 2 the raffinose monolaurate solution and curve 3 tha commercial 5 solution.

A comparison of a saccharose monolaurate containing Cyclosporins solution with the commercial solution in olive oil in a test in which thasa solutions ware administered orally to rats resulted in a bio-10 availability improvement of 26% of the solution according to tha invention.

The production of the solid solution use in the composition of the invention is preferably carried out in such manner, that the agent and 15 the sugar ester are dissolved together in a liquid solvent and the solvent is volatilised from the obtained mixture. Volatilisation can be realised by evaporation or by freeze drying. As a volatile solvent water or preferably ethanol are used. If water is used- volatilisation is preferably effected by freeze drying. The solid solution can thus 20 be prepared by dissolving the active compound and th® monoester together in a volatile solvent, volatilising the solvent and recovering the obtained solid solution.

The said solid solution can also be prepared by melting the monoester 25 by heatings, dissolving the active compound in the melt, solidifying by cooling and recovering the obtained solid solution. Additional pharmaceutical excipients can be added to the solid solution,, e.g. to lubricate, to thicken or to dye it. Excipients which are substantially water insoluble are solubilised under the influence of the monoester 30 and can also be incorporated in the solid solution.

Especially when the solid solution is obtained according to the firstly described process, an anti-microbiological treatment is possible before the solid solution is formed and filled in ampoules. 35 The anti-microbiological treatment can be easily integrated in the process of production,, if the solid solution is formed according to the secondly described process by raising the liquefaction temperature.

The weight ratios of the amount of active compound to the amount of monoester can be varied up to the maximum solubilisation capacity of the monoester.

The saccharose ester of Xauric acid is an excipient, widely distributed in the food industry and is easily biodegradable. The solubilisation capacity of the monoester, having a mono ester content of >80Z, for Ciclosporine in aqueous solutions at room temperature and at different monoester concentrations was as follows? TABLE 1 Saccharose monolaurate concentration in water, containing 0.9/f of weight of NaCl.

Solubilising capacity for Ciclosporine in mg/ml at room temperature. 1 3.5 6.5 3 20 1,5 mg/ml .5 8,0 10,0 13.0 16,0 35,0 The solubilising capacity in mg/ml and the concentration of the solubilisator solution in X of weight are plotted in Fig. 2; a constant ratio is shown. The Ciclosporine solid solution can thus be diluted with the brine to every desirable extent, without destabilisation and precipitation of the drug compound or the solution becoming opalescent.

From table 1 it is seen that a maximum concentrated aqueous solution of Ciclosporine can be obtained if the weight ratio of the monoester to Ciclosporine is 100s16.

As will be apppreciated, all components of pharmaceutical compositions of the invention will themselves be pharmaceutically acceptable, e.g., in relation to intravenous administration, intravenously applicable.

The following examples are illustrative of the present invention: A) Preparation of solid solution and their use EXAMPLE 1: A suitable saccharose monolaurate is, since it has a monoester weight content of >80%* the commercially available product L-1S95 of Mitsubishi-Kasei Food Corporation. Tokyo 104, Japan-'The product has an HLB-value of at least 12-3. Tha purity of the lauryl ester residue is about 95%. The melting point is about 35°C, the decomposition temperature is about 235dC. The surface tension of an aqueous solution containing an amount of 0.1% of weight of monoester is about 72.0 dyn/cm at 25°C. 1000 mg of this saccharose monolaurate product and 160 mg of Ciclosporine are dissolved in 20ml of ethanol and the solvent evaporated in a Rotavaporisator to yield the desired solid solution,. The residue is pulverised in a mortar under dry conditions, since the monoester is hygroscopic.

EXAMPLE 2% 1000 mg of the saccharose monolaurate of Example 1 are mixed with 160 tog of Ciclosporine and the mixture heated to 150°C while stirring. The obtained clear solution is cooled to room temperature to yield the desired solid solution and than processed further as described in Example 1. example 3« a) 1000 mg of the saccharose monolaurate employed in Example 1 and 30 rag of Proquazone (Biarison*) are dissolved in 20ml of 100 % ethanol and the solvent evaporated completely in a Rotavaporisator to yield the desired solid solution. The residue is reduced to a fine powder in a mortar and is mixed with 10 mg of magnesium stearate as a lubricator. b) A similar solid solution is obtained by substituting the Proquazone ingredient with 30 mg of Progesterone.

EXAMPLE 4: Solid solutions having the following compositions are obtainable «% analogously to Example 1.

SOLID SOLUTION CICLOSPORINE CONTENT SACCHAROSE MONOESTER CONTENT * 120 mg 1000 mg Saccharose monocaproate B 130 mg 1000 mg Saccharose monomyristate 250 mg ISOOag Saccharose monooleate *Honoester content for all listed esters >80 X.

The obtained solid solutions are completely soluble in water.

EXAMPLE 5: Solid solutions containing Cyclosporin® in 1000 mg of raffinose 30 monolaurate and in 1000 mg of raffinose monooleate respectively (monoester content >80a) are prepared using the evaporation method.

In the raffinose monolaurate 135 ag of Ciclosporine and. in raffinose monooleate 200 mg of Ciclosporine could be dissolved. The obtained solid solutions are completely soluble in water.

EXAMPLE 6: 2000 mg of saccharose monolaurate (monoester content >80%) and 320 mg of Ciclosporine are dissolved in 50 ml of an aqueous solution containing 10% of weight of ethanol and the liquid micellar solution is filled in ampoules for^ injection and lyophilised under sterile conditions. The thus obtained solid solution in the ampoule can be dissolved within 30 seconds by shaking in a 0.9% HsCl containing aqueous solution to yield a clear solution as product.

EXAMPLE 7; 362 mg of a solid solution prepared according to the method of Example 1 are mixed with 375 sag of water free citric acid and 150rng of sodium bicarbonate and the mixture pressed. The thus obtained effervescent tablet contains 50mg of Ciclosporine and dissolves within 2.5 minutes is? water without leaving a residue. The obtained solution is adminsterable orally to provide effective Ciclosporine therapy, e.g. on administration of one or several such dosages, e.g. 2 to Ax per day.

EXAMPLE 8; 181.25 mg of a solid solution, prepared according to the method of Example 1 containing 25 ag of Ciclosporine are mixed while stirring with 198.75 mg of viscous liquid paraffin and filled into hard gelatine capsules. The release rate of Ciclosporine from the obtained oral unit dosage form is measured in water at 37°C: Time (min.) % of weight of Ciclosporine standard dissolved deviation mean value (n=s3) 3 2P2 14 3,5 29 6,8 65 7S0 60 98 0S6 120 98 0f6 180 98 0.6 EXAMPLE 9; 1000 mg of saccharose monolaurate (monoester content >80%) and 30 mg of Proquazone (Biarison*) are processed according to the evaporation method to a solid solution. The povder is moulded with 1.0 g of Adeps solidus Ph. Eur,, to a suppository, thus diminishing the hygroscopic!ty.

Preparation of a liquid saicellar solution and its use For human application the solid solution is preferably transformed into a liquid (aqueous) micellar solution™ of which generally a dosis is used corresponding to en amount of 40 to 2000 mg of Ciclosporine for oral or intravenous application. For the oral application the higher dosage and for intravenous application the lower dosage within the range are taken.

EXAKPLE 10; 16 mg of Ciclosporine are solubilised in 1 ml of an isotonic aqueous solution of 10% of weight of saccharose monolaurate with a monoester amount of >80% of weight. Tha solution is used for the treatment of Psoriasis by intralesional injection. Repeated injection is effective in the treatment of Psoriasis.

Example 11; i s. 1000 mg of saccharose monolaurate having a monoester content of >80% by weight and 160 mg of Ciclosporine are dissolved in a liquid mixture of 16 ml of 1,2-propvlene glycol and 91 ml of distilled water, sterilised by filtration and filled in an ampoule for injection. The dosage of 1.5 mg of Ciclosporine pro ml of solubilisate 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-hydroxy benzoic acid methyl ester as a substantially water insoluble excipient, Proquazone (Biarison*) and Progesterone as substantially water insoluble pharmaceuti cally active compounds., clear solubilisate solutions are prepared with saccharose monolaurate having a monoester content of >802. In an aqueous solution of solubilisate (102 by weight) 8 mg of p-hydroxybenzoic acid methyl ester, 3 mg of Proquazone and 3 mg of Progesterone can be solubilised p§:r ml. The solubilisate 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

punas

1. A pharmaceutical composition comprising a) a subtantially water insoluble pharmaceutical active polypeptide and b) saccharose monolaurate or raffinose monolaurate.

2. A pharmaceutical composition comprising a solid solution of a) a pharmaceutical^ active compound in b) a water soluble monoester of a saturated or unsaturated (Cs_xa) fatty acid and a polyol.

3. A composition according to claim 2 wherein b) comprises a water soluble monoester of a saturated or unsaturated (C«.i«) fatty acid and a saccharide.

4. A composition according to claim 3 wherein b) comprises a monoester of a disaccharid«t.

5. A composition according to claim 4 wherein b) comprises a monoester of saccharose™

6. A composition according to claim 3 wherein b) comprises a monoester of a trisaccharide.

7. A composition according to claim 6 wherein b> comprises a monoester of raffinose.

8. A composition according to claim 3 wherein b) comprises a monoester of a saccharide containing a glucose unit.

9. A composition according to claim 3 wherein, b) comprises a( monoester of a saccharide containing s fructose unit.

10. A composition according to claim 3 wherein b) comprises a monoester of a saccharide ..containing a galactose unit.

11. 1. A composition according to any one of claiims 2 to 10 wherein b) comprises a monoester of caproic acid (C«), caprylic acid (C8), capric acid (Ci0» lauric acid (Cj.2, myristic aeid (Cm), palmitic acide (Cjs), oleic acid (Cj.®), ricinoleic acid or 12-hydroxystearic acid (Ci8)•

12. A composition according to claim 5 wherein b) comprises a monoester of a (C6_i4) fatty acide.

13. A composition according to claim 6 wherein b) comprises a monoester of a (0®_j,s) fatty acid.

14. A composition according to any one of claims 2 to 13 wherein b) comprises a monoester having an HL3-value of at least 10.

15. A composition according to any osae of elaims 2 to 14 wherein b) comprises a monoester having monoester content of at least 80Z by weight.

16. A composition according to any one of claims 2 to 15 wherein a) comprises a substantially water insoluble phamaceutically active compound.

17. A composition according to any one of claims 2 to 16 wherein a) comprises a pharmaceutically active polypeptide.

18. A composition according to claim 17 wherein a) comprises a substantially water insoluble pharmaceutical^ active polypeptide. 5 10 15 20 25 30

19. A composition according to claim 18 wherein a) has a molecular weight of from 500 to 1500.

20. A composition according to claim 18 wherein a) is a cyclosporin

21. A composition according to 20 wherein a) is Cyclosporin.

22. A composition according to claim 20 or 21 comprising up to 30^ by weight of cyclosporin based on the total weight of cyclosporin plus component b).

23. A composition according to any one of claims 20 or 22 comprising at least 1% by weight of cyclosporin based on the total weighx of cyclosporin plus component b)-

24. A composition according to any one of clamis 2 to 5. 8,9 and 11 to 24 wherein b) comprises saccharose monolaurate.

25. A composition according to claim 24 wherein a) comprises a cyclosporin present in an amount up to 161 by weight based on the total weight of components a) plus b).

26. A composition according to any one of claims 2,3 and 6 to 23 wherein b) comprises raffinose monolaurate. \

27. A composition according to claim 26 wherein a) comprises a cyclosporin present in an amount up to X3»5£ by weight based on the total weight of components a) plus b).

28. A pharmaceutical composition according to any one of claims 1 to 27 in the form of a capsule, pellet, granulate, tablet, ampoule, gel, suppository or globulus. 35

29. A pharmaceutical composition comprising a) a substantially water insoluble pharmaceutically active polypeptide and b) a water soluble monoester of a saturated or uns&tured (C^„18) fatty aeid and a polyol in solution in an aqueous medium or in a solvent which is miscibla with water. i

30. A composition according to claim 29 wherein a) is a cyclosporin. 5

31. A composition according claim 30 wherein a) is a Cyclosporin.

32. A composition according to claim 30. comprising at least 0.35% by weight of a cyclosporin.

33. A composition according to any oae of claims 29 to 32 for oral, buccal,, lingual., percutaneous, intracutaneous, occular. cutaneous, vaginal, rectal or parenteral administration.

34. A composition according to any one of claims 29 to 32 for intravenous administration.

35. A composition according to claim 1. additionally comprising a substantially water insoluble excipient.

36. A composition according to claim 1 for intravenous administration.

37. A composition according to 20 vherein the cyclosporin is present as the dissolved or dispersed phase of said solid solution entirely or substantially entirely in molecular distribution.

38. A composition according to claim 37 comprising at least IX by weight of cyclosporin. 30

40. A composition according to claim 39 comprising 20 to 250 mg cyclosporin per unit dosage, 35

41. A composition according to claim 40 comprising 25 to 100 mg 10 15 20 25 30 cyclosporin per unit dosage.

42. A composition according to clai 41 comprising 50mg cyclosporin per

43. A composition according to any one of claims 39 to 42 wnerain the ratio of mono-esters cyclosporin is frosa 10:0.5 to 10s3.0 p.p.v.

44. A composition according to claim 43 wherein the ratio of mono-esters cyclosporin is from 10;1.0 to 10s2.0 p„p„w.

45. A composition according to claim 44 wherein the ratio of mono-ester: cyclosporin is fro® I0sl.2 to 10:1.6 p.p.v.

46. ,. A pharmaceutical composition comprising a) a substantially water insoluble pharmaceutical active polypeptide and b) saccharose monolaurate or raffinose monolaurate substantially as hereinbefore described by way of Example,

47. A pharmaceutical composition comprising a solid solution of a) a pharmaceuticallv active compound in b) a water soluble monoester of a saturated or unsaturated (Cg=lg) fatty acid and a polyol substantially as hereinbefore described by way of Example.

48. A pharmaceutical composition comprising a) a substantially water insoluble pharmaceutically active polypeptide and b) a water soluble monoester of a saturated or unsaturated (Cg^g) fatty acid and a polyol in solution in an aqueous medium or in a solvent which is miscible with water substantially as hereinbefore described by way of Example., Dated this 13th day of September, 1988. unit dosage. by: tqwtms & cq#s Ap ants' Agents (Signed) ^ 5 D^mouth Roems Dublin 6.