AU628787B2

AU628787B2 - Water soluble monoesters as solubilisers for pharmacologically active compounds and pharmaceuticals excipients

Info

Publication number: AU628787B2
Application number: AU22172/88A
Authority: AU
Inventors: Lorenz Hahn
Original assignee: Sandoz AG
Current assignee: Novartis AG
Priority date: 1987-09-15
Filing date: 1988-09-13
Publication date: 1992-09-24
Anticipated expiration: 2008-09-13
Also published as: LU87335A1; FR2620336B1; GB2209671A; ES2012118A6; IL87746A0; AT395819B; JPH01151526A; GB2209671B; FI884192A0; HU205010B; FI94837B; SE503279C2; BE1001204A5; KR890004694A; NZ226163A; MY103769A; NO179434B; PT88492B; IE61195B1; NO884052L

Description

N

I

628787 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION NAME ADDRESS OF APPLICANT: 6 *0 4 4 4 44 0 44 0 4 4 40« 4a 4 4* 0 44* 9Q e 0 J 4 4« 4 4 Sandoz Ltd.

CH-4002 Basle Switzerland NAME(S) OF INVENTOR(S): Lorenz HAHN ADDRESS FOR SERVICE: DAVIES COLLISON Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

COMPLETE SPECIFICATION FOR THE INVENTION ENTITLED: "Water Soluble Monoesters as Solubilisers for Pharmacologically Active Compounds and Pharmaceuticals Excipients".

The following statement is a full description of this invention, including the performing it known to me/us:best method of 1A The invention relates to pharmaceutical compositions based on the use of vater soluble monoesters of saturated or unsaturated (C6-.

1 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-propylene glycol.

[By the term "water soluble" as used herein is meant: having a 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 1 g monoester per 30 ml water.

The term "aqueous medium" is to be understood to include systems i 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 comprises at least 75 preferably at least 90 most especially at least 95 water by weight.J More particularly the present invention provides, in a first aspect: A) a pharmaceutical composition comprising a) a substantially water t' insoluble pharmaceutically active polypeptide and b) saccharose

S

-2 monolaurate or raffinose monolaurate.

In a further aspect the present invention also provides: B) a pharmaceutical composition comprising a solid solution of a) a pharmaceutically active flmpom,- in b) a water soluble monoester of a saturated or unsaturated (C6- 18 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 substanti4lly water insoluble pharmaceutically active polypeptide and b) a water soluble monoester of a saturated or unsaturated (C 6 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 more than 1 at room temperature.

Substantially water insoluble polypeptides as defined above are thus polypeptides requiring at least 100 ml 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 e.g. not more than ca.

0.004 Z 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 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). Bence, it follows, that for the used agent the applied monoesters alone were not satisfactory 7 solubilisers. Additionally it appeared that the saccharose monoesters 3 vere not suitable as solubilisers at all for the used agent (cf. page 2, lines 70-72). The products obtained are indicated for e.g.

intradermal injection but not as suitable for intravenous injection (page 8, column 2, lines 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 of the active substance employing a wide variety of non-ionic solubilisers (esters and ethers). In the examples many polyoxyethylene derivatives are discussed including inter al. sorbitan monopalmitate and sorbitan oleate. Most solubilisers are not water soluble themselves and thus not intravenously injectable. In particular the 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 are also mentioned in the description (not in the examples) incidentally and only the monopalmitic and the monostearic acid esters are specified (page 4, line 11). These compounds too do not meet the requirement of the instant invention, that should they be water soluble. No suggestion can be found to use vater soluble monoesters for the improvement of the water solubility of pharmaceutically 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 2, line 53), and agents, eg. 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 already have relatively good water solubility by nature (cf. page 1, lines 17-21 and page 2, lines 19-20). The obtained aqueous mixtures 0 00 4 4 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. Esters which are applied are mostly not water soluble solubilisers, e.g. saccharose palmitate, saccharose tearate or a sorbitan fatty acid ester.

Saccharcse oleate 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 fatty acid ester and Ciclosporine is sonicated, to provide an oral liquid preparation. No indication can be found to use the obtained dispersion for intravenous administration. For a dispersion containing 0.35% of Ciclosporine in water (3,5 ,ag/ml) a concentration of 0.2% ester is employed. According to the instant invention solutions comprising 0.35% of Ciclosporine by weight are obtainable using a 2.3% solution of the water soluble saccharose monolaurate 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 difficult4to find water soluble excipients, which solubilise the pharmaceutically active compounds in aqueous media to provide solutions which are stable at all dilution stages without forming a precipitate, and which are additionally pharmaceutically acceptable.

Liquid galenical forms, which are satisfactory from a pharmaceutical and medical viewpoint and which contain, in particular, substantially water insoluble polypeptides, especially cyclopeptides such as the \yclosporins, have long been sought. Excipients used in available coamercial forms possess poor palatability or are associated with a tg, risk of anaphylactic shock. Tensides containing ethylene oxide unito or such having amine or amide structures are no longer acceptable from a pharmaceutical or medical viewpoint.

Surprisingly, it has now been found that in this respect unobjectionable water soluble monoesters of saturated or unsaturated (C6-Ia) fatty acids and polyols, 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 pharmaceutically active compounds, These monoesters can dissolve the active compound sufficiently. By addition of water or other aqueous media, aqueous micelar solutions are obtained from 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 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 undex comprising solid solutions are obtainable in which the pharmaceutically active, e.g. substantially water insoluble, pharmaceutically active zxa polypeptide, for example cyclosporin the dissolved or disperse phase) is entirely or substantially ,entirely present in molecular distribution, or in which the water soluble fatty acid ester the solvent o continuous phase) and the water insoluble pharmaceutically active gam\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 i I I 6 invention are monoesters of disaccharides, e.g. maltose, or, especially, saccharose, as well as of trisaccharides, e.g. raffinose.

Preferred are 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 caprylic acid capric acid (Cio), lauric acid (Cli), myristic acid (C14), palmitic acid (C 16 oleic acid (CIs), ricinoleic acid (C 18 or 12-hydroxystearic acid (Cia) esters.

In the fatty acid esters used in the compositions of the invention, the lipophilicity of the acid moiety is, by the choice of its length, in balance with the hydrophilicity of the polycl, e.g. saccharide, moiety. Preferably (C6-14) acid residues are connected with disaccharides and (Cs-ls) 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 saccharose monocaproate, saccharose monolaurate, saccharose monomyristate, saccharose monooleate and saccharose monoricinoleate, raffinose 4* monocaproate, raffinose monolaurate, raffinose monomyristate, raffinose monopalmitate and raff!nose 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 above. Such compositions may optionally include pharmaceutical excipients which are substantially insoluble in water.

t 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 more preferably at least 90 X 4 I 41 I 7 by veight, i.e. the said fatty acid esters preferably contain less than 20 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.

Pharmaceutically active compounds comprised in the compositions o e invention as defined under above are vater soluble or, p erably, substantially vater insoluble, e.g. Proquazone (al-iso rpyl-7-methyl- 4-phenyl-2(lH)-quinazolinone) which has a vater ubility of belov 0.1 g/100 ml; xanthine derivatives, e.g. the*phyllin; tricyclic compounds, for exarple tricyclic anti pressiva or e.g. ketotifen; azulene derivatives, e.g. guaja ene, or steroids, e.g. Prednisone.

Water soluble pharm utically active compounds are included in relation to th nvention as defined under since such agents are as advan eous as substantially vater insoluble agents in combination vi vater soluble monoesters, since their bioavailability becomes improved.

Preferred pharmaceutically active compounds in compositions of the invention as defined under are polypeptides, especially 1 substantially water insoluble polypeptides having a molecular veight

I

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 vater solubility of belov 0.004 g/100 ml.

t St The cyclosporins comprise a class of structurally distinct cyclic, S' poly-N-methylated undecapeptides having valuable pharmaceutical, in particular immunosuppressive, anti-inflammatory and anti-parasitic, in particular anti-protozoal activity. The first of the cyclosporins to be isolated and the "parent" compound of the class, is the naturally occurring fungal metabolite Ciclosporine, also known as Cyclosporin A, A )0 i_ 8 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 and 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 (Thr 2 (Val2)- and (Nva 2 Ciclosporine (also known as cyclosporins C, D and G respectively), as well as various semi-synthetic derivatives thereof, such as their dihydro derivatives as disclosed in US Patents Nos. 4,108,985; 4,210,581 and 4,220,641) including e.g. (Dihydro-MeBmtL)-(Val 2 )-Ciclosporine (also known as dihydrocyclosporin D) and other natural and artificial cyclosporins such as those disclosed in European Patent Publication No. 0,058,134 Bl, for example ((D)-Sers]-Ciclosporine; UK Patent Application No. 2,115,936 A, for example (O-Acetyl-(D)- Ser']-Ciclosporine; and European Patent Application No. 86810112.2, for example (Val] 2 -[(D)Methylthio-Ser] 3 and [Dihydro-MeBmtl]-(Val] 2 -[(D)-Methythio-Sar]-Ciclosporine.

[In accordance with now conventional nomenclature for the cyclosporins, these are definded herein by reference to the structure of Ciclosporine Cyclosporin This is done by first indicating those residues in the molecule which differ from those present in Ciclosporine and then Applying the term "Ciclosporine" to characterise the remaining residues which are identical to those present in Ciclosporine. Ciclosporine has the formula I A-B-Sar-MiLeu-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLet.-eVal- 1 2 3 4 5 6 7 8 9 10. 11 (I) -9wherein A represents thQ [N-methyl-(4R)-4-but-2E-en-l-yl-4-methyl-(L)threonyl] residue of formula I1

CH

3 x

I

CH

2 HO CH CH (R)

CH

3

-N-CH-CO-

(S)

CH

3 in which is -CHuCH- (trans), which residue is abbreviated as -HeBmt-, and B is the alpha-aminobutyric acid residue, abbreviated as -aAbu-.

Accordingly (Thr 2 )-Ciclosporine (cyclosporin C) is the compound of formula I, wherein A has the meaning given above and B is -Thr-, and (Dihydro-MeBmtUl-(Val,)-Ciclosporine (dihydrocyclosporin D) is the p zompound of formula 1, wherein A represents the -dihydro-MeBmtresidue of formula II above in which Ia -CH2-CH 2 and B is -Val-].

As the "parent" compound of the class, Ciclosporine has so far received the most attention. The primary area of elinical a e investigation for Ciclosporine has been as an immunosuppressive agent, t CCin particular in relation to its application to recipients of organ transplants, e.g. heart, lung, combin d heart-lung, liver, kidney, pancreatic, bone marrow, skin and corneal transplants and, in particular, allogenic organ transplants. In this field Ciclosporine has achieved a remarkable success and reputation and is now pt, commercially available and widely employed in clinic.

4 ,t 4" *4 10 At the same time, applicability of Ciclosporine to various autoimmune diseases and to inflammatory conditions, in particular inflammatory conditions with an aetiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases, has been intensive and reports and results in vitro, in ani, l models and in clinical trials are vide-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 thrombocyto.aznia), systemic lupus seythematosus, polychondritis, sclerodonia, Uegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory 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), t uveitis (anterior and posterior), conjunctivitis (e.g.

S* 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).

4 A further area of investigation has been potential applicability as an anti-parasitic, in particular anti-protozoal agent, with possible uses suggested including treatment of malaria, coccidiomycosis and *4 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 SANDIMMUN) varies considerably from subject to 11 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 HPLC, 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 mg/kg day for initating therapy, reducing to 3/5 10 mg/kg day. Intravenous infusion is at ca. 3-5 mg/kg day for initiating therapy reducing to ca. 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 invent.ion as defined under preferably comprise at least 7Z, particularly at least 1X0% by weight of pharmaceutically active, substantially water insoluble pharmaceutically 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 cyclospcrin based on the total weight of ester plus cyclosporin. Lowest concentration is only determined in relation t to the therapy to be applied but should not be below iX by weight.

Compositions as defined under comprising a cyclosporin in saccharose monolaurate or in raffinose monolauratt are preferred. In the first pure monoester solid solutions containing up to 16%, 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 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 vith 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.

L- ii- i r~3 12 fine particulate, product, optionally together vith 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 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 mg cyclosporin per unit dosage, Suitably the ratio of water soluble fatty acid ester to eyclosporin 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, for administration 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. Where 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.

13 Solid solutions comprising the ompositions 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 the invention provides pharmaceutical compositions comprising solutions as defined under 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, especl1ally in higher concentration, is only possible after vigorous agitation. For this reason, the most simple method is, !irstly preparing the solid active compound solution in the monoester, after which diluting with water can be carried out without problinns, Dissolving the active compound in the liquified a rronoester and subsequently diluting the obtained mixture, after an optional intermediate treatment with hot ethanol, with water is known from the GB-Patent 1.134,878 (page 3p lines 22-32 and page 6, lines 04 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 substantially clear. 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 44 *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 *4 precipitate or deposit on ultracentrifugation.

Compositions in accordance with the invention comprising solutions in aqueous media may of course comprise or be presar't together with 14 urther components other than water. They may for example also 'oorate water miscible components. Such compositions equally .a solutions as defined in which other non water soluble, 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 purposes of i.v. administration compositions in accordance with the invention comprising liquid solutions will p'eferably 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 be employed as or as components of occular formulations, e.g. eye drops.

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

The invention also provides compositions as defined under and (C) *,above for oral, buccal, lingual, occular, cutaneous, intracutaneous, percutaneous, vaginal or rectal administration. The compositions Sdefined under 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 *a are the state of the art for Ciclosporine.

te A comparison of Ciclosporine and saccharose or raffinose monolaurate 6 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 S'o, the distribution of the active compound in the body is the same. In 15 Figure 1 the concentrations are plotted in ng/ml and the time t in hours. Curve 1 presents the saccharose monolaurate solution, curve 2 the raffinose monolaurate solution and curve 3 the commercial solution.

A conparison of a saccharose 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% of the solution according to the 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 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 efftcted by freeze drying. The solid solution can thus be prepared by dissolving the active compound and the monoester 4 together in a volatile solvent, volatilising the solvent and 0 t recovering the obtained solid solution.

The said solid solution can also be prepared by melting the monoester by heating, 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 vater insoluble are solubilisjd under the influence cf the monoester and can also be incorporated in the solid solution.

I',

1 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.

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 16 temperature.

The weight ratios of the amount of active compound to the amou~nt of monoester can be varied up to the maximum soliubilisation capacity of the monoester.

The saccharose ester of lauric acid is an excipient, widely distributed in the food industry and is easily biodegradbl-1. The solubilisation capacity of 'Che monoester, having a degree of purity of for Ciclospoine in aqueous solutions at room temperature and at different monoester concentrations was as follows: Akl 920327,dbdatLI IZ21'2res,16 ~l r r i 1 i~ s i 17 TABLE I Saccharose monolaurate concentration Solubilising capacity for in water, containing 0.9% of weight Ciclosporira in mg/ml at room of NaCl. temperature.

1 1,5 mg/ml 10,0 8 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 car e obtained if the weight ratio of the monoester to Ciclosporine is 100:16.

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: 18- A) Preparation of solid solution and their use EXAMPLE 1: A suitable saccharose monolaurate is, since it has a monoester weight content of the commercially available product L-1695 of Mitsubishi-Kasei Food Corporation, Tokyo 104, Japan. The pLoduct has an HLB-value of at least 12.3. The purity of the lauryl ester residue is about 95%. The melting point is about 0 C, the decomposition temperature is about 2350C. The surface tension of an aqueous solution containing an amount of 0.1% of weight of monoester is about 72.0 dyn/cm at 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 mg of Ciclosporine and the mixture heated to 150 0 C while stirring. The obtained clear solution is cooled to room temperature to yield the desired solid solution and then processed further as described in Example 1.

c, EXAMPLE 3: i t t a) 1000 mg of the saccharose monolaurate emp in Example 1 and 1 mg of Proquazone (Biarisons) aret olved in 20ml of 100 ethanol and the solvent orated completely in a Rotavaporisator to yield the de i solid solution. The residue is reduced to a fine po dein a mortar and is mixed vith 10 mg of magnesium I searate as a lubricator.

r Li~l-lll. l~ I- I 19 EXAMPLE 3: Solid solutions having the folloving compositions are obtainable analogously to Example 1.

SOLID SOLUTION CICLOSPORINE

CONTENT

120 mg 130 mg 250 mg SACCHAROSE MONOESTER CONTENT 1000 mg Saccharose monocaproate 1000 mg Saccharose monomyristate 1500mg Saccharose monooleate 4~ *4444 p 4 4Oi 4.4 4*1 0 8* p.

8.4 4 4 4 4 4 'a 4' '4 *Minoester cnrtent for all listed esters >80 The obtained solid solutions are completely soluble in vater.

EXAMPLE 4: Solid solutions containing Ciclosporine in 1000 mg of raffinose monolaurate and in 1000 mg of raffinose monooleate respectively (monoester content )>80X) are prepared using the evaporation method.

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

L

20 EXAMPLE3: 2000 mg of saccharose monolaurate (monoester content 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% NaCI containing aqueous solution to yield a clear solution as product.

EXAMPLE 6: 362 mg of a solid solution prepared according to the method of Example 1 are mixed with 375 mg of water free citric acid and 150mg of sodium bicarbonate and the mixture pressed. The thus obtained effervescent tablet contains 50mg of Ciclosporine and dissolves within 2.5 minutes in 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 4x per day.

EXAMPLE 7 181.25 mg of a solid solution, prepared according to the method of 'Example I containing 25 mg of Ciclosporine are mixed while stirring with 198.75 mg of viscous liquid paraffin and filled into hard gelatins capsules. The release rate of Ciclosporine from the obtained oral unit dosage form is measiared in water at 37*C:

L(

21 Time (min.) 120 180 of weight of Ciclosporine dissolved mean value (n-3) 3 14 29 65 98 98 98 standard deviation 2,2 6,8 0,6 0,6 0,6 S. *t 4 5 o #5 itt

S

4 .4 t SS 4a 4 9t S ~i 4 St

I

*4 *4 4

S

I'

I C

SI

4 1 4 I EXAMPLE 9: 1000 mg of saccharose monolaurate (nonoe content and mg of Proquazone (BiarisonR) rocessed according to the evaporation method solid solution. The powder is moulded with 1.0 g of Ade s solidus Ph. Eur. to a suppository, thus diminishing r<the hygroscopicity.

B) Preparation of a liquid micellar 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 an 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 lover dosage within the range are taken.

EXAMPLE 8.: 16 mg of Ciclosporine are solubilised in 1 ml of an isotonic aqueous solution of 10X of weight of saccharose monolaurate with a I_ c_ 22 monoester amount of >80% of weight. The solution is used for the treatment of Psoriasis by intralesional injection. Repeated injection is effective in the treatment of Psoriasis.

Example q: 1000 mg of saccharose monolaurate having a monoester content of 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, ste ilised 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 1U: Vith p-hydroxy benzoic acid methyl ester as a sus- antially water insoluble excipient, Proquazone (Biarison nd Progesterone as substantially water insoluble pharm f tically active compounds, clear solubilisate solutions rT prepared with saccharose monolaurate having a mn ester content of In an aqueous solution of sol isate (10X by weight) 8 mg of p-hydroxybenzoic 4* 0 S' acid methn lester, 3 mg of Proquazone and 3 mg of Progesterone can be Cubilised per 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.

0 4 4 It 0 «c

Claims

4. -23- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A pharmaceutical composition comprising a) a substantially water insoluble pharmaceutically active polypeptide and b) saccharose monolaurate or raffinose monolaurate. 2. A pharmaceutical composition comprising a solid solution of a) a paly p--pid-e pharmaceutically active copoundsin b) a vater soluble monoester of a saturated or unsaturated (C6- 1 fatty acid and a polyol. 3. A composition according to claim soluble monoester of a saturated and a saccharide. 4. A composition according to claim monoester of a disaccharide. A composition according to claim monoester of saccharose.
6. A composition according to claim monoester of a trisaccharide.
7. A composition according to claim monoester of raffinose. 2 wherein b) comprises a water or unsaturated (C 6 a) fatty acid 3 wherein b) comprises a 4 wherein b) comprises a 3 wherein b) comprises a 6 wherein b) comprises a 6 (1 6 6 4 #6 o
8. A composition according to claim 3 wherein b) comprises a monoester of a saccharide containing a glucose unit. ii 6 4*o 6 #4 #64* 6 66 66i 90327,dbdat12,22172.res,23 24
9. A composition according to claim 3 wherein b) comprises a monoester of a saccharide containing a fructose unit. A composition according to claim 3 wherein b) comprises a monoester of a saccharide containing a galactose unit.
11. A composition according to any one of claims 2 to 10 wherein b) comprises a monoester of caproic acid caprylic acid capric acid (Clo, lauric acid (Cl 2 myristic acid (C 14 palmitic acid. (C 16 oleic acid (C 18 ricinoleic acid (C 18 or
12-hydroxystearic acid (C 1 12. A composition according to claim 5 wherein b) comprises a monoester of a (C6-14) fatty acid.
13. A comp~osition according to claim 6 wherein b) comprises a monoester of a 1 g) fatty acid.
14. A composition according to any one of claims 2 to 13 wherein b) comprises a monoester having an HLB-valum of at least A composition according to any one of claimrs 2 to 14 wherein b) comprises a monoester having a degree of purity of at least 809% by weight,,
16. A composition acdording to any one of claims 2 to 15 wherein a) comprises a substantially water insoluble pharmaceutically active
17. A comperition according to any one of cliin 2 1,,iii-16F comprises a pharmaceutically active pol Pt
18. A cou.posit ording to claim 17 wherein a) comprises a st-anti~1lly water insoluble pharmaceU tictally active polypetide. at t a 4, 17. A composition according to claim 16 wherein a) has a molecular weight of from 500 to 1500. 18. A composition according to claim 16 wherein a) is a cyclosporin.
19. A composition according to claim 18 wherein a) is Ciclosporin.
20. A composition according to claim 18 or 19 comprising up to 30% by weight of cyclosporin based on the total weight of cyclosporin plus component b). 21, A composition according to any one of claims 18 or 20 comprising at least 1% by weight of cyclosporin based on the total weight of cyclosporin plus component b). *4 2. 22. A composition according to any one of claims 2 to 8, 9 and 11 to 21 wherein b) comprises 4 ,ccharose monolaurate.
23. A composition according to claim 22 wherein a) comprises a cyclosporin present in an amount up to 16% by weight based on t' a total weight of components a) plus b). I I 1*11 24, A composition according to any one of claims 2, 3 and 6 to 21 wherein b) comprises raf inose monolaurate. A composition according to claim 24 wherein a) comprises a cyclosporin present in an amount up to 13.5% by Weight based on the total weight of components a) plus b).
26. A pharmaceutical composition according to any one of claims 1 to 25 in the form of a capsulet pellet, 920603,bda 125.22 72.eS,2 -26- granulate, tablet, ampoule c L, suppository or globulus..
27. A pharmaceutical composition comprising a) a substantially water insoluble pharmaceutically active polypeptide and b) a water soluble monoester of a saturated or unsaturated (C6- 18 fatty acid and a polyol in solution in an aqueous medium or in a solvent which is miscible with water.
28. A composition according to claim 27 wherein a) is a cyclosporin.
29. A composition according to claim 28 wherein a) is a Ciclosporin. A composition according to claim 28, comprising at least 0.35% by weight of a cyclosporin.
31. A composition according to any one of claims 27 to for oral, buccal, lingual, percutaneous, intracutaneous, occular, cutaneous, vaginal, rectal or parenteral administration.
32. A composition according to any one of claims 27 to for intravenous administration.
33. A composition acording to claim 1, additionally comprising a substantially water insoluble excipient.
34. A composition according to claim 1 for intravenous administration.
35. A composition according to claim 18 wherein the cyclosporin is present as the dissolved or dispersed phase of said solid solution entirely or substantially entirely in molecular distribution. 920603,dbdat 125,22172,res,26 rr _li r_?-ir i' A -27-
36. A composition according to claim 35 comprising at least 7% by weight of cyclosporin.
37. A composition according to claim 35 or 36 in unit dosage form for oral administration.
38. A composition according to claim 37 comprising 20 to 250 mg cyclosporin per unit dosage.
39. A composition according to claim 238 comprising to 100 mg cyclosporin per unit dosage. A composition according to claim 39 comprising 50 mg cyclosporin per unit dosage.
41. A composition according to any one of claims 37 to wherein the ratio of mono-ester: cyclosporin is from 10:0.5 to 10:3.0 p.p.w. of 20 42. A composition according to claim 41 wherein the Sratio of mono-ester: cyclosporin is from 10:1.0 to S10:2.0 p,p.w. t 43, A composition according to claim 42 wherein the 25 ratio of mono-ester: cyclosporin is from 10:1.2 to 10:1.6 p.p.w.
44. Pharmaceutical compositions, substantially as hereinbefore described with reference to the Examples. DATED this 3rd day of June, 1992 Sandoz Ltd. By Its Patent Attorneys DAVIES COLLTSON CAVE 920603,dbdat. 125,22172,res,27