SK1996A3 - Pharmaceutical composition for solubilisation of hardly soluble active substance in the carrier and preparation method thereof - Google Patents

Abstract

Pharmaceutical prepn. comprises () a pharmaceutically active agent which is sparingly soluble in water; and (b) a carrier compsn. comprising (i) at least one polyglycerine fatty acid ester and/or at least one sorbitan fatty acid ester, (ii) at least 1 conventional pharmaceutical oil contg. a triglyceride as lipophilic component and (iii) at least 1 nonionic surfactant with a HLB value of at least 10. The active agent is pref. a cyclosporin, rapamycin, tacrolimus, deoxyspergualine, nifedipine, nimodipine, etoposide, ibuprofen or alpha-lipoic acid. The active agent has a solubility, in distilled water, of less than 500mg/1000ml. The active agent concn. is 1-30 wt.%, based on the carrier compsn. The carrier compsn. comprises 10-50 wt.% component (i), 5-40 wt% component (ii) and 10-50 wt % component (iii).

Description

Technical field

The invention relates to pharmaceutical compositions containing sparingly soluble active substances and to processes for the preparation of such compositions.

BACKGROUND OF THE INVENTION

In general, administration of the pharmaceutical active by oral administration, such as tablets, capsules or dragees, has advantages over other forms of administration, for example parenteral. On the whole, the diseases to be injected are considered to be more severe than those in which the administration of tablets, capsules or dragees is almost invisible. It is particularly advantageous in these dosage forms that the patient may administer them alone, while the parenteral dosage forms must be administered by a physician or qualified medical assistance, with a few exceptions.

After administration and disintegration of the oral dosage form, the active ingredient is treated with a liquid in the gastrointestinal tract, for example, gastric or intestinal juice. Many active agents to be administered orally have lipophilic properties and are therefore poorly soluble in the aqueous environment of the gastrointestinal tract. This reduces the amount of active substance capable of resorption and hence its bioavailability. This generally leads to the need to use higher doses of the active substance to be administered. This results in increased biological variability and undesirable efficacy mismatches.

So-called solubilizers, for example hydrophilic cosolvents such as ethanol, propylene glycol, liquid polyethylene glycols or lipophilic solubilizers such as lecithin, fatty acid esters of polyglycols or fatty acid esters of glycerol polyglycols, have been described to improve the solubility of poorly soluble active substances. The use of such solubilizers is problematic due to the reduced tolerance and insufficient stability of the dosage form, for example by its separation effect.

It has therefore been proposed in German Published Application No. 40 05 190 to use partial esters of fatty acids with glycerol or partial esters with propylene glycol. These adjuvants (co-surfactants) have the disadvantage that they can only be obtained within a narrow range of HLB 2 to 3. This allows only a limited variation in the weight ratios of the individual carrier components in order to adapt to the different solubilities of the active substances to be dissolved.

SUMMARY OF THE INVENTION

It is an object of the present invention to increase or improve the solubility, resorptive capacity and, consequently, the bioavailability of the active substances to be administered orally, by selecting in particular suitable excipients.

This object is achieved by the invention, which relates in particular to a preferred pharmaceutical composition for improved solubilization of a water-soluble active ingredient in a carrier. The carrier according to the invention consists of the following components:

(a) approximately 10 to 50% by weight, based on the weight of the carrier, of a co-surfactant which is substantially pure or present as a mixture with a hydrophilic lipophilic balance of less than 10 (Griffin HBL) selected from polyglycerol fatty acid esters; sorbitan fatty acid esters,

b) about 5 to 40% by weight, based on the weight of the carrier, of a pharmaceutically acceptable oil which is substantially pure or present as a mixture and which comprises triglyceride as the major lipophilic component, and

c) about 10 to 50% by weight, based on the weight of the carrier, of a substantially pure or mixture of nonionic surfactant present with an HLB value greater than 10 and optionally other pharmaceutically acceptable excipients.

In addition, the present invention also provides a process for the manufacture of a pharmaceutical composition comprising a solubilized water-soluble active ingredient in a carrier consisting of said components. The composition is suitable for filling into forms for oral dosage units, for example, starch capsules, hard gelatin capsules or soft gelatin capsules.

The terms used hereinbefore and hereinafter are defined in the description of the invention as follows:

The term pharmaceutical composition defines a mixture of a solubilized, water-insoluble active ingredient or a mixture of the active ingredients in a carrier consisting of said ingredients which can be formulated into oral dosage forms, preferably starch, hard gelatin or soft gelatin capsules.

The term solubilized or solubilized in a sparingly water-soluble active ingredient or active ingredient mixture defines a dispersion process by the action of a suitable solubilizing agent which enhances the dispersing ability of the substance so that the therapeutically effective dose is completely dissolved or at least becomes a partial dissolution process bioavailable. The term dispersant defines a measure for the formation of microemulsions, true molecular solutions of active ingredients and excipients in water, as well as colloidal solutions, for example association colloid or molecular colloid solutions which are clear or opalescent and possibly after filtration, in particular using sterile filters of approximately diameter 5 to 10 µm pores, do not contain any solid particles, or, for example, micellar solutions or sphero colloids, which can only be resolved in the ultracentrifuge. The dispersing ability can be reported, for example, in mg or mmol per liter of water.

A sparingly water-soluble active ingredient or active ingredient mixture has a water solubility of less than 500 mg / 1000 ml, preferably less than 200 mg / ml.

Particularly suitable sparingly soluble active substances are immunosuppressive agents with a macrolide structure, for example cyclosporin A, cyclosporin G, rapamycin, tacrolimus, deoxyspergualin, mycophenolate mofetil, gusperimus, non-steroidal anti-inflammatory drugs, e.g. , diclofenac, piroxicam, meloxicam, tenoxicam, naproxen, ketoprofen, flurbiprofen, fenoprofen, felbinac, sulidac, etodolac, oxyfenbutazone, phenylbutazone, nabumetone, dihydropyridine derivatives with cardiovascularipin activity, nitrodipipine, nitodisipipine, nipradedipine, nilvadipine, lacidipine, benidipine, masnidipine, fumidipine, niguldipine, neurotherapeutics such as α-lipoic acid, muramyl peptides such as muramyldipeptide or muramyltripeptide, romurtide, fat-soluble vitamins such as vitamin A, D, E or F; alkaloids, for example, vincropectin, nincristine, vinblastine, reserpine, codeine, ergot alkaloids, for example bromocriptine, dihydroergotamine, dihydroergocristine, antitumor agents, for example chlorambucil, etoposide, teniposide, idoxifen, tallimustine, tirimine, tinarpine, teloxantrinin, teloxantrinine miltefosine, trophosphamide, teloxantrone, melphalan, lomustine, 4,5-bis- (4'-fluoroanilino) phthalimide, immunomodulators such as thymoctonan, presatide copper (I) acetate; anti-infective agents such as erythromycin, daunorubicin, graminicin, doxorubicin, amphotericin B, gentamycin, leukomycin, streptomycin, ganefromycin, rifamexil, ramoplanin, spiramycin; antifungals such as fluconazole, ketoconazole, intraconazole, β-receptor antagonists such as famotidine, cimetidine, ranitidine, roxatidine, nizatidine, omepramol, protein kinase inhibitors such as N- [4-methyl-3- (4-pyridin-3-ylpyrimidine-2) -ylamino) -phenyl] -benzamide, N-benzoylstaurosporine; HIV-1 protease inhibitors, for example BOC-Phe ^c Phe-Val-Phe-morpholine or its O- [2- (2-methoxyethoxy) acetoxy] derivative; leukotriene antagonists such as N- [4- (5-cyclopentyloxycarbonylamino-1-methylindol-3-ylmethyl) 5

-3-methoxybenzoyl] -2-vinyloxy] benzenesulfonamide.

Particularly preferred are cyclosporins, rapamycin, tacrolimus, deoxyspergualin, mycophenolate mofetil, nifedipine, nimodipine, etoposide, ibuprofen and α-lipoic acids.

Instead of containing the active ingredient in free acid or base form alone, the active ingredient in the pharmaceutical composition may be in the form of a pharmaceutically acceptable salt, such as hydrobromide, hydrochloride, mesylate, acetate, succinate, lactate, tartrate, fumarate , sulfate, maleate and the like.

The concentration of active ingredient or combination of active ingredients is determined by the dose to be administered. It may represent 1 to 30% by weight, preferably 5 to 20% by weight, in particular 5 to 12% by weight, based on the weight of the carrier.

The carrier for said active substances or combination of active substances is defined as follows:

Requirements substantially pure in relation to the component contained in the carrier defines a degree of purity greater than 90%, preferably greater than 95%, of this component before mixing it with the other components of the carrier. Preferably, the components defined as substantially pure have a clearly defined structure and composition.

The components present in the carrier as a mixture may be mixtures of natural substances, the composition of which depends on the raw material itself, its isolation and further processing. The components of such mixtures are listed in the manufacturer's specifications.

The polyglycerol fatty acid ester of component (a) consists essentially of a substantially pure polyglycerol fatty acid ester or a mixture of polyglycerol fatty acid esters, the polyglycerol preferably containing up to and including 10 glycerol units which are esterified with 1 to 10 acyl residues saturated or unsaturated carboxylic acids containing an even number of 8 to 20 carbon atoms.

The acyl radical of a saturated carboxylic acid containing an even number of 8 to 20 carbon atoms that esterifies polyglycerol preferably has a straight chain of 12, 14, 16 and 18 carbon atoms, for example, n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or an n-octadecanoyl residue.

The acyl residue of an unsaturated carboxylic acid having an even number of 8 to 20 carbon atoms that esterifies polyglycerol preferably has a straight chain of 12, 14, 16 and 18 carbon atoms and contains 1 double bond, for example a 9-cis-dodecenoyl residue, 9-cis -tetradecenoyl, 9-cis-hexadecenoyl or 9-cis-octadecenoyl.

The names in parentheses may also be used for the indicated acyl residues.

In addition, the following names may also be used for the acyl radicals mentioned:

9-cis-dodecenoyl (lauroleoyl), 9-cis-tetradecenoyl (myristoleoyl), 9-cis-hexadecenoyl (palmitoleoyl), 6-cis-octadecenoyl (petroseloyl), 6-trans-octadecenoyl (petroselaidoyl), 9-cis-octadec (oleoyl), 9-trans-octadecenoyl (elaidoyl), 11-cis-octadecenoyl (vaccenoyl), 9-cis-icosenoyl n-dodecanoyl (lauroyl), n-tetradecanoyl n-hexadecanoyl (palmitoyl), n-octadecanoyl (g) , (myristoyl), (stearoyl), n-icosanoyl (arachidoyl).

Suitable fatty acid esters of polyglycerol with a clearly defined structure are, for example, diglycerol monocaprate, diglycerol monolaurate, diglycerol diisostearate, diglycerol monoisostearate, diglycerol tetrastearate (polyglyceryl-2-tetrastearate), triglycerol monooleateate (triglycerol monooleateate) triglycerol mono-isostearate, hexaglycerol dioleate, (polyglycerol-6-dioleate), hexaglycerol distearate, (polyglycerol-6-distearate), decaglycerol dioleate, (polyglycerol-10-dioleate), decaglycerol tetraoleate, (polyglycerol-deca-oleateol), ), decaglycerol decastearate, (polyglycerol-10-decastrate). the CTFA nomenclature is enclosed in brackets. These products are commercially available under the trademark Caprol ^R (trademark of Karlshams USA Inc., Columbus, Ohio). Exact product designation: CAPROL 2G4S, 3GO, 3GS, 6G20, 6G2S, 10G20, 10G40, 10G100, 10G10S. Other products are available from Solvay Alkali GmBH, D-3002 Hannover under the designation DGLC-MC, DGLC-ML, DGLC-DISOS, DGLC-MISOS, TGLC-ML and TGLC-MISOS.

The mixture of different fatty acid esters with polyglycerol is defined by the names deca-glycerol mono-di-oleate, polyglycerol ester of mixed fatty acids, polyglycerol ester of fatty acids, polyglycerol caprate, cocoate, laurate, lanolinate, isostearate or ricinolate and can be obtained on the market under the words " and Homodan ^R (trademarks of Grinsted Products, Grinsted, Denmark), with the exact product names: TRIODAN 20, 55, R90 and HOMODAN MO, Radiamuls ³ * (trademark of Petrofina (FIN), Brussels, Belgium), the exact product name RADIAMULS Poly 2253, the name CAPROL PGE 860 or the word marks Plurol ^R (trademarks of Gattefossé Establissements, Saint-Priest, France), the exact product designation PLUROL Stearique WL 1009 or PLUROL Oleique WL 1173. Other products available under PGLC-C 1010 PGLC-C 0810, PGLC-C 1010 / S, PGLC-L T 2010, PGLC-LAN 0510 / S, PGLC-CT 2010/90 ISOS T UE, PGLC-R UE, PGLC-ISOS 0410 of Solvay Alkali GmbH, D-3002 Hannover.

Said polyglycerol fatty acid esters meet the conditions set forth in Foodechemical Codex FCC III under Monographs on p. 232 concerning the description, requirements and tests. Of particular importance are product descriptions published by the listed manufacturers with data for the product concerned, in particular specifications such as monoester content, drop point, free glycerol, free fatty acid, iodine number, form, antioxidants, HLB value, properties and durability.

Said polyglycerol fatty acid esters meet in particular the requirements of E 475 of the European Community Ingredients Regulation (EC Directive 74/329) and U.S. Pat. FDA Code 21 CRF § 172.854.

The sorbitan fatty acid ester of component (a) preferably comprises a sorbitan fatty acid ester of substantially pure or a mixture of different fatty acid esters of sorbitan, wherein the sorbitan is esterified with 1 to 3 acyl residues of a straight or straight chain saturated or unsaturated carboxylic acid containing an even number of 8 to 20 carbon atoms.

The acyl residue of a saturated carboxylic acid having an even number of 8 to 20 carbon atoms that esterifies sorbitan is preferably straight chain and contains 12, 14, 16 and 18 carbon atoms, for example n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl and an n-octadecanoyl residue.

The acyl radical of an unsaturated carboxylic acid having an even number of 8 to 20 atoms preferably has a straight chain and contains 12, 14, 16 and 18 carbon atoms, for example an oleyl radical.

Suitable sorbitan fatty acid esters are in particular sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan quioleate, sorbitan trioleate and sorbitan tristearate. These products can be obtained on the market under the word mark Span ^R (trademark of Atlas, Wilmington, USA), with the exact names SPAN 20, 40, 60, 65, 80 and 85, Arlacel ¹ * (trademark of Atlas form), with exact product names: ARLACEL 20, 40, 60, 80, 83, 85 and C, Crill ^R (trademark of Croda Chemicals, Co wick Halí, Snaith Goole, GB), with exact product names: CRILL 1, 3 and 4 , Dehymuls ^R (Trademark of Henkel, Dtisseldorf, Germany), with exact product names DEHYMLUS SML, SMO, SMS, SSO, Famodan ^R (Trademark of Grinsted Products, Grinsted, Denmark), with exact product names FAMODAN MS and TS, Capmul ^R (Trademark of Karlshamns USA Inc., Columbus, Ohio), with exact names CAPMUL S and 0, Radiasurf ^R (Trademark of Petreofina (FIN), Brussels, Belgium), with exact product names RADIASURF 7125, 7135, 7145 and 7155.

Said sorbitan fatty acid esters and said polyglycerol fatty acid esters meet the conditions set forth in the British Pharmacopeia (specific monograph) or in Ph. Helv. VI. Of particular importance are the product descriptions published by the said manufacturers with data for the product in question, in particular specifications such as form, color, HLB value, viscosity, increasing melting point and solubility.

Component a) has an HLB value of less than 10. The carrier is present in an amount of 10 to 50% by weight, preferably 15 to 40% by weight, more preferably 15 to 20% by weight, based on the total weight of the carrier. Component a) may also consist of a mixture of said polyglycerol fatty acid esters or a mixture of said sorbitan fatty acid esters or a mixture of said polyglycerol fatty acid esters with said sorbitan fatty acid esters.

The pharmaceutically acceptable oil b) is a triglyceride of natural origin or a synthetic or semi-synthetic, substantially pure triglyceride. Preference is given to a triglyceride of natural origin in which the glycerol is esterified with acyl residues of saturated or unsaturated carboxylic acids containing an even number of 8 to 20 carbon atoms. Such acyl radicals are as defined above, for example, an n-dodecanoyl radical, n-tetradecanoyl radical, n-hexadecanoyl radical, n-octadecanoyl radical or oleyl radical.

Suitable triglycerides of natural origin are, for example, peanut oil, sesame oil, sunflower oil, olive oil, corn germ oil, soybean oil, castor oil, cottonseed oil, rapeseed oil, thistle oil, grape oil, fish oil or neutral oil.

Component b) is present in the carrier in an amount of about 5 to 40% by weight, preferably 10 to 35% by weight, based on the total weight of the carrier. Component (b) may also consist of mixtures of said pharmaceutically acceptable oils.

The nonionic surfactant of component c) having an HLB value greater than 10 is preferably an amphiphilic substance whose hydrophilic component consists of polyethylene oxide, wherein the average molecular weight of the polyethylene oxide moiety is about 600 to 2500, corresponding to 15 to 60 ethylene oxide units.

Suitable nonionic surfactants are, for example, the reaction products of natural or hydrogenated castor oil with ethylene oxide. Such products can be obtained, for example, under the trademarks Cremophor ¹ *, Niccol ^R and Emulgin ^R. Suitable nonionic surfactants are also fatty acid esters of polyoxyethylene sorbitan (polysorbates), for example, POE- (20) sorbitan monolaurate, POE- (20) sorbitan monopalmitate, POE- (20) sorbitan entriesterate, POE- (20) sorbitan monourea 20) -sorbitantrioleát. as well as polyoxyethylene fatty acid esters such as POE (20,30,40,50) stearate. Such products are commercially available under the trademarks Tween ^R and Myrj ^R.

Component c) is present in the carrier in an amount of about 10 and 50% by weight, preferably 20 to 45% by weight, based on the total weight of the carrier. Component c) may also consist of mixtures of said pharmaceutically acceptable nonionic surfactants.

Suitable pharmaceutically acceptable adjuvants are added to the carrier in such an amount as to supplement the amounts of components (a), (b) and (c) as well as the active compounds or the active compound combination to 100% by weight. The adjuvants may be present in the carrier in an amount of 0% to 75% by weight. Supplementary excipients are subject to the choice of pharmaceutical dosage form. In the case of liquid dosage forms such as drops, suspensions, or capsules, pharmaceutically acceptable conventional solvents such as ethanol, propanol, isopropanol, propylene glycol, polyethylene glycol, glycerol or water or mixtures thereof are added.

In addition, commonly used excipients can be added, for example preservatives such as benzyl alcohol, ethanol, p-hydroxybenzoic acid ester, sorbic acid; antioxidants such as tocopherols, butylhydroxyanisole, butylhydroxytoluol, ascorbic acid, ascorbyl palmitate; stabilizers such as citric acid, tartaric acid, ethylenediaminetetraacetic acid (EDTA); flavoring or flavoring substances.

For gelatine capsule fillers, usually a preservative or plasticizer is suitable to provide a stable gelatin shell. Such excipients are, for example, sorbitol, sorbitan, polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, methylcellulose or silica.

The present invention also provides a process for the preparation of a pharmaceutical composition as defined above, characterized in that they are mixed with one another in any order of components a), b) and c) and optionally further pharmaceutically acceptable excipients, dispersing a sparingly water-soluble pharmaceutically active ingredient. optionally, the compound and dispersion are formulated in a suitable, orally administrable form.

The dispersion of the active ingredient or combination of active ingredients may be effected by mixing components (a), (b) and (c) as well as other excipients. Alternatively, the active ingredient or active ingredient combination may be dispersed in a single ingredient or in a mixture of the two ingredients and the remaining ingredients added. Solubilization or dispersion processes can be accelerated by heating the individual components or mixtures thereof. Preference is given to reaction conditions which promote the formation of a colloidal dispersion phase.

In the presence of oxygen-sensitive active substances, the process according to the invention is carried out under a protective atmosphere, for example under nitrogen, helium or argon. The oxygen present in the liquid components may be removed beforehand by the application of a vacuum, for example at 0.005 to 0.01 MPa, or by ultrasound. A double-walled reaction vessel with stirrer is suitable for this process.

The incorporation from the orally administrable form is carried out in a manner known per se. For the manufacture of oral liquid forms such as drops, suspensions, emulsions and the like, conventional methods are used, as described in standard publications such as Hagers Handbuch der Pharmazeutischen Praxis or Remington's Pharmaceutical Science.

The capsules are preferably two-piece gelatin capsules, which are optionally prepared with the addition of glycerol or sorbitol and are dissolved immediately by the action of gastric juices. Alternatively, starch capsules can be used, for example, Capsugel / Warner Lambert products sold under the trademark Capill ^R. Other excipients and fillers, such as lactose, starch, lubricants, such as starch or magnesium stearate, may be mixed into the capsules. Liquids such as lecithin, fats, oils, paraffin oil or liquid polyethylene glycol may be sufficiently contained in the soft capsules. Depending on the dosage, 0 to 4, preferably 0 to 4, size capsules are suitable depending on the dosage

2. Shionogi, Casugel or Scherer products are suitable.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate the invention without limiting its scope as defined above. The active substances mentioned therein represent all the above-mentioned active substances. Temperature data is in degrees Celsius.

Example 1

Recipe for filling into soft gelatine capsules; amounts in mg per finished capsule; soft gelatin capsule format: 22 min, elongated

Cyclosporin A (USP XXII / Pharm. Eur.) 100.0

2. P0E- (40) -hydrogenated castor oil 400.0

3. (CREMOPHOR RH 40, NICCOL HCO 40, SIMULSOL 1293)

3. Fatty acid di / tri / tetraglycerol ester238.0 (FCC / TRIODAN 20)

4. sesame oil (DAB 10) 160.0

5. α-tocopherol (DAB 10) 2.0

6. ethanol (DAB 10) 100.0

Components 2 to 4 are mixed while heating to 40 ° in a stainless steel kettle equipped with a stirrer. The solution was then degassed by vacuum. The antioxidant 5 is added to the clear solution, followed by the dispersion of the active substance cyclosporin A. After the addition of ethanol, the whole batch is stirred until a clear solution is obtained. After cooling to about 20 °, the solution is filled into soft gelatin capsules. In order to compensate for the evaporative loss, the dose contains 30 to 60 mg of ethanol in comparison with the above formula.

The walls of the soft gelatin capsules contain, in addition to gelatin, excipients which affect their consistency, for example glycerol and / or propylene glycol or sorbitol and / or mannitol. The walls may further comprise pigments or dyes, for example titanium dioxide, iron oxide, quinoline yellow or coquinine carmine A.

Example 2

Formulation for filling into hard gelatine capsules or starch capsules, quantities in kg per dose

1. Nifedipine (DAB 10)

2. POE- (20) sorbitan monooleate (polysorbate 20 Pharm. Eur., TWEEN 20)

3. triglycerol mono / dioleate (FCC-CAPROL 3G0)

4. neutral oil (MIGLYOL 812, CAPTEX 300/400)

20.0

168.0

28.0

84.0

All the ingredients of the recipe were mixed at 45 ° in a 300 L heated double-walled boiler and mixed until a clear solution was obtained. Doses of 300 mg clear, cooled solution are filled into size 1 hard gelatin capsules, which have rendered opaque titanium dioxide / iron oxide mixtures opaque.

The filled capsules are provided with sealing tape. Because of the light sensitivity of nifedipine, all process operations must be performed without daylight access.

Example 3

Recipe for filling into a glass bottle. The composition is suitable for oral administration as a drip solution which is filled into 40 ml drop bottles. Quantity data in grams.

1. Nimodipine (DAB 10) 3.0

2. P0E- (60) -hydrogenated castor oil15.0 (CREMOPHOR RH 60, NICCOL HCO 60, SIMULSOL 1294)

3. Sorbitan monolaurate (BCP 1973, SPAN 20) 8.5

4. Sunflower oil (DAB 10) 8.5

5. propylene glycol5.0

The preparation of the solution is carried out analogously to Example 2.

Example 4

Recipe for filling into soft gelatine capsules; quantity data in mg per finished capsule, soft gelatin capsule format: 4 minimum, oblong

1. tacrolimus10.0

2. POE- (35) -ricin oil (CREMOPHOR EL) 72.0

3. Sorbitan monooleate (SPAN 80) 72.0

4. neutral oil32.0

5. α-tocopherol1,0

6. propylene glycol (DAB 10) 5.0

The preparation of the capsules is carried out analogously to the example

1. Propylene glycol is particularly suitable for imparting consistency to capsule walls.

Example 5

Recipe for filling hard gelatine capsules; the quantity data refer to a cartridge size 0

1. α-Lipoic acid100.0

2. POE- (40) -stearate (US / NF, MYRJ 52 S) 80.0

3. Tetraglycol stearate (FCC, TRIODAN 55) 215.0

4. sesame oil 160.0

5. butylhydroxyanisole 0.5

The preparation of the solution is carried out analogously to the example

2. The sensitivity of lipoic acid to oxygen shall be taken into account.

Example 6

Recipe for filling soft gelatine capsules; quantity data in mg per finished capsule, soft gelatin capsule format: 6 minima, oblong

1. Rapamycin20.0

2. POLYSORBAT 80 (TWEEN 80) 150.0

3. sorbitan monooleate25.0

4. neutral oil75.0

5. Ascorbyl palmitate 0.5

6. Benzyl alcohol (DAB 10) 5.0

The preparation is carried out analogously to Example 1, with benzyl alcohol being added last.

Example 7

Recipe for filling into soft gelatine capsules; data in mg per finished capsule.

1. Etoposide

2. P0E- (40) -hydrogenated castor oil

3. Di- / tri- / tetraglycerol laurate (TGLC-laurate T2010 Solvay Alkali GmbH)

4. Corn germ oil

5. Ethanol

100.0

400.0

160.0

230.0

100.0

The preparation is carried out analogously to Example 1.

Example 8

Recipe for filling soft gelatine capsules; quantity data in mg per finished capsule, soft gelatin capsule format: 9.5 minim, elongated

1. S (+) - ibuprofen 100.0

2. POLYSORBAT 60 (TWEEN 60) 210.0

3. Hexaglycerol dioleate (CAPROL 6G20) 130.0

4. Castor oil60.0

The preparation is carried out analogously to Example 1.

Claims (10)

PATENT CLAIMS A pharmaceutical composition for solubilizing a sparingly soluble active ingredient in a carrier, characterized in that the carrier comprises: (a) approximately 10 to 50% by weight, based on the weight of the carrier, of a co-surfactant that is substantially pure or present as a mixture with a hydrophilic lipophilic balance of less than 10 (Griffin HLB) selected from polyglycerol fatty acid esters; sorbitan fatty acid esters, (b) about 5 to 40% by weight, based on the weight of the carrier, of a pharmaceutically acceptable oil which is substantially pure or present as a mixture and which contains triglyceride as the major lipophilic component, and c) about 10 to 50% by weight, based on the weight of the carrier, of a substantially pure or mixture of nonionic surfactant present with an HLB value greater than 10 and optionally other pharmaceutically acceptable excipients. Pharmaceutical composition according to claim 1, for solubilizing approximately 1 to 30% by weight, based on the weight of the carrier, of an active substance with a solubility of less than 500 mg / 1000 ml in pure water, characterized in that the active substance is cyclosporin, rapamycin, tacrolimus, deoxyspergualin, mycophenolate mofetil, nifedipine, nimodipine, etoposide, ibuprofen or α-lipoic acid. Pharmaceutical composition according to claim 1 or 2, characterized in that the active substance is cyclosporin A. Pharmaceutical composition according to claims 1 to 3, characterized in that component a) consists of a substantially pure fatty acid ester with polyglycerol or mixtures thereof, wherein the polyglycerol contains up to and including 10 glycerol units which are esterified with 1 to 10 acyl residues saturated or unsaturated carboxylic acids having an even number of 8 to 20 carbon atoms. Pharmaceutical composition according to claim 4, characterized in that component a) comprises substantially pure polyglyceryl-2-tetrastearate, polyglyceryl-3-monooleate, polyglyceryl-3-stearate, polyglyceryl-6-dioleate, polyglyceryl as the fatty acid ester of polyglycerol. -6-distearate, polyglyceryl-10-dioleate, polyglyceryl-10-tetraoleate, polyglyceryl-10-decaoleate or polyglyceryl-10-deca-stearate or mixtures thereof. Pharmaceutical composition according to claims 1 to 3, characterized in that component a) comprises a substantially pure sorbitan fatty acid ester or a mixture thereof, wherein the sorbitan is esterified with 1 to 3 acyl residues of saturated or unsaturated carboxylic acids having from 8 to 20 carbon atoms. A pharmaceutical composition according to claim 6, wherein component a) comprises substantially pure monolaurate, monopalmitate, monostearate, tristearate, monooleate, sesquioleate or trioleate of a mixture of these components as sorbitan fatty acid ester. according to the claims, component b) of the composition, in that an acceptable peanut oil 8. Pharmaceutical labeled pharmaceutical oil, sunflower oil, olive oil, germ, soybean oil, seeds, rapeseed oil, grains, fish oil or non-ionic surfactant with from 15 to 60 ethylene oxide units 1 to 7, containing as oil, sesame oil from corn castor oil, cottonseed oil of thistle oil, grape oil neutral oil and component c) contains a hydrophilic component consisting of A process for the manufacture of a pharmaceutical composition according to claim 1, characterized in that they are mixed with one another in any order of components a), b) and c) and optionally further pharmaceutically acceptable water-soluble excipients, dispersing in this mixture a sparingly water-soluble pharmaceutical active ingredient. optionally, the substance and dispersion are brought into a suitable, orally administrable form. Method according to claim 9, characterized in that the dispersion is filled into starch, hard gelatin or soft gelatin capsules.