WO2011063774A2

WO2011063774A2 - Pectin complexes of steroids and pharmaceutical compositions based thereon

Info

Publication number: WO2011063774A2
Application number: PCT/CZ2010/000120
Authority: WO
Inventors: Vladimir Kral; Zbynek Oktabec; Josef Jampilek; Tomas Pekarek; Bohumil Proksa; Jiri Dohnal; Anna Malovikova; Anna Ebringerova; Anna Rezacova
Original assignee: Zentiva, K.S.
Priority date: 2009-11-25
Filing date: 2010-11-25
Publication date: 2011-06-03
Also published as: WO2011063776A2; WO2011063774A3; WO2011063776A3; CZ2009790A3; WO2011063775A2; WO2011063775A3; CZ302789B6

Abstract

The present solution relates to a method of manufacturing a pharmaceutical composition containing an active substance in the form of an adduct (complex) with a pectin, optionally in a mixture with a glucan. The resulting adduct is characterized by higher solubility in water as compared with the original pharmaceutically active substance. The adduct (complex) consisting of the active substance and pectin is then used for preparing a dosage form with targeted (controlled) release in the intestine.

Description

Pectin complexes of steroids and pharmaceutical compositions based thereon Technical Field: The present application relates to water-soluble complexes of steroids with pectins. The active substance is in the form of an adduct (complex) with a pectin or a modified pectin. The resulting adduct is characterized by higher solubility in water as compared with the original pharmaceutically active substance. The adduct (complex) composed of the active substance and a pectin is then used for preparing a pharmaceutical composition for obtaining medical dosage forms with targeted release in the intestine.

Background Art:

The active pharmaceutical ingredient (API) is a substance with ability to interact with a human or animal organism. The result of this interaction is therapy or prophylaxis of a disease in humans or animals; medical diagnosing or restoration, adaptation or influencing of their physiological functions.

Solubility in different solvents is a characteristic property of the given substance. For achieving pharmacological activity of an API, the active substance should be well soluble in physiological fluids so that it would be available at the place of absorption. Solubility of the substance in water correlates significantly with its solubility in physiological fluids and is the first limiting factor of good absorption and thus bio-distribution. Concerning pharmaceutical formulation, trouble-free substances are those with solubility in water higher than 1%. In case this condition is not met, a solution is sought how to increase solubility.

In principle, solubility of a medicine can be influenced by two methods - chemical (formation of salts provided the molecule can be ionized; synthetic modification of the molecule for increasing hydrophilicity; preparation of so-called prodrugs) or physical (by addition of auxiliary substances, or solubilizers).

Not only solubility is an important factor but also speed of dissolving, i.e. rate of transfer of the dissolved substance into the solution. This is a physical-chemical property that can be influenced by the shape of crystals (crystal modifications, polymorphs), particle size, surface properties of the substance, and the like. There are several methods of increasing API solubility - formation of molecular complexes with solubilizers (an example is increasing of solubility of PAMBA (p-aminobenzoic acid) in the presence of caffeine); however, the most used are inclusion complexes with natural or synthetic-modified cyclodextnns. Association of API with cyclodextnn depends on size of cyclodextrin cavity, on effective dimensions of the complexed substance, and, last but not least, on non-bonding interactions of API and cyclodextrin. However, certain disadvantage of this method of increasing solubility is low selectivity of complexing, as well as the fact that the cyclodextrins themselves are not completely biologically inert.

To some extent, soluble salts of organic polybasic acids and hydroxyacids have also a character of molecular complexes.

Solubility can also be increased by adding surface-active substances - surfactants/detergents. These substances form micelles in aqueous environment. Hydrophilic parts of the surfactant molecule are oriented to outer aqueous environment; on the contrary, lipophilic parts of the molecule are oriented to the micelle centre. This„vesicle" can enclose a low-soluble API. Another method is based on using co-solvents - mostly alcohols - usually ethanol, glycerol, propyleneglycol or polyethyleneglycols.

Pectin is a natural substance, a polymer composed of saccharide units the basic structure of which consists of a chain of poly a-(l→4)-D-galacturonic acid alternating with a-(l→2)-L- rhamnosyl-a-(l-→4)-D-galacturonosyl sections. The basic chain can be branched; the side chain typically contains neutral saccharides, such as L-arabinose, D-galactose, D-xylose, etc. The carboxyl groups of D-galacturonic acid can be methylated; properties of the pectin then depend on the degree of esterification. In the presence of bivalent cations, mainly calcium, low-methylated pectins form a gel. High-methylated pectins (with more than 45% of esterified carboxyl groups) can also form a gel. However, this property results from formation of hydrogen bonds and hydrophobic interactions at pH about 3 or in the presence of saccharides. Another method of modifying the basic skeleton of pectin consists in replacement of the methyl groups of the D-galacturonic acid ester by other alkyl or arylalkyl groups; in addition, a possibility exists of replacing the ester group by an amide, mono- or dialkylamide group. Pectins

Pectins, which have so far been used predominantly as food additives, are a group of heteropolysaccharides of variable composition. They contain at least 65% by weight of galacturonic acid as the basic structural unit. This can be present as free acid, the methylester, amidated pectin or acetamide.

Formula 1 depicts the structure of the pectin monomer unit composed of galacturonic acid, ester, and amide group. Formula 2 depicts the structure of the pectin chain composed of galacturonic acid.

Formula 1

Formula 2 Polymeric structure of a pectin

Pectins intended for use are formed of a linear chain containing at least 65% by weight of D- galacturonic acid units. This ' polymer is often called polygalacturonic acid. Units of galacturonic acid in the chain can be either free or naturally esterified with methanol to different degrees (67 - 73% by weight, on average).

The free carboxyl groups of galacturonic acid can be neutralized by various cations. However, pectins are formed from more complex protopectins, which are present in plant tissues and contain also various neutral saccharides, including rhamnose, galactose, arabinose, and smaller amounts of other saccharides. These saccharide units are present in an irregular structure. Using of purified enzyme has proved that a pectin extract prepared under very mild conditions contains both linear blocks composed of homopolygalacturonic acid.

Linear sequences of units of a-D-galacturonic acid are terminated with an a-L- rhamnopyranose unit bound by an a-(l→2) glycosidic bond. The content of rhamnose in pectins is usually 1 to 4% by weight. These sections of the pectin molecule are called rhamnogalacturonans. In addition to the main chains of galacturonic acid interrupted by rhamnose, pectins also contain various neutral saccharides in side chains. L-Arabinose and D- galactose are present in greatest amounts. D-Xylose, D-glucose, D-mannose, L-fucose, and D- gluconic acid are present less frequently.

Below shown is general structure of a modified pectin used for completion of an API by gel formation for controlled release, or a pectin gel composed of the potassium salt of pectan in the presence of the API (steroid hormone) after addition of a calcium chloride solution.

The principle of physical cross-linking for the pectin derivatives used is shown below.

Use of pectins and related polysaccharides in formulations

So far, pectins have been used in pharmaceutics as active substances in treating diabetes (US 2007/0167395); for control of blood glucose level (CN1883501); therapy of ulcer disease in combination with colloidal bismuth (CN1698895; CN1634132); as anti-tumour substances after pectin depolymerization (WO2006/002106); as transdermal delivery form of a pectin gel with an opioid (WO2005/102294); microcapsules composed of combination of a pectin and an alginate for formulation of folic acid (Madziva, H. et al. J. Microencapsul 2005, 22, 343); in encapsulation of simvastatin in a gel composed of an alginate/pectin and calcium (WO2005/072709); in intranasal application in combination of fentanyl, a pectin, a poloxamer, and chitosan (WO2004/062561) or buprenorphin in combination with chitosan (WO2003/080021) or Pluronic F127, a pectin and apomorphine (WO99/27905); in therapy of allergy as an anti-histamine (WO2004/026317); in treatment of obesity or metabolic syndrome (WO2004/022074); in topical preparations intended for restoration of mucous membrane (JP2004059440), in regenerative medicine in combination with a polyhydroxybutyrate for formation of a biodegradable film (DE10212553); in dosage forms modified against abusing hypnotics, sedatives, and psychostimulants (WO2003/105808); in treating hyperlipidemia in combination of a pectin and unsaturated fatty acids (DEI 0214005; DE20205184); as an auxiliary substance improving mechanical properties of tablets in combination with ascorbic acid (WO2003/020265); or pectins have been used as substances eliminating lipids and sterols from the human organism (Kay R.M., Truswell A.S. Am. J. Clin. Nutr. 1977, 30, 171; Rotenberg S., Jakobsen P.E. Zatschr. Tierphysiol. Tierernaehr. Futtermittelk. 197), 42, 299; Ross J.K., Leklem J.E. Am. J. Clin. Nutr. 1981, 34, 2068; Judd P,A., Truswell A,S. Br. J. Nutr. 1982, 48, 451 ; Shireman R.B. et al. Nutr. Rep. Intl. 1987, 35, 1313; EP 0 285 568; Gomathy R. et al. J. Biosci. (Bangalore) 1989, 14, 301 ; Terpstra A. et al. J. Nutr. 1998, 128, 1944; Aprikian O. et al. J. Nutr. 2003, 133, 1860; Dongowski G., Lorenz A. J. Nutr. Biochem 2004, 15, 196).

As a food supplement, pectin was used in combination with inulin (RU2169002), or lactoferrin (WO2002047612); in combination with oat bran, glucosamine for elimination of non-digested fat (US 6 200 574, US 5 891 441); as a component of hydrophilic matrix in combination with a plant protein, dextrin, and sucrose, pectin was used for formulation of carotenoids (WO2007/017539); covalently bound anti-tumour substances with a pectin were designed as a prodrug for targeted transport of API (CN101045163); pectin was used for a gastroresistant formulation of rifaximin in therapy of inflammatory diseases of stomach (WO2006/094737); pectin was used for encapsulation of lipophilic vitamins (US2005/0238675); as an active substance for removing cholesterol from the body (MD2518); as a substance stabilizing „pectin/heparin binding growth factors" (US 6 313 103); in formulation of fexofenadine in combination with hydroxypropyl-P-cyclodextrin (EP 1 121 123); as a component of the transport system of diacerhein in treatment of diarrheic diseases (EP 0 809 995) and also in combination with aluminium magnesium phosphate in therapy of gastrointestinal disorders (RO 107 187).

Another field of pectin application is preparation of dosage forms, typically gel-based in the presence of calcium for controlled release of the drug in the lower part of GIT (Chourasia M.K., Jain S.K. J. Pharm. Sci. 2003, 6, 33; Sinha V.R., Kumria R. Int. J. Pharm. 2001, 224, 19), such as, for example, a formulation of venlafaxine in combination with polyvinylpyrrolidone (US 6 703 044); a formulation of metal-specific enzymes (WO2008/059062); theophylline (Wu B. et al. Eur. J. Pharm. Biopharm. 2008, 69, 294); dexamethasone in combination with chitosan (Coucha A.M. et al. Mans. J. Pharm. Sci. 2006, 22, 17); 5-fluorouracil in formation of a protective film with ethylcellulose (Wei H. et al. J. Pharm. Sci. Technol. 2007, 61, 121 ; Jain, A. et al. J. Drug Target. 2007, 15, 285); a formulation of indometacin (Wei X. et al. Int. J. Pharm. 2006, 318, 132); quercetin (Onteiro, L.M. et al. Latin Amer. J. Pharm. 2007, 26, 179); nisin in combination with hydroxypropylmethylcellulose (Ugurlu T. et al. Eur. J. Pharm. Biopharm. 2007, 67, 202); metronidazole for therapy of amabiasis (Mundargi R.C. et al. Drug Dev. Ind. Pharm. 2007, 33, 255; Yassin, A.B. et al. J. Pharm. Sci. 2001, 28, 212; Nasra M.A. et al. Asian J. Pharm. Sci. 2007, 2, 18); non-steroid anti-inflammatory substances; (IN2003MU00418); adsorbents for rectal application (WO2006/122835); flurbiprofen in .. microsponges " with HPMC (Orlu M. et al. Int. J. Pharm. 2006, 318, 103); 5-aminosalicylic acid in combination with HPMC (Turkoglu M. et al. Eur. J. Pharm. Biopharm. 2002, 53, 65); ropivacaine (Ahrabi S.F. et al. Eur. J. Pharm. Sci. 2000, 10, 43); budesonide in combination with guar gum (EP 0 974 344); corticosteroids (US 5 849 327; WO97/25980); in combination with xyloglucan for oral administration (Itoh K. et al. Int. J. Pharm. 2008, 356, 95); as a protective film for coating tablets (US2007/0292480); for two-phase release of indometacin in combination with HPMC and calcium (Wu B. et al. Eur. J. Pharm. Biopharm. 2007, 67, 707); for sigmoid release in combination with chitosan and Eudragit (Ghaffari A. Eur. J. Pharm. Biopharm. 2007, 67, 175); a formulation of diclofenac in combination with maize starch containing high concentration of amylose (Desai, K.G. J. Biomat. Appl. 2007, 21, 217); in combination with chitosan for coating tablets (Hiorth M. et al. Int. J. Pharm. 2006, 308, 25); formulation of lactoferrin for gradual release in oral cavity; (WO2005/084703), or ambroxol and paracetamol (Miyazaki S. et al. Int. J. Pharm. 2005, 297, 38; Kubo W. et al. Drug Dev. Ind. Pharm. 2004, 30, 593); for formation of microcapsules in formulation of prednisolone (Muhiddinov Z. et al. J. Microencap. 2004, 21, 729); in making acid-resistant formulations of pravastatin (WO 2003080026); microcapsules containing nimesulide (Saravanan M. et al. Indian Drugs 2002, 39, 368); in producing a matrix for controlled release of highly soluble substances (W099/21551 ; Naggar V.F. et al. Pharma Sciences 1992, 2, 227); for a controlled release formulation of oxymorphone (WO2003/004033).

For its good mucoadhesive properties (Thirawong N. et al. Eur. J. Pharm. Biopharm. 2007, 67, 132; Hagesaether E. et al. Drug Dev. Ind. Pharm 2007, 33, 417), pectin was used in dosage forms using adhesion onto buccal mucosa (US2004/0241223; Nafee N.A. et al. Drug Dev. Ind. Pharm. 2004, 30, 985); adhesion onto intestinal mucosa (Shen Z. et al. Pharm. Res. 2002, 19, 391); in combination of pectin and HPMC (Miyazaki S. et al. Int. J. Pharm. 2000, 204, 127), transdermal applications (W097/43989; EP 0 719 135; IN 192518; EP 0 975 367); in ocular applications in combination of pectin with a polyacrylate or polyvinylalcohol (Chetoni P. et al. Boll. Chim. Farm. 1996, 135, 147).

In the form of nanoparticles, pectin was used in formulation of calcitonin in a pectin-liposomal complex (Thirawong N. et al. J. Contr. Rel. 2008, 125, 236), and of various therapeutic peptides (WO2007/ 129926) and insulin (Cheng K., Lim L.Y. Proc. Int. Symp. Contr. Rel. Bioact. Mat. 2000, 27, 992). Complexes of DNA and cationic lipids prepared by microencapsulation were also prepared in the presence of pectins (Harvey R.D. et al. NanoBiotechnology 2005, 1, 71). Transport systems based on nanoparticles (US2004/0136961), or S/O/W pectin microcapsules (Kawakatsu T. et al. Colloids and Surfaces, A: Physicochemical and Engineering Aspects 2001, 189, 257), have been described.

Currently, targeted (controlled) transport into the intestine is becoming more and more important. This method of transport enables both local effect of the drugs (for instance, in ulcerous colitis, Crohn disease or other idiopathic intestinal inflammations, or microbial inflammations of the intestine) and specific transport into the intestine for systemic use, which should prevent absorption of the drug in higher parts of the digestive tract (Jain A. et al. Drug Targeting 2007, 15, 285; Cavalcanti O.A. et al. Drug Develop. Ind. Pharm. 2002, 28, 157).

As carriers, natural or chemically modified polysaccharides are mostly used, such as inulin, amylose, pectins, dextran, chitosans, chondroitin, etc. The drug can be then released from them in the intestine by simple change of pH of the environment or by decomposition activated by intestinal microflora (Kumar P. et al. Curr. Drug Delivery 2008, 5, 186; Patel M.M. et al. Pharm. Dev. Technik. 2009, 14, 62, Schacht E. et al. J. Control Release 1996, 39, 327; Rama P.Y.V. et al. J. Control Release 1998, 51, 281 ; Tozaki H. et al. J. Pharm. Sci. 1997, 86, 1016; Ashford M. et. al. J. Control. Release 1994, 30, 225; IPC8 Class: AA61K900FI USPC Class: 424111 ; IPC8 Class: AA61K3846FI USPC Class: 424946).

Currently, various polysaccharides are used for targeted (controlled) transport into the intestine, the concept being based on the fact that the polysaccharide is not metabolized by human enzymes but first in the intestine by bacterial enzymes of the microflora; this simple principle enables targeted release of the drug from the polysaccharide matrix: for instance, for diltiazem, indometacin (Ravi, V. et al. Ind. J. Pharm. Sci. 2008, 70, 1 1 1). This method of transport is also utilized for metronidazole (Mundargi R.C. et al. Drug Develop. Industrial Pharmaceutics 2007, 33, 255), diclofenac (Cheng G. et al. World J. Gastroenterol. 2004, 10, 1769), celecoxib (Krishnaiah Y.S. et al. J Drug Targ 2002, 10, 247), or, for instance, for 5- fluorouracil (Krishnaiah YS, et al. Eur. J. Pharm. Sci. 2002, 16, 185).

Summary of Invention

The invention provides water-soluble complexes of steroids with pectins, or with pectin derivatives obtained by re-esterification or by amidation. Surprisingly, formation of such complexes, or adducts, results in increased solubility of steroidal pharmaceutical active substances (API) in water. This effect is of great importance for utilization of these substances in pharmaceutics.

The adducts are prepared by stirring an aqueous solution of the pectin with a solution of the API in a water-miscible solvent (for instance, methanol or ethanol). After the complex formation is complete, either the organic solvent is evaporated and the aqueous suspension is used for preparation of the dosage form, or the solvents are evaporated and the solid evaporation residue is used for preparation of the dosage form.

Detailed Description of Invention

The invention provides a pharmaceutical composition, characterized in that the steroidal active substance (API) is in the form of an adduct with a pectin. Surprisingly, formation of such adducts results in increased solubility of lipophilic, low-soluble active substances (API) in water.

The structures of model API's are shown below.

Cholesterol 4-cholesten-3 -one

Cholic acid Dehydrocholic acid

Testosterone propionate

Generally, an adequate solubility is the primary prerequisite of efficiency of the drug in the organism. Solubility of a substance is its characteristic property that can be influenced chemically, in particular by preparing prodrugs, or physically by using various auxiliary complexing substances. Owing to the wide pharmaceutical acceptability of pectins documented above as well es their variability, allowing the fine tuning of their complexing properties through the proper substitution, the exploitation of complexes according to this invention for steroid solubilization represents an exceptionally advantageous option among plenty of other excipients potentially useful for the same purpose.

The complexes according to invention can be used for preparing pharmaceutical compositions in which the active substance is in the form of an adduct with a pectin, together with one or more pharmaceutically acceptable excipients. A medicinal product prepared using these complexes can have significantly better properties than a non-complexed drug; it has considerably higher solubility, bioavailability and stability. Steroidal API included in complexes according to the invention can be a a natural steroid hormone or any synthetic deri vative in which the steroid carbon skeleton can be identified.

In an embodiment of the invention, the adducts are prepared by stirring an aqueous solution of the pectin with a solution of the API in a water-miscible solvent (for instance, methanol ethanol or acetone). After the complex formation is complete, either the organic solvent is evaporated and the aqueous solution is used for preparing the dosage form, or the solvents are evaporated and the solid evaporation residue is used for preparing the dosage form.

In another embodiment, water-immiscible solvents such as, for instance, toluene, dichloromethane, chloroform, esters of acetic acid with C₂-C₅ alcohols, or alcohols having carbon atoms number of C₄-C₆ can be used as a solvent for the complex-forming API. The formation of the complex can be then easily followed by a spectroscopical estimation of the growing API concentration in the aqueous phase. The complex-containing aqueous phase can be either directly used for the preparation of a pharmaceutical dosage form, or dried and the solid complex subsequently used for the same purpose. The pectin used for the complex preparation can be polygalacturonic acid or a mixture composed of derivatives of this acid. Polygalacturonic acid derivative can be selected from the group consisting of: free acid, acid ester or amide, preferably in the form of the methylester or acetamide. The pectin can contain 65% and more weight units of galacturonic acid; preferably the content of galacturonic acid is more than 80% by weight. Modification of the pectin, i.e. modification of the carboxylate to the respective esters is usually less than 15%. The esters are formed with Ci-Cio alcohols and further with benzylalcohol or cholesterol.

The amide derivatives of pectins used include the respective amides prepared by aminolysis of the esters, wherein the amide is derived from primary and secondary amines with 1 to 10 carbon atoms.

The molecular weight of the pectin derivatives is usually higher than 1 ^χ 10⁵ Dalton, preferably it ranges between 150 and 120 kD.

The pectin can be a polymer composed of saccharide units the basic structure of which is a chain of poly a-(l→4)-D-galacturonic acid alternating with a-(l→2)-L-rhamnosyl-a-(l→4)- D-galacturonosyl sections; the basic chain can be branched and the side chain contains the neutral saccharides pentoses and hexoses and the carboxyl group can be esterified by Ci-C₁₂ aliphatic alcohols or monoalkyl- or dialkyl-amidated with Ci-C₆ alkyls.

The solubility of the pectin derivatives which can be used for the preparation of the complexes according to the invention ranges between 0.1 and 20% by weight in water in the pH range of 5 to 10.

The pharmaceutical compositions prepared according to the invention can be used, for example, for: - Controlled and targeted transport of hydrophobic or hydrophilic drugs;

- Controlled transport of a drug using oral application of the dosage form containing 1 to 30% by weight of the active substance;

- Controlled transport of a drug using depot intramuscular application with a content of 1 to 50% by weight of API in the drug form;

- Topical dosage forms containing 1 to 30% by weight of API;

- Formation of self-emulsification systems (SEDDS) containing steroid hormones or their synthetic derivatives.

The final dosage form may further contain a matrix, which is preferably composed of the sodium salt of dextran or the sodium salt of carboxymethylcellulose.

The above-mention preparation method is described in detail in the following examples/figures. The generated complexes were characterized by means of near-infrared (NIR) and FT-Raman spectroscopy. The analysis results (characterized complexes) are shown in the attached figures.

Changes were observed in the NIR spectra of all mentioned samples when compared with the spectra of individual starting materials. On the basis of the documented subtraction spectra, it can be established that this is not just cumulative/addition spectra. The comparison of the subtraction spectra of the resulting complex and the polysaccharide alone with the spectra of both components gave an unequivocal evidence for a complex formation in all cases documented here.

Near infrared spectra were recorded using a Smart Near-IR UpDrift™, Nicolet™ 6700 FT-IR Spectrometer (Thermo Scientific, USA).; accumulation of 128 scans, resolution 8 cm^"1.

FT-Raman spectra were accumulated by FT-Raman spectrometer RFS 100/S (Bruker, Germany); accumulation of 256 scans resolution 4 cm^"1; laser power 250 mW.

Evaluated pectins in solution (DE = degree of esterification, DA = degree of amidation):

Pectin I (pectin potassium salt, DE 64%), cone. (5mg/ml), pH = 5.22

Pectin II (pectin potassium salt, DE 26%), cone. (5mg/ml), pH = 6.08

Pectin III (benzyl pectinate, DE7 %), cone. (5mg/ml), pH = 6.97

Pectan VI (sec-dibutylamide of pectan, DE 78%, DA 14%), cone. (5mg/ml), pH = 3.30 Releasing of model API from the complex 1/7 (Pectin I + testosterone) in solution at various pH values:

Solubility of testosterone-propionate in an aqueous solution of pectin I at pH 3; 5.2; and 6 was estimated to be 0.62 mg of testosterone propionate in 1 mg of pectin in an aqueous solution of concentration 5 mg pectin/ml. Solubility is virtually unchanged with changing pH.

Without a pectin, the solubility of testosterone propionate in water and in buffers of given pH is virtually zero (immeasurable).

Brief Description of Drawings

Fig. 1 : NIR spectra of a pectin I/cholesterol complex (on the top centre) compared with the starting materials cholesterol (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 2: NIR spectra of a pectin I/cholestenone complex (on the top centre) compared with the starting materials cholestenone (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 3: NIR spectra of a pectin I/cholic acid complex (on the top centre) compared with the starting materials cholic acid (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 4: NIR spectra of a pectin I/dehydrocholic acid complex (on the top centre) compared with the starting materials dehydrocholic acid (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom). Fig. 5: NIR spectra of a pectin I/pregnenolone acetate complex (on the top centre) compared with the starting materials pregnenolone acetate (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 6: NIR spectra of a pectin I/androstan-3,17-dione complex (on the top centre) compared with the starting materials androstan-3,17-dione (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 7: NIR spectra of a pectin I/testosterone propionate complex (on the top centre) compared with the starting materials testosterone propionate (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 8: NIR spectra of a pectin II/cholesterol complex (on the top centre) compared with the starting materials cholesterol (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 9: NIR spectra of a pectin II/cholestenone complex (on the top centre) compared with the starting materials cholestenone (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 10: NIR spectra of a pectin Il/cholic acid complex (on the top centre) compared with the starting materials cholic acid (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 11 : NIR spectra of a pectin Il/dehydrocholic acid complex (on the top centre) compared with the starting materials dehydrocholic acid (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 12: NIR spectra of a pectin II/pregnenolone acetate complex (on the top centre) compared with the starting materials pregnenolone acetate (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 13: NIR spectra of a pectin II/androstan-3,17-dione complex (on the top centre) compared with the starting materials androstan-3,17-dione (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 14: NIR spectra of a pectin II/testosterone propionate complex (on the top centre) compared with the starting materials testosterone propionate (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 15: NIR spectra of a pectin Ill/cholesterol complex (on the top centre) compared with the starting materials cholesterol (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 16: NIR spectra of a pectin III/cholestenone complex (on the top centre) compared with the starting materials cholestenone (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 17: NIR spectra of a pectin Ill/cholic acid complex (on the top centre) compared with the starting materials cholic acid (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 18: NIR spectra of a pectin Ill/dehydrocholic acid complex (on the top centre) compared with the starting materials dehydrocholic acid (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 19: NIR spectra of a pectin III/pregnenolone acetate complex (on the top centre) compared with the starting materials pregnenolone acetate (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom). Fig. 20: NIR spectra of a pectin III/androstan-3,17-dione complex (on the top centre) compared with the starting materials androstan-3,17-dione (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 21 : NIR spectra of a pectin Ill/testosterone propionate complex (on the top centre) compared with the starting materials testosterone propionate (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 22: NIR spectra of a sec.dibutylamide of pectan IV/cholestenone complex (on the top centre) compared with the starting materials cholestenone (completely at the top) and sec.dibutylamide of pectan IV (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 23: Raman spectra of a pectin I/cholesterol complex (on the top centre) compared with the starting materials cholesterol (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 24: Raman spectra of a pectin I/cholestenone complex (on the top centre) compared with the starting materials cholestenone (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 25: Raman spectra of a pectin I/cholic acid complex (on the top centre) compared with the starting materials cholic acid (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 26: Raman spectra of a pectin I/dehydrocholic acid complex (on the top centre) compared with the starting materials dehydrocholic acid (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 27: Raman spectra of a pectin I/pregnenolone acetate complex (on the top centre) compared with the starting materials pregnenolone acetate (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 28: Raman spectra of a pectin I/androstan-3,17-dione complex (on the top centre) compared with the starting materials androstan-3,17-dione (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 29: Raman spectra of a pectin I/testosterone propionate complex (on the top centre) compared with the starting materials testosterone propionate (completely at the top) and potassium salt of pectin I (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 30: Raman spectra of a pectin II/cholesterol complex (on the top centre) compared with the starting materials cholesterol (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 31 : Raman spectra of a pectin II/cholestenone complex (on the top centre) compared with the starting materials cholestenone (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 32: Raman spectra of a pectin Il/cholic acid complex (on the top centre) compared with the starting materials cholic acid (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 33: Raman spectra of a pectin Il/dehydrocholic acid complex (on the top centre) compared with the starting materials dehydrocholic acid (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 34: Raman spectra of a pectin II/pregnenolone acetate complex (on the top centre) compared with the starting materials pregnenolone acetate (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom). Fig. 35: Raman spectra of a pectin II/androstan-3,17-dione complex (on the top centre) compared with the starting materials androstan-3,17-dione (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 36: Raman spectra of a pectin II/testosterone propionate complex (on the top centre) compared with the starting materials testosterone propionate (completely at the top) and potassium salt of pectin II (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 37: Raman spectra of a pectin Ill/cholesterol complex (on the top centre) compared with the starting materials cholesterol (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 38: Raman spectra of a pectin Ill/cholestenone complex (on the top centre) compared with the starting materials cholestenone (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 39: Raman spectra of a pectin Ill/cholic acid complex (on the top centre) compared with the starting materials cholic acid (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 40: Raman spectra of a pectin Ill/dehydrocholic acid complex (on the top centre) compared with the starting materials dehydrocholic acid (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 41 : Raman spectra of a pectin Ill/pregnenolone acetate complex (on the top centre) compared with the starting materials pregnenolone acetate (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 42: Raman spectra of a pectin III/androstan-3,17-dione complex (on the top centre) compared with the starting materials androstan-3,17-dione (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Fig. 43: Raman spectra of a pectin Ill/testosterone propionate complex (on the top centre) compared with the starting materials testosterone propionate (completely at the top) and benzyl pectinate III (on the bottom centre) and the subtraction result of the complex and the starting pectin (completely at the bottom).

Working Examples: Example 1

An aqueous solution of potassium pectinan, DE 64% by weight, D-galacturonan 87% by weight, (50 mg in 10 ml of water) and an ethanolic solution of cholesterol (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized by means of near infrared spectrometry (NIR) and Raman spectrometry.

Example 2

An aqueous solution of potassium pectinan, DE 64% by weight, D-galacturonan 87% by weight, (50 mg in 10 ml of water) and an ethanolic solution of 4-cholesten-3-one (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized.

Example 3

An aqueous solution of potassium pectinan, DE 64% by weight, D-galacturonan 87% by weight, (50 mg in 10 ml of water) and an ethanolic solution of cholic acid (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized.

Example 4

An aqueous solution of potassium pectinan, DE 64% by weight, D-galacturonan 87% by weight, (50 mg in 10 ml of water) and an ethanolic solution of dehydrocholic acid (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized. Example 5

An aqueous solution of potassium pectinan, DE 64% by weight, D-galacturonan 87% by weight, (50 mg in 10 ml of water) and an ethanolic solution of pregnenolone acetate (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized.

Example 6

An aqueous solution of potassium pectinan, DE 64% by weight, D-galacturonan 87% by weight, (50 mg in 10 ml of water) and an ethanolic solution of androstan-3,17-dione (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized.

Example 7

An aqueous solution of potassium pectinan, DE 64% by weight, D-galacturonan 87% by weight, (50 mg in 10 ml of water) and an ethanolic solution of testosterone propionate (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized.

Example 8

An aqueous solution of potassium pectinan, DE 26%» by weight, D-galacturonan 85% by weight, (50 mg in 10 ml of water) and an ethanolic solution of cholesterol (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized by means of near infrared spectrometry (NIR) and Raman spectrometry.

Example 9

An aqueous solution of potassium pectinan, DE 26% by weight, D-galacturonan 85% by weight, (50 mg in 10 ml of water) and an ethanolic solution of 4-cholesten-3-one (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized.

Example 10

An aqueous solution of potassium pectinan, DE 26%> by weight, D-galacturonan $5% by weight, (50 mg in 10 ml of water) and an ethanolic solution of cholic acid (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized. Example 11

An aqueous solution of potassium pectinan, DE 26% by weight, D-galacturonan 85% by weight, (50 mg in 10 ml of water) and a ethanolic solution of dehydrocholic acid (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized.

Example 12

An aqueous solution of potassium pectinan, DE 26% by weight, D-galacturonan 85%) by weight, (50 mg in 10 ml of water) and an ethanolic solution of pregnenolone acetate (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized.

Example 13

An aqueous solution of potassium pectinan, DE 26% by weight, D-galacturonan 85% by weight, (50 mg in 10 ml of water) and an ethanolic solution of androstan-3,17-dione (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized.

Example 14

An aqueous solution of potassium pectinan, DE 26% by weight, D-galacturonan 85% by weight, (50 mg in 10 ml of water) and an ethanolic solution of testosterone propionate (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized.

Example 15

An aqueous solution of pectan benzylester, DE 7% by weight, D-galacturonan 85% by weight, (50 mg in 10 ml of water) and an ethanolic solution of cholesterol (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized by means of near infrared spectrometry (NIR) and Raman spectrometry.

Example 16

An aqueous solution of pectan benzylester, DE 7% by weight, D-galacturonan 85% by weight, (50 mg in 10 ml of water) and an ethanolic solution of 4-cholesten-3-one (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized. Example 17

An aqueous solution of pectan benzylester, DE 7% by weight, D-galacturonan 85% by weight, (50 mg in 10 ml of water) and an ethanolic solution of cholic acid (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized.

Example 18

An aqueous solution of pectan benzylester, DE 7% by weight, D-galacturonan 85% by weight, (50 mg in 10 ml of water) and an ethanolic solution of dehydrocholic acid (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized.

Example 19

An aqueous solution of pectan benzylester, DE 7% by weight, D-galacturonan 85% by weight, (50 mg in 10 ml of water) and an ethanolic solution of pregnenolone acetate (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized.

Example 20

An aqueous solution of pectan benzylester, DE 7% by weight, D-galacturonan 85% by weight, (50 mg in 10 ml of water) and an ethanolic solution of androstan-3,17-dione (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized.

Example 21

An aqueous solution of pectan benzylester, DE 7%, D-galacturonan 85%, (50 mg in 10 ml of water) and an ethanolic solution of testosterone propionate (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized.

Example 22

An aqueous solution of pectan dibutylamide, DE 78% by weight, DA 14% by weight, (50 mg in 10 ml of water) and an ethanolic solution of 4-cholesten-3-one (10 mg in 10 ml of ethanol) were mixed at room temperature. This mixture was stirred for 1 hour. The liquid was then evaporated and the dried product characterized. Example 23

An aqueous solution of potassium pectinan, DE 64% by weight, D-galacturonan 87% by weight, (50 mg in 10 ml of water) and a solution of 4-cholesten-3-one (10 mg) in 10 ml dichloromethane were mixed at room temperature. This mixture was stirred for 1.5 hour. The organic layer was then separated and the water layer evaporated to dryness. The dried product was characterized.

Example 24

An aqueous solution of potassium pectinan, DE 64% by weight, D-galacturonan 87% by weight, (50 mg in 10 ml of water) and a solution of pregnenolone acetate (10 mg) in 10 ml dichloromethane were mixed at room temperature. This mixture was stirred for 1.5 hour. The organic layer was then separated and the water layer evaporated to dryness. The dried product was characterized.

Example 25

An aqueous solution of potassium pectinan, DE 26% by weight, D-galacturonan 85% by weight, (50 mg in 10 ml of water) and a solution of 4-cholesten-3-one (10 mg) in 10 ml dichloromethane were mixed at room temperature. This mixture was stirred for 1.5 hour. The organic layer was then separated and the water layer evaporated to dryness. The dried product was characterized.

Example 26

An aqueous solution of potassium pectinan, DE 26% by weight, D-galacturonan 85% by weight, (50 mg in 10 ml of water) and a solution of pregnenolone acetate (10 mg) in 10 ml dichloromethane were mixed at room temperature. This mixture was stirred for 1.5 hour. The organic layer was then separated and the water layer evaporated to dryness. The dried product was characterized. Example 27

An aqueous solution of pectan benzylester, DE 7% by weight, D-galacturonan 85% by weight, (50 mg in 10 ml of water) and a solution of 4-cholesten-3-one (10 mg) in 10 ml dichloromethane were mixed at room temperature. This mixture was stirred for 1.5 hour. The organic layer was then separated and the water layer evaporated to dryness. The dried product was characterized. Example 28

An aqueous solution of pectan benzylester, DE 7% by weight, D-galacturonan 85% by weight, (50 mg in 10 ml of water) and solution of pregnenolone acetate (10 mg) in 10 ml dichloromethane were mixed at room temperature. This mixture was stirred for 1.5 hour. The organic layer was then separated and the water layer evaporated to dryness. The dried product was characterized.

Example 29

An aqueous solution of pectan benzylester, DE 7% by weight, D-galacturonan 85% by weight, (50 mg in 10 ml of water) and solution of cholesterol (10 mg) in 10 ml dichloromethane were mixed at room temperature. This mixture was stirred for 1.5 hour. The organic layer was then separated and the water layer evaporated to dryness. The dried product was characterized.

Claims

1. A water-soluble complex of a steroidal pharmaceutically active substance (API) with pectin.

2. The complex according to claim 1, characterized in that the pectin is polygalacturonic acid or a derivative of said acid.

3. The complex according to claim 2, characterized in that polygalacturonic acid is selected from the group consisting of the free acid, an at least partially esterified acid, and an acid which is at least partially derivatized to an amide.

4. The complex according to claims 2 or 3, characterized in that polygalacturonic acid is in the form of the methylester or acetamide.

5. The complex according to claims 1-4, characterized in that the active substance is in the form of an adduct with a pectin consisting of galacturonic acid units, wherein the proportion of units of said acid in the pectin is at least 65% by weight, preferably more than 80% by weight.

6. The complex according to claims 1-5, characterized in that the active substance is selected from the group consisting of cholesterol, 4-cholesten-3-one, cholic acid, dehydrocholic acid, pregnenolone acetate, 5-pregnan-3p-ol-20-one acetate, androstan- 3,17-dione, and testosterone propionate.

7. The complex according to claims 1-5, characterized in that said pectin is a polymer composed of saccharide units, the basic structure of which is a chain of poly-a-(l→4)- D-galacturonic acid alternating with a-(l→2)-L-rhamnosyl-a-(l→4)-D-galacturonosyl sections; the basic chain being optionally branched and the side chain optionally containing residues of the neutral saccharides pentoses and hexoses; and the carboxyl group being optionally esterified by Cj-Cn aliphatic alcohols, or monoalkyl- or dialkyl-amidated with Ci-C₆ alkyls.

8. The complex according to claim 3, characterized in that modification of said pectin, i.e., modification of the carboxylate to respective esters, is lower than 15%.

9. The complex according to claim 8, characterized in that esters are formed with at least one compound selected from the group consisting of CI -CJO alcohols, benzylalcohol and cholesterol.

10. The complex according to claims 1-5, characterized in that the molecular weight of the pectin derivatives is in the range of 150-120 kD.

1 1. The complex according to claims 1-5, characterized in that the average molecular weight is higher than 1 ^χ 10⁵ Dalton.

12. The complex according to claims 1-5, characterized in that solubility of the pectin derivatives used is from 0.1 to 20% by weight in water of pH ranging from 5 to 10.

13. The complex according to claims 3 or 4, characterized in that said amide derivatives of said pectins are the respective amides prepared by aminolysis of said esters, wherein the amide is derived from primary and secondary amines with 1 - 10 carbon atoms.

14. A pharmaceutical composition, characterized in that it contains the complex of any one of the preceding claims and at least one pharmaceutically acceptable excipient.

15. A method of manufacturing the pharmaceutical composition defined in claim 14, characterized in that the active substance dissolved in a water-miscible organic solvent is mixed with an aqueous solution of the pectin; the solvent is then removed and the solid residue is used for preparing said pharmaceutical composition.

16. A method of manufacturing the pharmaceutical composition defined in claim 14, characterized in that the active substance dissolved in a water-immiscible organic solvent is mixed with an aqueous solution of the pectin, the organic phase is separated, the aqueous layer is then dried and the solid residue is used for preparing said pharmaceutical composition.

17. The method according to any of claims 15 or 16, characterized in that the organic solvent used is selected form the group consisting of ethanol, methanol, acetone toluene, dichloromethane, chloroform, esters of acetic acid with C₂-C₅ alcohols, or C₄- C₆ alcohols.

18. Use of the pharmaceutical composition defined in claim 14 for the manufacture of a medicament for controlled release and/or targeted delivery.

19. Use according to claim 18 for a dosage form intended for oral application and containing 1 to 30% by weight of the active substance.

20. Use according to claim 18 for a dosage form intended for depot intramuscular application and containing 5 to 50% by weight of API.

21. Use according to claim 18 for liquid dosage forms containing 1 to 20% by weight of API.

22. Use according to claim 18 for topical dosage forms containing 1 - 30% by weight of API.

23. Use according to claim 18 for preparing self-emulsifying systems (SEDDS) containing steroid hormones or their synthetic derivatives.

24. Use according to claim 18 for preparing self-emulsifying systems (SEDDS) containing steroid hormones or their synthetic derivatives in combination with organic solvents and/or oils.

25. Use according to claim 18 for preparing self-emulsifying systems (SEDDS) containing steroid hormones or their synthetic derivatives in combination with mono- and diacylglycerols.

26. Use according to claim 18 for targeted transport of drugs into the intestine.