IE913649A1

IE913649A1 - Galactomannan derivatives for coating or embedding¹medicinally active substances

Info

Publication number: IE913649A1
Application number: IE364991A
Authority: IE
Original assignee: Asta Medica Ag
Priority date: 1990-10-18
Filing date: 1991-10-17
Publication date: 1992-04-22
Also published as: CS315091A3; HUT58263A; EP0481240B1; PT99254A; IL99760A0; FI914909L; ATE146191T1; DE4131292A1; KR920008060A; DE59108407D1; ZA918292B; ES2095894T3; AU636800B2; JP3020684B2; CA2053569A1; NO914077L; EP0481240A3; HU913245D0; JPH04264102A; BR9104502A

Abstract

Galactomannans whose hydroxyl groups are completely or partially in the form of low molecular weight aliphatic, araliphatic and/or aromatic ether or ester groups, and 20 to 80% of the mannose units present in the galactomannan chain form continuous mannose blocks of 2 to 20 mannose units which are not substituted by galactose groups, for encasings and/or embeddings of solid and/or liquid active substances, which release these active substances only in the colon or in the presence of glycolytic enzymes, process for the preparation thereof and pharmaceutical compositions prepared using such galactomannans are described.

Description

ASTA-Pharma Aktiengesellschaft, a Company organised under the laws of Germany, of Weismullerstrasse 45, D-6000 Frankfurt am Main 1, Germany. te 9i8649 Galactomannan derivatives for coating or embedding medicinally active substances The preparation of hydrophilic polymers, for example hydroxypropyl methylcellulose or carboxymethyl galactomannans for the production of non-medicinal formulations containing antimicrobial active substances is known (EP-A-0,285,209). Hydroxyalkyl ethers of polygalactomannans are moreover known as stabilizers for carbon-water mixtures (EP-A-0,209,122) as well as for the clarification of water (US patent No. 3,830,736). US patent No. 3,740,388 relates to a process for the preparation of carboxylalkyl ethers of polygalactomannans, it being possible to use reaction products of this kind in the form of complex compounds with calcium as a thickening agent.

A number of galactomannan esters as well as galactomannan ethers are also described in the literature. These galactomannan ethers are, however, obtained using a very laborious process. What is more, the average degree of substitution of these known products lies between 0.1 and 1.6, that is, it is considerably lower than the degree of substitution of the compound of the invention (see Bartl, H., Falbe, J., Houben-Weyl Methoden der organischen Chemie, Volume E 20/3, Thieme, Stuttgart, 1987; Carson, J.F., Maclay, W.D., J. Am. Chem. Soc., 70, 1948, 293; Heyne, E. , Whistler, R.L., J. Am. Chem. Soc., 70, 1948, 2249).

Whilst the reference J. Am. Chem. Soc., 70, 1948, 2249 as well as the reference Swanson, J.W., J. Am. Chem. Soc., 71, 1949, 1511 refer to methyl galactomannans with a higher degree of substitution, the mannans prepared in this manner have a lower molecular weight than those of the invention, i.e. although they are methyl galactomannans, they have a substantially lower molecular weight than the galactomannan derivatives of the invention. - 2 The present invention therefore relates to new galactomannans, the hydroxygroups of which are wholly or partially present in the form of low molecular weight aliphatic, araliphatic and/or aromatic ether or ester groups and in which 20 to 80%, preferably 30 to 80% or 30 to 70%, in particular 40 to 60% or also 45 to 55% of the mannose units present in the galactomannan chain form connected mannose blocks of 2 to 20, preferably 5 to 20 mannose units, which are not substituted by galactose groups, for coating and/or embedding solid and/or liquid active substances which only release these active substances in the colon or in the presence of glycolytic enzymes.

These galactomannans are preferably those, the ether groups of which consist of C^-Cg-alkoxy groups (in particular C2-C4-alkoxy groups), phenyl-C1-C4-alkoxy groups or phenoxy groups and where the ester groups consist of C3-C22_alkanoyloxy groups, preferably C3-C16-alkanoyloxy groups. The molecular weight of the galactomannans of the invention lie between 104 and 108 in particular 105 and 106 g.

In statistical terms, the mannose/galactose ratio of the basic galactomannan chain lies for example between 2 : 1 and 20 : 1, preferably between 4 : 1 to 10 : 1. On average the free hydroxy groups of the basic galactomannan in this case are 80 to 100% etherified and/or esterified.

The straight basic chain of the galactomannans of the invention consist of mannopyranose units in 1.4-linkage. The galactose molecules are glycosidically linked to this chain via the CH2-OH groups of the mannose links.

The new galactomannan derivatives of the invention can for example be used to coat or embed medicinally active substances or also to prepare foils.

The galactomannan derivatives of the invention are new. It was surprisingly found that these galactomannan derivatives of the invention only release active substances embedded herein or coated by galactomannan derivatives of this kind in the colon or only in the presence of glycolytic enzymes, but not for example - 3 in the medium of the gastric juice or in the medium of the small intestine.

The galactomannan derivatives of the invention are thus particularly suitable for the preparation of medicinal formulations where the active substances have to be or need to be protected from the influences of gastric juice and small intestine juice and these active substances are only supposed to be released in the colon. Hitherto, it has generally been necessary to administer the corresponding active substances parenterally.

This object is not, or only inadequately, fulfilled by hitherto known medicinal forms for the release of active substances in the colon, in which the medicinal substances or medicinal substance cores are coated with polymers or embedded in polymers. The film coatings or embedding materials used herefor consist of conventional film formers which are modified by cross linkage with azo groups (Saffran et al., U.S. Pat. 4,663,308) or of mixtures thereof (Rubinstein et al., J. Pharm. 30, 95 to 99 (1986)).

The working group around Saffran polymerized methacrylates with various monomers such as styrol and an azo component capable of polymerization, for example divinylazobenzene. This was intended to produce cross linked polymers. Degradation of these polymers in the colon could not be shown, even after 8 days. Degradation within minutes or a few hours is, however, required for the proposed purpose of application. Moreover, primary aromatic amines as possible degradation products constitute a possible toxicological problem.

The working group around Rubinstein used mixtures of various polymethacrylates, in which the resulting film coatings change their permeability or solubility depending on the pH value.

Active substances coated with these coatings or embedded in these polymers can only be released in a diffusion-controlled manner.

Diffusion-controlled release is, however, too slow since the time of release and absorption in the colon is limited. In addition, the commencement of release is unfortunately also dependent on a rise in the pH value of the intestinal contents. However, the pH value in the section of the intestine in question is already substantially constant. This means that the time at which release begins depends on the speed of transport of the intestinal contents. Film coatings of this kind therefore already begin to swell in the proximal or distal ileum and then release the active substance in the Colon ascendens through the film coating swollen to its maximum extent. A medicinal form of this kind leads at best to low and non-reproducible bioavailability.

It is also extremely surprising that, it is possible in accordance with the invention, to synthesize higher substituted, film-forming galactomannans in one synthesis step which, on the one hand, pass unscathed through the gastrointestinal tract and, on the other hand, are quickly degraded in the colon. This was also unexpected since the working group around Isogai had shown that etherified polysaccharides with saturated aliphatic substituents could only be obtained up to an average degree of substitution of 2.5 (Isogai, A., J. Appl. Polym. Sci. 29., 3873 - 3882 (1984)). The film coatings made from higher substituted ethylgalactomannans of the invention are, on the one hand, able to survive the gastrointestinal tract unscathed. On the other hand they are rapidly degraded in the colon. This was particularly surprising because other working groups, for example Wrick M.G., J. Polym. SCI. A-l, 6, 1965 (1968) refuted the enyzymatic degradability of derivatized polysaccharides.

Hitherto known lower substituted galactomannans have solubility, swelling and degradability properties which the galactomannans of the invention do not have, especially in the colon.

In contrast, if the galactomannans of the invention are used to coat or embed medicinally active substances, the medicinally active substances reach the colon without loss of efficacy and are only released there.

The invention also relates to a method for the preparation of the new galactomannan derivatives in accordance with the claims.

The preparation of the galactomannan ethers of the invention is carried out by reacting known, naturally occurring galactomannans or synthetically prepared galactomannans with molecular weights between 104 and 108 g in an inert solvent (for example dimethylacetamide, dimethylformamide, dimethyl sulphoxide) with Cj-Cg-alkyl halides (for example C2-C4-alkyl halides), to phenyl-C1-C4-alkyl halides or phenyl halides at temperatures between 20 and 35°C, optionally in the presence of alkali. The halides may preferably be the bromides. It is, however, also possible to use the chlorides or iodides. Alkali is preferably added in the form of alkalihydroxides, in particular NaOH.

The addition of alkali depends on the size of the batch. For example in the case of a batch of 2.8 g to 3.2 g of galactomannan, 110 g to 130 g alkali are used (for example in the form of NaOH).

Less alkali is needed for larger batches (for example 15% less), for smaller batches, more alkali is needed (for example 5% to 10% more).

It is also possible to obtain mixed ethers with the above described process, i.e. ethers which contain alkyl radicals as well as phenylalkyl radicals or phenyl radicals in the same molecule, by using mixtures of the corresponding halide starting substances as reaction components.

The esters of the invention must be prepared under anhydrous conditions. The solvents that may be used are: dimethylformamide, dimethylacetamide, dimethyl sulphoxide.

Esterification can also be carried out without solvents in the melt. In this case, the polymer solvent can be the acylating reagent or the reaction partner, for example alkaloyl halide or alkaloyl anhydride.

The esterification reaction occurs for example at temperatures between 70 and 160°C, or at the boiling point of the solvent, through reaction of the corresponding galactomannans with molecular weights between 104 and 108 g, with C3-C22-alkanoyl halides, preferably C3-C16-alkanoyl halides or C3-C22-alkanoyl anhydrides, preferably C3-C16-alkanoyl anhydrides.

This acylation is expediently conducted in the presence of basic compounds, such as pyridine.

The basic substances should be present in excess in relation to the starting alkanoyl compound, for example in excess of 0.1 to 0.2 per Mol of the alkanoyl starting component.

The starting galactomannans used are for example naturally occurring galactomannans, for example galactomannans of guar seed flour, tara seed flour, locust bean gum.

The mannose-galactose ratio varies, depending on the plant of origin, from 1 : 1 to about 7 : 1. In general it is between 2 : 1 and 4 : 1 or also 2 : 1 to 3 : 1. It is, however, also possible to adjust the mannose-galactose ratio of these starting galactomannans at a higher level by treating the polysaccharide with alpha-galactosidase in the conventional manner (see for example McCleary, B.V. , Carbohyd. Res., 92., 269, (1981).

In addition to the mannose-galactose ratio it is also possible to use the viscosity of an aqueous solution of the polysaccharide to characterize the starting galactomannans. The viscosity depends on the molecular weight and hence also on the degree of milling of the galactomannan-containing seeds. The molecular weight of the galactomannans can be between 104 and 108 g depending on origin and method of measurement. By means of milling it is possible to reduce the molecular weight of the polysaccharides and to adjust to a desired range.

The desired molecular weight range is preferably 105 to 106.

In addition to the polysaccharide, commercially available galactomannan-containing flours also contain about 5% of low molecular weight sugar, 1% oily components, 3% cellulose and 5% proteins. The galactomannan therefore has to be separated from their accompanying substances. It is also necessary to purify accompanying substances, such as proteins and lipids, as well as to subsequently precipitate the galactomannans with subsequent swelling of the polymers, as for example described in Example 1. The purification method described in Example 1 is generally applicable, it only being necessary to adjust the centrifugal force during centrifuging. For example, if high molecular weight or mannose-richer galactomannans are present, it is necessary to centrifuge at a correspondingly lower speed in order to also keep mannose-richer molecules in solution. The purified galactomannans are tested for nitrogen content. No nitrogen may be determinable in a protein-free polysaccharide after purification.

The galactomannan derivatives of the invention preferably have no more free hydroxyl groups or only a few free hydroxyl groups, that is they preferably have a statistical degree of substitution of 3. On average 80 to 100 % of the free hydroxy groups available are etherified and/or esterified, preferably 90 to 100%.

The invention relates in particular to the use of the galactomannan derivatives of the invention to prepare film coatings and embedding materials of pharmaceutical active substances, in particular of orally applicable active substances or orally applicable medicinal formulations with release of active substance in the colon. It is achieved in that the active substances or formulations with active substances, for example, granulates, pellets or tablets, are coated with or embedded in the galactomannan derivatives of the invention.

The coating of the active substances or of the pharmaceutical formulations, i.e. the formulations in which the active substances are worked together with conventional or necessary pharmaceutical auxiliary substances, is carried out according to methods known in pharmaceutical technology or the conventional methods for coating medicinal forms. The embedding of therapeutic active substances is also conducted according to methods known in pharmaceutical technology. In so doing the galactomannan derivatives of the invention are used instead of hitherto conventional plastic or meltable embedding materials, for example waxes, hydrated caster oil, plastics such as cellulose ethers or esters, poly(meth)acrylic acid esters. In addition it is also possible to use conventional pharmaceutical auxiliary substances and additives such as softeners (especially in the case of coatings), flavouring agents, sweeteners, auxiliary substances such as talcum, calcium carbonate, mannitol, cellulose powder, soluble colourants and pigments.

If used, the auxiliary substances are for example added to the coating mixture in amounts of 10 to 100 % by weight, preferably from 2 0 to 40 % by weight, related to the weight of the galactomannans used.

The flavouring agents, sweeteners and colourants are added to the mixtures in small amounts, for example of 0.001% to 2%.

Further information on conventional auxiliary substances and additives are given in the technical literature, for example in the monograph by J.H. Saunders and K.C. Frisch High Polymers, published by Interscience Publishers 1962 and 1964.

Information on the coating of medicinally active substances or medicinal formulations with the galactomannan derivatives of the invention.

Here it is for example also possible to use conventional softeners (e.g. dibutylsebacate, citric and tartaric acid esters, glycerol and glycerol esters, phthalic acid esters and similar substances). It is also possible to add water soluble substances such as polyethylene glycols, polyvinyl pyrrolidone, copolymerisates of polyvinyl pyrrolidone and polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose. Solids such as talcum and/or magnesium stearate can also be added to the coating or to the tablet mixtures.

Coating is effected by spraying solutions in organic solvents or suspensions or dispersions of the stated substances in organic solvents or water, it also being possible to add additional auxiliary substances to optimize their processing characteristics, such as surface-active substances, pigments. The spraying is carried out for example in a coating drum or in perforated drums or in an air suspension or fluidized air bed process (for example Glatt fluidized air bed equipment WLSD5). The coating can also be carried out in the coacervation process during which so-called microcapsules or microparticles are formed.

Coating can also be carried out by coagulation of aqueous dispersions or suspensions of the previously mentioned substances by mixing the active substance with the dispersion and removing the water by drying.

Coated active substance particles and coated granulates can be pressed into tablets; coated pellets can be filled into hard gelatine capsules.

During coating of active substance particles or granulates which contain the particles of active substance more coating material is generally used than in pellets or tablets since the surface which has to be covered is substantially larger than in the case of pellets or tablets.

Since tablets are generally larger than pellets, the surface to be covered is correspondingly smaller in the case of tablets.

It is possible to use 0.02 to 0.5 parts by weight of galactomannan derivative as coating material to 1 part by weight of active substance or medicinal formulation. A weight ratio of one part active substance and 0.04 to 0.3 parts by weight of coating material is preferred, 0.05 to 0.2 parts by weight of coating material to 1 part by weight of active substance is particularly preferred. Application of the coating material in solution, suspension or dispersion occurs at elevated temperature, preferably in a stream of air.

The temperature of the added air is for example 70 to 90°C; the temperature of the exhaust air is for example up to 40°C.

Embedding the active substances or binding to the galactomannan derivatives of the invention.

In this case 1 part by weight of active substance is used with for example 0.05 to 5.0 parts by weight of galactomannan derivative, preferably 0.08 to 3.0 parts by weight, 0.1 to 2.0 parts by weight being particularly preferred. The preparation of these formulations occurs at temperatures between 10°C and 100°C.

The preparation of these forms of administration can for example be effected: a) by dissolving or dispersing the active substances or their salts in the galactomannan derivatives of the invention or mixtures thereof also with melting of the cited substances and subsequent cooling, crushing, optionally adding other substances such as water soluble substances or substances that swell in water and pressing into tablets. The cooling of the melts and crushing can also be combined in one step by dispersing the melts in cold water or subjecting them to spray hardening.

Swelling substances that may for example be used are: methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (Pharmacoat, Methocel E (cellulose mixed ethers with propoxy and methoxy substituents), alginic acid and its salts (Na salt, Ca salt, also mixtures of sodium alginate and calcium salts for example CaHPO4), starches, carboxymethyl starches, carboxymethyl celluloses and their salts (for example Na salt), gum arabic, karaya gum, ghatti gum, agar-agar, carragheen, xanthan gum, propyleneglycol alginate, pectin, tragacanth. b) by mixing the active substances with the galactomannan derivatives of the invention and optionally swelling substances or mixtures of these substances, also with use of heat and for example pressing the mixtures, optionally after adding further auxiliary substances, into tablets or forming pellets or granulates. c) by mixing the active substances with solutions of the galactomannan derivatives of the invention in organic solvents such as for example ethanol, ethyl acetate, acetone or isopropanol, possibly mixing with carrier materials such as celluloses, as well as subsequent evaporation of the solvents and mixing the embedded active substances with additional auxiliary substances and processing into shaped bodies, such as tablets, granulates or pellets. d) by moistening a mixture of the active substances and of the galactomannans of the invention and optionally the swelling substances mentioned with organic solvents such as ethanol, ethyl acetate, acetone or isopropanol, possibly with addition of binding agents such as polyvinyl pyrrolidone or copolymers of polyvinyl pyrrolidone and polyvinyl acetate, granulating the mixture obtained, subsequent drying, optional addition of additional auxiliary substances and for example pressing the mixture into tablets. e) by mixing the active substances with a solution of the galactomannan derivatives of the invention in polyethylene glycol of molecular weight 200 to 1500, optionally with addition of other auxiliary substances such as stearates or swelling agents and for example encapsulating the mass obtained into soft or hard gelatine capsules.

Quite generally, the preparation of these medicinal formulations is carried out in manner known per se, it also being possible to use the known and conventional pharmaceutical auxiliary substances as well as other conventional carrier and diluting agents in addition to the galactomannan derivatives of the invention. Carrier and diluting agents of this kind which may for example be used are those which are mentioned or recommended in the following literature references as auxiliary substances for pharmacy, cosmetics and related fields: Ullmanns Encyklopadie der technischen Chemie, Volume 4 (1953), page 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 et seq. H.V.Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie und angrenzende Gebiete; Pharm. Ind., Issue 2, 1961, page 72 et seq.; Dr. H.P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, 2nd edition, Editio Cantor, Aulendorf in Wurttemberg 1981.

Examples of conventional auxiliary substances, carrier substances and diluting agents are gelatines, natural sugars such as raw sugar or lactose, lecithin, pectin, starches (e.g. corn starch) as well as starch derivatives, cyclodextrins and cyclodextrin derivatives, polyvinyl pyrrolidone, gelatines, gum arabic, alginic acid, tylose, talcum, silicic acid (for example colloidal) or highly disperse SiO2, levulose, tragacanth, sodium chloride, stearates, magnesium and calcium salts of fatty acids with 12 to 22 carbon atoms, in particular saturated (for example stearates), polyethylene glycol with a mean molecular weight between 200 and 20,000, preferably between 200 and 5,000, in particular between 200 and 1,000, or their mixtures and/or polymerisates of vinyl pyrrolidone and/or mixed polymerisates of vinyl pyrrolidone and vinyl acetate, esters of aliphatic saturated or unsaturated fatty acids (2 to 22 carbon atoms, in particular 10 to 18 carbon atoms) with monovalent aliphatic alcohols (1 to 20 carbon atoms) or multivalent alcohols such as glycols, glycerol, diethylene glycol, pentaerythritol, sorbitol, mannitol, etc. which may optionally also be etherified, benzylbenzoate, dioxolanes, glycerin formals, tetrahydrofurfuryl alcohol, polyglycol ethers with to C12 alcohols, dimethyl acetamide, lactamides, lactates, ethyl carbonates, silicones (in particular medium-viscous polydimethyl siloxanes), calcium carbonate, sodium carbonate, calcium phosphate, sodium phosphate, magnesium carbonate, gum arabic, alginic acid, stearates, fats and similarly acting substances.

In addition, the forms of administration can also contain substances active at the interface. Examples of these are: alkali soaps such as alkali salts of higher fatty acids (for example Na palmitate, Na stearate) or their derivatives (for example Na ricinolacetate sulfate esters); sulfurated compounds or sulfonated compounds formed by reacting higher fatty alcohols with sulphuric acid or chlorosulfonic acid and used for example as sodium salts (for example sodium lauryl sulphate, sodium cetyl sulphate, sodium stearyl sulphate, sodium cetyl sulphonate); salts of the gallic acids, saponines; guaternary ammonium compounds; partial fatty acid esters of sorbitane; partial fatty acid esters and fatty acid esters of polyoxyethylene sorbitane; sorbitol ethers of polyoxyethylene; fatty acid esters of polyoxyethylene; fatty alcohol ethers of polyoxyethylene; fatty acid esters of saccharose; fatty acid esters of polyglycerol; proteins, lecithins.

The forms of administration may also contain celluloses, in particular if coprimates are to be produced. Those which may be considered are: purified cellulose (sold for example as ElcemaR) or microcrystalline cellulose as sold for example under the trade mark AvicelR. It is, however, also possible to use other filling agents such as calcium hydrogen phosphate, lactose, starches (for example potato starch, corn starch), glucose, mannitol and saccharose as well as filling agents with a binding agent function such as microcrystalline cellulose, hydrolysed or IE 913θ49 partially degraded starches and microcrystallizates of cellulose powder and lactose.

In addition the forms of administration may contain sedimentation retardants such as highly disperse silicic acids which have a surface of 50 to 500 m2/g, in particular 100 to 400 m2/g (determined using the BET method). These are for example commercially available under the trade mark AerosilR.

It may also be appropriate to use mould lubricants in the form of administration. Those that can be cited are: talcum or siliconized talcum, calcium and magnesium stearate, stearic acid, paraffin, hydrated fats and oils, silicone oil emulsion.

Other auxiliary substances which may be considered are substances which encourage disintegration (so-called disintegrants), such as : cross-linked polyvinyl pyrrolidone, sodiumcarboxymethyl starch, sodiumcarboxymethyl cellulose, formaldehyde gelatine, formaldehyde casein, polyacrylic acid, ultraamylopectin.

It is also possible to add stabilizers, colourants, antioxidants and complex formers (for example ethylene diamine tetraacetic acid) and the like as well as to add acids such as citric acid, tartaric acid, maleic acid, fumaric acid.

Antioxidants that may for example be used are sodium metabisulphite, cysteine, ascorbic acids and their esters (for example -palmitate), flavonoids, gallic acid alkyl ester, butylhydroxyanisol, nordihydroguaiaretic acid, tocopherols as well as tocopherols + synergists (substances that bind heavy metals through complex formation, for example lecithin, ascorbic acid, citric acid, phosphoric acid).

Preservatives that may for example be used are sorbic acid, - 15 p-hydroxybenzoic acid esters (for example low alkyl esters), benzoic acid, sodium benzoate, trichloroisobutyl alcohol, phenol, creosol, benzethonium chloride and formalin derivatives.

Plasticizing agents for the galactomannan derivatives of the invention that may be considered are: citric and tartaric acid esters (acetyltriethyl-, acetyltributyl-, tributyl-, triethyl-citrate); glycerol and glycerol esters (glycerol diacetate, -triacetate, acetylated monoglycerides, caster oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl-, D-(2-methoxy- or ethoxyethyl)-phthalate, ethylphthalyl- and butylphthalylethyland butylglycolate); alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyl-, di(2-methoxy- or ethoxyethyl adipate); benzophenone; diethyl- and dibutylsebacate, -succinate, -tartrate; diethyleneglycol dipropionate; ethyleneglycol diacetate, -dibutyrate, -dipropionate; tributyl phosphate, tributyrin; polyethyleneglycol sorbitane monooleate; sorbitane monooleate.

To apply the galactomannan derivatives of the invention it is possible to use solvents from the group of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic carbons, halogenated solvents, cycloaliphatic, heterocyclic solvents and mixtures thereof. Typical solvents are, inter alia, acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methylisobutyl ketone, methylpropy1 ketone, n-hexane, n-heptane, ethylglycol monoethyl ether, ethyleneglycol monoethylacetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclo octane, benzene, toluene, naphtha, 1,4-dioxan, tetrahydrofuran, diethylene glycol dimethyl ether, water and mixtures thereof, such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol and ethylene dichloride and methanol as well as mixtures IE 91364® thereof. These solvents are removed again during the coating process.

Active substances that can advantageously be formulated with the galactomannan derivatives of the invention are for example in particular medicinally active substances which are digested in the small intestine and can consequently not be given orally, preferably peptide medicaments. Examples are: peptides, cardiovascular remedies, antirheumatic/analgesic agents, agents for treating diseases of the colon (Morbus Chron, Colitis ulcerosa), antiasthmatic agents, antifibrolytic agents, antihaemorrhagic agents, antitumour agents, enzyme preparations, antibiotics, antimycotics, substances acting on the CNS (central nervous system).

Examples of peptide active substances are in particular ACTH (adrenocorticotropic hormone), corticostatin, calcitonin, insulin, oxytocin, somatostatin and analogs, LHRH analogs, bombesin analogs, cholecystokinin and derivatives, endothelin and analogs, thrombin inhibitors, peptide growth factors (for example IGF, EGF, NGF) magainine (PGS peptides), gastrin analogs, bradykinin analogs, parathormon analogs, neurokinin and analogs, VIP and analogs, ANP (atrial natriuretic peptide) and analogs, neokyotrophin and analogs, angiotensin analogs, encephalins, dynorphins, dermorphins, deltorphins, renin-inhibiting peptides, tumour growth factor peptides, MSH (melanocyte stimulating hormone) analogs, mitotoxins, tyrphostines, chromogranin A, thymopentin, TRH and analogs, substance P, tuftsin, fibronectin and peptidic immunomodulators such as cyclosporin A, FK 506, neuropeptide Y and NPK.

Medicinal forms which release the active substance in the presence of glycolytic enzymes advantageously include coated solid medicinal formulations which are coated with the galactomannan derivatives of the invention, such as coated tablets, capsules, film-coated tablets, pellets or microparticles. The medicinally active substances are released - 17 in the colon after oral administration by glycolytic degradation of the polymer.

Glycolytic enzymes that may be considered here are: mannases, mannosidases, galactosidases such as beta-D-mannase, beta-D-mannosidase, alpha-D-mannosidase, beta-D-galactanase, beta-D-galactosidase, alpha-D-galactosidase, beta-D-glucosidase and alpha-D-glucosidase, beta-D-g1ucurοnidase, alpha-L-arabinosidase, beta-D-fucosidase, beta-D-xylanase, beta-D-xylosidase, pectinase.

It is optionally also possible to add glycolytic enzymes of this kind separately to the medicinal formulations of the invention, it then being necessary to select a formulation that releases these glycolytic enzymes at the site of action. This can for example be effected in the following manner: Two-compartment formulations for insertion into the bladder or other body cavities contain the active substance, for example an antibiotic, in one compartment coated with the galactomannans of the invention whereas glycolytic enzymes are inserted into the 2nd compartment. By coating the 2nd compartment with acid- or alkali soluble films, for example of the polyacrylate type (for example eudragits), the activation of the enzymes and then the release of the active substance can be directed in dependence of the pH value of the environment in such a way that the polyacrylate film only becomes permeable for the water needed to activate the enzyme within a specific pH range.

Example 1 Galactomannan methyl ether (degree of substitution 3.0) Purified, protein-free galactomannan is used obtained from locust bean gum with degree of grinding 175. g locust bean gum (Vidogum L 175, Unipectin AG, Eschenz/Switzerland) are moistened with 70 g methanol in a 5 litre Erlenmeyer flask to produce a lump-free solution with water. The mixture is made up to 5 litres with boiled distilled water and stirred over night.

The suspension is then centrifuged at 6500 g for about 2 0 minutes. The supernatant solution is decanted off from the proteins. 2.5 litres in each case of this solution are mixed with the same volume of methanol and shaken. The pure white precipitating galactomannan is filtered off and washed out several times with methanol. The purified polymer is suspended in methanol and stored closed in a refrigerator. The polymer is filtered off from methanol and 100 g weighed into a 1 litre pear-shaped flask.

Another sample of 5 g is dried in a drying cabinet at 120°C and weighed in order to calculate the dry mass of galactomannan used in the synthesis. This should be between 2.8 g and 3.2 g.

After addition of 215 ml dimethyl sulphoxide, the suspension is gassed with nitrogen in a rotation evaporator and the methanol is rotated off at 45°C under a water jet vacuum. The polymer pulp so obtained is transferred under nitrogen gassing into a 2 litre brown glass three-necked flask with KPG stirrer * and intensive cooler (temperature 5°C).

A stirrer driven by an electric motor and introduced into the stirring vessel through a ground closure.

After 15 minutes 120 g sodium hydroxide are added with stirring. Immediately thereafter the remaining 200 ml dimethyl sulphoxide are added. This batch is stirred for one hour. The polymer pump is then mixed with 626 ml iodine methane. The temporarily generated slight heat (30°C) is not taken off. A reaction temperature of 20°C to 25°C is maintained for the remainder of the reaction time.

After 48 hours the reaction mixture is allowed to stand and the supernatant is decanted into a 1 litre brown glass pear-shaped flask.

The contents of this flask are ventilated with nitrogen in a rotation evaporator and drawn off in a water jet vacuum at 65°C until no more solvent is transferred. The remaining dimethyl sulphoxide is then drawn off in an oil rotary slide valve vacuum at 65°C over a cooling trap (liquid nitrogen).

The residue rotated off is collected and mixed with 1 to 2 litres peroxide-free diethyl ether. The suspension is added to a 2 litre three-necked flask and stirred over night under reflux at room temperature.

The ether extract is then suction filtered and the filtration residue washed out several times with diethyl ether. The accumulated filtrates are drawn off in a rotation evaporator under a water jet vacuum at 40°C until phase separation occurs and the polymer separates out in almost pure form. The remaining yellow dimethyl sulphoxide phase is decanted off from the polymer.

The polymer is pressed out on filter paper and dissolved in methanol. The concentrated, highly viscous methanol solution (ca. 100 ml) is added to 5 litres hot water (60°C) with stirring. The precipitated polymer is heated on a petri dish in a drying cabinet at 60°C until the polymer has separated from the water. - 20 The polymer is then pressed out on filter paper and dried in a drying cabinet at 120°C. After being weighed, the polymer is dissolved in chloroform and cast into petri dishes. These are left to dry at room temperature with exclusion of dust until a film is formed. Very high-tensile, resilient films are obtained that are clear and colourless.

If the synthesis is carried out on a larger scale (for example using more than 12 g galactomannan), it becomes increasingly important to remove the heat of reaction at the beginning of the reaction. It is undesirable to heat the reaction mixture over 35°C since yellow by-products would otherwise be formed. These by-products greatly discolour the ethyl galactomannan and are very difficult to remove. For this reason, in the case of larger batches, the reaction mixture should be cooled to 20°C using a water bath and stirred vigorously.

To achieve an over 80% yield the entire reaction mixture must be constantly intermixed. In the case of smaller scale syntheses a KPG stirrer at medium revolution count is sufficient. For larger batches there is, however, a risk that either the educts will be insufficiently mixed or that the suspended galactomannan filaments will wind themselves around the stirrer shaft and will not react. It is therefore necessary to use more elaborate stirrers. If only a large-paddled stirrer is used, the pitch line velocity at the stirrer paddle and the shearing force are too great. g locust bean gum (Vidogum L 175, Unipectin AG, Example 2 Galactomannan ethyl ether (degree of substitution 3.0) Purified, protein-free galactomannan is used obtained from locust bean gum with degree of grinding 175.

Eschenz/Switzerland) are moistened with 70 g methanol in a 5 litre Erlenmeyer flask to produce a lump-free solution with water. The mixture is made up to 5 litres with boiled distilled water and stirred over night.

The suspension is then centrifuged at 6500 g for about 20 minutes. The supernatant solution is decanted off from the proteins. 2.5 litres in each case of this solution are mixed with the same volume of methanol and shaken. The pure white precipitating galactomannan is filtered off and washed out several times with methanol. The purified polymer is suspended in methanol and stored closed in a refrigerator. The polymer is filtered off from methanol and 100 g weighed into a 1 litre pear-shaped flask.

Another sample of 5 g is dried in a drying cabinet at 120°C and weighed in order to calculate the dry mass of galactomannan used. This should be between 2.8 g and 3.2 g.

After addition of 215 ml dimethyl sulphoxide, the suspension is gassed with nitrogen in a rotation evaporator and the methanol is rotated off at 45°C under a water jet vacuum. The polymer pulp so obtained is transferred under nitrogen gassing with KPG stirrer * and intensive cooler (temperature 5°C).

A stirrer driven by an electric motor and introduced into the stirring vessel through a ground closure. - 22 After 15 minutes 120 g sodium hydroxide are added with stirring. Immediately thereafter the remaining 200 ml dimethyl sulphoxide are added. This batch is stirred for one hour. The polymer pump is then mixed with 745 ml bromomethane. The temporarily generated slight heat (30°C) is not taken off. A reaction temperature of 20°C to 25°C is maintained for the remainder of the reaction time.

The polymer is pressed out on filter paper and dissolved in methanol. The concentrated, highly viscous methanol solution (ca. 100 ml) is added to 5 litres hot water (60°C) with stirring. The precipitated polymer is heated on a petri dish in a drying cabinet at 60°C until the polymer has separated from the water.

IE 913649 The polymer is then pressed out on filter paper and dried in a drying cabinet at 120°C. After being weighed, the polymer is dissolved in chloroform and cast into petri dishes. These are left to dry at room temperature with exclusion of dust until a film is formed. Very high-tensile, resilient films are obtained that are clear and colourless.

To achieve an over 80% yield the entire reaction mixture must be constantly intermixed. In the case of smaller scale syntheses a KPG stirrer at medium revolution count is sufficient. For larger batches there is, however, a risk that either the educts will be insufficiently mixed or that the suspended galactomannan filaments will wind themselves around the stirrer shaft and will not react. It is therefore necessary to use more elaborate stirrers. If only a large-paddled stirrer is used, the pitch line velocity at the stirrer paddle and the shearing force are too great.

Example 3 Acetylgalactomannan ethyl ether (mixed substitution) Purified, protein-free galactomannan is used obtained from locust bean gum with degree of grinding 175. g locust bean gum (Vidogum L 175, Unipectin AG, - 24 Eschenz/Switzerland) are moistened with 70 g methanol in a 5 litre Erlenmeyer flask to produce a lump-free solution with water. The mixture is made up to 5 litres with boiled distilled water and stirred over night.

* A stirrer driven by an electric motor and introduced into the stirring vessel through a ground closure.

After 15 minutes 120 g sodium hydroxide are added with stirring. Immediately thereafter the remaining 200 ml dimethyl sulphoxide are added. This batch is stirred for one hour. The polymer pump is then mixed with 745 ml bromomethane. The temporarily generated slight heat (30°C) is not taken off. A reaction temperature of 20°C to 25°C is maintained for the remainder of the reaction time.

After 2 hours the reaction mixture is allowed to stand and the supernatant is decanted into a 1 litre brown glass pear-shaped flask.

The polymer is then pressed out on filter paper and dried in a drying cabinet at 120°C.

The polymer is dissolved in 250 ml acetanhydride and transferred to a 1 litre round-bottom flask with reflux condenser and magnetic stirrer. After addition of 300 to 350 ml pyridine the mixture is heated to boiling point for 5 hours with stirring.

The hot reaction solution is then added to 8 to 10 1 water and the precipitated polymer washed in methanol. The pressed out polymer is then dissolved in a little chloroform and precipitated again in 5 1 methanol.

The polymer is then dried in a drying cabinet at 80°C. After being weighed, the polymer is dissolved in chloroform and cast into petri dishes. These are left to dry at room temperature with exclusion of dust until a film is formed. Very high-tensile, resilient films are obtained that are clear and colourless.

Claims

1. Galactomannans, the hydroxy groups of which are totally or partially present in the form of low molecular weight aliphatic, araliphatic and/or aromatic ether or ester groups and in which 20 to 80 % of the mannose units present in the galactomannan chain form connected mannose blocks having 2 to 20 mannose units which are not substituted by galactose groups.

2. Galactomannans, the hydroxy groups of which are totally or partially present in the form of low molecular weight aliphatic, araliphatic and/or aromatic ether or ester groups and in which 20 to 80 % of the mannose units present in the galactomannan chain form connected mannose blocks having 2 to 20 mannose units which are not substituted by galactose groups for coating and/or embedding solid and/or liquid active substances which only release these active substances in the colon or in the presence of glycolytic enzymes.

3. Galactomannans according to Claim 1, characterized in that the ether groups consist of C^^-Cg-alkoxy groups, phenyl-C·^C 4 -alkoxy groups or phenoxy groups and the ester groups of C 3 -C 22 alkanoyloxy groups.

4. Galactomannan derivatives according to one or several of the preceding claims, characterized in that the molecular weight of the galactomannans of the invention is between 10 4 and 10®, in particular 10 5 and 10®.

5. Galactomannan derivatives according to one or several of the preceding claims, characterized in that the mannose/galactose ratio of the basic galactomannan chain lies between 2 : 1 and 20 : 1, preferably 4:1.

6. Galactomannan derivatives according to one or several of the preceding claims, characterized in that on average 80 to 100 % of the free hydroxy groups of the basic galactomannan present are etherified and/or esterified.

7. A process for the preparation of galactomannans, the hydroxy groups of which are totally or partially present in the form of low molecular weight aliphatic, araliphatic and/or aromatic ether or ester groups and in which 20 to 80 % of the mannose units present in the galactomannan chain form connected mannose blocks having 2 to 20 mannose units, which are not substituted by galactose groups, characterized in that known naturally occurring galactomannans or synthetically prepared galactomannans with molecular weights between 10 4 and 10® g are reacted with Cy-Cg-alkyl halides, phenyl-C 1 -C 4 -alkyl halides or phenyl halides in an inert solvent at temperatures between 20 to 35 °C, optionally in the presence of alkali or with C 3 -C 22 -alkanoyl halides, without solvents or in an anhydrous inert solvent at temperatures between 70 °C and the boiling temperature of the solvent, optionally in the presence of basic compounds.

8. A medicinal formulation characterized in that the medicinally active substances or their physiologically acceptable salts optionally with addition of other conventional auxiliary substances and additives are a) coated with one or several of the galactomannan derivatives of the invention or b) embedded in one or several of the galactomannan derivatives of the invention according to Claim 1 or bound thereto.

9. A medicinal formulation according to Claim 8, characterized in that the forms of administration for oral application contain 0,001 to 500 mg of active substance.

10. A process for the preparation of medicinal formulations, characterized in that one part by weight of medicinally active substance, which may also be present in the form of a physiologically acceptable salt, is processed with 10 5 to 10 -2 parts by weight of galactomannans, the hydroxy groups of which are totally or partially present in the form of low molecular weight aliphatic, araliphatic and/or aromatic ether or ester groups and in which 20 to 80 % of the mannose units present in the galactomannan chain form connected mannose blocks having 2 to 20 mannose units which are not substituted by galactose groups as well as optionally other conventional pharmaceutical auxiliary substances and additives.

11. A process for the preparation of medicinal formulations, characterized in that one part by weight of medicinally active substance, where this may also be present in the form of a physiologically acceptable salt, is coated with 10 5 to 10“ 2 parts by weight of galactomannans, the hydroxy groups of which are totally or partially present in the form of low molecular weight aliphatic, araliphatic and/or aromatic ether or ester groups and in which 20 to 80 % of the mannose units present in the galactomannan chain form connected mannose blocks having 2 to 20 mannose units which are not substituted by galactose groups a) in a manner known per se or b) embedded in a manner known per se in glactomannans of this type or bound thereto, it also being possible optionally to process therewith other conventional pharmaceutical auxiliary substances and additives, the products so obtained optionally being pressed into tablets or filled into capsules.

12. A process according to Claim 11, characterized in that the coating of the active substances is carried out by spraying or coagulation using solutions, suspensions or dispersions of the galactomannans of the invention in organic agents or water.

13. A process according to Claim 11, characterized in that the embedding of the active substances is carried out a) by dissolving or dispersing the active substances in the galactomannans of the invention; b) by mixing the active substances with the galactomannans of the invention; c) by mixing the active substances with solutions of the galactomannans of the invention in organic agents; d) by moistening a mixture of the active substances and the galactomannans of the invention optionally in the presence of swelling agents in organic solvents and by subseguent granulation; or e) by mixing the active substances with a solution of the galactomannans of the invention in polyethylene glycols and optionally subseguently filling the product obtained into capsules. .

14.The use of the galactomannans manufacture foils. of the invention to

15. A galactomannan according to Claim 1, substantially as hereinbefore described and exemplified.

16. A process for the preparation of a galactomannan according to Claim 1, substantially as hereinbefore described and exemplified.

17. A galactomannan according to Claim 1, whenever prepared by a process claimed in Claim 7 or 16.

18. A medicinal formulation according to Claim 8, substantially as hereinbefore described.

19. Use according to Claim 14, substantially as hereinbefore described.