CA1338236C - Esters of alginic acid - Google Patents

Abstract

Total, water-insoluble esters of alginic acid with alcohols are provided herein. In such esters, the alcohol is selected from the group consisting of aliphatic, arali-phatic, cycloaliphatic, aliphatic-cycloaliphatic and heterocyclic alcohols. These esters possess interesting and valuable bioplastic and pharmaceutical qualities and may be used in numerous fields, including surgery and medicine.

Description

This application is a division of Application Serial No. 540,467 filed June 24th, 1987.
This invention relates to total, water-insoluble esters of alginic acid with alcohols which are acceptable from a pharmacological point of view.
This invention also relates to pharmaceutical preparations containing, as an active ingredient, one or more alginic acid esters as described above, as well as medicaments containing a pharmacologically-active substance or an association of pharmacologically-active substances and a carrying vehicle comprising a total ester of alginic acid.
Alginic acid is a natural acidic polysaccharide extracted from so-called brown algae (PhaecoPhvceae) with a high molecular weight varying between 30,000 and 200,000, and containing chains formed by D-mannuronic acid and L-guluronic acid. The degree of polymerization varies according to the type of alga used for extractions, the season in which the algae were gathered and the place of origin of the algae, as well as the age of the plant itself. The main species of brown algae used to obtain alginic acid are, for example, MacrocYstis pyrifera, Laminaria cloustoni, Laminaria hyperborea, Laminaria flexicaulis, Laminaria digitata, Ascophyllum nodosum, and Fucus serratus.
Alginic acid is found in these algae as an extensive constituent of the cell walls in the form of a mixture of some of its alkaline earth metal or alkali metal salts, especially sodium salt. This mixture is also known as "algin". These salts are normally extracted in aqueous conditions with a sodium carbonate solution. It is possible to obtain alginic acid directly from this extract by precipitation with an acid, for example, a mineral acid, e.g., hydrochloric acid. An indirect preparation procedure involves first making an insoluble calcium salt by adding a soluble calcium salt, e.g., calcium chloride, and, after washing this salt, obtaining alginic acid by treatment with an acid.
Alginic acid or alkaline earth metal or alkali metal alginates may, however, also be obtained microbiologically, for instance, by fermentation with Pseudomonas aeruqinosa or mutants of Pseudomonas putida, Pseudomonas fluorescens or Pseudomonas mendocina.
The metal salts of alginic acid, especially the alkali metal and alkaline earth metal salts, have interesting chemical and physical properties and are therefore widely used in industry. Thus, for example, the solutions of alkali metal or alkaline earth alginates are extremely suitable, due to their viscosity, and their adjustability by temperature and pH, for the preparation of gels which may be widely used in the food industry, for the prepara-tion of ice creams, milk puddings and many other types of cakes and puddings. Another property which is widely exploited in the field of alimentation is the ability of alginates to retain water. For this reason, they are used, for example, for the conservation of many types of frozen - 1 33 823~

foods. A third property of alginates is their power to emulsify and to stabilize emulsions; for this reason, too, these salts are important in the food industry, where they are used for the preparation of condiments and for the stabilization of many types of drinks, e.g., beer or fruit juices, sauces and syrups.
The ability of alginate solutions to form films and fibres has been exploited in the paper industry, in making adhesive labels, in textile printing and dyeing, and in the preparation of sanitary, medical and surgical articles.
Alginates are used as emulsifiers for the preparation of polishes, antifoam agents and lactics and as stabilizers in the ceramic and detergent industries. (For a more detailed list see, for example, "The Polysaccharides", Vol.
2, by Paul A. Sandford and John Baird, Copyright 1983 by Academic Press., Inc.).
Alginic acid and its salts have also been used in the pharmaceutical, medical, surgical and cosmetic fields, for example, for the preparation of medicaments for topical use and sanitary and surgical articles. For example, German Offenlegungsschrift 3,017,221 (20.11.1980), discloses an "artificial skin" for use in serious lesions of the skin, for example, following burns, in which an ointment containing a soluble alginate of an alkali metal or an alkaline earth metal is applied topically to the skin and is treated in situ with a soluble calcium salt. This causes the formation of insoluble calcium alginate, trans-forming the layer of ointment into an easily tolerated, -4 l 33~236 biologically-protective film, with structural and mechani-cal physical characteristics similar to those of natural skin.
Calcium alginate has been used for the manufacture of fibres for use in the pharmaceutical industry [see French Patent Application No. 2,418,8Zl (28.9.1979)]. Rumanian Patent No. 70,069 (30.6.1980) contains a description of a healing and antiseptic medicament for skin wounds, made from calcium alginate fibres. Calcium alginate is also used as a hemostatic agent in the form of bandages or gauzes containing fibres of the salt. Other medicaments based on calcium alginate are used for the treatment of sinoids, fistulas, and in the treatment of nosebleeds. In Galenism, sodium and calcium alginates are also used as disintegrators for pills, and sodium alginate is also used for its binding properties.
Two alginic acid esters or salts of such esters, e.g., ethylene glycol and propylene glycol esters are also used in industry in many of the above-mentioned fields are. The latter is used, for example, as an emulsifier and stabi-lizer for foodstuffs. (See, for example, "Martindale" -The Extra Pharmacopoeia, p. 931, and "The Polysaccharides", Vol. 2, Copyright by Academic Press, Inc. 1983, pp. 448-449). The above-mentioned esters have been obtained by reaction of alginic acid, or its salt or its partial salt, with ethylene oxide or propylene oxide respectively. This preparation process is also the basis of patents for the preparation of the above-mentioned alginic acid esters and esters of bivalent alcohols by reaction of an aliphatic hydrocarbon epoxide, possibly substituted or interrupted by hetero atoms in the carbon atom chain [see, for example:
U.S. Patents Nos. 2,463,824, 2,426,125, and 2,463,824;
5German Offenlegungsschriften 2,161,415, 2,046,966, 2,641,303, and 2,529,086; Japanese Patents Nos. 2027 ('59) and 7,247,858; and French Patent No. 2,247,204].
The alginic acid esters obtainable by the action of the above-mentioned epoxides on the free acid or its salts 10are partial esters [see A.B. Steiner, Industrial and Engineering Chemistry, Vol. 43, pp. 2073 - 2077, (1951)], with a maximum degree of esterification of 80% of all the existing carboxylic groups in the case of glycol esters with a low molecular weight, and a very low degree in the 15case of glycol esters with long chains. It has not been possible until now to prepare total esters by this process.
Monovalent alcohol esters, both aliphatic and arali-phatic have also been mentioned in the literature. A
methyl ester of alginic acid may be obtained by reaction of 20alginic acid in an ethereal solution of diazomethane. tSee Zeitschrift fuer physiologische Chemie, Vol. 293, p. 121, 1953; A.B.Steiner, Industrial and Engineering Chemistry, Vol. 43, p. 2073, 1951; and U.K. Patent No. 768,309]. It seems, however, that the products obtained by reaction with 25diazomethane are not really alginic acid esters but rather are methyl esters of an alginic acid partially etherified to the hydroxy alcohol groups, as described, for example, in Example 4 of the above-mentioned U.K. patent. One `- 1 3 3 8 2 3 6 methyl ester has also been obtained by reaction of dimethyl sulphate on a soluble salt of alginic acid in an organic solvent with low solubility in water, but in the presence of water [see U.S. Patent No. 2,860,130]. The product obtained, referred to as methyl alginic acid or methyl alginate, is not to be considered as a pure ester, since it is known that sugar hydroxyls are easily etherified with this methylating agent. This example, therefore, also is truly a mixed ester-ether.
Also mentioned in literature are alginic acid esters of monovalent alcohols, with no indication, however, of their preparation process and no description of their chemical and physical properties. As no preparation process is known, apart from the above-mentioned reaction with diazomethane and dimethyl sulphate, it is probable that the use of homologues of these esterifying agents to obtain esters of the homologous series of the methyl ester are not practical at all, or at the most they result in mixed products, as in the case of methyl products. [See for example U.S. Patent No. 4,216,104 in which a propyl alginate is mentioned with no indication of its origin or preparation process, and Japanese Kokai No. 55-132781, page 5, in which ethyl, butyl, lauryl, oleyl, phenyl and benzyl esters are mentioned, with no indication as to how they are obtained].
On the basis of these facts, therefore, it is presumed that, of all alginic acid esters, only those esters of bivalent alcohols are known, and more precisely, only the t 338236 partial esters with glycols. By the known process used in industry, it is difficult to achieve complete esterifica-tion. In the commercial product, no less than 10% of the carboxyls remain unesterified in their free carboxy form, possibly salified.
Objects of principal aspects of this invention are therefore the provision of new total, water-insoluble alginic esters, e.g., those already mentioned, and new processes for their preparation.
An object of another aspect of this invention is to provide novel pharmaceutical compositions including such esters.
An object of yet another aspect of this invention is to provide novel pharmaceutical preparations including such esters.
By one broad aspect of this invention, total, water-insoluble esters of alginic acid with an alcohol which is selected from the group consisting of aliphatic, aralipha-tic, cycloaliphatic, aliphatic-cycloaliphatic and hetero-cyclic alcohols are provided herein.
Such compounds possess interesting and valuable bio-plastic qualities, so that they may be used in numerous fields, e.g. in surgery and medicine, as described and claimed in the above-identified parent application.
By one variant thereof, the alcohol may include: (a) an aliphatic radical with a maximum of 34 carbon atoms; (b) an araliphatic radical with only one benzene ring, and in which the aliphatic chain has a minimum of 4 carbon atoms;

- J 33823~

(c) a cycloaliphatic radical which is monocyclic or poly-cyclic with a maxlmum of 34 carbon atoms; (d) an aliphatic-cycloaliphatic radical which is monocyclic or polycyclic with a maximum of 34 carbon atoms; or (e) a heterocyclic radical with a maximum of 34 carbon atoms in which the hetero atoms are selected from the group consisting of oxygen, sulfur and nitrogen.
In a variation of such variant, a) the aliphatic, cycloaliphatic, aliphatic-cycloaliphatic or heterocyclic radicals may be substituted by one or two functional groups selected from the group consisting of amino, hydroxy, mercapto, aldehydo, keto, carboxyl, hydrocarbyl, dihydro-carbylamino, ether, ester, thioether, thioester, acetal, ketal, carbalkoxy and carbamidic groups and carbamidic groups substituted by one or two alkyl groups, the hydro-carbyl radicals in these functional groups having a maximum of 6 carbon atoms; or b) the araliphatic radicals may be substituted in the benzene residue with 1-3 substituents selected from the group consisting of methyl, hydroxy and halogen, or may be substituted in the aliphatic portion with one or two functional groups selected from the group consisting of methyl, ethyl, diethyl, pyrrolidine and piperidine groups.

By still another variation of such variant, a) the hydrocarbyl radicals of the functional groups are Cl~4 alkyl groups; or b) the amino or substituted carbamidic groups are Cl8 alkylene amine or Cl8 alkylene carbamidic groups; or c) the cycloaliphatic, aliphatic-cycloaliphatic or hetero-cyclic moieties are monocyclic with a maximum of 12 carbon atoms and the ring has between 5 and 7 carbon atoms.
By another variant thereof, the aliphatic radical may be derived from a member selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, amyl alcohol, pentyl alcohol, hexyl alcohol, octyl alcohol, glycerin, tartronic alcohol, lactic acids, gly-colic acid, malic acid, tartaric acid, citric acid, amino-ethanol, aminopropanol, n-aminobutanol or their dimethyl or diethyl derivatives in the amino moiety, choline, pyrroli-dinylethanol, piperidinylethanol, piperazinylethanol, piperazinyl-n-propyl alcohol, piperazinyl-n-butyl alcohol, monothioethylene glycol, myricyl alcohol, citronellol, geraniol, nerol, nerolidol, linalool, farnesol and phytol.
By yet another variant thereof, the alcohol may be selected from the group consisting of alkaloids, phenyl-ethylamines, phenothiazine drugs, thioxanthene drugs, anticonvulsants, antipsychotics, antiemetics, analgesics, hypnotics, anorexica, tranquilizers, muscle relaxants, coronary vasodilators, adrenergic blockers, narcotic antagonists, antineoplastics, antibiotics, antivirals, peripheral vasodilators, carbonic anhydrase inhibitors, antiasthmatics, anti-inflammatories and sulfamidics.
Preferred total, water-insoluble esters of alginic acid include the total, water-insoluble methyl ester of alginic acid; the total, water-insoluble ethyl of alginic acid; the total, water-insoluble tert-butyl ester of alginic acid; and the total, water-insoluble benzyl ester of alginic acid.
By another aspect of the present invention, a process is provided for the preparation of total, water-insoluble esters of alginic acid with an alcohol which is selected from the group consisting of aliphatic, araliphatic, cyclo-aliphatic, aliphatic-cycloaliphatic and heterocyclic alcohols, which process comprises: reacting, in an organic solvent, a solubilized quaternary ammonium salt of alginic acid with a selected esterification agent which is gradually added to the dissolved quaternary ammonium salt.
By a variant of this aspect, the organic solvent may be an aprotic solvent, e.g., dimethylsulfoxide. By another variant of this aspect, the quaternary ammonium salt may be a lower tetraalkyl ammonium salt of alginic acid, e.g., tetrabutylammonium alginate.
By yet another variant of this aspect, the process may include the further step of adding an organic solvent to precipitate out the ester of alginic acid, and/or the further step of recovering, washing and drying the so-produced total, water-insoluble ester of alginic acid.
By still another variant of this aspect, the quater-nary ammonium salt of alginic acid may be prepared by passing an alkali metal salt of alginic acid through a quaternary ammonium salt ion exchange resin, and recovering the quaternary ammonium salt of alginic acid.
By a variation of such variant, the quaternary ammo-nium salt ion exchange resin is a sulfonic acid resin, e.g., a Cl - C6 tetraalkyl ammonium salt. By another variation of such variant, the esterification agent may be a compound of the Formula:
A-X (I) wherein A is a radical selected from the group consisting of aliphatic, araliphatic, cycloaliphatic, aliphatic-cyclo-aliphatic and heterocyclic of such variants, and X is a halogen atom. By still another variation of such variant, A is selected from the group consisting of methyl, ethyl, i-propyl, t-butyl and benzyl radicals.
By another aspect of this invention, a pharmaceutical composition is provided comprising an effective amount of a total, water-insoluble alginic acid ester with an alcohol which is selected from the group consisting of aliphatic, araliphatic, cycloaliphatic, aliphatic-cycloaliphatic and heterocyclic alcohols, together with a pharmaceutically-acceptable excipient.
By a variant of this aspect, the alcohol includes:
a) an aliphatic radical with a maximum of 34 carbon atoms;
b) an araliphatic radical with only one benzene ring, and in which the aliphatic chain therein has a maximum of 4 carbon atoms; c) a cycloaliphatic radical which is mono- or polycyclic with a maximum of 34 carbon atoms; d) an alipha-tic-cycloaliphatic radical which is mono- or polycyclic with a maximum of 34 carbon atoms; or e) a heterocyclic radical with a maximum of 34 carbon atoms in which the hetero atoms are selected from the group consisting of oxygen, sulfur and nitrogen.

-12 l 338236 By one variation of such variant, the aliphatic, cycloaliphatic, aliphatic-cycloaliphatic and heterocyclic radicals may be substituted by one or two functional groups selected from the group consisting of amino, hydroxy, S mercapto, aldehydo, keto, carboxyl, hydrocarbyl, dihydro-carbylamino, ether, ester, thioether, thioester, acetal, ketal, carbalkoxy and carbamidic groups and carbamidic groups substituted by one or two alkyl groups, the hydro-carbyl radicals in these functional groups having a maximum of 6 carbon atoms; or the araliphatic radicals are substi-tuted in the benzene residue with 1-3 substituents selected from the group consisting of methyl, hydroxy and halogen, or are substituted in the aliphatic portion with one or two functional groups selected from the group consisting of ethyl, diethyl, pyrrolidine and piperidine groups.
By another variation of such variant, the hydrocarbyl radicals of the functional groups are C1~4 alkyl groups; or the amino or substituted carbamidic groups are Cl8 alkylene amine or C~8 alkylene carbamidic groups; or the cycloali-phatic, aliphatic-cycloaliphatic or heterocyclic moieties are monocyclic with a maximum of 12 carbon atoms and the ring has between 5 and 7 carbon atoms.
By still another variant of this aspect, the alcohol is selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, amyl alcohol, pentyl alcohol, hexyl alcohol, octyl alcohols glycerin, tartronic alcohol, lactic acids, glycolic acid, .~

13 1 338~36 malic acid, tartaric acid, citric acid, aminoethanol, aminopropanol, n-aminobutanol or their dimethyl or diethyl derivatives in the amino moiety, choline, pyrrolidinyl-ethanol, piperidinylethanol, piperazinylethanol, piper-azinyl-n-propyl alcohol, piperazinyl-n-butyl alcohol, mono-thioethylene glycol, myricyl alcohol, citronellol, gera-niol, nerol, nerolidol, linalool, farnesol and phytol.
By another variant of this aspect, the alcohol is selected from the group consisting of alkaloids, phenyl-ethylamines, phenothiazine drugs, thioxanthene drugs,anticonvulsants, antipsychotics, antiemetics, analgesics, hypnotics, anorexica, tranquilizers, muscle relaxants, coronary vasodilators, adrenergic blockers, narcotic antagonists, antineoplastics, antibiotics, antivirals, peripheral vasodilators, carbonic anhydrase inhibitors, antiasthmatics, anti-inflammatories and sulfamidics.
Specific pharmaceutical compositions according to aspects of this invention comprise: an effective amount of the total, water-insoluble methyl ester of alginic acid, together with a pharmaceutically-acceptable excipient; or of an effective amount of the total, water-insoluble ethyl ester of alginic acid, together with a pharmaceutically-acceptable excipient; or of an effective amount of the total, water-insoluble isopropyl ester of alginic acid, together with a pharmaceutically-acceptable excipient; or of an effective amount of the total, water-insoluble tert-butyl ester of alginic acid, together with a pharmaceuti-cally-acceptable excipient; or of an effective amount of -14 l 338236 the total, water-insoluble benzyl ester of alginic acid, together with a pharmaceutically-acceptable excipient.
By a further aspect of this invention, a pharmaceu-tical preparation is provided comprising at least one pharmacologically-active substance; and a carrying vehicle constituted by a total, water-insoluble ester of alginic acid with an alcohol selected from the group consisting of aliphatic, araliphatic, cycloaliphatic, aliphatic-cycloali-phatic and heterocyclic alcohols.
By a variant of this aspect, the alcohol includes: an aliphatic radical with a maximum of 34 carbon atoms; or an araliphatic radical with only one benzene ring, and in which the aliphatic chain has a maximum of 4 carbon atoms;
or a cycloaliphatic radical which is mono- or polycyclic with a maximum of 34 carbon atoms; or an aliphatic-cyclo-aliphatic radical which is mono- or polycyclic with a maxi-mum of 34 carbon atoms; or a heterocyclic radical with a maximum of 34 carbon atoms in which the hetero atoms are selected from the group consisting of oxygen, sulfur and nitrogen.
By a variation of such variant, the aliphatic, cyclo-aliphatic, aliphatic-cycloaliphatic and heterocyclic radi-cals may be substituted by one or two functional groups selected from the group consisting of amino, hydroxy, mercapto, aldehydo, keto, carboxyl, hydrocarbyl, dihydro-carbylamino, ether, ester, thioether, thioester, acetal, ketal, carbalkoxy and carbamidic groups and carbamidic groups substituted by one or two alkyl groups, the hydro-1 33~236 15carbyl radicals in these functional groups having a maximum of 6 carbon atoms; or the araliphatic radicals may be sub-stituted in the benzene residue with 1-3 substituents selected from the group consisting of methyl, hydroxy and halogen; or may be substituted in the aliphatic portion with one or two functional groups selected from the group consisting of ethyl, diethyl, pyrrolidlne and piperidine groups. By another variation of such variant: the hydro-carbyl radicals of the functional groups are Cll4 alkyl groups; or the amino or substituted carbamidic groups are Cl8 alkylene amine or C~8 alkylene carbamidic groups; or the cycloaliphatic, aliphatic-cycloaliphatic or heterocyclic moieties are monocyclic with a maximum of 12 carbon atoms and the ring has between 5 and 7 carbon atoms.
By another variant of this aspect, the alcohol is a member selected from the group consisting of methyl alco-hol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, amyl alcohol, pentyl alcohol, hexyl alcohol, octyl alcohols glycerin, tartronic alcohol, lactic acids, glycolic acid, malic acid, tartaric acid, citric acid, aminoethanol, aminopropanol, n-aminobutanol or their dimethyl or diethyl derivatives in the amino moiety, choline, pyrrolidinyl-ethanol, piperidinylethanol, piperazinylethanol, piper-azinyl-n-propyl alcohol, piperazinyl-n-butyl alcohol, monothioethylene glycol, myricyl alcohol, citronellol, geraniol, nerol, nerolidol, linalool, farnesol and phytol.

16 l 338236 By another variant of this aspect, at least one of the alcohols in the total water-insoluble alginic acid ester is derived from a therapeutically-active alcohol. By a varia-tion of such variant, the alcohol is a member selected from the group consisting of alkaloids, phenylethylamines, phenothiazine drugs, thioxanthene drugs, anticonvulsants, antipsychotics, antiemetics, analgesics, hypnotics, anorexica, tranquilizers, muscle relaxants, coronary vaso-dilators, adrenergic blockers, narcotic antagonists, anti-neoplastics, antibiotics, antivirals, peripheral vasodi-lators, carbonic anhydrase inhibitors, antiasthmatics, anti-inflammatories and sulfamidics.
Specific pharmaceutical preparations according to aspects of this invention include those wherein: the total, water-insoluble ester of alginic acid is the methyl ester of alginic acid; or the total, water-insoluble ester of alginic acid is the ethyl ester of alginic acid; or the total, water-insoluble ester of alginic acid is the isopro-pyl ester of alginic acid; or the total, water-insoluble ester of alginic acid is the tert-butyl ester of alginic acid; or the total, water-insoluble ester of alginic acid is the benzyl ester of alginic acid.
The present invention in one of its broad aspects thus provides a simple and very convenient procedure for the preparation of total, water-insoluble alginic esters, based on the treatment of quaternary ammonium salts of alginic acid with conventional alkylating agents in organic, preferably aprotic, solvents, e.g., in dimethylsulfoxide, making a large number of new the total, water-insoluble esters of alginic acid available, especially those total, water-insoluble esters of monovalent alcohols, e.g., homo-logues of methyl ester, and esters of aromatic, arali-phatic, alicyclic and heterocyclic alcohols.
By another aspect of this invention, the new processmay be used for the preparation of esters deriving from substituted alcohols, in particular known esters of biva-lent aliphatic alcohols, obtainable by the reaction of alginic acid with aliphatic epoxides, as described above, and new total, water-insoluble esters of such bivalent alcohols.
As provided in the above-identified parent Application Serial No. 540,467, new, total, water-insoluble alginic esters of aspects of the present invention may be used in various sectors of industry and in the pharmaceutical, sanitary, surgical and cosmetic fields, where metal alginates or the esters of aliphatic bivalent alcohols of the type of propyleneglycol esters of alginic acid are already used, for example, in the food or cosmetic industries.
With the discovery of the new total, water-insoluble alginic esters as provided by the present application, a new use of alginic esters in general has also been provided for the new total, water-insoluble esters and for those already known. This new use is their use as vehicles for pharmaceutically-active substances, especially those with a topical, oral or rectal action, but also those for paren-18 1 33823~
teral administration, as provided in the present divisionalapplication. The use of known alginic esters of bivalent alcohols was previously limited to the function of emul-sifying agents, emulsion stabilisers, thickening agents and possibly related uses. No use in the pharmaceutical, sanitary, medical, surgical or cosmetic fields was envisaged for those esters. The invention now provided by the present application therefore, ln another aspect, also provides pharmaceutical preparations containing a new, total, water-insoluble alginic ester as vehicle for the active substances.
In such pharmaceutical preparations, the active sub-stance may also be vehicled by the new, total, water-insoluble esters which have a pharmacologically-active substance as their alcohol component. Of the pharma-ceutical preparations now provided by the present applica-tion, therefore, particularly interesting are those con-taining a new, total, water-insoluble alginic ester deriving from a therapeutically-active alcohol, e.g., those mentioned hereafter, that is, new, total, water-insoluble esters comprised of alginic acid esterified with the alcohol moiety of a therapeutically-active compound.
The use of the above-mentioned alkaline earth metal and alkali metal alginates of the prior art in the various sectors of industry, pharmaceutics, surgery and above all in the food industry, presented some disadvantages when they were used in acid conditions, because of the resulting release of alginic acid with low solubility which may separate in the solid state. Also, in the presence of calcium ions, some insoluble products containing calcium alginate may separate, and for this reason alkaline earth metal and alkali metal alginates have been unsuitable for use in liquids containing the above-mentioned ions, for example, in products containing milk or milk derivatives.
For this reason the above-mentioned soluble salts of alginic acid have, in the past, been substituted by the above-mentioned glycol esters, especially propylene glycol ester, in those cases in which it was essential to maintain a good level of solubility in acid conditions, or in the presence of calcium salts, e.g., when the alginate was used as emulsifier or emulsion stabiliser. The glycol esters of alginic acid are however toxic to a certain extent and their use must be limited. This is due to the intrinsic toxicity of the glycol residue, the part which is absorbed and metabolised.
The present invention now makes available to the above-mentioned various industrial and scientific fields, an assortment of new products with properties essentially similar to those of alkaline earth metal and alkali metal alginates or the already known glycol esters, but with effects which are more in keeping with the requirements of increasingly perfected products, and these effects naturally vary from case to case according to the use to which the new products are put. It is important to under-score, first and foremost, the superiority of the new, monovalent, total, water-insoluble esters according to the l 338236 present invention over the above-known glycol esters, since the monovalent alcohol residues are metabolised in the organism to degraded products which are less toxic than the glycols. This is naturally true of new, total, water-insoluble esters deriving from alcohols which do not con-tain toxic substitutes, especially aliphatic, cycloali-phatic, monovalent alcohols. These new, total, water-insoluble esters, as provided by the present invention, will be of great advantage above all in sanitary or surgi-cal articles, as described and claimed in the above-identi-fied parent application.
The low level of toxicity of the total, water-insol-uble esters of numerous monovalent alcohols of alginic acid according to aspects of the present invention may be exploited in the pharmaceutical, cosmetic and sanitary-surgical fields, where the new, total, water-insoluble alginic esters may be used as biodegradable plastic materials with various functions as the case may be. Thus, for example, the new, total, water-insoluble alginic esters may be used as additives for the wide range of polymeric materials used for sanitary and surgical articles according to the above-identified parent application, e.g., polyure-thanes, polyesters, polyolefins, polyamides, polysiloxanes, vinyl and acrylic polymers, with the effect of rendering these materials biocompatible. In this case, the addition of a new, total, water-insoluble alginic ester is carried out, for example, by coating the surface of these mater-ials or by dispersion in the same or by a combination of -- ~ 33823~

both procedures. These materials may be used for the manufacture of various sanitary and medical articles, e.g., cardiac valves, intraocular lenses, vascular clips, pace-makers and the like, including these types of articles dis-cussed in U.S. Patent No. 4,500,676.
In the cosmetic and pharmaceutical fields, the new total, water-insoluble alginic esters of aspects of the invention may be used for the preparation of ointments, creams and other types of medicaments for topical appli-cation or cosmetic products, e.g., sunshield creams, wherethey act as stabilisers and emulsifiers having a greater degree of stability than the alkali metal alginates of the prior art, especially with regard to higher temperatures, and a lesser degree of toxicity compared to glycol esters.
In pharmaceuticals, they may be used to the same advantage as disintegrators for pills or as a binding agent, but above all, according to a particularly important aspect of the present invention, as a vehicle for pharmacologically-active substances, especially those for topical use. This vehicling action of the new, total, water-insoluble esters may be carried out various ways, specifically including:
1) where the total, water-insoluble alginic ester serves as vehicle and is associated mechanically, and/or physically mixed with the active substance; and 2) where the total, water-insoluble alginic ester is esterified with an alcohol which represents the active substance.
Apart from these two variations, combinations of the same may be used, for example, a combination of (1) and - ~ 33823~

(2). In the case of variation (2), it is possible to vary and combine the alcohol residues in the new, total, water-insoluble alginic ester, and it is possible to have total, water-insoluble esters of a mixed character, in which the alcohol residues derive partly from pharmacologically-inactive alcohols and partly from pharmacologically-active alcohols. It is possible to have, in the same new, total, water-insoluble ester, both inactive alcohol residues and residues of therapeutically-active alcohols.
A first group of new, total, water-insoluble esters useful according to aspects of the present invention, suit-able for use in the above-mentioned industrial sectors, e.g., in the preparation of sanitary, medical and surgical articles, as described and claimed in the above-identified parent application, etc., is represented by those new, total, water-insoluble esters in which the properties of the alginic component are the properties to be exploited.
These new, total, water-insoluble esters derive from alco-hols of the aliphatic, aromatic, araliphatic, cycloalipha-tic or heterocyclic series which have no toxic or pharmaco-logical action, e.g., for example, the saturated alcohols of the aliphatic series or simple alcohols of the cycloali-phatic series. Examples of these alcohols are mentioned hereinafter.
A second group of new, total, water-insoluble esters for use in therapy in according to aspects of the present invention is represented by the new, total, water-insoluble esters in which the pharmacological qualities of the 23 l 338236 alcohol component are dominant, that is, new, total, water-insoluble alginic acid esters with pharmacologically-active alcohols, e.g., steroidal alcohols, e.g., those of the cortisone type. These new, total, water-insoluble esters possess properties which are qualitatively similar to those of the alcohol, but with a wider range of action. Even as compared to already known esters of such- pharmaceutically-active alcohols, the new, total, water-insoluble alginic esters of aspects of the present invention, ensure a more balanced, constant and regular pharmacological action and generally cause a marked retard effect of the active alco-hol component.
A third group of new, total, water-insoluble alginic acid esters according to aspects of the present invention and representing a particularly original and useful aspect of the same, is that of the new, total, water-insoluble esters of a more mixed character compared to the two previous groups. That is, new, total, water-insoluble esters in which part of the carboxylic groups of alginic acid are esterified with a pharmacologically-inactive alcohol, or with an alcohol, the activity of which is negligible. By suitably dosing the percentages of the two types of alcohols as the esterifying component, it is possible to obtain new, total, water-insoluble esters with the same activity as the pharmacologically-active alcohol and having those qualities mentioned above increased stability and bioavailability compared to the desired and characteristic activity of the pharmacologically-active 24 l 338236 alcohol and due to the ester groups of the pharmacologi-cally-inert alcohol.
A fourth group of new, total, water-insoluble esters according to aspects of the present invention is repre-sented by those of a mixed character in which the estergroups derive from two different therapeutically-active substances. In this case also, the new, total, water-insoluble esters are total, that is, all of the carboxylic groups derive from two different therapeutically-active alcohols, for example, from a cortisone steroid and from an antibiotic. It is possible, however, to prepare new, total, water-insoluble esters with three or more alcoholic components, for example, new, total, water-insoluble esters in which a part of the carboxylic groups is esterified with a therapeutically-active alcohol, and another part of which is esterified with a therapeutically-inactive alcohol.
Most of the new total, water-insoluble esters of alginic acid, in contrast to their salts, present a certain degree of solubility in organic solvents. This solubility depends on the percentage of esterified carboxylic groups and of the type of alkyl group bound to the carboxyl. For example, a new, total, water-insoluble ester of alginic acid thus obtained presents good solubility at room tem-perature, in dimethylsulfoxide, for example. The new, total, water-insoluble esters which are a particular aspect of the present invention, have no substitution, solubility in water. Thus, for example, the new, total, water-insol-uble esters of monovalent alcohols, e.g., lower and higher -alkyl esters, are insoluble in water and aqueous solutions.
The new, total, water-insoluble esters of bivalent alco-hols, e.g., the new, total, water-insoluble ester of the glycols, e.g., ethylene glycol, and isobutylene glycol also have such solubility characteristics.
These solubility characteristics, together with the marked viscoelastic properties of the new, total, water-insoluble esters of aspects of the present invention, make them suitable for use in the manufacture of sanitary and medical articles as described and claimed in the above-identified parent application, which are insoluble in saline and have the particular desired form. Such articles may be prepared, for example, by dissolving a new, total, water-insoluble ester of alginic acid in a first organic solvent, giving the extremely viscous solution the form of the desired article and lastly by extracting the organic solvent with a second solvent which can be mixed with the first, but in which the new, total, water-insoluble alginic acid ester is insoluble, for example, an alcohol, or water.
The present invention in other aspects also include the use of the new, total, water-insoluble alginic esters in general, that is, the new ones and those already des-cribed in literature, for the new applications described here, for example their use as vehicles for pharmaco-logically-active substances, both in the form of new, total, water-insoluble alginic esters with therapeutically-active alcohols, and as new, total, water-insoluble alginic esters of inert alcohols to mix with therapeutically-active -bases as well as the pharmaceutical medicaments or prepara-tions resulting from this use of new, total, water-insol-uble alginic esters.
In summary, thereafter, the main aspect of the present invention is represented by new, total, water-insoluble esters of alginic acid with an alcohol of the aliphatic, araliphatic, cycloaliphatic or heterocyclic series.
Another aspect of the present invention is represented by a new process for the preparation of new, total, water-insoluble alginic esters characterised by the treatment ofa quaternary ammonium salt of alginic acid with an etheri-fying agent in an aprotic solvent.
Another aspect of the present invention is represented by the use of new, total, water-insoluble alginic esters as vehicles for pharmaceutically-active substances and by pharmaceutical preparations or medicaments containing:
1) a pharmacologically-active substance or an association of pharmacologically-active substances; and 2) a carrying vehicle containing a new, total, water-insoluble ester of alginic acid, or a pharmacologically-active preparation or medicaments containing a new, total, water-insoluble ester of alginic acid in which at least one ester group derives from an alcohol as described above.
As described hereinbefore, alcohols of the aliphatic series for use as esterifying components of the carboxy groups of alginic acid according to aspects of the present invention, include, for example, those with a maximum of 34 carbon atoms, which may be saturated or unsaturated and 1 338Z3~

which may possibly also be substituted by other free or functionally modified groups, e.g., amino, hydroxy, alde-hydo, keto, mercapto, carboxy groups or by groups deriving from the same, e.g. hydrocarbyl or dihydrocarbylamino [hereafter the term "hydrocarbyl" should be taken to mean not only monovalent radicals of hydrocarbons e.g., the CnH2n+~
type, but also bivalent or trivalent radicals, e.g., "alky-lenes" - CnH2n - or "alkylidenes" = CnH2n], ether or ester groups, acetal or ketal groups, thio-ether or ester thio-ester groups and esterified carboxy groups or carbamidic or carbamidic groups substituted by one or two hydroxy groups, by nitrile groups or by halogens.
In the above groups containing hydrocarbyl radicals, these are preferably lower aliphatic radicals, e.g., alkyls, with a maximum of 6 carbon atoms. These alcohols may also be interrupted in the carbon atom chain by hetero-atoms, e.g., oxygen, nitrogen or sulfur. Preference is given to alcohols substituted with one or two of such func-tional groups.
Alcohols of the above group which may be used prefer-entially, according to aspects of the present invention, are those with a maximum of 12 and especially with a maxi-mum of 6 carbon atoms and in which the hydrocarbyl radicals in the above mentioned amino, ether, ester, thioether, thioester, acetal, or ketal groups represent alkyl groups with a maximum of 4 carbon atoms, and also in the esteri-fied carboxy or substituted carbamidic groups, the hydro-carbyl groups are alkyls with the same number of carbon 28 1 33823~
atoms, and in which the amino or carbamidic groups may be alkyleneamino or alkylenecarbamidic groups with a maximum of 8 carbon atoms. Of these alcohols, those to be men-tioned first and foremost are the saturated and unsubsti-tuted ones, e.g., methyl, ethyl, propyl, isopropyl alco-hols, n-butyl alcohol, isobutyl, tert-butyl alcohols, amyl, pentyl, hexyl, octyl, nonyl, and dodecyl~alcohols and above all those with a linear chain, e.g., n-octyl or n-dodecyl alcohols. Of the substituted alcohols of this group, the bivalent alcohols should be listed, e.g., ethylene glycol, propylene glycol or butylene glycol, the trivalent alco-hols, e.g., glycerin, aldehydo alcohols, e.g., tartronic alcohol, carboxy alcohols, e.g., lactic acids, for example, ~ -oxypropionic acid, glycolic acid, malic acid, tartaric lS acids, and citric acid, amino alcohols, e.g., aminoetha-nol, aminopropanol, n-aminobutanol and their dimethyl and diethyl derivatives in the aminic function, choline, pyrro-lidinylethanol, piperidinylethanol, piperazinylethanol and the corresponding derivatives of n-propyl or n-butyl alco-hols, monothioethylene glycol or its alkyl derivatives, forexample, the ethyl derivative in the mercapto function.
Of the higher saturated aliphatic alcohols, those worthy of special mention are, for example, cetyl alcohol and myricyl alcohol, but especially important, according to aspects of the present invention, are the higher unsatur-ated alcohols with one or two double bonds, e.g., espe-cially those contained in many essential oils and having an -29 ~ 338236 affinity with terpenes, e.g., citronellol geraniol, nerol, nerolidol, linalool, farnesol phytol.
Of the lower unsaturated alcohols, consideration should be given to propargyl alcohol.
of the araliphatic alcohols, those which may be men-tioned above all are those with only one benzene residue and in which the aliphatic chain has a maximum of 4 carbon atoms, in which the benzene residue may also be substituted by between 1 and 3 methyl or hydroxy groups, or by halogen atoms, especially chlorine, bromine or iodine, and in which the aliphatic chain may be substituted by one or more func-tional groups selected from the group consisting of free amino groups or monomethyl groups, or dimethyl groups or pyrrolidine or piperidine groups. Of these alcohols, benzyl alcohol and phenethyl alcohol are especially preferred.
The alcohols of the cycloaliphatic or aliphatic cyclo-aliphatic series may derive from mono or polycyclic hydro-carbons and may have a maximum of 34 carbon atoms. Of the alcohols derived from cyclic monoanular hydrocarbons, special mention should be given to those with a maximum of 12 carbon atoms, with rings preferably containing between 5 and 7 carbon atoms, possibly substituted, for example, by between one and three lower alkyl groups, e.g., methyl, ethyl, propyl or isopropyl groups. Specific alcohols of this group are cyclohexanol, cyclohexanediol, 1,2,3-cyclo-hexanetriol and l,3,5-cyclohexanetriol (phloroglucitol), inositol, the alcohols deriving from p-menthane, e.g., carbomenthol, menthol, ~ and ~ - terpineol, 1-terpineol, 4-terpineol and piperitol, or a mixture of these alcohols known as "terpineol", and 1,4- and 1,8-terpin. Alcohols deriving from hydrocarbons with condensed rings are, for example, those of the thujane, pinane, camphane groups, particularly thujanol, sabinol, pinol hydrate, D- and L-borneol and D- and L-isoborneol.
Polycyclic aliphatic cycloaliphatic alcohols for use in obtaining the total, water-insoluble esters of aspects of the present invention are sterols, cholic acids and steroids, e.g., sexual hormones and the synthetic ana-logues, in particular corticosteroids and their deriva-tives. Thus for example it is possible to use: choles-terol, dihydrocholesterol, epidihydrocholesterol, copro-stanol, epicoprostanol, sitosterol, stigmasterol, ergo-sterol, cholic acid, deoxycholic acid, lithocholic acid, estriol, estradiol, equilenin, equilin and their alkyl derivatives, as well as their ethynyl propynyl derivatives in position 17, for example 17-~-ethynyl-estradiol or 7-~-methyl-17~-ethynyl-estradiol, pregnenolone, pregnanediol, testosterone and its derivatives, e.g., 17-~-methyl-1,2-dehydrotestosterone, the alkyl derivatives in position 17 of testosterone and of 1,2-dehydro-testosterone, e.g., 17~-ethynyltestosterone, 17~-propynyltestosterone, norgestrel, hydroxyprogesterone, corticosterone, deoxycorticosterone, 19-nortestosterone, 19-nor-17~-methyltestosterone and 19-nor-17~-ethynyltestosterone, cortisone, hydrocortisone, ~_ 1 33823~6 prednisone, prednisolone, fludrocortisone, dexamethasone, betamethasone, paramethasone, flumethasone, fluocinolone, fluprednylidene, clobetasol, beclomethasone, aldosterone, deoxycorticosterone, alphaxolone, alphadolone, bolasterone and anti-hormones, e.g., cyproterone.
Useful as esterifying components for the new, total, water-insoluble esters of alginic acid, according to aspects of the present invention, are genins (aglycons) of cardioactive glycosides, e.g., digitoxigenin, gitoxigenin, digoxigenin, strophantidin, tigogenin and saponins.
Other alcohols which may be used, according to aspects of the present invention, are the vitamin ones, e.g., axerophthol, vitamins D2 and D3, aneurine, lactoflavine, ascorbic acid, riboflavine, thiamine, and pantothenic acid.
Of the heterocyclic alcohols, the following are preferred according to aspects of the present invention:
furfuryl alcohol, alkaloids and derivatives, e.g., atro-pine, scopolamine, cinchonine, cinchonidine, quinine, morphine, codeine, nalorphine, N-butylscopolammonium bromide, ajmaline; phenylethylamines, e.g., ephedrine, isoproterenol, epinephrine; phenothiazine drugs, e.g., perphenazine, pipothiazine, carphenazine, homofenazine, acetophenazine, fluphenazine, N-hydroxyethyl-promethazine chloride; thioxanthene, drugs, e.g., flupenthixol, clopen-thixol; anticonvulsants, e.g., meprophendiol, antipsychoticdrugs, e.g., opipramol; antiemetics, e.g., oxypendyl; anal-gesics, e.g., carbetidine, phenoperidine and methadol; hyp-notics, e.g., etodroxizine; anorexics, e.g., benzhydrol and diphemethoxidine; muscle relaxants, e.g., cinnamedrine, diphylline, mephenesin, methocarbamol, chlorphenesin, 2,2-diethyl-1,3-propanediol, quaifenesin, idrocilamide; coro-nary vasodilators, e.g., dipyridamole and oxyfedrine; adre-nergic blockers, e.g., propanolol, timolol, pindolol,bupranolol, atenolol, metoprolol, practolol; antineoplas-tics, e.g., 6-axauridine, cytarabine, floxuridine; antibio-tics, e.g., chloramphenicol, thiamphenicol, erythromycin, oleandomycin, lincomycin; antivirals, e.g., idoxuridine;
peripheral vasodilators, e.g., isonicotinyl alcohol; car-bonic anhydrase inhibitors, e.g., sulocarbilate; anti-asthmatics and anti-inflammatories, e.g., tiaramide; sulf-amidics, e.g., 2-p-sulfanylanilinoethanol.
The new, total, water-insoluble esters of alginic acid, according to aspects of the present invention, have the following general formula:

- XORl ~02~I
o ~ _O ~ O

- I ~ ~Y H H ~ Y

wherein Rl and R2 are each independently hydrogen or an alcoholic moiety selected from the group consisting of aliphatic, araliphatic, cycloaliphatic and heterocyclic radicals.

-33 l 33~236 As discussed above, in some cases, total, water-insol-uble alginic acid esters in which the ester groups derive from one or more hydroxy substances with therapeutic action, may be of special interest, and naturally include all possible variations of the same. Especially inter-esting are those substances in which two different types of ester groups deriving from drugs of a hyaroxy character are present. In particular, it is possible to have total, water-insoluble alginic esters deriving, on the one hand from an anti-inflammatory steroid, e.g., one of those mentioned above, and on the other hand from a vitamin, from an alkaloid or from antibiotic, e.g., one of those listed here.
The degree of esterification of alginic acid with the above-mentioned alcohols depends first and foremost on the special properties desired from the various fields of application. For example, they may possess a greater or lesser degree of lipophilia or hydrophilia with regard to such tissues, for example, the skin. Usually, a high degree of esterification to the point of total esteri-fication of alginic acid increases its lipophilic character and therefore decreases its solubility in water, and this provides total, water-insoluble esters useful in aspects of the present invention. For a use in therapy according to aspects of the present invention of the new total, water-insoluble esters, for example, it is of the utmost impor-tance to regulate the degree of esterification in order to ensure good and increased lipophilia compared to metal -- -- ---34 l 338236 alginates. Naturally, it is necessary to consider also the influence of the molecular size of the same esterifying component, which usually has an inversely proportional influence on hydrosolubility.
As has been disclosed previously, esterification of the carboxy groups of alginic acid may play several roles to be exploited in various fields, for example, in medi-cine, using the new, total, water-insoluble esters as therapeutic agents or in surgery using them as plastic articles, as described and claimed in the above-identified parent application. For use in therapy, esterification of an alcohol which can in itself be considered therapeu-tically-active, e.g., anti-inflammatory corticosteroids, for example, with alginic acid as a means of improving therapeutic efficacy.
With regard to similar therapeutically-active alcohols, alginic acid therefore acts as a particularly-efficient vehicle which is compatible with the biological environment. Many of these pharmacologically-active alcohols appear in the above list of alcohols for use in esterification, according to aspects of the present inven-tion. The possible applications of the corresponding new, total, water-insoluble esters therefore are evident, since their indications are the same as those for the free alcohols. Again, as has already been described, in partial esters with therapeutically-active alcohols, it is possible to esterify all of the remaining carboxy groups of the alginic component with pharmacologically-inert alcohols, 35 1 3 3~236 for example saturated lower aliphatic alcohols, for example, ethyl or isopropyl alcohols to provide new, total, water-insoluble esters, according to aspects of the present invention.
One particularly interesting aspect of the present invention is the possibility of preparing more stable drugs than those available up to now. It is possible, for example, to obtain drugs with a "retard" action with the total, water-insoluble alginic esters with therapeutically active alcohols.
For cosmetic purposes, according to aspects of the present invention, it is preferable to use new, total, water-insoluble esters of alginic acid with pharmacologi-cally-inert alcohols, for example, saturated or unsaturated aliphatic alcohols, for example, unsubstituted alcohols of this type with straight or ramified chains, for example, between 1 and 8 carbon atoms, e.g., those specifically men-tioned. Of particular interest also are unsaturated alcohols, for example with one or more double bonds, e.g., vinyl or allyl alcohols, and the condensed derivatives, e.g., especially polyvinyl alcohol or polyvalent alcohols, e.g., glycerin. In this case, also, mixed total, water-insoluble esters may be used according to the particular use for which they are intended.
Cycloaliphatic alcohols also useful, according to aspects of the present invention, for example, are those derived from cyclopentane or cyclohexane and from their derivatives which are substituted by lower alkyl groups, for example, alkyls with between 1 and 4 carbon atoms, especially from methyl groups. Particularly interesting are total, water-insoluble esters with cycloaliphatic and aliphatic-cycloaliphatic alcohols derived from terpenes, those mentioned above, and from therapeutically-active alcohols, which can otherwise be used in cosmetics.
While not an aspect of the present invention, the present disclosure teaches salts with organic bases, especially azotized bases and, therefore, aliphatic, araliphatic, cycloaliphatic or heterocyclic amines. These ammonium salts may derive from therapeutically-acceptable amines or nontoxic but therapeutically-inactive amines, or from amines with a therapeutic action. The first type are aliphatic amines, for example mono-, di- and tri-alkyl-amines with alkyl groups with a maximum of 8 carbon atomsor arylalkylamines with the same number of carbon atoms in the aliphatic part and where aryl means a benzene group possibly substituted by between 1 and 3 methyl groups or halogen atoms or hydroxy groups. The biologically-inactive bases for the formation of the salts may also be cyclic, e.g., monocyclic alkyleneamines with rings of between 4 and 6 carbon atoms, possibly interrupted in their ring by heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, e.g., piperazine or morpholine, or may be substituted, for example by amino or hydroxy functions e.g. aminoethanol, ethylenediamol, ethylenediamine, ephe-drine or choline.

37 t 338236 The biologically-active amines which may be used for salification and whose therapeutic action may be put to use are all known azotized and basic drugs, e.g., those in the following groups: alkaloids, peptides, phenothiazine, benzodiazepine, thioxanthenes, hormones, vitamins, anti-convulsants, antipsychotics, antiemetics, anesthetics, hypnotics, anorexics, tranquilizers, muscle relaxants, coronary vasodilators, antineoplastics, antibiotics, anti-bacterials, antivirals, antimalarials, carbonic anhydrase inhibitors, nonsteroid anti-inflammatories, vasoconstric-tors, cholinergic agonists, cholinergic antagonists, adre-nergic agonists, adrenergic antagonists, and narcotic antagonists.
Examples of specific useful drugs are all those drugs mentioned above having azotized basic groups providing the new, total, water-insoluble alginic esters with therapeuti-cally-active alcohols or those mentioned hereafter, for example, the various antibiotics.
The vehicling action of the new, total, water-insol-uble alginic esters opens up possibilities for new medica-ments wherein the components are: 1) a pharmacologically-active substance or an association or mixture of two or more such substances; and 2) a new, total, water-insoluble alginic ester as described above.
As provided, according to aspects of the present invention, the new, total, water-insoluble alginic esters for use in these medicaments are, above all, those in which the esterifying alcohol is itself not pharmacologically-38 ~ 33~3~
active, for example, a simple aliphatic alcohol, as des-cribed above. Included, however, are medicaments of this type in which the total, water-insoluble ester is also pharmaceutically-active, for example, in the case of one of the new, total, water-insoluble esters described above deriving from pharmacologically-active alcohols.
As provided, according to aspects of the present invention, the use of new, total, water-insoluble alginic esters as a vehicle is particularly useful in ophthal-mology, where it is possible to observe a particularcompatibility of the new products with the corneal epithe-lium, thereby showing excellent tolerability, with no sen-sitization effect. Furthermore, when the medicaments are administered in the form of concentrated solution with elastic-viscous characteristics or in solid form, it is possible to obtain transparent, homogenous and stable films on the corneal epithelium with excellent adhesive quali-ties, guaranteeing prolonged bioavailability of the drug and therefore representing first class products with a retard effect. These ophthalmic medicaments are especially valuable in the veterinary field, considering that there are no veterinary preparations for ophthalmic use contain-ing chemical agents. Usually, preparations intended for human use are utilized, and sometimes these do not guaran-tee a specific range of action or they do not allow for theparticular conditions in which treatment must take place.
This is the case, for example, of infective keratoconjunc-tivitis, pink eye or IBK, an infection which usually 39 q 33~3~
afflicts cattle, sheep and goats. Presumably for these three species there exist specific etiological factors.
More precisely, in cattle the main microorganism involved seems to be Moraxella bovis (even though other agents of a viral origin should not be excluded, for example the Rinotracheitis virus, Micoplasma in sheep, Rickettsia and Chlamydia, Rickettsia in goats).
The disease occurs in an acute form and tends to spread rapidly: in the initial stages, the symptomatology is characterised by blepharospasm and excessive watering of the eye, followed by purulent exudate, conjunctivitis and keratitis, often associated with high temperature, reduced appetite and reduced milk production. Particularly serious are the corneal lesions which in their final stages may even result in perforation of the cornea itself. The clinical course varies from a few days to several weeks.
A wide range of treatments based on chemical agents are used, administered both topically (often associated with - steroid anti-inflammatories), and systemically. Examples of these are: tetracyclines, as oxytetracycline, peni-cillins, e.g. cloxacillin and benzylpenicillin, sulfamides, polymyxin B (associated with miconazole and prednisolone), chloramphenicol and tilosina. Topical treatment of the disease, despite its apparent simplicity, is still an open problem, since for one reason or another, with the ophthal-mic preparations in use heretofore it has not been possible to obtain therapeutically-efficient concentrations of anti-biotic or sulfamidic in the lachrymal secretion. This is l 33823~
quite understandable in the case of solutions, if one thinks of the mainly inclined position of the head in the above-mentioned animals, but it is also true of the semi-solid medicaments since the excipients commonly used in them do not have the necessary qualities of adhesion to the corneal surface, lacking generally a sufficiently high concentration of active substance and being unable to obtain optimum distribution of the same (presence of a distribution gradient). These drawbacks to conventional collyriums in use in ophthalmology have for example been described by Slatter et al. in "Austr.Vet.J.," 1982, 59 (3), pp. 69-72.
By using the new, total, water-insoluble esters, according to aspects of the present invention, these diffi-culties can be overcome. The presence of the new, total,water-insoluble alginic ester as vehicle in ophthalmic drugs allows for the formulation of excellent preparations with no concentration gradient of the active substance and therefore with homogeneity, transparency and excellent adhesion to the corneal epithelium, with no sensitisation effects, with excellent vehicling of the active substance and possibly with a retard effect.
The above-mentioned properties of the new medicaments, according to aspects of the present invention, may of course also be used to advantage in fields other than ophthalmology: they may be applied in dermatology and in infections of the mucus, for example of the mouth. They 41 1 3382~6 may also be used to obtain a systemic effect thanks to transcutaneous absorption, for example in suppositories.
All these applications are possible both in human and veterinary medicine. In human medicine, the new medica-ment, according to aspects of the present invention, isparticularly suitable for use in pediatrics. The inven-tion, according to aspects of the present invention, there-fore also includes, in particular, any one of these thera-peutic applications.
For the sake of brevity, in the following text, reference to the active substance of component (1), according to aspects of the present invention, should be understood to include the association or mixture of two or more active substances.
Component (1) as described above is a pharmacologi-cally-active substance. Such substances can first of all be generically catalogued with respect to their use in the various fields of therapy, beginning with the distinction between human and veterinary medicine, and then specifying the various sectors of application with respect to the organs or tissues to be treated, e.g., ophthalmology, dermatology, otolaryngology, gynecology, angiology, neuro-logy, or any type of pathology of internal organs with can be treated by topical application, for example, rectal applications. According to one particular aspect of the present invention, the pharmacologically-active substance (1) is first and foremost a substance for ophthalmic use.
According to a further criterion, the pharmacologically-42 l 338236 active substance (1) should be identified according to itseffect and can therefore, for example, be an anesthetic, analgesic, anti-inflammatory, vasoconstrictor, antibac-terial, or antiviral drug. In the field of ophthalmology, the indications can, in particular, be for example: miotic, anti-inflammatory, wound healing or antimicrobial effects.
Component (1) may also be, according to an aspect of the present invention, an association of two or more active substances, as contained in many known medicaments. For example, in ophthalmology, it is possible to associate an antibiotic with an antiphlogistic and a vasoconstrictor or several antibiotics with one or more antiphlogistics, or one or more antibiotics with a mydriatic or a myotic or wound healer or an anti-allergic agent, etc. For example, it is possible to use the following associations of ophthalmic drugs: kanamycin + phenylephrine + dexameth-asone phosphate, kanamycin + betamethasone phosphate +
phenylephrine, or similar associations with other antibio-tics used in ophthalmology, e.g., rolitetracycline, neo-mycin, gentamycin, or tetracycline.
In dermatology it is possible to use, according toaspects of the present invention, as active component (1), associations of various antibiotics, e.g., erythromycin, gentamycin, neomycin, gramicidin, polymyxin B, between themselves, or such antibiotics with anti-inflammatory agents, for example corticosteroids, for example hydrocor-tisone + neomycin, hydrocortisone + neomycin + polymyxin B
+ gramicidin, dexamethasone + neomycin, fluorometholone +

-43 l 33823~
neomycin, prednisolone + neomycin, triamcinolone + neomycin + gramicidin + nystatin, or any other association used heretofore in conventional dermatological preparations.
The associations of various active substances are not, of course, limited to these fields, but in all the above sectors of medicine it is possible to use associations similar to those already in use for ~he pharmaceutical preparations known to the art.
According to one particular aspect of the present invention, it is possible to prepare the medicaments of this type starting with the previously isolated and possibly purified salts and, in their solid anhydrous state, as an amorphous powder, which on contact with the tissue to be treated constitute a concentrated aqueous solution of a gelatinous character with viscous consistency and elastic properties. These qualities are also main-tained at stronger dilutions and it is therefore possible to use, instead of the above anhydrous salts, solutions more or less concentrated in water or saline, possibly with the addition of other excipients or additives, e.g., other mineral salts to regulate the pH and osmotic pressure. It is also possible, of course, to use salts for the prepara-tion of gels, inserts, creams or ointments, containing other excipients or ingredients used in traditional formu-lations of these pharmaceutical preparations.
According to a main aspect of the present invention,however, the medicaments containing the new, total, water-insoluble alginic ester are used with therapeutically-- - --44 1 33823~
active or inactive substances as a vehicle alone (excepting possibly an aqueous solvent). Also included, in aspects of the present invention, are the mixtures obtainable from all types of medicaments described here and also mixtures of such medicaments, as well as possibly mixtures of the new total, water-insoluble alginic esters with free alginic acid.
Examples of pharmacologically-active substances (1) which may be used in ophthalmic medicaments, according to aspects of the present invention, are: basic and non-basic antibiotics, for example, aminoglycosides, macrolides, tetracyclines and peptides, e.g., gentamycin, neomycin, streptomycin, dihydrostreptomycin, kanamycin, amikacin, tobramycin, spectinomycin, erythromycin, oleandomycin, carbomycin, spiramycin, oxytetracycline, rolitetracycline, bacitracin, polymyxin B, gramicidin, colistin, chloram-phenicol, linomycin, vancomycin, novabiocin, ristocetin, clindamycin, amphotericin B, griseofulvin, and nystatin and possibly their salts, e.g., sulfates or nitrates, or asso-ciations of these between themselves or with other activeprinciples, e.g., those mentioned hereafter.
Other ophthalmic drugs which may be used to advantage according to aspects of the present invention, are: other anti-infectives, e.g., diethylcarbamazine, mebendazole, sulfamidics, e.g., sulfacetamide, sulfadiazine, sulfisox-azole; antivirals and anti-tumorals, e.g., iododeoxyuri-dine, adenine arabinoside, trifluorothymidine, acyclovir, ethyldeoxyuridine,bromovinyldeoxyuridine,5-iodo-5'-amino--~ 338236 2',5'-dideoxyuridine; steroid anti-inflammatory agents, e.g., dexamethasone, hydrocortisone, prednisolone, fluoro-metholone, medrisone and possibly their esters, for example, phosphoric acid esters; nonsteroid anti-inflam-matories, for example, indomethacin, oxyphenbutazone, flur-biprofen; wound healers, e.g., epidermal growth factor EGF;
local anesthetics, e.g., benoxinate, proparacaine and possibly their salts; cholinergic agonists, e.g., pilocar-pine, methacholien, carbamylcholine, aceclidine, physo-stigmine, neostigmine, and demecarium and possibly theirsalts; cholinergic antagonist drugs, e.g., stropine and its salts; adrenergic agonist drugs, e.g., noradrenaline, adrenalin, naphazoline, methoxamine and possibly their salts; adrenergic antagonist drugs e.g., propanolol, timolol, pindolol, bupranolol, atenolol, metoprolol, oxpre-nolol, practolol, butoxamine, sotalol, butethrin, and labe-talol and possibly their salts.
Associations or mixtures of such drugs between them-selves and possibly with other principles may also be used as component (1), according to aspects of the present invention, if instead of only one active substance (1), associations of active substances are used, e.g., those reported above, the salts of the basic active substances and the total, water-insoluble ester of alginic acid may be mixed with salts of one or more of such basic substances, or possibly mixed salts of this type with a certain number of further acid groups of the polysaccharide salified with the above mentioned metals or bases. For example, it is ~ 1 3 3 8 2 3 6 possible to prepare salts of total, water-insoluble esters of alginic acid with a pharmacologically-inactive alcohol, for example, a lower alkanol, and with a certain percentage of the acid groups salified with the antibiotic kanamycin, another percentage salified with the vasoconstrictor phenylephrine, and a remaining percentage of the free acid groups being salified, for example, with sodium or one of the other above mentioned metals. It is possible to mix this type of mixed salt too, with free alginic acid or its fractions or their metal salts, as indicated above for the medicaments constituted by salts of only one active sub-stance with the above-described polysaccharide esters.
Examples of active substances which may be used, according to aspects of the present invention, on their own or in association between themselves or with other active principles in dermatology are: therapeutic agents, e.g., anti-infective, antibiotic, antimicrobial, anti-inflam-matory, cytostatic, cytotoxic antiviral, anesthetic agents, and prophylactic agents, e.g., sun shields, deodorants, antiseptics and disinfectants. Of the antibiotics, may be mentioned erythromycin, bacitracin, gentamycin, neomycin, aureomycin, gramicidin and associations of the same, anti-bacterials and disinfectants, nitrofurazone, mafenide, chlorhexidine, and 8-hydroxyquinoline derivatives and possibly their salts; anti-inflammatories, above all corti-costeroids, e.g., prednisolone, dexamethasone, flumetha-sone, clobetasol, acetonide of triamcinolone, betamethasone or their esters, e.g., valerianates, benzoates, and dipro--47 l 3 3 8 236 prionates; of the cytotoxics, fluorouracil, methotrexate, and podophyllin; or of the anesthetics, dibucaine, lido-caine, or benzocaine.
This list is of course only for exemplary purposes and any other agents described in literature may be used.
From the examples discussed for ophthalmology and dermatology, it is possible to determine by analogy which medicaments, according to aspects of the present invention, may be used in the other fields of medicine mentioned above, e.g., otolaryngology or odontology or internal medi-cine. For example, in endocrinology, it is possible to use preparations absorbed intradermally or through the mucus, for example, by rectal or nasal absorption, e.g., nasal sprays or preparations for inhalation into the oral cavity or pharynx. These preparations may therefore be, for example, anti-inflammatories, or vasoconstrictors or vaso-pressors, e.g., those already mentioned for ophthalmology, vitamins, antibiotics, e.g., those mentioned above, hor-mones, chemotherapeutics, antibacterials, etc., again as mentioned above for use in dermatology.
According to the chemically new and original procedure described herein and claimed, according to aspects of the present invention, the new, total, water-insoluble alginic acid esters may be prepared to advantage starting with quaternary ammonium salts of alginic acid with an etheri-fying agent in a preferably aprotic organic solvent, e.g., dialkylsulfoxides, dialkylcarboxamides, e.g., in particular lower alkyl dialkylsulfoxides, above all dimethylsulfoxide, and lower alkyl dialkylamides of lower aliphatic acids, e.g. dimethyl or diethyl formamide or dimethyl or diethyl-acetamide. It is possible, however, to use other solvents which are not always aprotic, e.g., alcohols, ethers, ketones, esters, especially aliphatic or heterocyclic alco-hols and ketones with a low boiling point, e.g., hexa-fluoroisopropanol and trifluoroethanol. The reaction is brought about preferably at a temperature of between 0 and 100C, and especially between 25 and 75, for example at 30o.
Esterification is preferably carried out by gradually adding the esterifying agent to the above-mentioned ammo-nium salt dissolved in one of the solvents mentioned, for example, in dimethylsulfoxide. As alkylating agents, those mentioned above can be used, especially hydrocarbyl halides, for example, alkyl halides.
The preferred esterification process, therefore, comprises reacting, in an organic solvent, a quaternary ammonium salt of alginic acid with a stoichiometric 0 quantity of a compound of the formula:
A-X, wherein A is selected from the group consisting of an ali-phatic, araliphatic, cycloaliphatic, aliphatic-cycloali-phatic and heterocyclic radicals and X is a halogen atom, and wherein the stoichiometric quantity of A-X is deter-mined by the degree of esterification desired, namely, total esterification.

~ 338236 As starting quaternary ammonium salts, it is prefer-able to use lower ammonium tetraalkylates, the alkyl groups preferably having between 1 and 6 carbon atoms. Mostly, the alginate of tetrabutylammonium is used. These quater-nary ammonium salts can be prepared by reacting a metal salt of alginic acid, preferably one of those mentioned above, especially a sodium or a potassium salt, in aqueous solution with a sulfonic resin salified with the quaternary ammonium base. The tetraalkyl ammonium alginates deriving from lower alkyls, especially alkyls with between 1 and 6 carbon atoms, are new and form another aspect, according to aspects of the present invention. Unexpectedly, these salts proved to be soluble in the above aprotic solvents, and esterification of alginic acid according to the new procedure, according to aspects of the present invention, is therefore made particularly easy and gives abundant yields. Only by using this procedure, therefore, is it possible exactly to dose the number of carboxy groups of alginic acid to be esterified.
One variation of the previously specified process, of an aspect of the present invention, consists in reacting a potassium or sodium salt of alginic acid, suspended in a suitable solution, e.g., dimethylsulfoxide, with a suitable alkylating agent in the presence of a catalyzing quantity of a quaternary ammonium salt, e.g., tetrabutylammonium iodide. The new procedure makes it possible to obtain, as already stated, the new, total, water-insoluble esters of alginic acid and also substituted alcohols, e.g., glycols, which were previously unobtainable.
To prepare new, total, water-insoluble esters, accord-ing to aspects of the present invention, it is possible to use alginic acids of any origin, for example, the acids extracted from the above-mentioned natural starting mater-ials. The preparation of these acids is described in literature: it is preferable to use purified alginic acids.
The present disclosure also teaches modifications of the process for the preparation of the new, total, water-insoluble esters in which a procedure is interrupted at any stage or which start with an intermediate compound followed by the remaining stages, or in which the starting products are formed in situ.
The following Examples do not in any way limit the scope of the present disclosure.
Example 1 - PreParation of the tetrabutylammonium salt of alqinic acid.
10m.Eq. of sodium salt of alginic acid, corresponding to 2g. of dry compound, are solubilized in 300 ml of distilled water. The solution is then passed through a thermostatic column at 4C cont~;n;ng 15 ml of sulfonic resin (e.g. that known by the Trade-mark DOWEXTM 50x8) in the form of tetrabutylammonium. The sodium-free eluate is frozen and freeze-dried.
Yield 3.3 g.

~ ~ 3 8 ? 3~

Example 2 - Preparation of the (~artial) ethyl ester of alqinic acid - 10% of the carboxY qrouPs esterified - 90%
of the carboxY qrou~s salified.
10 g (23.9 m.Eg.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria hyperborea) are solubilized in 400 ml of DMS0 at 25C. 0.377 g (2.39 m.Eg.) of ethyl iodide are added.

The solution is well agitated for 12 hours at 30C.
a) To completely convert the carboxy salts of tetrabutylammonium residues to sodium salt form, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H~O, cooling it from the outside in a bath of H2O~ice.
The solution is slowly poured by regular drops - and under agitation in 2000 ml of ethyl acetate.
The precipitate is separated by filtration, washed three times with 100 ml of acetone/H2O
5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 6 g.
b) To convert the carbo~y salts of tetrabutyl-ammonium residues to calcium salt form, the procedure is as above, substituting calcium chloride for the sodium chloride.
Yield: 6.1 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

Example 3 - PreParation of the (Partial) ethyl ester of alginic acid - 30% of the carboxY qroups esterified -70% of the carboxy qrouPs salified.
10 g (23 . 9 m.Eq. ) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from AscoPhYllum nodosum) are solubilized in 400 ml of DMSO

-1 ~3823~5 at 25C. 1.31 g (7.18 m.Eq.) of ethyl iodide are added.
The solution is well agitated for 12 hours at 30C.
a) For complete conversion of the carboxy salts of tetrabutylammonium residues to sodium salt, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
- The solution is slowly poured by regular drops and under agitation in 2000 ml of ethyl acetate.
The precipitate is separated by filtration, washed three times with 100 ml of acetone/H2O
5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 5 g.
b) To convert the carboxy salt of tetrabutylammonium residues to calcium salts, the procedure is as above, substituting calcium chloride for the sodium chloride.
Yield: 5.1 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

ExamPle 4 - PreParation of the (Partial) ethYl ester of alginic acid - 50% of the carboxy qroups esterified -50~ of the carboxY ~rouPs salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Macrocystis Pyrifera) are solubilized in 400 ml of DMSO
at 25C. 1.88 g (11.9 m.Eq.) of ethyl iodide are added.
The solution is well agitated for 12 hours at 30C.
a) For complete conversion of the carboxy salts of tetrabutylammonium residues to sodium salt, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
The solution is slowly poured by regular drops and under agitation in 2000 ml of ethyl acetate.
The precipitate is separated by filtration, washed three times with 100 ml of acetone/H2O
5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 4.5 9.
b) To convert the carboxy salt of tetrabutylammo-nium residues to calcium salts, the procedure is as above, substituting calcium chloride for the sodium chloride.
Yield: 4.6 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

Example 5 - PreParation of the (Partial) ethyl ester of alqinic acid - 70% of the carboxY grouPs esterified -30% of the carboxy grouPs salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from -_ 55 _ 1 3 3 8 2 3 6 Laminaria hYPerborea) are solubilized in 400 ml of DMSO
at 25C. 2.64 g (16.7 m.Eq.) of ethyl iodide are added.
The solution is well agitated for 12 hours at 30C.
a) For complete conversion of the carboxy salts of tetrabutylammonium residues to so~ium salt, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
The solution is slowly poured by regular drops and under agitation in 2000 ml of ethyl acetate.
The precipitate is separated by filtration, washed three times with 100 ml of acetone/H2O
5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 4 g.
b) To convert the carboxy salt of tetrabutylammo-nium residues to calcium salts, the procedure is as above, substituting calcium chloride for the sodium chloride.
Yield: 4.2 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

ExamPle 6 - PreParation of the (Partial) ethYl ester of alqinic acid - 9o~ of the carboxy qrouPs esterified -10% of the carboxY qrouPs salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from MacrocYstis PYrifera) are solubilized in 400 ml of DMSO
at 25C. 3.39 g (21,5 m.Eq.) of ethyl iodide are added.
The solution is well agitated for 12 hours at 30C.
a) For complete conversion of the carboxy salts of tetrabutylammonium residues to sedium salt, to the resulting solution is added 2,5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
The solution is slowly poured by regular drops and under agitation in 2000 ml of ethyl acetate.
The precipitate is separated by filtration, washed 3 times with 100 ml of acetone/H2O 5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 5.5 g.
b) To convert the carboxy salt of tetrabutylammo-nium residues to calcium salts, the procedure is - as above, substituting calcium chloride for the sodium chloride.
Yield: 5.6 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

Example 7 - Preparation of the (Partial) isoproPYl ester of alqinic acid - 90% of the carboxY qrouPs esterified -10% of the carboxY qrouPs salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from -AscoPhYllum nodosum) are solubilized in 400 ml of DMSO
at 25C. 3.73 g (21.5 m.Eq.) of isopropyl iodide are added.
The solution is well agitated for 12 hours at 30C.
a) For complete conversion of the c~rboxy salts of tetrabutylammonium residues to sodium salt,- to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
The solution is slowly poured by regular drops and under agitation in 2000 ml of ethyl acetate.
The precipitate is separated by filtration, washed 3 times with 100 ml of acetone/H2O 5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 4.2 g.
b) To convert the carboxy salt of tetrabutylammo-nium residues in calcium salts, the procedure is as above, substituting the sodium chloride for calcium chloride.
Yield: 4 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

ExamPle 8 - PreParation of the (Partial~ isoPropyl ester of alginic acid - 70% of the carboxy groups esterified -30% of the carboxy groups salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from ..

Laminaria hyPerborea) are solubilized in 400 ml of DMSO
at 25C. 2.9 g (16.7 m.Eq.) of isopropyl iodide are added.
The solution is well agitated for 12 hours at 30C.
a) For complete conversion of the carboxy salts of tetrabutylammonium residues to sodium salt, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
The solution is slowly poured by regular drops and under agitation into 2000 ml of ethyl acetate. The precipitate is separated by filtra-tion, washed 3 times with 100 ml of acetone/
H2O 5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 4 g.
b) To convert the carboxy salts of tetrabutylammo-nium residues in calcium salts, the procedure is as above, substituting the sodium chloride for calcium chloride.
Yield: 3.8 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

ExamPle 9 - PreParation of the (Partial) isoProPYl ester of alqinic acid - 50% of the carboxY qroups esterified -50% of the carboxy grouPs salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from ~ 3~8~

., Macrocystis pYrifera) are solubilized in 400 ml of DMSO
at 25C. 2.07 g (11.9 m.Eq.) of isopropyl iodide are added.
The solution is well agitated for 12 hours at 30C.
a) For complete conversion of the carboxy salts of tetrabutylammonium residues to sodium salt, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
The solution is slowly poured by regular drops and under agitation into 2000 ml of ethyl acetate. The precipitate is separated by filtration, washed 3 times with 100 ml of - acetone/H2O 5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 4.2 g.
b) To convert the carboxy salt of tetrabutylammo-nium residues in calcium salts, the procedure is as above, substituting the sodium chloride for calcium chloride.
Yield: 4.2 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

ExamPle 10 - PreParation of the (Partial) isoProPYl ester of alqinic acid - 30% of the carboxy grouPs esterified - 70% of the carboxy groups salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from ..
AscophYllum nodosum) are solubilized in 400 ml of DMSO
at 25C. 1.24 g (7.18 m.Eq.) of isopropyl iodide are added.
The solution is well aqitated for 12 hours at 30C.
a) For complete conversion of the c-arboxy salts of tetrabutylammonium residues to sodium salt, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
The solution is slowly poured by regular drops and under agitation into 2000 ml of ethyl acetate. The precipitate is separated by filtration, washed 3 times with 100 ml of acetone/H2O 5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 5.5 g.
b) To convert the carboxy salt of tetrabutylammo-nium residues in calcium salts, the procedure is as above, substituting the sodium chloride for calcium chloride.
Yield: 5.4 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

Example 11 - PreParation of the (Partial) isoProPYl ester of alqinic acid - 10% of the carboxY qroups esterified - 90% of the carboxY grouPs salified.
10 g (23.9 m.Eq.~ of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from - 61 - 1 ~ 3 8 236 Laminaria hyperborea) are solubilized in 400 ml of DMSO
at 25C. 0.42 g (2.3 m.Eq.) of isopropyl iodide are added.
The solution is well agitated for 12 hours at 30C.
a) For complete conversion of the carboxy salts of tetrabutylammonium residues to sodium salt, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
The solution is slowly poured by règular drops and under agitation in 2000 ml of ethyl acetate.
The precipitate is separated by filtration, washed 3 times with 100 ml of acetone/H2O 5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 5.8 g.
b) To convert the carbo~y salt of tetrabutylammo-nium residues in calcium salts, the procedure is as above, substituting the sodium chloride for calcium chloride.
Yield: 5.8 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups~, 4th Edition, John Wiley and Sons Publication.

ExamPle 12 - PreParation of the (Partial) terbutYl ester of alqinic acid - 90% of the carboxY qroups esterified -10% of the carboxY qrouPs salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from -AscoPhyllum nodosum) are solubilized in 400 ml of DMSO
at 25C. 4.1 g (21.5 m.Eq.) of terbutyl iodide are added.
The solution is well agitated for 12 hours at 30C.
a) For complete conversion of the carboxy salts of tetrabutylammonium residues to sodium salt, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
The solution is slowly poured by regular drops and under agitation into 2000 ml of ethyl acetate. The precipitate is separated by filtration, washed 3 times with 100 ml of acetone/H2O 5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 4 g.
b) To convert the carboxy salt of tetrabutylammo-nium residues in calcium salts, the procedure is as above, substituting the sodium chloride for calcium chloride.
Yield: 4.1 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

ExamPle 13 - PreParation of the (Partial) terbutyl ester of alginic acid - 70% of the carboxY qroups esterified -30% of the carboxy qrouPs salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from -Laminaria hYPerborea) are solubilized in 400 ml of DMSO
at 25C. 3.14 g (16.7 m.Eq.) of terbutyl iodide are added.
The solution is well agitated for 12 hours at 30C.
a) For complete conversion of the carboxy salts of tetrabutylammonium residues to sodium salt, to the resulting solution is added 2,5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
The solution is slowly poured by regular drops and under agitation in 2000 ml of ethyl acetate.
The precipitate is separated by filtration, washed 3 times with 100 ml of acetone/H2O 5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 5 g.
b) To convert the carbo~y salt of tetrabutylammo-nium residues in calcium salts, the procedure is as above, substituting the sodium chloride for calcium chloride.
Yield: 5 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 16~-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

ExamPle 14 - Preparation of the (partial) terbutyl ester of alqinic acid - 50% of the carboxy qroups esterified -50% of the carboxy grouPs salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from ., MacrocYstis pyrifera) are solubilized in 400 ml of DMSO
at 25C. 2.25 g (11.9 m.Eq.) of terbutyl iodide are added.
The solution is well agitated for 12 hours at 30C.
a) For complete conversion of the c~rboxy salts of tetrabutylammonium residues to sodium salt, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
The solution is slowly poured by regular drops and under agitation into 2000 ml of ethyl acetate. The precipitate is separated by filtration, washed 3 times with 100 ml of acetone/H2O 5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 5.4 g.
b) To convert the carboxy salt of tetrabutylammo-nium residues in calcium salts, the procedure is as above, substituting the sodium chloride for calcium chloride.
Yield: 5.4 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

ExamPle 15 - PreParation of the (Partial) terbutYl ester of alqinic acid - 30% of the carboxy qroups esterified -70% of the carboxy groups salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained - 65 - 1 338-23~

from Laminaria hyPerborea) are solubilized in 400 ml of DMSO at 25C. 1.34 g (7.18 m.Eq.) of terbutyl iodide are added.
The solution is well agitated for 12 hours at 30C.
a) For complete conversion of the carboxy salts of tetrabutylammonium residues to sodium salt, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath o~f H2O/ice.
The solution is slowly poured by regul`ar drops and under agitation into 2000 ml of ethyl acetate. The precipitate is separated by filtration, washed 3 times with 100 ml of acetone/H2O 5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 5.5 g.
b) To convert the carboxy salt of tetrabutylammo-nium residues in calcium salts, the procedure is as above, substituting the sodium chloride for calcium chloride.
Yield: 5.7 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

Example 16 - PreParation of the (partial) terbutYl ester of alginic acid - 10% of the carboxy grouPs esterified -90% of the carboxY groups salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from - 66 - 1 3 ~ ~ ~ 3 6 Macrocystis PYrifera) are solubilized in 400 ml of DMSO
at 25C. 0.45 g (2.39 m.Eq.) of terbutyl iodide are added.
The solution is well agitated for 12 hours at 30C.
a) For complete conversion of the c~rboxy salts of tetrabutylammonium residues to sodium salt, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
The solution is slowly poured by regular drops and under agitation into 2000 ml of ethyl acetate. The precipitate is separated by filtration, washed 3 times with 100 ml of acetone/H2O 5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 5 g.
b) To convert the carboxy salt of tetrabutylammo-nium residues in calcium salts, the procedure is as above, substituting the sodium chloride for calcium chloride.
Yield: 5 y.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organ1c analysis via functional groups", 4th Edition, John Wiley and Sons Publication. - -Example 17 - PreParation of the (Partial) benzYl ester of alginic acid - 90% of the carboxy qrouPs esterified -10% of the carboxY grouPs salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of -1 33~2~6 ..
alginic acid (prepared from alginic acid obtained from AscophYllu.n nodosum) are solubilized in 400 ml of DMSO
at 25C. 3.76 g (21.5 m.Eq.) of benzyl bromide and 0.1 g of tetrabutylammonium iodide are added.
The solution is well agitated for 12_hours at 30C.
a) For complete conversion of the carbo~y salts of tetrabutylammonium residues to sodium salt, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
The solution is slowly poured by regular drops and under agitation into 2000 ml of ethyl acetate. The precipitate is separated by filtration, washed 3 times with 100 ml of acetone/H2O 5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 5 g.
b~ To convert the carboxy salt of tetrabutylammo-nium residues in calcium salts, the procedure is as above, substituting the sodium chloride for calcium chloride.
Yield: 5 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

ExamPle 18 - Preparation of the (Partial) benzyl ester of alqinic acid - 70% of the carboxy grouPs esterified -30% of the carboxY qrouPs salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of - 68 - 1 3 3 8 23 ~

alginic acid (prepared from alginic acid obtained from Laminaria hYPerborea) are solubilized in 400 ml of DMSO
at 25C. 2.9 g (16.7 m.Eq.) of benzyl bromide and 0.1 g of tetrabutylammonium iodide are added.
The solution is well agitated for lZ hours at 30C.
a) For complete conversion of the carboxy salts of tetrabutylammonium residues to sodium salt, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
The solution is slowly poured by regular drops and under agitation into 2000 ml of ethyl acetate. The precipitate is separated by filtration, washed 3 times with 100 ml of acetone/H2O 5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 4.6 g.
b) To convert the carboxy salt of tetrabutylammo-nium residues in calcium salts, the procedure is as above, substituting the sodium chloride for calcium chloride.
Yield: 4.5 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

ExamPle 19 - PreParation of the (Partial) benzYl ester of alqinic acid - 50% of the carboxY qrouPs esterified -50% of the carboxY qrouPs salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of - 69 - 1 3 3 8 2 3 f3 alginic acid (prepared from alginic acid obtained from AscoPhyllum nodosum) are solubilized in 400 ml of DMSO
at 25C. 2.1 g (11.9 m.Eq.) of benzyl bromide and 0.1 g of tetrabutylammonium iodide are added.
The solution is well agitated for 12-hours at 30C.
a) For complete conversion of the carboxy salts of tetrabutylammonium residues to sodium salt, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
The solution is slowly poured by regular drops and under agitation into 2000 ml of ethyl acetate. The precipitate is separated by filtration, washed 3 times with 100 ml of acetone/H2O 5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 4.2 g.
b) To convert the carboxy salt of tetrabutylammo-nium residues in calcium salts, the procedure is as above, substituting the sodium chloride for calcium chloride.
Yield: 4.3 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

ExamPle 20 - Preparation of the (Partial) benzyl ester of alginic acid - 30% of the carboxY qrouPs esterified -70% of the carboxy grouPs salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of ., alginic acid (prepared from alginic acid obtained from AscoPhYllum nodosum) are solubilized in 400 ml of DMSO
at 25C. 1.25 g (7.18 m.Eq.) of benzyl bromide and 0.1 g of tetrabutylammonium iodide are added.
The solution is well agitated for 12-hours at 30C.
a) For complete conversion of the carboxy salts of tetrabutylammonium residues to sodium salt, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice.
The solution is slowly poured by regular drops and under agitation into 2000 ml of ethyl acetate. The precipitate is separated by filtration, washed 3 times with 100 ml of acetone/H2O 5:1 and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 6 g.
b) To convert the carboxy salt of tetrabutylammo-nium residues in calcium salts, the procedure is as above, substituting the sodium chloride for calcium chloride.
Yield: 6.1 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

ExamPle 21 - PreParation of the (Partial) benzyl ester of alqinic acid - 10% of the carboxy grouPs esterified -90% of the carboxY grouPs salified.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from MacrocYstis Pyrifera) are solubilized in 400 ml of DMSO
at 25C. 0.42 g (2.39 m.Eq.) of benzyl bromide and 0.1 g of tetrabutylammonium iodide are added.
The solution is well agitated for 12 ~ours at 30C.
a) For complete conversion of the carboxy salts of tetrabutylammonium residues to sodium salt, to the resulting solution is added 2.5 g of NaCl dissolved in 50 ml of distilled H2O, cooled from the outside with a bath of H2O/ice. The solution is slowly poured by regular drops being kept in agitation into 2000 ml of ethyl acetate.
The precipitate is separated by filtration, washed 3 times with 100 ml of acetone/H2O 5:1 - and 3 times with 100 ml of pure acetone, then vacuum dried.
Yield: 5 g.
b) To convert the carboxy salt of tetrabutylammo-nium residues in calcium salts, the procedure is as above, substituting the sodium chloride for calcium chloride.
Yield: 5 g.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

ExamPle 22 - PreParation of the methYl ester of alginic .
8.35 g (20 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from ` -1 ~82~

AscoPhYllum nodosum) are solubilized in 400 ml of DMSO
at 25C. 3.66 g (25 m.Eq.) of methyl iodide are added.
The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl aceta~e (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 4 g of the compound named in the title are obtained.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

Example 23 - PreParation of the benzYl ester of alqinic acid.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from MacrocYstis PYrifera) are solubilized in 400 ml of DMSO
at 25C. 4.45 g (26 m.Eq.) of benzyl bromide and 0.1 g of tetrabutylammonium iodide are added.
The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 5 g of the compound named in the title are obtained.

73 _ 1 338236 Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

Example 24 - PreParation of the terbutYl ester of alqinic acid.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria hyPerborea) are solubilized in 400 ml of DMS0 at 25C. 4.8 g (26 m.Eq.) of terbutyl iodide are added.
The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.S 1 of ethyl acetate (or toluene). The precipitate is-filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 3.8 g of the compound named in the title are obtained.
Quantitative determination of the ester groups is carried out~by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

ExamPle 25 - PreParation of the isoProPyl-ester of alginic acid.
10 g (23,9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria hYPerborea) are solubilized in 400 ml of DMSO

-- 74 - 1 3 3 8 2 3 ~

at 25C. 4.4 g (26 m.Eq.) of isopropyl iodide are added.
The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl acetate (OE toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 4.5 g of the compound named in the title are obtained.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

1 33~36 ExamPle 26 - PreParation of the ethyl ester of alqinic acid.
10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from AscoPhYllum nodosum) are solubilized in 400 ml of DMSO
at 25C. 4 g (26 m.Eq.) of ethyl iodide are added.
The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 4.5 g of the compound named in the title are obtained.
Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

- 76 - 1 33~23~

ExamPle 26A - PreParation of the amikacin salt of alqinic acid Partially esterified with ethanol - 75% of carboxYlic qrouPs esterified with ethanol - 25% of carboxylic qrouPs salified with amikacin.
147 mg of amikacin (1 m.Eq.) are solubilized in 20 ml of water.
0.81 g of a 75% ethyl ester of alginic acid and sodium salt at 25% (corresponding to 1 m.Eq. of a monomeric unit relative to the non-esterified carboxyl), are solubilized in 400 ml of water. The solution is eluted in a thermostatic column at 20 and containing 2 ml of sulfonic resin (Dowex 50 x 8) in H~ form.
The sodium-free eluate is gathered under agitation in the solution of amikacin base. The resulting solution is instantly frozen and freeze-dried.
Microbiological determination carried out on St.
aureus ATCC 29737 in comparison to standard amikacin, shows a content of 8.5% in weight of amikacin base, corresponding to the theoretically calculated value.

Example 26B - PreParation of erYthromycin salt of alginic acid PartiallY esterified with ethanol - 75% of carboxylic grouPs esterified with ethanol - 25% of carboxYlic qrouPs salified with erYthromycin.
0.81 g of a 75% ethyl ester of alginic acid and sodium salt at 25% (corresponding to l m.Eq. of a monomeric unit relative to the non-esterified c~arboxyl), are solubilized in 400 ml of water. The solution is eluted in a thermostatic column at 20 containing 2 ml of sulfonic resin (Dowex 50 x 8) in H+ form.

~ 77 ~ ~33~2~6 To the sodium-free eluate are added 734 mg of erythromycin base (1 m.E.q.). The resulting solution is instantly frozen and freeze-dried.
Microbiological determination on St. aureus ATCC
6538 in comparison to standard erythromycin, shows a content of 31.7% in weight of erythromycin base, corresponding to the theoretically calculated weight.

Example 26C - Preparation of streptom~cine salt of alginic acid partiall~ esterified with ethanol - 75% of carboxylic qrouPs esterified with ethanol - 25% of carboxylic ~rouPs salified with streptomycine.
243 mg of streptomycine sulphate (1 m.Eq.) are solubilized in 20 ml of water. The solution of eluted in a thermostatic column at 5 containing 2 ml of quaternary ammonium resin (Dowex 1 x 8) in OH~form.
The sulphate-free eluate is gathered in a thermostatic container at a temperature of 5.
0.81 g of a 75% ethyl ester of alginic acid and 25%
sodium salt (corresponding to 1 m.Eq. of a monomeric unit relative to the non-esterified carboxyl), are solubilized in 400 ml of water. The solution is eluted in a thermostatic column at 20 and containing 2 ml of sulphonic resin tDowex 50 x 8) in H+ form.
The sodium-free eluate is gathered under agitation in the solution of streptomycine base. The resulting solution is instantly frozen and freeze-dried.
Microbiological determination on B. subtiiis ATCC
6633 in comparison with streptomycine standard, shows a content of 10.9% in weight of streptomycine base, corresponding to the theoretically calculated content.

Example 26D - PreParation of the (partial and mixed ethanol and fluorocortisone esters (C21) of alqinic acid - 40% of carboxylic grouPs esterified with ethanol - 20%
of carboxYlic qroups esterified with fluorocortisone (C21) - 40% of salified carboxylic qrouPs (Na).
8.35 g of the tetrabutylammonium salt of alginic acid (prepared from Laminaria hYPerborea) corresponding to 20 m.Eq. of a monomeric unit are solubilized in 350 ml of dimethylsulfoxide at 25, 0.62 g (4 m.Eg.) of ethyl iodide are added and the solution is kept for 24 hours at 300.
0.89 g (2 m.Eq.) of 9C~-fluoro-21-bromo-4-pregnene-11~ , 17 ~ -diol-3, 20-dione are added and the solution is kept for 24 hours at 30.
A solution is then added containing 100 ml of water and 5 g of sodium chloride and the resulting mixture is slowly poured into 2,000 ml of acetone under constant agitation. A precipitate is formed which is filtered and washed three times with 100 ml of acetone/water 5:1 and three times with 100 ml acetone and finally vacuum dried for eight hours at 30.
3.5 g of the partial and mixed ethanol and fluorocortisone ester in the title are obtained.
Quantitative determination of fluorocortisone, after mild alkaline hydrolysis with hydroalcoholic solution of Na2CO3 and extraction with chloroform, is carried out according to British Pharmacopea, 1980.
Quantitative determination of the ethoxyls is carried out according to R.H. Cundiff and P.C. Markunas [Anal. Chem. 33, 1028-1030 (1961)].

1 3 3 ~

ExamPle 26E - Preparation of the (Partial) fluorocortisone esters (C21) of al~inic acid - 20% of esterified carboxylic qrouPs - 80% of salified carboxYlic ~roups (Na).

4.18 g of the tetrabutylammonium salt of alginic acid (prepared from Laminaria hYperboreat corresponding to 10 m.Eq. of a monomeric unit are solubilized in 210 ml of dimethylsulfoxide at 25, 0.89 g (2 m.Eq.) of gc~
-fluoro-21-bromo-4-pregnene-1 ~ , 17~ -diol-3,20-dione are added and the resulting solution is kept for 12 hours at 30.
A solution is then added containing 62 ml of water and 5 g of sodium chloride and the resulting mixture is slowly poured into 2,000 ml of acetone under constant agitation. A precipitate is formed which is filtered and washed three times with 100 ml of acetone/water 5:1 and three times with acetone and finally vacuum dried for eight hours at 30.
The product is then dissolved in 300 ml of water containing 1% of sodium chloride and the solution is slowly poured into 1,500 ml of acetone under constant agitation. A precipitate is formed which is filtered and washed twice with 100 ml of acetone/water 5:1 and three times with 100 ml of acetone and finally vacuum dried for 24 hours at 30. 1.5 g of the partial fluorocortisone compound in the title are obtained.
Quantitative determination of fluorocortisone after mild alkaline hydrolysis with hydroalcoholic solution of Na2C03 and extraction with chloroform, is carried out according to sritish Pharmacopea, 1980, p. 196.

Example 26F - PreParation of the (mixed) ethanol and hYdrocortisone esters (C21) of alginic acid - 80% of carboxYlic qrouPs esterified with ethanol - 20% of carboxylic ~rouPs esterified with hYdrocortisone (C~lL.
4.18 g of the tetrabutylammonium salt of alginic acid (prepared from Laminaria hYperborea) corresponding to 10 m.Eq. of a monomeric unit are solubilized in 210 ml of dimethylsulfoxide at 25, 1.25 g (8 m.Eq.) of ethyl iodide are added and the solution is kept at 30 for 12 hours.
0.85 g (2 m.Eq.) of 21-bromo-4-pregnene~ , 17~ -diol-3,20-dione are added and the solution is kept for 24 hours at 30.
A solution is then added containing 100 ml of water and 5 g of sodium chloride and the resulting mixture is slowly poured into 2,000 ml of acetone under constant agitation. A precipitate is formed which is filtered and washed three times with 100 ml of acetone/water 5:1 and three times with 100 ml of acetone and finally vacuum dried for eight hours at 30.
1.8 g of the mixed ethanol and hydrocortisone ester compound in the title are obtained. Quantitative determination of hydrocortisone, after mild alkaline hydrolysis with hydroalcoholic solution of Na2CO3 and extraction with chloroform, is carried out according to British Pharmacopea, 1980.
Quantitative determination of the ethoxyls is carried out according to R.H. Cundiff and P.C. Markunas ~Anal. Chem. 33, 1028-1030)].

ExamPle 26G - PreParation of the (partial) hYdrocortisone esters (C21) of alqinic acid - 20~ of esterified carboxYlic qroups - 80% of salified carboxYlic ~rouPs (Na).
8.35 g of the tetrabutylammonium salt of alginic acid (prepared from MicrocYstis pYrifera~ corresponding to 2-0 m.Eq. of a monomeric unit are solubilized in 350 ml of dimethylsulfoxide at 25, 0.850 g. (2 m.Eq.) of 21-bromo-4-pregnene-11~ , 17 ~-diol-3,20-dione are added and the resulting solution is kept for 24 hours at 30.
A solution is then added containing 100 ml of water and 5 g of sodium chloride and the resulting mixture is slowly poured into 2,000 ml of acetone under contant agitation. A precipitate is formed which is filtered and whashed three times with 100 ml of acetone/water 5:1 and three times with acetone and finally vacuum dried for eight hours at 30.
The product is then dissolved in 300 ml of water containing 1% of sodium chloride and the solution is slowly poured into 1,500 ml of acetone under constant agitation. A precipitate is formed which is filtered and washed twice with 100 ml of acetone/water 5:1 and three times with 100 ml of acetone and finally vacuum dried for 24 hours at 30.
3 g of the partial hydrocortisone compound in the title are obtained.
Quantitative determination of hydrocortisone after mild alkaline hydrolysis with hydroalcoholic solution of Na2C03 and extraction with chloroform, is carried out according to British Pharmacopea, 1980, p. 224.

- 82 - ~ 3 3 8 23 6 Example 26H - Preparation of the (mixed) ethanol and fluorocortisone ester (C21) of alqinic acid - 80% of carboxylic qroups esterified with ethanol - 20% of carboxylic qroups esterified with fluorocortisone (C21L.
4.18 g of the tetrabutylammonium salt of alginic acid (prepared from MacrocYstis pYrifera~ corresponding to 10 m.Eq. of a monomeric unit are solubilized in 210 ml of dimethylsulfoxide at 25, 1.25 g (8 m.Eq.) of ethyl iodide are added and the solution is kept for 24 hours at 3oo.
0.89 g (2 m.Eq.) of 9~ - fluoro-21-bromo-4-pregnene-11~ , 17~X-diol-3~20-dione are added and the solution is kept for 24 hours at 30.
A solution is then added containing 100 ml of water and 5 g of sodium chloride and the resulting mixture is slowly poured into 2,000 ml of acetone under constant agitation. A precipitate is formed which is filtered and washed three times with 100 ml of acetone/water 5:1 and three times with 100 ml of acetone and finally vacuum dried for eight hours at 30.
1.7 g of the mixed ethanol and fluorocortisone ester compound featured in the title are obtained.
Quantitative determination of fluorocortisone, after mild alkaline hydrolysis with hydroalcoholic solution of Na2CO3 and extraction with chloroform, is carried out according to British Pharmacopea, 1980.
Quantitative determination of the ethoxyls is carried out according to R.H. Cundiff and P.C. Markunas tAnal. Chem. 33, 1028-1030 (1961)].

--Example 26I - Preparation of the (Partial and mixed) ethanol and hydrocortisone ester fC21) of alginic acid -40% of car~oxylic qroups esterified with ethanol - 20% of carboxylic ~roups esterified with hYdrocortisone (C21~) -40% of salified carboxYlic groups (Na).
4.18 g of the tetrabutylammonium sa~t of alginic acid (prepared from Macrocystis pyrifera) corresponding to 10 m.Eq. of a monomeric unit are solubilized in 210 ml of dimethylsulfoxide at 25, 0.62 g (4 m.Eq.) of ethyl iodide are added and the solution is kept for 24 hours at 3oo.
0.85 g (2 m.Eq.) of 21-bromo-4-pregnene-11~ , 17~ -diol-3,20-dione are added and the solution is kept for 24 hours at 30.
A solution is then added containing 200 ml of water and 5 g of sodium chloride and the resulting mixture is slowly poured into 2,000 ml of acetone under constant agitation. A precipitate is formed which is filtered and washed three times with 100 ml of acetone/water 5:1 and three times with 100 ml of acetone and finally vacuum dried for eight hours at 30.
1.7 g of the partial and mixed ethanol and hydrocortisone ester compound in the title are obtained.
Quantitative determination of hydrocortisone, after mild alkaline hydrolysis with hydroalcoholic solution of Na2C03 and extraction with chloroform, is carried out according to British Pharmacopea, 1980.
Quantitative determination of the ethoxyls is carried out according to R.H. Cundiff and P.C. Markunas tAnal. Chem. 33, 1028-1030 (1961)].

1 338~36 -As noted hereinbefore, one object of the present invention is the provision of pharmaceutical preparations containing one or more total, water-insoluble alginic acid esters as described above, or medicaments resulting from association of one such total, water-insoluble ester with a pharmacologically-active substance as described above, that is, medicaments in which the total, water-insoluble alginic ester acts as a vehicle substance.
The pharmaceutical preparations of aspects of the present invention containing therapeutically-active total, water-insoluble alginic esters, possibly in the form of the above medicaments resulting from the association of compo-nents (1) and (2), contain the usual excipients and may be destined for oral, rectal, parenteral, subcutaneous, local or intradermal use. They are therefore in solid or semisolid form, for example pills, tablets, gelatin cap-sules, capsules, suppositories, soft gelatin capsules. For parenteral and subcutaneous use, it is possible to use forms intended for intramuscular and intradermal admini-stration, or suitable for intravenous infusion or injec-tions. It is therefore possible to present active com-pounds as solutions or as freeze-dried powders to unite with one or more excipients or diluents acceptable from a pharmaceutical point of view and convenient for the above uses and of compatible osmolarity with the physiological fluids. For local use, preparations in spray form should be considered, for example, nasal sprays, creams or oint-- 1 33~236 ments for topical use or suitably prepared plasters for intradermal administration.
The preparations, according to aspects of the present invention, may be intended for administration to man or animal. These contain preferably between 0.01% and 10% of active component for the solutions, sprays, ointments and creams and between 1% and 100% and preferably between 5%
and 50% of the active compound for the preparation in solid form. The dosage to be administered depends on the parti-lo cular indication, and on the desired effect of chosenadministration route. The daily dosage of these prepara-tions may be estimated from those in use for the corres-ponding known preparations for the corresponding uses of the therapeutically-active alcohol, whose action is to be exploited. In this may, for example, the dosage of a total, water-insoluble alginic ester with cortisone may be derived from its content in this same steroid and from its usual dosage in the known pharmaceutical preparation.
one particular form of pharmaceutical preparations, according to aspects of the present invention, is repre-sented by the above-described medicaments constituted by the association of a total, water-insoluble alginic ester and an active substance, for example, for topical use.
These may also be in solid form, for example, as freeze-dried powders containing only the two components (1) and(2) as a mixture or separate. When these medicaments in solid form come into contact with the epithelium to be treated, they form more or less concentrated solutions 86 ~ 338236 according to the nature of the particular epithelium to be treated, with the same characteristics as the solutions previously prepared in vitro and which represent another particularly important aspect of the invention provided by the heretofore-mentioned divisional application. These solutions are preferably made with distilled water or sterile saline and preferably contain no other pharmaceu-tical vehicle except the total, water-insoluble alginic ester or one of its salts.
The concentrations of these solutions may also vary greatly, for example, between 0.01 and 75%, both for each of the two components considered separately, and for their mixture or salts. Preference is given, in particular, to solutions with a pronounced elastic-viscous character, for example, with a content of between 10% and 90% of the medi-cament or of each of its components.
Of particular importance are medicaments of this type, both in anhydrous form (freeze-dried powders) or as concen-trated solutions or diluted in water or saline, possibly with the addition of additive or auxiliary substance, e.g., in particular disinfectant substances or mineral salts acting as buffers or others, used for ophthalmic purposes.
Of the medicaments according to aspects of the present invention, those to be chosen, as the case may be, are those with a degree of acidity suitable for the zone to which they are to be applied, that is with a physiologi-cally-tolerable pH. Adjustment of the pH, for example in the above mentioned salts of the total, water-insoluble -87 ~ 3~
alginic acid esters with a basic active substance, may be effected by suitably regulating the quantities of polysac-charide, its salts and of the basic substance itself. In this way, for example, if the acidity of a new, total, water-insoluble alginic ester salt with a basic substance is too high, the excess of free acid groups can be neutra-lized with the above-mentioned inorganic bases, for example, with sodium, potassium or ammonium hydrate.
Preparation of the salts according to aspects of the present invention, may be carried out in the known way, by bringing into contact solutions or aqueous suspensions or in organic solvents of the two components (1) and (2) and possibly of bases or basic salts of the above-mentioned alkaline metals or alkaline earth metals or magnesium or aluminum in calculated quantities, and isolating the salts in anhydrous amorphous form according to the known methods.
It is possible, for example, first of all to prepare aqueous solutions of the two components (1) and (2), freeing these components from aqueous solutions of their salts with suitable ion-exchangers, uniting the two solu-tions at a low temperature, for example, between 0 and 20C, if the salts thus obtained are easily soluble in water it is freeze-dried, while salts with poor solubility can be separated by centrifugation or filtration or decan-tation and possibly subsequently dried.
For these associated medicaments too, the dose isbased on that of the active principles used singly and may therefore be easily determined by those skilled in the art, 88 l 338236 considering the doses recommended for the corresponding known medicaments.
In the cosmetic articles according to aspects of the present invention, the new, total, water-insoluble alginic esters and their salts may be mixed with the excipients commonly used in this field and are, for example, those already listed above for the pharmaceutical preparation.
Above all, creams, ointments, lotions may be used for topical use in which the total, water-insoluble alginic ester or one of its salts may constitute the active cos-metic principle possibly with the addition of other cos-metically active principles, e.g., steroids, for example pregnenolone, or one of the principles previously reported.
In these preparations, the total, water-insoluble alginic ester may be an ester with a cosmetically active alcohol, e.g., dexpanthenol, or also an ester with an alcohol having no cosmetic action, e.g., lower aliphatic alcohol, for example, one of those already quoted: the effect is due to the intrinsic cosmetic properties of the polysaccharide component, e.g., in the case of free alginic acid or of its salts.
The cosmetic articles may however, be used on various other active principles, for example, disinfectant sub-stances, sun shields, water-repellents, regenerating or antiwrinkle substances, or odoriferous substances, espe-cially perfumes. In this case, the new, total, water-insoluble alginic ester itself may be the active ingredient and may derive from alcohols with these same properties, 89 l 33823~
for example, from higher aliphatic alcohols or terpene alcohols in the case of perfumes, or act above all as a vehicling substance, for instance, with those properties which are associated with it. Particularly important, according to aspects of the present invention, therefore, are cosmetic compositions similar to the medicaments described above in which the pharmaceutically-active component (1) is substituted by a cosmetological factor, and the respective salts. Use of the above total, water-insoluble esters deriving from alcohols used in the perfumeindustry represents a great step ahead in the advance of technique, since it allows a slow, constant and protracted release of the odoriferous principles.
The following are particular exemplary pharmaceutical 5 preparations according to aspects of the present invention.
Formulation 1 - Collirium containing cortisone of which 100 ml contain:
- partial ester of alginic acid with cortisone, g.
0.200 - ethyl p. hydroxybenzoate, gr. 0.010 - methyl p. hydroxybenzoate, gr. 0.050 - sodium chloride, gr. 0.0900 - water for injectable preparations/q.b.a., ml. 100 Formulation 2 - Injectable solution containing hydro-cortisone of which 100 ml contain:
- partial ester of alginic acid with hydrocor-tisone, gr. 0.1 - water for injectable preparations/g.b.a., ml 100 1 33~236 Formulation 3 - Cream containing a partial ester of alginic acid with ethyl alcohol, of which 100 gr. contain:
- partial ester of alginic acid with ethyl alcohol, r. 0.2 - Polyethylene glycol monostearate 400, gr. 10.000 - CETIOL V (Trade-mark), gr. 5.000 - LENETTE SX (Trade-mark for an emulsifying wax), gr. 2.000 - Paraoxybenzoate of methyl, gr. 0.075 - Paraoxybenzoate of propyl, gr. 0.050 - Sodium dihydroacetate, gr. 0.100 - Glycerine F.U., gr. 1.500 - Sorbitol 70, gr. 1.500 - Test cream, gr. 0.050 - Water for injectable preparations/q.b.a., gr.
100. 00 Important applications of aspects of the invention as described and claimed in the above-identified parent appli-cation, are related to the sanitary and surgical articles, the methods for their manufacture and their uses. The invention, as described and claimed in the above-identified parent application, therefore includes all the articles similar to those already on the market made with alginic acid but containing a new, total, water-insoluble alginic ester or one of its salts in place of the free acid or one of its salts.
Completely new surgical and sanitary articles according to aspects of the present invention, as described -91 7 33823~, and claimed in the above-identified parent application, are represented by the new, total, water-insoluble esters of alginic acid regenerated as such from appropriate organic solutions and capable of being made into sheet and thread form, thus obtaining films, sheets and threads for use in surgery, as skin auxiliaries and substitutes in cases of serious damage to this organ, e.g., following burns, or as suture threads in surgical operations. The invention as disclosed and claimed in another of the aspects of the above-identified parent application, includes, in parti-cular, these uses and a preparation procedure for such articles consisting in the formation of a solution of the total, water-insoluble alginic ester or of one of its salts in an appropriate organic solvent, for example, a ketone, an ester or an aprotic solvent, e.g., an amide of a car-boxylic acid, especially a dialkylamide or of an aliphatic acid with between 1 and 5 carbon atoms and deriving from alkyl groups with between 1 and 6 carbon atoms, parti-cularly by an organic sulfoxide, that is a dialkylsulfoxide with alkyl groups with a maximum of 6 carbon atoms, e.g., especially dimethylsulfoxide or diethylsulfoxide and, most preferably, a fluorurate solvent with a low boiling point, e.g. especially hexafluoroisopropanol.
An aspect of the invention as described and claimed in the above-identified parent application, then consists in making these solutions into sheets or threads and in removing the organic solvent by contact with a second organic or aqueous solvent, capable of being mixed with the -92 l 338236 first solvent and in which the new, total, water-insoluble alginic ester is not soluble, especially a lower aliphatic alcohol, for example, ethyl alcohol (for wet spinning), or should a solvent with a fairly low boiling point have been used to prepare the solutions of the total, water-insoluble alginic esters, removing such solvent under dry conditions with a current of gas, and especially suitably, heated nitrogen (e.g., dry spinning). Excellent results can also be obtained with combination dry-wet spinning.
The threads obtained with the new, total, water-insoluble alginic acid esters, as described and claimed in the above-identified parent application, may be used for the preparation of gauzes to be used for the medication of wounds and in surgery, as described and claimed in the above-identified parent application. The gauzes have the exceptional advantage of biodegradability in the organism, made possible by the naturally-existing enzymes. These enzymes divide the total, water-insoluble ester into alginic acid and the corresponding alcohol, when a new, total, water-insoluble alginic ester deriving from a thera-peutically-acceptable alcohol is used, e.g., ethyl alcohol.
These gauzes and also the above-described threads may therefore also be left inside the organism after surgery, being then slowly absorbed after the previously mentioned process of degradation.
In the preparation of the above-described sanitary and surgical articles, as described and claimed in the above-identified parent application, it is convenient to add conventional plasticizing materials in order to improve their mechanical characteristics, e.g., as in the case of threads to improve their resistance to knots and tangles.
Such plasticizers may, for example, be alkaline salts of fatty acids, for example, sodium stearate or sodium palmi-tate, the new, total, water-insoluble esters of organic acids with a high number of carbon atoms, etc.
Another application of the new, total, water-insoluble esters, as described and claimed in the above-identified parent application, is represented by the preparation of capsules for subcutaneous implantation of medicaments or of microcapsules for injection, for example by subcutaneous or intramuscular route, where their biodegradability is exploited by the esterases present in the organism.
Of great importance, as described and claimed in the above-identified parent application, also is the prepara-tion of microcapsules made with new, total, water-insoluble alginic esters, solving the problem previously connected with their use, up till now very limited, for the same reasons as those set out previously, opening up a wide field of application where a "retard" effect is desired after administration by injection.
A further application of the new, total, water-insolu-ble esters in the field of medicine and surgery involves the preparation of a wide variety of solid inserts, e.g., plates, discs, laminas, etc. substituting for those made of metal or synthetic plastic material already in use, in cases where such inserts are to be removed after a certain ~ 338236 period of time, as described and claimed in the above-identified parent application. Preparations based on animal collagens, being of a proteinaceous nature, often give rise to unpleasant reactions, e.g., inflammation or rejection symptoms. In the case of new, total, water-insoluble alginic esters, according to aspects of the present invention, this danger does not exist.
Part of the applications in the medical-surgical field, as described and claimed in the above-identified parent application, using these new, total, water-insoluble esters, according to aspects of the present invention, relates to the provision of preparations using expansile materials, especially in the forms of sponges, for the medication of wounds or various types of lesion.
The following preparations exemplify the medical articles, as described and claimed in the above-identified parent application, containing the new, total, water-insoluble alginic esters, according to aspects of the present invention.
Exam~le 27 - Preparation of films usinq esters of alginic acid.
A solution is prepared in dimethylsulfoxide of the n-propyl ester of alginic acid with a concentration of 180 mg/ml.
By means of a stratifier, a thin layer of solution is spread on a glass sheet; the thickness must be 10 times greater than the final thickness of the film. The glass is immersed in ethanol which absorbs the dimethylsulfoxide but 1 3~8236 does not solubilize the HY ester which becomes solid. The film is detached from the glass sheet, is repeatedly washed with ethanol, then with water and then again with ethanol.
The resulting sheet is dried in a press for 48 hours ~e ~

/

E~amPle 28 - Preparation of threads usinq esters of alqinic acid.
A soIution is prepared in dimethylsulfoxide of the benzyl ester of alginic acid with a concentration of 200 mg/ml. The solution thus obtained is pressed by means of a pump through a threader with 0.5 mm holes.
The threader is immersed in ethanol/dimethyl-sulfoxide 80:20 (this concentration is kept constant by continuous addition of ethanol); when the solution in dimethylsulfoxide is soaked in this way it tends to lose most of the dimethylsulfoxide and the thread solidifies.
The thread is stretched while it still has a content of dimethylsulfoxide, is then repeatedly stretched and washed with ethanol. The thread is dried in nitrogen current.

ExamPle 29 - PreParation of a sponqY material made with alqinic esters.
1 g of benzyl ester of alginic acid in which all the carboxylic groups are esterified (obtained for example as describedlin Example 23) are dissolved in 5 ml of dimethylsulfoxide. To each 10 ml of solution prepared, a mixture of 31.5 g of sodium chloride with a degree of granularity corresponding to 300~, 1.28 g of sodium bicarbonate and 1 g of citric acid is added and~the whole is homogenized in a mixer.
The pasty mixture is stratified in various ways, for instance by means of a mange consisting of two rollers which turn opposite each other at an adjustable distance between the two. Regulating this distance the paste is passed between the rollers together with a strip of silicone paper which acts as a support to the layer of paste thus formed. The layer is cut to the desired dimensions of length and breadth, removed from the silicone, wrapped in filter paper and emerged in a suitable solvent, such as water. The sponges thus obtained are washed with a suitable solvent such as water and possibly sterilized with gamma rays.

ExamPle 30 - PreParation of a sPonqy material made with alginic acid esters.
In the manner described in Example 29, it is possible to prepare spongy materials with other alginic acid esters. In the place of dimethylsulfoxide it is possible to use, if desired, any other solvent capable of dissolving the chosen ester. In the place of sodium chloride it is possible to use any other solid compound which is insoluble in the solvent used to dissolve the hyaluronic acid ester, but which is however soluble in the solvent used to precipiate the hyaluronic ester after the above mentioned mechanical treatment, and finally which has the correct degree of granularity to obtain the type of pores desired in the sponge material.
In the place of sodium bicarbonate and citric acid it is possible to use other couples of similar compounds, that is, compounds which react~to each other in suspension or solution of the solvent used to dissolve alginic acid in such a way as to form a gas, such as carbon dioxide, which has the effect of producing a less compact spongy material. In this way it is possible to use, in the place of sodium bicarbonate, other bicarbonates or alkali metal or alkaline earth car-bonates and in place of citric acid, to use other acids in solid form, e.g., tartaric acid.

_ 1 338236 SUPPLEMENTARY DISCLOSURE

The Principal Disclosure provided new, total, water-insoluble ester of alginic acid with an alcohol selected from the group consisting of aliphatic, araliphatic, cyclo-aliphatic, aliphatic-cycloaliphatic and heterocyclic alcohols.
By variants of such teachings, the alcohol was a) an aliphatic radical with a maximum of 34 carbon atoms; b) an araliphatic radical with only one benzene ring, and in which the aliphatic chain has a maximum of 4 carbon atoms;
c) a cycloaliphatic radical which is mono- or polycyclic with a maximum of 34 carbon atoms; d) an aliphatic-cyclo-aliphatic radical which is mono- or polycyclic with a maxi-mum of 34 carbon atoms; or e) a heterocyclic radical witha maximum of 34 carbon atoms in which the hetero atoms are selected from the group consisting of oxygen, sulfur and nitrogen.
In other variants of such teachings: the aliphatic, cycloaliphatic, aliphatic-cycloaliphatic and heterocyclic radicals are substituted by one or two functional groups selected from the group consisting of amino, hydroxy, mercapto, aldehyde, keto, carboxyl, hydrocarbyl, dihydro-carbylamino, ether, ester, thioether, thioester, acetal, ketal, carbalkoxy and carbamidic groups and carbamidic groups substituted by one or two alkyl groups, the hydro-carbyl radicals in these functional groups having a maximum of 6 carbon atoms.

-1 ~382~
_ By specific variants of such teachings: the aliphatic radical is derived from a member selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, amyl alcohol, pentyl alcohol, hexyl alcohol, octyl alcohols glycerin, tartronic alcohol, lactic acids, glycolic acid, malic acid, tartaric acid, citric acid, aminoethanol, aminopropanol, n-aminobutanol or their dimethyl or diethyl derivatives in the amino moiety, choline, pyrrolidinylethanol, piperidinylethanol, piper-azinylethanol, piperazinyl-n-propyl alcohol, piperazinyl-n-butyl alcohol, monothioethylene glycol, myricyl alcohol, citronellol, geraniol, nerol, nerolidol, linalool, farnesol and phytol.
Specific examples of such new, total, water-insoluble esters were the methyl, ethyl, isopropyl, tert-butyl, and benzyl esters.
The Principal Disclosure also provided a process for the preparation of new, total, water-insoluble esters of alginic acid with an alcohol selected from the group con-sisting of aliphatic, araliphatic, cycloaliphatic, ali-phatic-cycloaliphatic and heterocyclic alcohols, which process comprised: reacting, in an organic solvent, a solu-bilized quaternary ammonium salt of alginic acid with aselected esterification agent which was gradually added to the dissolved quaternary ammonium salt.

The Principal Disclosure also provided a pharma-ceutical composition comprising an effective amount of a new, total water-insoluble ester of alginic acid with an alcohol selected from the group consisting of aliphatic, araliphatic, cycloaliphatic, aliphatic-cycloaliphatic and heterocyclic alcohols, together with a pharmaceutically-acceptable excipient.
The Principal Disclosure also provided a pharmaceu-tical preparation comprising: a) at least one pharmacologi-cally-active substance; and b) a carrying vehicle consti-tuted by a new, total, water-insoluble ester of alginic acid with an alcohol selected from the group consisting of aliphatic, araliphatic, cycloaliphatic, aliphatic-cyclo-aliphatic and heterocyclic alcohols.
The purposes of the present Supplementary Disclosureare: to provide further new, total, water-insoluble esters of alginic acid with a wide variety of alcohols; to provide additional processes for preparing such esters; to provide additional pharmaceutical compositions; and to provide additional pharmaceutical preparations.
Accordingly, the present invention, as now provided by the present Supplementary Disclosure, provides, as a broad aspect thereof, new, total, water-insoluble ester of alginic acid with an alcohol which is selected from the group consisting of cyclohexyl, sec-butyl, cyclobutyl, decyl, dodecyl, 2-phenylethyl, heptyl, hexyl, propyl,- n-octyl, 2,6-dichlorobenzyl, 4-tert-butylbenzyl, heptadecyl, octadecyl, 3-phenylpropyl, 3,4,5-trimethoxybenzyl, cinn-amyl, nonyl, n-pentylic, isopentylic, a mixture of ethyl and prednisolonyl alcohols, a mixture of ethyl and dexa-methasonyl alcohols, a mixture of ethyl and cortisonylalcohols, a mixture of ethyl and hydrocortisonyl alcohols, and a mixture of ethyl and desoxycorticosteronyl alcohols.
In one variant of such aspect, the alcohol may be selected from the group consisting of cyclohexyl, sec-butyl, cyclobutyl, decyl, dodecyl, 2-phenylethyl, heptyl, hexyl, propyl, n-octyl, 2,6-dichlorobenzyl, 4-tert-butyl-benzyl, heptadecyl, octadecyl, 3-phenylpropyl, 3,4,5-trime-thoxybenzyl, cinnamyl, nonyl, n-pentylic, and isopentylic alcohols.
In another variant of such aspect, the alcohol may be selected from the groups consisting of a mixture of ethyl and prednisolonyl alcohols, a mixture of ethyl and dexa-methasonyl alcohols, a mixture of ethyl and cortisonyl alcohols, a mixture of ethyl and hydrocortisonyl alcohols, and a mixture of ethyl and desoxycorticosteronyl alcohols.
In yet another variant of such aspect, the alcohol may be selected from the group consisting of the (mixed) etha-nolic and prednisolonic esters (C2l) of alginic acid - 80%
of carboxylic groups esterified with ethanol - 20% of car-boxylic groups esterified with prednisolone (C21); the (mixed) ethanolic and dexamethasonic esters (C2~) of alginicacid - 80% of carboxylic groups esterified with ethanol -20% of carboxylic groups esterified with dexamethasone (C21); the (mixed) ethanolic and cortisonic esters (C21) of SD 103 l 33823~
alginic acid - 80% of carboxylic groups esterified with ethanol - 20% of carboxylic groups esterified with corti-sone (C21); the (mixed) ethanolic and hydrocortisonic esters (C2~) of alginic acid - 80% of carboxylic groups esterified with ethanol - 20% of carboxylic groups esterified with hydrocortisone (C21); and the (mixed) ethanolic and desoxy-corticosteronic esters (C2l) of alginic acid - 80% of car-boxylic groups esterified with ethanol - 20% of carboxylic groups esterified with desoxycorticosterone (C2l).
Specific variants of this aspect include the following: the new, total, water-insoluble cyclohexyl ester of alginic acid; the new, total, water-insoluble sec-butyl ester of alginic acid; the new, total, water-insoluble cyclobutyl ester of alginic acid; the new, total, water-insoluble decyl ester of alginic acid; the new, total, water-insoluble dodecyl ester of alginic acid; the new, total, water-insoluble 2-phenylethyl ester of alginic acid;
the new, total, water-insoluble heptyl ester of alginic acid; the new, total, water-insoluble hexyl ester of alginic acid; the new, total, water-insoluble propyl ester of alginic acid; the new, total, water-insoluble n-octyl ester of alginic acid; the new, total, water-insoluble 2,6-dichlorobenzyl ester of alginic acid; the new, total, water-insoluble 4-tert-butylbenzyl ester of alginic acid;
the new, total, water-insoluble heptadecyl ester of alginic acid; the new, total, water-insoluble octadecyl ester of alginic acid; the new, total, water-insoluble 3-phenyl-propyl ester of alginic acid; the new, total, water-insol-uble 3,4,5-trimethoxybenzyl ester of alginic acid; the new, total, water-insoluble cinnamyl ester of alginic acid; the new, total, water-insoluble nonyl ester of alginic acid;
the new, total, water-insoluble n-pentylic ester of alginic acid; the new, total, water-insoluble isopentylic ester of 0 alginic acid; the new, total, water-insoluble mixed etha-nolic and prednisolonic esters (C2l) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with prednisolone (C21); the new, total, water-insoluble mixed ethanolic and dexamethasonic esters (C2l) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esteri-fied with dexamethasone (C21); the new, total, water-insoluble mixed ethanolic and cortisonic esters (C2l) of alginic acid, in which 80% of carboxylic groups are esteri-fied with ethanol, and in which 20% of carboxylic groups are esterified with cortisone (C21); the new, total, water-insoluble mixed ethanolic and hydrocortisonic esters (C2l) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with hydrocortisone (C21); and the new, total, water-insoluble mixed ethanolic and desoxycor-ticosteronic esters (C2l) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with desoxycorti-costerOne ( C21 ) -By another aspect of the present invention, as now5 provided by the present Supplementary Disclosure, a process is provided for the preparation of new, total, water-insol-uble esters of alginic acid with an alcohol selected from the group consisting of cyclohexyl, sec-butyl, cyclobutyl, decyl, dodecyl, 2-phenylethyl, heptyl, hexyl, propyl, n-octyl, 2,6-dichlorobenzyl, 4-tert-butylbenzyl, hepta-decyl, octadecyl, 3-phenylpropyl, 3,4,5-trimethoxybenzyl, cinnamyl, nonyl, n-pentylic, isopentylic, a mixture of ethyl and prednisolonyl alcohols, a mixture of ethyl and dexamethasonyl alcohols, a mixture of ethyl and cortisonyl alcohols, a mixture of ethyl and hydrocortisonyl alcohols, and a mixture of ethyl and desoxycorticosteronyl alcohols, which process comprises: a process for the preparation of total, water-insoluble esters of alginic acid with an alcohol selected from the group consisting of cyclohexyl, sec-butyl, cyclobutyl, decyl, dodecyl, 2-phenylethyl, heptyl, hexyl, propyl, n-octyl, 2,6-dichlorobenzyl, 4-tert-butylbenzyl, heptadecyl, octadecyl, 3-phenylpropyl, 3,4,5-trimethoxybenzyl, cinnamyl, nonyl, n-pentylic, isopentylic, a mixture of ethyl and prednisolonyl, a mixture of ethyl and dexamethasonyl alcohols, a mixture of ethyl and corti-sonyl alcohols, a mixture of ethyl and hydrocortisonyl alcohols, and a mixture of ethyl and desoxycorticosteronyl alcohols, which process comprises: reacting, in a dimethyl-sulfoxide solvent, a solubilized quaternary ammonium salt -_ 1 338236 of alginic acid with a esterification agent which is a com-pound of the Formula:
A-X (I) wherein A is a radical respectively selected from the group consisting of cyclohexyl, sec-butyl, cyclobutyl, decyl, dodecyl, 2-phenylethyl, heptyl, hexyl, propyl, n-octyl, 2,6-dichlorobenzyl, 4-tert-butylbenzyl, heptadecyl, octa-decyl, 3-phenylpropyl, 3,4,5-trimethoxybenzyl, cinnamyl, nonyl, n-pentylic, isopentylic, a mixture of ethyl and prednisolonyl, a mixture of ethyl and dexamethasonyl alcohols, a mixture of ethyl and cortisonyl alcohols, a mixture of ethyl and hydrocortisonyl alcohols, and a mixture of ethyl and desoxycorticosteronyl alcohols and X
is a halogen atom, said esterification agent being gra-dually added to the dissolved quaternary ammonium salt.
By one variation of such process, the quaternary ammonium salt is tetrabutylammonium alginate.
By other variations of such process, the process may comprise adding an organic solvent to precipitate out the ester of alginic acid; or may further comprise recovering, washing and drying the ester of alginic acid.
By other variations of such process the esterification agent is: iodocyclohexane; or 2-iodobutane; or bromocyclo-butane; or 1-bromodecane; or l-bromododecane; 2-phenyl-ethylbromide; or heptyl bromide; or hexyl bromide; or propyl iodide; or 1-bromooctane; or 2,6-dichlorobenzyl bromide; or 4-tert-butylbenzyl bromide; or heptadecyl bromide; or octadecyl bromide; or 3-phenylpropyl bromide;

or 3,4,5-trimethoxybenzyl chloride; or cinnamyl bromide; or l-bromononane; or n-pentyl bromide; or isopentyl bromide;
or ethyl iodide and 21-bromo-11,17-dihydroxypregnane-1,4-diene-3,20-dionel; or ethyl iodide and 9-fluoro-21-bromo-11,17-dihydroxy-16-methylpregnane-1,4-diene-3,20-dione; or ethyl iodide and 21-bromo-4-pregnane-17d-ol-3,11,30-trione;
or ethyl iodide and 21-bromo-4-pregnane-ll,B,17~-dial-3,20-dione; or ethyl iodide and 21-bromo-4-pregnane-3,20-dione.
The present invention, as now provided by the present Supplementary Disclosure, also provides a pharmaceutical composition comprising an effective amount of a new, total, water-insoluble alginic acid ester with an alcohol selected from the group consisting of cyclohexyl, sec-butyl, cyclo-butyl, decyl, dodecyl, 2-phenylethyl, heptyl, hexyl, propyl, n-octyl, 2,6-dichlorobenzyl, 4-tert-butylbenzyl, heptadecyl, octadecyl, 3-phenylpropyl, 3,4,5-trimethoxy-benzyl, cinnamyl, nonyl, n-pentylic, isopentylic, a mixture of ethyl and prednisolonyl alcohols, a mixture of ethyl and dexamethasonyl alcohols, a mixture of ethyl and cortisonyl alcohols, a mixture of ethyl and hydrocortisonyl alcohols, and a mixture of ethyl and desoxycorticosteronyl alcohols, together with a pharmaceutically-acceptable excipient.
By variants thereof, in such pharmaceutical composi-tions, the total, water-insoluble alginic acid ester is:
the new, total, water-insoluble cyclohexyl ester of alginic acid; or is the new, total, water-insoluble sec-butyl ester SD 108 l 338236 of alginic acid; or is the total, water-insoluble cyclo-butyl ester of alginic acid; or is the new, total, water-insoluble decyl ester of alginic acid; or is the new, total, water-insoluble dodecyl ester of alginic acid; or is the new, total, water-insoluble 2-phenylethyl ester of alginic acid; or is the new, total, water-insoluble heptyl ester of alginic acid; or is the new, total, water-insol-uble hexyl ester of alginic acid; or is the new, total, water-insoluble propyl ester of alginic acid; or is the new, total, water-insoluble n-octyl ester of alginic acid;
or is the total, water-insoluble 2,6-dichlorobenzyl ester of alginic acid; or is the new, total, water-insoluble 4-tert-butylbenzyl ester of alginic acid; or is the new, total, water-insoluble heptadecyl ester of alginic acid; or is the total, water-insoluble octadecyl ester of alginic acid; or is the total, water-insoluble 3-phenylpropyl ester of alginic acid; or is the new, total, water-insoluble 3,4,5-trimethoxybenzyl ester of alginic acid; or is the new, total, water-insoluble cinnamyl ester of alginic acid;
or is the new, total, water-insoluble nonyl ester of alginic acid; or is the total, water-insoluble n-pentylic ester of alginic acid; or is the new, total, water-insol-uble isopentylic ester of alginic acid; or is the new, total, water-insoluble mixed ethanolic and prednisolonic esters (C2l) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with prednisolone (C21); or ~- 1 33~236 is the new, total, water-insoluble mixed ethanolic and dexamethasonic esters (C2l) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which S 20% of carboxylic groups are esterified with dexamethasone (C2l); or is the new, total, water-insoluble mixed ethanolic and cortisonic esters (C2l) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with cortisone 0 (C21); or is the new, total, water-insoluble mixed ethanolic and hydrocortisonic esters (C21) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with hydrocortisone (C21); or is the new, total, water-insoluble mixed ethanolic and desoxycorticosteronic esters (C2~) of alginic acid, in which 80% of carboxylic groups are esteri-fied with ethanol, and in which 20% of carboxylic groups are esterified with desoxycorticosterone (C2l).
The present invention, as now provided by the present Supplementary Disclosure, also provides a pharmaceutical preparation comprising: a) an effective amount of at least one pharmacologically-active substance; and b~ a carrying vehicle consisting of a total, water-insoluble ester of alginic acid with an alcohol selected from the group consisting of cyclohexyl, sec-butyl, cyclobutyl, decyl, dodecyl, 2-phenylethyl, heptyl, hexyl, propyl, n-octyl, 2,6-dichlorobenzyl, 4-tert-butylbenzyl, heptadecyl, octadecyl, 3-phenylpropyl, 3,4,5-trimethoxybenzyl, cinn-amyl, nonyl, n-pentylic, isopentylic, a mixture of ethyl and prednisolonyl alcohols, a mixture of ethyl and dexa-methasonyl alcohols, a mixture of ethyl and cortisonyl ethyl, a mixture of ethyl and hydrocortisonyl alcohols, and a mixture of ethyl and desoxycorticosteronyl alcohols.
By variants thereof in such pharmaceutical prepara-tion, the new, total, water-insoluble alginic acid ester is: the new, total, water-insoluble cyclohexyl ester of alginic acid; or is the new, total, water-insoluble sec-butyl ester of alginic acid; or is the new, total, water-insoluble cyclobutyl ester of alginic acid; or is the new, total, water-insoluble decyl ester of alginic acid; or is the total, water-insoluble dodecyl ester of alginic acid;
or is the total, water-insoluble 2-phenylethyl ester of alginic acid; or is the new, total, water-insoluble heptyl ester of alginic acid; or is the new, total, water-insol-uble hexyl ester of alginic acid; or is the new, total, water-insoluble propyl ester of alginic acid; or is the new, total, water-insoluble n-octyl ester of alginic acid;
or is the new, total, water-insoluble 2,6-dichlorobenzyl ester of alginic acid; or is the total, water-insoluble 4-tert-butylbenzyl ester of alginic acid; or is the new, total, water-insoluble heptadecyl ester of alginic acid; or is the new, total, water-insoluble octadecyl ester of alginic acid; or is the total, water-insoluble 3-phenyl-propyl ester of alginic acid; or is the total, water-insol-uble 3,4,5-trimethoxybenzyl ester of alginic acid; or is the new, total, water-insoluble cinnamyl ester of alginic acid; or is the new, total, water-insoluble nonyl ester of ~~ SD 111 1 ~3~
alginic acid; or is the new, total, water-insoluble n-pentylic ester of alginic acid; or is the new, total, water-insoluble isopentylic ester of alginic acid; or is the new, total, water-insoluble mixed ethanolic and predni-solonic esters (C2l) of alginic acid, in which 80% of car-boxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with prednisolone (C21); or is the total, water-insoluble mixed ethanolic and dexamethasonic esters (C2l) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with dexamethasone (C21); or is the new, total, water-insoluble mixed ethanolic and cortisonic esters (C2l) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with cortisone (C21); or is the new, total, water-insoluble mixed ethanolic and hydrocortisonic esters (C2l) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with hydrocortisone (C21); or is the new, total, water-insoluble mixed ethanolic and desoxycorticosteronic esters (C2l) of alginic acid, in which 80% of carboxylic groups are esteri-fied with ethanol, and in which 20% of carboxylic groups are esterified with desoxycorticosterone (C2l).

The following are further examples of the present invention as now provided by the Supplementary Disclosure.

SD 112 1 3 3 ~ 2 3 6 Example 31 - PreParation of the cYclohexYl ester of alqinic acid 10 g (23.9 m. Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria h~per-borea) are solubilized in 400 ml of DMSO at 25C.
5.5g (26 m.E~.) of Iodocyclohexane are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 2.5 l of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 3 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99%.
-Example 32 - Preparation of the sec-butyl estQr of al~inic acid 10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria hYPer-borea) are solubilized in 400 ml of DMS0 at 25C.
4.8 g (26 m.Eq.) of 2-Iodobutane are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 l of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 3.5 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99%.

'X~

1 33823~

Example 33 - Prepar~tion of the cYclobutYl e~ter of alqinic acid 8.35 g (20 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Ascol~hyllum nodosum) are solubilized in 400 ml of DMS0 at 25C.
3.4 g (25 m.Eq.) of Bromocyclobutane are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 4 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99%.

1 3~82~

Example 34 - Preparation of the Decyl ester of al~inic acid 8.35 g (20 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from AscophYllum nodosum) are solubilized in 400 ml of DMS0 at Z5C.
5.54 g (25 m.Eq.) of l-Bromodecane are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 l of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 4 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

- The degree of esterification is at least 99%.

_ ~ ~3~3~

Example 35 - Preparation of the DodecYl ester of al~inic Acid 8.35 g (20 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Ascophyllum nodosum) are solubilized in 400 ml of DMS0 at 25C.

6.23 g (25 m.Eq.) of l-Bromododecane are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way, 4 g of the compound named in the title, are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 9g%.

-1 33~8236 Example 36 --Preparation of the 2-Phenylethyl ester of alqinic acid 10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Macrocystis pyrifera) are solubilized in 400 ml of DMS0 at 25C.
4.8 g (26 m.Eq.) of 2-Phenylethylbromide and 0.1 g of tetrabutyl-ammonium iodide are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 5 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99%.

-Example 37 - PreParation of the Re~t~l ester of alqinic aci~

10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Macrocystis ~yrifera) are solubilized in 400 ml of DMSO at 25C.
5 g (28 m.Eq.) of Heptyl bromide and 0.1 g of tetrabutylammonium iodide are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 4.5 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99~.

-- SD 119 1 338~36 Example 38- PreParation of the ~exYl e~ter of al~inic acid 10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Macrocystis Pyrifera) are solubilized in 400 ml of DMS0 at 25C.
4.3 g (26 m.Eq.) of Hexyl bromide and 0.1 g of tetrabutylammonium iodide are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 4 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99%.

-SD 120 1 3 3 8 ~ 3 6 Example 39 - PreParation of the PropYl ester of al~inic acid 10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Ascoph~llum nodosum) are solubilized in 400 ml of DMS0 at 25C.
4.4 g t26 m.Eq.) of Propyl iodide are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 4.5 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99%.

X

Example 40 - PreParat~on of the n-octYl ester of alqinic acid 8.35 g (20 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Asco~hyllum nodosum) are solubilized in 400 ml of DMS0 at 25C.
4.83 g (25 m.Eq.) of l-bromo octane are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 l of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 3.4 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99%.

Example 41 - PreParation of the 2,6-~ichlorobenzyl ester of alqinic a C i `~1 8.35 g (20 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from AscoPhYllum nodosum) are solubilized in 400 ml of DMS0 at 25C.
5.99 g (25 m.Eq.) of 2,6-dichlorobenzyl bromide are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 3.8 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

-The degree of esterification is at least 99~.

-1 3~8;~36 Example 42 - Preparation of the 4-terbutylbenzyl eQter of alc~inic acid 8.35 g (20 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Ascophyllum nodosum) are solubilized in 400 ml of DMS0 at 25C.
5.67 g (25 m.Eq.) of 4-terbutylbenzyl bromide are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 3.5 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99%.

-SD124 ~ 338236 Example 43 - PreParation of the heptadecYl ester of ~l~inic acid 8.35 g (20 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Asco~h~llum nodosum) are solubilized in 400 ml of DMS0 at 25C.
8.0 g (25 m.Eq.) of heptadecyl bromide are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 l of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 4 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99%.

Example 44 - PreParation of the octa~ecyl ester of ~lqinic acid 8.35 g (20 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Ascophyllum nodosum) are solubilized in 400 ml of DMS0 at 25C.
8.37 g (25 m.Eq.) of octadecyl bromide are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 3.5 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99%.

Example 45 - Preparation of the 3-phenylpropyl ester of alginic acid 10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria hYPer-borea) are solubilized in 400 ml of DMSO at 25C.
5.18 g (26 m.Eq.) of 3-phenylpropyl bromide are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 l of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 4.0 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99%.

Example 46 - PreParation of the 3,4,5-trimethoxybenzyl ester of alginic acid 10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria hYper borea) are solubilized in 400 ml of DMS0 at 25C.
5.64 g (26 m.Eq.) of 3,4,5-trimethoxybenzyl chloride are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.S 1 of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 3.8 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99%.

SD128 ~ ~3~23~

Example 47 - Preparation of the cinnamYl ester of alginic acid 10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria hYPer-borea) are solubilized in 400 ml of DMS0 at 25C.
5.15 g (26 m.Eq.) of cinnamyl bromide are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 3.7 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99~.

Example 48 - PreParation of the nonyl ester of alginic acid 10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria h~per-borea) are solubilized in 400 ml of DMS0 at 25C.
5.4 g (26 m.Eq.) of l-bromononane are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 3.9 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99g6.

SD 130 1 3 3 8 2 3 ~

Example 49 - PreDaration of the n-pentYlic ester of alqinic acid 10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria hyper-borea) are solubilized in 400 ml of DMS0 at 25C.
3.95 g (26 m.Eq.) of n-pentyl bromide are added and 0.2 g of tetrabutylammonium iodide are added.

The solution is well agitated for 12 hours at 30C, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 3.8 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by-the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99~.

1 33~

Example 50~ - PreParation of the isoPentYl~c ester of alginic acid 10 g (23.9 m.Eq.) of the tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria hyPer-borea) are solubilized in 400 ml of DMS0 at 25C.
3.95 g (26 m.Eq.) of isopentyl bromide are added and 0.2 g oftetrabutylammonium iodide are added.

The solution is well agitated for 12 hours at 30c, and then slowly poured by regular drops and under agitation into 3.5 1 of ethyl acetate (or toluene). The precipitate is filtered and then washed 4 times with ethyl acetate and lastly vacuum dried for 24 hours at 30C. In this way 3.8 g of the compound named in the title are obtained.

Quantitative determination of the ester groups is carried out by the saponification method described on pages 169-172 of "Quantitative organic analysis via functional groups", 4th Edition, John Wiley and Sons Publication.

The degree of esterification is at least 99%.

IX~

--- SD 132 1 33;8 ~
Example 51 - PreParation of tho ~mixed) ethanolic ~nd prednisolonic esters (C21) of al~inic acid - 80% of c~rboxylic ~roups esterified with ethanol - 20% of carboxYlic ~roupq esterified with prednisolone (C2l).
4.18 g of the tetrabutylammonium salt of alginic acid (prepared from Macrocystis pyrifera) corresponding to 10 m.Eq. of a monomeric unit are solubilized in 210 ml of dimethylsulfoxide at 25C, 1.25g (8 m.Eq.) of ethyl iodide are added and the solution is kept for 24 hours at 30C.
0.85 g (2 m.Eq.) of 21-bromo-11,17-dihydroxypregnane-1,4 -diene-3,20-dione are added and the solution is kept for 24 hours at 30C.
A solution is then added containing 100 ml of water and 5 g of sodium chloride and the resulting mixture is slowly poured into 2,000 ml of acetone under constant agitation. A precipitate is formed which is filtered and washed three times with 100 ml of acetone/water 5:1 and three times with 100 ml of acetone and finally vacuum dried for eight hours at 30C.
1.7 g of the compound featured in the title are obtained.
Quantitative determination of prednisolone, after mild alkaline hydrolysis with hydroalcoholic solution of Na2C03 and extraction with chloroform, is carried out according to British Pharmacopeia.
Quantitative determination of the ethoxyls is carried out according to R. H. Cundiff and P.C. Markunas [Anal. Chem. 33, 1028-1030 (1961)].
The degree of esterification is at least 99%.

-- SD 133 7 33~ 23~

ExamPle 52 - Preparation of the (mixed) ethanolic and dexA-methaqonic esters (C21) of alqinic acid - 80% of carboxylic qrouPs esterified with ethanol - 20% of carboxylic qrouPs esterified with dexamethasone (C21).
4.18 g of the tetrabutylammonium salt of alginic acid (prepared from Macrocystis pyrifera) corresponding to 10 m.Eq. of a monomeric unit are solubilized in 210 ml of dimethylsulfoxide at 25C, 1.25g (8 m.Eq.) of ethyl iodide are added and the solution is kept for 24 hours at 30C.
0.91 g (2 m.Eq.) of 9-fluoro-21-bromo-11,17-dihydroxy-16-methylpregnane-1,4-diene-3,20-dione are added and the solution is kept for 24 hours at 30C.
A solution is then added containing 100 ml of water and 5 g of sodium chloride and the resulting mixture is slowly poured into 2,000 ml of acetone under constant agitation. A precipitate is formed which is filtered and washed three times with 100 ml of acetone/water 5:1 and three times with 100 ml of acetone and finally vacuum dried for eight hours at 30C.
1.6 g of the compound featured in the title are obtained.
Quantitative determination of dexamethasone, after mild alkaline hydrolysis with hydroalcoholic solution of NazCO3 and extraction with chloroform, is carried out according to British Pharmacopeia.
Quantitative determination of the ethoxyls is carried out according to R. H. Cundiff and P.C. Markunas [Anal. Chem. 33, 1028-1030 (1961)~.
The degree of esterification is at least 99~.

ExamPle 53 - PreParation of the (mixed) ethanolic and cortisonic eater ~C2~) of alginic acid - 80% of c~rbox~,rlic ~rouPs esterified with ethanol - 20% of car~ox~,rlic ~roups esterified with cortisone (czl) .
4.18 g of the tetrabutylammonium salt of alginic acid (prepared from Macrocystis pyrifera) corresponding to 10 m.Eq. of a monomeric unit are solubilized in 210 ml of dimethylsulfoxide at -25C, 1.25g (8 m.Eq.) of ethyl iodide are added and the solution is kept for 24 hours at 30C.
0.85 g (2 m.Eq.) of 21-bromo-4-pregnane-17d-ol-3,11,30-trione are added and the solution is kept for 24 hours at 30C.
A solution is then added containing 100 ml of water and 5 g of sodium chloride and the resulting mixture is slowly poured into 2,000 ml of acetone under constant agitation. A precipitate is formed which is filtered and washed three times with 100 ml of acetone/water 5:1 and three times with 100 ml of acetone and finally vacuum dried for eight hours at 30C.
1.9 g of the compound featured in the title are obtained.
Quantitative determination of cortisone, after mild alkaline hydrolysis with hydroalcoholic solution of Na2C03 and extraction with chloroform, is carried out according to British Pharmacopeia.
Quantitative determination of the ethoxyls is carried out according to R. H. Cundiff and P.C. Markunas [Anal. Chem. 33, 1028-1030 (1961)~
The degree of esterification is at least 99%.

-~ 1 3 3 8 2 3 6 Example 54 - PreParat~on of the ~mixed~ ethanolic ~nd hYdro-cortisonic e~ter (C21) of algin~c acid - 80% of carboxylic ~roups esterified with ethanol - 20% of carboxYlic groups esterified with hYdrocorti~one (C2~).
4.18 g of the tetrabutylammonium salt of alginic acid (prepared from Macrocystis pyrifera) corresponding to 10 m.Eq. of a monomeric unit are solubilized in 210 ml of dimethylsulfoxide at 25C, 1.25g (8 m.Eq.) of ethyl iodide are added and the solution is kept for 24 hours at 30C.
0.85 g (2 m.Eq.) of 21-bromo-4-pregnane-11~,17~-dial-3,20-dione are added and the solution is kept for 24 hours at 30C.
A solution is then added containing 100 ml of water and 5 g of sodium chloride and the resulting mixture is slowly poured into 2,000 ml of acetone under constant agitation. A precipitate is formed which is filtered and washed three times with 100 ml of acetone/water 5:1 and three times with 100 ml of acetone and finally vacuum dried for eight hours at 30C.
1.7 g of the compound featured in the title are obtained.
Quantitative determination of hydrocortisone, after mild alkaline hydrolysis with hydroalcoholic solution of Na2C03 and extraction with chloroform, is carried out according to British Pharmacopeia.
Quantitative determination of the ethoxyls is carried out according to R. H. Cundiff and P.C. Markunas [Anal. Chem. 33, 1028-1 03 0 (1961 ) ] .
The degree of esterification is at least 99%.

1 33823~
Example 55 - PreParation of the (mixed) ethanolic and desoxy-corticosteronic e~ter (C2l) of alqinic acid - 80% of carobox~lic qroups ~sterified with othanol - 20% of carboxylic qrouPs e~t~ri-fied with desox~corticost~rone (C2l).
4.18 g of the tetrabutylammonium salt of alginic acid (prepared from Laminaria hyperborea) corresponding to 10 m.Eq. of a monomeric unit are solubilized in 210 ml of dimethylsulfoxide at 25C, 1.25g (8 m.Eq.) of ethyl iodide are added and the solution is kept for 24 hours at 30C.
0.66 g (2 m.Eq.) of 21-bromo-4-pregnane-3,20-dione are added and the solution is kept for 24 hours at 30C.
A solution is then added containing 100 ml of water and 5 g of sodium chloride and the resulting mixture is slowly poured into 2,000 ml of acetone under constant agitation. A precipitate is formed which is filtered and washed three times with 100 ml of acetone/water 5:1 and three times with 100 ml of acetone and finally vacuum dried for eight hours at 30C.
1.9 g of the mixed ethanolic and desoxycorticosteronic ester compound featured in the title are obtained.
Quantitative determination of desoxycorticosteronic, after mild alkaline hydrolysis with hydroalcoholic solution of Na2C03 and extraction with chloroform, is carried out according to British Pharmacopeia.
Quantitative determination of the ethoxyls is carried out according to R. H. Cundiff and P.C. Markunas [Anal. Chem. 33, 1028-1030 (1961)]. The degree of esterification is at least 99%.

~ . .

Claims (153)

1. Total, water-insoluble esters of alginic acid with an alcohol selected from the group consisting of aliphatic, araliphatic, cycloaliphatic, aliphatic-cycloaliphatic and heterocyclic alcohols.

2. Total, water-insoluble esters of alginic acid according to claim 1, wherein: said alcohol includes:
a) an aliphatic radical with a maximum of 34 carbon atoms;
b) an araliphatic radical with only one benzene ring, and in which the aliphatic chain therein has a maximum of 4 carbon atoms;
c) a cycloaliphatic radical which is mono- or polycy-clic with a maximum of 34 carbon atoms;
d) an aliphatic-cycloaliphatic radical which is mono-or polycyclic with a maximum of 34 carbon atoms; or e) a heterocyclic radical with a maximum of 34 carbon atoms in which the hetero atoms are selected from the group consisting of oxygen, sulfur and nitrogen.

3. Total, water-insoluble esters of alginic acid according to claim 2, wherein:
a) said aliphatic, cycloaliphatic, aliphatic-cycloali-phatic and heterocyclic radicals are substituted by one or two functional groups selected from the group consisting of amino, hydroxy, mercapto, aldehydo, keto, carboxy, hydro-carbyl, dihydrocarbylamino, ether, ester, thioether, thioester, acetal, ketal, carbalkoxy and carbamidic groups and carbamidic groups substituted by one or two alkyl groups, the hydrocarbyl radicals in these functional groups having a maximum of 6 carbon atoms; or b) said araliphatic radicals are substituted in the benzene residue with 1-3 substituents selected from the group consisting of methyl, hydroxy and halogen, or are substituted in the aliphatic portion with one or two functional groups selected from the group consisting of ethyl, diethyl, pyrrolidine and piperidine groups.

4. Total, water-insoluble esters of alginic acid according to claim 3, wherein:
a) said hydrocarbyl radicals of said functional groups are C1-14 alkyl groups;
b) said amino or substituted carbamidic groups are C1-8 alkylene amine or C1-8 alkylene carbamidic groups; or c) said cycloaliphatic, aliphatic-cycloaliphatic or heterocyclic moieties are monocyclic with a maximum of 12 carbon atoms and the ring has between 5 and 7 carbon atoms.

5. Total, water-insoluble esters of alginic acid according to claim 2, wherein said aliphatic radical is derived from a member selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, amyl alcohol, pentyl alcohol, hexyl alcohol, octyl alcohols glycerin, tartronic alcohol, lactic acids, gly-colic acid, malic acid, tartaric acid, citric acid, amino-ethanol, aminopropanol, n-aminobutanol or their dimethyl or diethyl derivatives in the amino moiety, choline, pyrroli-dinylethanol, piperidinylethanol, piperazinylethanol, piperazinyl-n-propyl alcohol, piperazinyl-n-butyl alcohol, monothioethylene glycol, myricyl alcohol, citronellol, geraniol, nerol, nerolidol, linalool, farnesol and phytol.

6. Total, water-insoluble esters of alginic acid according to claim 1, wherein: said alcohol moiety is a member selected from the group consisting of alkaloids, phenylethylamines, phenothiazine drugs, thioxanthene drugs, anticonvulsants, antipsychotics, antiemetics, analgesics, hypnotics, anorexica, tranquilizers, muscle relaxants, coronary vasodilators, adrenergic blockers, narcotic antagonists, antineoplastics, antibiotics, antivirals, peripheral vasodilators, carbonic anhydrase inhibitors, antiasthmatics, anti-inflammatories and sulfamidics.

7. The total, water-insoluble methyl ester of alginic acid.

8. The total, water-insoluble ethyl ester of alginic acid.

9. The total, water-insoluble isopropyl ester of alginic acid.

10. The total, water-insoluble tert-butyl ester of alginic acid.

11. The total, water-insoluble benzyl ester of alginic acid.

12. A process for the preparation of total esters of alginic acid with alcohols selected from the group con-sisting of aliphatic, araliphatic, cycloaliphatic, ali-phatic-cycloaliphatic and heterocyclic alcohols, which process comprises: reacting, in an organic solvent, a solubilized quaternary ammonium salt of alginic acid with a selected esterification agent which is gradually added to the dissolved quaternary ammonium salt.

13. A process according to claim 12, wherein: said organic solvent is an aprotic solvent.

14. A process according to claim 13, wherein: said aprotic solvent is dimethylsulfoxide.

15. A process according to claim 12, wherein: said quaternary ammonium salt is a lower tetraalkyl ammonium salt of alginic acid.

16. A process according to claim 15, wherein: said quaternary ammonium salt is tetrabutylammonium alginate.

17. A process according to claim 12, which further comprises: adding an organic solvent to precipitate out said ester of alginic acid.

18. A process according to claim 12, which further comprises: recovering, washing and drying said ester of alginic acid.

19. A process according to claim 12, wherein: said quaternary ammonium salt of alginic acid is prepared by passing an alkali metal salt of alginic acid through a quaternary ammonium salt ion exchange resin; and including the step of recovering said quaternary ammonium salt of alginic acid.

20. A process according to claim 19, wherein: said quaternary ammonium salt ion exchange resin is a sulfonic acid resin.

21. A process according to claim 20, wherein: said quaternary ammonium salt of sulfonic acid is a C1-C6 tetraalkyl ammonium salt.

22. A process according to claim 12, wherein said selected esterification agent is a compound of the Formula A-X (I) wherein A is a radical selected from the group consisting of aliphatic, araliphatic, cycloaliphatic, aliphatic-cycloaliphatic and heterocyclic radicals, and X is a halogen atom.

23. A process according to claim 22 wherein: A is selected from the group consisting of methyl, ethyl, i-propyl, t-butyl and benzyl radicals.

24. A pharmaceutical composition comprising an effective amount of a total water-insoluble ester of alginic acid with an alcohol selected from the group consisting of aliphatic, araliphatic, cycloaliphatic, aliphatic-cycloaliphatic and heterocyclic alcohols, together with a pharmaceutically-acceptable excipient.

25. The pharmaceutical composition of claim 24, wherein said alcohol includes:
a) an aliphatic radical with a maximum of 34 carbon atoms;

b) an araliphatic radical with only one benzene ring, and in which the aliphatic chain therein has a maximum of 4 carbon atoms;
c) a cycloaliphatic radical which is mono- or polycy-clic with a maximum of 34 carbon atoms;
d) an aliphatic-cycloaliphatic radical which is mono-or polycyclic with a maximum of 34 carbon atoms; or e) a heterocyclic radical with a maximum of 34 carbon atoms in which the hetero atoms are selected from the group consisting of oxygen, sulfur and nitrogen.

26. The pharmaceutical composition of claim 25 wherein:
a) said aliphatic, cycloaliphatic, aliphatic-cyclo-aliphatic and heterocyclic radicals are substituted by one or two functional groups selected from the group consisting of amino, hydroxy, mercapto, aldehydo, keto, carboxy, hydrocarbyl, dihydrocarbylamino, ether, ester, thioether, thioester, acetal, ketal, carbalkoxy and carbamidic groups and carbamidic groups substituted by one or two alkyl groups, the hydrocarbyl radicals in these functional groups having a maximum of 6 carbon atoms; or b) said araliphatic radicals are substituted in the benzene residue with 1-3 substituents selected from the group consisting of methyl, hydroxy and halogen, or are substituted in the aliphatic portion with one or two functional groups selected from the group consisting of ethyl, diethyl, pyrrolidine and piperidine groups.

27. The pharmaceutical composition of claim 26 wherein:
a) said hydrocarbyl radicals of said functional groups are C1-14 alkyl groups;
b) said amino or substituted carbamidic groups are C1-8 alkylene amine or C1-8 alkylene carbamidic groups; or c) said cycloaliphatic, aliphatic-cycloaliphatic or heterocyclic moieties are monocyclic with a maximum of 12 carbon atoms and the ring has between 5 and 7 carbon atoms.

28. The pharmaceutical composition of claim 25 comprising an effective amount of an alginic acid with an alcohol selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, amyl alcohol, pentyl alcohol, hexyl alcohol, octyl alcohols glycerin, tartronic alcohol, lactic acids, glycolic acid, malic acid, tartaric acid, citric acid, aminoethanol, aminopropanol, n-aminobutanol or their dimethyl or diethyl derivatives in the amino moiety, choline, pyrrolidinyl-ethanol, piperidinylethanol, piperazinylethanol, piper-azinyl-n-propyl alcohol, piperazinyl-n-butyl alcohol, monothioethylene glycol, myricyl alcohol, citronellol, geraniol, nerol, nerolidol, linalool, farnesol and phytol.

29. The pharmaceutical composition of claim 24 wherein said alcohol is selected from the group consisting of alkaloids, phenylethylamines, phenothiazine drugs, thioxanthene drugs, anticonvulsants, antipsychotics, antiemetics, analgesics, hypnotics, anorexica, tran-quilizers, muscle relaxants, coronary vasodilators, adrenergic blockers, narcotic antagonists, antineoplastics, antibiotics, antivirals, peripheral vasodilators, carbonic anhydrase inhibitors, antiasthmatics, anti-inflammatories and sulfamidics.

30. A pharmaceutical composition comprising an effective amount of the methyl ester of alginic acid, together with a pharmaceutically-acceptable excipient.

31. A pharmaceutical composition comprising an effective amount of the ethyl ester of alginic acid, together with a pharmaceutically-acceptable excipient.

32. A pharmaceutical composition comprising an effective amount of the isopropyl ester of alginic acid, together with a pharmaceutically-acceptable excipient.

33. A pharmaceutical composition comprising an effective amount of the tert-butyl ester of alginic acid, together with a pharmaceutically-acceptable excipient.

34. A pharmaceutical composition comprising an effective amount of the benzyl ester of alginic acid, together with a pharmaceutically-acceptable excipient.

35. A pharmaceutical preparation comprising:
a) at least one pharmacologically-active substance;
and b) a carrying vehicle constituted by a total, water-insoluble ester of alginic acid with an alcohol selected from the group consisting of aliphatic, araliphatic, cycloaliphatic, aliphatic-cycloaliphatic and heterocyclic alcohols.

36. The pharmaceutical preparation of claim 35 wherein said alcohol includes:
a) an aliphatic radical with a maximum of 34 carbon atoms;
b) an araliphatic radical with only one benzene ring, and in which the aliphatic chain has a maximum of 4 carbon atoms;
c) a cycloaliphatic radical which is mono- or polycyclic with a maximum of 34 carbon atoms;
d) an aliphatic-cycloaliphatic radical which is mono-or polycyclic with a maximum of 34 carbon atoms; or e) a heterocyclic radical with a maximum of 34 carbon atoms in which the hetero atoms are selected from the group consisting of oxygen, sulfur and nitrogen.

37. The pharmaceutical preparation of claim 36 wherein:
a) said aliphatic, cycloaliphatic, aliphatic-cycloaliphatic and heterocyclic radicals are substituted by one or two functional groups selected from the group consisting of amino, hydroxy, mercapto, aldehydo, keto, carboxy, hydrocarbyl, dihydrocarbylamino, ether, ester, thioether, thioester, acetal, ketal, carbalkoxy and carbamidic groups and carbamidic groups substituted by one or two alkyl groups, the hydrocarbyl radicals in these functional groups having a maximum of 6 carbon atoms; or b) said araliphatic radicals are substituted in the benzene residue with 1-3 substituents selected from the group consisting of methyl, hydroxy and halogen, or are substituted in the aliphatic portion with one or two functional groups selected from the group consisting of ethyl, diethyl, pyrrolidine and piperidine groups.

38. The pharmaceutical preparation of claim 37, wherein a) said hydrocarbyl radicals of said functional groups are C1-14 alkyl groups;
b) said amino or substituted carbamidic groups are C1-8 alkylene amine or C1-8 alkylene carbamidic groups; or c) said cycloaliphatic, aliphatic-cycloaliphatic or heterocyclic moieties are monocyclic with a maximum of 12 carbon atoms and the ring has between 5 and 7 carbon atoms.

39. The pharmaceutical preparation of claim 36 wherein said alcohol is a member selected from the group consisting of methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, amyl alcohol, pentyl alcohol, hexyl alcohol, octyl alcohols glycerin, tartronic alcohol, lactic acids, glycolic acid, malic acid, tartaric acid, citric acid, aminoethanol, aminopropanol, n-aminobutanol or their dimethyl or diethyl derivatives in the amino moiety, choline, pyrrolidinylethanol, piperidinylethanol, piperazi-nylethanol, piperazinyl-n-propyl alcohol, piperazinyl-n-butyl alcohol, monothioethylene glycol, myricyl alcohol, citronellol, geraniol, nerol, nerolidol, linalool, farnesol and phytol.

40. The pharmaceutical preparation of claim 35 wherein at least one of said alcohol in said total alginic acid ester is derived from a therapeutically-active alcohol.

41. The pharmaceutical preparation of claim 40 wherein said alcohol is a member selected from the group consisting of alkaloids, phenylethylamines , phenothiazine drugs, thioxanthene drugs, anticonvulsants, antipsychotics, antiemetics, analgesics, hypnotics, anorexica, tranquilizers, muscle relaxants, coronary vasodilators, adrenergic blockers, narcotic antagonists, antineoplastics, antibiotics, antivirals, peripheral vasodilators, carbonic anhydrase inhibitors, antiasthmatics, anti-inflammatories and sulfamidies.

42. The pharmaceutical preparation of claim 35 wherein said total, water-insoluble ester of alginic acid is the methyl ester of alginic acid.

43. The pharmaceutical preparation of claim 35 wherein said total, water-insoluble ester of alginic acid is the ethyl ester of alginic acid.

44. The pharmaceutical preparation of claim 35 wherein said total, water-insoluble ester of alginic acid is the isopropyl ester of alginic acid.

45. The pharmaceutical preparation of claim 35 wherein said total, water-insoluble ester of alginic acid is the tert-butyl ester of alginic acid.

46. The pharmaceutical preparation of claim 35 wherein said total, water-insoluble ester of alginic acid is the benzyl ester of alginic acid.

Claims

47. Total, water-insoluble esters of alginic acid with an alcohol selected from the group consisting of cyclohexyl, sec-butyl, cyclobutyl, decyl, dodecyl, 2-phenylethyl, heptyl, hexyl, propyl, n-octyl, 2,6-dichloro-benzyl, 4-tert-butylbenzyl, heptadecyl, octadecyl, 3-phenylpropyl, 3,4,5-trimethoxybenzyl, cinnamyl, nonyl, n-pentylic, isopentylic, a mixture of ethyl and predni-solonyl alcohols, a mixture of ethyl and dexamethasonyl alcohols, a mixture of ethyl and cortisonyl alcohols, a mixture of ethyl and hydrocortisonyl alcohols, and a mixture of ethyl and desoxycorticosteronyl.

48. The total, water-insoluble cyclohexyl ester of alginic acid.

49. The total, water-insoluble sec-butyl ester of alginic acid.

50. The total, water-insoluble cyclobutyl ester of alginic acid.

51. The total, water-insoluble decyl ester of alginic acid.

52. The total, water-insoluble dodecyl ester of alginic acid.

53. The total, water-insoluble 2-phenylethyl ester of alginic acid.

54. The total, water-insoluble heptyl ester of alginic acid.

55. The total, water-insoluble hexyl ester of alginic acid.

56. The total, water-insoluble propyl ester of alginic acid.

57. The total, water-insoluble n-octyl ester of alginic acid.

58. The total, water-insoluble 2,6-dichlorobenzyl ester of alginic acid.

59. The total, water-insoluble 4-tert-butylbenzyl ester of alginic acid.

60. The total, water-insoluble heptadecyl ester of alginic acid.

61. The total, water-insoluble octadecyl ester of alginic acid.

62. The total, water-insoluble 3-phenylpropyl ester of alginic acid.

63. The total, water-insoluble 3,4,5-trimethoxybenzyl ester of alginic acid.

64. The total, water-insoluble cinnamyl ester of alginic acid.

65. The total, water-insoluble nonyl ester of alginic acid.

66. The total, water-insoluble n-pentylic ester of alginic acid.

67. The total, water-insoluble isopentylic ester of alginic acid.

68. The total, water-insoluble mixed ethanolic and prednisolonic esters (C21) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with prednisolone (C21).

69. The total, water-insoluble mixed ethanolic and dexamethasonic esters (C21) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with dexamethasone (C21).

70. The total, water-insoluble mixed ethanolic and cortisonic esters (C21) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with cortisone (C21).

71. The total, water-insoluble mixed ethanolic and hydrocortisonic esters (C21) of alginic acid, in which 80%
of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with hydrocortisone (C21).

72. The total, water-insoluble mixed ethanolic and desoxycorticosteronic esters (C21) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with desoxycorticosterone (C21).

73. A process for the preparation of total, water-insoluble esters of alginic acid with an alcohol selected from the group consisting of cyclohexyl, sec-butyl, cyclobutyl, decyl, dodecyl, 2-phenylethyl, heptyl, hexyl, propyl, n-octyl, 2,6-dichlorobenzyl, 4-tert-butylbenzyl, heptadecyl, octadecyl, 3-phenylpropyl, 3,4,5-trimethoxy-benzyl, cinnamyl, nonyl, n-pentylic, isopentylic, a mixture of ethyl and prednisolonyl, a mixture of ethyl and dexamethasonyl alcohols, a mixture of ethyl and cortisonyl alcohols, a mixture of ethyl and hydrocortisonyl alcohols, and a mixture of ethyl and desoxycorticosteronyl alcohols, which process comprises: reacting, in a dimethylsulfoxide solvent, a solubilized quaternary ammonium salt of alginic acid with a esterification agent which is a compound of the Formula:
A-X (I) wherein A is a radical respectively selected from the group consisting of cyclohexyl, sec-butyl, cyclobutyl, decyl, dodecyl, 2-phenylethyl, heptyl, hexyl, propyl, n-octyl, 2,6-dichlorobenzyl, 4-tert-butylbenzyl, heptadecyl, octadecyl, 3-phenylpropyl, 3,4,5-trimethoxybenzyl, cinn-amyl, nonyl, n-pentylic, isopentylic, a mixture of ethyl and prednisolonyl, a mixture of ethyl and dexamethasonyl alcohols, a mixture of ethyl and cortisonyl alcohols, a mixture of ethyl and hydrocortisonyl alcohols, and a mixture of ethyl and desoxycorticosteronyl alcohols and X
is a halogen atom, said esterification agent being gradually added to the dissolved quaternary ammonium salt.

74. A process according to claim 73, wherein: said quaternary ammonium salt is tetrabutylammonium alginate.

75. A process according to claim 73, which further comprises: adding an organic solvent to precipitate out said ester of alginic acid.

76. A process according to claim 73, which further comprises: recovering, washing and drying said ester of alginic acid.

77. A process according to claim 73 wherein said esterification agent is iodocyclohexane.

78. A process according to claim 73 wherein said esterification agent is 2-iodobutane.

79. A process according to claim 73 wherein said esterification agent is bromocyclobutane.

80. A process according to claim 73 wherein said esterification agent is 1-bromodecane.

81. A process according to claim 73 wherein said esterification agent is 1-bromododecane.

82. A process according to claim 73 wherein said esterification agent is 2-phenylethylbromide.

83. A process according to claim 73 wherein said esterification agent is heptyl bromide.

84. A process according to claim 73 wherein said esterification agent is hexyl bromide.

85. A process according to claim 73 wherein said esterification agent is propyl iodide.

86. A process according to claim 73 wherein said esterification agent is 1-bromooctane.

87. A process according to claim 73 wherein said esterification agent is 2,6-dichlorobenzyl bromide.

88. A process according to claim 73 wherein said esterification agent is 4-tert-butylbenzyl bromide.

89. A process according to claim 73 wherein said esterification agent is heptadecyl bromide.

90. A process according to claim 73 wherein said esterification agent is octadecyl bromide.

91. A process according to claim 73 wherein said esterification agent is 3-phenylpropyl bromide.

92. A process according to claim 73 wherein said esterification agent is 3,4,5-trimethoxybenzyl chloride.

93. A process according to claim 73 wherein said esterification agent is cinnamyl bromide.

94. A process according to claim 73 wherein said esterification agent is 1-bromononane.

95. A process according to claim 73 wherein said esterification agent is n-pentyl bromide.

96. A process according to claim 73 wherein said esterification agent is isopentyl bromide.

97. A process according to claim 73 wherein said esterification agent is ethyl iodide and 21-bromo-11,17-dihydroxypregnane-1,4-diene-3,20-dione.

98. A process according to claim 73 wherein said esterification agent is ethyl iodide and 9-fluoro-21-bromo-11,17-dihydroxy-16-methylpregnane-1,4-diene-3,20-dione.

99. A process according to claim 73 wherein said esterification agent is ethyl iodide and 21-bromo-4--pregnane-17d-ol-3,11,30-trione.

100. A process according to claim 73 wherein said esterification agent is ethyl iodide and 21-bromo-4--pregnane-11.beta.,17.alpha.-dial-3,20-dione.

101. A process according to claim 73 wherein said esterification agent is ethyl iodide and 21-bromo-4--pregnane-3,20-dione.

102. A pharmaceutical composition comprising an effective amount of a total, water-insoluble alginic acid ester with an alcohol selected from the group consisting of cyclohexyl, sec-butyl, cyclobutyl, decyl, dodecyl, 2-phenylethyl, heptyl, hexyl, propyl, n-octyl, 2,6-dichloro-benzyl, 4-tert-butylbenzyl, heptadecyl, octadecyl, 3-phenylpropyl, 3,4,5-trimethoxybenzyl, cinnamyl, nonyl, n-pentylic, isopentylic, a mixture of ethyl and prednisolonyl alcohols, a mixture of ethyl and dexamethasonyl alcohols, a mixture of ethyl and cortisonyl alcohols, a mixture of ethyl and hydrocortisonyl alcohols, and a mixture of ethyl and desoxycorticosteronyl alcohols, together with a pharma-ceutically-acceptable excipient.

103. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble cyclohexyl ester of alginic acid.

104. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble sec-butyl ester of alginic acid.

105. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble cyclobutyl ester of alginic acid.

106. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble decyl ester of alginic acid.

107. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble dodecyl ester of alginic acid.

108. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble 2-phenylethyl ester of alginic acid.

109. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble heptyl ester of alginic acid.

110. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble hexyl ester of alginic acid.

111. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble propyl ester of alginic acid.

112. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble n-octyl ester of alginic acid.

113. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble 2,6-dichlorobenzyl ester of alginic acid.

114. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble 4-tert-butylbenzyl ester of alginic acid.

115. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble heptadecyl ester of alginic acid.

116. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble octadecyl ester of alginic acid.

117. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble 3-phenylpropyl ester of alginic acid.

118. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble 3,4,5-trimethoxybenzyl ester of alginic acid.

119. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble cinnamyl ester of alginic acid.

120. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble nonyl ester of alginic acid.

121. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble n-pentylic ester of alginic acid.

122. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble isopentylic ester of alginic acid.

123. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble mixed ethanolic and predni-solonic esters (C21) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with prednisolone (C21).

124. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble mixed ethanolic and dexametha-sonic esters (C21) of alginic acid, in which 80% of carboxy-lic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with dexamethasone (C21).

125. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble mixed ethanolic and cortisonic esters (C21) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with cortisone (C21).

126. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble mixed ethanolic and hydrocorti-sonic esters (C21) of alginic acid, in which 80% of carboxy-lic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with hydrocortisone (C21).

127. The pharmaceutical composition of claim 102 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble mixed ethanolic and desoxycorti-costeronic esters (C21) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with desoxycorti-costerone (C21).

128. A pharmaceutical preparation comprising:
a) an effective amount of at least one pharmaco-logically-active substance; and b) a carrying vehicle consisting of a total, water-insoluble ester of alginic acid with an alcohol selected from the group consisting of cyclohexyl, sec-butyl, cyclo-butyl, decyl, dodecyl, 2-phenylethyl, heptyl, hexyl, propyl, n-octyl, 2,6-dichlorobenzyl, 4-tert-butylbenzyl, heptadecyl, octadecyl, 3-phenylpropyl, 3,4,5-trimethoxy-benzyl, cinnamyl, nonyl, n-pentylic, isopentylic, a mixture of ethyl and prednisolonyl alcohols, a mixture of ethyl and dexamethasonyl alcohols, a mixture of ethyl and cortisonyl ethyl, a mixture of ethyl and hydrocortisonyl alcohols, and a mixture of ethyl and desoxycorticosteronyl alcohols.

129. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble cyclohexyl ester of alginic acid.

130. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble sec-butyl ester of alginic acid.

131. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble cyclobutyl ester of alginic acid.

132. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble decyl ester of alginic acid.

133. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble dodecyl ester of alginic acid.

134. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble 2-phenylethyl ester of alginic acid.

135. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble heptyl ester of alginic acid.

136. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble hexyl ester of alginic acid.

137. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble propyl ester of alginic acid.

138. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble n-octyl ester of alginic acid.

139. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble 2,6-dichlorobenzyl ester of alginic acid.

140. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble 4-tert-butylbenzyl ester of alginic acid.

141. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble heptadecyl ester of alginic acid.

142. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble octadecyl ester of alginic acid.

143. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble 3-phenylpropyl ester of alginic acid.

144. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble 3,4,5-trimethoxybenzyl ester of alginic acid.

145. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble cinnamyl ester of alginic acid.

146. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble nonyl ester of alginic acid.

147. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble n-pentylic ester of alginic acid.

148. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble isopentylic ester of alginic acid.

149. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble mixed ethanolic and predniso-lonic esters (C21) of alginic acid, in which 80% of carboxy-lic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with prednisolone (C21).

150. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble mixed ethanolic and dexametha-sonic esters (C21) of alginic acid, in which 80% of carboxy-lic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with dexamethasone (C21).

151. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble mixed ethanolic and cortisonic esters (C21) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with cortisone (C21).

152. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble mixed ethanolic and hydrocor-tisonic esters (C21) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with hydrocortisone (C21).

153. The pharmaceutical preparation of claim 128 wherein said total, water-insoluble alginic acid ester is the total, water-insoluble mixed ethanolic and desoxycorti-costeronic esters (C21) of alginic acid, in which 80% of carboxylic groups are esterified with ethanol, and in which 20% of carboxylic groups are esterified with desoxycorti-costerone (C21).