KR920000487B1 - New esters of alginic acid - Google Patents

Abstract

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Description

Novel alginic acid esters and salts thereof

The present invention relates to alginic acid esters in which all or part of the carboxyl groups of alginic acid are esterified and salts of partial esters thereof with pharmacologically acceptable metals or organic bases.

The compounds of the present invention have interesting and valuable bioforming and pharmaceutical properties, which can be used in all fields, for example from cosmetics to surgical and pharmaceutical products. In addition, the present invention contains a carrier comprising at least one of the above-mentioned alginic acid esters or a salt thereof and a combination of 1) a pharmacologically active substance or pharmacologically active substance and 2) a whole or partial ester of alginic acid as an active ingredient. It also includes drugs.

In addition, the present invention includes alginate ester or various uses of the medicament in the field of medicine, surgery or cosmetics, and a novel method for preparing alginic acid ester.

Alginic acid is a natural acid polysaccharide extracted from so-called phaecophyceae, having a high molecular weight in the range of about 30,000 to 200,000, and having a chain formed of D-mannuronic acid and L-gluronic acid. The degree of polymerization varies with the type of algae used for extraction, the season from which the algae was collected, the algae's origin, and the year of growth of the algae 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, Fucus serratus and the like. Alginic acid is found in algae as a broad component of cell walls in the form of some mixtures of its alkali salts, in particular in the form of sodium salts. This mixture is also known as "algin". These salts are usually extracted in the form of an aqueous solution using sodium carbonate solution, and precipitated directly from the extract with an inorganic acid such as hydrochloric acid to obtain alginic acid.

According to an indirect preparation method, an insoluble calcium salt is first added by adding a soluble calcium salt such as chloride, and the salt is washed and then treated with an acid to obtain alginic acid.

However, alginic acid or alkaline alginate can be obtained by fermentation by microbiological methods such as Pseudomonas aeruginosa or mutants of Pseudomonas Putida, Pseudomonas Fluorescens or Pseudomonas mendocina.

Metal salts of alginic acid, in particular alkali and alkaline earth metal salts, have important physicochemical properties and are therefore widely used in the industry. Thus, for example, solutions of alkali or alkaline earth metal alginic acid salts can be controlled by viscosity, temperature and pH for the preparation of gels which can be widely used in the food industry for the production of ice cream, milk pudding and many other types of cakes and puddings. Due to very suitable.

Another property of alginates widely used in the nutrition field is its moisturizing properties, and for this reason alginates are used for the preservation of various frozen foods, for example.

The third property of alginates is their emulsification power and ability to stabilize emulsions, which is why these salts are important in the food industry and for the manufacture of seasonings and for the stabilization of different types of drinks, such as beer or fruit juices, sauces and syrups. Used.

Film and fiber forming capabilities of alginate solutions have been used in the papermaking industry, in the manufacture of adhesive labels, in textile printing and dyeing, and in the manufacture of hygiene, pharmaceutical and surgical products.

Alginates are used as emulsifiers for the manufacture of brighteners, antifoams, lactates, and stabilizers in the ceramic and detergent industries (see Paul A. Sandford and John Baird, “The Polysaccharides,” Volume 2, published by Academic Press., Inc.). See copyright 1983). Alginic acid and its salts have also been used in the pharmaceutical, pharmaceutical, surgical and cosmetic fields, for example in the manufacture of topical medicines and in the manufacture of hygiene and surgical articles. For example, German Patent Publication No. 3,017,221 (November 20, 1908) describes “artificial skin” for use in severe injury of the skin after a burn, in which case it contains a soluble alginate of alkali metal. The ointment is applied topically to the skin and is treated by itself with soluble calcium salt. This forms insoluble calcium alginate, transforming the ointment layer into a biologically readily acceptable protective film that has structural, mechanical, physical and properties similar to the original skin.

Calcium alginate has been used in the manufacture of fibers for use in the pharmaceutical industry.For example, French Patent Application No. 2,418,821 (September 28, 1979) and Romania Patent No. 70,069 (June 30, 1980) Agents for the treatment and antiseptic disinfection of skin wounds made from calcium fibers are described. Calcium alginate is also used as a hemostatic agent in the form of a bandage or gauze containing fiber of salt. Other agents based on calcium alginate are used for the treatment of sinoids and fistulas and for the treatment of nasal blood (nose).

In the herbal medicine system, sodium alginate and calcium are also used as disintegrants for pills, and sodium alginate is also used as a binder.

In the various industries, two alginic acid esters or salts of such esters are used, more specifically ethylene glycol and propylene glycol esters. Propylene glycol esters are used, for example, as emulsifiers and stabilizers in foods (“Martindale” —The Extra Pharmacopoeia, P.931 and “The Polysacharide”, Volume 2, published by Academic Press., Inc. Copyright 1983. P448- 449). The ester is obtained by reacting alginic acid or a salt or partial salt thereof with ethylene oxide or propylene oxide, respectively. This process is also based on patents for the preparation of dihydric alcohols obtained by reaction of the alginic acid esters and aliphatic hydrocarbon epoxides which are optionally substituted or interrupted by heteroatoms in the carbon atom chain (US Pat. No. 2,463,824, 2,426,125, German Patent Publication No. 2,161,415, 2,046,966, 2,641,303, 2,529,086, Japanese Patent No. 2027, Japanese Patent Publication No. 47,858 / 1972, and French Patent No. 2,247,204. Reference).

Alginate esters that can be obtained by reaction of the epoxide with free alginic acid or salts thereof are partial esters (AB Steiner, Industrial and Engineering Chemistry, Vol. 43, P. 2023-2077, 1951), wherein low molecular weight glycols In the case of ester, about 80% of the whole carboxyl group in which maximum esterification exists exists, and in the case of glycol ester which has a long chain, esterification degree is very low. To date it has not been possible to produce esters wholly esterified by this method.

In addition, monohydric alcohol esters are described in the literature for both aliphatic and arylaliphatic, among which methyl ester of alginic acid obtained by reaction of alginic acid in etheric solution of diazomethane is a representative example (Zeitschrift fuer physiologische chemie, Vol. 293, P. 121, 1953, ABSteiner, Industrial and Engineering chemistry, Vol 43, P. 2073, 1951 and British Patent 768,309.

However, the product obtained by reaction with diazomethane is not actually an alginic acid ester, but rather a methyl ester of alginic acid partially etherified with a hydrocylic alcohol group, for example, as described in Example 4 of the British patent. . The methyl esters are also obtained by reacting dimethyl sulfate with soluble salts of alginic acid in an organic solvent of low solubility in water, but in the presence of water. The product thus obtained (called methyl alginic acid or methyl alginate) is not considered pure ester because the hydroxyl groups of the sugar are known to be easily etherified with this methylating agent. In this case, therefore, it is in fact a mixed ester ether.

In addition, alginic acid esters of monohydric alcohols are described in the literature, but their preparation methods and physicochemical properties are not described at all.

Aside from the reaction between diazomethane and dimethyl sulfate, a production method is not known, it is not practical to use homologs of these esterification agents to obtain homologous esters of methyl esters, or at most Only in the case of methyl products, a mixed product is obtained (see US Pat. No. 4,216,104, in which case neither the source of propyl alginate nor the method of preparation thereof is described, only propyl alginate is described). Japanese Patent Application Laid-Open No. 55-132,781, page 5, in which case ethyl, butyl, lauryl, oleyl, phenyl and benzyl esters are described, but how these esters are obtained Not listed at all).

Therefore, based on this fact, it is presumed that only esters of dihydric alcohols, more particularly partial esters with glycols, are known among the alginic acid esters, which achieves complete esterification by the known methods used in the art. This is difficult because in commercial products more than 10% of the carboxyl groups remain unesterified in the form of free carboxyl groups, or in some cases are chlorinated.

Therefore, it is a main object of the present invention to provide novel alginic acid esters and novel methods for their preparation as described above.

The present invention relates to novel polysaccharide esters, more particularly to alginic acid esters and methods for their preparation.

The present invention also encompasses the use of such alginate esters in the fields of food, paper, textiles, cosmetics, industry, pharmaceuticals, medicine, and surgery, and also includes many industrial fields, for example, food, cosmetics, pharmaceutical products, medical care. It also includes new products containing alginic acid esters used in plastic materials that can be broken down into surgical microorganisms. The novel esters according to the invention include all alginic acid esters and partially alginic acid esters. In the case of partial esters, unesterified carboxyl groups can be chlorided with metals or organic bases, and as industrial products containing them, these salts form part of the invention.

The present invention relates to the treatment of a number of novel alginic acid esters, especially homologues of monohydric alcohols such as homologues of methyl esters, by treatment of quaternary ammonium salts of alginic acid with conventional alkylating agents in organic solvents, preferably aprotic solvents such as dimethylsulfoxide and Simple and very convenient methods of preparing alginic acid esters based on obtaining esters of aromatic, arylaliphatic, cycloaliphatic, and heterocyclic alcohols. In addition, the novel process of the present invention provides for esters derived from substituted alcohols, in particular known esters of dihydric aliphatic alcohols which can be obtained by reaction of alginic acid with aliphatic epoxides, as described above, and novel novel of such dihydric alcohols. It can be used to prepare the whole ester.

The novel alginic acid esters can be used in the industrial and pharmaceutical, hygienic, surgical and cosmetic fields of various sectors, where esters of aliphatic dihydric alcohols in the form of metal alginate or propylene glycol esters of alginic acid are already used, for example, in the food or cosmetic industry. Has been.

The present invention therefore encompasses both the use of novel esters and corresponding articles such as cosmetics, hygiene products, surgical products, pharmaceuticals, or food products and their auxiliaries, in particular emulsifiers, emulsion stabilizers and extenders, as well as industrial products and related uses. do.

The discovery of novel alginic acid esters according to the present invention has led to the general use of alginic acid esters as well, i.e. new uses for novel alginic acid esters and known alginic acid esters.

This new use is useful not only as excipients for pharmacologically active substances, especially as excipients for topical, oral or rectal administration, but also as excipients for parenteral administration.

The use of alginic acid esters of known dihydric alcohols has been limited to the functions of emulsifiers, emulsion stabilizers, extenders and related uses, which have no use in the pharmaceutical, hygiene, medical, surgical or cosmetic fields. The present invention therefore also encompasses the use as described above and pharmaceutical compositions containing alginic acid esters as excipients of the respective products, in particular the active substances.

The active substance can also be excised with novel esters having pharmacologically active substances as alcoholic components. Therefore, among the pharmaceuticals of the present invention, particularly important are those containing alginate esters derived from therapeutically active alcohols, ie esters consisting of alginic acid esterified with the alcoholic portion of the therapeutically active compound, as described below. to be.

The present invention also encompasses partially alginic acid esters with metal or organic bases. In the following description “alginic acid ester” means both the ester itself and its salts. In particular, in the medicament, at least one pharmacologically active ingredient is used, in addition to the pharmacologically active or inactive alginic acid ester, and also for the pharmacologically active use of some or all of the carboxyl groups of the partially alginic acid esters. It can be excised with a phosphorus basic substance.

The concentration of alkaline alginates in various industrial fields, ie pharmaceuticals, medical supplies, the food industry, etc., is disadvantageous when used in acidic conditions due to the release of alginic acid with low solubility that can be separated in the solid state. In addition, in the presence of calcium ions, insoluble products containing calcium alginate may be separated to some extent, which is why alkaline alginates are used in products containing calcium ions, such as milk or derivatives thereof. It is inappropriate.

For this reason, the soluble salts of alginic acid are required to maintain good solubility in acidic conditions or in the presence of calcium salts, for example when the alginate is used as an emulsifier or emulsion stabilizer, for example in beer or fruit juice. It has been replaced by glycol glycols, in particular propylene glycol esters.

However, the glycol esters of alginic acid are somewhat toxic and their use should be limited. This is due to the inherent toxicity of glycol residues that are absorbed and metabolized.

The present invention enables the requirement of a new product having an effect similar to the properties of alkaline alginate or glycol ester known in the various industrial and scientific fields, but with further increasing requirements of the complete product, which effects are new. The use of the product will naturally vary from case to case.

It is important to emphasize first that the monohydric esters according to the invention are superior to known glycol esters, since the monohydric alcohol residues are metabolized into degradation products with less toxicity than glycols in the organism.

This is natural in the case of esters derived from toxic substituents, especially alcohols which do not contain aliphatic, cycloaliphatic, monohydric alcohols. Such novel esters will be of greatest benefit in the food industry for the use described above.

The low toxicity of the many monohydric alcohol esters of alginic acid according to the invention can be used mainly in the pharmaceutical, cosmetic, and hygiene-surgical fields, in which case the new alginic acid ester can be decomposed into microorganisms with different functions in some cases. It can be used as a plastic material.

Thus, for example, alginic acid esters are used as additives for a wide range of polymeric materials, such as sanitary and surgical articles, such as polyurethanes, polyesters, polyolefins, polyamides, polysiloxanes, vinyls and acrylic polymers, to provide microorganisms in these materials. And the effect will be available. In this case, the addition of daily ether is performed, for example, by coating the surfaces of these materials, dispersing them in these materials, or using these two methods in combination. These materials can be used in the manufacture of a variety of hygiene and medical products such as heart valves, intraocular lenses, blood vessel clips, face-makers, and the like, which are described in US Pat. No. 4,500,676.

In the field of cosmetics and pharmaceuticals, the alginic acid esters of the present invention can be used in the manufacture of cosmetics such as ointments, creams and other forms of topical agents, or sunscreen creams, in which case the alginic acid esters are particularly alkaline alginates for high temperatures. It acts as a stabilizer and emulsifier that is more stable than salts and less toxic than glycol esters.

Alginate esters in the pharmaceutical field can be used with the same advantages as disintegrants, or binders of pills, but above all can be used as excipients of pharmacologically active substances, in particular topically active substances, by a particularly important aspect of the present invention. The excitation of the new alginic acid ester can be done in a number of ways, in particular in the following way.

(1) Alginic acid esters act as excipients and are mechanically and physically mixed with the active substance.

(2) Alginic acid ester (part) is chlorided with active substance.

(3) Alginic acid esters are esterified with alcohols representing the active substances.

In addition to the above three methods, a combination of these methods may be used, for example, a combination of (1) and (2) or a combination of (1) and (3). In the case of methods (2) and (3), the alcohol moiety in the alginic acid ester can be changed or combined, or the basic component in the salt thereof can be changed or combined, and the ester can have mixing properties, where the alcohol moiety Is partially derived from a pharmacologically inactive alcohol or partially derived from an active alcohol, which is the same for salts. The same ester can have both inert basic residues and residues of therapeutically active organic bases, as in the case of metal salts.

The first group of esters according to the invention suitable for the production of hygiene, pharmaceutical and surgical products, cleaning agents, household goods, etc., as well as the above-mentioned industrial fields such as the food, paper, textile and printing industries, are characterized by the properties of the alginic acid component. Ester.

Such esters are derived from aliphatic, aromatic, arylaliphatic, cycloaliphatic or heterocyclic alcohols, such as aliphatic saturated alcohols or cycloaliphatic simple alcohols, which are nontoxic or have pharmacological action.

Examples of these alcohols are described below.

A second group of esters for use in therapy are esters with good pharmacological properties of the alcohol component, ie alginate esters with pharmacologically active alcohols (eg steroidal alcohols), for example, cortisone type esters.

These esters have qualitative properties similar to alcohols, but have a broader range of functions. Compared with known esters of these pharmacologically active alcohols, alginic acid esters are more balanced, consistent, and ensure regular pharmacological action and generally exhibit a significant sustained effect of the active alcohol component.

The third group of alginic acid esters according to the invention is in particular an inherent useful aspect and is esters having more mixed properties compared to the two groups.

That is, some of the carboxyl groups of alginic acid are esterified with pharmacologically active alcohols, and others are esterified with alcohols that are not pharmacologically different, or whose activity is negligible. When the two alcohols as esterification components are adjusted to an appropriate percentage, they have the same activity as the pharmacologically active alcohols, and due to the ester groups of the pharmacologically inert acid relative to the desired unique activity of the pharmacologically active alcohols Esters with increased stability and bioavailability can be obtained.

The fourth group of esters is those in which the ester group has mixing properties derived from two different therapeutically active substances. This may also be esterified in part or in whole, ie only a portion of the carboxyl group is derived from two different therapeutically active alcohols such as cortisone steroids and antibiotics, while other carboxyl groups are free or For example, alkali metals, in particular sodium, or all carboxyl groups can be esterified with the alcohols.

However, esters having three or more alcoholic components, such as part of a carboxyl group, are esterified with therapeutically active alcohols, while others are esterified with therapeutically active alcohols other than the above, Three portions can be esterified with a therapeutically inert alcohol, and the fourth portion can be chlorinated with a metal or therapeutically active or inert base, or a free form ester can be prepared.

Most of the alginic acid esters exhibit a constant solubility in organic solvents in contrast to their salts. This solubility depends on the percentage of esterified carboxyl groups and the type of alkyl group bonded to the carboxyl group. For example, all esters of alginic acid thus obtained are excellent in solubility in room temperature and dimethyl sulfoxide.

On the other hand, totally novel and specific esters of the present invention have poor solubility in water. Thus, the total esters of monohydric alcohols, such as, for example, lower and higher alkyl esters, are not only poorly soluble or insoluble in water and aqueous solutions, but also, for example, ethylene glycol, propylene glycol, trimethylene glycol, butylene glycol and iso The novel total esters of dihydric alcohols, such as the total esters of glycols such as butylene glycol, are also poorly soluble or insoluble in water and aqueous solutions.

These solubility properties, together with the remarkable viscoelastic properties of the esters, make them suitable for use in the manufacture of hygiene and surgical articles insoluble in saline and having certain desired forms.

Such articles may be prepared, for example, by dissolving alginic acid esters in an organic solvent, making a highly viscous solution in the form of the desired article, and finally, an organic solvent may be mixed therewith but the alginic acid ester is insoluble For example, it can be prepared by extracting with alcohol or water.

Of all the esters described above, when the carboxyl group is in the free state, these carboxyl groups can be chlorinated with metals or organic bases, for example alkali metals or alkaline earth metals, ammonia or azo organic bases.

The present invention encompasses the use of the novel alginic acid esters in all the aforementioned fields, in particular the industrial use of the novel alginic acid esters in the manufacture of nutritional, cosmetic, pharmaceutical and medical, household and industrial products, in particular in the manufacture of hygiene and surgical products. do.

In addition, the present invention generally encompasses the use of novel alginic acid esters, i.e., novel and already published in the literature, e.g., the form of the alginic acid ester having a therapeutically active alcohol and the therapeutically active substance or treatment. Alginic acid esters of inert alcohols admixed with active active bases, both as excipients for pharmacologically active substances, as well as medicaments or formulations using such alginic acids. In all cases, the free carboxyl groups are inert but can be chlorided with a therapeutically acceptable base. In addition, the present invention includes all the industrial products and pharmaceuticals described above.

Therefore, the main object of the present invention is to exclude all or partial esters in which the acid portion of the alginic acid is aliphatic, arylaliphatic, cycloaliphatic or heterocyclic type of alcohol and all or part esters and partial esters of alginic acid with dihydric aliphatic alcohol. To provide salts of partial esters with inorganic or organic bases.

A second object of the present invention is to treat a quaternary ammonium salt of alginic acid with an etherifying agent in an aprotic solvent and optionally, free carboxyl groups with an inorganic or organic base to obtain partial alginic acid esters. It is to provide a novel manufacturing method of.

A third object of the present invention is the use of novel alginic acid esters and salts thereof and their respective products, replacing alginate metal salts or alginate salts of aliphatic dihydric alcohols in the relevant industry or in the fields of cosmetics, pharmaceutical or hygiene-surgical applications. To provide field and industrial supplies.

A fourth object of the present invention is to provide the use of alginic acid ester as an excipient for pharmacologically active substance and to provide a medicament or formulation containing the following substances.

(1) A pharmacologically active substance or a combination of pharmacologically active substances.

(2) a carrier containing all or part esters of alginic acid or partial esters with salts of inorganic or organic bases, or salts with inorganic or organic bases, wherein at least one ester group or chlorinated carboxyl group is alcoholically or therapeutically active; Pharmaceutical compositions or formulations containing alginic acid esters each derived from a phosphorus base.

Alcohols useful for the preparation of new esters

The aliphatic heat alcohol used for esterifying the component of the carboxyl groups of the alginic acid according to the present invention may be, for example, saturated or unsaturated, and other free or amino, hydroxy, aldehyde, keto, mercapto, Functionally modified groups such as carboxyl groups, or hydrocarbonyl or dihydrocarbonyl amino (hereinafter referred to as "hydrocarbyl" is not only monovalent groups of hydrocarbons such as C _n H _2-1 , but also "alkylene" -C ether or ester group, acetal or ketal group, thioether or thioester group derived from the same as the above, such as _n H _2n -or "alkylidene" = C _n H _2n ) And up to 34 carbon atoms, which may be substituted by etherified carboxyl groups or carbamidis, with one or two hydroxy groups, with a nitrile group or with a carbamide group substituted with halogen, etc. With things.

Lower aliphatic groups such as alkyl having up to six carbon atoms in the group containing the hydrocarbyl groups are preferred. In such alcohols, heteroatoms such as oxygen, nitrogen and sulfur may be inserted in the carbon atom chain. Preferred alcohols are those substituted with one or two of the aforementioned functional groups.

The alcohol having the above-mentioned group for use in the present invention preferably has a maximum of 12 carbon atoms, in particular a maximum of 6 carbon atoms, in which case the above-mentioned amino, ether, ester, thioether, thioester, acetal, maximum carbon atoms 4 Among the ketal groups represented by the alkyl groups and also esterified carboxyl or substituted carbamide groups, the hydrocarbyl groups are alkyl groups having the same number of carbon atoms as described above, and the amino or carbamide groups are alkyleneamino or alkylenecarba having up to 8 carbon atoms. It may be a medic group.

The first of these alcohols are saturated and unsaturated alcohols, methyl, ethyl, propyl, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, amyl, pentyl, hexyl, octyl, nonyl and dode And a straight chain such as n-octyl or n-dodecyl alcohol. Among the substituted alcohols of this group, dihydric alcohols are ethylene glycol, propylene glycol or butylene glycol, trihydric alcohols such as glycerin, aldehyde alcohols such as tartron alcohol, lactic acid, for example α-oxypropionic acid, glycolic acid, Amino alcohols such as carboxylic alcohols such as malic acid, tartaric acid, citric acid, aminoethanol, aminopropanol, n-aminobutanol and dimethyl and diethyl derivatives of amine function thereof, choline, pyridininylethanol, pyridinylethanol, piperazinyl Ethanol and derivatives corresponding to n-propyl or n-butyl alcohol, monothioethylene glycol or alkyl derivatives thereof, for example trihydric alcohols such as mercapto-functional ethyl derivatives.

Of the higher saturated aliphatic alcohols that are of particular worth mentioning are, for example, cetyl alcohol and myrisil alcohols, but of particular importance for the purposes of the present invention are higher unsaturated alcohols having one or two double bonds contained in most essential oils. And affinity with terpenes such as citronerole, geraniol, nerrol, nerolidol, linarol, farnesol and phytol.

Of particular importance among lower unsaturated alcohols are propargyl alcohols. Of the arylaliphatic alcohols, the first to be considered are those having only one benzene residue, in which case the aliphatic chain has up to 4 carbon atoms and the benzene residue may be substituted with 1 to 3 methyl or hydroxy groups, or halogen atoms , Especially chlorine, bromine or iodine, and the aliphatic chain may be substituted by free amino groups or one or more functional groups selected from mono and dimethyl groups or by pyrrolidine or piperidine groups.

Of these alcohols, benzyl alcohol and phenethyl alcohol are particularly preferred.

Alicyclic or aliphatic alicyclic alcohols may be derived from mono or polycyclic hydrocarbons and may have up to 34 carbon atoms. Among the alcohols derived from cyclic monocyclic hydrocarbons, particular mention may be made of, for example, one to three lower alkyl groups, ie, methyl, ethyl, propyl or isopropyl groups, etc., having up to twelve carbon atoms, Alcohol with a ring containing seven carbon atoms. Specific alcohols of this group include cyclohexanol, cyclohexanediol, 1,2,3-cyclohexanetriol and 1,3,5-cyclohexanetriol (fluorogitolitol), inositol, carbomenthol, menthol, p- such as α and γ-terpineol, 1-terpineol, 4-terpineol and pepperitol, or mixtures of these alcohols known as “terpineol”, 1,4- and 1,8-terpene Alcohol derived from mentan.

Alcohols derived from hydrocarbons with condensed rings are, for example, tuzan, pinane, campan groups, in particular tuzanol, savinol hydrate, D- and L-bornone and D- and L-isobornone.

The polycyclic aliphatic alicyclic alcohols used to obtain the esters of the present invention are steroids, especially corticosteroids and derivatives thereof, such as sterols, chloric acid and sex hormones and synthetic analogs.

Thus, for example, cholesterol, dihydrocholesterol, epidihydro cholesterol, coprostanol, epicoprostanol, cytosterol, stigmasterol, ergosterol, chloric acid, deoxychloric acid, lithochloric acid, estriol, estradiol Ethynyl propynyl derivatives at position 17, as well as equirenin, equirin and alkyl derivatives thereof, for example 17-α-ethynyl-estradiol or 7-α-methyl-17-α-ethynyl-estra Diols, pregnenolone, pregnandiol, testosterone and derivatives thereof such as 17-α-methyltestosterone, 1,2-dihydrotestosterone, 17-α-methyl-1,2-dihydrotestosterone, testosterone and , Alkyl derivative at position 17 of 1,2-dihydrotestosterone, for example 17-α-ethynyltestosterone, 17-α-propynyltestosterone, norgestrel, hydroxyprogesterone, corticosteroid Ron, deoxycorticosterone, 19-nortestosterone, 19-nor-17-α-methyltestosterone and 19-nor-17-α-methyltestosterone and 19-nor-17-α-ethynyltestosterone, cortisone, hydro Cortisone, prednisone, prednisolone, fludrocortisone, dexamethasone, betamethaneson, paramethaneson, flumethaneson, fluorcinolone, fluprednilidene, clobetasol, beclomethasone, aldosterone, deoxycorticos Antihormones such as theron, alphazolone, alphadolone, bolosterone and cyproterone can be used.

Useful esterification components for preparing the esters of the present invention are the genins (aglycones) of cardioactive glucosides such as dioxytoxygenin, gigoxigenin, ditoxygenin, stropantidine, tigogenin and saponin.

Other alcohols used in the present invention are vitamins such as axeloftol, vitamins D ₂ and D ₃ , anurine, lactoflavin, ascorbic acid, riboflavin, thiamine, and pantothenic acid.

Among the heterocyclic alcohols, preference is given to: furfuryl alcohol, alkaloids and atropine, scopolamine, cinconine, cinconidine, quinine, morphine, codeine, nalnorphine, N-butylscopol ammonium bromide, azu Alkaloid derivatives such as marine; Phenylethylamines such as ephedrine, isoproterenol, and epinephrine; Phenothiazines such as perphenazine, pipeothiazine, caffeazine, homophenazine, acetophenazine, flufenazine, and N-hydroxyethyl-promethazine-chloride; Thioxanthenes such as flufentic sol and clofentic sol; Antipsychotics such as anticonvulsants such as mepropendiol and opipramol; Anti-caking agents such as oxyfendil; Analgesics such as carvetidine, phenoferidine and metadol; Hypnotics such as etodroxyzine; Edible inhibitors such as benzhydrol and difemethoxydine; Minor trunculizers such as hydroxyzine; Muscle relaxants such as cinnamedrin, diphylline, mefenesin, metocarbamol, chlorophenesin, 2,2-diethyl-1,3-propanediol guapenesine, and idrosilamide; Coronary vasodilators such as dipyridamole and oxyphedrine, and adrenergic effect blocking agents such as propanolone, timolol, pindolol, bupranolol, atenolol, metoprolol, and fructolol; Antitumor agents, such as 6-azauridine, cytarabine, and phloxuridine; antibiotics such as chloramphenicol, thiamphenicol, erythromycin, oleandomycin, and lincomycin; Anti-barrier agents such as idoxuridine; Peripheral vasodilators such as isonicotinyl alcohol; Carbon dehydratase inhibitors such as sulfocarate; Anti-inflammatory agents such as anti-asthmatic agents and tiaramides; Sulfases such as 2-p-sulfanylanilinoethanol and the like.

All and partial esters of alginic acid according to the present invention include compounds represented by the following general formula and pharmacologically acceptable salts thereof, except that the partial esters are partial esters of dihydric alcohols.

Wherein R ¹ and R ² each independently represent a hydrogen or moiety derived from an alcohol selected from aliphatic, aryl aliphatic, cycloaliphatic and heterocyclic groups.

As noted above, alginic acid esters in which the ester group is derived from one or more hydroxy components with therapeutic action are of particular importance, and all possible natural variants thereof are also important.

Particularly important esters are the presence of two different types of ester groups derived from drugs with hydroxy properties and the remaining carboxyl groups being free, such as metals or bases to be described later, possibly the bases themselves being therapeutically active, eg esters. One or several of the bases having the same or similar action as the oxidizing component.

In particular, it may comprise, on the one hand, derived from the anti-inflammatory steroid and on the other hand vitamins or alkaloids or alginic acid esters derived from the antibiotic.

The degree of esterification of alginic acid with the alcohol depends on the particular properties desired in various applications, for example, on the degree of lipophilic or hydrophilicity to the skin tissue.

Increasing the degree of esterification of alginic acid in order to make the total esterification adequately increases its lipophilic properties, thus reducing the solubility in water.

For the therapeutic use of the novel esters of the invention, for example, in order to ensure a sufficient degree of solubility in water, for example 10 mg / ml, in spite of good and increased lipophilicity compared to metal alginate salts, It is most important to adjust. In addition, it is also necessary to consider the influence of the molecular size of the same esterification component, which has an inverse relationship to the solubility in water in general.

As mentioned above, the esterification of the carboxy group of alginic acid can only serve a variety of roles, for example in the medical field using esters as therapeutic agents or in the surgical field using esters as plastic materials.

As mentioned above, alcohols which already have therapeutic activity as a means of enhancing therapeutic activity, such as anti-inflammatory corticosteroids and alginic acid, have been esterified.

Therefore, for similar therapeutically active alcohols, alginic acid acts as a particularly effective carrier that can be fully incorporated into the biological environment, with most of these pharmacologically active alcohols being incorporated into the alcohols for use in the esterification of the present invention. And therefore identical to the applicable partial free alcohol of the corresponding ester. In other words, in the case of the partial ester esterified with the therapeutically active alcohol as described above, some or all of the remaining carboxyl groups of the alginic acid component are pharmacologically exemplified by saturated lower fatty alcohols such as ethyl or isopropyl alcohol. It can be esterified with an inert alcohol.

One particularly important aspect of the present invention is that drugs can be prepared that are more stable than the drugs available so far. For example, alginic acid esters that can be esterified with a therapeutically active alcohol and chlorided with a therapeutically active alcohol can produce drugs with a "delayed" effect.

For cosmetic use pharmacologically inert alcohols of alginic acid, for example saturated or unsaturated aliphatic alcohols, ie in the form of straight or branched chains, in particular in whole or in part with unsubstituted alcohols having from 1 to 8 carbon atoms as described above Preference is given to using esters.

Also of particular importance are condensation derivatives such as polyvinyl alcohols such as unsaturated alcohols having one or more double bonds such as vinyl or allyl alcohols and glycerin, polyhydric alcohols such as glycerin. In this case, a mixed ester can also be used according to the specific use desired.

In addition, alicyclic alcohols are useful, for example, derived from cyclopentane or cyclohexane and derivatives substituted with lower alkyl groups, for example alkyl having 1 to 4 carbon atoms, in particular methyl groups. Of particular interest are esters with cycloaliphatic and aliphatic-alicyclic alcohols derived from the above terpenes or from therapeutically active alcohols which can be used in cosmetics. In particular, the alcohols used for hygiene and surgical articles are the same as those used for the cosmetics.

In the ester according to the invention, the proportion of esterification groups can vary greatly depending on the use of the product, in particular according to the use of the various applications mentioned above. Thus, for the production of hygiene-surgical articles it is preferred to use full or partial esters with a high degree of esterification, for example, all esterified with about 80% to 100% of all carboxy groups.

Of particular interest are partial esters in which all of the carboxyl groups of alginic acid are esterified from 5% to 90%, particularly preferably for use in nutrition, cosmetics and pharmaceuticals in a proportion of 50 to 80%.

The proportion of ester groups of different forms in the mixed partial esters is of course various, for example in the case of two types of such groups, the ratio is preferably from 0.1: 1 to 1: 0.1, even if it is the whole ester Yes. The ester used for therapeutic purposes preferably has a ratio of 0.5: 1 to 1: 0.5. This ratio is the same also in the case of all esters, and in the case of partial ester, it is preferable to refer to the said ratio with respect to the number of esterifications contained.

Basic compounds useful for preparing salts of novel partial esters

For other partial esters of the invention, the non-esterified carboxyl groups may be free or chlorinated. Bases which form such salts are selected according to the ultimate purpose of the product. Inorganic salts may be formed from alkali metals such as potassium, in particular sodium and ammonium, or derivatives of alkaline earth metals or ammonium salts such as calcium or magnesium.

Of particular importance are those salts which are chlorided with organic bases, in particular aliphatic, arylaliphatic, cycloaliphatic, or heterocyclic amines.

The ammonium salt may be derived from a therapeutically acceptable amine or a nontoxic but therapeutically active amine. As the aliphatic amine of the first form, for example, mono-, di- and tri-alkylamine having an alkyl group having a maximum carbon number of 8, an arylalkylamine having a maximum carbon number of 8 at the aliphatic portion, etc. are preferable. Aryl represents a benzene group which may be substituted with 1 to 3 methyl groups, halogen atoms or hydroxy groups. The physiologically inert base for forming the salt is a ring such as monocyclic alkyleneamine having 4 to 6 carbon atoms in which heteroatoms such as nitrogen, oxygen and sulfur can be inserted into the ring, such as piperazine or morpholine, For example, it may be substituted by amino or hydroxy groups such as aminoethanol, ethylenediamol, ethylenediamine, ephedrine or choline.

It is also possible to form quaternary ammonium salts of partial esters, for example tetraalkylammonium salts having the above-described carbon atoms, preferably in the form of quaternary alkyl groups having 1 to 4 carbon atoms, for example methyl groups. have.

All of the above physiologically active amines which can be used for chloride and can take advantage of their therapeutic action are all basic nitrogen-containing drugs;

Alkaloids, peptides, phenothiazines, benzodiazepines, thioxanthenes, hormones, vitamins, anticonvulsants, antipsychotics, anti-nausea drugs, anesthetics, hypnotics, appetite suppressants, stabilizers, muscle relaxants, coronary vascular relaxants, antitumor agents, antibiotics , Antibacterial, antiviral, antimaleic, carbonic anhydrase inhibitor, nonsteroidal anti-inflammatory, vasoconstrictor, choline agonist, choline antagonist, adrenaline agonist and adrenergic antagonist.

All of the above agents having a nitrogen-containing basic group with respect to the alginic acid ester esterified by the therapeutically active alcohol, as well as the drugs to be described below, for example various antibiotics, are examples of particularly useful drugs.

[Use of New Ester as Carrier of Drug]

Partial esters are chlorinated by such therapeutically active bases and the use of the salts thereof may include partial or total esters or one of the above therapeutically acceptable but physiologically inert substances, for example sodium The simple case of addition of an active substance such as salts salted with alkali metals such as these shows a special case in which the alginic acid ester acts as an excipient.

Therefore, the carrier action of the alginic acid ester

1) a pharmacologically active substance or a combination or mixture of two or more such substances; And

2) It is another object of the present invention to show the possibility for a novel drug containing one of the alginic acid esters or salts thereof. Alcohols which are particularly esterified in alginic acid esters for use in the medicament, for example simple fatty alcohols as described above, are not themselves pharmacologically active. However, the present invention includes agents contained in the pharmacologically active form of the esters as in the case of one of the esters derived from pharmacologically active alcohols.

In such agents, if partial esters of alginic acid are used, the residual carboxyl groups are preferably chlorided with therapeutically neutral inorganic or organic bases, especially alkali metals such as sodium or ammonium. When the active substance (1) or a combination of the corresponding substances has a basic group, such as an antibiotic containing an amino group, for example, if a partial ester of alginic acid in which the free carboxyl group remains is used, the free carboxyl group of alginic acid and The basic substance produces a salt. These basic substances are, of course, in excess, and thus have a basic salt, so that the novel agents according to the invention will in particular comprise partial esters of alginic acid partially chlorinated by such pharmacologically active basic substances.

The non-esterified carboxyl group may also be chlorided with a therapeutically active base in the case of a nonbasic carrier material.

Alginic acid esters as carriers are particularly useful in ophthalmology, which exhibits excellent resistance without sensitization due to the specific combination of the new product with corneal epithelium. Furthermore, when the drug is administered in the form of a viscoelastic concentrated solution or in solid form, it has excellent adhesion and is very thin and uniform to represent a first-class product having a delay effect by continuously guaranteeing the biochemical usefulness of the drug. And stable corneal epithelium. Such ophthalmic agents are particularly useful in the field of veterinary medicine, given that no ophthalmic veterinary preparations that do not contain chemicals exist to date. In general, agents that can be used in humans are useful, and sometimes these agents do not warrant a particular range of action or cannot be used due to specific conditions of the treatment area. For example, in the case of infectious keratoconjunctivitis of bovine or sheep and goats, congested eyes, or IBK, there are probably specific etiological factors for these three animals. More particularly, the major microorganisms associated with cattle are Moraxella. bovis (eg, Rinotracheitis virus and Micoplasma in sheep, and Richkettsia and Chlamydia, Rickettsia in goats).

The disease develops in an acute form and spreads rapidly, initially characterized by spectacles and excessive tears, followed by purulent exudate, conjunctivitis and keratitis, sometimes with high fever and loss of appetite and milk yield. Symptoms. Even more serious are the lesions of the cornea, which may even form holes in the cornea itself at the last stage. The beds vary from days to weeks, using a wide range of chemicals, depending on the drug, and regularly administered locally (sometimes combined with steroid anti-inflammatory drugs). Examples of such drugs include tetracyclines such as oxytetracycline, penicillins such as cloxacillin and benzylphenicillin, sulfamides, polymyxin B (combination of myconazole and prednisolone), chloramphenicol and tallow Gina is back.

Although the local treatment of the disease is very simple, there is a problem that it is not possible to obtain a therapeutically useful antibiotic or sulfamide concentration for tear secretion, such as ophthalmic drugs that have been used so far for one or two reasons. In particular, in the case of a solution, if the slanted area of the animal head is considered, the carrier commonly used therein does not have an excellent degree of adhesion to the corneal surface, and there is a lack of a sufficiently high concentration of the active ingredient (the dispersion component of Present) Semi-solid drugs are preferred because they cannot be dispersed completely.

The drawbacks to conventional eye drops for ophthalmic use are described, for example, in Slatter et al. vet. J. ”1982. 59 (3), pp. Explained in 69-72.

The esters of the present invention can be used to eliminate these drawbacks. Alginic acid esters as carriers in ophthalmic drugs form preparations without concentrating the actives and have excellent homogeneity, transparency and excellent adhesion and sustaining effect to the corneal epithelium without sensitization.

Of course, the properties of the new agents described above can be used in addition to the ophthalmic field, i.e., in the dermatological field and mucous membranes, for example, oral infections.

In addition, the properties of the new drugs described above can be obtained systemic effect by transdermal absorption, for example in the case of suppositories. All these applications are possible for both human and veterinary medicines.

In the case of human medicines, the new drugs are particularly suitable for pediatric use. The present invention therefore particularly encompasses any of these therapeutic applications.

In addition, the following reference to the active substance of component (1) according to the present invention means a combination or mixture of two or more active substances.

Component (1) as described above is a pharmacologically active substance, which may first be divided into human and veterinary drugs in general and enumerate these uses in the treatment of you, followed by ophthalmology, Dermatology, otolaryngology, gynecology, vasculature, neurology, or internal organ pathology that can be treated by topical application, such as rectal application, specifies your application to the organ or tissue to be treated.

According to a particular aspect of the invention the pharmacologically active substance 1 is first used for ophthalmic use.

According to another criterion of the pharmacologically active substance, its use should be identified according to its effect, such as anesthetics, analgesics, anti-inflammatory agents, vasoconstrictors, antibiotics and antiviral agents.

In ophthalmology, indications are particularly mobilized, anti-inflammatory, wound healing and antimicrobial effects.

In addition, component (1) may be a combination of two or more active agents as contained in many agents known according to the invention. For example, in the field of ophthalmology, antibiotics may be combined with anti-inflammatory and vasoconstrictive agents, or one or more antibiotics may be combined with mobilizers, wound healing agents, anti-allergic agents and the like. For example, ophthalmic combinations such as:

Combination agents similar to ganamycin + phenylephrine + dexamethasone phosphate, kanamycin + betamethasone phosphate + phenylephrine or other antibiotics used in the ophthalmic field such as loritetracycline, neomycin, gentamycin, tetracycline,

In the field of dermatology, combinations of various antibiotics such as erythromycin, gentamicin, neomycin, gramicidine, polymyxin B, or combinations of such antibiotics with anti-inflammatory agents; For example hydrocortisone + neomycin, hydrocortisone + neomycin + polymyxin B + gramicidine, fluoromethorone + neomycin, dexamethasone + neomycin, prednisolone + neomycin, triamcinolone + neomycin + gramicidine + niacin Statins or other combinations used in conventional dermatological preparations can be used as the active ingredient (1).

Of course, combinations of various active ingredients are not limited to these fields, but it is possible to use combinations similar to those already used for pharmaceutical compositions known in the art in all pharmaceutical fields.

In the above case where the active substance (1) has basic properties, the salts obtained as partial esters of alginic acid may be in various forms. That is, all of the residual carboxyl groups can be chlorinated or only part of them, which is obtained as ester-acid salts or ester-neutral salts. The number of acidic groups that remain free is important for the preparation of a medicament with a particular pH.

According to a particular aspect of the present invention, it is possible to prepare a medicament in the form of a solid anhydride such as an amorphous powder as an isolated and possibly purified salt, which is a concentrated aqueous solution of gelatinous form with viscoelasticity upon contact with the treatment site. It consists of.

In addition, this property is maintained even after diluting more than the concentrated aqueous solution, and instead of the anhydrous salt, in order to control pH and osmotic pressure, an aqueous solution in which mineral salts and other carriers and additives are added, or a solution slightly concentrated in physiological saline may be used. have.

It is also possible to use salts in the preparation of gels, inserts, creams or ointments containing other carriers or ingredients used in conventional formulations in the manufacture of such pharmaceuticals.

However, according to the main aspect of the present invention, in the case of a drug containing an alginic acid ester or a salt thereof, a carrier except an aqueous solvent is used as a therapeutically active or inactive substance alone.

Mixtures obtained from all types of medicaments and mixtures of such medicaments and mixtures of novel alginate esters of free alginic acid or salts thereof, such as sodium salts, are also included in the present invention.

Examples of pharmacologically active substances (1) used in the ophthalmic preparations according to the invention are as follows:

Basic and nonbasic antibiotics such as gentamicin, neomycin, streptomycin, dihydrostreptomycin, kanamycin, amikacin, tobramycin, spectinomycin, erythromycin, oleandomycin, carbomycin, spiramycin , Oxytetracycline, loritetracycline, vacitracin, polymyxin B, gramicidine, colistin, chloramphenicol, lincomycin, vancomycin, novobiocin, ristocetin, clindamycin, amphotericin B, glycopolbin, Amino glycosides, macrolides, tetracyclines and peptides, such as niastatin, and sulfates, salts of nitrates, and combinations with other active active ingredients such as the examples therebetween or as mentioned later.

Other eye drops with advantages according to the invention are as follows.

; Anti-infectives such as diethylcarbazine, mebendazole, and sulfamides such as sulfacetamide, sulfadiazine, sulfioxazole.

; Iododeoxyuridine, adenine arabinoside, trifluorothymidine, acyclovir, ethyldeoxyuridine, bromovinyldeoxyuridine, 5-iodo-5'-amino-2 ', 5' Antiviral agents and anticancer agents such as dideoxyuridine.

; Steroidal anti-inflammatory agents such as dexamethasone, hydrocortisone, prednisolone, fluorometholone, medridone, and their esters, such as eg phosphate esters.

; Nonsteroidal anti-inflammatory agents, such as indomethacin, oxyphenbutazone, and flubifurophene.

; Wound healing agents such as epidermal growth factor EGF.

; Local anesthetics such as benoxysin, proparacaine and possible salts thereof.

; Cholinergic agonists such as pilocalpine, methicholine, carbamylcholine, aceclidine, physostigmine, neostigmine, demecarium and possible salts thereof.

; Cholinergic antagonists such as atropine and its salts.

; Adrenergic agonists such as noradrenaline, adrenaline, napazoline, methoxamine and possible salts thereof.

; Adrenergic antagonists such as propanolol, tomolol, pindolol, bufranolol, atenolol, metopanolol, oxprenolol, frectolol, butoxamine, sotalol, butetrin, labetalol and possible salts thereof.

In addition, combinations or mixtures of them and possibly other ingredients and combinations or mixtures of these agents can be used as component (1) according to the invention. If a combination of the actives is used in place of only one active substance (1), the salt of the basic active substance and the partial ester of alginic acid may be a mixed salt of one or more of the basic substances or with the metals or bases May be a mixed salt with any number of said acidic groups of polysaccharide to be chlorided.

For example, pharmacologically inert alcohols such as lower alkanols and some% of the acidic groups are chlorided with the antibiotic kanamycin and some% with the vasoconstrictor phenylephrine and the remainder sodium or It is possible to prepare salts of partial esters of alginic acid which can be chlorided with one of the metals mentioned above.

For a medicament consisting of the polysaccharide ester and a salt of only one active substance, it is also possible to prepare such free alginic acids or fractions thereof or mixed salts of these forms with metal salts thereof.

Examples of combinations with themselves or with other active substances useful in the combination or dermatology are as follows.

; Therapeutic preparations, such as an anti-infective agent, an antibiotic, a bactericide, an anti-inflammatory agent, cytostatic, cytotoxic, antiviral anesthetic, and propyl lactic agents, such as a light-shielding agent and a deodorant, an antiseptic, and a disinfectant.

Among the antibiotics are erythromycin, bacitracin, gentamicin, neomycin, oreomycin, gramicidine and combinations thereof. Antibacterial and disinfectants include nitro purazone, maphenide, chlorhexidine, 8-hydroxyquinoline derivatives and possible salts thereof, in particular prednisolone, dexamethasone, flumethasone, clabetasol, acetonide of triamcinolone, betamethaneson Anti-inflammatory agents of corticosteroids such as gluconate, benzoate, benzoate, dipropionate, and their esters. Among the cytokines, fluorouracil, methotrexate, grapepilin, and anesthetics such as dibucaine, lidocaine, and bezocaine. .

Of course, this is for illustrative purposes only and other drugs described in the literature can be used.

From the examples discussed for ophthalmology or dermatology, it can be confirmed by the homologue that the agents according to the invention can be used in other areas of the medicament and then in theology or dentistry or internal medicine.

For example, in endocrinology, agents may be used that absorb through the mucosa, such as rectal or nasal absorption, such as intradermal or nasal dispersants or agents for inhalation into the oral or pharynx.

Thus, such preparations are anti-inflammatory or vasoconstrictors or vasopressors, vitamins, antibiotics, etc., as already mentioned for ophthalmology, and in dermatology, hormones, chemotherapeutic agents, antibacterial agents, etc., also mentioned above. This can be

[Method for producing alginic acid ester]

According to the inventive chemically novel and inventive process, the alginic acid esters are preferably aprotic organic solvents, such as dialkylsulfoxides, dialkylcarboxes, for example lower alkyl dialkyl sulfoxides, in particular dimethylsulfoxide. Prepared by starting with quaternary ammonium salt of alginic acid together with esterification agent in aprotic organic solvents such as lower side and lower alkyl dialkalamide of lower fatty acids such as dimethyl or diethylformamide or dimethyl or diethylacetamide It is preferable. However, other solvents such as aliphatic or heterocyclic alcohols and ketones having low boiling points, such as hexafluoro isopropanol and trifluoroethanol, such as alcohols, ethers, ketones and esters, which are not aprotic, may also be used. This reaction is preferably carried out at a temperature between about 0 ° and 100 ° C., preferably between 25 ° and 75 ° C., more preferably at a temperature of about 30 °.

For example, it is preferable to advance the esterification reaction by gradually adding an esterifying agent to the ammonium salt dissolved in one of the above solvents such as dimethyl sulfoxide. As the alkylating agent it is possible to use the abovementioned agents, in particular halogenated hydrocarbyl, for example halogenated alkyl.

Therefore, a preferred esterification process involves reacting a quaternary ammonium salt of alginic acid with a stoichiometric amount of a compound represented by general formula AX in an organic solvent, where A is aliphatic, arylaliphatic, alicyclic, Is selected from aliphatic-alicyclic and heterocyclic groups, X is a halogen atom, and the stoichiometric amount of the general formula AX is determined according to the degree of esterification desired.

The quaternary ammonium salt as a starting material is preferably a lower ammonium tetraalkyl salt containing an alkyl group having 1 to 6 carbon atoms, and an alginate salt of tetrabutylammonium is usually used. Such quaternary ammonium salts can be prepared by reacting a metal salt of alginic acid, preferably one of those described above, in particular an aqueous solution with a sulfon resin in which sodium or potassium salts are chlorided with a quaternary ammonium base. In particular, the tetraalkylammonium alginate derived from lower alkyl having 1 to 6 carbon atoms is novel, and it is another object of the present invention to provide it.

In particular, since the salts have been proved to be soluble in the aprotic solvent described above, the esterification of alginic acid according to the novel process can be carried out very easily and results in high yields. Therefore, by using the above process, the number of carboxyl groups of esterified alginic acid can be accurately measured.

One variation of this process is to react the potassium or sodium salt of alginic acid suspended in a suitable solution such as dimethylsulfoxide with a suitable alkylating agent in the presence of a catalytic amount of a quaternary ammonium salt such as tetrabutylammonium iodide. According to the novel process, as described above, it is possible to obtain the total ester of alginic acid substituted with alcohol such as alginic acid and glycol, which has not been conventionally obtained.

In order to prepare other novel esters in the present invention, for example, any alginic acid extracted from the natural starting materials can be used, the preparation of such acids is described in the literature and it is preferred to use purified alginic acid. Do.

In the partial esters of the present invention, all or part of the carboxy moiety can be chlorided by adding an amount of base to obtain the desired stoichiometric degree of chloride.

By accurately measuring the degree of chloride, esters having a wide range of different dissociation constants can be prepared, thereby obtaining a solution in which the desired pH or itself can be applied for therapeutic purposes.

The present invention also encompasses modifications to the process for the preparation of the novel esters and salts thereof, in which case the process can be involved in any step, or when starting with an intermediate compound according to the remaining steps, or starting If the material is a natural product it will include all.

The present invention will be described in detail based on the following examples, but the scope of the present invention is not limited only to the following examples.

Example 1

[Production of Tetrabutylammonium Salt of Alginic Acid]

10 m.Eq. of sodium alginate salt equivalent to 2 g of the dry compound was dissolved in 300 ml of distilled water, and the solution was passed through a temperature control tube at 4 ° C. containing 15 ml of tetrabutyl ammonium sulfone resin (Dowex 50 × 8). . The sodium-glass eluate is frozen and dried.

Yield: 3.3 g

Example 2

[Production of (partial) ethyl ester of alginic acid-esterified carboxyl group 10% and chlorinated carboxyl group 90%]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from algiic acid obtained from Laminaria hyperborea) was dissolved in 400 ml of DMSO at a temperature of 25 ° C., and 0.377 g (2.39 m.Eq.) of ethyl iodide was added thereto. I was.

The solution was then stirred well for 12 hours at a temperature of 30 ° C.

a) In order to completely convert the carboxy salt of the tetrabutylammonium moiety to the sodium salt form, a solution of 2.5 g of NaCl dissolved in 500 ml of distilled water while cooling from the outside in a water / ice bath was added to the solution. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 6 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety into the form of calcium salt.

Yield: 6.1 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 3

[Preparation of (partial) ethyl ester of alginic acid-30% esterified carboxyl group and 70% chlorinated carboxyl group]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alganic acid (prepared from alginic acid obtained from Ascophyllum nodosum) was dissolved in 400 ml of DMSO at a temperature of 25 ° C, and 1.31 g (7.18 m.Eq.) of ethyl iodide was added. The solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) A solution of the carboxy salt of the tetrabutylammonium moiety completely converted to the sodium salt form was added to the solution and cooled externally with water / salt bicarbonate. The solution was slowly added dropwise in 2000 ml ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 10 ml of acetone / water (5: 1), three times with 100 ml of pure acetone, and then vacuum dried.

Yield: 5 g

b) As described above, except that the carboxy salt of the tetrabutylammonium moiety is replaced with the sodium chloride chloride for conversion to calcium salt.

Yield: 5.1 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 4

[Preparation of (partial) ethyl ester of alginic acid-50% esterification carboxyl group and 50% chloride carboxyl group]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Macrocystis pyrifera) was dissolved in 400 ml of DMSO at a temperature of 25 ° C, and 1.88 g (11.9 m.Eq.) of methyl iodide was added.

The solution was stirred well for 12 hours at a temperature of 30 ° C. next,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise in 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1), three times with 100 ml of pure acetone, and then vacuum dried.

Yield: 4.5 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 4.6 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 5

[Preparation of (partial) ethyl ester of alginic acid-70% esterified carboxyl group and 30% chlorinated carboxyl group]

10 g (12.3 m. Eq.) Of tetrabutylammonium (made of alginic acid obtained from Laminaria hyperborea) of alginic acid were dissolved in 400 ml of DMSO at a temperature of 25 ° C., and 2.64 g (16.7 m. Eq.) Of ethyl iodide was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 4 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 4.2 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 6

[Production of (partial) ethyl ester of alginic acid-90% esterified carboxyl group and 10% chlorinated carboxyl group]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria hyperborea) was dissolved in 400 ml of DMSO at a temperature of 25 ° C., and 3.39 g (21.5 m.Eq.) of ethyl iodide was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 5.5 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 5.6 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 7

[Production of (partial) isopropyl ester of alginic acid-90% esterified carboxyl group and 10% chlorinated carboxyl group]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Ascophyllum nodosum) was dissolved in 400 ml of DMSO at a temperature of 25 ° C, and 3.73 g (21.5 m.Eq.) of isopropyl iodide was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 4.2 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 4 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 8

[Production of (partial) isopropyl ester of alginic acid-70% esterified carboxyl group and 30% chlorinated carboxyl group]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria hyperborea) was dissolved in 400 ml of DMSO at a temperature of 25 ° C., and 2.9 g (16.7 m.Eq.) of isopropyl iodide was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 4 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 3.8 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 9

[Production of (partial) isopropyl ester of alginic acid-50% esterified carboxyl group and 50% chlorinated carboxyl group]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Macrocystis pyrifera) was dissolved in 400 ml of DMSO at a temperature of 25 ° C, and 2.07 g (11.9 m.Eq.) of isopropyl iodide was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 4.2 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 4.2 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 10

[Production of (partial) isopropyl ester of alginic acid-30% esterified carboxyl group and 70% chlorinated carboxyl group]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Ascophyllum nodosum) was dissolved in 400 ml of DMSO at a temperature of 25 ° C., and 1.24 g (7.18 m.Eq.) of isopropyl iodide was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 5.5 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 5.4 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 11

[Production of (partial) isopropyl ester of alginic acid-esterified carboxyl group 10% and chlorinated carboxyl group 90%]

10 g (23.9 m.Eq.) of tetrabutylammonium (made with alginic acid obtained from Laminaria hyperborea) of alginic acid were dissolved in 400 ml of DMSO at a temperature of 25 ° C., and 0.42 g (2.3 m. Eq.) Of isopropyl iodide was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 5.8 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 5.8 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 12

[Production of (partial) thibutylester of alginic acid-90% esterified carboxyl group and 10% chlorinated carboxyl group]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Ascophyllum nodosum) was dissolved in 400 ml of DMSO at a temperature of 25 ° C, and 4.1 g (21.5 m.Eq.) of terbutyl iodide was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 4 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 4.1 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 13

[Production of (partial) terbutyl esters of alginic acid-70% esterified carboxyl group and 30% chlorinated carboxyl group]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria hyperborea) was dissolved in 400 ml of DMSO at a temperature of 25 ° C., and 3.14 g (16.7 m. Eq.) Of thibutyl iodide was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 5 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to change the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 5 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 14

[Production of (partial) thibutylester of alginic acid-50% esterified carboxyl group and 50% chlorinated carboxyl group]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (made with alginic acid obtained from Macrocystis pyrifera) was dissolved in 400 ml of DMSO at a temperature of 25 ° C, and 2.25 g (11.9 m.Eq.) of terbutyl iodide was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 5.4 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 5.4 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 15

[Production of (partial) thibutyl esters of alginic acid-30% esterified carboxyl group and 70% chlorinated carboxyl group]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria hyperborea) was dissolved in 400 ml of DMSO at a temperature of 25 ° C, and 1.34 g (7.18 m.Eq.) of terbutyl iodide was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 5.5 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 5.7 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 16

[Production of (partial) thibutylester of alginic acid-esterified carboxyl group 10% and chlorinated carboxyl group 90%]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Macrocystis pyrifera) was dissolved in 400 ml of DMSO at a temperature of 25 ° C, and 0.45 g (2.39 m.Eq.) of terbutyl iodide was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 5 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 5 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 17

[Production of (partial) benzyl esters of alginic acid-90% esterified carboxyl group and 10% chlorinated carboxyl group]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Ascophyllum nodosum) was dissolved in 400 ml of DMSO at a temperature of 25 ° C., 3.76 g (21.5 m.Eq.) of benzyl bromide and tetrabutylammonium iodide 0.1 g was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 5 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 5 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 18

[Production of (partial) benzyl esters of alginic acid-70% esterified carboxyl group and 30% chlorinated carboxyl group]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (made with alginic acid obtained from Laminaria hyperborea) was dissolved in 400 ml of DMSO at a temperature of 25 ° C., 2.9 g (16.7 m.Eq.) of benzyl bromide and tetrabutylammonium iodide 0.1 g was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 4.6 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 4.5 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 19

[Production of (partial) benzyl esters of alginic acid-50% esterified carboxyl group and 50% chlorinated carboxyl group]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Ascophyllum nodosum) was dissolved in 400 ml of DMSO at a temperature of 25 ° C., 2.1 g (m.Eq.) of benzyl bromide and tetrabutylammonium iodide 0.1 g was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 4.2 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 4.3 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 20

[Production of (partial) benzyl esters of alginic acid-30% esterified carboxyl group and 70% chlorinated carboxyl group]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Ascophyllum nodosum) was dissolved in 400 ml of DMSO at a temperature of 25 ° C., 1.25 g (7.18 m.Eq.) of benzyl bromide and tetrabutylammonium iodide 0.1 g was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 6 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 6.1 g

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 21

[Production of (partial) benzyl esters of alginic acid-esterified carboxyl group 10% and chlorinated carboxyl group 90%]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Macrocystis pyrifera) was dissolved in 400 ml of DMSO at a temperature of 25 ° C., 0.42 g (2.39 m.Eq.) of benzyl bromide and tetrabutylammonium iodide 0.1 g was added.

After the solution was stirred well at a temperature of 30 ° C. for 12 hours,

a) In order to completely convert the carboxy salt of the tetrabutylammonium residue to the sodium salt, the solution was added to an aqueous solution of 2.5 g of NaCl dissolved in 50 ml of distilled water and cooled externally with a water / ice bath. The solution was slowly added dropwise into 2000 ml of ethyl acetate with stirring, and the precipitate was separated by filtration, washed three times with 100 ml of acetone / water (5: 1) and three times with 100 ml of pure acetone, followed by vacuum drying.

Yield: 5 g

b) As described above, except that the sodium chloride is replaced with calcium chloride to convert the carboxy salt of the tetrabutylammonium moiety to the calcium salt.

Yield: 5 g

Example 22

[Production of Methyl Ester of Alginic Acid]

8.35 g (20 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Ascophyllum nodosum) were dissolved in 400 ml of DMSO at a temperature of 25 ° C, and 3.66 g (25 m.Eq.) of methyl iodide was added.

The solution was stirred well for 12 hours at a temperature of 30 ° C. and then slowly added dropwise to 3.5 L of ethyl acetate (or toluene) with continued stirring. The precipitate is filtered off, washed four times with ethyl acetate and then vacuum dried for 24 hours at a temperature of 30 ° C. As a result, 4 g of the target compound was obtained.

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 23

[Production of benzyl ester of alginic acid]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Macrocystis pyrifera) was dissolved in 400 ml of DMSO at a temperature of 25 ° C., 4.45 g (26 m.Eq.) of benzyl bromide and tetrabutylammonium iodide 0.1 g was added.

The solution was stirred well for 12 hours at a temperature of 30 ° C. and then slowly added dropwise to 3.5 L of ethyl acetate (or toluene) with continued stirring. The precipitate is filtered off, washed four times with ethyl acetate and then vacuum dried for 24 hours at a temperature of 30 ° C. As a result, 5 g of the target compound was obtained.

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 24

[Production of Thibutyl Ester of Alginic Acid]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria hyperborea) was dissolved in 400 ml of DMSO at a temperature of 25 ° C., and 4.8 g (26 m.Eq.) of tbutyl iodide was added.

The solution was stirred well for 12 hours at a temperature of 30 ° C. and then slowly added dropwise to 3.5 L of ethyl acetate (or toluene) with continued stirring. The precipitate is filtered off, washed four times with ethyl acetate and then vacuum dried for 24 hours at a temperature of 30 ° C. As a result, 3.8 g of the target compound was obtained.

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 25

[Production of isopropy ester of alginic acid]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Laminaria hyperborea) was dissolved in 400 ml of DMSO at a temperature of 25 ° C., and 4.4 g (26 m.Eq.) of isopropyl iodide was added.

The solution was stirred well for 12 hours at a temperature of 30 ° C. and then slowly added dropwise to 3.5 L of ethyl acetate (or toluene) with continued stirring. The precipitate is filtered off, washed four times with ethyl acetate and then vacuum dried for 24 hours at a temperature of 30 ° C. As a result, 3.8 g of the target compound was obtained.

Quantitative analysis of the ester group was carried out by the saponification method described on pages 169-12 of "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication. The solution was stirred well for 12 hours at a temperature of 30 ℃

Example 26

[Production of ethyl ester of alginic acid]

10 g (23.9 m.Eq.) of tetrabutylammonium salt of alginic acid (prepared from alginic acid obtained from Ascophyllum nodosum) was dissolved in 400 ml of DMSO at a temperature of 25 ° C, and 4 g of ethyl iodide (26 m.Eq.) was added.

The solution was stirred well for 12 hours at a temperature of 30 ° C. and then slowly added dropwise to 3.5 L of ethyl acetate (or toluene) with continued stirring. The precipitate is filtered off, washed four times with ethyl acetate and then vacuum dried for 24 hours at a temperature of 30 ° C. As a result, 3.8 g of the target compound was obtained.

Quantitative analysis of the ester group was carried out by the saponification method described in "Quantitative organic analysis viafunctional groups", 4th Ed., John Wiley and Sons Publication, pages 169 to 172.

Example 27

Preparation of amikacin salt of partially esterified alginic acid with ethanol-75% carboxyl group esterified from ethanol and 25% carboxyl group chlorinated with amikacin

147 mg (1 m.Eq.) of amikacin is dissolved in 20 ml of water. In addition, 0.81 g of 75% ethyl ester and 25% sodium salt of alginic acid (corresponding to 1 m.Eq. of monomers for non-esterified carboxyl) were dissolved in 400 ml of water, and the solution was added to a sulfone resin of type H ⁺ (Dowex 50 ×). 8) was eluted in a temperature control tube at 20 ° C containing 2 ml.

The sodium glass eluate was collected in the amikacin base solution with stirring and immediately freeze-dried.

Microbiological assays on St aureus ATCC 29737 compared to standard amikacin resulted in an 8.5% content by weight of amikacin base, corresponding to theoretical calculations.

Example 28

Preparation of erythromycin salt of partially esterified alginic acid with ethanol-75% of carboxyl group esterified with ethanol and 25% of carboxyl group chlorinated with erythromycin

0.81 g of 75% ethyl ester and 25% sodium salt of alginic acid (corresponding to 1 m.Eq. of monomers for non-esterified carboxyl) were dissolved in 400 ml of water, and the solution was then sulfone resin of type H ⁺ (Dowex 50 × 8) was eluted in a temperature control tube at 20 ° C containing 2 ml.

To the obtained sodium free eluate, 724 mg (1 m.Eq.) of erythromycin base was added, and immediately freeze-dried.

Compared to standard erythromycin, 31.7% content is shown in the weight ratio of erythromycin base, which corresponds to the determination theoretical result of the microbiological assay on St aureus ATCC 6538.

Example 29

Preparation of streptomycin salts of partially esterified alginic acid with ethanol-75% carboxyl esterified with ethanol and 25% carboxyl chloride with streptomycin

Sulfate glass obtained by dissolving 243 mg (1 m.Eq.) of streptomycin sulfate in 200 ml of water and eluting it in a temperature control tube at 5 ° C. containing 2 ml of OH ^- type quaternary ammonium resin (Dowex 1 × 8). The eluate was collected on a thermostat at 5 ° C.

2 ml of H ⁺ sulfone resin (Dowex 50 × 8) was dissolved in 400 ml of water in which 0.81 g of 75% ethyl ester and 25% sodium salt of alginic acid (corresponding to 1 m.Eq. of monomers for non-esterified carboxyl) were dissolved in 400 ml of water. It eluted to the temperature control tube of 20 degreeC containing.

The resulting sodium glass eluate was collected in a streptomycin base solution with stirring, and freeze-dried immediately.

Microbiological assays on B subtilis ATCC 6633 compared to standard streptomycin showed a 10.9% content by weight ratio of streptomycin, corresponding to theoretical calculations.

Example 30

Ethanol and fluorocortisone partial mixed esters of alginic acid (40% carboxyl esterified with C ₂ -ethanol, 20% carboxyl esterified with fluorocortisone and 40% carboxyl chloride (Na))

8.35 g of tetrabutylammonium of alginic acid (manufactured from Laminaria hyperborea) corresponding to 20 m.Eq of the monomer was dissolved in 350 ml of DMSO at a temperature of 25 ° C., and 0.62 g of ethyl iodide (4 m.Eq.) was added, followed by 30 ° C. It was left under temperature for 24 hours.

0.89 g (2 m.Eq.) of 9α-fluoro-21-bromo-4-pregnene-11β, 17α-diol-3,20-dione was added and left at a temperature of 30 ° C. for 24 hours.

A solution containing 100 ml of water and 5 g of sodium chloride was added and the solution was slowly added dropwise to 2,000 ml of acetone with continuous stirring. The precipitate formed was filtered, washed three times with 100 ml of 1 mole of acetone (5: 1), washed three times with 100 ml of acetone and vacuum dried for 8 hours at a temperature of 30 ° C.

As a result, 3.5 g of partially mixed ester of the ethanol and fluorocortisone was obtained. After weak alkali hydrolysis of Na ₂ CO ₃ hydroalcohol solution and extraction with chloroform, quantitative analysis of fluorocortisone was carried out according to British Pharmacopea (1980), and quantification of ethoxyl was carried out by RHCundiff and PCMarkunas [Anal. Chem. 33, 1028 to 1030 (1961).]

Example 31

(C ₂₁ ) Preparation of (partial) fluorocortisone esters of alginic acid-esterified carboxyl group 20% and chlorinated carboxyl group (Na) 80%

4.18 g of tetrabutylammonium salt of alginic acid (prepared from Laminaria hyperborea) corresponding to the unit 10 m. Eq. Was dissolved in 210 ml of DMSO at a temperature of 25 ° C., 9α-fluoro-21-bromo-4-pregnene-11β, The solution obtained by adding 0.89 g (2 m.Eq.) of 17α-diol-3,20-dione was left at a temperature of 39 ° C. for 12 hours.

A solution containing 62 ml of water and 5 g of sodium chloride was added to the solution and slowly added dropwise to 2,000 ml of acetone with continuous stirring. The precipitate formed is filtered, washed twice with 100 ml of acetone / water (5: 1) solution, three times with acetone and then vacuum dried for 8 hours at a temperature of 30 ° C. The product was then dissolved in 300 ml of 1% sodium chloride water and slowly added to 1500 ml of acetone with constant stirring.

The precipitate formed was filtered, washed twice with 100 ml of acetone / water (5: 1), three times with 100 ml of acetone, and then vacuum dried at a temperature of 30 ° C. for 24 hours. As a result, 1.5 g of said partial fluorocortisone ester compound is obtained.

After weak alkali hydrolysis with Na ₂ CO ₃ hydroalcohol solution and extraction with chloroform, quantitative analysis of fluorocortisone was performed according to British Pharmacopea (1980, P196).

Example 32

80% of carboxyl groups esterified with ethanol and hydrocortisone (mixed) ester of alginic acid (C ₂₁ ) -ethanol and 20% of carboxyl groups esterified with hydrocortisone (C ₂₁ )

4.18 g of tetrabutylammonium salt of alginic acid (manufactured from Laminaria hyperborea) corresponding to 10 m.Eq of the unit was dissolved in 210 ml of DMSO at a temperature of 25 ° C., and 1.25 g (8 m.Eq.) of ethyl iodide was added to the solution. It was left for 12 hours at a temperature of ℃.

Then, 0.85 g (2 m.Eq) of 21-bromo-4-pregnene-11β, 17α-diol-3,20-dione was added thereto and left at a temperature of 30 ° C. for 24 hours, followed by 100 ml of water and 5 g of sodium chloride. The solution was added and slowly added dropwise to 2,000 ml of acetone with continuous stirring. The precipitate formed was filtered, washed three times with 100 ml of acetone / water (5: 1) solution, three times with 100 ml of acetone, and then vacuum dried for 8 hours at a temperature of 30 ° C.

1.8 g of the said ethanol and hydrocortisone mixed ester compound are obtained. After weak alkali hydrolysis with Na ₂ CO ₃ hydroalcohol solution and extraction with chloroform, quantification of hydrocortisone is carried out according to British Pharmacopea (1980), and the quantification of ethoxyl is carried out by RHCundiff and PCMarkunas [Anal. Chem. 33, 1028-1030].

Example 33

Preparation of (partial) hydrocortisone ester (C ₂₁ ) of alginic acid-20% esterified carboxyl group and 80% chlorinated carboxyl group (Na)

8.35 g of tetrabutylammonium salt of alginic acid (manufactured from Microcystis pyrifera) corresponding to 20 m.Eq of the unit is dissolved in 350 ml of DMSO at a temperature of 25 ° C., and 21-bromo-4-pregnene-11β, 17α-diol-3 The solution to which 0.850 g of 20-dione was added was left at a temperature of 30 ° C. for 24 hours.

A solution containing 100 ml of water and 5 g of sodium chloride is added thereto, and the solution is slowly added to 2,000 ml of acetone with continuous stirring. The precipitate formed was filtered off, washed three times with 100 ml of acetone / water (5: 1) solution, washed three times with acetone and then vacuum dried for 8 hours at a temperature of 30 ° C.

The product was then dissolved in 300 ml of water containing 1% sodium chloride and slowly added to 1,500 ml of acetone with continuous stirring. The precipitate formed was filtered, washed twice with 100 ml of acetone / water (5: 5) solution, washed three times with 100 ml of acetone and then vacuum dried at a temperature of 30 ° C.

As a result, 3 g of the partial hydrocortisone compound was obtained. After weak alkali hydrolysis with Na ₂ CO ₃ hydroalcohol solution and extraction with chloroform, quantification of hydrocortisone was performed according to British Pharmacopea (1980, p224).

Example 34

Preparation of ethanol and fluorocortisone (mixed) esters of alginic acid (C ₂₁ ) -80% carboxyl esterified with ethanol and 20% carboxyl esterified with fluorocortisone (C ₂₁ )

4.18 g of tetrabutylammonium salt of alginic acid (manufactured from Macrocystic pyrifera) corresponding to unit 10 m.Eq was dissolved in 210 ml of DMSO at a temperature of 25 ° C., and a solution containing 1.25 g of ethyl iodide (8 m.Eq) was added at a temperature of 30 ° C. It was left for 24 hours under.

0.89 g (2 m.Eq.) of 9α-fluoro-21-bromo-4-pregnene-11β, 17α-diol-3-, 20-dione was added thereto and left for 24 hours at a temperature of 30 ° C. I was.

The solution obtained by adding 100 ml of water and 5 g of sodium chloride-containing solution was slowly added to 2000 ml of acetone while continuing to stir. The precipitate formed was filtered, washed three times with 100 ml of acetone / water (5: 1), three times with 100 ml of acetone, and then vacuum dried at a temperature of 30 ° C. for 8 hours.

1.7 g of the ethanol and fluorocortisone mixed ester compound were obtained. After weak alkali hydrolysis with Na ₂ CO ₃ hydroalcohol solution and extraction with chloroform, quantitative analysis of fluorocortisone is carried out according to British Pharmacopea (1980), and the quantification of ethoxyl is described by RHCundiff and PCMarkunas [Anal. Chem. 33, 1029-1030 (1961).

Example 35

Preparation of ethanol and hydrocortisone (partial mixture) ester of alginic acid (C ₂₁ )-40% of carboxyl esterified with ethanol, 20% of carboxyl esterified with hydrocortisone (C ₂₁ ) and carboxyl chloride (Na) 40 %

4.18 g of tetrabutylammonium salt of alginic acid (manufactured from Macrocystis pyrifera) corresponding to 10 m.Eq of a unit was dissolved in 210 ml of DMSO at a temperature of 25 ° C. and 0.62 g of ethyl iodide (4 m.Eq) was added at a temperature of 30 ° C. It was left for 24 hours.

0.85 g (2 m.Eq) of 21-bromo-4-pregnene-11β, 17α-diol-3,20-dione was added thereto, and left for 24 hours at a temperature of 30 ° C.

Then 200 ml of water and 5 g of sodium chloride containing solution were added to the solution and slowly added to 2,000 ml of acetone with continued stirring. The precipitate formed was filtered, washed three times with 100 ml of acetone / water (5: 1) solution, washed three times with 100 ml of acetone, and then vacuum dried for 8 hours at a temperature of 30 ° C.

1.7 g of the ethanol and hydrocortisone partial mixed ester compound are obtained. After weak alkali hydrolysis with Na ₂ CO ₃ hydroalcohol solution and extraction with chloroform, quantification of hydrocortisone is carried out according to British Pharmacopea (1980), and the quantification of ethoxyl is carried out by RHCundiff and PCMarkunas [Anal. Chem. 33, 1028-1030 (1961).

[Pharmaceutical Formulation of Alginic Acid Ester]

The present invention is to provide a pharmaceutical formulation containing at least one drug in which the alginic acid ester or one of the alginic acid esters is bound to the pharmacologically active substance as described above, wherein the alginic acid ester Acts as an excipient for the active substance.

The pharmaceutical preparations in the form of the above-mentioned pharmaceutical agents in which components (1) and (2) are combined and containing therapeutically active alginic acid esters include common carriers and are oral, rectal, parenteral, subcutaneous, topical or subcutaneous. As such, they can be used in the form of solid or semi-solid, for example pills, tablets, gelatin capsules, suppositories, soft gelatin capsules and the like. Parenteral and subcutaneous forms can be used for intramuscular or intradermal administration, or forms suitable for intravenous infusion or injection, so that they are suitable for physiological solution and have osmotic properties. It is also possible to provide an effective compound in the form of a solution or lyophilized powder for binding to these compounds.

Topical applications include disperse preparations, for example, cost-effective dispersants, topical creams or ointments, or formulated plasters suitable for intradermal administration.

The formulations of the present invention are intended for administration to humans or animals, and preferably in the form of solvents, dispersants, ointments, and creams, the active ingredient contains 0.01 to 10%, the solid preparation contains 1 to 100%, Preferably 5 to 50%. In addition, the dosage will vary depending on the particular instructions or the desired effect and the choice of route of administration, and the daily dosage of these agents can be estimated from the daily dosage of those agents known in the field of therapeutically active alcohols, for example The dosage of the alginic acid ester esterified with cortisone can be estimated from the content in this same steroid and the general dosage of known pharmaceutical agents.

For example, a special form of one of the topical pharmaceutical preparations is represented by these agents, which are constituted by a bond between an alginic acid ester and an active substance, which are also mixed or separate from only two components (1) and (2). It may be a solid such as a freeze-dried powder contained as. When contacting these solid agents with the treated epithelium, they form a somewhat concentrated solution according to the properties of the particular epithelium to be treated, which represents another particularly important aspect of the present invention having the same properties as the solution prepared in vitro. do. The solutions are preferably prepared with distilled water or sterile saline, and in particular do not contain other pharmaceutical carriers other than the alginic acid esters or salts thereof.

The concentrations of these solutions vary widely, for example between 0.01 and 75% for each of the two components and for mixtures or salts thereof.

Particularly preferred are solutions having good elasticity-viscosity, for example solutions having a content of 10-90% of the medicament or each component thereof.

Of particular importance is anhydrous (freeze-dried powder) or in the form of a concentrate or diluted in water or saline, possibly with additives or auxiliaries, such as inorganic salts acting as fungicides or buffers or other substances used for ophthalmology. It is a drug.

Among the medicaments of the present invention, those which are optionally chosen are those having a suitable acidity, ie physiologically resistant pH, for the application site. For example, in the salt salted with the basic active substance of the alginic acid ester, the pH can be adjusted by appropriately adjusting the amounts of the polysaccharide, its salt, and the basic substance itself.

In this way, for example, if the acidity of the alginic acid ester salt with the basic substance is too high, the excess free acidic group can be neutralized with the inorganic base such as sodium, potassium or ammonium hydrate.

The salts according to the invention are known by contacting solutions or aqueous suspensions or organic solvents of the two components (1) and (2) and possibly bases or basic salts of the alkali metals or alkaline earth metals or magnesium or aluminum described above in theoretical amounts. The salts can be separated into chlorides in anhydrous amorphous state by the method.

For example, an aqueous solution of two components (1) and (2) is first prepared and the two solutions are kept at a low temperature, for example 0 ° C. to 20 ° C., using a suitable ion exchanger to liberate both components from the aqueous solution of salt, The salt thus obtained is easily dissolved in water and lyophilized, while if the solubility of the salt is poor, it can be centrifuged, filtered or separated and subsequently dried.

In addition, the dosage for the combination drug is based on that of the active ingredient used as a single ingredient, and thus can be easily determined by those skilled in the art in view of the recommended dosage for the corresponding known drug.

In the cosmetics according to the invention, the alginic acid esters and salts thereof can be mixed with carriers customarily used in the art, for example those already described above for pharmaceutical compositions. For topical use, creams, ointments and lotions are preferentially used, in which case one of the alginic acid esters or salts thereof is effective in the addition of steroids, for example pregnenolone, or cosmetically effective ingredients such as one of the above ingredients. Ingredients can be followed.

In these formulations, the alginic acid esters are esters with alcohols effective for cosmetics, such as dextrosethenol, or lower aliphatic alcohols, for example, with non-functional alcohols such as one of those already cited. . The effect is due to the intrinsic cosmetic properties of the polysaccharide component as in the case of free alginic acid or salts thereof.

However, cosmetics may be based on a variety of other ingredients, such as bactericides, light-shielding agents, waterproofing agents, regenerative or anti-wrinkle substances or fragrances, especially fragrances. In this case, the alginic acid ester itself can be the active ingredient and acts as a carrier material having the property of being derived from or preferentially combined with, for example, alcohols of the same nature, for example perfumes, higher aliphatic alcohols or terpenal alcohols.

Of particular importance is therefore a cosmetic composition similar to the medicament described above, in which case the pharmacologically active substance (1) is replaced by a cosmetic ingredient and its respective salt. The use of the above-mentioned esters derived from alcohols used in the fragrance industry has made great advances in the art as they allow slow and constant sustained release of the aromatic components.

Examples of pharmaceutical preparations according to the present invention are as follows.

[Title 1]

100 ml of a cortisone-containing eye drop containing the following ingredients was prepared.

[Title 2]

100 ml of a hydrocortisone-containing eye drop containing the following ingredients was prepared.

[Title 3]

100 g of a partial ester containing cream of alginic acid with ethyl alcohol containing the following ingredients were prepared.

[Alginate-containing medicines]

One important application according to the invention relates to the already mentioned hygiene and surgical articles and their manufacture and methods of use thereof. Therefore, the present invention includes all products similar to those already commercially available with alginic acid containing alginic acid esters or one of its salts, instead of free acid or one of its salts, such as inserts or ophthalmic lenses.

The completely novel surgical and hygienic materials according to the present invention can be recycled as is from a suitable organic solution into sheets and yarns and used in skin organs, for example as skin supplements and substitutes in case of severe injury after burns, Surgical seals, films and sheets used as sutures in surgical operations can be obtained.

In particular, the invention relates to the use of such materials and to suitable organic solvents such as ketone esters or amides of carboxylic acids, in particular dialkylamides or aliphatic acids having 1 to 5 carbon atoms and alkyl groups having 1 to 6 carbon atoms. Aprotic solvents such as amides, in particular organic sulfoxides, in particular dialkylsulfoxides having alkyl groups having up to six carbon atoms such as dimethylsulfoxide or diethylsulfoxide, and most preferably especially hexafluoroisopro Plates and the like include methods for forming surgical and sanitary materials by forming solutions of alginic acid esters or salts thereof in low boiling fluorate solvents.

In addition, the present invention provides a solution of these organic or aqueous solvents, in particular lower aliphatic alcohols such as ethyl alcohol (wet spinning), which can be mixed with a first solvent with an organic solution in a sheet or yarn and in which the alginic acid ester is not dissolved. If the solvent is connected to remove the solvent, or if a solvent having a very low boiling point is used to prepare a solution of the alginic acid derivative, it is composed of removing this solvent under dry air, especially under moderately heated nitrogen stream (dry spinning). In addition, dry-wet spinning can provide good results.

Yarns obtained from alginic acid esters can be used in the manufacture of gauze for wound and surgical use. These gauze has the particular advantage of biochemical degradability in organisms made possible by naturally occurring enzymes. These enzymes decompose the ester into alginic acid and the corresponding alcohol when the alginic acid ester is derived from a therapeutically acceptable alcohol such as ethyl alcohol.

Therefore, these gauze and the yarn described above are also left in the organism after surgery and then slowly absorbed through the above-described degradation process.

In the manufacture of the above-mentioned hygienic and surgical articles, it is convenient to add a plastic material to improve the mechanical properties as in the case of yarn, and to improve resistance to entanglement with knots.

Such plasticizers are, for example, alkali salts of fatty acids, such as sodium stearate or sodium palmitate, stearers of organic acids having a large number of carbon atoms.

Another application of the novel esters according to the invention is the preparation of subcutaneous capsules of medicaments, or microcapsules for injection, for example by subcutaneous or intramuscular administration, in which case biochemical degradability is present in esterases present in the organism. Used by.

Also important is the preparation of microcapsules made of alginic acid esters, the use of which has been very limited due to problems with the use of these products, but the new esters solve the conventional problem and thus have a "sustained" effect after administration by injection. The application of the new esters in applications requiring a wide range of solid inserts, such as plates, discs, laminas, etc., is a substitute for inserts made of metal or synthetic plastic materials that have been used conventionally when inserts have to be removed after a certain period of time. .

Formulations based on animal collagen sometimes cause unpleasant reactions, such as inflammation or rejection, due to their proteinaceous properties, but there is no such risk with alginic acid esters.

Part of the application in the medical-surgical field of the novel esters according to the invention is in the form of preparations, especially sponges, using intumescent materials used to treat wounds or various forms of damage.

Examples of the medical material containing the alginic acid ester according to the present invention are as follows.

Example 36

[Production of Film Using Ester of Alginic Acid]

N-propyl ester of alginic acid with a concentration of 180 mg / ml in DMSO was prepared.

Using a stratifier, the solution should be thinly coated on the pane, where the thickness should be at least ten times greater than the thickness of the final film. The pane was immersed in ethanol which absorbed DMSO but did not dissolve the HY ester which solidified. The film was separated from the pane and washed repeatedly with ethanol and water.

The film obtained was dried for 48 hours in a press at 30 ° C.

Example 37

[Preparation of yarn using alginic acid ester]

Alginic acid benzyl ester having a concentration of 200 mg / ml in DMSO was prepared and the solution was pressurized through a threader with a 0.5 mm hole using a pump.

The threader was immersed in an ethanol / DMSO (80:20) solution (this concentration is kept constant with the continuous addition of ethanol).

In this way, when the solution was wetted in DMSO, the solution would attempt to discharge most of the DMSO and the seal solidified.

The yarn with still DMSO content was repeatedly drawn, washed with ethanol and dried under a stream of nitrogen.

Example 38

[Production of sponge using alginic acid ester]

1 g of benzyl ester of alginic acid in which all the carboxy groups were esterified (prepared in Example 23 above) was dissolved in 5 ml of DMSO.

To 10 ml of the prepared solution, 31.5 g of sodium chloride having a particle size of 300 µ, 1.28 g of sodium bicarbonate, and 1 g of citric acid were added, and the solution was homogenized in a mixer. The paste mixture was layered in a number of ways, for example using a compaction roller consisting of two rollers which can adjust the gap between the two and rotate opposite each other. While adjusting the distance between the rollers, a silicon layer serving as a support for the paste layer formed was passed through the rollers with the operation. The layers thus formed were cut to the desired length and width, separated from the silicon pieces, wrapped with filter paper, and then briefly immersed in a suitable solvent such as water. The resulting sponge was washed with a suitable solvent such as water and sterilized as much as possible using gamma rays.

Example 39

[Production of sponge using alginic acid ester]

Using the same method as in Example 38, it is possible to prepare a sponge with other alginic acid esters. If desired, other solvents may be used in place of DMSO which can dissolve the ester to be used.

It is also insoluble in the solvent used for dissolving the hyaluronic acid ester, but can be dissolved in the solvent used for precipitating the hyaluronic acid ester after the mechanical treatment as described above, and finally has a suitable particle size for forming a desired hole on the sponge. Eggplant may also be used in place of sodium chloride.

Another pair of similar compounds may be used in place of sodium bicarbonate and citric acid, i.e. in a suspension or solution of the solvent used to dissolve the alginic acid, a gas such as carbon dioxide, which has the effect of forming a less dense sponge, may be used. Any other pair of compounds that react with each other in a generating manner can be used. Thus, instead of sodium bicarbonate, other bicarbonates or carbonates of alkali or alkaline metals may be used, and solid other acids such as tartaric acid may be used instead of citric acid.

As the present invention is as described above, it is apparent that the present invention can be diversified in many different ways, and such modifications do not depart from the spirit and scope of the present invention. All modifications that can be easily implemented by those skilled in the art to which the present invention pertains are intended to be included in the following claims.

Claims (28)

All, partial esters of alginic acid in which the acid moiety of alginic acid is esterified by alcohol, and the moieties derived from said alcohol in salts of these partial esters with inorganic and organic bases, are a) aliphatic groups of up to 6 carbon atoms, b) aliphatic An arylaliphatic group having a maximum carbon atom of 4 and having only one benzene ring, or c) a cortisone derivative having a hydroxyl group at the 21-position, wherein the partial ester is not a partial ester of a divalent aliphatic alcohol All, partial esters of alginic acid and salts of these partial esters. The alginic acid ester according to claim 1, wherein the aliphatic group having a maximum carbon atom of 6 is one selected from the group consisting of ethyl, ethyl, isobutyl, n-butyl, isobutyl and tert-butyl. The alginic acid ester according to claim 1, wherein the arylaliphatic group is derived from benzyl alcohol or steroid. The alginic acid ester according to claim 1, wherein the cortisone derivative is one selected from the group consisting of hydrocortisone and fludrocortisone. The alginic acid ester according to claim 1, wherein the total ester of alginic acid is that all carboxy groups thereof are esterified. The alginic acid ester according to claim 1, wherein the partial ester of alginic acid is esterified with all of its carboxy groups being at least 5% and at most 95%. 2. The salt of the partial ester of alginic acid according to claim 1, wherein the partial ester of alginic acid acts with alkali metal, alkaline earth metal, magnesium or aluminum to form its salt. 2. The salt of partial ester of alginic acid according to claim 1, wherein the partial ester of alginic acid acts with an aliphatic, arylaliphatic, cycloaliphatic or heterocyclic amine base to form salts thereof. The salt of the partial ester of alginic acid according to claim 8, wherein the amine is a therapeutically acceptable base. A quaternary ammonium salt of alginic acid is reacted with an etherifying agent in an organic solution and, if necessary, a chloride of the free carboxyl group in the produced alginic acid ester, wherein the partial alginate, the total ester and the salt of this partial ester are prepared. . The method of claim 10, wherein the resulting alginic acid ester is a partial ester of alginic acid. 12. The method of claim 11, wherein the partial ester is further reacted with an alkali salt to chloride the free carboxyl group in the partial ester. The method of claim 10, wherein the organic solvent is an aprotic solvent. The method of claim 13, wherein the aprotic organic solvent is dimethyl sulfoxide. The method of claim 10 wherein the quaternary ammonium salt of alginic acid is a lower tetraalkyl ammonium salt of alginic acid. The method of claim 15 wherein the quaternary ammonium salt of alginic acid is tetrabutylammonium alginate. The method of claim 10, wherein the resulting ester of alginic acid is precipitated by adding an organic solvent. 18. The process of claim 17, wherein the precipitated ester of alginic acid is recovered, washed and dried. The method according to claim 10, wherein the quaternary ammonium salt of alginic acid is recovered as the quaternary ammonium salt of alginic acid by passing an alkali salt of alginic acid through a quaternary ammonium salt ion exchange resin. 20. The method of claim 19, wherein the quaternary ammonium salt ion exchange resin is a sulfonic acid resin. 21. The method of claim 20, wherein the quaternary ammonium salt of sulfonic acid is a tetraalkylammonium salt of 1 to 6 carbon atoms. The method of claim 12, wherein the alkali salt is selected from sodium or potassium. The method according to claim 10, wherein the esterifying agent is a compound represented by the following general formula (I). A-X (I) In the above formula, A is a group selected from aliphatic and arylaliphatic, and X represents a halogen atom. 24. The method of claim 23, wherein A is selected from the group consisting of methyl and ethyl, isopropyl, tert-butyl and benzyl groups. Reacting alginic acid with a stoichiometric amount of alcohol, the stoichiometric amount being determined according to the degree of esterification desired. The method of claim 25, wherein the alcohol is a fatty alcohol. The method of claim 25, wherein the alcohol is an arylaliphatic alcohol. The method of claim 25, wherein the alcohol is a cortisone derivative having a hydroxyl group at the 21-position.