Hydrophilic polymers, articles and methods of making same

The invention relates to a process for the preparation of a carrier for a pharmaceutical or flavoring preparation.

It is known per se to produce hydrophilic polymers, in particular crosslinked hydrophilic polymers, and it is also known to prepare them in the form of shaped body hydrogels in aqueous solution by copolymerization, wherein a predominant amount of a monoester of acrylic acid or methacrylic acid and a bifunctional Alcohol having a esterifiable hydroxyl group and at least one additional hydrophilic functional group, in aqueous solution with a small amount of a diester of one of these acids and an alcohol having at least two esterifiable hydroxyl groups (see U.S. Patent Nos. 2,976,576 and 3,220,960).

It is known that the prior art molded hydrophilic polymers prepared in an aqueous system are industrially useful as carriers for pharmaceutical compositions. Thus, it has been recognized by those skilled in the art that drug formulations can be dissolved in the aqueous component of the known shaped body hydrogels, thus allowing a gradual release of the pharmaceutical preparations; however, the resulting solutions are difficult to handle and store, and the pharmaceutical preparations are subject to air oxidation, degradation, decomposition, volatilization, etc.

In the previously known processes, it has been necessary to prepare a solid or shaped body of the hydrophilic polymer and then to dissolve the drug or flavor preparation in the aqueous components of such a shaped body. Moreover, in the hitherto known modes of operation utilizing mixed polymerization in an aqueous solution, it has not been possible to directly produce a foam by adding one of the usual foaming agents, such as sodium bicarbonate, because it is more likely to have a semi-gelatinous hydrogel product than that desired, hard, friable foam arose, and it was not possible to convert such a semi-gelatinous product into a friable foam or a compressible powder.

Moreover, in the hitherto known procedures which use the known redox catalysts such as sodium bicarbonate and ammonium persulfate, potassium sulfate, sodium thiosulfate and ammonium persulfate or potassium sulfate, the completion of the polymerization reaction was carried out at temperatures above 0 ° C, and thereby the formation of a prepolymer, preferably in the form of a liquid casting syrup, dyed as such, pigmented, can be thickened and then hardened to produce solid carriers, for example in the form of a hard, friable foam, for medicines or flavorings.

In addition, only incomplete (namely up to about 95%) polymerized through in the process known hitherto and further such a polymer, the excessively large amounts of water (more than 30 wt .-%, even up to 80 wt .-%) when it was equilibrated in aqueous solutions.

The aim of the invention is to provide a process for the preparation of a carrier for a drug or flavor preparation, by which process the described disadvantages are eliminated. The process according to the invention is characterized in that 100 parts by weight of a water-soluble, polymerizable hydroxyalkyl monoester of an α, β-unsaturated carboxylic acid, eg of acrylic or methacrylic acid containing from 0.05 to 15, preferably from 0.1 to 0.2 parts by weight of a polymerizable diester of one of said olefinic acids and an alcohol having at least two esterifiable hydroxyl groups in the absence of solvent and in Presence of sufficient for the polymerization amount of a free-radical-producing vinyl polymerization catalyst and optionally a foaming agent to be polymerized. Preferably, the diester is used in an amount of 0.05 to 10 parts by weight.

The inventively available supports, which are prepared in an anhydrous state, are substantially completely (ie, about 99.5%) fully polymerized and unable to absorb more than about 30% by weight of water when dissolved in aqueous solutions be equilibrated. You easily pick up the desired drug or flavor preparations and hold them properly until the product is moistened.

The carriers prepared in an anhydrous system can be obtained directly as prepolymerized liquid pourable syrups which can be used for direct in-situ polymerization in the form of cast or formed bodies, which may contain the usual foaming agents such as sodium bicarbonate, hard friable foams which can be brought directly into the swollen state or ground into powder.

Since the process according to the invention proceeds in an anhydrous system, it is possible directly and simply to obtain compressible powders which are suitable as carriers for pharmaceutical preparations or natural or synthetic flavorings. The powders obtainable according to the present invention are compact in shape and have the necessary stability and shelf life, making it possible to use them as carriers for drug and flavor preparations which undergo chemical reactions such as air oxidation, evaporation and degradation.

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Nr.306229

A further advantage resulting from the strength of the powders obtainable according to the invention is that, when encapsulating the powder carrying pharmaceutical preparations or flavorings, greater stability and a longer shelf life are present than hitherto.

The polymer powders according to the invention, which contain encapsulated pharmaceutical preparations or flavorings, can be reconverted to solution as desired, thus providing superior quality drug or flavor solutions because the encapsulation prevents the degradation of the drug or flavor component by air access and volatilization losses ,

The casting syrup obtainable by the process according to the invention can then be dyed and pigmented in a suitable manner and its viscosity can be increased to the desired value by adding appropriate thickening agents.

The pouring syrup can be hardened, whereby a product in a rigid or swollen state or in the form of a foam can be obtained. The polymer obtained from the cured casting fluids has good mechanical strength, reversible liquid absorbency, and the ability to maintain its shape in a liquid medium and regain its shape upon elastic recovery deformation.

Prior to the addition of dyes, pigments, thickeners and other additives, the liquid casting syrups are added to an excess amount of water to form a polymer precipitate. The latter is soluble in highly polar organic solvents, the polymer solution is used to form carriers for drug or flavor preparations.

According to the invention, the carriers for pharmaceutical and flavor preparations can also be prepared by suspension polymerization of the monoester with the diester in a non-polar medium, such as a silicone oil or mineral oil. The catalyst-containing monomers are dispersed in the non-polar medium in the form of small droplets which then polymerize to form finely divided beads or beads. Such beads can be dissolved in polar organic solvents to make the carriers for pharmaceutical or flavor preparations. The suspension polymerization is preferably carried out in an oil bath at temperatures in the range of 50 to 150 ° C until the bubbling is completed. The ratio of suspension oil to monomers is preferably about 5: 1 to about 10: 1. The ratios of catalyst to monomers are preferably about 0.05 to 1.0 parts to 100 parts of monomer.

Suitable hydroxyalkyl monoesters of an α, ω-unsaturated carboxylic acid include, for example, 2-hydroxyethyl methacrylate and hydroxypropyl methacrylate. Suitable free-radical catalysts are, for example, tert-butyl peroctoate, isopropyl percarbonate and benzoyl peroxide. Suitable diesters are, for example, ethylene glycol dimethacrylate, 1,3-butylene glycol dimethacrylate and 1,4-butylene glycol dimethacrylate.

The use of the free radical-providing catalysts is useful in concentrations which are of the order of 0.05 to 1 g of catalyst per 100 g of polymerizable hydroxyalkyl monoester, the preferred range being between 0.1 and 0.2 g per 100 g of monoester ,

The mechanical properties of the carriers obtainable according to the invention and their ability to retain water as a homogeneous constituent are greatly influenced by the amount of diester crosslinking agent. Concentrations of 0.05 to 15 g of crosslinking agent per 100 g of 2-hydroxyethyl methacrylate have proven to be expedient for the process according to the invention, the preferred range being between 0.1 and 1 g, in particular between 0.1 and 0.2 g of crosslinking agent per 100 g of polymerizable hydroxyalkyl monoester.

The polymerization of the above-mentioned reaction components can be accelerated by heat application, or it can also by certain selection of the catalyst and the amount thereof, the application of heat ceases and yet rapid polymerization is already initiated at room temperature. In the cases where heat is used for curing, temperatures of about 20 to about 150 ° C have been found to be suitable, with temperatures of 20 to 100 ° C have been found to be particularly useful and the preferred range between about 40 and 80oC The reaction is advantageously carried out in an inert or anaerobic atmosphere, wherein carbon dioxide or nitrogen can serve as a protective gas. It is known that the presence of oxygen inhibits the polymerization reaction and then either requires a longer reaction time or has to use higher polymerization temperatures.

In the hydrophilic polymer base material, one or more additives, for example synthetic resins, rosin esters, phenoxy resins, silicone resins, low molecular weight polyisobutylenes, synthetic polymers and prolamins, can be incorporated.

The mixture is heated or otherwise cured in the absence of solvents to produce thermosetting polymeric materials having properties superior to the properties of the major constituents of the formulation. Property improvements of lesser extent can be achieved by using small amounts of other crosslinking glycol dimethacrylates.

In general, in such cases, 2-hydroxyethyl methacrylate, together with the to be crosslinked

No. 306,229 monomeric ethylene glycol dimethacrylate, in an amount of 10 to 50 wt .-% (more preferably 50% range) with 90 to 50 wt .-% of a commercially available resin type coumarone / indene resins or their phenol-modified Modification products in the presence of a free-radical-providing catalyst, such as tert-butyl peroctoate, isopropyl percarbonate and the like., Mixed and heated for about 30 min at temperatures of 40 to 200 ° C. In order to increase the compatibility of the components with each other, organic or inorganic solvents are used. The quantitative limits given above are also observed for the additional components of the phenoxy resins and silicone resins type.

The resulting polymers can be obtained either in the form of films or in the form of rods which are suitable for grinding into fine powders. By mixing the reaction components with foaming agents, such as sodium bicarbonate, before curing, the polymer can be obtained in the form of a foam which can be easily ground to a fine powder with the aid of a shearing means. The pulverulent polymers are preferably obtained from foams. As stated, amounts of foaming agent of from 1 to 10 g per 100 g of the reaction components are sufficient.

The polymer powders obtained by any of the above-described procedures are mixed with drugs or natural or synthetic flavors or essences dissolved in a suitable solvent, and the mixture is placed on a mechanical mill so as to intimately mix solution and powder achieve. The solution is then filtered and dried by evaporation in air or by heating with air circulation. After evaporation of the solvent, the drug or flavor or essence is retained by the powder. Due to the extremely high hydrophilicity of the hydrophilic polymer obtainable according to the present invention and because it is characterized by a reversible liquid absorbency, the powders may be reconstituted in solution as desired to yield solutions containing co- ordinated drugs or flavors or essences.

The drugs, such as antibiotics that are water or alcohol soluble, may be added prior to polymerization, or the final polymeric product may be dipped in a solution of these substances.

The polymerization of the casting solutions may be accelerated by application of heat, or the heat application may be eliminated by appropriate selection of the catalyst and the amount thereof, and yet rapid polymerisation may be initiated at room temperature. In the cases where heat is used for curing, temperatures of about 20 to 150 ° C are maintained, with temperatures of 20 to 100 ° C have been found to be particularly useful and the preferred range between about 40 and 80 ° C. The reaction is advantageously carried out in an inert or anaerobic atmosphere, wherein carbon dioxide or nitrogen can serve as a protective gas. It is known that the presence of oxygen inhibits the polymerization reaction and then either requires a longer reaction time or has to use higher polymerization temperatures.

The invention is illustrated in the following examples, which, however, merely illustrate the invention, but are not intended to limit it in any way.

Example 1: 2-Hydroxyethyl methacrylate (100 g) is mixed with tert-butyl peroctoate in a weight ratio of 0.15: 100 g of methacrylate. Then, ethylene glycol dimethacrylate is added in a concentration of 0.20 g / 100 g of 2-hydroxyethyl methacrylate together with 1 g of the foaming agent sodium bicarbonate. The mixture is heated to 70 ° C and the resulting solid friable polymer foam is crushed to a fine powder of a mesh size of 80 mesh. The polymer powder thus formed is mixed with a solution containing a natural anise flavor and the resulting mixture is ground for about 8 hours on a mechanical rolling mill. The polymer powder absorbs the aroma. The solution is then filtered and the residue is dried at room temperature.

Example 2: 2-Hydroxyethyl methacrylate (100 g) is mixed with tert-butyl peroctoate (0.2 g). Then, ethylene glycol dimethacrylate (0.2 g) is added, u.zw. together with 4 g of sodium bicarbonate as foaming agent. The mixture is heated to 70 ° C, and the resulting solid, friable polymer foam is crushed to a fine powder of a mesh size of 80 mesh. The polymer powder formed is mixed with an amount of the antibiotic phenoxymethylpenicillin dissolved in ethyl alcohol sufficient to gradually release 1,200,000 units / g, and the resulting mixture is placed on a mechanical mill until the polymer powder has absorbed an amount of antibiotic in the desired concentration. The solution is then filtered and the residue dried in vacuo.

Example 3: 2-Hydroxyethyl methacrylate (100 parts) is stirred with 0.05 part of tert-butyl peroctoate in a nitrogen atmosphere for 30 minutes at a temperature of 40 ° C. The resulting mixture is cooled to 25 ° C, and so much tert-butyl peroctoate is added that the total amount of tert-butyl peroctoate added to the system is 0.15 part. At the same time, ethylene glycol dimethacrylate (0.1 part) is added. The casting solution is mixed with peppermint oil, a flavoring agent, in an amount of 10 parts. The thus-flavored casting solution is set aside and may, if desired, be used to form molded products in the form of shaped articles or in powder form

No. 306229 can be used. According to another embodiment, the flavoring agent may be added together with the catalyst used in the preparation of the polymer.

Example 4: Distilled 2-hydroxyethyl methacrylate (100 g) is stirred with 0.1 g of tert-butyl peroctoate in an anaerobic atmosphere at 25 to 70 ° C for 15 to 40 min. The resulting mixture is cooled to 25 ° C, and so much tert-butyl peroctoate is added that the total concentration of tert-butyl peroctoate in the system is 0.2 g per 100 g of 2-hydroxyethyl methacrylate. At the same time, when the catalyst concentration is brought to the theoretical value, ethylene glycol dimethacrylate is added in a concentration of 0.2 to 100 g of 2-hydroxyethyl methacrylate. The pouring syrup is added with an alcoholic solution of menthol (10 parts) to obtain a menthol-containing prepolymer pouring syrup.

Example 5: Suitably purified 2-hydroxyethyl methacrylate is added with 0.15 g

Isopropyl percarbonate stirred in an anaerobic atmosphere at room temperature. Than it will be

Ethylene glycol dimethacrylate added in a concentration of 0.1 g / 100 g of 2-hydroxyethyl methacrylate. The casting solution is added to the antibiotic phenoxymethylpenicillin of Example 2, dissolved in ethyl alcohol, in such an amount that 1200,000 units / g of pouring syrup are available for gradual reproduction. The resulting pouring syrup is set aside as a stock solution for later pouring or other uses. The pouring syrup and the cast piece formed therefrom are used either in a particular shape or in powder form as a pharmaceutical carrier for the antibiotic. The application of the casting syrup or The molded or powdered preparations made therefrom have the advantage of allowing the degradation or loss of efficacy suffered by the antibiotic in the usual pharmaceutical carriers, thereby prolonging the shelf-life or the useful life of the antibiotic preparation. In addition, the hydrophilic polymer used in the invention has the highly desirable advantageous properties that whether it is in dry form or in the form of a product filled with a solvent, the penetration of microbial and fungal contaminants such as Gram-negative and Gram positive microorganisms, yeasts, molds and viruses prevented. This characteristic property is of particular importance in the presence of contaminants, as in the contamination of penicillin by various yeast species.

Example 6: Distilled 2-hydroxyethyl methacrylate (100 g) is stirred with 0.05 g of tert-butyl peroctoate for 14 to 40 minutes in an anaerobic atmosphere at 25 to 70 ° C. The resulting mixture is cooled to 25 ° C and additional tert-butyl peroctoate is added in such an amount that the total concentration of tert-butyl peroctoate in the system is 0.15 g / 100 g of 2-hydroxyethyl methacrylate is. Now, ethylene glycol dimethacrylate is added in a concentration of 0.15 g / 100 g of 2-hydroxyethyl methacrylate, and at the same time the catalyst concentration is brought to the theoretical content. Peppermint oil (1 L, 10 parts) is also added as a flavoring to the casting syrup to obtain an aromatized prepolymer syrup which is storable. After curing and granulation, the flavorant-carrying granules are added as a flavor releasing component to chewing gum, gelatin, and heartburn tablets.

Example 7: Distilled 2-hydroxyethyl methacrylate (100 g) is stirred with 0.1 g of tert-butyl peroctoate in an anaerobic atmosphere at 25 to 70 ° C for 15 to 40 min. The resulting mixture is cooled to 25 ° C, and so much tert-butyl peroctoate is added that the total concentration of tert-butyl peroctoate in the system is 0.2 g per 100 g of 2-hydroxyethyl methacrylate. At the same time, when the catalyst concentration is brought to the theoretical value, ethylene glycol dimethacrylate is added in a concentration of 0.2 g to 100 g of 2-hydroxyethyl methacrylate. 0.15 g of tert-butyl peroctoate are added to 90 g of this base casting syrup with stirring over 15 to 40 minutes at 25.degree.-70.degree. C. in an anaerobic atmosphere, the amount of monomer used being adjusted so that 90 g of a finished product are added Casting syrups arise. The resulting mixture is cooled to 25 ° C and so much t-butyl peroctoate is added that the total concentration of tertiary butyl peroctoate in the system is 0.15 g / 100 g 2-hydroxyethyl methacrylate amounts. Ethylene glycol dimethacrylate is added in a concentration of 0.15 g / 100 g of 2-hydroxyethyl methacrylate at the same time that the catalyst concentration is brought to the theoretical level. Thereafter, peppermint oil (10 g) is added to the casting syrup to form the flavored stock solution.

Example 8: Distilled 2-hydroxyethyl methacrylate (100 g) is stirred with 0.1 g of tert-butyl peroctoate in an anaerobic atmosphere at 25 to 70 ° C for 15 to 40 min. The resulting mixture is cooled to 25 ° C, and so much tert-butyl peroctoate is added that the total concentration of tert-butyl peroctoate in the system is 0.2 g per 100 g of 2-hydroxyethyl methacrylate. At the same time, when the catalyst concentration is brought to the theoretical value, ethylene glycol dimethacrylate is added in a concentration of 0.2 to 100 g of 2-hydroxyethyl methacrylate. The obtained casting syrup may be used as a carrier for ethinodioldiacetate as a progestagen component plus mestranol (17 a -ethynyl estradiol-3-methyl ether) as an estrogen component. An advantage of using the obtained

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No. 306,229 hydrophilic polymers as a carrier for drug or flavor preparations is that they allow a desired slow release or timely adjusted release of the active ingredient. The time within which the drug is re-dispensed can be readily adjusted by the amount of crosslinking agent used, the surface area to volume ratio in the molded article, and the concentration or concentration gradient of the biologically active substance incorporated. The speed of reproduction of the active ingredient is increased by the use of solvents in the casting solution.

Example 9: Purified 2-hydroxyethyl methacrylate (100 g) is mixed with 0.2 g of ethylene glycol dimethacrylate and 1 g of benzoyl peroxide. The monomer solution is filtered by means of a nozzle, which is fine

Droplet is sprayed into a nitrogen-containing chamber maintained at a temperature of 150 ° C. After the spraying of the monomers was complete, 36 g of polymer beads suitable for impregnation with flavors or fragrances could be removed from the bottom of the chamber.

Example 10: Purified 2-hydroxyethyl methacrylate (100 g) is mixed with 15 g of ethylene glycol dimethacrylate, 10 g of orange oil and 0.3 g of tert-butyl peroctoate. The solution will be in one

250 ml polypropylene cup glass, which is placed in an oven maintaining a nitrogen atmosphere and a temperature of 80 ° C for 3 hours to effect the polymerization. The casting cylinder thus obtained is friable and can be easily crushed to a powder which quickly releases the orange oil in contact with hot water.