WO1978000011A1

WO1978000011A1 - Form of implant medicament and preparation process

Info

Publication number: WO1978000011A1
Application number: PCT/DE1978/000003
Authority: WO
Inventors: H Bisson; P Speiser
Original assignee: Garching Instrumente; H Bisson; P Speiser
Priority date: 1977-06-07
Filing date: 1978-06-07
Publication date: 1978-12-21
Also published as: DE2856901D2; EP0006853A1

Abstract

A form of implant medicament for oral and/or parenteral application having one or more medicaments enclosed in a polymer matrix whereby, under physiological conditions, the matter slowly hydrolyses into non-toxic combinations, that can be eliminated physiologically, and, in doing so, liberates the medicament or medicaments, is formed of the product of polycondensation of a dicarboxylic acid, a hydroxy monocarboxylic acid and/or one physiologically will tolerated amino acid, or made of several of these acids and, if necessary, of one or more of the polyols 1,2-propanediol, inosite, pyridoxal, D-panthenol, pentaerythrite, adonite, and preparation of the implant medicament, and in which the still water soluble polycondensate together with the medicament disperses when stirred in a slightly polar dispersing medium and the condensation of the polycondensate is completed until full water insolubility is reached.

Description

Depot drug form and process for its manufacture.

The invention relates to a depot pharmaceutical form for oral and / or parenteral administration from one or more medicaments enclosed in a polymer matrix, the matrix produced by polycondensation of at least bifunctional carboxylic acids with polyols slowly hydrolyzing into non-toxic, excretable compounds under physiological conditions and thereby releases the drug or drugs.

Such depot pharmaceutical forms are known from US Pat. No. 3,978,203, in particular in the form of surgical sutures, and medical implants. In the depot pharmaceutical forms described there, the matrix consists of polymeric condensation products which, by reacting di- and tricarboxylic acids of the type that occur in the citric acid cycle, be produced with physiologically compatible polyols. In particular, citric acid, cis-aconitic acid, isocitric acid, α-ketoglutaric acid, succinic acid, fumaric acid, malic acid and oxaloacetic acid or glycerol, mannitol, sorbitol and glycerol esters are used as starting components for the polymer matrix.

A process for the production of such depot pharmaceutical forms is also known from the cited US patent, in which a polyester, which forms the polymer matrix, is first known from one of the di- or tricarboxylic acids and one of the polyols mentioned by polycondensation in a manner known per se The powdered or finely ground drug desired as active ingredient is then ground together with the solid polyester in a ball mill, and the uniformly ground mixture is then sintered under pressure and at elevated temperature to a desired external shape.

The known depot pharmaceuticals have the disadvantage that they often hydrolyze too quickly under physiological conditions, ie they release the active substance enclosed in the polymer matrix too quickly. The known method for producing the depot pharmaceutical forms, on the other hand, has the disadvantage that only very temperature-resistant active ingredients can be incorporated into the polymeric matrix, since active ingredients that are sensitive to temperature would be destroyed during sintering.

The object of the invention is to avoid these disadvantages and to create a depot pharmaceutical form which is more hydrolysis-resistant, simple to manufacture and easily brought into any external form suitable for oral and, above all, parenteral administration.

Another object of the invention is to provide a method for producing depot pharmaceutical forms of the initially to create named genus, which also makes it possible to incorporate very temperature-sensitive active ingredients into the polycondensation products used as the matrix.

This object is achieved according to the invention in that the matrix of the polycondensation product from a dicarboxylic acid, hydroxymonocarboxylic acid and / or a physiologically compatible amino acid or from several of these acids and optionally from one or more of the polyols, 1,2-propanediol , Inositol, pyridoxol, D-panthenol, pentaerythritol, adonit.

It has surprisingly been found that the self-condensation of physiologically compatible dicarboxylic acids, hydroxymonocarboxylic acids and amino acids as well as the polycondensation of these acids with the polyols listed above in detail, which differ from the polyols previously used for this by a higher number of primary ones ^'Hydroxyl¬ groups differ to much hydrolysebeständigeren depot dosage forms leads to the materials enclosed therein Wirk¬ slower and more uniform release than the known depot dosage forms.

According to the invention, particularly advantageous depot pharmaceutical forms are characterized in that the matrix of polylactic acid or the self-condensation product of. p-aminobenzoic acid exists.

Because of the film-forming properties of the polycondensate, the matrix consisting of polylactic acid has the advantage that the desired active ingredient is light and very uniform, even with very fine distribution and very small particle sizes

Distribution can be incorporated. The polycondensate made from p-aminobenzoic acid is also special because of its particularly simple and inexpensive manufacture can be used advantageously.

The depot pharmaceutical forms according to the invention can be used particularly advantageously if they have the outer form of

Have micropellets with an average diameter of 10 -9 to 10 m, ie their average diameters are in the nanometer or micrometer range. They can then not only be implanted during parenteral administration, such as the depot medication known from US Pat. No. 3,978,2-03, but they can even be suspended directly in¬ in a suitable physiologically compatible liquid jit.

The object on which the invention is based is further achieved by a process for the preparation of the depot drug form according to the invention by producing a polycondensate soluble in organic solvents in a manner known per se and adding the desired drug (s) to the polycondensate, which is characterized in that the still water-soluble polycondensate together with. the drug is dispersed in a weakly polar dispersant with stirring and the condensation is completed until the polycondensate is insoluble in water.

Advantageous embodiments of the method according to the invention consist in that silicone oil is used as the dispersant, that the condensation is carried out at a temperature of 120 to 200 ° C. and that the condensation is carried out under a pressure of 10 to 14 mm Hg .

With the method according to the invention it is achieved for the first time that depot pharmaceutical forms can be produced which can be administered not only orally or by implantation, which always requires a surgical procedure involving risk, but also subcutaneously, intramuscularly or can be applied peritoneally by simple injection.

A further development of the method according to the invention, which also allows very temperature-sensitive active ingredients to be incorporated into the matrix, consists in the polycondensate being solubilized together with the medicament in an aqueous surfactant solution, heated to a temperature of 20 to 60 ° C. with stirring and from the Solution fails.

The polycondensation of the dicarboxylic acids, hydroxymonocarboxylic acids, amino acids and polyols used according to the invention is known per se and is described, for example, in.Houben-Weyl, "Methods of Organic Chemistry", 4th edition, vol. 14/2, Georg Thieme Verlag, Stuttgart , 1963, page 2 ff. VV Korshak, S.V. Vinogradova, "Polyesters", Pergamon Press, Oxford 1965, pages 153-251.

Batzer, Macromolecular Chemistry, 7.82, 1951

W.H. Carother, J. Am. Che. Soc, 51, 2560, 1929

RE. Wilfong, U. Polym. Sci., 54, 385, 1961.

To produce the matrix by polycondensation, the following are used in particular as dicarboxylic acid according to the invention: fumaric acid, succinic acid, glutaric acid, adipic acid, sugar acid, tartaric acid; as hydroxymonocarboxylic acid: lactic acid, ß-hydroxybutyric acid, p-hydroxybenzoic acid, cholic acid, gluconic acid, glucuronic acid, glucoheptonic acid; as amino acid: serine, hydroxyproline, homoserine, aminosuccinic acid, glutamic acid, lysine, p-aminobenzoic acid, and all other amino acids in the body in the corresponding physiological form; as polyol: 1, 2-propanediol, inositol, pyridoxol, D-panthenol, pentaerythritol, adonite.

If appropriate, the acids mentioned can also be in the form of their Anhydrides, acid chlorides, esters or lactones are polycondensed.

Of the polyols mentioned, pentaerythritol and 1,2-propanediol are preferred, since pentaerythritol, owing to its four primary hydroxyl groups, which ensure a high esterification rate, leads quickly to crosslinked, water-insoluble polyesters upon condensation with one of the acids mentioned while 1,2-propanediol, whose toxicological properties correspond to glycerol, forms much more hydrolysis-resistant polyester than glycerol.

According to the invention, the tricarboxylic acids known per se for the production of depot medicinal forms, citric acid, cis-azonitic acid, isocitric acid and the like with the above-mentioned polyols, preferably pentaerythritol and 1,2-propanediol, can also be used to produce the polymeric matrix.

By varying the condensation components, polymer matrices with a wide variety of properties can be achieved which influence the release of the active ingredient or ingredients incorporated therein.

In the process according to the invention, a polycondensate which is soluble in organic solvents is first prepared by conventional methods, and the drug selected as active ingredient is added to this polymer in solid form or in a suitable solvent with constant stirring and condensed until the polycondensate formed is insoluble in water. The pole condensate obtained in this way can be pulverized in a suitable manner to the desired grain size and, for example, injected intramuscularly after sterilization in physiological saline On the other hand, the powder obtained in this way can also be tablet-coated directly or moistened in small proportions by means of an appropriate organic solvent and processed further to form crust granules. Tablets or any other desired shape can be pressed from this granulate without additional auxiliaries. The compressed products produced in this way are suitable for implantation in the human or animal body.

The silicone oil which is preferably used as a weakly polar dispersant in the process according to the invention can, for example, be of the dimethylpolysiloxane type.

Polycondensates which are soluble in organic solvents and in which at least one starting component is unsaturated, for example fumaric acid, can, after incorporation of the active ingredient and solubilization in an aqueous surfactant solution, for example in 15% polyoxyethylene-sorbitan-mbnolaurate solution, at temperatures between 20 ° and 60 ° _C. that is, they can also be polymerized at room temperature, so that even temperature-sensitive active ingredients can be easily incorporated into the polycondensates without decomposition and without losing their effectiveness.

example 1

29.3 g of anhydrous lactic acid are mixed with 300 mg of p-toluenesulfonic acid and 40 g of benzene pa, mixed well and brought to the boil with constant stirring. The condensation water which forms is removed azeotropically with the benzene in a modified Kutscher-Steudel apparatus. After 16 hours, a further 330 mg of p-toluenesulfonic acid are added. At this time, 3.5 ml of water had already been separated. After 160 hours there was a total of 5.2 ml of water separated and a perfect stirring of the polyester still partially dissolved in benzene is no longer possible at this time. The .benzene was then removed from the reaction mixture, the remaining polyester was dissolved in 100 ml of methylene chloride and precipitated three times from cold methanol. The catalyst can also be removed by an amberlite ion exchanger.

In this way, 23.6 g of polylactic acid with a melting point of approx. 160 ° C. and an average molecular weight of 9000 are obtained. The polycondensate has film-forming properties.

1.8 g of this polylactic acid and 0.2 g of hydrocortisone are dissolved in a just sufficient amount of dioxane and incorporated into 50 ml of silicone oil (viscosity: 100 centistokes, density: 0.968 g / cm ³ at 25 ° C.). This disperse. is stirred for a few hours at room temperature until all the solvent has been removed. This process can be accelerated by using a vacuum.

After the solvent has been distilled off, the temperature is raised to 180 ° C. and the mixture is stirred for a further 40 minutes under the stated vacuum.

The dispersion is now quickly cooled, diluted with hexane and the resulting polycondensate micropellets are separated from the silicone oil by centrifugation. The silicon residues are removed by resuspending the microspheres in hexane and then centrifuging.

The silicone oil can be reused after distilling off the hexane. A fine powder of micropellets is obtained, the diameter of which does not exceed 50 μm.

The active substance is released with a delay.

Example 2

20 g of p-aminobenzoic acid are heated in a 250 ml round-bottomed flask to 200 ° C. while gassing with nitrogen and then condensed under constant stirring for 30 minutes under vacuum. A hard polycondensate is obtained which is very readily soluble in methylene chloride and dimethylformamide, but is insoluble in water. 2.2 g of the polycondensate obtained in this way are mixed with 300 mg of N-acetyl-p-aminophenol as the active ingredient and both are dissolved in the amount of dimethylformamide just required. Methylene chloride and ethyl acetate are also suitable as solvents.

Under vacuum and rapid stirring (high-speed stirrer Tornado), the polymer drug solution in 50 g of silicone oil (of the same quality as in Example 1) is then slowly dripped from 150 to 170 ° C. and the procedure is then continued as in Example 1.

Micropellets containing active ingredient are obtained, the size of which can be changed by varying the amounts of solvent and silicone used and the stirring speed of the high-speed stirrer.

The active ingredient is released from the pellets with a delay.

Example 3

0.9 g of a polyester which was prepared from equimolar amounts of fumaric acid and 2-propanediol and a molecular weight of 1300, are mixed together with 0.1 g testosterone acetate and 0.024 g benzoyl peroxide and 3 ml dichloroethane until a homogeneous mass is formed. After the dichloromethane has been evaporated off, the viscous mass is sucked into a polytetrafluoroethylene tube 10 cm long and 1 mm in diameter at 60 to 70 ° C.

The hose ends are welded and subjected to a heat treatment of 120 ° C for 100 minutes.

The polymerized polyester can then be easily "peeled" out of the tube.

The active substance-containing polyester stick can be applied parenterally with an appropriate device without a major surgical intervention being necessary.

If an accelerated, non-physiological release test is carried out in absolute ethanol at elevated temperature (37 ° C), 69% of the active ingredient is released from the polymer sticks after 48 hours. In the amount of absolute ethanol used, the testosterone acetate used would dissolve within seconds.

Example 4.

5.7 g of tartaric acid (0.038 mol) are melted and then 3.924 g of pentaerythritol (0.028 mol) are added. After the pentaerythritol has also melted clearly, 5 minutes are polycondensed at 170 ° C. with stirring and reduced pressure (10 to 14 mm HG). 6.67 g are placed in this condensate

Theophylline substance stirred in and condensed for a further 15 minutes under vacuum at 170 ° C and then the temperature raised to 190 to 200 ° C. At this temperature, the vacuum is maintained for a further 20 minutes. You get 17.5 g of a very hard polycondensate at room temperature. with theophylline, which can be pulverized and releases the active ingredient with a delay.

The pulverized polycondensate can easily be briquetted and, after treatment in a dry granulator, can be tabletted directly without the aid of an additive. In this way, implant tablets are obtained which contain only active ingredient and polyester and are characterized by a delayed release of active ingredient.

Example 5

2 g of the polycondensate prepared according to Example 4 are dissolved together with 500 mg of paracetamol in 5 ml of dimethylformamide. This solution is placed in a dropping funnel, which is attached to a three-necked flask. 30 g of silicone oil (of the same quality as in Example 1) are placed in the flask and heated to 1-80 ° C. . -

Under vacuum (10 to 14 mm Hg) and rapid stirring (high-speed stirrer Tornado), 2 g of the polycondensation-paracetamol-dimethylformamide solution are added dropwise very slowly, the solvent being distilled off and the polycondensation being continued, until the polymer particles no longer dissolve in water.

After working up the dispersion as in Example 1, a fine powder of micropellets is obtained, the diameter of which is less than 100 μm.

Example 6

According to the usual methods, equimolar amounts of fumaric acid and T, 2-propanediol become a still flowable polycondensate manufactured. 2 g of this polycondensate are mixed with 0.4 g styrene and 0.05 g testosterone, which is dissolved in 1 g ether, and solubilized dropwise in a 15% aqueous polyoxyethylene sorbitan monolaurate solution with constant stirring.

After gassing with nitrogen for 10 minutes, the clear solubilizate is mixed with 0.1 g ammonium persulfate and 0.001 g tetramethyl. ethylenediamine added and with constant stirring and nitrogen fumigation _. Heated to 40 ° C for 12 hours.

After the polymerization, the polymer particles are precipitated by adding methanol, which are then centrifuged and washed several times. The aqueous suspension of these polymer particles is lyophilized.

In this way, particles in the nanometer range are obtained which contain testosterone as a pharmacologically active substance and release them with a delay. These nanoparticles are suitable for parenteral administration.

Example 7

1 g of a polyester made of fumaric acid and 1,2-propanediol with a molecular weight of 1300 is dissolved together with 0.05 g of benzoyl peroxide and 0.2 g of norgestrel in 10.0 g of methylene chloride. This solution is mixed thoroughly with 5.0 g of Tween 80 and then slowly added dropwise from a burette in 50 ml of aqua destillata, which is constantly stirred. After the solubilization, the temperature is raised to 50 to 60 ° C. and the mixture is stirred for 6 to 8 hours while gassing with nitrogen. 0.03 g of a tert-arylalkylamine is then added to the outer phase and the mixture is stirred at 40 to 50 ° C. for a further 12 hours.

Polyester pellets in the nanometer range are obtained.

Claims

Patent claims

1. Depot drug form - for oral and / or parenteral application from one or more medicaments enclosed in a polymer matrix, the matrix produced by polycondensation of at least bifunctional carboxylic acids with polyols slowly converting into non-toxic, under physiological conditions, Excretable compounds hydrolyzed and thereby releases the medicament ^(s) , characterized in that the matrix of the polycondensation product consists of a dicarboxylic acid, hydroxymonocarboxylic acid and / or a physiologically compatible amino acid or of several of these acids and optionally of one or more the polyols 1, 2-propanediol, inositol, pyridoxol, D-panthenol, pentaerythritol, adonite.

2. Depot pharmaceutical form according to claim 1, characterized in that the matrix consists of polylactic acid.

3. Depot form according to claim 1, characterized marked. net, that the matrix of the ^{Selbstkondens'} ationsprodukt of p-aminobenzoic acid consists.

4. Depot pharmaceutical form according to one of claims 1 to 3, characterized in that it consists of micropellets with an average diameter of 10 -9 to 10-4 m.

5. A process for the preparation of the depot pharmaceutical form according to one of claims 1 to 4 by producing a polycondensate soluble in organic solvents in a manner known per se and adding the desired drug (s) to the polycondensate, characterized in that the still water-soluble Dispersed polycondensate together with the drug in a weakly polar dispersant with stirring and the condensation is completed until the polycondensate is insoluble in water.

6. The method according to claim 5, characterized in that silicone oil is used as the dispersant.

7. The method according to claim 5 or 6, characterized gekennzeich¬ net that the condensation is carried out at a temperature of 120 - 200 ° C.

8. The method according to any one of claims 5 to 7, characterized in that the condensation is carried out under a pressure of 10-14 mm Hg.

9. The method according to claim 5, characterized in that the polycondensate is solubilized together with the medicament in an aqueous surfactant solution, with stirring to a

Temperature of 20 - 60 ° C warmed and precipitated from the solution.

10. The method according to claim 9, characterized in that polyoxyethylene sorbitan monolaurate solution is used as the aqueous surfactant solution.