DE2259070A1 - SOLID PHARMACEUTICAL PREPARATION FORM - Google Patents

Description

DR. JUR. DIiL-CHEM-WALTER BEIL

ALFRtU HOiEPrCMES

DR. JUR. HiL-GiEM, H.-J. WOLFF ~ l

DR. JUR. HANS CHR. AX

FRANKFURT AM MAIN-HOCHST

AOEtONSf «ASSE St

Our, Mr. 18 272

The Upjohn Company
Kalamazoo, Mich., V.St.A ,.

Solid pharmaceutical preparation form. .

The present invention relates to a medicament-containing one pharmaceutical preparation> which can be placed or implanted in a living body. Such forms of preparation deliver the drug in the body while the carrier substance that makes up the formulation or device has been produced, is not absorbed, but only serves as a matrix and during the residence time remains essentially unchanged in the body. This type of administration is in contrast to an administration in the form of a solution of the substance that makes the drug trans ^ -. ported, for example in the case of oral administration channels or, implanted tablets or aqueous solutions or the like.

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It is known that a silicone type rubbery polymer is a non-absorbable carrier matrix which diffuses the drug into a surrounding liquid, see Dziuk and Cook, "Passage of Steroids through Silicone Rubbers ", Endocrinology, 78, 2o3 (1966). U.S. Patent 3 279 996 describes the use of a polysiloxane rubber as an implantation agent for devices, that deliver a diffusible drug. The US patent 3,545,439 describes an annular device which can be incorporated into the body and which is a elastic polymer substance such as a polysiloxane or polyurethane elastomer, nylon, Dacron, Teflon or Polyethylene. Also numerous drugs that are distributed via such polymer-containing devices are described in referenced U.S. Patents 3,279,996 and 3,545,439. Other relevant descriptions can be found in Folkman and Edmonds, Circulation Research 10, 632 (1962); Polkman and Long, J. Surg. Res. 43, 139 (1964) and Powers, J. Parasitology 51, 153 (April 1965).

Very different types of polymer materials will suffice tolerated, non-toxic and non-absorbable, for example linear organosiloxanes, which are hardened by yeast (Vulcanization) can be converted into rubber. These linear organopolysiloxanes »e.g. dimethylpolysiloxane, are known as the conventional polysiloxanes. Also suitable are the polysiloxanes of the RTV type, which are at room temperature be converted into the rubber state in the presence of a catalyst. U.S. Patent 3,279,996 describes various conventional silicone rubbers that may be used to improve tensile strength and other physical properties of the cured rubber May contain fillers such as silica. The named patent also describes the commercially

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available RTV silicone rubbers. From further patent literature the production of conventional silicone rubbers is known, for example from US patents 2,5o4,137 and 2,890,188 and those disclosed in U.S. Patent 3,279 named patents. Other suitable non-toxic, non-absorbable and tolerable, permeable to drugs Polymer materials are, for example, nylon, a product obtained by polymerizing the hexaniethylenediamine salt8 of adipic acid available polyamide resin »Dacron, a synthetic fiber made from terephthalic acid and ethylene glycol from E.I. DuPont de Nemours and Co., -Teflon, a tetrafluoroethylene polymer from E.I. DuPont de Nemours and Co., as well as in a known manner Polyurethane elastomers made from polyisocyanate and polyhydroxy compounds. The polyhydroxy compounds, e.g. Polyesters, polyethers and the like., Are reacted with the isocyanates to form rubber-like products, the as grindable rubbers in casting processes or as thermal deformable resins can be used, see. U.S. Patents 2,871,218 and 3,015,650. Another polymer example is Called polyethylene, which is obtained by polymerizing ethylene (from natural gas or by cracking crude oil) will be produced. The "Modern Plastics Ex ^ yclopedls-a" 'for 1968 (Sept. 1967, Vol. 45, No. 1a, McGrawHill, New York, N.Y., USA) describes the production of the plastic materials mentioned, in particular also their form properties, temperatures and pressures * details of the polymers can be found in the encyclopedia mentioned, tables on pp. 29-46. Regarding the non-absorbability and non-toxic The nature of the polymeric materials is suggested by the US patent 3 272 2o4 the use of Vinyon N, Nylon, Orion, Dacron, Teflon and the like as non-absorbable, reinforcing materials for the manufacture of prostheses. These materials have the advantage that they are not part of the body tissue. This is also the case with the invention

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according to the improved device or preparation form Case, which is particularly advantageous in that it is easily inserted and held, but not part of the Tissue of the user, for example a human being or an animal, e.g. dogs, cattle and horses. The device according to the invention, the active substance of which can be continued to be released as desired, is due to the Economics of the administration of previous preparation forins substantially superior.

The polymer materials mentioned above are compatible with the body environment, in which they are used, compatible in such a way that neither an absorption of the polymer takes place, another adverse effect on the environment. Rather, the drug is merely targeted for the local area or systemic effect absorbed by the body. The present invention thus relates to an improved pharmaceutical Form of preparation from a compatible polymer substance, which contains a medicament which can be distributed therein. The preparation form or device can be used in a living Mammalian bodies are introduced, for example into the body of a human or into the body of valuable ones Cross-blooded animals such as dogs, sheep, cattle and horses. The drug diffuses through the polymer device, is absorbed by the surrounding body fluid and exerts the desired effect as long as the device is left in the body. The polymer substance is compatible and non-absorbable and can be practically unchanged removed from the body as soon as one wishes to end drug treatment. As long as the If the device is located in the body, treatment continues, but this occurs when the device is removed is terminated. The invention has an advantage

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such that the amount of drug required in the device is reduced, - by accommodating the drug in an outer shell made of polymer material, which has a core encased from drug-free polymer material »

An in vitro test method uses a polymer material, e.g. a polysiloxane tube, which is connected to the respective Drug filled and plugged at the ends with polysiloxane cement. After about 43 hours of setting or curing if the filled tube is immersed e.g. in 50 ml normal saline solution, which is in a suitable container, then shake at body temperature for about 24 hours. The spectroscopic examination of the liquid, for example in the case of medroxyprogesterone acetate using the isonicotinic acid hydrazide method, shows that the drug passes through the silicone into the saline solution, in which it is then detected in this in vitro test. For tests in vivo an appropriately sized device is placed with a known amount of a drug, e.g., medroxyprogesterone acetate, inserted into a monkey's vagina in a polysiloxane rubber ring for about 2 months, after which it is found that the initial drug content was greatly reduced.

Another test method in vivo, with which one the suitability of a polymer material for use according to the present Invention can determine is carried out as follows: 150 mg medroxyprogesterone acetate are with 615 mg "Polysiloxane Elastomer 382" (Dow Corning Company) mixed well, elastic containers about 4 cm long and 0.48 cm in diameter are then made from the mixture. You get Different doses of the drug when this material is cut into appropriate lengths. That Product is then sterilized and subcutaneously in the shoulder

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BATH ORIGINAL

area of female had with normal menstrual cycle introduced. Daily examinations of the vaginal cytology, the conclusions on the release of the Lledroxyprogesteronacetats allows, for periods of 2 to 6 weeks at doses of 18.75 mg for 6 weeks in 4 animals of 37.5 mg for 2 weeks in 4 animals and 56.25 mg for 2 weeks in 4 animals. The cycle is omitted in the otherwise normally reacting female rats. It follows that the drug is through Diffusion through the drug-permeable polymer is released and its physiological effects via the Vaginal tract exercises. In addition to the results in vivo, the determination of the final content of the silicon-elastic Material of drug a total release of 4 »4 resp. 5 or 5 | 2 mg from a carrier 0.5 »1.0 or 1.5 cm Size.

The preparation forms according to the invention contain the amount of medicament which is sufficient to achieve the desired physiological effect, for example for contraception. For example, the following dose ranges are suitable for various drugs:

Digitoxin 5-50 mg; Triiodothyronine 1-1o mg; Isoproterenol 100 mg-2 g; Atropine 10-25o mg; Histamine 1-1o mg; Nitrogen mustard 50 mg-2 g; Vitamin B ^ o, 5-1oo mg; Pyrimethamine 50 mg-1 G; Estradiol 0.5-1oo mg; Progesterone 50 mg-2 g; Androstenedione 50 mg-2 g; Testosterone 50 mg-2 g; Cortisone 100 mg-2.5 g; Medroxyprogesterone acetate 50 mg-2 g; Melengostrol acetate 50 mg-2 g; Chlormadinone 50 mg-2 g. The amount of active ingredient, For example, the amount of a locally effective antimicrobial agent, calculated on the basis of the known, effective amounts for similar vaginal applications. Other possible drugs are, for example

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Antidotes against ulcers and antisecretory agents, for example methscopölamine, in doses of 75 mg-2 g, anticoagulants, e.g. diphenadione, in doses of 75 mg-1 g, hypocholesteremic agents, e.g. 3-methyl-5-isoxazolecarboxylic acid in doses of 2oo mg to 2 g _s anti-tumor agents, e.g. cytarabine, in doses of 100 mg-3 gj. Appetite suppressants such as D-amphetamine in doses of 100 mg-2 g, tranquilizers and sedatives such as thiothixene and sharkoperidol in doses of 50 mg to 2 g, hypoglycemic agents such as 1- ^ p- / ~ 2- (5-chloro-o ~ anisamido ) -äthyl7-phenyl j-sulfonyl-3-cyclohexylurea in doses of 100 mg to 2 _S 5 gs hypotensive agents such as mecamylamine in doses of 100 mg to 1.5 g, antibacterial and antimalarial agents such as 7-deoxy 7 (S) -chlorlincomycin in doses of 2-7 g _s N-demethyllincomycin in doses of 2.7 g, 4'-pentyl-N-demethyl-7 (S) -chlorlincomycin in doses of 1-5 g ₅ antihypertensive agents such as angiotensinamide in doses of 100 mg-2 g, glucocorticoids such as dexamethasone "in doses of 10-25 mg, prostaglandins, _{e.g. PGE 18} PGEp, PGA ₁ as antidotes against ulcers and antisecretory agents and as agents for inhibiting platelet adhesion in doses of 0.5-10 mg, PGFp for contraception in doses of 0.5 to 20 mg. The above values only relate to quantity ranges of the individual active ingredients fe, the exact dose of which depends on the age and condition of the patient and the desired effect. The quantities are calculated in such a way that the following doses are released daily: 0.1 mg for the heart-stimulating agent Digitoxin, 5-100 mg for the metabolic stimulant triiodothyronine, 5-30 mg for the bronchodilator isoproterenol, for the anti-anemic one Means vitamin B ₁₂ 10-3oo meg, for the antimalarial drug pyrimethamine 1-5 mg, ^x for the estrogen estradiol 1-5oo meg, for the progesterone 0.1-2 mg, for the androgens androstenedione and testosterone 0.1-1-1 mg , for the glucocorticoid cortisone 5, o-5o mg, for the progestogens medroxyprogesterone

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acetate, melengöstrol acetate and chlormadinone o, o1-io mg, for methscopolamine 3-2o mg, for diphenadione 3-5 mg, for 3-methyl-5-isoxazolecarboxylic acid 1o-3o mg, for cytarabine 6o-3oo mg, for D-amphetamine 5-3o mg, for thiothixene 2-3o mg, for haloperidol 2-15 mg, for the hypoglycanic cyclohexylurea derivative 5-5o mg, for mecamylamine 2-1o mg, for the iiincomycin derivatives 25o-5oo mg, 25o-5oo mg or i25-3oo mg, ^ Uf angiotensinamide o, 7-3o mg, for dexamethasone ο, 2-2 mg and for the prostaglandins 1-1oo meg.

Depending on the anatomy of the living being to be treated, the size of the annular device changes, for example an outer diameter for human use of about 60-80 mm. The diameter of the king itself is about 5 to 10 mm. Used for the purpose of additional Holding properties if an endless spiral spring or flat spring is used, the diameter of this varies Metal part of the ring with the diameter of the device. The overall diameter of the ring-shaped according to the invention Medicinal preparations have approximately the following values for the individual animal species: for sheep and pigs 2o-65 mm, for dogs at 5-5o mm, for cats at 5-3o mm, for cows at 50-100 mm and for horses at 50-150 mm. These Figures refer to the overall diameter. The ring diameter naturally varies with the overall diameter and with the respective species. Suitable annular devices may have an approach that the Removal facilitated. The polymer materials used are those which, according to the above-cited Modern Plastics Encyclopedia can be deformed in a manner known per se. These polymer materials, for example the Organopolysiloxanes, which can be in a liquid or pasty state, can be used directly with the drugs,

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for example with melengöstrol acetate or ivledroxyprogesterone acetate, are mixed, before the semi-liquid material together with the catalyst, for example tin (II) oetoate, fills into the mold. Should the device be a spring for Have hold, it is usually placed in the middle of the semi-liquid material in the mold, whereupon they are covered with more drug-containing polymeric material.

The invention will be further based on the accompanying drawings explained. Figure 1 shows in perspective an embodiment the invention.

FIG. 2 shows a section along the line II-II in FIG.

Figure 3 shows in perspective a further embodiment of the Invention,

FIG. 4 is the photographic reproduction of a section through an annular arrangement with a central core and outer shell.

FIG. 5 shows a photographic reproduction of a section through the ring according to FIG. 4 after 3 weeks of leaching in distilled water,

Figure 6 is a photographic representation of a section by a conventional hanging device without a central core and outer shell and.

Figure 7 is a photographic representation of the cross section through the ring according to FIG. 6 after leaching in distilled water for 3 weeks.

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BADORIGiNAi

Figure 8 graphically shows the rate of release of a drug.

As can be seen from Figures 1 and 2, which is a preferred embodiment Represent the invention, the preparation form consists of an elastic Hing io for introduction into the Vagina, which consists of a drug-free polymer core 11 and a polymer coating 12 with the drug 13 consists. To avoid the core wall and the ring wall being too close, the following three-stage molding process is used to produce a precisely centered core according to FIG. 2:

1st stage:

For the corresponding amount of dimethylpolysiloxane (Dow Corning Silastic 382) o, 36 wt .- ^ u tin (II) octoate are added, then mix well. The mixture is poured into both halves of a mold that has a 62.2 mm polymer core Outside diameter and 3.6 km in cross-section. The mold is closed tightly, then hardened.

2nd stage:

The drug-free polymer core is in one half of its Form placed, one half of an outer form (65 now outer diameter and 6.4 mm cross-sectional diameter) is with a Polymer gel filled which contains $ 1.386 medroxyprogesterone acetate and 0.36? o stannous octoate. Then it will be like that The filled mold half is placed over the core obtained in the first stage, followed by hardening.

3rd stage:

As soon as the mold has hardened according to step 2, the other half of the outer mold is covered with the drug-containing polymer

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mixed filled. The half and the already hardened half from the second stage are connected to one another and the overall arrangement is hardened again.

The average weight of the outer coating of ring 1o is 4.49 g * with an average core weight of 2.17 g · With a concentration of medroxyprogesterone acetate of $ 1.38 is the total medroxyprogesteronaeetate content 61.96 mg. As can be seen from FIG. 8, in the case of such a structure, the amounts of released medicament are in spite of lower Total content essentially equal to the amounts obtained from a conventional gate direction with significantly higher Drug content are dispensed.

Under the conditions prevailing in vivo as well as in vitro A zone of exhaustion is created as a result of the drug's diffusion from the polymer. There are none in this zone solid drug particles present. So that the drug is released from the cored ring in the same amount becomes like a completely filled Hing, the zone of exhaustion that arises in a given period of time must not be greater than the distance between the outer surface and the core surface. The dimensions of the placebo heart will be chosen so that this requirement is met.

FIGS. 4 and 5 show the zones resulting when the ring according to FIG. 1 is used. From Figure 4 is the Outer cover 13 filled with medicament and the medicament-free one Inner core 11 can be seen. After use, as can be seen from FIG. 5, there is an exhaustion zone 14, since the medicament has diffused out of the coating zone 12. In the conventionally manufactured ring according to FIG Drug in area 13 in front of which it, apart

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of the zone of exhaustion 14, even after use, see FIG. 7. The zones of exhaustion 14 are shown in FIGS Figure 7 the same size.

FIG. 3 shows a further embodiment in perspective the invention. It consists of a cylindrical body suitable for implantation. This can for example be in In the area of the ears, e.g. in animals such as cows.

It will be apparent to those skilled in the art that numerous structural modifications to the above examples are within the scope of the present invention Invention are possible. For example, one can have multiple drug-containing coatings at different concentrations provide the same drug or coatings with different drugs in an advantageous combination. Further you can get the core with a feather or equivalent. Middle] .η equip for tension.

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Claims (2)

Claims 1 · Solid pharmaceutical preparation form made of a non-toxic elastic polymer and a diffusible polymer Drug, wherein the polymer releases the drug during residence time in a living mammal through a drug-free central core made of the polymer and a coating of finite thickness surrounding it. the same polymer mixed with a drug. 2. Preparation form according to claim 1 in the form of a ring. 3 · Preparation form according to claim 1 in the form of a cylindrical Body. 4. Preparation form according to claim 2, characterized in that that the polymer consists of dimethylpolysiloxane and the diffusible drug consists of medroxyprogesterone acetate. For: The Upjohn Company Dr H, J. WoIff Lawyer 309825/11. 29 Blank page