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Publication numberUS3920805 A
Publication typeGrant
Publication dateNov 18, 1975
Filing dateDec 17, 1973
Priority dateDec 9, 1971
Publication numberUS 3920805 A, US 3920805A, US-A-3920805, US3920805 A, US3920805A
InventorsRoseman Theodore J
Original AssigneeUpjohn Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Pharmaceutical devices and method
US 3920805 A
Images(3)
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Description  (OCR text may contain errors)

United States Patent [191 Roseman Nov. 18, 1975 PHARMACEUTICAL DEVICES AND METHOD [75] Inventor:- Theodore J. Roseman, Portage,

Mich.

[731 Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: Dec. 17, 1973 [21] Appl. No.: 425,600

Related US. Application Data [63] Continuation of Ser. No. 206,437, Dec. 9, 1971,

3,566,874 3/1971 Shepherd et a1 128/349 OTHER PUBLICATIONS Mishell et al. Am. J. Obstet. Gynec. 107: 100-107 May 1, 1970, Contraception by Means of a Silastic Vaginal Ring lmpregnated with medroxyprogesterone Acetate.

Mishell et al. Fertility & Sterility 21199-103 Feb. 1970, Contraceptive Effect of Varying Dosages of Progestogen in Silastic Vaginal Rings.

Barkor Candd. Vet. J1. 7/912189-192 Sept. 1966, Progestin Impregnated Vaginal Pessaries for Estrous Cycle Synchronization in Sheep.

Primary Examiner-Shep K. Rose Attorney, Agent, or Firm-John J. Killinger; Roman Saliwanchik [57] ABSTRACT A solid pharmaceutical device formed of a nontoxic resilient polymer and medication releasable therefrom during residence in a living mammal. The device has a nonmedicated core of the polymer encircled by a medicated coating of the polymer. Reduced content of diffusible medication is achieved.

2 Claims, 8 Drawing Figures US. Patent Nov. 18, 1975 Sheet 1 of3 3,920,805

figure f/yure 3 U8. Patent Nov. 18, 1975 Sheet 2 of 3" 3,920,805

figure 5 figure 4 figure 6 4 RATE (mg./day ring) U.S. Patent Nov. 18, 1975 Sheet3 of3 3,920,805

il O o o l l I l l l l l J 4 a 12 1e 20 TIME (Days) In virro release rates of medraxypragesre'rane acetate from dimethylpolysiloxane rings.

0 Ring MM /00 mg. owe/sea f/zroz/g/muf, .05 1'0 Figures 6 0/20 7.

O fP/ng w/ffi 6/.96 mg. 075 arsed /'/2 outer coo/mg,

0s m F/gz/res 4 and PHARMACEUTICAL DEVICES AND METHOD This application is a continuation of Ser. No. 206,437, filed Dec. 9, 1971, now abandoned.

BACKGROUND OF THE INVENTION This invention arises in the field of medicated devices for placement or implantation in a living body. Such devices release the medication whilst the carrier substance of which the device is formed is not absorbed but merely acts as a matrix and is itself substantially unchanged during the time of residence in the body. This is in contrast to release of a medication by solution of the substance used to transport the medication as in an oral or implanted tablet or an aqueous solution or like medicament.

It is known that a rubbery silicone-type polymer provides a nonabsorbed carrier matrix from which medication will diffuse into a surrounding liquid; Dziuk and Cook, Passage of Steroids through Silicone Rubber, Endocrinology, 781208 (1966). US. Pat. No. 3,279,996 discloses the use of a polysiloxane rubber as an implantation agent for devices dispensing diffusible medication. US. Pat. No. 3,545,439 discloses a ring device for body placement containing a resilient polymeric substance such as a polysiloxane or polyurethrane elastomer, also nylon, dacron, teflon, polyethylene. A wide variety of medication for dispensing via the polymeric devices is disclosed in US. Pat. No. 3,279,996 and US. Pat. No. 3,545,439. Other relevant descriptions and disclosures are found in several publications, viz., Folkman and Edmonds, Circulation Research 101632 (1962); Folkman and Long, J. Surg. Res. 432139 (1964) and Powers, J. Parasitology 512153 (Apr. 1965).

Widely varying types of polymeric material are suitable in providing compatible, nontoxic and nonabsorbable properties, for example organopolysiloxane of the linear type converted to rubber by heat curing (vulcanization). These linear organopolysiloxanes are known as the conventional type, for example dimethylpolysiloxane. Likewise suitable are those known as the RTV type which are converted to the rubbery state at room temperature in the presence of a catalyst. US. Pat. No. 3,279,996 describes various conventional silicone rubbers which may or may not contain fillers, such as silica, to enhance tensile strength and the other physical properties of the cured rubber. This patent also describes commercially available RTV silicone rubbers.

Other patent literature shows the preparation of conventional silicone rubbers, illustratively US. Patents Warwick, US. Pat. No. 2,504,137; Konkle et al., US. Pat. No. 2,890,188; and other patents set forth in the US. Pat. to Long et al., No. 3,279,966. Other suitable nontoxic, nonabsorbable, compatible, drugpermeable polymeric materials are, for example, nylon, a polyamide resin made by polymerization of the hexamethylenediamine salt of adipic acid; dacron, a synthetic fiber made by E. I. DuPont de Nemours and Co. from teraphthalic acid and ethylene glycol; teflon, a tetrafluoroethylene polymer manufactured by E. I. DuPont de Nemours and Co.; polyurethane elastomer prepared according to known methods from polyisocyanate and polyhydroxyl material. The polyhydroxyl materials, for example polyesters, polyethers and the like, are reacted with isocyanates to yield rubberlike products for use as rnillable gums or in casting systems or as thermo processable resins. See US. Pat. Nos. 2,871,218 and 2 3,015,650. Another exemplary polymer is polyethylene, prepared by polymerization of ethylene, usually prepared from natural gas or the cracking of crude oil. Modern Plastics Encyclopedia for 1968, Sept. 1967, Vol. 45, No. la, McGrawJ-Iill, New York, N.Y., describes the preparation of the aforesaid suitable plastic materials, especially in reference to their molding qualities, compression molding temperatures, and compression molding pressures. Details on the aforesaid polymers are given in the plastic properties chart of the aforesaid Encyclopedia, pages 29 through 46, inclusive. In reference to the non-absorbability and nontoxic nature of the aforesaid polymeric material, US. Pat. No. 3,272,204 refers to the use of vinyon N, nylon, orlon, dacron, teflon, and the like as nonabsorbably, reinforcing strands for the preparation of prostheses. Such strands have the advantage that they do not become a part of the body tissues. So it is with the improved device of the present invention, which is particularly advantageous because of its ready insertion and ready retention but does not become or form any part of the tissue of the mammal utilizing the device, for example human and animal, such as dogs, cattle, and horses. In this respect, the present device, with its medication contained therein for continued medication as desired, is greatly superior due to economy of medication.

The aforesaid polymeric substances are compatible with a body environment in which they are used in that no breakdown or absorption of the polymer occurs nor is there any deleterious effect on the body environment, only the medication being absorbed for the desired local or systemic effects.

BRIEF SUMMARY OF THE INVENTION This invention relates to an improved pharmaceutical device formed of compatible polymeric substance and containing therein difiusible medication. The device is suited for placement within a living mammalian body, for example man and valuable warm blooded animals such as dogs, sheep, cattle and horses. The medication diffuses through'the polymeric device, is absorbed by the surrounding body fluids and exerts its desired effect as long as the device is retained within the body. The polymeric substance is compatible and nonabsorbable being removable in total unchanged when it is desired to terminate treatment with the medication. Thus, continuing treatment is provided during the bodys retention of the device and treatment is terminated upon removal. The present invention provides improvement by reducing the amount of medication required in the device by locating the medication in an outer coating of polymeric material which encircles a core of nonmedicated polymeric material.

An in vitro method of test utilizes polymeric material, e.g., polysiloxane tubing which is loaded with the par ticular drug and plugged at the ends with polysiloxane cement. After allowing about 48 hours for setting or curing, the filled link of tubing is placed in, for example, 50 ml. of normal saline in a suitable container and shaken at approximately body temperature for about 24 hours. Spectroscopic analysis of the liquid, for example by the isonicotinic hydrazide method for medroxyprogesterone acetate, shows that the drug is capable of permeating through the silastic into the saline material, in which it can be demonstrated by the in vitra test. For in vivo testing, placement of a suitable size device containing a known amount of medicaments, e. g., medroxyprogesterone acetate in a polysi- 3 loxane, molded-rubber ring and retention in the vagina of the monkey for a period of about 2 months shows that the initial content of the drug is appreciably reduced.

An additional, in vivo, technique for determining the suitability of the polymeric material for use in the preparation of the inventive device is as follows: 150 mg. of medroxyprogesterone acetate is well mixed with 615 mg. of polysiloxane elastomer 382 (Dow Corning Company) to prepare resilient containers approximately 4 cm. long and 0.48 cm. in diameter. Different dosages of the drug are obtained by cutting the required length of the material. The material is sterilized and can be inserted subcutaneously into the scapular region of normally cycling female rats. Daily records of vaginal cytology, which reflect the release of the medroxprogesterone acetate, are made for periods of 2 to 6 weeks at dosages of 18.75 mg. for 6 weeks in four animals, 37.5 mg. for 2 weeks in four animals, and 56.25 mg. for 2 weeks in four animals. Cycling is prevented in the otherwise normally cycling female rats. This shows that the active medicament is released by diffusion through the drug-permeable polymer and exerts its physiological efi'ect via the vaginal tract. In addition to the in vivo data in the rats, it was found by measuring the final content of the medicament in the silastic material that average total release of 4.4 mg, mg. and 5.2 mg. occurred from elastomeric carrier material of 0.5, 1.0 and 1.5 cm. in size, respectively.

The amount of medication in each of the devices is that sufficient for bringing about the desired physiologic effect, for example, the amount sufficient for controlling fertility. Given in ranges of active ingredients, suitable amounts for individual drugs in the device are as follows: digitoxin, 5 to 50 mg; triiodothyronine, l to mg.; isoproterenol, 100 mg. to 2 Gm.; atropine, 10 to 250 mg.; histamine, l to 10 mg.; nitrogen mustard, 50 mg. to 2 Gm.; vitamin B 0.5 to 100 mg.; pyrimethamine, 50 mg. to l Gm.; estradiol, 0.5 to 100 mg; progesterone, 50 mg. to 2 Gm.; androstenedione, 50 mg. to 2 Gm.; testosterone, 50 mg. to 2 Gm.; cortisol, 100 mg. to 2.5 Gm.; medroxyprogesterone acetate, 50 mg. to 2 Gm.; melengestrol acetate, 50 mg. to 2 Gm.; chlormadinone, 50 mg. to 2 Gm. The amount of any additive medication, for example locally effective antimicrobial agent, is calculated on the basis of the known amounts useful in similar vaginal applications. Other principal active medicaments are, for example, antiulcer and antisecretory agents, for example methscopolamine, 75 mg. to 2 Gm.; anticoagulant, for example diphenadione, 75 mg. to l Gm.; hypocholesteremic agent, for example 3-methyl-5-isoxazole carboxylic acid, 200 mg. to 2 Gm.; anti-tumor drugs, for example cytarabine, 100 mg. to 3 Gm.; appetite depressant, for example D- amphetamine, 100 mg. to 2 Gm.; tranquilizers and sedatives, thiothixene and haloperidol, 50 mg. to 2 Gm.; hypoglycemic agent, 1 p-2-(5-chloro-o-anisamido) ethyl phenyl sulfonyl-3-cyclohexylurea, 100 mg. to 2.5 Gm.; hypotensive agent, mecamylamine, 100 mg. to 1.5 Gm.; antibacterial and antimalarial agents, 7- deoxy-7(S)-chlorolincomycin, 2 to 7 Gm., N-demethyl lincomycin, 2 to 7 Gm., 4'-pentyl-N-demethyl-7(S)- chlorolincomycin, l to 5 Gm.; antihypertensive agent, for example angiotensin amide, 100 mg. to 2 Gm.; glucocorticoid, for example dexamethasone, 10 to 250 mg.; prostaglandins, for example PGE PGE PGA, as antiulcer and antisecretory agents and for inhibition of blood platelet-stickiness, 0.5 to 10 mg.; PGF for control of fertility, 0.5 20 mg. The aforesaid amounts are ranges of active ingredients to be included in the device, the exact amount depending upon the age, condition of the patient, and the particular effect desired. These amounts are calculated to provide predetermined daily release dosages as follows: for the cardiac stimulant digitoxin, 0.1 to 0.2 mg; for the metabolic stimulant triiodothyronine, 5 to mcg.; for the bronchodilator isoproterenol, 5 to 30 mg; for the antianemia agent vitamin B 10 to 300 mcg.; for the antimalarial pyrimethamine, l to 5 mg; for the estrogen estradiol, l to 500 mcg.; for the progestogen progesterone, 0.1 to 20 mg; for the androgens androstenedione and testosterone, 0.1 to 10 mg.; for the glucocorticoid cortisol, 5.0 to 50 mg; for the progestogens medroxyprogesterone acetate, melengestrol acetate, and chlormadinone, 0.01 to 10 mg.; for the methscopolamine, 3 to 20 mg; for the diphenadione, 3 to 5 mg; for the 3-methyl- 5-isoxazole carboxylic acid, 10 to 30 mg; for the antitumor drug cytarabine, 60 to 300 mg.; for D-amphetamine, 5 to 30 mg; for thiothixene, 2 to 30 mg.; for haloperidol, 2 to 15 mg.; for the hypoglycemic cyclohexylurea compound, 5 to 50 mg; for the hypotensive mecamylamine, 2 to 10 mg; for the antibacterial, antimalarial lincomycin agents, 250 to 500 mg, 250 to 500 mg. and to 300 mg., respectively; for the angiotensin amide, 0.7 to 30 mg; for the dexamethasone, 0.2 to 2 mg; and for the prostaglandins, l to 100 mcg.

Depending upon the anatomyl the anatomy particular species involved, the improved ring device will vary in size, for example in the case of the human from about 60 mm. diameter to about 80 mm. diameter, these dimensions being overall dimensions; the diameter of the actual ring itself will be in the neighborhood of about 5 to 10 mm. In the case where an endless helical spring or flat spring structure is used for additional tensing property, the diameter of this metallic part of the ring will vary with that of the device itself. Overall dimensions of the improved medicated ring for use in other species are approximately as follows: for sheep and swine, 20 to 65 mm.; for dogs, 5 to 50 mm.; for cats, 5 to 30 mm.; for cattle, 50 to 100 mm.; and for horses, 50 to mm. These dimensions are overall dimensions. As will be apparent, the actual diameter of the ring itself varies with the overall size and with the particular species. Suitably the annular devices may incorporate a tab for assistance in removal. The polymeric materials are, as disclosed in the aforesaid Modern Plastics Encylopedia, those that are suitable for molding in manners known to those familiar with this art. Those polymeric materials, for instance the organopolysiloxanes, which are in a liquid state or paste state, can be directly mixed with the drug, for example melengestrol acetate or medroxyprogesterone acetate, and the semifiuid material placed into the mold for compression molding with the addition of a catalyst, for example stannous octoate. In case the device is to contain a spring structure for tension properties, this is usually centered in the semifluid material while it is in the mold and thereafter covered by additional drug-containing polymeric material for the compression moldmg.

BRIEF DESCRIPTION OF THE DRAYVING FIG. 1 is a perspective view of a tangible embodiment of the concept of the invention.

FIG. 2 is a sectional view taken along the line II II in FIG. 1.

FIG. 3 is a perspective view of an alternate embodiment.

FIG. 4 is a photographic cross-sectional view of a ring emodirnent with central core and outer coating.

FIG. 5 is a photographic cross-sectional view of the ring of FIG. 4 after three weeks leaching in distilled water.

FIG. 6 is a photographic cross-sectional view of a conventional ring device without central core and outer coating.

FIG. 7 is a photographic cross-sectional view of the ring of FIG. 6 after three weeks leaching in distilled water.

FIG. 8 is a graphic representation of release rates of medication.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS As set forth in FIGS. 1 and 2 which portray together a preferred embodiment of the invention a device of the invention takes the form of a resilient individual ring 10 for vaginal placement with a centered nonmedicated polymeric core 11 and a polymeric coating 12 containing the medication 13. To avoid too close proximity of the edge of the core to the edge of the ring, a three step molding process is used to provide a precisely centered core as in FIG. 2.

First Step. Add 0.36% by weight of stannous octoate to q.s. dimethylpolysiloxane (Dow Corning Silastic 382). Mix well. Place the mix into two halves of a mold to provide a centered polymeric core of 62.2 mm. outside diameter and 3.6 mm. cross-sectional diameter. Tighten the mold with wing nut. Cure.

Second Step. Place the cored nonmedicated polymeric core into one-half of its mold. Fill one-ha1f of an outer mold (65 mm. outside diameter and 6.4 mm. cross-sectional diameter) with medicated polymeric mixture containing 1.386% medroxyprogesterone acetate and 0.36% stannous octoate. Place the filled one-half over the core of the first step and cure.

Third Step. After the mold of the second step is cured,

the other half of the outer mold is filled with the medicated polymeric mixture. This half plus the cured half of the second step are bonded together and the whole is cured again.

The average weight of the outer coating of 10 rings is 4.49 Gm. with an average core weight of 2.17 Gm. At

6 61.96 mg. As shown in FIG. 8 the release rates are substantially the same despite the lesser overall amount of medication.

Under in vitro and in vivo conditions a zone of depletion results as medication diffuses from the polymer. This zone is void of solid medication particles. In order for the medication to be released from the core ring at the same rate as a completely filled ring, the zone of depletion over the given time interval must not be greater than the distance from the surface of the device to the surface of the core. The dimensions of the placebo core are designed to meet this requirement.

FIGS. 4 and 5 show the zones which result upon use of the ring of FIG 1. In FIG. 4 there is the medication filled outer coating 13 and the inner nonmedicated core 11. After use as shown in FIG. 5 there is a zone of depletion 14 as the medication diffuses out of the coating 12. In the conventionally filled ring of FIG. 6 there is the medication containing area 13 which remains the same in FIG. 7 except for the zone of depletion 14. The zones of depletion 14 in FIG. 5 and also 14 in FIG. 7 are the same.

FIG. 3' is a perspective view of an alternate embodiment of the inventive concept. It is a solid cylinder for implantation. For example, in the ear region of an animal such as a cow.

It will be apparent to those of skill in the revelant art that there are obvious structural variants by means of which the inventive concept can be practiced. Included therein but not limited thereto are a plurality of outer medicated coatings of different concentrations of the same medicament or coatings of different medicaments useful in combination. Also spring or equivalent means can be included in the core to provide tension.

I claim:

1. A solid pharmaceutical device formed as a vaginal ring of a nontoxic resilient medication diffusing organopolysiloxane polymer and an effective vaginal dosage amount of a medication diffusible therein which releases said medication during residence in the vaginal cavity of a living mammal consisting essentially of, in

combination, a nonmedicated central core of said poly-' mer and an encircling finite thickness of a medicated coating of said polymer.

2. The device of claim 1 which is formed of dimethylpolysiloxane with a centered metallic, endless, helical or flat tensioning spring molded in the nonmedicated central core and the diffusible medication is medroxyprogesterone acetate.

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Classifications
U.S. Classification424/432, 128/832
International ClassificationA61M31/00, A61K9/20, A61D7/00, A61K9/00
Cooperative ClassificationA61K9/0036, A61D7/00, A61M31/002, A61K9/2036
European ClassificationA61M31/00D, A61K9/20H6D2, A61K9/00M8B, A61D7/00