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Publication numberUS3279996 A
Publication typeGrant
Publication dateOct 18, 1966
Filing dateAug 28, 1962
Priority dateAug 28, 1962
Also published asDE1467861A1
Publication numberUS 3279996 A, US 3279996A, US-A-3279996, US3279996 A, US3279996A
InventorsFolkman Moses Judah, Jr David M Long
Original AssigneeFolkman Moses Judah, Jr David M Long
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Polysiloxane carrier for controlled release of drugs and other agents
US 3279996 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

Oct 18 1966 y D. M. LQNG, JR., ETA

POLYSILOXANE CARRIER FOR CONTROLLE B RELEASE DRUGS AND OTHER AGENTS Filed Aug. 28, 1962 INTENSITY OF BEAT TIME INTERVAL IN 0.2 SECOND-" INVENTORfr DAVID M. LONG JR. MOSES JUDAH FLKMAN BY fl-J/Mm/L/ ATTORNEY United States Patent 0 3,279,996 PGLYSHLGXANE CARRIER FOR CONTRGLLED RE- LEASE 0F DRUGS AND OTHER AGENTS David M. Long, In, Boston, Mass. (1028 Rand Road,

Villa Park, Ill. 60101), and Moses Judah Folkman,

Boston, Mass. (24 St. Marys St., Newton Lower Falls,

Mass. 02162) Filed Aug. 28, 1962, Ser. No. 220,105 16 Claims. (Cl. 167-82) The invention described herein may be manufactured and used by or for the Government of the United States of America for governmental purposes without the payment of any royalties thereon or therefor.

Our invention relates generally to a method and means for introducing a therapeutic agent into a living organism and more particularly, it relates to a polysiloxane carrier that allows for controlled release of drugs and other agents within a specified region or organ of the body.

In the past, drugs or pharmaceutical preparations have been mixed with carrier agents, such as beeswax, peanut oil, stearates, etc., and injected intra-muscularly into the body. The carrier is then slowly broken down within the body allowing a slow release of the drug. Such carriers do not give satisfactory results because they often produce undesirable effects, such as foreign body reaction and scar formation; in addition, granulomas (benign fibrous tumors) and sterile abscesses are formed at the site of the injection. In most cases the rate of release of the therapeutic agent is so rapid that frequent injections become necessary with only small amounts of active agent in each injection. Furthermore, the bulk of the carrier substance limits the amount of active agent that may be used in each injection. A further practical drawback to this form of introducing medication follows from the fact that injections are active for only a few days or a week.

Heretofore, containers of many types have been designed for use within the body cavities whereby medical preparations are allowed to escape from the containers through tiny openings or perforations. Experience has proven that the tiny openings and perforations are rapidly plugged with body tissues, and the dispensing action ceases in a matter of hours or a few days. More elaborate arrangements for depositing medication within the body, involved the use of a dense tablet form which is formed with a smooth, compact surface, a portion of said surface is covered with a protective, undissolvable coating, while the remaining surface of tablet is exposed to the action of the body fluids. Obviously, resorption of medication from an exposed surface in which the medicinal substance is accessible to fluids cannot be definitely controlled or predicted during dissolution of the entire tablet.

We have now discovered a method for introducing therapeutic agents into the body by means of a novel implantate that is capable of providing a uniform release of powerful drugs for long periods, as much as several years. The novel implantate can release the desired amount of active agent directly into a malfunctioning organ for immediate use and at a constant dosage rate, without interruptions or variations in the supply as is generally the case with all of the previous methods noted above. Unlike the common practices of administering medication, orally or by injections, we now provide a method in which the :active agent does not encounter an uncertain course through the fluid streams in order for it to reach the area of its utility. Instead, the desired medication is made readily available in situ from an implanted carrier which releases the active agent in relatively minute amounts yet cumulatively the agent released in a sustained time interval may reach any effective dosage level. The novel carrier of our invention can also be maintained within the body as an active dispenser of medication throughout the body system and to function effectively for prolonged periods without ill effects, whereby the implanted carrier becomes virtually an artificial gland.

It is an object of the present invention to provide a method and means for implanting a drug or other agent within an organ or region of the body for relatively slow, prolonged release thereof at a constant rate.

Another object of the present invention is to provide a novel drug carrier which can be implanted into the body for long term, direct application of a drug without the disadvantages of frequent injections or by way of digestion and absorption.

Another object of the invention is to provide a chemical pacemaker for regulating the functions of the heart by means of a slow, prolonged release of a powerful drug.

A further object of the invention is to provide an implantate within the body that releases a drug at a predetermined rate based upon pharmaceutical requirements.

A still further object of the invention resides in the use of a carrier within the body for slow prolonged release of a dry, powdered drug in situ thereby preserving the drug in its more stable form until it is made available to the body.

And yet a further object of the invention is to provide a substantial increase in efficiency in the use of drugs and other agents which have a beneficial effect for a certain organ or region of the animal organism, by encapsulating said drugs to dispense them directly in the designated organ or body region at a therapeutic nate.

Still further objects and advantages of the present invention will appear from the following detailed description taken in connection with the accompanying drawings, in which:

FIG. 1 is a perspective view, partly in section, of a preferred embodiment of the present invention;

FIG. 2 is a perspective view illustrating a modification of the drug carrier shown in FIG. 1;

FIG. 3 shows a further modification of the invention in which the implantate is in the form of an artificial aortic valve;

FIG. 4 shows a oardiograph of a heart beat indicating restored heart function as a result of an implanted drug carrier; and

FIG. 5 shows a drug carrier in accordance with the invention implanted in the muscle of the heart.

We have discovered in accordance with the present invention that a drug carrier may be formed in the shape of a container, capsule, or medicated solid which contains within an enclosed space or structure thereof a suitable drug for the purpose of implanting said carrier and drug within a living organism. Specifically, the capsule or other carrier is implanted within the tissues of an organ or in a particular region of the body for controlled release of the drug at a substantially constant level of dosage and for a long duration. The term drug is used in the specification and claims hereof in its broad sense as synonymous to therapeutic agent, medicament and the like, and it is to be understood that all of such terms are intended to be inclusive of hormones, vitamins, antibiotics, anticoagulants, cancericidal agents, spermicidal agents, vasoactive agents and other medicinals and medications effective to treat undesirable conditions existing in or on an animal body or in the body fluids.

A preferred form of our invention comprises a drug carrier formed of an organopolysiloxane rubber composition (more generically known as a silicone rubber), which is non-reactive toward the drug, non-toxic to the body, and known to be compatible with living tissue even after prolonged implantation in the living organism. The silicone can be either a conventional silicone rubber, or a composition chaarcterized by room temperature vulcanizing, i.e., RTV silicone rubber. Either form of silicone rubber can be fabricated into a suitable container, such as hollow tubing, capsule, pellet and the like, or alternately, the silicone rubber may be formed into a prosthetic device capable of retaining within its polymer structure a suitable medication. Another embodiment of our invention is the direct injection of an RTV silicone rubber-drug fluid mixture into a body tissue, as explained in greater detail further on in the specification.

The silicone rubber carrier in accordance with the present invention permits slow passage or diffusion of the drug contained therein to the outer surface of the polymer wall where it is absorbed by the body fluids. The drug is preferably used in the dry, powdered form, since the solid form as a rule is found to be more stable, and the drug composition is thus advantageously stored within the body until it is released from the polymer carrier.

The invention in its broadest aspect is directed to the phenomenon of diffusion in which a powder, semi-solid or liquid migrates through a polymer wall at a relatively low rate. The mechanism by which diffusion or migrating action is achieved, may be explained on the basis of a gradient effect in which the enclosed substance relieves its internal concentration by spreading out into the adjacent medium. This action ordinarily would cease when suflicient substance has reached the outer surface or boundary of the adjacent medium. In the present case, however, the migrant molecules are advantageously being removed from the outer surface of the polymer wall by body fluids and by tissue absorption, and the migrating action continues indefinitely, or until the migrant medicinal substance has been completely consumed.

The powders, semi-solids, etc. which are capable of penetrating the polymer wall are generally those that show appreciable solubility in the polymer composition. More-over, the ease with which these substances pass interstitially between elastomer molecules will depend to a great extent on the silicone rubber composition which is utilized in the drug carrier.

As noted above, the silicone rubber employed in this invention can be either a conventional one or an RTV type. These rubbery products are now well known in the art.

By conventional silicone rubber we refer to those sytsems which are converted to the rubbery state (i.e., they are cured or vulcanized) by the action of heat. The silicone polymers in such systems are predominantly linear organopolysiloxanes, having a preferred average degree of substitution of from about 1.98 to 2.02 organic groups attached directly to silicon (by carbon-silicon linkage) per silicon atom. The organic groups attached to silicon are preferably monovalent hydrocarbon radicals such as alkyl, aryl, alkenyl, alkaryl and aralkyl, and of these the methyl, phenyl, and vinyl radicals are most preferred. Halogenated monovalent hydrocarbon radicals may also be present as the organic groups in the silicone polymer, typical examples being chl-orophenyl and 1,1,1-trifluoropropy1 radicals.

Variation of the organic groups in the silicone polymer can be used to vary the solubility of the drug in the polymer, and hence can to some extent control the speed of migration of the drug through the polymer. Also, drugs which are insoluble in one type of polymer may be soluble in a different type of polymer. It is obvious that the choice of organic substitution in the polymer should take into consideration any slightly toxic or foreign body reactions brought about by the presence of that polymer in the body. Pure dimethylpolysiloxanes and dimethyl-polysiloxanes which have a minor amount (for example, up to about 0.5 molar percent) of methylvinylsiloxane units present have been studied more extensively from the toxicological standpoint than any others and have been. found to be completely inert in the body, ence these are the most preferred polymers for use in our invention. There are some uses of our invention which are outside of the body, however, and in such cases any foreign body reaction which might be characteristic of a particular polymer would be of little or no concern.

The conventional silicone rubber formulation usually contains a filler to enhance the tensile strength and other physical properties of the cured rubber. Many types of such fillers are Well known in the art. The socalled reinforcing silica fillers develop the best propertics, however, and silicone rubber containing them has been found to be inert in extensive studies involving implanting the rubber in many different body tissues. For these reasons, the silica fillers are preferred. Examples of reinforcing silica fillers include silica aerogel, fume silica, and other forms of silica having a relatively high pore volume and surface area. If desired, the silica fillers can have organosiloxy groups attached to the surface thereof through siloxane bonding to improve the handling properties of the uncured silicone rubber formulation.

It is typical of the conventional silicone nubber formulations that they contain a peroxy vulcanizing agent. Again a host of suitable agents is known to the art, but when our invention is to be used by implanting the silicone rubber within the body, we prefer the use of benzoyl peroxide or dichlorobenzoyl peroxide. These agents decompose during the vulcanization and are not present in the finished rubber.

The patent literature showing the preparation of the above discussed silicone rubber is extensive. Illustrative US. patents include Warrick No. 2,541,137, K-onkle et al. No. 2,890,188, Youngs No. 2,723,966, Tyler No. 2,863,846, and Johannson No. 3,002,951.

The RTV silicone rubbers are also commercially available materials and are known to the art. In general they employ the same silicone polymers as discussed above (although the polymers often contain a greater amount of silicon-bonded hydroxy groups by being deliberately endblocked with such groups). The fillers discussed above can also be used if fillers are desired, and the cross-linking is achieved by introducing components such as the orthosilicates, polysilicates, and siloxanes containing silicon-bonded hydrogen atoms. This type of silicone rubber formulation will cure at room temperature when an appropriate catalyst is added, thus it is at least a two component system in which the catalyst is added just prior to use of the product. Typically the catalysts are metal salts of canboxylic acids, and when the invention is to be used by implanting the silicone rubber within the body, stannous 2-ethylhexoate is the preferred specie of catalyst.

It is sometimes desirable to inoonponate or attach a silicone rubber sponge composition in the silicone rubber drug-carrier to be used as an anchoring means for the implanted unit, as described in greater detail below. The sponged or foamed type of silicone rubber is also a commercially available product, and can be obtained in an RTV form. Such systems generally employ an organosiloxane polymer containing a relatively great amount of siliconabonded hydroxy groups, another organopolysiloxane polymer containing silicon-bonded hydrogen atoms, and fillers and metal salt catalysts as in the previously discussed RTV systems. In this case, the catalyst not only brings about a conversion to the rubbery state, but also releases hydrogen gas from the hydrogen substituted polymer, this gas being the sponging or foaming agent for the system.

Another commercially available RTV silicone rubber which can be used in this invention to form a solid (i.e., non-sponged) rubber product is a one component system in the sense that no catalyst need be added. In this system, the silicone polymer employed is one which contains two acyloxy group's (preferably acetoxy groups) attached to terminal silicon atoms. The usual fillers can be present in this type of product. When exposed to atmospheric moisture, the acyloxy groups hydrolyze to form new trifunctional siloxane units within the polymer which act as the cross-linking bridges necessary to produce the final rubbery product.

The vanious RTV silicone rubber products discussed above can be prepared as described in detail in, for ex ample, US. Patents No. 2,927,907 (Polmanteer) and No. 3,035,016 (Bruner), and in British Patents No!. 798,669 and No. 804,199.

The silicone rubber may bemolded into a capsule or pellet having any convenient wall thickness and containing therein a drug or active agent-one which has bee found to be capable of diifusing into and permeating the silicone rubber wall--the capsule or pellet having a surface substantially free of pores, perforations or semipermeable surface areas. The drug molecules included therein will have a definite or characteristic rate of diffusion through the container wall, which will in effect establish the dosage rate and the amount of drug which is released from a coherent surface in a given time interval. Thus, the amount of drug which is released over an extended period is based on the rate at which the drug diffuses through the silicone rubber and also on the ability of the living tissues in the body to absorb the drug from the surface of the container. By limiting the transference surface of the container, as will be explained presently in greater detail, the amount of drug that reaches the surface may be eifectively controlled.

The novel implantate may be varied in many ways, but it is most desirable to shape the dispensing drug carriers into tubular form of given lengths and volume capacity and having a calibrated rate of release for specified drug compositions. Hollow, tubular cartridges or capsules molded into a continuous, uniform dispensing surface and incorporating therein a preferred quantity of active agent may be made available to the medical and surgical profession as standard dispensing units. If it is desired to decrease the amount of drug which is to be released in a given period, a portion of the dispensing silicone rubber surface may be coated with a more impervious plastic substance to limit the effective transference area from which drug diffusion and absorption can occur. Alternately, a tubular container may be provided with an inner metallic or plastic casing having a number of port holes of a given dimension through which diffusion and transference action of the contained drug may be substantially regulated. Standard implantates of a specified length will provide a prescribed dosage of drug during a 24-hour interval. The implantates may also be designated in terms of desired physiological effects which they are capable of producing: A heart drug in a given tubular length may be prescribed as capable of generating on the average a given number of heart beats, for example, 70, 80, or 90 heart beats per minute.

Desirably, in carrying out the present invention, hollow, tubular containers are formed of silicone rubber having a wall thickness sufficient to provide a resilient tubular structure that is self-supporting and that does not collapse or bend while implanted Within the tissues of the body. While the thickness of the container determines initially the time interval which is required for the drug molecules to penetrate the polymer wall, the thickness of the silicone rubber does not affect the dispensing rate of the present carrier. After the drug has penetrated the 6 wall, the migration of drug molecules is primarily a function of the solubility of the drug in the silicone rubber composition, and they will in effect penetrate a thin or thick wall at substantially equal rates.

It is also advantageous to provide polysiloxane carriers in the form of prosthetic devices for the body into which medication is incorporated by any suitable means. For example, anti-coagulants, such as heparin or Versene (ethylenediaminetetraacetic acid) may be impregnated into vascular or intravascular prostheses in order that their relatively slow rate of release from the carrier will provide sufficient protection against thrombosis. The medication may be introduced into the polysiloxane composition during the forming process of the device, or it may be diifused into the finished product. For example, the drug carrier may be formed by immersing the prosthetic device into a saturated solution of herapin, Versene, or other drug in a suitable solvent, such as alcohol, acetone, xylene or water.

Further modifications in the formation of drug carriers involves the use of relatively fluid polysiloxane of the RTV type and a medication dissolved therein. The fluid mixture is injected into the tissues along With a catalyst to cause the fluid polysiloxane to polymerize in situ and form a solid implant capable of providing a relatively slow release of medication. A mixture of parts by weight of a fluid hydroxy end-blocked dimethylpolysiloxane (having a viscosity of about 10,000 centistrokes 25 C.) and 3 parts of ethylpolysilicate may be combined with 250 grams of penicillin and a suitable catalyst, for example, sta-nnous Z-ethylhexoate in an amount of about 0.5 percent based on the weight of the fluid polysiloxane. After the injected mixture has polymerized to a solid state, the penicillin is released slowly within the tissues. Fillers can be omitted from the injectable RTV material because strength of the rubber is not important. The presence of fillers, however, is not objectionable as long as an injectable consistency remains in the fluid.

In connection with the embodiments of the invention illustrated in the drawing, the drug carrier of FIG. 1 is a length of silicone rubbing tubing 1, shown in cross-section as comprising a wall 2 and a confined space 3 containing therein an active agent 4, for example, dry vitamin B powder. The ends of the tubing are sealed with an RTV silicone rubber 5. The latter consists of methyldiacetoxysilyl end-blocked dimethylpolysiloxane fluid, and a fume silica filler. A period of about 24 hours is necessary for the seals to cure. A specific example of a carrier formed in this manner comprises about 1 cm. length of silicone rubber tubing having an inside diameter of 0.140

inch and a wall thickness of 0.030 inch. This rubber was prepared by extruding a mixture of about 75 parts polymer, 24 parts fume silica and 1 part 2,4-dichlorobenzoyl peroxide. The mixture was cured 30 seconds at 730 F. and vulcanized by heating for 2 hours at 400 F. The polymer was a dimethylpolysiloxane containing about 0.14 mole percent methylvinylsiloxane units copolymerized therewith. The tubing is filled with about 20,000 micrograms of tri-iodothyronine.'

By utilizing the means set forth above, implantates have been employed in the body and the desired effects produced have been quantitatively correlated. A drug carrier produced in the manner described and containing 10,000 micrograms of a triiodothyronine in a silicone rubber tube having a length of 14 mm. will release approximately 10 micrograms of the drug in a 24-hour period and generally provide a heart rate in a dog of about beats per minute. When a drug carrier 24 mm. long is used in the same manner and containing the same drug, it will release approximately 30 micrograms in a 24-hour period, and the heart beat is stepped up to about 200 beats per minute.

An implantation involving the use of a heart drug is performed by surgery and involves the insertion of a polysiloxane capsule containing a relatively large amount of dry powder. A capsule containing 30,000 micrograms of digitoxin may be safely utilized within the body without any undue or irregular release of drug. The capsule containing the drug is initially sterilized and all surface digitoxin that may have been released to the surface is carefully removed. The capsule is then implanted by surgery in the myocardium of the heart. The digitoxin is released at a rate of about micrograms per day producing an excitable focus on the heart. This focus then drives the heart at nearly physiologic rates. There is no systemic effect from the use of the drug since it is released in very low concentrations. It is axiomatic that the drug is dispensed in such low concentrations yet has been found to be effective because the entire drug released in this manner is utilized directly within the heart area. Moreover, the drug need not be sterilized, since migration through the polymer Wall involves molecular size whereas bacteria are many order of magnitude larger and are effectively screened out.

The embodiment of FIG. 2 illustrates the use of an open cell silicone rubber sponge layer 6 attached to the capsule surface 1 by any suitable means, as for example, by slipping a sponge sleeve 6 over the capsule surface. The sponge layer has been found to serve as an anchoring means for the capsule within a cavity created in the tissue to receive the capsule; the sponge expands in the cavity and prevents movement of the capsule. Moreover, it serves as a matrix for the absorption of fluid, fibrin or connective tissue in the surrounding areas after implantation. Finally, the sponge layer also acts as a wick for the transport of drug from the capsule surface to the muscle site.

As pointed out above, it is possible according to the invention to fabricate a silicone rubber prosthesis, as the aortic valve, shown in FIG. 3 in which an anti-coagulant may be impregnated into the prothesis material to protect the valve from thrombi formation.

By utlizing a silicone rubber carrier within the myocardium of the heart, an excitable focus is produced, as shown in the cardiograph record of FIG. 4. Prior to an implant surgery on a dog with complete heart block, a fixed heart rate of approximately 55 beats per minute is indicated at A. After a sealed silicone rubber tubing (as above described and being approximately 17 mm. long) containing 20,000 micrograms of tri-iodothyronine powder was implanted through an incision 7 in the left ventricle of the heat, as shown in FIG. 5, a heart rate of 150 beats per minute was generated. The electrocardiograph indicates at B the impulses arising from the site of the implant, about 8 hours following the implantation.

The implantate may in some cases provide a basal level of drug, while additional dosages may be supplemented by oral medication or by injection. Thus the drug requirements of a patient may be more effectively controlled by providing some of the drug requirement from the implantate, while the practitioner can increase or vary the 1nedication by means of supplemental doses.

Heating increases the diffusion rate so that a capsule which has been heated will start diffusion of medication more rapidly. The capsule may also include more than one drug, one drug which diffuses rapidly becomes quickly available to the body, while a less diffusable drug becomes available at a later time, after the first drug has served its purpose.

Whereas the novel implantate has been described above with reference to its use in dispensing drugs in the living tissues of animals, such as dogs, evidence developed in our work indicates an equally effective use of the implantate in the human body.

Our method of introducing drugs into the living organism provides a drug carrier which is readily tolerated in living tissues and which does not deteriorate by implantation in the living body. Therefore, the drug carrier may be implanted within the organ or body region to be treated to provide constant release of the drug directly within the region in which it will produce the desired beneficial effect. For example, a capsule containing dry nitrogen mustard may be implanted in (or adjacent to) a cancerous mass.

It is now feasible to utilize drugs of more suitable compositions that are more effective within a specified body region and that eliminate extraneous injection media and oral preparations that masked or merely accommodated the active therapeutic agent in its course through the body. More effective therapeutic agents 'with greater physiological activity are now contemplated as a result of this invention, whereas the previous methods of administration were not able to utilize them in their active form. For superior results can be achieve-d by our method since the active drug composition is not mixed with a carrier agent thus avoiding any interaction between the active drug and the carrier. In prior art methods the active agent was often combined chemically with an inactive carrier molecule which had to become separated in vivo before the active agent could be used in therapy. In accordance with the present invention, however, it is possible to utilize the most powerful drug in direct application in any desired concentration for immediate results without the precarious course of the previous carriers.

Another important advantage of the present invention is that the silicone rubber implantate is not dependent upon the gradual decomposition or removal of the carrier. The container or capsule remains intact and unchanged. In the previous methods, the active molecule mus-t initially be detached and freed from the carrier as is the case with the use of beeswax or peanut oil, in order for the drug agent to regain its therapeutic effect.

The drug employed in the present silicone rubber carrier remains dry even with implantates that have been in use in the body for many months. Thus it can be readily appreciated that this method is specifically important for compounds that are highly unstable in the wet form and which could not be utilized effectively by previous means of implantation or injection.

It is also within the purview of the present invention to employ a container made of silicone rubber composition, as described'herein, which incorporates within the composition a suitable anti-coagulant, such as heparin or Versene. As is now apparent from the previous discussion, desirable and beneficial results can be attained by means of the novel container in storing and preserving whole blood. The undesirable effect of coagulation, which occurs when the blood is removed from its normal environment in the living organism, is effectively suppressed by placing the blood in a silicone rubber container that has been impregnated with an anti-coagulant. The minimal daily release of anti-coagulant from the container composition will prevent coagulation and thus preserve Whole blood in its normal state without the usual practice of preserving the blood in ACD solution or by excessive use of anti-coagulants.

The silicone rubber container of the present invention is use-d to dispense minimum daily amounts of anti-coagulant to the blood thereby obviating the need for large amounts of preservatives. The blood may now be stored for periods of up to 21 days in its normal state, and preferably in accordance with the preferred practice at a temperature of about 4 C., and utilized directly in blood transfusions and for other purposes which require normal, whole blood, relatively free of foreign substances.

The invention may be utilized in connection with drug carriers containing any desired medical or pharmaceutical type illustrated for example by any of the anti-infectives. Such preparation include antibacterial-s, i.e., sulfathiozole; antibiotics, i.e., penicillin; antifungal agents; i.e., Nystatin; antimalarials, i.e., atabrine and the antiprotozoans, i.e., hydroxystilbamide isothionate. Antineoplastic agents, which include, for example, nitrogen mustard, previously mentioned in the specification; cardiovascular agents, which include digitalis, quinidine and nitroglycerine; con- 9 traceptives, for instance spermicidal agents such as hexylresorcinol, may also be utilized in accordance with the present invention. Hormones and the synthetic substitutes and antagonists as represented by the thyroid hormones and by insulin may be used with beneficial results. Immunological agents including for example, tetanus toxoid, renal acting agents, for example, acetozolomide, skeletal muscle relaxants and their antagonists, for example, Mephenesin, central nervous system stimulants, for example, ephedrine; and central nervous system depressants, which include the barbiturates in all their various chemical modifications are also included in the invention. Anesthetics which may be used in the novel drug carrier, include procaine, an antihistamine, i.e., benadryl; a detoxicant, dimercaprol; an enzyme, i.e., hyaluronidase and an agent affecting blood formation, i.e., liver extract. A radioactive isotope which may be included in the novel carrier is iodine 131-tagged albumen. Specific proteins find utility in accordance with the invention, as represented by gamma globulin.

Examples of additional drugs which may be included in the present drug carriers with beneficial results in accordance with this invention include adrenal corticotrophic hormone; adrenal cortical hormones, such as aldosterone, desoxy corticosterone, hydrocortisone and cortisone; parathromone, pituitrin, testosterone.

While we have described our invention in conjunction with certain drugs and specific implantate structures, it will be realized that these materials and structures may be varied without departing from the spirit and scope of the invention, which is the method and means of introducing drugs into the body from a dense-surface, plastic implantate over a prolonged period. The drugs and silicone rubber carrier can be varied to provide various dosage rates of selected drugs that provide a large number of physiological and therapeutic requirements. Other variations which do not depart from the spirit of the invention will occur to those skilled in the art.

What is claimed is:

1. An implantate for releasing a drug in the tissues of a living organism comprising a drug enclosed in a capsule formed of silicone rubber, said silicone rubber making limited area contact with said drug, said drug being soluble in and capable of diffusing through said silicone rubber to the outer surface of said capsule at a constant rate.

2. A drug carrier capable of releasing a drug at a constant rate when implanted in a living organism comprising a drug enclosed in a sealed container formed of silicone rubber, said drug being soluble in and capable of diffusing through the silicone rubber to the outer surface of said container at a constant rate.

3. A drug carrier capable of releasing a drug at a constant rate when implanted in a living organism comprising a prosthesis formed of silicone rubber, said prosthesis containing therein a drug which is soluble in and capable of diffusing through said silicone rubber to the outer surface of said prosthesis at a constant rate.

4. An implantate for releasing a drug in the tissues of a living organism comprising a drug dispersed in a silicone rubber which has been vulcanized in situ in said tissues, said drug being soluble in and capable of diffusing through said silicone rubber to the outer surface thereof at a constant rate.

5. An implantate for releasing a drug in the tissues of a living organism comprising a capsule formed of silicone rubber, said silicone rubber consisting essentially of dimethylpolysiloxane, and a drug enclosed in said capsule which is soluble in and capable of diffusing through said silicone rubber to the outer surface of said capsule ata constant rate to the outer surface of said capsule at a constant rate.

6. An implantate for releasing a drug in the tissues of a living organism comprising a capsule formed of estrodiol, progesterone and silicone rubber, said silicone rubber consisting essentially of an organopolysiloxane which contains on the average from about 1.98 to about 2.02 organic groups per silicon atom, said group being selected from the radicals consisting of monovalent hydrocarbon radicals and halogenated hydrocarbon radicals, and a drug enclosed in said capsule which is soluble in and capable of diffusing through said silicone rubber to the outer surface of said capsule at a constant rate. 0

7. An implantate for releasing a drug in the tissues of a living organism comprising a capsule formed of silicone rubber, said silicone rubber consisting essentially of dimethylpolysiloxane, which contains on the average from about 1.98 to about 2.02 organic groups per silicon atom, and up to 0.5 mol percent of methylvinylpolysiloxane, and a drug enclosed in said capsule which is soluble in and capable of diffusing through said silicone rubber to the outer surface of said capsule at a constant rate.

8. A drug carrier capable of releasing a drug at a constant rate when implanted in a living organism comprising a sealed, tubular container and a drug enclosed in said container, said container being formed of a section of silicone rubber tubing and the ends of said tubing being sealed with a layer of silicone rubber, said drug being soluble in and capable of diffusing through said silicone rubber tubing to the outer surface thereof at a constant rate.

9. The method of introducing a drug into an animal body which comprises injecting within a region of said body a mixture of a drug with an organopolysiloxane fluid which undergoes vulcanization at room temperature to silicone rubber, said drug being soluble in and .capable of diffusing through the silicone rubber to the outer surface thereof at a constant rate.

10. A drug carrier in accordance with claim 8 in which the silicone rubber of said end-sealing layers is formed of cured methyldiacetoxysilyl end-blocked dimethylpolysiloxane and contains a fume silica filler.

11. An implantate in accordance with claim 5 in which the silicone rubber contains a reinforcing silica filler.

12. A drug carrier which is capable of releasing a drug at a constant rate comprising a sealed, tubular container and a drug within said container, said container being formed of a silicone rubber tubing having an inside diameter of about 0.140 inch and a wall thickness of about 0.030 inch, the ends of said tubing being sealed with a silicone rubber composition, said drug being soluble in and capable of diffusing through said silicone rubber tubing to the outer surface thereof at a constant rate.

13. A drug carrier in accordance with claim 2 including a layer of silicone rubber sponge on the outer surface of said container, said sponge having an open cell structure to provide fluid access to said surface.

14. A method of introducing a drug into an animal body which comprises implanting within the living tissues of said body a capsule formed of silicone rubber and containing a drug which is soluble in and capable of diffusing through said silicone rubber to the outer surface thereof at a constant rate, and allowing said capsule to remain therein for a desired time interval to provide a controlled release of said drug through said silicone rubber.

15. A method of preserving Whole blood with a minimum amount of anti-coagulant which comprises placing said blood in a container formed of silicone rubber, which is impregnated with a solid anti-coagulant composition soluble in and capable of diffusing through said siilcone rubber to the outer surface thereof at a constant rate and storing said blood in said container, said silicone rubber providing a relatively low rate of release of said composition sufiicient to prevent coagulation during storage.

16. A container for storing whole blood comprising a silicone rubber vessel in which the silicone rubber is impregnated with a solid anti-coagulant composition soluble in and capable of diffusing through said silicone rubber to the outer surface thereof at a constant rate to provide a relatively low rate of release of said composition sufficient to prevent coagulation of said blood during storage.

References Cited by the Examiner UNITED STATES PATENTS Goldman 128-272 Yen et al. 167-82 Polin 206-5 Erikson 206-5 Cole 206-5 Feinstone 167-82 Levesque 167-82 Barton et a1. 128-272 12 OTHER REFERENCES J.A.P.A., vol. 46, No. 12, December 1957, pp. 705720.

M-cGregor: Silicones in Medicine and Surgery, DOW Corning Corp., Midland, Michigan, 1957 (44-page booklet) pp. 21, 23, 24, 28, 34, 35, 41, and 43 relied on.

The Bulletin, vol. 3, No. 1, Dow Corning Corp., Midland, Michigan, January 1961.

The Bulletin, vol. 4, No. 3, Dow Corning Corp., Midland, Michigan, July 1962.

JULIAN S. LEVITT, Primary Examiner.

FRANK CACCIAPAGLIA, Examiner.

G. A. MENTIS, Assistant Examiner.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US2504482 *Jun 17, 1949Apr 18, 1950Premo Pharmaceutical Lab IncDrain-clear container for aqueous-vehicle liquid pharmaceutical preparations
US2512192 *May 26, 1948Jun 20, 1950American Cyanamid CoSilicone resin medicament coating
US2846057 *Feb 9, 1954Aug 5, 1958Polin Herbert SpencerDevices for dosage control
US2855933 *Apr 4, 1952Oct 14, 1958American Hospital Supply CorpFluid receptacle
US2895475 *Dec 3, 1956Jul 21, 1959Everett L ColeContainer for collecting, storing and dispensing biological fluids
US2951011 *Dec 17, 1956Aug 30, 1960Feinstone Wolffe HarrySilicone composition for the relief of gastro-intestinal distress and method of using same
US2987445 *Oct 10, 1958Jun 6, 1961Rohm & HaasDrug composition
US3105613 *May 9, 1960Oct 1, 1963Baxter Don IncBlood container
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3365728 *Dec 18, 1964Jan 30, 1968Edwards Lab IncUpholstered heart valve having a sealing ring adapted for dispensing medicaments
US3371352 *Jan 19, 1965Mar 5, 1968Edwards Lab IncHeart valve for quick implantation having provision for ingrowth of tissue
US3499445 *Aug 16, 1966Mar 10, 1970Phytogen Prod IncAnimal husbandry
US3511684 *May 17, 1967May 12, 1970Abbott LabMethod of treating polymeric resin to display nonthrombogenicity
US3548417 *Sep 5, 1967Dec 22, 1970Kischer Jane NHeart valve having a flexible wall which rotates between open and closed positions
US3576176 *Sep 23, 1969Apr 27, 1971Pickett John E PCooperative histologic tissue capsule and capsule rack
US3596292 *Feb 20, 1969Aug 3, 1971Franklin InstituteHair implant structure
US3598127 *Jun 6, 1968Aug 10, 1971Wepsic James GCatheter having antibacterial substance therein provided with means permitting slow release of said substance
US3640269 *Oct 24, 1969Feb 8, 1972Delgado Jose M RFluid-conducting instrument insertable in living organisms
US3640741 *Feb 24, 1970Feb 8, 1972Hollister IncComposition containing gel
US3659600 *Feb 24, 1970May 2, 1972Charles River Foundation TheMagnetically operated capsule for administering drugs
US3678756 *Sep 23, 1969Jul 25, 1972Hans W EstinCapsules and method for testing capsules for wall integrity
US3726972 *Oct 27, 1970Apr 10, 1973Monsanto CoHalosilane-protein crosslink as ruminant feed material
US3797485 *Mar 26, 1971Mar 19, 1974Alza CorpNovel drug delivery device for administering drug into blood circulation in blood vessel
US3804088 *Jul 31, 1972Apr 16, 1974Lilly Co EliRemovable implantate for administering physiological active agents to animals
US3811444 *Dec 27, 1972May 21, 1974Alza CorpBioerodible ocular device
US3832458 *Dec 6, 1971Aug 27, 1974River C FoundationHydrophilic silicone composition and method
US3873713 *Jul 2, 1973Mar 25, 1975Hoffmann La RocheStabilized particulate vitamin c composition
US3898701 *Jan 17, 1974Aug 12, 1975Russa JosephImplantable heart valve
US3905360 *Jul 23, 1973Sep 16, 1975Alza CorpIntrauterine device for governing the reproductive process
US3911911 *Mar 27, 1974Oct 14, 1975Reese Hospital MichaelAnti-fertility device
US3916898 *Jul 10, 1970Nov 4, 1975Searle & CoAdministration of medicaments and the like
US3921636 *Apr 22, 1974Nov 25, 1975Alza CorpNovel drug delivery device
US3934274 *Oct 29, 1974Jan 27, 1976Hartley Jr John HDeflatable mammary augmentation prosthesis
US3944064 *Oct 26, 1973Mar 16, 1976Alza CorporationSelf-monitored device for releasing agent at functional rate
US3946106 *Oct 24, 1974Mar 23, 1976G. D. Searle & Co.Polysiloxanes
US3948262 *Mar 10, 1975Apr 6, 1976Alza CorporationNovel drug delivery device
US3967618 *Mar 6, 1975Jul 6, 1976Alza CorporationDrug delivery device
US3971376 *Oct 2, 1974Jul 27, 1976Ceskoslovenska Akademie VedMethod and apparatus for introducing fluids into the body
US3987797 *Dec 11, 1974Oct 26, 1976Ethicon, Inc.Antimicrobial sutures
US3992518 *Sep 29, 1975Nov 16, 1976G. D. Searle & Co.Crosslinking silicone polymers
US4012497 *Sep 23, 1975Mar 15, 1977Schering AktiengesellschaftVaginal rings
US4053580 *Sep 20, 1976Oct 11, 1977G. D. Searle & Co.Microsealed pharmaceutical delivery device
US4162676 *Aug 4, 1977Jul 31, 1979Dow Corning CorporationCured silicone rubber and calcium hydroxide
US4191741 *Sep 22, 1978Mar 4, 1980Eli Lilly And CompanyRemovable drug implant
US4198976 *Oct 11, 1977Apr 22, 1980The Procter & Gamble CompanyVaginal contraceptive
US4200090 *Jan 15, 1979Apr 29, 1980The Procter & Gamble CompanyVaginal contraceptive and method of using
US4210644 *Feb 23, 1978Jul 1, 1980The Johns Hopkins UniversityMale contraception
US4219016 *Dec 7, 1978Aug 26, 1980The Procter & Gamble CompanyVaginal contraceptive
US4228032 *Nov 6, 1978Oct 14, 1980Dow Corning CorporationSilicone rubber compounded with calcium hydroxide
US4230686 *Dec 23, 1976Oct 28, 1980Schering AktiengesellschaftSustained release
US4264575 *Apr 8, 1980Apr 28, 1981Eli Lilly And CompanyContraceptive methods and compositions
US4264576 *Apr 8, 1980Apr 28, 1981Eli Lilly And CompanyContraceptive methods and compositions
US4264577 *Apr 8, 1980Apr 28, 1981Eli Lilly And CompanyContraceptive methods and compositions
US4264578 *Apr 8, 1980Apr 28, 1981Eli Lilly And CompanyContraceptive methods and compositions
US4298002 *Sep 10, 1979Nov 3, 1981National Patent Development CorporationHydrogel of acrylic polymer allowing flow of steroids; grafting; glandular disorders; antibody inhibitors
US4301800 *May 19, 1980Nov 24, 1981Baxter Travenol Laboratories, Inc.Blood bags having an insert member
US4304010 *Oct 12, 1979Dec 8, 1981Sumitomo Electric Industries, Ltd.Tubular polytetrafluoroethylene prosthesis with porous elastomer coating
US4304226 *Mar 3, 1980Dec 8, 1981The Procter & Gamble CompanyVaginal contraceptive
US4309776 *May 13, 1980Jan 12, 1982Ramon BerguerIntravascular implantation device and method of using the same
US4321711 *Oct 12, 1979Mar 30, 1982Sumitomo Electric Industries, Ltd.Polytetrafluroethylene containing an anticoagulatn conded to an elastomer cointaining an coagulant
US4341728 *Dec 20, 1979Jul 27, 1982The Population Council, Inc.Method for making an IUD with shrinking of a medicated attachment onto a support
US4343788 *Jun 29, 1979Aug 10, 1982The Procter & Gamble CompanyAntimicrobial polymer compositions
US4344431 *Aug 4, 1980Aug 17, 1982University Of DelawarePolymeric article for dispensing drugs
US4384960 *Nov 13, 1979May 24, 1983Polley R DIodine dispenser and method of dispensing iodine
US4392848 *Jun 25, 1979Jul 12, 1983The Procter & Gamble CompanyCatheterization
US4479795 *Jul 27, 1982Oct 30, 1984The Procter & Gamble CompanyFor catheters
US4485814 *Sep 5, 1979Dec 4, 1984Yoon In BOne-piece compound elastic occluding member
US4555398 *Sep 22, 1983Nov 26, 1985Chisso CorporationThermosetting or thermoplastic resin mold
US4690683 *Jul 2, 1985Sep 1, 1987Rutgers, The State University Of New JerseyTransdermal varapamil delivery device
US4731080 *May 20, 1986Mar 15, 1988Galin Miles ACoated intraocular lens
US4803076 *Sep 4, 1986Feb 7, 1989Pfizer Inc.Controlled release device for an active substance
US4888009 *Oct 31, 1986Dec 19, 1989Abiomed, Inc.Prosthetic heart valve
US4888416 *Mar 30, 1987Dec 19, 1989International Minerals & Chemical Corp.Mixing with ionic detergent and drying
US4894231 *Jul 28, 1987Jan 16, 1990Biomeasure, Inc.Therapeutic agent delivery system
US4898733 *Nov 4, 1985Feb 6, 1990International Minerals & Chemical Corp.Layered, compression molded device for the sustained release of a beneficial agent
US4917685 *May 16, 1986Apr 17, 1990International Minerals & Chem. Corp.Porous membrane confining active materials and stabilizers
US4951657 *Apr 22, 1988Aug 28, 1990Dow Corning CorporationBlock copolymer of polyurethane and polysiloxane
US4955899 *May 26, 1989Sep 11, 1990Impra, Inc.Longitudinally compliant vascular graft
US4960415 *Nov 18, 1988Oct 2, 1990Merck Patent GmbhDevice for inserting in wounds and wound cavities
US4973320 *Aug 2, 1988Nov 27, 1990Firma Carl FreudenbergPolysiloxane-urethane copolymer
US4985253 *Feb 16, 1990Jan 15, 1991Sumitomo Pharmaceuticals Company, LimitedSustained release composition for pharmaceutical substances comprising a silicone elastomer carrier
US5008112 *Dec 16, 1985Apr 16, 1991International Minerals & Chem. CorporationDevice for the extended delivery of diffusible agents
US5100422 *May 26, 1989Mar 31, 1992Impra, Inc.Expanded polytetrafluoroethylene layer and nonporous elastomer coating for vascular patches
US5104400 *Aug 28, 1991Apr 14, 1992Impra, Inc.Coating outer wall of polytetrafluoroethylene tube with elastomer; drying; opening tube; cutting patch from flat sheet
US5141748 *Feb 17, 1989Aug 25, 1992Hoffmann-La Roche, Inc.Implant drug delivery device
US5152782 *May 26, 1989Oct 6, 1992Impra, Inc.Non-porous coated ptfe graft
US5182317 *Jun 17, 1991Jan 26, 1993Cardiopulmonics, Inc.Amine-Functional Siloxane, Polyoxyethylene Spacer, Bioactive Molecules
US5219580 *Jun 8, 1990Jun 15, 1993Rhone-Poulenc ChimieThermoplastic silicone shaped articles for controlled release of iodine values to domestic water supplies
US5262451 *Jul 5, 1988Nov 16, 1993Cardiopulmonics, Inc.Multifunctional thrombo-resistant coatings and methods of manufacture
US5340583 *May 6, 1993Aug 23, 1994Allergan, Inc.Case of polymeric material and antimicrobial compound, possibly covalently bonded; nonleachable
US5342693 *Mar 22, 1993Aug 30, 1994Cardiopulmonics, Inc.Bioactive molecules coavalently bonded to siloxane coating through polyether chains; membrane for blood gas exchange
US5422118 *Sep 21, 1992Jun 6, 1995Pure Pac, Inc.Transdermal administration of amines with minimal irritation and high transdermal flux rate
US5515117 *Apr 19, 1994May 7, 1996Allergan, Inc.Antimicrobial lenses and lens care systems
US5591445 *Oct 10, 1995Jan 7, 1997Regents Of The University Of MinnesotaFor stimulating peristaltic contractions of intestines, barium chloride or neurotransmitter dispersed in silicone matrix
US5810836 *Nov 7, 1996Sep 22, 1998Myocardial Stents, Inc.Device and method for trans myocardial revascularization (TMR)
US6168801Mar 19, 1999Jan 2, 2001Cardiac Pacemakers, Inc.Controlled release drug delivery
US6304786Mar 29, 1999Oct 16, 2001Cardiac Pacemakers, Inc.Implantable lead with dissolvable coating for improved fixation and extraction
US6476079 *Dec 23, 1999Nov 5, 2002Leiras OyDevices for the delivery of drugs having antiprogestinic properties
US6584363Jul 16, 2001Jun 24, 2003Cardiac Pacemakers, Inc.Implantable lead with dissolvable coating for improved fixation and extraction
US6645241Feb 6, 2001Nov 11, 2003Ernst Peter StreckerEndoprosthesis that can be percutaneously implanted in the patient's body
US6756048Sep 6, 1999Jun 29, 2004Sumitomo Pharmaceuticals Company, LimitedLong time drug-sustained release preparation
US7217286Aug 24, 2006May 15, 2007Cordis CorporationLocal delivery of rapamycin for treatment of proliferative sequelae associated with PTCA procedures, including delivery using a modified stent
US7218971Jun 24, 2003May 15, 2007Cardiac Pacemakers, Inc.Implantable lead with dissolvable coating for improved fixation and extraction
US7223286Sep 28, 2004May 29, 2007Cordis CorporationLocal delivery of rapamycin for treatment of proliferative sequelae associated with PTCA procedures, including delivery using a modified stent
US7229473Aug 24, 2006Jun 12, 2007Cordis CorporationLocal delivery of rapamycin for treatment of proliferative sequelae associated with PTCA procedures, including delivery using a modified stent
US7247312Oct 31, 2000Jul 24, 2007Dainippon Sumitomo Pharma Co., Ltd.Hydrophobic polymer carrier containing dispersed particles of an active ingredient that is slightly water soluble or insoluble (especially a vaccine), carbonate particles, and particles of a compound that reacts with the carbonate in an aqueous solution to generate CO2, which accelerates release rate
US7300662Apr 21, 2004Nov 27, 2007Cordis CorporationLocal delivery system is coated with rapamycin or other suitable drug, agent or compound and delivered intraluminally for the treatment and prevention of neointimal hyperplasia following percutaneous transluminal coronary angiography, lower systemic toxicity
US7601363Mar 19, 2007Oct 13, 2009Dainippon Sumitomo Pharma Co., Ltd.Water solubility; silicones; vaccines
US7625410Jan 23, 2006Dec 1, 2009Boston Scientific Scimed, Inc.Stent device and method
US7763077Dec 24, 2003Jul 27, 2010Biomerix CorporationRepair of spinal annular defects and annulo-nucleoplasty regeneration
US7803395May 17, 2004Sep 28, 2010Biomerix CorporationBiodurable, reticulated elastomeric matrices that are resiliently-compressible; crosslinked polycarbonate-urea-urethane, open-cell foam; tissue engineering; biodurable scaffolds; biocompatible; grafting; orthopedics; tissue repair and regeneration long-term
US8067022Jul 20, 2001Nov 29, 2011Boston Scientific Scimed, Inc.Therapeutic inhibitor of vascular smooth muscle cells
US8097642Feb 27, 2007Jan 17, 2012Boston Scientific Scimed, Inc.Therapeutic inhibitor of vascular smooth muscle cells
US8133501Feb 28, 2003Mar 13, 2012Boston Scientific Scimed, Inc.Implantable or insertable medical devices for controlled drug delivery
US8158670Jan 4, 2007Apr 17, 2012Boston Scientific Scimed, Inc.Therapeutic inhibitor of vascular smooth muscle cells
US8197839 *Jul 1, 2002Jun 12, 2012Virbac CorporationA miniature coated tablet or covered rod implant; smaller size and larger payloads than immediate release tablets; veterinary medicine
US8236048Apr 27, 2004Aug 7, 2012Cordis CorporationDrug/drug delivery systems for the prevention and treatment of vascular disease
US8303609Sep 28, 2001Nov 6, 2012Cordis CorporationCoated medical devices
US8419793 *Mar 12, 2010Apr 16, 2013Mentor Worldwide LlcCoating with antimicrobial agents
US8420153 *Sep 19, 2008Apr 16, 2013Mentor Worldwide LlcCoating with antimicrobial agents
US8685427Jul 31, 2002Apr 1, 2014Boston Scientific Scimed, Inc.Controlled drug delivery
US8691264Feb 24, 2012Apr 8, 2014Boston Scientific Scimed, Inc.Implantable or insertable medical devices for controlled drug delivery
US8750983Sep 20, 2004Jun 10, 2014P Tech, LlcTherapeutic system
USRE28536 *Mar 4, 1971Sep 2, 1975 Animal husbandry
DE2547378A1 *Oct 23, 1975Apr 29, 1976Searle & CoVorrichtung mit abgeschlossenen mikrokammern zur abgabe eines arzneimittels
DE2918522A1 *May 8, 1979Nov 15, 1979PfizerVerbessertes system bzw. verbesserte vorrichtung zur kontrollierten und kontinuierlichen abgabe von chemikalien waehrend einer laengeren zeitspanne
EP0013949A2 *Jan 18, 1980Aug 6, 1980Hoechst AktiengesellschaftDepot body on the basis of silicon rubber and method for its preparation
EP0050867A1 *Oct 24, 1981May 5, 1982Schering AktiengesellschaftVaginal ring
EP0056697A2 *Jan 11, 1982Jul 28, 1982Robert W. RandInjectable compositions suitable for use in inductively heating neoplasms
EP0219076A2 *Oct 10, 1986Apr 22, 1987Sumitomo Pharmaceuticals Company, LimitedSustained release composition
EP1553899A2 *Oct 22, 2003Jul 20, 2005The Biomerix CorporationMethod and system for intravesicular delivery of therapeutic agents
EP2089486A2 *Nov 20, 2007Aug 19, 2009Steven J. FerryCoating system
WO1981001650A1 *Nov 24, 1980Jun 25, 1981Dow CorningSilicone gel-filled silicone rubber article possessing reduced surface-bleed
WO1986001415A1 *Aug 30, 1985Mar 13, 1986Geistlich Soehne AgDevice for inserting in wounds and wound cavities
WO1987000042A1 *Jun 27, 1986Jan 15, 1987Univ New JerseyTransdermal verapamil delivery device
WO1989000839A1 *Jul 27, 1988Feb 9, 1989Biomeasure IncTherapeutic agent delivery system
WO1989012478A1 *Jun 21, 1989Dec 28, 1989Hansjoerg JustDilatation catheter
WO1990013332A1 *May 9, 1990Nov 15, 1990Cedars Sinai Medical CenterStent with sustained drug delivery
WO2000029464A1 *Oct 26, 1999May 25, 2000Ala Sorvari JuhaNovel membrane or matrix for controlling drug permeation
WO2006037182A1Oct 6, 2005Apr 13, 2006Agri Biotech Pty LtdAntibody production method
Classifications
U.S. Classification424/424, 623/1.42, 206/.5, 206/5, 435/2
International ClassificationA61K9/20, C08L83/04, A61M31/00
Cooperative ClassificationA61K9/2036, C08G77/20, C08G77/24, C08G77/18, C08L83/04, A61M31/002
European ClassificationA61K9/20H6D2, C08L83/04, A61M31/00D