US3765414A - Drug release system - Google Patents

Drug release system Download PDF

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US3765414A
US3765414A US3765414DA US3765414A US 3765414 A US3765414 A US 3765414A US 3765414D A US3765414D A US 3765414DA US 3765414 A US3765414 A US 3765414A
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means
membrane
body
device
wall
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M Arlen
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Valera Pharmaceuticals Inc
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Valera Pharmaceuticals Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61DVETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
    • A61D7/00Devices or methods for introducing solid, liquid, or gaseous remedies or other materials into or onto the bodies of animals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A61M31/002Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time

Abstract

There is disclosed a device and method for delivery of a chemotherapeutic over a prolonged period of time to the body. In case the therapeutic has an adverse effect on the body the device can be flushed and a more suitable therapeutic substituted.

Description

D United States Patent 1 1 1 1 1 3,765,414

Arlen Oct. 16, 1973 [54] DRUG RELEASE SYSTEM 3,220,960 11/1965 Wichterle et a1. 128/ 127 X 3,310,051 3/1967 Schulte 128/350 R X [751 Arlen Great Neck 3,313,289 4/1967 Kapral 128/1 R 7 1 3,527,220 9/1970 Summers 128/260 3] Ass'gnee 3 sc'ences Inc New 3,640,269 2/1972 Delgado 3,641,237 2/1972 Gould et a1. 128/260 [22] Filed: Mar. 10, 1972 [21] Appl. No.: 233,685 Primary Examiner-Aldrich F. Medbery Attorney-John W. Malley et a].

[52] US. Cl 128/260, 3/1, 128/1 R, 128/2 F, 128/2.05 R, 128/213, 128/350 R,

,. 128/214 R [57] ABSTRACT 2; g g' f 5/00 q gyg g There is disclosed a device and method for delivery of l 1 1 60/2 5 a a chemotherapeutic over a prolonged period of time to the body. In case the therapeutic has an adverse effect on the body the device can be flushed and a more [56] uNlTE g gzz$s gzfrsNTs suitable therapeutic substituted.

2,976,576 3/1961 Wichterle et a1. 128/214 R 38 5 Drawing Figures DRUG RELEASE SYSTEM The present invention relates to a device and method for the delivery of chemotherapeutic agents in human or veterinary medicine, e.g. in the treatment of humans simplest form comprises a hollow chamber for receipt of a medicament, a tube for introducing medicament to the chamber, a tube for removing medicament from the chamber, a relatively thick body wall for such a chamber and a relatively thin membrane for controlled release of medicament to the human or veterinary host.

The process and device of the present invention permits the release of any desired medicament on a timed basis which can be as short as an hour or several hours but which can be as long as days, months or even years.

The device can also be used to permit the varying of medicine. Thus the device permits the rotation of medicaments as desired. Alternatively in the case of allergy or anaphylactic reaction, or if the patient is toxic to the medicine for example, the chamber can be flushed immediately to remove the adversely reacting material, e.g. if a patient is being given penicillin and has a reaction thereto. the penicillin can be flushed out and streptomycin introduced into the chamber. z

The medicament (or mixture of medicaments) can be released on a flat curve or in any way or concentration as desired.

An additional function of the device is to overcome heretofore toxic, tissue or side-effect reactions encountered using present day methods of administering medicaments such as pills, injections, etc.

The devices can be fabricated from a wide variety of polymeric materials such as natural rubber; synthetic rubbers, e.g. cis-isoprene rubber, rubbery butadienestyrene copolymer, rubbery butadiene-acrylonitrile co- I polymer, polychloroprene, butyl rubber (e.g. isobutylene-butadiene copolymer 98.5 1.5, see also U.S. Pat. No. 2,356,128), ethylene-propylene-terpolymer rubber (e.g. ethylene-propylene-norbornadiene or ethylenepropylene-cyclooctatriene, ethylene-propylenedodecatriene, etc. polyvinyl pyrrolidone, silicone polymers, e.g. rubbery, polydimethyl siloxane such as a medical grade silastic, polyvinyl chloride and vinyl chloride copolymers, e.g. vinyl chloride-vinyl acetate copolymer (87 l3), N-methyl acrylamide polymers,

'N-butyl acrylamide polymers, diacetone acrylamide polymers, polyvinyl alcohol, polyvinyl acetate, cellulosics, e.g. cellulose acetate, cellulose acetate-propionate, ethyl cellulose, methyl cellulose, carboxymethyl cellulose and hydroxy ethyl cellulose, ethylene-vinyl acetate.

copolymer, polyurethanes, e.g. toluene diisocyanate reacted with polytetramethylene glycol or with ethylene glycol-propylene glycol-adipate-maleate, polyimides, e.g. from methylene dianiline or oxydianiline and pyromellitic anhydride, polyamides, e.g. nylon 6, nylon 6,6, nylon 6,11, polyacrylonitrile, polyethers, polyesters, e.g. polyethylene terephthalate, polymerized propylene glycol adipate maleate, fluoroplastics, e.g. polytetrafluoroethylene (Teflon), tetrafluoroethylene-hexafluoropropylene copolymer, polyvinylidene fluoride, polymerized olefins, e.g. polyethylene, polypropylene, ethylene-propylene copolymer (e.g. 50:50), polyisobutylene, polybutylene, polystyrene, high impact modified polystyrene (e.g. polystyrene blended with a minor amount of rubber, polysulfones, polycarbonates such as Lexan (bisphenol A polycarbonate), polyacrylates and methacrylates, e.g. polyethyl acrylate, polymethyl methacrylate, polybutyl methacrylate,

poly 2-ethylhexyl acrylate, polyalkoxyalkyl acrylates and methacrylates, e.g. polymers, methoxyethyl acrylate, ethoxyethyl acrylate, butoxyethyl acrylate, methoxypropyl acrylate, methoxyethyl methacrylate, ethoxyethyl methacrylate and methoxypropyl methacrylate, hydroxyethoxyethyl methacrylate, hydroxypropoxypropyl methacrylate, hydroxyethoxyethyl acrylate.

The preferred polymers are hydrophilic polymers made from a monomer which is a hydroxy lower alkyl acrylate or methacrylate, or hydroxy lower alkoxy lower alkyl acrylate or methacrylate, e.g., 2- hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, diethylene glycol monoacrylate, diethylene glycol monomethacrylate, 2-hydroxypropyl acrylate, 2- hydroxypropyl methacrylate, 3-hydroxypropyl acrylate, 3-hydropropyl methacrylate and dipropylene gly col monomethacrylate. The polymers produced from slurries of monomers are organic solvent soluble, e.g. alcohol soluble, but water insoluble. They can beprepared for example as shown 'in Shepherd U.S. Pat. No. 3,618,213 e.g. example 36a, or Chromacek U.S. Pat, No. 3,575,946.

The hydroxyalkyl'acrylate or methacrylate less preferably can also be replaced by vinyl pyrrolidone, acrylamide, methacrylamide, N-propyl acrylamide, N- isopropyl methacrylamide, N-methylacrylamide, N-methylmethacrylamide, N-methylol acrylamide and N-methylol methacrylamide, N-Z-hydroxyethyl acrylamide, N-Z-hydroxyethyl methacrylamide. However, these'monomers usually form water soluble ho'rnopolymers and hence they require the presence of a crosslinking agent or copolymerization with a sufficient amount of the hydroxyalkyl acrylates and methacrylates to render the copolymers water insoluble.

Other ethylenically unsaturated monomers can be used in conjunction with the above monomers or copolymers to constitute hydrophilic polymeric matrixes suitable for the entrapment of enzymes. They include neutral monomers such as acrylonitrile, methacrylo-- nitrile, vinyl acetate, alkyl acrylates and methacrylates, alkoxyalkyl acrylates and methacrylates.

Examples of alkyl acrylates and methacrylates include methyl acrylate, ethyl acrylate, butyl acrylate, 2- ethylhexyl acrylate, methyl methacrylate and butyl methacrylates. Examples of suitable alkoxyalkyl acrylates and methacrylates are methoxyethyl acrylate, methoxyethyl methacrylate, ethoxyethyl acrylate ethoxyethyl methacrylate, propoxyethyl acrylate, butoxyethyl methacrylate, methoxypropyl acrylate, ethoxypropyl methacrylate. These comonomers when used in an amount preferably not higher than 50 percent (and usually between 0.5 and 20 percent) of the monomeric mixture contribute to improve the mechanical properties of the gel. They should not be used in an amount to impair the hydrophilic nature of the polymer. Other vinyl monomers bearing ionizable functional groups can be copolymerized with the hydroxyalkyl acrylates or methacrylates to constitute ionogenic matrixes which can be useful when a basic or acidic environment isrequired for the stability or the optimum activity of enzymes. They include acidic type monomers such as acrylic acid, methacrylic acid, maleic acid, fumaric acid, itaconic acid, aconitic acid, cinnamic acid, cro tonic acid, carboxylic acid, propiolic acid, citraconic acid, vinyl sulfonic acid, p-vinylbenzenesulfonic acid, partial esters such as mono-2-hydroxyethyl itaconate, mono-2-hydroxypropyl citraconate, mono-2- hydroxyethyl maleate, mono-Z-hydroxypropyl fumarate, monomethyl itaconate, monoethyl itaconate, monomethyl cellosolve itaconate (Methyl Cellosolve is the monoethyl ether of diethylene glycol), monomethyl Cellosolve maleate, mono-2-hydroxyethyl aconitate.

They also include basic type monomers such as aminoethyl methacrylate, dimethyl aminoethyl methacrylate, monomethylaminoethyl methacrylate, tbutylaminoethyl methacrylate, p-aminostyrene, oaminostyrene, 2-amino-4-vinyltoluene, diethylaminoethyl acrylate, dimethylaminoethyl acrylate, tbutylaminoethyl acrylate, piperidinoethyl acrylate, piperidinoethyl methacrylate, morpholinoethyl acrylate, morpholinoethyl methacrylate, 2-viny1 pyridine, 3-vinyl pyridine, 4-vinyl pyridine, 2-ethyl-5-vinyl pyridine, dimethylaminopropyl acrylate,- dimethylamino propyl methacrylate, dipropylaminoethyl acrylate, dimethylaminoethyl vinyl ether, dimethylaminoethyl vinyl sulfide, diethylaminoethyl vinyl ether, aminoethyl vinyl ether, Z-pyrrolidinoethyl methacrylate, 3- (dimethylaminoethyl)-hydroxypropyl acrylate, 3- (dimethylaminoethyl)-2-hydroxypropyl methacrylate,

2-aminoethyl acrylate, 2-aminoethyl methacrylate. The

alkylaminoethyl acrylates and methacrylates are preferred in this group. These ionogenic monomers should not be used in sufficient amounts to render the hydroxyalkyl acrylates or'methacrylates water soluble. Multipolymers prepared from a mixture of 3,4 or more of the above monomers can be used. These monomers are usually used in an amount of 0.1 20 percent, preferably 1 to 15 percent of the total monomers.

When it is necessary to render the membrane insoluble in organic solvents, this can be done by sparingly cross-linking the entrapping polymer. Preferably, the

cross-linking agent is added in an amount of 1 to percent most preferably, not over 2.0 or 2.5 percent, although from 0.05 to percent or even percent, of cross-linking agents can be used. Cross-linking renders the otherwise organic solvent soluble or water soluble polymers insoluble, although it does not impair the hydrophilic properties.

Typical examples of cross-linking agents include ethylene glycol diacrylate, ethylene glycol dimethacrylate, 1,4-butylene dimethacrylate, diethylene glycol dimethacrylate, propylene glycol dimethacrylate, diethylene glycol dimethacrylate, dipropylene glycol dimethacrylate, diethylene glycol diacrylate, dipropylene glycol diacrylate, divinyl benzene, divinyl toluene, diallyl tartrate, allyl pyruvate, allyl mala'te, divinyl tartrate, triallyl melamine, N,N- methylene bisacrylamide, diallyl maleate, divinyl ether, diallyl monoethylene glycol citrate, ethylene glycol vinyl allyl citrate, allyl vinyl maleate, diallyl itaconate, ethylene glycol diester of itaconic more preferably are copolymers containing a small amount, e.g. 0.05 to 20 percent preferably 0.1 to 2 percent of a cross-linking agent to give a sparingly crosslinked polymer. Examples of such cross-linking agents are ethylene dimethacrylate, propylene dimethacrylate, butylene dimethacrylate, ethylene diacrylate, butylene diacrylate, diethylene glycol diacrylate, diethylene glycol dimethacrylate, dipropylene glycol dimethacrylate, triethylene glycol diacrylate, triethylene glycol dimethacrylate, tartaric acid dimethacrylate, methylene bis acrylamide, triallyl cyanurate or other crosslinking agents such as disclosed in Wichterle US. Pat. No. 3,220,960 or Shepherd US. Pat. No. 3,575,123 or Shepherd US. Pat. No. 3,577,512 or Shepherd US. Pat. No. 3,618,213 can be used. The entire disclosure of the Wichterle patentand the three Shepherd patents is hereby incorporated by reference. 'The hydroxyalkyl acrylate (with or without the cross-linking agent can be copolymerized with a minor amount, e.g. 0.1 to 49 percent, usually not over 20 percent, of another monoethylenically unsaturated monomer, e.g. methyl methacrylate, vinyl pyrrolidone, vinyl acetate, methoxyethyl methacrylate, ethoxyethyl methacrylate, butyl acrylate, etc. The hydrophilic polymer such as a HEMA polymer can'be prepared in anhydrous form, e.g. as disclosed in Shepherd US. Pat. No. 3,618,213 or as a hydrogel a shown in'Wichterle US. Pat. No. 3,220,960.

The device employed in the present invention can be fabricated by utilizing conventional procedures such as injectionmolding, film casting, ultrasonic welding, heat sealing, cement bonding, etc. and can-be prepared as a-single sided membrane, a double sided membrane or a total (i.e. overall) membrane device. The devices can be rigid, semi rigid or flexible.

As medicaments there can beemployed compounds such as procaine penicillin, 5-fluorouracil, adrenaline (epinephrine) steroids and other hormones such as testosterone, estradiol, diethyl stilbesterol, a mixture of ethynylestradiol and mestranol, andro'sterone, norethandrolone (Nilevar), estrone, stilbesterol, progesterone, ll-dehydroprogesterone, desoxycorticosterone, hydrocortisone acetate, corticosterone, cortisone, 9-alpha-fluorohydrocortisone, insulin, lincomycin hydrochloride, penicillin, streptomycin, phenoxymethyl penicillin, chloramphenicol, sulfanilamide, sulfaguanidine, sulfathiazole, tetracycline, clorotetracycline, hydroxytetracycline, bacitracin, neomycin, polymyxin, gramicidin, erythromycin, sulfacetamide, sulfamethizole, thyroxin sulfisoxazole, antivirals such as idox- "uridine, nitrofurazone, sodium propionate, anti alleracid, divinyl sulfone, hexahydro-l, 3, S-triacryltriazine,

triallyl phosphite, diallyl ester of benzene phosphonic genics such as antazoline, methapyrilene, chlorpheniramine, pyrilamine and prophenpyridamine, anti inflammatories such as dexamethasone, dexamethasone 21-,

phosphate, fluocinolone, prednisolone, prednisolone acetate and prednisolone 21-phosposphate, decongestants such as phenylephrine, naphazoline and tetrahyerine, digitoxin, digitalis, atabrine, heparin, hydroxystilbamide, benadryl dl-amphetamine sulfate, dextro amphetaminesulfate, vitamins, e.g. Vitamin B Vitamin 8;, Vitamin E, Vitamin K, Vitamin C (ascorbic acid), tranquilizers, e.g. reserpine, chlorpromazine hydrochloride, alkaloids, e.g. belladonna, atropine sulfate, hyoscine hydrobromide, chlorpheniramine maleate, quinidine salts, theophylline salts, ephedrine salts, pyrilamine maleate, enzymes, e.g. pepsin, trypsin, alphaamylase, phosphatases, glyoxalase, cytochrome oxidase, d-amino acid oxidase, l-amino acid oxidase, hyaluronidase.

When the polymer employed for the device to control'the flow of medicament is made of a polymer which has a tissue reaction e.g. silicone, polyvinyl alcohol, Teflon and most of the other polymers which are tissue irritating, it is preferred to eliminate the tissue irritation by employing a polymer of a hydroxyalkyl acrylate or methacrylate, e.g. a HEMA polymer, as a thin biocompatible overall coating.

There are a number of different designs for the devices used in the present invention. Several of these are shown in the accompanying drawings wherein FIG. 1 is a vertical elevation of one type of device according to the invention;

FIG. 2 is a vertical elevation of an alternative device;

FIG. 3 is a view of a bag device according to the invention having a non-toxic coating;

FIG. 4 is a vertical elevation of a device similar to that of FIG. 1 but having a biologically acceptable coating; and

FIG. 5 is a vertical elevation of a device similar to that of FIG. 2 but having a biologically acceptable coatmg.

Referring more specifically to FIG. 1, there is disclosed an implantable device in the shape of half of a capsule having a relatively thick body wall 4 on the body of the device, e.g. a hydrophilic hydrogel copoly mer of hydroxyethyl methacrylate with 0.2 percent of ethylene dimethacrylate and having a relatively thin membrane end wall 6 of the same material. The wall 4 has two straight portions 8 and 10 joined by an arcuate portion 12.

The wall 4 and membrane end wall 6 enclose a hollow chamber 14 which can be filled with a drug through entry channel or tube 16. In the event it is necessary to flush out and replace the drug, this can be accomplished for example by passing a cleaning fluid or a different drug through channel or tube l6'into chamber 14 and forcing the old drug out through exit channel or tube 18. Tubes 16 and 18 can be closed off by any suitable valve outside the body. Tubes 16 and 18 can be made of the same material as the rest of the device or any other suitable material, e.g. Teflon, Silastic, polyvinyl chloride, rubber, etc. The membrane 6 canbe of the same material as the wall 4 or it can be made of a different material.

In the form of the invention as shown in FIG. 2, the implant device 20 is basically in the form of an O ring having a relatively thick front wall 22 and a back wall (not shown). The side walls 28 and 30 each are of a re]- atively thin membrane. There are also provided fluid entry channel 34 and fluid exit channel 36 into drug receiving chamber 38. The implant device, for example, can be essentially in the form of a ring similar 'to that in FIG. 2 of Kapral US. Pat. No. 3,313,289.

In the embodiment shown in FIG. 2 the two membrane sides can be of the same or different thickness.

, If they are of the same thickness and made of the same material, e.g. hydroxyethyl methacrylate copolymer, then the rate of diffusing materials out of the chamber will be the same. However, the rates can be varied by changing the relative thickness of the two membranes, e.g. l.l:l, l.5:l, 2:1, 4:l or lO:l so that the rates ofdiffusion will be different. Thiscan be important when it is desired to introduce the same medicament simultaneously to different body organs.

The embodiment shown in FIG. 3. is in the form of a bag 40 having a single body wall 42 of polytetrafluoroethylene surrounding central drug receiving cavity 44 and a non toxic extremely thin external membrane 46 of a hydrophilic polymer of hydroxyethyl methacrylate with 0.1% ethylene dimethacrylate as a cross-linking agent. There are also provided fluid entry channel 48 and fluid exit channel 50.

The device of FIG. 4 is similar to that of FIG. 1 except that the body wall 4 and the membrane 6 are made of a biologically toxic material, e.g. Silastic (rubbery polydimethyl siloxane) and there is an overall very thin coating 52 of biocompatible material such as HEMA polymer for both the body wall and the membrane. The membrane and body wall can be of different materials, e.g. the body wall can'b'e polytetrafluoroethylene and the membrane Silastic.

The device of FIG. 5 is similar to that of FIG. 2 except that the walls and membranes are made of a toxic material, e.g. Silastic, and the walls and membrances 1 have an overall very thin coating 54 of biocompatible material such as a copolymerof HEMA with 0.2 per cent of die'thylene glycol dimethacrylate. Different rates of diffusion of the medicament through membranes 28 and 30 can be provided by making them of different thicknesses or by making them of different materials which can have the same or different thick The body wall can be as thick as 7 mm. The permeable y can be in liquid or solid form. They also can be intromembrane can be from 0.1 to 2 mm. thick but usually is not over 1 mm. and preferably is 0.2 to 0.5 mm. It should not be over one-half the thickness of the body wall. The body wall can be reinforced if desired, e.g. with Dacron (polyethylene terephthalate) fibers or other fibers either medially or externally.

When a coating of biologically compatible material is employed over a more biologically toxic material, the outer material should be very thin, e.g. 0.01 to 0.1 micron. In the total device the inner membrane is employed to control the flow of medicament and the outer coating is solely for the purpose of preventing tissue reaction and should therefore be as thin as possible so as not to interfere with such flow.

According to the present invention there can be filled into the inner cavities in the devices of the drawings a medicament, such for example any of those specified above, or mixture of medicaments. The medicaments duced into the cavity in the form of a solution or suspension in water or other biologically acceptable liquid.

The device of the invention can be implanted subcutaneously, intramuscularly, interperitoneally or adjacent to any body organ or by any other conventional manner of implantation.

The device can be used to deliver medically active ingredients (I) to a specific area of the body, e.g. an organ such as the liver, gall bladder, stomach wall, or a lung, placed between two organs, e.g. between the pancreas and the duct leading into the intestines; (2) placed adjacent to an inoperative mass, e.g. a tumor such as a Schwanoma, (3) placed within a functioning organ system to release active ingredients to stimulate or reduce activity of the system, e.g. an implant directly into the peritoneum or into the stomach or the uterus.

As previously stated the device having a hollow, fillable chamber. with ingress and egress through small hollow tubes can be formed by any conventional method. The hollow tubes at the time of implant can be brought out through the skin. The entry and exit tubes can be removed at any time if desired by gentle manipulation.

The present invention is especially effective as a method of delivery of antitumor compounds in high concentrations in the area of tumor growth. The implantable device of the invention containing the antitumor agent is placed against the tumor at the time of surgery. Because of its high degree of biologic acceptability (see Levowitz, Trans. Amer. Soc. for Artificial lnternal Organs l4,82(l968) Hydron (a commercially available copolymer of 100 parts of 2-hydroxyethyl methacrylate with about 0.2 parts of ethylene glycol dimethacrylate) is particularly suitable as set forth supra for forming the walls and membranes of the devices since it evokes little or no fibroblastic reaction at implantation sites. 1

The use of the device of the invention permits flexibility in administering chemotherapeutic agents. Thus a drug can be discontinued at the first sign of to'xity and if the drug is ineffective, it can be readily changed.

Using S-fluorouracil (S-FU) and the device of FIG. 2 with Hydron as the material of the body walls and membranes. The device was an O ring with two membranes. The S-FU was employed as a solution of 50 mg/ml. in water. It was found that within 30 minutes mgs. of S-F U were absorbed in each gram of Hydron with a gradual incease to mg/gm. of Hydron in 90' minutes.

Elution of S-FU from Hydron pledgets soaked in 0.5 percent 5-F U for five days was studied in 0.1 molar phosphate buffer and human plasma. This pattern of release was constant over the first 4 days and gradually tapered off over an interval of 120 hours.

In vivo studies in rabbits showed a similar rate of release occurred with 65 percent of the S-FU entering the tissues and body fluids in the first 48 hours.

The use of individual pelletsof Hydron saturated with 5- F U and implanted into the peritoneal cavity of CF white mice was found to offer protection against the growth of Ehrlichs ascites tumor cells. Five days after challenging implanted mice with Ehrlichs ascites tumor cells, 21/22 mice were alive with the Hydron treatment versus 18/22 animals having Hydron with just water. On the 21st day, 17/22 animals receiving the Hydron plus chemotherapeutic agent were alive versus 4/22 having received control Hydron plus water pledgets. Thus it appeared that thejHydron plus chemotherapeutic agent offered significant protection in the mice.

However, polymer saturated with antitumor drugs cannot deliver effective serum or tissue levels.'The implantable device of the invention, e.g. an O ring of the type described using various membrane thicknesses. In vivo studies revealed fairly predictable straight line curves for release of the antitumor agent 5-FU with a window size of 1 cm. in diameter and 0.15 mm membrane thickness, 1 mg of 5-FU was eluted from the chamber per hour. A 1 mm. thick membrane window allowed 0.5 mg of S-FU to be eluted per hour.

Studies employing this device implanted into the peritoneal cavity of dogs indicated that a rapid uptake of 5-F U into surrounding tissues occurred. The uptake appeared selective in that high concentrations of agents reached those tissues in contact with the reservoir and rapidly tapered off at more distant sites. Even those tissues with known predilection for the agent appeared spared.

What is claimed is: i

1. A body implant device for delivery of a medicament over a long period of time comprising a chamber adapted to receive a medicament, body wall means sufficiently thick to be resistant to fluid flow therethrough partially surrounding said chamber, relatively thin fluid permeable membrane means engaging said wall means and completing the surrounding of said chamber, said membrane means permitting transport of fluids between the body and said chamber, said membrane means being not over one-half the thickness of said wall means, said wall means and said membrane means being made of a water insoluble hydrophilic non toxic biocompatible polymer of a hydroxy lower alkyl acrylate or methacrylate, first conduit means for feeding medicament to said chamber and second conduit means for rapid removal of medicament from said chamber.

2. A body implant device according to claim 1 ineluding a medicament;

7. A body implant device according to claim 1 wherein the wall means has a thickness of 2 to 7 mm.

and the permeable membrane means has a thickness of 0.1 to 2 mm.

8. A body implant device according to claim 7 wherein the permeable membrane means is 0.2 to 0.5

9. A body implant device according to claim 1 having at least two permeable membrane means of different thicknesses, the rate of fluid transport through the two membrane means being inversely proportional to their thickness.

10. A body implant device fordelivery of a medicament over a long period of time comprising a chamber adopted to receive a medicament, body wall means sufficiently thick to be resistant to fluid flow therethrough at least partially surrounding said chamber, relatively thin fluid permeable membrane means engaging said wall means and completely surrounding both said chamber and said wall means, said membrane means permitting transport of fluids between the body and said chamber, said membrane means being not over one-half the thickness of said wall means, said wall means and said membrane means being made of a biologically incompatible material and an extremely thin coating of a water insoluble hydrophilic non toxic, biocompatible polymer of a hydroxy lower alkyl acrylate or methacrylate surrounding all externally exposed portions of said wall means and said membrane means, said coating being sufficiently thinthat it does not interfere with fluid transport through said membrane means, a first conduit means for feeding medicament to said chamber and a second conduit means for rapid removal of medicament from said chamber.

11. A body implant device according to claim including a medicament.

12. A body implant device according to claim 10 wherein said first and second conduit means both pass through said'wall means to said chamber.

13. A body implant device according to claim 10 wherein said wall means partially surrounds said chamber and said membrane means completes the surrounding of said chamber.

14. A body implant device according to claim 13 having a single membrane means.

15. A body implant device according to claim 13 having a plurality of spaced apart membrane means 16. A body implant device according to claim 15 having at least two permeable membrane means of different thicknesses the rate of fluid transport through the two membrane means being inversely proportional to their thicknesses.

17. A body implant device according to claim 10 wherein the hydroxy lower alkyl acrylate or methacrylate is hydroxyethyl methacrylate.

18. A body implant device according to claim 10 wherein the wall means has a thickness of 2 to 7 mm., the permeable membrane means has a thickness of 0.1 to 2 mm. and the coating has a thickness of 0.01 to 0.1 micron.

19. A body implant device according to claim 18 wherein the permeable membrane means is 0.2 to 0.5

20. A body implant device for delivery of a medicament over a long period of time comprising a chamber adapted to receive a medicament, body wall means sufficiently thick to be resistant to fluid flow therethrough partially surrounding said chamber, relatively thin fluid permeable membrane means engaging said wall means and completing the surrounding of said chamber, said membrane means permitting transport of fluids between the body and said chamber, said membrane means being not over one-half the thickness of said wall means, said wall means and said membrane means being made of a water insoluble hydrophilic non toxic polymer of a member of the group consisting of hydroxy lower alkyl acrylates, hydroxy lower alkyl methacrylates, hydroxy lower alkoxy lower alkyl acrylates, hydroxy lower alkoxy lower alkyl methacrylates, vinyl pyrrolidone, acrylamide, methacrylamide, N-lower alkyl acrylamide, N-lower alkyl methacrylamide N- hydroxy lower alkyl acrylamide and N-hydroxy lower alkyl methacrylamide first conduit means for feeding medicament to said chamber and second conduit means for rapid removal of medicament from said chamber.

21. A body implant device according to claim 20 including a medicament.

22. A body implant device according to claim 20 wherein said first and second conduit means both pass through said wall means to said chamber.

23. A body implant device according to claim 20 having a single membrane means.

24. A body implant device according to claim 23 wherein the wall means and the membrane means are made of a member of the group consisting of hydroxy lower alkyl acrylates and hydroxy lower alkyl methacrylates.

25. A body implant device according to claim 24 wherein the wall means and the membrane means are made of hydroxy-ethyl methacrylate.

26. A body implant device according to claim 20 having a plurality of spaced apart membrane means.

27. A body implant device according to claim 20 wherein the wall means has a thickness of 2 to 7 mm. and the permeable membrane means has a thickness of 0.1 to 2 mm.

28. A body implant device according to claim 20 wherein the permeable membrane means is 0.2 to 0.5

29. A body implant device according to claim 20 having at least two permeable membrane means to different thicknesses, the rate of fluid transport through the two membrane means being inversely proportional to their thickness.

30. A body implant device for delivery of a medicament over a long period of time comprising a chamber adopted to receive a medicament, body wall means sufficiently thick to be resistant to fluid flow therethrough at least partially surrounding said chamber, relatively thin fluid permeable membrane means engaging said wall means and completing the surrounding of said chamber, said membrane means permitting transport of fluids between the body and said chamber, said membrane means being not over one-half the thickness of said wall means, said wall means and said membrane means being made of a biologically incompatible material and an extremely thin coating of a water insoluble hydrophilic non toxic, biocompatible polymer of a member of the group consisting of hydroxy lower alkyl acrylates, hydroxy lower alkyl methacrylates, hydroxy lower alkoxy lower alkyl acrylates, hydroxy lower alkoxy lower alkyl methacrylates, vinyl pyrrolidone, acrylamide, methacrylamide, N-lower alkyl acrylamide, N- lower alkyl methacrylamide, N-hydroxy lower alkyl acrylamide and N-hydroxy lower alkyl methacrylamide surrounding all externally exposed portions of said wall means and said membrane means, saidcoating being sufficiently thin that it does not interfere with fluid transport through said membrane means, a first conduit means for feeding medicament to said chamber and a second conduit means for rapid removal of medicament from said chamber.

31. A body implant device according to claim 30 including a medicament.

32. A body implant device according to claim 30 wherein said membrane means completely surrounds said wall means.

33. A body implant device according to claim 30 wherein said wall means partially surrounds said chamtheir thicknesses.

37. A body implant device according to claim 30 wherein the wall means has a thickness of 2 to 7 mm., the penneable membrane means-has a thickness of 0.1 to 2 mm. and the coating has a thickness of 0.01 to 0.1 micron.

38. A body implant device according to claim 18 wherein the permeable membrane means is 0.2 to 0.5

Notice of Adverse Decision in Interference In Interference No. 98,706, involving Patent No. 3,765,414, DRUG RE- LEASE SYSTEM, final judgment adverse to the patentee was rendere Aug. 28, 1974, as to claims 17, 1014, 17 20-25 and 30-34.

[Ojfiez'al Gazette December 24, 1.974.]

Claims (38)

1. A body implant device for delivery of a medicament over a long period of time comprising a chamber adapted to receive a medicament, body wall means sufficiently thick to be resistant to fluid flow therethrough partially surrounding said chamber, relatively thin fluid permeable membrane means engaging said wall means and completing the surrounding of said chamber, said membrane means permitting transport of fluids between the body and said chamber, said membrane means being not over one-half the thickness of said wall means, said wall means and said membrane means being made of a water insoluble hydrophilic non toxic biocompatible polymer of a hydroxy lower alkyl acrylate or methacrylate, first conduit means for feeding medicament to said chamber and second conduit means for rapid removal of medicament from said chamber.
2. A body implant device according to claim 1 including a medicament.
3. A body implant device according to claim 1 wherein said first and second conduit means both pass throuGh said wall means to said chamber.
4. A body implant device according to claim 1 having a single membrane means.
5. A body implant device according to claim 1 having a plurality of spaced apart membrane means.
6. A body implant device according to claim 1 wherein the hydroxy lower alkyl acrylate or methacrylate is hydroxyethyl methacrylate.
7. A body implant device according to claim 1 wherein the wall means has a thickness of 2 to 7 mm. and the permeable membrane means has a thickness of 0.1 to 2 mm.
8. A body implant device according to claim 7 wherein the permeable membrane means is 0.2 to 0.5 mm.
9. A body implant device according to claim 1 having at least two permeable membrane means of different thicknesses, the rate of fluid transport through the two membrane means being inversely proportional to their thickness.
10. A body implant device for delivery of a medicament over a long period of time comprising a chamber adopted to receive a medicament, body wall means sufficiently thick to be resistant to fluid flow therethrough at least partially surrounding said chamber, relatively thin fluid permeable membrane means engaging said wall means and completely surrounding both said chamber and said wall means, said membrane means permitting transport of fluids between the body and said chamber, said membrane means being not over one-half the thickness of said wall means, said wall means and said membrane means being made of a biologically incompatible material and an extremely thin coating of a water insoluble hydrophilic non toxic, biocompatible polymer of a hydroxy lower alkyl acrylate or methacrylate surrounding all externally exposed portions of said wall means and said membrane means, said coating being sufficiently thin that it does not interfere with fluid transport through said membrane means, a first conduit means for feeding medicament to said chamber and a second conduit means for rapid removal of medicament from said chamber.
11. A body implant device according to claim 10 including a medicament.
12. A body implant device according to claim 10 wherein said first and second conduit means both pass through said wall means to said chamber.
13. A body implant device according to claim 10 wherein said wall means partially surrounds said chamber and said membrane means completes the surrounding of said chamber.
14. A body implant device according to claim 13 having a single membrane means.
15. A body implant device according to claim 13 having a plurality of spaced apart membrane means.
16. A body implant device according to claim 15 having at least two permeable membrane means of different thicknesses the rate of fluid transport through the two membrane means being inversely proportional to their thicknesses.
17. A body implant device according to claim 10 wherein the hydroxy lower alkyl acrylate or methacrylate is hydroxyethyl methacrylate.
18. A body implant device according to claim 10 wherein the wall means has a thickness of 2 to 7 mm., the permeable membrane means has a thickness of 0.1 to 2 mm. and the coating has a thickness of 0.01 to 0.1 micron.
19. A body implant device according to claim 18 wherein the permeable membrane means is 0.2 to 0.5 mm.
20. A body implant device for delivery of a medicament over a long period of time comprising a chamber adapted to receive a medicament, body wall means sufficiently thick to be resistant to fluid flow therethrough partially surrounding said chamber, relatively thin fluid permeable membrane means engaging said wall means and completing the surrounding of said chamber, said membrane means permitting transport of fluids between the body and said chamber, said membrane means being not over one-half the thickness of said wall means, said wall means and said membrane means being made of a water insoluble hydrophilic non toxic polymer of a member of the group consisting of hydroxy lOwer alkyl acrylates, hydroxy lower alkyl methacrylates, hydroxy lower alkoxy lower alkyl acrylates, hydroxy lower alkoxy lower alkyl methacrylates, vinyl pyrrolidone, acrylamide, methacrylamide, N-lower alkyl acrylamide, N-lower alkyl methacrylamide N-hydroxy lower alkyl acrylamide and N-hydroxy lower alkyl methacrylamide first conduit means for feeding medicament to said chamber and second conduit means for rapid removal of medicament from said chamber.
21. A body implant device according to claim 20 including a medicament.
22. A body implant device according to claim 20 wherein said first and second conduit means both pass through said wall means to said chamber.
23. A body implant device according to claim 20 having a single membrane means.
24. A body implant device according to claim 23 wherein the wall means and the membrane means are made of a member of the group consisting of hydroxy lower alkyl acrylates and hydroxy lower alkyl methacrylates.
25. A body implant device according to claim 24 wherein the wall means and the membrane means are made of hydroxy-ethyl methacrylate.
26. A body implant device according to claim 20 having a plurality of spaced apart membrane means.
27. A body implant device according to claim 20 wherein the wall means has a thickness of 2 to 7 mm. and the permeable membrane means has a thickness of 0.1 to 2 mm.
28. A body implant device according to claim 20 wherein the permeable membrane means is 0.2 to 0.5 mm.
29. A body implant device according to claim 20 having at least two permeable membrane means to different thicknesses, the rate of fluid transport through the two membrane means being inversely proportional to their thickness.
30. A body implant device for delivery of a medicament over a long period of time comprising a chamber adopted to receive a medicament, body wall means sufficiently thick to be resistant to fluid flow therethrough at least partially surrounding said chamber, relatively thin fluid permeable membrane means engaging said wall means and completing the surrounding of said chamber, said membrane means permitting transport of fluids between the body and said chamber, said membrane means being not over one-half the thickness of said wall means, said wall means and said membrane means being made of a biologically incompatible material and an extremely thin coating of a water insoluble hydrophilic non toxic, biocompatible polymer of a member of the group consisting of hydroxy lower alkyl acrylates, hydroxy lower alkyl methacrylates, hydroxy lower alkoxy lower alkyl acrylates, hydroxy lower alkoxy lower alkyl methacrylates, vinyl pyrrolidone, acrylamide, methacrylamide, N-lower alkyl acrylamide, N-lower alkyl methacrylamide, N-hydroxy lower alkyl acrylamide and N-hydroxy lower alkyl methacrylamide surrounding all externally exposed portions of said wall means and said membrane means, said coating being sufficiently thin that it does not interfere with fluid transport through said membrane means, a first conduit means for feeding medicament to said chamber and a second conduit means for rapid removal of medicament from said chamber.
31. A body implant device according to claim 30 including a medicament.
32. A body implant device according to claim 30 wherein said membrane means completely surrounds said wall means.
33. A body implant device according to claim 30 wherein said wall means partially surrounds said chamber and said membrane means completes the surrounding of said chamber.
34. A body implant device according to claim 33 having a single membrane means.
35. A body implant device according to claim 33 having a plurality of spaced apart membrane means.
36. A body implant device according to claim 35 having at least two permeable membrane means of different thicknesses the rate of fluid transport through the two membrane means being inversely proportional to their thicknesses.
37. A body implant device according to clAim 30 wherein the wall means has a thickness of 2 to 7 mm., the permeable membrane means has a thickness of 0.1 to 2 mm. and the coating has a thickness of 0.01 to 0.1 micron.
38. A body implant device according to claim 18 wherein the permeable membrane means is 0.2 to 0.5 mm.
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Cited By (32)

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Publication number Priority date Publication date Assignee Title
US3896806A (en) * 1971-01-08 1975-07-29 Ceskoslovenska Akademie Ved Implant for directed infusion of biologically active substances
US3908201A (en) * 1972-06-30 1975-09-30 Ici Ltd Prosthetics
US3946734A (en) * 1975-02-19 1976-03-30 The United States Of America As Represented By The Secretary Of State Apparatus for controlling the release of a drug
US3952741A (en) * 1975-01-09 1976-04-27 Bend Research Inc. Controlled release delivery system by an osmotic bursting mechanism
US3958562A (en) * 1974-05-30 1976-05-25 Hakim Company Limited Implantable pressure sensor
US3971376A (en) * 1973-02-26 1976-07-27 Ceskoslovenska Akademie Ved Method and apparatus for introducing fluids into the body
US3977404A (en) * 1975-09-08 1976-08-31 Alza Corporation Osmotic device having microporous reservoir
US4034758A (en) * 1975-09-08 1977-07-12 Alza Corporation Osmotic therapeutic system for administering medicament
US4167045A (en) * 1977-08-26 1979-09-11 Interface Biomedical Laboratories Corp. Cardiac and vascular prostheses
US4178361A (en) * 1973-09-10 1979-12-11 Union Corporation Sustained release pharmaceutical composition
US4179757A (en) * 1972-02-22 1979-12-25 Owens-Illinois, Inc. Biocompatible articles having high permeability to gases derived from polysulfones
US4286584A (en) * 1978-06-16 1981-09-01 Infusaid Corporation Septum locating apparatus
US4298002A (en) * 1979-09-10 1981-11-03 National Patent Development Corporation Porous hydrophilic materials, chambers therefrom, and devices comprising such chambers and biologically active tissue and methods of preparation
US4309776A (en) * 1980-05-13 1982-01-12 Ramon Berguer Intravascular implantation device and method of using the same
EP0075762A1 (en) * 1981-09-25 1983-04-06 Siemens Aktiengesellschaft Implantable infusion apparatus
US4382441A (en) * 1978-12-06 1983-05-10 Svedman Paul Device for treating tissues, for example skin
US4452776A (en) * 1979-08-20 1984-06-05 Eye Research Institute Of Retina Foundation Hydrogel implant article and method
US4464178A (en) * 1981-11-25 1984-08-07 Dalton Michael J Method and apparatus for administration of fluids
EP0134340A1 (en) * 1983-08-22 1985-03-20 The University of Utah Research Foundation Peritoneal injection catheter apparatus
US4557724A (en) * 1981-02-17 1985-12-10 University Of Utah Research Foundation Apparatus and methods for minimizing cellular adhesion on peritoneal injection catheters
US4632671A (en) * 1985-04-12 1986-12-30 Dalton Michael J Conduit anchor adapted to receive stylet
US4639244A (en) * 1983-05-03 1987-01-27 Nabil I. Rizk Implantable electrophoretic pump for ionic drugs and associated methods
US4687480A (en) * 1984-09-14 1987-08-18 Commonwealth Scientific And Industrial Research Organization Controlled release capsule
US4705039A (en) * 1984-07-28 1987-11-10 Takasago Medical Industry, Co., Ltd. Subsidiary device for suturing an intestine
US5024671A (en) * 1988-09-19 1991-06-18 Baxter International Inc. Microporous vascular graft
US5630843A (en) * 1994-06-30 1997-05-20 Rosenberg; Paul H. Double chamber tissue expander
US20050136114A1 (en) * 2003-12-19 2005-06-23 Council Of Scientific And Industrial Research Taste masked pharmaceutical compositions comprising bitter drug and pH sensitive polymer
US20050164299A1 (en) * 2003-06-03 2005-07-28 Bay Materials Llc Phase change sensor
US20060054097A1 (en) * 2004-09-10 2006-03-16 Evans James A Release mechanism to interact with biota, in particular fauna that may outgrow available habitat
US20060222756A1 (en) * 2000-09-29 2006-10-05 Cordis Corporation Medical devices, drug coatings and methods of maintaining the drug coatings thereon
WO2008102247A3 (en) * 2007-02-23 2009-10-15 University Of The Witwatersrand, Johannesburg A polyamide rate-modulated monolithic drug delivery system
US8303609B2 (en) 2000-09-29 2012-11-06 Cordis Corporation Coated medical devices

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US3220960A (en) * 1960-12-21 1965-11-30 Wichterle Otto Cross-linked hydrophilic polymers and articles made therefrom
US3310051A (en) * 1963-12-10 1967-03-21 Rudolf R Schulte Surgical reservoir for implantation beneath the skin
US3313289A (en) * 1964-06-23 1967-04-11 Frank A Kapral Implant chamber
US3527220A (en) * 1968-06-28 1970-09-08 Fairchild Hiller Corp Implantable drug administrator
US3641237A (en) * 1970-09-30 1972-02-08 Nat Patent Dev Corp Zero order release constant elution rate drug dosage
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US2976576A (en) * 1956-04-24 1961-03-28 Wichterle Otto Process for producing shaped articles from three-dimensional hydrophilic high polymers
US3220960A (en) * 1960-12-21 1965-11-30 Wichterle Otto Cross-linked hydrophilic polymers and articles made therefrom
US3310051A (en) * 1963-12-10 1967-03-21 Rudolf R Schulte Surgical reservoir for implantation beneath the skin
US3313289A (en) * 1964-06-23 1967-04-11 Frank A Kapral Implant chamber
US3527220A (en) * 1968-06-28 1970-09-08 Fairchild Hiller Corp Implantable drug administrator
US3640269A (en) * 1969-10-24 1972-02-08 Jose M R Delgado Fluid-conducting instrument insertable in living organisms
US3641237A (en) * 1970-09-30 1972-02-08 Nat Patent Dev Corp Zero order release constant elution rate drug dosage

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3896806A (en) * 1971-01-08 1975-07-29 Ceskoslovenska Akademie Ved Implant for directed infusion of biologically active substances
US4179757A (en) * 1972-02-22 1979-12-25 Owens-Illinois, Inc. Biocompatible articles having high permeability to gases derived from polysulfones
US3908201A (en) * 1972-06-30 1975-09-30 Ici Ltd Prosthetics
US3971376A (en) * 1973-02-26 1976-07-27 Ceskoslovenska Akademie Ved Method and apparatus for introducing fluids into the body
US4178361A (en) * 1973-09-10 1979-12-11 Union Corporation Sustained release pharmaceutical composition
US3958562A (en) * 1974-05-30 1976-05-25 Hakim Company Limited Implantable pressure sensor
US3952741A (en) * 1975-01-09 1976-04-27 Bend Research Inc. Controlled release delivery system by an osmotic bursting mechanism
US3946734A (en) * 1975-02-19 1976-03-30 The United States Of America As Represented By The Secretary Of State Apparatus for controlling the release of a drug
US3977404A (en) * 1975-09-08 1976-08-31 Alza Corporation Osmotic device having microporous reservoir
US4034758A (en) * 1975-09-08 1977-07-12 Alza Corporation Osmotic therapeutic system for administering medicament
US4167045A (en) * 1977-08-26 1979-09-11 Interface Biomedical Laboratories Corp. Cardiac and vascular prostheses
US4286584A (en) * 1978-06-16 1981-09-01 Infusaid Corporation Septum locating apparatus
US4382441A (en) * 1978-12-06 1983-05-10 Svedman Paul Device for treating tissues, for example skin
US4452776A (en) * 1979-08-20 1984-06-05 Eye Research Institute Of Retina Foundation Hydrogel implant article and method
US4298002A (en) * 1979-09-10 1981-11-03 National Patent Development Corporation Porous hydrophilic materials, chambers therefrom, and devices comprising such chambers and biologically active tissue and methods of preparation
US4309776A (en) * 1980-05-13 1982-01-12 Ramon Berguer Intravascular implantation device and method of using the same
US4557724A (en) * 1981-02-17 1985-12-10 University Of Utah Research Foundation Apparatus and methods for minimizing cellular adhesion on peritoneal injection catheters
EP0075762A1 (en) * 1981-09-25 1983-04-06 Siemens Aktiengesellschaft Implantable infusion apparatus
US4511355A (en) * 1981-09-25 1985-04-16 Siemens Aktiengesellschaft Infusion device intended for implantation in a living body
US4464178A (en) * 1981-11-25 1984-08-07 Dalton Michael J Method and apparatus for administration of fluids
US4639244A (en) * 1983-05-03 1987-01-27 Nabil I. Rizk Implantable electrophoretic pump for ionic drugs and associated methods
EP0134340A1 (en) * 1983-08-22 1985-03-20 The University of Utah Research Foundation Peritoneal injection catheter apparatus
US4705039A (en) * 1984-07-28 1987-11-10 Takasago Medical Industry, Co., Ltd. Subsidiary device for suturing an intestine
US4687480A (en) * 1984-09-14 1987-08-18 Commonwealth Scientific And Industrial Research Organization Controlled release capsule
US4632671A (en) * 1985-04-12 1986-12-30 Dalton Michael J Conduit anchor adapted to receive stylet
US5024671A (en) * 1988-09-19 1991-06-18 Baxter International Inc. Microporous vascular graft
US5630843A (en) * 1994-06-30 1997-05-20 Rosenberg; Paul H. Double chamber tissue expander
US20060222756A1 (en) * 2000-09-29 2006-10-05 Cordis Corporation Medical devices, drug coatings and methods of maintaining the drug coatings thereon
US8303609B2 (en) 2000-09-29 2012-11-06 Cordis Corporation Coated medical devices
US20050164299A1 (en) * 2003-06-03 2005-07-28 Bay Materials Llc Phase change sensor
US20070249059A1 (en) * 2003-06-03 2007-10-25 Stewart Ray F Phase change sensor
US7794657B2 (en) * 2003-06-03 2010-09-14 Cantimer, Inc. Phase change sensor
US20050136114A1 (en) * 2003-12-19 2005-06-23 Council Of Scientific And Industrial Research Taste masked pharmaceutical compositions comprising bitter drug and pH sensitive polymer
US20060054097A1 (en) * 2004-09-10 2006-03-16 Evans James A Release mechanism to interact with biota, in particular fauna that may outgrow available habitat
US7156049B2 (en) * 2004-09-10 2007-01-02 The United States Of America As Represented By The Secretary Of The Army Release mechanism to interact with biota, in particular fauna that may outgrow available habitat
WO2008102247A3 (en) * 2007-02-23 2009-10-15 University Of The Witwatersrand, Johannesburg A polyamide rate-modulated monolithic drug delivery system
US20100323007A1 (en) * 2007-02-23 2010-12-23 University Of The Witwatersrand, Johannesburg A polyamide rate-modulated monolithic drug delivery system
US8277841B2 (en) 2007-02-23 2012-10-02 University of The Witwatersand, Johannesburg Polyamide rate-modulated monolithic drug delivery system

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FR2175749B3 (en) 1976-02-13 grant
NL7303376A (en) 1973-09-12 application
FR2175749A1 (en) 1973-10-26 application
DE2311843A1 (en) 1973-09-20 application
JPS491093A (en) 1974-01-08 application

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