CA1063934A - Microsealed pharmaceutical delivery device - Google Patents
Microsealed pharmaceutical delivery deviceInfo
- Publication number
- CA1063934A CA1063934A CA238,197A CA238197A CA1063934A CA 1063934 A CA1063934 A CA 1063934A CA 238197 A CA238197 A CA 238197A CA 1063934 A CA1063934 A CA 1063934A
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutical
- biologically acceptable
- silicone polymer
- microsealed
- delivery device
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
- A61K9/0039—Devices retained in the uterus for a prolonged period, e.g. intrauterine devices for contraception
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
- A61K9/2036—Silicones; Polysiloxanes
Abstract
Abstract of the Disclosure The present invention is concerned with a pharmaceutical delivery device comprising a biologically acceptable silicone polymer matrix having microsealed compartments of 10-200 microns throughout, wherein the microsealed compartments contain a pharmaceutical in a hydrophilic solvent system. The biologically acceptable silicone polymer matrix is formed by in situ cross linking of a liquid, biologically acceptable silicone polymer in an emulsion of pharmaceutical in the hydrophilic solvent system and liquid biologically acceptable silicone polymer.
The biologically acceptable silicone polymer matrix is placed in a sealed or unsealed biologically acceptable polymer container. The rate of release of pharmaceutical is controlled by altering the solubility characteristics of the hydrophilic solvent system and/or the biologically acceptable polymer matrix, the rate of release being inde-pendent of time when the ratio of the partition coefficient of the pharmaceutical between the hydrophilic solvent system and biologically acceptable silicone polymer matrix to the solubility of the pharmaceutical in the hydrophilic solvent system is between 1 and 1014 ml/mcg.
The biologically acceptable silicone polymer matrix is placed in a sealed or unsealed biologically acceptable polymer container. The rate of release of pharmaceutical is controlled by altering the solubility characteristics of the hydrophilic solvent system and/or the biologically acceptable polymer matrix, the rate of release being inde-pendent of time when the ratio of the partition coefficient of the pharmaceutical between the hydrophilic solvent system and biologically acceptable silicone polymer matrix to the solubility of the pharmaceutical in the hydrophilic solvent system is between 1 and 1014 ml/mcg.
Description
~ 1063934 The present invention is concerned with phar-maceutical delivery device comprising a bi.ologically acceptable polymer container and an inner biologically acceptable silicone polymer matrix contained within the biologically acceptable polymer container, the inner biologically acceptable silicone polymer matrix having microsealed compartments throughout, the microsealed com-partments containing a pharmaceutical in a hydrophilic solvent system, wherein the ratio of the partition coef-ficient OL the pharmaceutical between hydrophilic solvent system and the inner biologically acceptable silicone , polymer matrix to the solubility of the pharmaceutical in hydrophilic solvent system is between 1 and 10 ml/mcg, the pharmaceutical being diffusible through the inner : biologically acceptable silicone polymer matrix and '. - biologically acceptable polymer container at a therapeu-tically effective constant rate when the microsealed phar-maceutical delivery device is in an aqueous environment, ' the hydrophilic solvent system being non-diffusible through the inner biologically acceptable silicone polymer matrix and biologically acceptable polymer container. ,.
-. Biologically acceptable polymer containers are containers adapted in size and shape for implanting in a body cavity or surgically under or on the skin of a, human or an animal in need of prolonged administration of a pharma-ceutical. For example, the biolGgically acceptable polymer .
. containers encompassed in this invention may be adapted to .
serve as a vaginal or an intrauterine insert; it may be adapted as an ophthalmic medicinal delivery device for inser-'' , - 2 - ~
~0~393~
tlon ln the narrow conrines between the eyeball and the ocular cavlty; lt may be surglcally inserted for parenteral administration, and may be adapted ror administration Or pharmaceuticals to the gastrointestinal tract. The biologically acceptable polymer container may be sealed or unsealed and in this latter aspect is sharply distin-guished from polymer membranes surrounding an inner polymer matrix described in U. S. Patent 3,710,795. For example, the container may be a length of flexible biolo-gically acceptable polymer tubing which is sealed or un-sealed and also may have additional perforations in the wall of the tubing such that as much as 40% of the inner biologically acceptable sillcone polymer matrix is exposed.
Materials used to form the biologically accept-able polymer contalner are those capable of forming thinwalls or coatings through which pharmaceuticals can pass at a controlled rate. Suitable polymers are biologically and pharmaceutlcally compatlble, non-allergenic, and in-soluble ln and non-lrritating to body fluids or tissues with which the device is contacted. The use of soluble polymers is to be avolded slnce dissolution or eroslon of the devlce would affect the release rate of the pharmaceutical release rate, as well as the capability of the device to remain in place for convenience of removal. Exemplary materials for fabrlcatlng the biologically acceptable polymer container include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, expecially the medical grade polydimethyl silo-xanes, neoprene rubber, chlorinated polyethylene, polyvinyl . . . .
. 10~;3934 chloride; vinyl chloride copolymers wlth vinyl acetate,poly methacrylate polymer(hydrogel), vinylldene chlorlde, ethylene, and propylene; polyethylene terephthalate; butyl rubber; epichlorohydrin rubbers; ethylene/vinyl alcohol copolymer; ethylene/vinyl acetate/vinyl alcohol terpolymer;
ethylene/vlnyloxyethanol copolymer; and the llke. For best results, the biologically acceptable polymer container should be selected from polymers of the above classes with glass transitlon temperatures below room temperature. The polymer may, but need not necessarlly, have a degree of crystalllnity at room temperature.
Polymers especially preferred for fabricating the biologically acceptable polymer contalners of this invention have the following formula:
CH3 i I 1 fH3 ;
- CH3 Si- 0 - -Si- 0 ~ Si CH3 CH CH2 f CH2 CH2 1 i 0--CH
wherein n is about 5000 and R is selected from the group comprising phenyl, alkyl radical containing from 1 to 7 carbon atoms, vinyl, or allyl or polycarbonate copolymers thereof. Suitable polymers for fabricating biologically acceptable polymer containers are described in U.S. Patent 3,279,9g6 and 3,710,795 as well as in Plastic Materials In Surg~ry by Block and Hastin~, Charles Thomas, Publisher, _4-Springrield, Illinois, 2nd Edltlon (1972). Desirable polymers are characterlzed but not llmited to the following phy~lcal parameters :
Test Value Durometer Hardne88(shore A) 45 to 70 Tenslle strength, psi 1100 Elongation 500_700%
Tear strength lbs/ln. 120-160 The inner biologically acceptable silicone polymer matrix is preferably fabricated from room temperature cross-linked silicone rubber (polydimethylsiloxane) suCh as silicone polymers of the formula:
~ IH3~ R' ~ fH3 o li- o Ii o~ o~ , CH3, ~ ~ I CH3 CH3- Si 0 -- CH3 - m wherein R'is alkoxy radical containing ~rom l to 7 carbon atoms, alkyl radical containing from 1-10 carbon atoms, phenyl, vinyl or allyl and wherein m is about 100-5000.
A saturated solution of pharmaceutical in water and hydrophilic solvent iS dispersed throughout liquid silicone polymer by means Or high speed stirring before cross-linking of the polymer. The polymer ls cross-linked leaving microsealed compartments filled with hydrophilic solvent-water-and pharmaceutical throughout the matrix.
The matrix may be constructed in SitU in a preshaped bio-logically acceptable polymer container or the matrlx may be prerormed and coated With a polymer membrane which serves as a blologlcally acceptable polymer contalner.
Methods of coating a matrlx wlth blologlcally acceptable polymers are descrlbed ln U. S. Patent 3,710,795. Deslrable but not exclusive polymers are characterized by the follow-lng physical parameters:
Durometer Hardness (Shore A) 45-100 Tensile Strength 300-1400 Elongation 100-300%
Tear Strength 20-120 ppl The hydrophilic solvent system serves to partltlon the pharmaceutlcal between the mlcrosealed compartments and the blologically acceptable slllcone polymer matrix. The hydrophilic solvent system must be compatible with the pharma-ceutical and must not permeate the polymer or the biologicallyacceptable sllicone polymer contalner. The hydrophillc solvent system Or the present invention comprlses water and water mis-cible solvents which increase the aqueous solubillty of the pharmaceutical. Glycols such as polyethylene glycol, propy-lene glycol, butylene glycol, glycerol formal, and glycofurolare suitable solvents with polyethylene glycol of molecular weight of about 400 belng preferred. Amides such as dimethy-lacetamide and N-(~-hydroxyethyl)lactamide are also useful as solvents; ethyl lactate, dioxolanes represent other desirable pharmaceutically compatible water mlscible solvents. Ionic and neutral surface active agents in aqueous concentrations above the critlcal miscelle concentration are effective hydrophilic solvent systems. P.H. Elworthy, A.T. Florence, and C.B.
Macfarlane, Solubillzatlon by Surface Active Agents, Chapman and Hall, 1968 describe the use and selection of ~, , surface actlve agents in pharmaceutlcal chemlstry. Pre-ferred surrace active agents are exemplified by sodlum dodecyl sulfate, polysorbates, cetyl trlmethylammonlum bromide, and cetyl-pyrldinlum chlorlde.
Pharmaceuticals permeable through the blologlcally acceptable lnner sllicone polymer matrix and blologically acceptable polymer container and meetlng the earlier de-flned solublllty requirement may be effectively adminlstered over a long perlod of tlme. Scheme I illustrates the re-quired solubillty relationship between the pharmaceutlcal, the hydrophllic solvent system and biologically acceptable silicone polymer matrix.
Scheme I
Crystalline Drug Dissolutlon (Cl)~ Mlcrosealed liquid compartment Elution in lPartition (Kb) Solutlon Permeatlon ~olymer phase Solublllty of a pharmaceutlcal (~1) ls measured by constant shaking for 24 hours an excess amount of powdered pharma-ceutlcal in 10 ml. of a hydrophilic solvent system at 37C.
The solutlon is f~ltered and the content of the pharmaceu-tical is measured.
Partltion coefficient (Kb) is measured by immersing a known surface area of biologically acceptable sillcone polymer matrix materlal in a solutlon of the pharmaceutical in the hydrophilic solvent system with constant shaking for 24 hours and then measuring the amount of pharmaceutical re- -malnlng ln the solvent system.
Kb ~ Ci - Cl Cl - lnltial concentratlon Ci of pharmaceutlcal Cl - equllibrium concentration of pharmaceutical Table I i9 illustratlve of the relatlon between Cl, Kb, release rate, and klnetlcs of release Or 17~-ethynyl-4-estrene-3~,17~-dlol 3,17-dlacetate (ethynodlol diacetate) in a hydrophllic solvent system Or polyethylene glycol havlng a molecular weight of about 400.
MICROSEALED CEUTICAL PARTI- _ RAT~ OF
LIQUIDS COM- SOLUBILIT COEFF: - Kb/Cl CEUTICAL
PARTMENTS(mcg/ml) EIENT (ml/mc~` (gm/lO~cm~) KINETICS~
100% P~G 400 45600 0.032 7.0x10-7 1095/dayl/2 Q _ tl/2 80% PEG 4004460 0.332 7.4x10-5 1203/dayl/~ Q _ tl/2 60% PEG 400437 3.385 7.8x10-3 319.4 day Q - t 50% PEG 400156 9.48 6.1x10-2 315.6 day Q - t 30% PEG 40064.6 22.9 0.~ 297.8 da~ Q - t *Q _ tl/2 r~ ~latlonship (matrix-controlled process) lndlcates that the amount of pharmaceutlcal released decreases with time and Q-t relationship (partition controlled process) indicates that a con-stant amount of pharmaceutical is released independent of time.
A wide variety of pharmaceuticals may be adminis-tered over a long period of time. Steroids, alkaloids, fatty acids and lipid soluble vitam~ns are typical pharmaceutical agents which may be incorporated into the microsealed compartments of the present pharmaceutical delivery device.
Representative pharmaceuticals which are advantageously administered by the present delivery device are: -Es~rogens: Mestranol, ethynyl estradiol, estrone, estradiol, estradlol-3-methyl ether, dlethylstilbestrol, and related estrogens and ester derivatlves thereof.
Progestins: Progesterone, 17a-ethynyl-4-estrene-3B,17~-diol diacetate, 17-ethynyl-11~-methyl-4-estrene-3B,17~-dlol 3,17-diacetate, 17-acetoxy~ -methyl-19-norpregn-4-en-3-one, dl-17-ethynyl-13~-ethyl-11~-methylgon-4-ene-3~,17~-dlol 3,17-dlacetate and related progestins and deriva-tives thereof.
Androgens: Testosterone, testosterone propionate, testoster-one phenylacetate and related androgens and ester deriva-tives thereof.
Adrenal Cortlcal Hormones:Desoxycortlcosterone acetate, prednisolone, and derivatives thereof.
Diuretics (Mineralcorticoid Blocking agents): 7-ethoxy-carbonyl-17-hydroxy-3-oxo-17-pregn-4-ene-21-carboxylic acid y-lactone, 17-hydroxy-7~-methoxycarbonyl-3-oxo-17~-pregn-4-ene-21-carboxylic acid y-lactone and related diuretics and derivatives thereof.
Vitamins: Vitamin E, vitamin K and derivatives thereof.
Anti-Protozoal Agents: Nitroimidazoles such as metronidazole.
Furthermore, simple derivatives of the pharma-ceuticals (such as ethers, esters, amides, etc.) which have desirable polymer solubility and release characteristics, but which are easily hydrolyzed by body fluids, enzymes, etc., can be employed.
The amount of drug incorporated in the drug delivery device varies depending on the particular drug, the desired therapeutic effect, and the time span for which the device provides therapy. Since a variety of devices in a variety of slzes and ~hapes are intended to provide dosage regimens for therapy rOr a variety of maladies, there is no critical upper limit in the amount of druK incorporated in the devlce.
The lower limit, too, will depend on the activity of the drug and the time span of its release from the device. Thus, it is not practical to define a range for the therapeutically effective amount of drug to be incorporated in or released by the device.
Those skilled in the pharmaceutical arts will know how to determine toxic levels of a given pharmaceutical, and the minimum effective dose. With this information a proper dosage form can be prepared by measuring the in vivo rate of elution of a given pharmaceutical by standard analytic tech-niques, e.g., spectroscopic or radio immunoassay analysis.
In vitro diffusion of the pharmaceutical from a delivery device may be determined by the methods of Chien and Lambert, J. Pharm. Sci., 63, 365 (1974) or by methods described in U. S. Patent 3,710,795.
A preferred embodiment of the present invention is a microsealed pharmaceutical delivery device comprising a biologically acceptable polymer container constructed of a molecularly oriented heat shrunk, stretched polymeric membrane having reserve elastic recovery stress, an inner biologically -- acceptable silicone polymer matrix of cross-linked silicone rubber wherein the biologically acceptable silastic polymer matrix has 10-200 micron microsealed compartments distributed throughout, said microsealed compartment containing a pharma-ceutical in a hydrophilic solvent system consisting of water and 20-70% polyethylene glycol, said microsealed compartments being formed by in situ cross-linking of the silicone rubber after it is mixed with the hydrophilic solvent system contain-ing a pharmaceutical, the pharmaceutical being diffusible through the inner biologically acceptable silicone polymer ,, matrix and biologically acceptable polymer container at a therapeutlcally efrectlve constant rate when the mlcrosealed pharmaceutlcal dellvery devlce i5 ln an aqueous envlronment, said hydrophlllc solvent being non-dlrruslble through the blologlcally acceptable slllcone polymer matrix and blologl-cally acceptable polymer container.
A most preferred embodiment Or the present inven-tlon is a mlcrosealed pharmaceutical delivery device comprising a b.ologically acceptable polymer contalner constructed Or silicone polymers of the formula ICH3 - R - CH3 'r~
CH3- Si Si- - O Si CH3 CH3 ~ IH2 CH3 CH2-- CH2 Si O-- -wherein n is about 5000 and R is phenyl, alkyl radical con-taining from 1-7 carbon atoms, vinyl or allyl or polycarbonate copolymers thereor, an inner biologically acceptable sillcone polymer matrix constructed of cross-linked silicone polymer of the formula O~ ~Si OlSi--0 H3 1 0 _ CH3 m .
, wherein R' i8 alkoxy radical containing ~rom 1-7 carbon atom~, alkyl radlcal containing from l-lO carbon atoms, phenyl, vinyl or allyl and wherein m i8 about 100 to 5000 and wherein the inner biologically acceptable slllcone polymer matrix has microsealed compartments distributed throughout, said micro-sealed compartments containing a pharmaceutical in a hydro-philic solvent system conslstlng o~ water and 20-70% poly-ethylene glycol, sald microsealed compartments being formed by in sltu cross-linking of the liquid silicone polymer after ._ _ it is emulsi~ied with hydrophilic solvent system containing the pharmaceutical, the pharmaceutical being diffusible through the inner biologically acceptable silicone polymer matrix and biologically acceptable polymer container at a therapeutically effective constant rate when the microsealed pharmaceutical delivery device ls in an aqueous environment, said hydrophilic solvent belng non-dlffusible through the inner biologically acceptable silicone polymer matrix and biologically acceptable polymer oontainer.
A biologically acceptable silicone polymer matrix containlng a pharmaceutical ln a hydrophllic solvent system ls prepared as follows: 2 parts of a 40% polyethylene glycol (molecular welght 380-420) ln water ls saturated with 2 parts of ethynodiol diacetate at 37C. by vigorous agitation for lO
minutes. To this mixture is added 6 parts of llquid silicone polymer of the formula ~ IH31 f CH2 - CH2 CH3 t--5~0--Sl--o~i_ o~
~N3- 1 - 0~
m m~ 5000 ~' ~" .
sold as Silastlc~ Medical Grade 382 Elastomer by Dow-Corning and this combination ls stlrred wlth a mech~nical mixer at 1000 rpm for 28 minutes. 0.015 Parts Or a cross-linking agent (stannous octanoate) i8 added to the combina-tion and stirring is continued for 2 minutes. The combina-tion is placed in a silicone rubber tublng (I.D. 3.18mm, O.D. 6.35mm sold by Dow-Cornlng as Medlcal Grade Silastic Tubing No. 601-365). Thls tublng is a sillcone polymer of the formula fH3 -ICH3 ~ fH3 CH3 - Si ~ -li O - Si CH3 CH3 CH2n CH3 n ~ 5000 The system is allowed to cross-link for 1 hour and then the tubing is sectioned to provide pharmaceutical delivery devices with the deslred amount of pharmaceutical. The ends of the sections may be sealed or left open and addi-tional openings may be made in the walls of the tubing - 15 to facilitate higher but still constant rates of release.
This device releases 315.6 mcg/cm2 per day of ethynodiol diacetate. Replacement of the ethynodiol diacetate with
-. Biologically acceptable polymer containers are containers adapted in size and shape for implanting in a body cavity or surgically under or on the skin of a, human or an animal in need of prolonged administration of a pharma-ceutical. For example, the biolGgically acceptable polymer .
. containers encompassed in this invention may be adapted to .
serve as a vaginal or an intrauterine insert; it may be adapted as an ophthalmic medicinal delivery device for inser-'' , - 2 - ~
~0~393~
tlon ln the narrow conrines between the eyeball and the ocular cavlty; lt may be surglcally inserted for parenteral administration, and may be adapted ror administration Or pharmaceuticals to the gastrointestinal tract. The biologically acceptable polymer container may be sealed or unsealed and in this latter aspect is sharply distin-guished from polymer membranes surrounding an inner polymer matrix described in U. S. Patent 3,710,795. For example, the container may be a length of flexible biolo-gically acceptable polymer tubing which is sealed or un-sealed and also may have additional perforations in the wall of the tubing such that as much as 40% of the inner biologically acceptable sillcone polymer matrix is exposed.
Materials used to form the biologically accept-able polymer contalner are those capable of forming thinwalls or coatings through which pharmaceuticals can pass at a controlled rate. Suitable polymers are biologically and pharmaceutlcally compatlble, non-allergenic, and in-soluble ln and non-lrritating to body fluids or tissues with which the device is contacted. The use of soluble polymers is to be avolded slnce dissolution or eroslon of the devlce would affect the release rate of the pharmaceutical release rate, as well as the capability of the device to remain in place for convenience of removal. Exemplary materials for fabrlcatlng the biologically acceptable polymer container include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, expecially the medical grade polydimethyl silo-xanes, neoprene rubber, chlorinated polyethylene, polyvinyl . . . .
. 10~;3934 chloride; vinyl chloride copolymers wlth vinyl acetate,poly methacrylate polymer(hydrogel), vinylldene chlorlde, ethylene, and propylene; polyethylene terephthalate; butyl rubber; epichlorohydrin rubbers; ethylene/vinyl alcohol copolymer; ethylene/vinyl acetate/vinyl alcohol terpolymer;
ethylene/vlnyloxyethanol copolymer; and the llke. For best results, the biologically acceptable polymer container should be selected from polymers of the above classes with glass transitlon temperatures below room temperature. The polymer may, but need not necessarlly, have a degree of crystalllnity at room temperature.
Polymers especially preferred for fabricating the biologically acceptable polymer contalners of this invention have the following formula:
CH3 i I 1 fH3 ;
- CH3 Si- 0 - -Si- 0 ~ Si CH3 CH CH2 f CH2 CH2 1 i 0--CH
wherein n is about 5000 and R is selected from the group comprising phenyl, alkyl radical containing from 1 to 7 carbon atoms, vinyl, or allyl or polycarbonate copolymers thereof. Suitable polymers for fabricating biologically acceptable polymer containers are described in U.S. Patent 3,279,9g6 and 3,710,795 as well as in Plastic Materials In Surg~ry by Block and Hastin~, Charles Thomas, Publisher, _4-Springrield, Illinois, 2nd Edltlon (1972). Desirable polymers are characterlzed but not llmited to the following phy~lcal parameters :
Test Value Durometer Hardne88(shore A) 45 to 70 Tenslle strength, psi 1100 Elongation 500_700%
Tear strength lbs/ln. 120-160 The inner biologically acceptable silicone polymer matrix is preferably fabricated from room temperature cross-linked silicone rubber (polydimethylsiloxane) suCh as silicone polymers of the formula:
~ IH3~ R' ~ fH3 o li- o Ii o~ o~ , CH3, ~ ~ I CH3 CH3- Si 0 -- CH3 - m wherein R'is alkoxy radical containing ~rom l to 7 carbon atoms, alkyl radical containing from 1-10 carbon atoms, phenyl, vinyl or allyl and wherein m is about 100-5000.
A saturated solution of pharmaceutical in water and hydrophilic solvent iS dispersed throughout liquid silicone polymer by means Or high speed stirring before cross-linking of the polymer. The polymer ls cross-linked leaving microsealed compartments filled with hydrophilic solvent-water-and pharmaceutical throughout the matrix.
The matrix may be constructed in SitU in a preshaped bio-logically acceptable polymer container or the matrlx may be prerormed and coated With a polymer membrane which serves as a blologlcally acceptable polymer contalner.
Methods of coating a matrlx wlth blologlcally acceptable polymers are descrlbed ln U. S. Patent 3,710,795. Deslrable but not exclusive polymers are characterized by the follow-lng physical parameters:
Durometer Hardness (Shore A) 45-100 Tensile Strength 300-1400 Elongation 100-300%
Tear Strength 20-120 ppl The hydrophilic solvent system serves to partltlon the pharmaceutlcal between the mlcrosealed compartments and the blologically acceptable slllcone polymer matrix. The hydrophilic solvent system must be compatible with the pharma-ceutical and must not permeate the polymer or the biologicallyacceptable sllicone polymer contalner. The hydrophillc solvent system Or the present invention comprlses water and water mis-cible solvents which increase the aqueous solubillty of the pharmaceutical. Glycols such as polyethylene glycol, propy-lene glycol, butylene glycol, glycerol formal, and glycofurolare suitable solvents with polyethylene glycol of molecular weight of about 400 belng preferred. Amides such as dimethy-lacetamide and N-(~-hydroxyethyl)lactamide are also useful as solvents; ethyl lactate, dioxolanes represent other desirable pharmaceutically compatible water mlscible solvents. Ionic and neutral surface active agents in aqueous concentrations above the critlcal miscelle concentration are effective hydrophilic solvent systems. P.H. Elworthy, A.T. Florence, and C.B.
Macfarlane, Solubillzatlon by Surface Active Agents, Chapman and Hall, 1968 describe the use and selection of ~, , surface actlve agents in pharmaceutlcal chemlstry. Pre-ferred surrace active agents are exemplified by sodlum dodecyl sulfate, polysorbates, cetyl trlmethylammonlum bromide, and cetyl-pyrldinlum chlorlde.
Pharmaceuticals permeable through the blologlcally acceptable lnner sllicone polymer matrix and blologically acceptable polymer container and meetlng the earlier de-flned solublllty requirement may be effectively adminlstered over a long perlod of tlme. Scheme I illustrates the re-quired solubillty relationship between the pharmaceutlcal, the hydrophllic solvent system and biologically acceptable silicone polymer matrix.
Scheme I
Crystalline Drug Dissolutlon (Cl)~ Mlcrosealed liquid compartment Elution in lPartition (Kb) Solutlon Permeatlon ~olymer phase Solublllty of a pharmaceutlcal (~1) ls measured by constant shaking for 24 hours an excess amount of powdered pharma-ceutlcal in 10 ml. of a hydrophilic solvent system at 37C.
The solutlon is f~ltered and the content of the pharmaceu-tical is measured.
Partltion coefficient (Kb) is measured by immersing a known surface area of biologically acceptable sillcone polymer matrix materlal in a solutlon of the pharmaceutical in the hydrophilic solvent system with constant shaking for 24 hours and then measuring the amount of pharmaceutical re- -malnlng ln the solvent system.
Kb ~ Ci - Cl Cl - lnltial concentratlon Ci of pharmaceutlcal Cl - equllibrium concentration of pharmaceutical Table I i9 illustratlve of the relatlon between Cl, Kb, release rate, and klnetlcs of release Or 17~-ethynyl-4-estrene-3~,17~-dlol 3,17-dlacetate (ethynodlol diacetate) in a hydrophllic solvent system Or polyethylene glycol havlng a molecular weight of about 400.
MICROSEALED CEUTICAL PARTI- _ RAT~ OF
LIQUIDS COM- SOLUBILIT COEFF: - Kb/Cl CEUTICAL
PARTMENTS(mcg/ml) EIENT (ml/mc~` (gm/lO~cm~) KINETICS~
100% P~G 400 45600 0.032 7.0x10-7 1095/dayl/2 Q _ tl/2 80% PEG 4004460 0.332 7.4x10-5 1203/dayl/~ Q _ tl/2 60% PEG 400437 3.385 7.8x10-3 319.4 day Q - t 50% PEG 400156 9.48 6.1x10-2 315.6 day Q - t 30% PEG 40064.6 22.9 0.~ 297.8 da~ Q - t *Q _ tl/2 r~ ~latlonship (matrix-controlled process) lndlcates that the amount of pharmaceutlcal released decreases with time and Q-t relationship (partition controlled process) indicates that a con-stant amount of pharmaceutical is released independent of time.
A wide variety of pharmaceuticals may be adminis-tered over a long period of time. Steroids, alkaloids, fatty acids and lipid soluble vitam~ns are typical pharmaceutical agents which may be incorporated into the microsealed compartments of the present pharmaceutical delivery device.
Representative pharmaceuticals which are advantageously administered by the present delivery device are: -Es~rogens: Mestranol, ethynyl estradiol, estrone, estradiol, estradlol-3-methyl ether, dlethylstilbestrol, and related estrogens and ester derivatlves thereof.
Progestins: Progesterone, 17a-ethynyl-4-estrene-3B,17~-diol diacetate, 17-ethynyl-11~-methyl-4-estrene-3B,17~-dlol 3,17-diacetate, 17-acetoxy~ -methyl-19-norpregn-4-en-3-one, dl-17-ethynyl-13~-ethyl-11~-methylgon-4-ene-3~,17~-dlol 3,17-dlacetate and related progestins and deriva-tives thereof.
Androgens: Testosterone, testosterone propionate, testoster-one phenylacetate and related androgens and ester deriva-tives thereof.
Adrenal Cortlcal Hormones:Desoxycortlcosterone acetate, prednisolone, and derivatives thereof.
Diuretics (Mineralcorticoid Blocking agents): 7-ethoxy-carbonyl-17-hydroxy-3-oxo-17-pregn-4-ene-21-carboxylic acid y-lactone, 17-hydroxy-7~-methoxycarbonyl-3-oxo-17~-pregn-4-ene-21-carboxylic acid y-lactone and related diuretics and derivatives thereof.
Vitamins: Vitamin E, vitamin K and derivatives thereof.
Anti-Protozoal Agents: Nitroimidazoles such as metronidazole.
Furthermore, simple derivatives of the pharma-ceuticals (such as ethers, esters, amides, etc.) which have desirable polymer solubility and release characteristics, but which are easily hydrolyzed by body fluids, enzymes, etc., can be employed.
The amount of drug incorporated in the drug delivery device varies depending on the particular drug, the desired therapeutic effect, and the time span for which the device provides therapy. Since a variety of devices in a variety of slzes and ~hapes are intended to provide dosage regimens for therapy rOr a variety of maladies, there is no critical upper limit in the amount of druK incorporated in the devlce.
The lower limit, too, will depend on the activity of the drug and the time span of its release from the device. Thus, it is not practical to define a range for the therapeutically effective amount of drug to be incorporated in or released by the device.
Those skilled in the pharmaceutical arts will know how to determine toxic levels of a given pharmaceutical, and the minimum effective dose. With this information a proper dosage form can be prepared by measuring the in vivo rate of elution of a given pharmaceutical by standard analytic tech-niques, e.g., spectroscopic or radio immunoassay analysis.
In vitro diffusion of the pharmaceutical from a delivery device may be determined by the methods of Chien and Lambert, J. Pharm. Sci., 63, 365 (1974) or by methods described in U. S. Patent 3,710,795.
A preferred embodiment of the present invention is a microsealed pharmaceutical delivery device comprising a biologically acceptable polymer container constructed of a molecularly oriented heat shrunk, stretched polymeric membrane having reserve elastic recovery stress, an inner biologically -- acceptable silicone polymer matrix of cross-linked silicone rubber wherein the biologically acceptable silastic polymer matrix has 10-200 micron microsealed compartments distributed throughout, said microsealed compartment containing a pharma-ceutical in a hydrophilic solvent system consisting of water and 20-70% polyethylene glycol, said microsealed compartments being formed by in situ cross-linking of the silicone rubber after it is mixed with the hydrophilic solvent system contain-ing a pharmaceutical, the pharmaceutical being diffusible through the inner biologically acceptable silicone polymer ,, matrix and biologically acceptable polymer container at a therapeutlcally efrectlve constant rate when the mlcrosealed pharmaceutlcal dellvery devlce i5 ln an aqueous envlronment, said hydrophlllc solvent being non-dlrruslble through the blologlcally acceptable slllcone polymer matrix and blologl-cally acceptable polymer container.
A most preferred embodiment Or the present inven-tlon is a mlcrosealed pharmaceutical delivery device comprising a b.ologically acceptable polymer contalner constructed Or silicone polymers of the formula ICH3 - R - CH3 'r~
CH3- Si Si- - O Si CH3 CH3 ~ IH2 CH3 CH2-- CH2 Si O-- -wherein n is about 5000 and R is phenyl, alkyl radical con-taining from 1-7 carbon atoms, vinyl or allyl or polycarbonate copolymers thereor, an inner biologically acceptable sillcone polymer matrix constructed of cross-linked silicone polymer of the formula O~ ~Si OlSi--0 H3 1 0 _ CH3 m .
, wherein R' i8 alkoxy radical containing ~rom 1-7 carbon atom~, alkyl radlcal containing from l-lO carbon atoms, phenyl, vinyl or allyl and wherein m i8 about 100 to 5000 and wherein the inner biologically acceptable slllcone polymer matrix has microsealed compartments distributed throughout, said micro-sealed compartments containing a pharmaceutical in a hydro-philic solvent system conslstlng o~ water and 20-70% poly-ethylene glycol, sald microsealed compartments being formed by in sltu cross-linking of the liquid silicone polymer after ._ _ it is emulsi~ied with hydrophilic solvent system containing the pharmaceutical, the pharmaceutical being diffusible through the inner biologically acceptable silicone polymer matrix and biologically acceptable polymer container at a therapeutically effective constant rate when the microsealed pharmaceutical delivery device ls in an aqueous environment, said hydrophilic solvent belng non-dlffusible through the inner biologically acceptable silicone polymer matrix and biologically acceptable polymer oontainer.
A biologically acceptable silicone polymer matrix containlng a pharmaceutical ln a hydrophllic solvent system ls prepared as follows: 2 parts of a 40% polyethylene glycol (molecular welght 380-420) ln water ls saturated with 2 parts of ethynodiol diacetate at 37C. by vigorous agitation for lO
minutes. To this mixture is added 6 parts of llquid silicone polymer of the formula ~ IH31 f CH2 - CH2 CH3 t--5~0--Sl--o~i_ o~
~N3- 1 - 0~
m m~ 5000 ~' ~" .
sold as Silastlc~ Medical Grade 382 Elastomer by Dow-Corning and this combination ls stlrred wlth a mech~nical mixer at 1000 rpm for 28 minutes. 0.015 Parts Or a cross-linking agent (stannous octanoate) i8 added to the combina-tion and stirring is continued for 2 minutes. The combina-tion is placed in a silicone rubber tublng (I.D. 3.18mm, O.D. 6.35mm sold by Dow-Cornlng as Medlcal Grade Silastic Tubing No. 601-365). Thls tublng is a sillcone polymer of the formula fH3 -ICH3 ~ fH3 CH3 - Si ~ -li O - Si CH3 CH3 CH2n CH3 n ~ 5000 The system is allowed to cross-link for 1 hour and then the tubing is sectioned to provide pharmaceutical delivery devices with the deslred amount of pharmaceutical. The ends of the sections may be sealed or left open and addi-tional openings may be made in the walls of the tubing - 15 to facilitate higher but still constant rates of release.
This device releases 315.6 mcg/cm2 per day of ethynodiol diacetate. Replacement of the ethynodiol diacetate with
2 parts of one of the following pharmaceuticals provides the indicated release rate:
Release Rate mcg/cm~ per day 17a-acetoxy-11~-methyl-19-norpregn-4-ene-
Release Rate mcg/cm~ per day 17a-acetoxy-11~-methyl-19-norpregn-4-ene-
3,20-dione 51.89 Desoxycorticosterone acetate 55~1 17-hydroxy-7~-methoxycarbonyl-3-oxo-17a-pregn-4-ene-21-carboxyllc acid y-lactone 63. o8 7-acetylthio-17-hydroxy-3-oxo-17a-pregn-
4-ene-21-carboxylic acid y-lactone 18.25 metronldazole 4.23 The present invention encompasses a method of distributing a pharmaceutical throughout a biologically acceptable silicone polymer comprising (a) emulsifying a mixture of a liquid biologically acceptable silicone polymer and hydrophilic solvent system containing a pharmaceutical and (b) in situ cross-linking of the liquid biologically acceptable silicone polymer to form a biolo-gically acceptable silicone polymer matrix, said biologi-cally acceptable silicone polymer matrix having microsealed compartments of 10 to 200 microns throughout, said micro-sealed compartments containing the pharmaceutical and the hydrophilic solvent system.
Preferably the present invention encompasses a method of distributing a pharmaceutical throughout a biologically acceptable sllicone polymer comprising:
(a) emulsifying a mixture of a biologically acceptable liquid silicon polymer of the formula ,, ~ fH3 I R" ~CH3 _ ~O - -Si- -o IS1 O- -S1 0 _ :~
CH3 ~ 1 _CH3 _ m ~H3 li- 0 L CH3 m wherein R" is alkoxy radical contalnlng from 1-7 carbon atoms, alkyl radical containlng from 1-10 carbon atoms, or allyl and m ls about 100-5000 with a pharmaceutical in a hydrophilic sol-vent system of 20-70% polyethylene glycol in water; and (b) in situ cross-llnking the biologlcally acceptable liquid silicone polymer to form a biologically acceptable silicon polymer matrix havlng microsealed compartments of 10-200 microns throughout, said microsealed compartment 8 contain-ing the pharmaceutlcal in the hydrophilic solvent syætem.
Thus, the present inventlon encompasses an improvement in known pharmaceutical delivery devices, the improvement comprising a biologically acceptable polymer matrix having 10-200 micron microsealed compartments throughout, the microsealed compartments containing a pharmaceutical in a hydrophllic solvent system, the improve-ment providing for control of the release rate of the -pharmaceutical as a function of time.
A number Or pharmaceutical delivery devices wherein a pharmaceutical is enclosed in a polymer are known. U.S.
Patent 3,279,996 describes an implantate comprising a pharma-ceutical delivery device consisting of a pharmaceutical en-closed in silicone polymer. The present device is particularly dlstinguished in that the pharmaceutical in a hydrophilic solvent sy~tem is contained in microsealed compartments distributed /
~063934 throughout the silicone polymer matrlx. U.S. Patent 3,279,996 describes in situ polymerlzatlon Or a liquld slllcone polymer containing a pharmaceutical in vivo, but there is no hydrophilic solvent to control the rate Or pharmaceutlcal release or for the formatlon Or microsealed compartments.
The presence of microsealed compartments was established by replacing the pharmaceutical wlth a hydrophilic dye and visually observing with the aid of a mlcroscope the locatlon of the dye in discrete mlcrosealed pockets. It has also been observed that pharmaceuticals which are highly soluble in sllicone polymer such as ethynodiol diacetate have a release rate from silicone rubber implantates proportlonal to the square root Or time (Tl/2) in the absence Or micro-sealed compartments containing a suitable hydrophillc solvent. A sillcone rubber capsule containing crystalline drug within as described in U. S. Patent 3,279,996 likewise has a rate Or release proportional to T1/2 and has an inherent danger of an overdose resulting ~rom a ruptured capsule. No such danger exists with the present pharmaceu-tical delivery device.
U. S. Patent 3,710,795 describes a pharmaceutical delivery device comprising an inner polymer matrix with crystalline pharmaceutical distributed throughou~ and an outer polymer membrane surrounding the inner polymer matrix. The present device ls particularly distinct in that the pharmaceutical in a hydrophilic solvent is contained ln mJcrosealed compartments throughout the inner polymer matrix. The delivery system described ln U. S. Patent 3,710,795 releases pharmaceutlcal at rates proportional to the square root of tlme (T1/2) where as in the delivery system of the present lnventlon the rate Or drug release may be altered from T1/2 to T0 (independent of time) by ad~usting the solubillty characteristlcs of the hydrophllic solvent syste~ (Table I). The use of 30-60% polyethylene glycol results in a rate of release independent of time (T0) whereas the use of larger percentages of polyethylene glycol results in a rate of release proportional to T1/2.
Thus, in the present system the relatlonship of the rate of release to time may be controlled by selection of an appropriate solvent. It is also noted that the delivery devices of the present invention do not have to be surrounded by an outer membrane. In fact, up to 40% of the inner matrix may be exposed. Exposing the inner matrix advantageously increases the rate of pharmaceutical released without altering the relationship of the release rate to time, i.e., in a constant rate dellvery device exposure of the inner matrix results in a higher but constant rate of release.
U. S. Patent 3,545,439 describes pharmaceutical delivery devices prepared by mixing the pharmaceutical with a liquid silicone rubber and then in situ cross-linking the liquid silastic rubber at room temperature.
The rate of pharmaceutical release profile from these devices is related to T1/2. The present devices are advan-tageous in that the relationship between rate of release and time may be controlled as mentloned above.
The following examples are set forth to illustrate the present invention and are not intended to limit the in-vention in spirit or in scope. It will be apparent to those skilled in the art that many modifications, both in ,, --lZ--" ~ .
~063934 materials and of methods may be practlced wlthout departing from the purpose and lntent Or thls dlsclosure. Throu~hout the examples herelnafter set forth, temperatures are glven ln degree~ Centigrade (0C) and relatlve amounts of materlals in parts by weight, except as otherwise indicated. The relationship between parts by weight and parts by volume i8 the same as that existing between grams and mllliliters.
~XAMPLE 1 2 Parts of a 40Z polyethylene glycol (molecular weight 380-420) in water was saturated with 2 parts of ethynodiol diacetate at 37C. by vigorous agitation for 10 minute3. To thls mixture was added 6 parts of silicone polymer of the formula _ o ~ 9t ~ - 5~ - ~
m ¦ m ~H3 - Si 0~
L CH3 ~ m 100-5000 sold as Sllastic~ Medical Grade 382 Elastomer by Dow-Corning and this combination was stirred with a mechanical mixer at 1000 rpm for 28 mlnutes. 0,015 Parts of a cross-linking agent stannous octanoate was added to the com-bination and stirring was continued for 2 minutes. The combination was placed in silicone polymer tubing (I.D.
3.18 mm, O.D. 6.35 mm sold by Dow-Corning as Medical Grade Silastic tubing No. 601-365). Thia tubing is a silicone polymer of the formula ICH3 _1H3 - 1 3 -CH3 Si - - Si - CH3 n 5000 ¦ 1 3 CH2 CH2 ISi O--~' ' ,' , ' ' .
The system was allowed to set for 1 hour and the tublng was sectioned to provide pharmaceutical delivery devices with the desired amount of pharmaceutlcal.
EXAMPLE Z
The silastic tubing was removed from the biolo-gically acceptable inner polymer matrix prepared in Example 1 and a molecularly bi-axially oriented, heat shrinkable polyethylene film, of 2 mil thickness was embossed about the inner matrix by using conventional metal stamping practice. The silicone polymer matrix was then sandwiched between two pieces of the heat shrinkable polyethylene in the embossed sections so that the matrix was completely enveloped by the film. The film was then heat sealed and cut around the periphery of the matrix. The enshrouded matrix was then heated for 3 seconds at about 149C. resulting in shrinkage of the film and effecting a tight and intimate contact of the film with the pharmaceutical containing silicone polymer matrix.
The heat shrunk polyethylene film may be par-tially removed to expose the inner polymer matrix to provide a somewhat higher but constant rate of release.
An emulsion of 2 parts of a 40% polyethylene glycol (molecular weight 380-420) in water was saturated with 2 parts of 17~-acetoxy-11~-methyl-19-norpregn-4-ene-3,20-dione at 37C. by vigorous agitation for 10 minutes.
To this mixture was added 6 parts of room temperature vul-canizlng sillcone polymer sold as Silastic~ Medlcal Grade . . .
~063934 382 elastomer by Dow-Corning and thls comblnatlon was stlrred with a mechanical mixer at 1000 rpm for 28 minutes. 0,015 Parts of a cross-linking agent (stannous octoate) was added to the combination and stlrring was contlnued for 2 minutes. The resulting emulsion was placed into heat shrinkable tubing composed of a copolymer of ethylene and vinyl acetate of 82% ethylene and 18%
vinyl acetate. The tubing was of the type rendered heat shrinkable by intermolecular cross-linking followed by molecular orientation as described earlier. The ends of the tubing may be sealed by heat sealing or by the insertion of plugs. The tubing was heat shrunk by ex-posure to air heated at about 138C for 5-15 seconds.
The tubing may be cut into sections and the ends sealed or left unsealed.
Following the procedure set out in Example 2, a biologically acceptable silastic polymer matrix con-taining 2 parts of progesterone in place of ethynodiol diacetate was enclosed with heat shrinkable rubber hydro-chloride film 1 mil thick by enclosing pre-set the biolo-gically acceptable silicone polymer matrix with molecularly orientated heat shrunk rubber hydrochloride film and heat shrinking at about 149C. for 5 seconds.
Following the procedure in Example 1, a device containing 17~-acetoxy-11~-methyl-19-norpregn-4-ene-3,20-dione was prepared by using 2 parts of that compound ln place of ethynodiol diacetate. This device releases -2~-17-acetoxy-11~-methyl-19-norpregn-4-ene 3,20-dlone at a rate of 51,89 mcg/cm per day.
Following the procedure in Example 1, a device containing desoxycorticosterone acetate was prepared by using 2 parts of that compound in place of ethynodiol diacetate. This device releases desoxycortisosterone acetate at a rate of 55,1 mcg/cm2 per day.
Following the procedure in Example 1, a device containing 17-hydroxy-7~-methoxycarbonyl-3-oxo-17a-pregn-4-ene-21-carboxylic acid y-lactone was prepared by using 2 parts of that compound in place of ethynodiol diacetate.
This device releases 17-hydroxy-7~-methoxycarbonyl-3-oxo-17a-pregn-4-ene-21-carboxyllc acid ~-lactone at a rate of 63,08 mcg/cm per day.
Following the procedure in Example 1, a device containing 7a-acetylthio-17-hydroxy-3-oxo-17a-pregn-4-ene-21-carboxylic acid y-lactone was prepared by using 2 parts of that compound in place of ethynodiol diacetate.
This device releases 7a-acetylthio-17-hydroxy-3-oxo-17a-pregn-4-ene-21-carboxylic acid ~-lactone at a rate of 18,25 mcg/cm2 per day.
, ~
Following the procedure in Example 1, a pharma-ceutical delivery device was prepared from 6 parts of -liquid sllicone polymer ~old as Silastic~ Medical Grade MDX-4 4210 by Dow-Corning and 1,9 part of ethynodlol diacetate and 0,1 part of mestranol in 2 parts 40% poly-ethylene glycol (molecular weight 400) in water.
Following the procedure ln Example 1, a pharma-ceutical delivery device was prepared from 6 parts of liquid sillcone polymer sold as Silastic~ Medical Grade MDX-4 4210 by Dow-Corning and 2 parts of dl-17-ethynyl-13B-ethyl-llB-methylgon-4-ene-3B,17B-diol 3,17-diacetate in 2 parts 40% polyethylene glycol (molecular weight 400) in water.
Preferably the present invention encompasses a method of distributing a pharmaceutical throughout a biologically acceptable sllicone polymer comprising:
(a) emulsifying a mixture of a biologically acceptable liquid silicon polymer of the formula ,, ~ fH3 I R" ~CH3 _ ~O - -Si- -o IS1 O- -S1 0 _ :~
CH3 ~ 1 _CH3 _ m ~H3 li- 0 L CH3 m wherein R" is alkoxy radical contalnlng from 1-7 carbon atoms, alkyl radical containlng from 1-10 carbon atoms, or allyl and m ls about 100-5000 with a pharmaceutical in a hydrophilic sol-vent system of 20-70% polyethylene glycol in water; and (b) in situ cross-llnking the biologlcally acceptable liquid silicone polymer to form a biologically acceptable silicon polymer matrix havlng microsealed compartments of 10-200 microns throughout, said microsealed compartment 8 contain-ing the pharmaceutlcal in the hydrophilic solvent syætem.
Thus, the present inventlon encompasses an improvement in known pharmaceutical delivery devices, the improvement comprising a biologically acceptable polymer matrix having 10-200 micron microsealed compartments throughout, the microsealed compartments containing a pharmaceutical in a hydrophllic solvent system, the improve-ment providing for control of the release rate of the -pharmaceutical as a function of time.
A number Or pharmaceutical delivery devices wherein a pharmaceutical is enclosed in a polymer are known. U.S.
Patent 3,279,996 describes an implantate comprising a pharma-ceutical delivery device consisting of a pharmaceutical en-closed in silicone polymer. The present device is particularly dlstinguished in that the pharmaceutical in a hydrophilic solvent sy~tem is contained in microsealed compartments distributed /
~063934 throughout the silicone polymer matrlx. U.S. Patent 3,279,996 describes in situ polymerlzatlon Or a liquld slllcone polymer containing a pharmaceutical in vivo, but there is no hydrophilic solvent to control the rate Or pharmaceutlcal release or for the formatlon Or microsealed compartments.
The presence of microsealed compartments was established by replacing the pharmaceutical wlth a hydrophilic dye and visually observing with the aid of a mlcroscope the locatlon of the dye in discrete mlcrosealed pockets. It has also been observed that pharmaceuticals which are highly soluble in sllicone polymer such as ethynodiol diacetate have a release rate from silicone rubber implantates proportlonal to the square root Or time (Tl/2) in the absence Or micro-sealed compartments containing a suitable hydrophillc solvent. A sillcone rubber capsule containing crystalline drug within as described in U. S. Patent 3,279,996 likewise has a rate Or release proportional to T1/2 and has an inherent danger of an overdose resulting ~rom a ruptured capsule. No such danger exists with the present pharmaceu-tical delivery device.
U. S. Patent 3,710,795 describes a pharmaceutical delivery device comprising an inner polymer matrix with crystalline pharmaceutical distributed throughou~ and an outer polymer membrane surrounding the inner polymer matrix. The present device ls particularly distinct in that the pharmaceutical in a hydrophilic solvent is contained ln mJcrosealed compartments throughout the inner polymer matrix. The delivery system described ln U. S. Patent 3,710,795 releases pharmaceutlcal at rates proportional to the square root of tlme (T1/2) where as in the delivery system of the present lnventlon the rate Or drug release may be altered from T1/2 to T0 (independent of time) by ad~usting the solubillty characteristlcs of the hydrophllic solvent syste~ (Table I). The use of 30-60% polyethylene glycol results in a rate of release independent of time (T0) whereas the use of larger percentages of polyethylene glycol results in a rate of release proportional to T1/2.
Thus, in the present system the relatlonship of the rate of release to time may be controlled by selection of an appropriate solvent. It is also noted that the delivery devices of the present invention do not have to be surrounded by an outer membrane. In fact, up to 40% of the inner matrix may be exposed. Exposing the inner matrix advantageously increases the rate of pharmaceutical released without altering the relationship of the release rate to time, i.e., in a constant rate dellvery device exposure of the inner matrix results in a higher but constant rate of release.
U. S. Patent 3,545,439 describes pharmaceutical delivery devices prepared by mixing the pharmaceutical with a liquid silicone rubber and then in situ cross-linking the liquid silastic rubber at room temperature.
The rate of pharmaceutical release profile from these devices is related to T1/2. The present devices are advan-tageous in that the relationship between rate of release and time may be controlled as mentloned above.
The following examples are set forth to illustrate the present invention and are not intended to limit the in-vention in spirit or in scope. It will be apparent to those skilled in the art that many modifications, both in ,, --lZ--" ~ .
~063934 materials and of methods may be practlced wlthout departing from the purpose and lntent Or thls dlsclosure. Throu~hout the examples herelnafter set forth, temperatures are glven ln degree~ Centigrade (0C) and relatlve amounts of materlals in parts by weight, except as otherwise indicated. The relationship between parts by weight and parts by volume i8 the same as that existing between grams and mllliliters.
~XAMPLE 1 2 Parts of a 40Z polyethylene glycol (molecular weight 380-420) in water was saturated with 2 parts of ethynodiol diacetate at 37C. by vigorous agitation for 10 minute3. To thls mixture was added 6 parts of silicone polymer of the formula _ o ~ 9t ~ - 5~ - ~
m ¦ m ~H3 - Si 0~
L CH3 ~ m 100-5000 sold as Sllastic~ Medical Grade 382 Elastomer by Dow-Corning and this combination was stirred with a mechanical mixer at 1000 rpm for 28 mlnutes. 0,015 Parts of a cross-linking agent stannous octanoate was added to the com-bination and stirring was continued for 2 minutes. The combination was placed in silicone polymer tubing (I.D.
3.18 mm, O.D. 6.35 mm sold by Dow-Corning as Medical Grade Silastic tubing No. 601-365). Thia tubing is a silicone polymer of the formula ICH3 _1H3 - 1 3 -CH3 Si - - Si - CH3 n 5000 ¦ 1 3 CH2 CH2 ISi O--~' ' ,' , ' ' .
The system was allowed to set for 1 hour and the tublng was sectioned to provide pharmaceutical delivery devices with the desired amount of pharmaceutlcal.
EXAMPLE Z
The silastic tubing was removed from the biolo-gically acceptable inner polymer matrix prepared in Example 1 and a molecularly bi-axially oriented, heat shrinkable polyethylene film, of 2 mil thickness was embossed about the inner matrix by using conventional metal stamping practice. The silicone polymer matrix was then sandwiched between two pieces of the heat shrinkable polyethylene in the embossed sections so that the matrix was completely enveloped by the film. The film was then heat sealed and cut around the periphery of the matrix. The enshrouded matrix was then heated for 3 seconds at about 149C. resulting in shrinkage of the film and effecting a tight and intimate contact of the film with the pharmaceutical containing silicone polymer matrix.
The heat shrunk polyethylene film may be par-tially removed to expose the inner polymer matrix to provide a somewhat higher but constant rate of release.
An emulsion of 2 parts of a 40% polyethylene glycol (molecular weight 380-420) in water was saturated with 2 parts of 17~-acetoxy-11~-methyl-19-norpregn-4-ene-3,20-dione at 37C. by vigorous agitation for 10 minutes.
To this mixture was added 6 parts of room temperature vul-canizlng sillcone polymer sold as Silastic~ Medlcal Grade . . .
~063934 382 elastomer by Dow-Corning and thls comblnatlon was stlrred with a mechanical mixer at 1000 rpm for 28 minutes. 0,015 Parts of a cross-linking agent (stannous octoate) was added to the combination and stlrring was contlnued for 2 minutes. The resulting emulsion was placed into heat shrinkable tubing composed of a copolymer of ethylene and vinyl acetate of 82% ethylene and 18%
vinyl acetate. The tubing was of the type rendered heat shrinkable by intermolecular cross-linking followed by molecular orientation as described earlier. The ends of the tubing may be sealed by heat sealing or by the insertion of plugs. The tubing was heat shrunk by ex-posure to air heated at about 138C for 5-15 seconds.
The tubing may be cut into sections and the ends sealed or left unsealed.
Following the procedure set out in Example 2, a biologically acceptable silastic polymer matrix con-taining 2 parts of progesterone in place of ethynodiol diacetate was enclosed with heat shrinkable rubber hydro-chloride film 1 mil thick by enclosing pre-set the biolo-gically acceptable silicone polymer matrix with molecularly orientated heat shrunk rubber hydrochloride film and heat shrinking at about 149C. for 5 seconds.
Following the procedure in Example 1, a device containing 17~-acetoxy-11~-methyl-19-norpregn-4-ene-3,20-dione was prepared by using 2 parts of that compound ln place of ethynodiol diacetate. This device releases -2~-17-acetoxy-11~-methyl-19-norpregn-4-ene 3,20-dlone at a rate of 51,89 mcg/cm per day.
Following the procedure in Example 1, a device containing desoxycorticosterone acetate was prepared by using 2 parts of that compound in place of ethynodiol diacetate. This device releases desoxycortisosterone acetate at a rate of 55,1 mcg/cm2 per day.
Following the procedure in Example 1, a device containing 17-hydroxy-7~-methoxycarbonyl-3-oxo-17a-pregn-4-ene-21-carboxylic acid y-lactone was prepared by using 2 parts of that compound in place of ethynodiol diacetate.
This device releases 17-hydroxy-7~-methoxycarbonyl-3-oxo-17a-pregn-4-ene-21-carboxyllc acid ~-lactone at a rate of 63,08 mcg/cm per day.
Following the procedure in Example 1, a device containing 7a-acetylthio-17-hydroxy-3-oxo-17a-pregn-4-ene-21-carboxylic acid y-lactone was prepared by using 2 parts of that compound in place of ethynodiol diacetate.
This device releases 7a-acetylthio-17-hydroxy-3-oxo-17a-pregn-4-ene-21-carboxylic acid ~-lactone at a rate of 18,25 mcg/cm2 per day.
, ~
Following the procedure in Example 1, a pharma-ceutical delivery device was prepared from 6 parts of -liquid sllicone polymer ~old as Silastic~ Medical Grade MDX-4 4210 by Dow-Corning and 1,9 part of ethynodlol diacetate and 0,1 part of mestranol in 2 parts 40% poly-ethylene glycol (molecular weight 400) in water.
Following the procedure ln Example 1, a pharma-ceutical delivery device was prepared from 6 parts of liquid sillcone polymer sold as Silastic~ Medical Grade MDX-4 4210 by Dow-Corning and 2 parts of dl-17-ethynyl-13B-ethyl-llB-methylgon-4-ene-3B,17B-diol 3,17-diacetate in 2 parts 40% polyethylene glycol (molecular weight 400) in water.
Claims (18)
1. A microsealed pharmaceutical delivery device comprising a biologically acceptable polymer container constructed of flexible medical grade silicone polymer hollow tubing having the formula wherein n is about 5000 and R is phenyl, alkyl radical con-taining from 1-7 carbon atoms, vinyl, allyl or polycarbonate copolymers thereof, with as many perforations in the wall of the tubing when unsealed at each end as to expose up to 40%
of an inner biologically acceptable silicone polymer matrix, said biologically acceptable silicone polymer matrix having the formula wherein R1 is alkoxy radical containing from 1-7 carbon atoms, alkyl radical containing from 1-10 carbon atoms, phenyl, vinyl or allyl and m is about 100-5000, said biologically acceptable silicone polymer matrix having 10-200 micron microsealed compartments throughout, said micro-sealed compartments containing hydrophilic solvent system comprising water and one or more water miscible solvents said hydrophilic solvent system saturated with a pharmaceutical wherein ratio of the partition coefficient of the pharmaceutical between the hydrophilic solvent system and inner biologically acceptable silicone polymer matrix to the solubility of the pharmaceutical in the hydrophilic solvent system is between 1 and 10-4 (ml/mcg), said pharmaceutical being diffusible through the inner biologically acceptable silicone polymer matrix and biologically acceptable polymer container at a constant rate when the microsealed pharmaceutical delivery device is in an aqueous environment, said hydrophilic solvent system being non-diffusible through the inner biologically acceptable silicone polymer matrix and biologically acceptable polymer container.
of an inner biologically acceptable silicone polymer matrix, said biologically acceptable silicone polymer matrix having the formula wherein R1 is alkoxy radical containing from 1-7 carbon atoms, alkyl radical containing from 1-10 carbon atoms, phenyl, vinyl or allyl and m is about 100-5000, said biologically acceptable silicone polymer matrix having 10-200 micron microsealed compartments throughout, said micro-sealed compartments containing hydrophilic solvent system comprising water and one or more water miscible solvents said hydrophilic solvent system saturated with a pharmaceutical wherein ratio of the partition coefficient of the pharmaceutical between the hydrophilic solvent system and inner biologically acceptable silicone polymer matrix to the solubility of the pharmaceutical in the hydrophilic solvent system is between 1 and 10-4 (ml/mcg), said pharmaceutical being diffusible through the inner biologically acceptable silicone polymer matrix and biologically acceptable polymer container at a constant rate when the microsealed pharmaceutical delivery device is in an aqueous environment, said hydrophilic solvent system being non-diffusible through the inner biologically acceptable silicone polymer matrix and biologically acceptable polymer container.
2. A microsealed pharmaceutical delivery device according to Claim 1 comprising an unsealed sectioned length of said flexible medical grade silicone polymer tubing as a biologically acceptable polymer container with said inner biologically acceptable silicone polymer matrix contained and set in situ within the biologically acceptable polymer container.
3. A microsealed pharmaceutical delivery device according to Claim 1 comprising an unsealed sectioned length of said flexible medical grade silicone polymer tubing as a biologically acceptable polymer container with said inner biologically acceptable silicone polymer matrix contained and allowed to set within the said biologically acceptable polymer container by placing therein a well-stirred emulsion of pharmaceutical saturated 30-60% polyethylene glycol molecular weight 380-420 in water as a hydrophilic solvent system, medical grade room temperature vulcanizing silicone polymer elastomer and stannous octanoate cross-linking agent.
4. A microsealed pharmaceutical delivery device according to Claim 1, 2 or 3 wherein the pharmaceutical is a progestin.
5. A microsealed pharmaceutical delivery device according to Claim 1, 2 or 3 wherein the pharmaceutical is an estrogen.
6. A microsealed pharmaceutical delivery device according to Claim 1, 2 or 3 wherein the pharmaceutical is an adrenocortical steroid.
7. A microsealed pharmaceutical delivery device according to Claim 1, 2 or 3 wherein the pharmaceutical is a diuretic.
8. A microsealed pharmaceutical delivery device according to Claim 1, 2 or 3 wherein the pharmaceutical is ethynodiol diacetate.
9. A microsealed pharmaceutical delivery device according to Claim 1, 2 or 3 wherein the pharmaceutical is 17.alpha.-acetoxy-11.beta.-methyl-19-norpregn-4-ene-3,20-dione.
10. A microsealed pharmaceutical delivery device according to Claim 1, 2 or 3 wherein the pharmaceutical is progesterone.
11. A microsealed pharmaceutical delivery device according to Claim 1, 2 or 3 wherein the pharmaceutical is desoxycorticosterone.
12. A microsealed pharmaceutical delivery device according to Claim 1, 2 or 3 wherein the pharmaceutical is 17-hydroxy-7.beta.-methoxycarbonyl-3-oxo-17.alpha.-pregn-4-ene-21-carboxylic acid .gamma.-lactone.
13. A microsealed pharmaceutical delivery device according to Claim 1, 2 or 3 wherein the pharmaceutical is 7.alpha.-acethyltio-17-hydroxy-3-oxo-17.alpha.-pregn-4-ene-21-carboxylic acid .gamma.-lactone.
14. A microsealed pharmaceutical delivery device according to Claim 1, 2 or 3 wherein the pharmaceutical is a combination of ethynodiol diacetate and mestranol or ethynyl estradiol.
15. A microsealed pharmaceutical delivery device according to Claim 1, 2 or 3 wherein the pharmaceutical is metronidazole.
16. A method for producing a microsealed pharmaceutical delivery device comprising a biologically acceptable polymer container constructed of flexible medical grade silicone polymer hollow tubing having the formula wherein n is about 5000 and R is phenyl, alkyl radical containing from 1-7 carbon atoms, vinyl, allyl or polycarbonate copolymers thereof, with as many perforations in the wall of the tubing when unsealed at each end as to expose up to 40% of an inner biologically acceptable silicone polymer matrix, said biologically acceptable silicone polymer matrix having the formula wherein R' is alkoxy radical containing from 1-7 carbon atoms, alkyl radical containing from 1-10 carbon atoms, phenyl, vinyl, or allyl and m is about 100-5000, said biologically acceptable silicone polymer matrix having 10-200 micron microsealed com-partments throughout, said microsealed compartments containing hydrophilic solvent system comprising water and one or more water miscible solvents, said hydrophilic solvent system saturated with a pharmaceutical wherein ratio of the partition coefficient of the pharmaceutical between the hydrophilic solvent system and inner biologically acceptable silicone polymer matrix to the solubility of the pharmaceutical in the hydrophilic solvent system is between 1 and 10-4 (ml/mcg), said pharmaceutical being diffusible through the inner biologically acceptable silicone polymer matrix and biologically acceptable polymer container at a constant rate when the microsealed pharmaceutical delivery device is in an aqueous environment, said hydrophilic solvent system being non-diffusible through the inner biologically acceptable silicone polymer matrix and biologically acceptable polymer container, characterized by:
a) emulsifying the hydrophilic solvent system containing the pharmaceutical and biologically acceptable liquid silicone polymer, b) in situ cross-linking biologically acceptable liquid silicone polymer to form the biologically acceptable silicone polymer matrix having 10-200 micron microsealed compartments throughout, and c) placing said biologically acceptable silicone polymer matrix in the biologically acceptable polymer container.
a) emulsifying the hydrophilic solvent system containing the pharmaceutical and biologically acceptable liquid silicone polymer, b) in situ cross-linking biologically acceptable liquid silicone polymer to form the biologically acceptable silicone polymer matrix having 10-200 micron microsealed compartments throughout, and c) placing said biologically acceptable silicone polymer matrix in the biologically acceptable polymer container.
17. A method for producing a microsealed pharmaceutical delivery device of Claim 16, characterized by allowing the biologically acceptable silicone polymer matrix to set in situ within the biologically acceptable polymer container comprising an unsealed sectioned length of flexible medical grade silicone polymer tubing.
18. A method for producing a microsealed pharmaceutical delivery device of Claim 16 or 17, characterized by allowing the biologically acceptable silicone polymer matrix to set within the biologically acceptable polymer container comprising an unsealed sectioned length of flexible medical grade silicone tubing by placing therein a well-stirred emulsion of pharmaceutical saturated 30-60% polyethylene glycol molecular weight 380-420 in water as a hydrophilic solvent system, medical grade room temperature vulcanizing silicone polymer elastomer and stannous octanoate cross-linking agent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/517,454 US3946106A (en) | 1974-10-24 | 1974-10-24 | Microsealed pharmaceutical delivery device |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1063934A true CA1063934A (en) | 1979-10-09 |
Family
ID=24059857
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA238,197A Expired CA1063934A (en) | 1974-10-24 | 1975-10-23 | Microsealed pharmaceutical delivery device |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US3946106A (en) |
| JP (1) | JPS6059202B2 (en) |
| AR (1) | AR206946A1 (en) |
| AT (1) | AT347594B (en) |
| AU (1) | AU499873B2 (en) |
| BE (1) | BE834785A (en) |
| CA (1) | CA1063934A (en) |
| DE (1) | DE2547378A1 (en) |
| DK (1) | DK141008B (en) |
| ES (1) | ES442017A1 (en) |
| FR (1) | FR2289207A1 (en) |
| GB (1) | GB1522846A (en) |
| IE (1) | IE42056B1 (en) |
| NL (1) | NL190102C (en) |
| ZA (1) | ZA756352B (en) |
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| US3992518A (en) * | 1974-10-24 | 1976-11-16 | G. D. Searle & Co. | Method for making a microsealed delivery device |
| US4053580A (en) * | 1975-01-01 | 1977-10-11 | G. D. Searle & Co. | Microsealed pharmaceutical delivery device |
| JPS52151504A (en) * | 1976-06-11 | 1977-12-16 | Hitachi Ltd | Alarm sending system |
| US4145408A (en) * | 1976-08-16 | 1979-03-20 | The Procter & Gamble Company | Controlled release article |
| HU174057B (en) * | 1976-09-17 | 1979-10-28 | Richter Gedeon Vegyeszet | Coating material for the regulated release of the active substance in biologically active preparations and process for preparing such preparations with regulated release of the active substance |
| US4191741A (en) * | 1978-09-22 | 1980-03-04 | Eli Lilly And Company | Removable drug implant |
| DE2902414A1 (en) * | 1979-01-23 | 1980-08-07 | Hoechst Ag | DEPOT BODY BASED ON SILICONE RUBBER AND METHOD FOR THE PRODUCTION THEREOF |
| DE2914463A1 (en) * | 1979-04-10 | 1980-10-23 | Hoechst Ag | MEDICAL DEVICES FOR PARENTERAL LIQUIDS |
| AU9131982A (en) * | 1981-12-07 | 1983-06-16 | Syntex (U.S.A.) Inc. | Contraceptive device releasing 1-substituted imadazoles |
| US4469671A (en) * | 1983-02-22 | 1984-09-04 | Eli Lilly And Company | Contraceptive device |
| GB8319766D0 (en) * | 1983-07-22 | 1983-08-24 | Graham N B | Controlled release device |
| US4563184A (en) * | 1983-10-17 | 1986-01-07 | Bernard Korol | Synthetic resin wound dressing and method of treatment using same |
| US5225196A (en) * | 1983-11-14 | 1993-07-06 | Columbia Laboratories, Inc. | Bioadhesive compositions and methods of treatment therewith |
| FR2570602B1 (en) * | 1984-09-21 | 1986-11-28 | Cird | PHARMACEUTICAL VEHICLE FOR ACTIVE SUBSTANCES IN THE FORM OF ANHYDROUS GEL |
| US4927687A (en) * | 1984-10-01 | 1990-05-22 | Biotek, Inc. | Sustained release transdermal drug delivery composition |
| DE3586713T2 (en) * | 1984-11-15 | 1993-05-13 | Hercon Lab | DEVICE FOR THE CONTROLLED DELIVERY OF DRUG ACTIVE SUBSTANCES. |
| US4806341A (en) * | 1985-02-25 | 1989-02-21 | Rutgers, The State University Of New Jersey | Transdermal absorption dosage unit for narcotic analgesics and antagonists and process for administration |
| US4720384A (en) * | 1985-05-03 | 1988-01-19 | E. I. Du Pont De Nemours And Company | Manufacture of hollow fine tubular drug delivery systems |
| US4673565A (en) * | 1985-05-03 | 1987-06-16 | E. I. Du Pont De Nemours And Company | Pharmaceutical compositions containing hollow fine tubular drug delivery systems |
| US4690683A (en) * | 1985-07-02 | 1987-09-01 | Rutgers, The State University Of New Jersey | Transdermal varapamil delivery device |
| US5266329A (en) * | 1985-10-31 | 1993-11-30 | Kv Pharmaceutical Company | Vaginal delivery system |
| US4959217A (en) * | 1986-05-22 | 1990-09-25 | Syntex (U.S.A.) Inc. | Delayed/sustained release of macromolecules |
| US5560922A (en) * | 1986-05-30 | 1996-10-01 | Rutgers, The State University Of New Jersey | Transdermal absorption dosage unit using a polyacrylate adhesive polymer and process |
| US5422118A (en) * | 1986-11-07 | 1995-06-06 | Pure Pac, Inc. | Transdermal administration of amines with minimal irritation and high transdermal flux rate |
| US4906475A (en) * | 1988-02-16 | 1990-03-06 | Paco Pharmaceutical Services | Estradiol transdermal delivery system |
| US5945125A (en) * | 1995-02-28 | 1999-08-31 | Temple University | Controlled release tablet |
| FR2766088B1 (en) * | 1997-07-17 | 2001-01-05 | Dow Corning Sa | DEVICES FOR CONTROLLED RELEASE OF A PHARMACEUTICAL AGENT, THEIR MANUFACTURE BY CO-EXTRUSION AND INTERMEDIATE ARTICLE |
| US6733767B2 (en) * | 1998-03-19 | 2004-05-11 | Merck & Co., Inc. | Liquid polymeric compositions for controlled release of bioactive substances |
| JP4428899B2 (en) | 1999-07-02 | 2010-03-10 | エルテーエス ローマン テラピー−ジステーメ アーゲー | A microreservoir system based on polysiloxane and an amphiphilic solvent. |
| JP2006506385A (en) * | 2002-10-22 | 2006-02-23 | ザ バイオメリックス コーポレーション | Methods and systems for intrathecal delivery of therapeutic agents |
| US20050043585A1 (en) * | 2003-01-03 | 2005-02-24 | Arindam Datta | Reticulated elastomeric matrices, their manufacture and use in implantable devices |
| EP1438942A1 (en) * | 2003-01-17 | 2004-07-21 | Schering Oy | An otorhinological drug delivery device |
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| US7763077B2 (en) | 2003-12-24 | 2010-07-27 | Biomerix Corporation | Repair of spinal annular defects and annulo-nucleoplasty regeneration |
| US20070190108A1 (en) * | 2004-05-17 | 2007-08-16 | Arindam Datta | High performance reticulated elastomeric matrix preparation, properties, reinforcement, and use in surgical devices, tissue augmentation and/or tissue repair |
| US20060116714A1 (en) * | 2004-11-26 | 2006-06-01 | Ivan Sepetka | Coupling and release devices and methods for their assembly and use |
| WO2008074027A1 (en) * | 2006-12-13 | 2008-06-19 | Biomerix Corporation | Aneurysm occlusion devices |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3279996A (en) * | 1962-08-28 | 1966-10-18 | Jr David M Long | Polysiloxane carrier for controlled release of drugs and other agents |
| US3416530A (en) * | 1966-03-02 | 1968-12-17 | Richard A. Ness | Eyeball medication dispensing tablet |
| US3545439A (en) * | 1968-01-04 | 1970-12-08 | Upjohn Co | Medicated devices and methods |
| US3518340A (en) * | 1968-04-15 | 1970-06-30 | Dow Corning | Method of forming silicone rubber drug carriers |
| US3845761A (en) * | 1970-06-02 | 1974-11-05 | Alza Corp | Intrauterine contraceptive anti-fertility device for the management of reproduction |
| US3832252A (en) * | 1970-09-29 | 1974-08-27 | T Higuchi | Method of making a drug-delivery device |
| US3710795A (en) * | 1970-09-29 | 1973-01-16 | Alza Corp | Drug-delivery device with stretched, rate-controlling membrane |
| AU454482B2 (en) * | 1970-11-05 | 1974-10-15 | Alza Corporation | Drug-delivery system |
| US3797485A (en) * | 1971-03-26 | 1974-03-19 | Alza Corp | Novel drug delivery device for administering drug into blood circulation in blood vessel |
| US3828777A (en) * | 1971-11-08 | 1974-08-13 | Alza Corp | Microporous ocular device |
| US3832458A (en) * | 1971-12-06 | 1974-08-27 | River C Foundation | Hydrophilic silicone composition and method |
-
1974
- 1974-10-24 US US05/517,454 patent/US3946106A/en not_active Expired - Lifetime
-
1975
- 1975-01-01 AR AR260899A patent/AR206946A1/en active
- 1975-10-07 ZA ZA756352A patent/ZA756352B/en unknown
- 1975-10-23 FR FR7532526A patent/FR2289207A1/en active Granted
- 1975-10-23 IE IE2310/75A patent/IE42056B1/en unknown
- 1975-10-23 BE BE161172A patent/BE834785A/en not_active IP Right Cessation
- 1975-10-23 DK DK478275AA patent/DK141008B/en not_active IP Right Cessation
- 1975-10-23 CA CA238,197A patent/CA1063934A/en not_active Expired
- 1975-10-23 ES ES442017A patent/ES442017A1/en not_active Expired
- 1975-10-23 NL NLAANVRAGE7512430,A patent/NL190102C/en not_active IP Right Cessation
- 1975-10-23 GB GB43554/75A patent/GB1522846A/en not_active Expired
- 1975-10-23 DE DE19752547378 patent/DE2547378A1/en active Granted
- 1975-10-23 AU AU85974/75A patent/AU499873B2/en not_active Expired
- 1975-10-23 JP JP50127859A patent/JPS6059202B2/en not_active Expired
- 1975-10-24 AT AT812775A patent/AT347594B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK141008C (en) | 1980-06-09 |
| GB1522846A (en) | 1978-08-31 |
| NL190102B (en) | 1993-06-01 |
| FR2289207A1 (en) | 1976-05-28 |
| DK141008B (en) | 1979-12-24 |
| ATA812775A (en) | 1978-05-15 |
| DE2547378A1 (en) | 1976-04-29 |
| JPS6059202B2 (en) | 1985-12-24 |
| US3946106A (en) | 1976-03-23 |
| DE2547378C2 (en) | 1990-03-15 |
| JPS5167719A (en) | 1976-06-11 |
| NL7512430A (en) | 1976-04-27 |
| FR2289207B1 (en) | 1979-09-14 |
| DK478275A (en) | 1976-04-25 |
| ES442017A1 (en) | 1977-06-16 |
| BE834785A (en) | 1976-04-23 |
| AT347594B (en) | 1979-01-10 |
| IE42056B1 (en) | 1980-05-21 |
| AU499873B2 (en) | 1979-05-03 |
| AU8597475A (en) | 1977-04-28 |
| NL190102C (en) | 1993-11-01 |
| ZA756352B (en) | 1977-05-25 |
| IE42056L (en) | 1976-04-24 |
| AR206946A1 (en) | 1976-08-31 |
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