CA1083041A - Sustained release drug delivery device and process for making same - Google Patents
Sustained release drug delivery device and process for making sameInfo
- Publication number
- CA1083041A CA1083041A CA257,322A CA257322A CA1083041A CA 1083041 A CA1083041 A CA 1083041A CA 257322 A CA257322 A CA 257322A CA 1083041 A CA1083041 A CA 1083041A
- Authority
- CA
- Canada
- Prior art keywords
- solute
- drug
- polymer
- mixture
- depots
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
Landscapes
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
SUSTAINED RELEASE DRUG DELIVERY DEVICE
AND PROCESS FOR MAKING SAME
ABSTRACT OF THE DISCLOSURE
Sustained release diffusional drug delivery devices for use in an aqueous body environment are disclosed.
The devices are in the form of an integral solid body that is sized and shaped for placement and retention in the environment and are made from a mixture of drug, polymer, and a small amount of discrete depots of an osmotically effective solute. The polymer is permeable to water and drug, insoluble in the environment, and impermeable to the solute. The solute depots are dispersed in the polymer such that they are encapsulated sub-stantially individually by a layer of polymer. When the device is placed in the environment, the depots imbibe water and burst the polymer layers surrounding them, thereby forming a network of interconnected pores through the device and thus increasing in situ the surface area from which drug may be released from the polymer to the environment. This in situ increase in surface area increases the rate of drug release from the device.
AND PROCESS FOR MAKING SAME
ABSTRACT OF THE DISCLOSURE
Sustained release diffusional drug delivery devices for use in an aqueous body environment are disclosed.
The devices are in the form of an integral solid body that is sized and shaped for placement and retention in the environment and are made from a mixture of drug, polymer, and a small amount of discrete depots of an osmotically effective solute. The polymer is permeable to water and drug, insoluble in the environment, and impermeable to the solute. The solute depots are dispersed in the polymer such that they are encapsulated sub-stantially individually by a layer of polymer. When the device is placed in the environment, the depots imbibe water and burst the polymer layers surrounding them, thereby forming a network of interconnected pores through the device and thus increasing in situ the surface area from which drug may be released from the polymer to the environment. This in situ increase in surface area increases the rate of drug release from the device.
Description
3~
Monolithic devices for sustainedly releasing drugs or other active agents are well known in the art One type of monolithic device consists of a shaped body of particulate, usually solid, drug dispersed in a polymer matrix that is permeable to the drug by diffusion~ See for instance United States Patent No~ 3,416,530~ In such devices the polymer matrix may be sub-stantially imper~orate and homogeneous, in which case the drug dissolves in ;
and permeates through the polymer itself~ -Monolithic devices in which the polymer matrix is initially micro- -porous are also known. In these n~croporous devices the pores of the matrix contain a drug-permeable liquid or gel medium in which the drug will prefer-entially dissolve and pe~meate through relative to the polymer itself. See for instance United States Patent No~ 3,828,777~
Another type of monolithic device for sustainedly releasing drugs :into aqueous body environments, such as the various caviti0s of the human body, is described in commonly assigned Canadian patent applica~ion serial no~ 198,003 filed 04/23/74 (corresponds to United States serial no. 354,359 ~Filed Q4/25/73 and now abandoned)~ These devices consist of a shaped body rnade from a mixture of discrete depots of a drug composition that is an ~ -osmotically effective solute and a water impermeable and drug impermeable 2Q polymer. The drug composition may consist of neat drug that is itself an osmotically ef~ective solute or a drug mixed with an additive, such as an inorganic salt, that is an osmotically ef~ective solute. The depots are dispersed in the polymer such that the depots are substantially individually surrounded or encapsulated by a layer of polymer~ Such devices release drug by an osmotic imbibition-bursting mechanism in which water is imbibed by the depots in a serially inward manner beginning with the depots at or nearest the exposed surface of the device, thereby dissolving those depots' contents and generating sufficient pressure to rupture the layers of polymer surrounding the depots and permit the drug composition to be released.
"
~' ~
~3~
The present invention provides a sustained release delivery device, for use in an aqueous body environment, that releases drug substantially by diffusion, said device: being in the form of an integral solid body that is sized and shaped or placement and retention in said environment; and being made from a mixture of a~ about 4% to about 75% by weight of a nonionic drug having a ::~
solubility in water from about 200 to abou~ 10,000 ppm, and being in the form of particles 1 to 250 microns, number average diameterJ in sizeJ
b) about Q.1% to about lQ% by weight of an osmotically effective solute in the form of discrete depots about 1 to about 250 ~icrons, number average diameter, in size andJ
c) about 2Q% to about 95% by weight of a polymer that is permeable to the dTug and to waterl is impermeable to the solute, is substantially insoluble in the en~ironment at least during the time that drug is being released and has a tensile strength of about 2,500 to 70,000 kPa, ~herein the depots of said solute are dispersed in the polymer such that said depots are surrounded substantially inclividually by a layer of polymerg whereby when the device is placed in the environment the depots imbibe water causing the respective polymer layer surro~mding the depots to rupture~ ~hereby forming a network of interconnected pores in the solid body and increasing in situ the effective surface area of the solid body, :~
said device heing a physiologically and pharmacologically acceptable device~
The present invention also provides a process for preparing a sustained release delivery device, for use in an aqueous body environment, that releases drug substantially by diffusion, said prvcess comprising forming a mixture of al about 4% to about 75% by weight of a nonionic drug having a 3Q ~olubility in water from about 200 to about 10,000 ppm, and being in the form of paTticles 1 to 250 microns, l~umber
Monolithic devices for sustainedly releasing drugs or other active agents are well known in the art One type of monolithic device consists of a shaped body of particulate, usually solid, drug dispersed in a polymer matrix that is permeable to the drug by diffusion~ See for instance United States Patent No~ 3,416,530~ In such devices the polymer matrix may be sub-stantially imper~orate and homogeneous, in which case the drug dissolves in ;
and permeates through the polymer itself~ -Monolithic devices in which the polymer matrix is initially micro- -porous are also known. In these n~croporous devices the pores of the matrix contain a drug-permeable liquid or gel medium in which the drug will prefer-entially dissolve and pe~meate through relative to the polymer itself. See for instance United States Patent No~ 3,828,777~
Another type of monolithic device for sustainedly releasing drugs :into aqueous body environments, such as the various caviti0s of the human body, is described in commonly assigned Canadian patent applica~ion serial no~ 198,003 filed 04/23/74 (corresponds to United States serial no. 354,359 ~Filed Q4/25/73 and now abandoned)~ These devices consist of a shaped body rnade from a mixture of discrete depots of a drug composition that is an ~ -osmotically effective solute and a water impermeable and drug impermeable 2Q polymer. The drug composition may consist of neat drug that is itself an osmotically ef~ective solute or a drug mixed with an additive, such as an inorganic salt, that is an osmotically ef~ective solute. The depots are dispersed in the polymer such that the depots are substantially individually surrounded or encapsulated by a layer of polymer~ Such devices release drug by an osmotic imbibition-bursting mechanism in which water is imbibed by the depots in a serially inward manner beginning with the depots at or nearest the exposed surface of the device, thereby dissolving those depots' contents and generating sufficient pressure to rupture the layers of polymer surrounding the depots and permit the drug composition to be released.
"
~' ~
~3~
The present invention provides a sustained release delivery device, for use in an aqueous body environment, that releases drug substantially by diffusion, said device: being in the form of an integral solid body that is sized and shaped or placement and retention in said environment; and being made from a mixture of a~ about 4% to about 75% by weight of a nonionic drug having a ::~
solubility in water from about 200 to abou~ 10,000 ppm, and being in the form of particles 1 to 250 microns, number average diameterJ in sizeJ
b) about Q.1% to about lQ% by weight of an osmotically effective solute in the form of discrete depots about 1 to about 250 ~icrons, number average diameter, in size andJ
c) about 2Q% to about 95% by weight of a polymer that is permeable to the dTug and to waterl is impermeable to the solute, is substantially insoluble in the en~ironment at least during the time that drug is being released and has a tensile strength of about 2,500 to 70,000 kPa, ~herein the depots of said solute are dispersed in the polymer such that said depots are surrounded substantially inclividually by a layer of polymerg whereby when the device is placed in the environment the depots imbibe water causing the respective polymer layer surro~mding the depots to rupture~ ~hereby forming a network of interconnected pores in the solid body and increasing in situ the effective surface area of the solid body, :~
said device heing a physiologically and pharmacologically acceptable device~
The present invention also provides a process for preparing a sustained release delivery device, for use in an aqueous body environment, that releases drug substantially by diffusion, said prvcess comprising forming a mixture of al about 4% to about 75% by weight of a nonionic drug having a 3Q ~olubility in water from about 200 to about 10,000 ppm, and being in the form of paTticles 1 to 250 microns, l~umber
2~
' . ." ' . . ' , , '. ' ". ' ' . ' '' , , " '`' `' ~33~
average diameter, in size, ~) about a.l% to about 10% by weight of an osmotically effective solute in the ~orm of discrete depots about l to about 250 micTons~ number average diameker, in size and c~ about 20% to about 95% by weight of a polymer that is permeable to the drug and to water, is impermeable to the solute3 is substantially insoluble in the environment at least during the time that drug is being released and has a tensile strength of about 2500 to 70,000 kPa and ~orl~ng said mixture into an integral solid body that is sized and shaped ~or placement and retention in said environment, sa;d process being characterized in ~hat before the maxture is formed into said body, said ~ ~
solute is dispersed in the polymer such that the depots of solute are;
substantially individually surrounded by a layer of polymer9 whereby when the device is placed in ~he environment the depots imbibe water causing the respective polymer layer surrounding the depots to rupture, thereby forming ~; a net~ork o interconnected pores in the solid body and increasing in situ rhe efective surface area of the solid body~ said device being a phys~iologically and pharmacologically acceptable device~
2~ In the drawings ... ..... .
Figure 1 is a graph relating to the devices of Example l with relea5e xate o~ hydrocortisone plotted against time;
Figure 2 is a graph relating to the devices of Example 2 with release rate of hydrocortisone plotted against time; and ~igure 3 is a graph relating to the devices of Example 3 with release Tate o~ idoxuridine plotted against time.
The devices of this invention are made from a mixture of three components: a nonionic drug, a polym~r, and a small amount of an osmotically e~ective solute. The mixture is formed into a solid body that is sized and shaped for placement at ~he desired body location, with the polymer serving as a matrix that binds the components into an integral mass. The nonionic '' ~'"' ''' ~ ~ -2a-drug is, of course, the therapeutic agent. The third component, the solute, normally plays no therapeutic role but is a means by which the effective surface area of the device is increased in situ. The nature of each compon-ent is extremely important to the overall functioning of the device.
The drug is nonionic and has a solubility in water in the range of about 200 and about 10,000 ppm. If the drug is highly soluble in water, it may tend to function as an osmotically effective solute and imbibe water. I~ that occurs, the drug is more likely to be released by the water imbibition-bursting mechanism described briefly above and in detail in commonly assigned Canadian patent application number 198,003 filed April 23, 1974, rather than by diffusion through the poly-mer. And if the drug is less soluble than about 200 ppm, it may not clear rapidly from the polymer surface and the release rate will be dependent upon boundary layer mixing instead of being dependent upon the rate of diffusion through the polymer. Preferably~ the drug has ., ~ .
.
~3~
:: ,. : : : - , :
~ 83~fl~1 i I ~RC 492A
. I .
1 ~ a solubility in water in the range of 300 and 5000 ppm. It 2 ¦ is also desirable that the drug be in a form in which it may
' . ." ' . . ' , , '. ' ". ' ' . ' '' , , " '`' `' ~33~
average diameter, in size, ~) about a.l% to about 10% by weight of an osmotically effective solute in the ~orm of discrete depots about l to about 250 micTons~ number average diameker, in size and c~ about 20% to about 95% by weight of a polymer that is permeable to the drug and to water, is impermeable to the solute3 is substantially insoluble in the environment at least during the time that drug is being released and has a tensile strength of about 2500 to 70,000 kPa and ~orl~ng said mixture into an integral solid body that is sized and shaped ~or placement and retention in said environment, sa;d process being characterized in ~hat before the maxture is formed into said body, said ~ ~
solute is dispersed in the polymer such that the depots of solute are;
substantially individually surrounded by a layer of polymer9 whereby when the device is placed in ~he environment the depots imbibe water causing the respective polymer layer surrounding the depots to rupture, thereby forming ~; a net~ork o interconnected pores in the solid body and increasing in situ rhe efective surface area of the solid body~ said device being a phys~iologically and pharmacologically acceptable device~
2~ In the drawings ... ..... .
Figure 1 is a graph relating to the devices of Example l with relea5e xate o~ hydrocortisone plotted against time;
Figure 2 is a graph relating to the devices of Example 2 with release rate of hydrocortisone plotted against time; and ~igure 3 is a graph relating to the devices of Example 3 with release Tate o~ idoxuridine plotted against time.
The devices of this invention are made from a mixture of three components: a nonionic drug, a polym~r, and a small amount of an osmotically e~ective solute. The mixture is formed into a solid body that is sized and shaped for placement at ~he desired body location, with the polymer serving as a matrix that binds the components into an integral mass. The nonionic '' ~'"' ''' ~ ~ -2a-drug is, of course, the therapeutic agent. The third component, the solute, normally plays no therapeutic role but is a means by which the effective surface area of the device is increased in situ. The nature of each compon-ent is extremely important to the overall functioning of the device.
The drug is nonionic and has a solubility in water in the range of about 200 and about 10,000 ppm. If the drug is highly soluble in water, it may tend to function as an osmotically effective solute and imbibe water. I~ that occurs, the drug is more likely to be released by the water imbibition-bursting mechanism described briefly above and in detail in commonly assigned Canadian patent application number 198,003 filed April 23, 1974, rather than by diffusion through the poly-mer. And if the drug is less soluble than about 200 ppm, it may not clear rapidly from the polymer surface and the release rate will be dependent upon boundary layer mixing instead of being dependent upon the rate of diffusion through the polymer. Preferably~ the drug has ., ~ .
.
~3~
:: ,. : : : - , :
~ 83~fl~1 i I ~RC 492A
. I .
1 ~ a solubility in water in the range of 300 and 5000 ppm. It 2 ¦ is also desirable that the drug be in a form in which it may
3 ¦ be easily mixed into the polymer, such as particles l to 250
4 ¦ microns, number average diameter, in size.
5 I The nature of the drug will depend upon the therapy for
6 ¦ which the device is intended. Drugs which produce a localized
7 ¦ effect at the administration site or a systemic effect at a
8 ¦ site remote from the administration site may be used. Such
9 ¦ drugs include inor~anic and organic compounds, for example, ~0 ¦ hypnotics, sedatives, psychic energi~ers, tranquilizers, anti-11 ¦ convulsants, muscle relaxants and anti-parkinson agents anti-l2 ¦ pyretics and anti-inflammatory agents, local anesthetics, anti-13 ¦ spasmodics and antiulcer agents, prosta~landins, anti-microbials 14 ¦ hormonal agents, estrogenic steroids, progestational steroids, ¦ such as for contraceptive purposes, sympathomimetic drugs, 16 1 cardiovascular drugs, diuretics, anti-parasitic agents, hypo-17 ¦ glycemic drugs and ophthalmic drugs. -~18 1 The solute must be osmotically effective. This means that 19 ¦ the solute must be sufficiently soluble in water to form a 20 ¦ solution that exhibits an osmotic pressure gradient across the 21 layer of polymer between the solute depot and the aqueous 22 environment of su~ficient magnitude to cause water from the 23 environment to be imbibed through the layer into the depot.
Solutes that are capable of forming saturated solutions that 2S exhibit relatively high osmotic gradients are preferred since 26 the depots will rupture more rapidly, and, correlati~elyt the 29 4_ 3~
.; , . . .
~ ~83all~L .
1 ¦ effective surface area of the device will increase in situ 2 1 more rapidly. Solutes having a ~ (osmotic pressure) in the 3 ¦ ~ange of 3000 and 30000 kPa are suitable. Examples of such 4 ¦ solutes are magnesium sulfate, magnesium chloride, sodium ¦ chloride, lithium chloride, potassium sulfate, sodium carbonate, 6 sodium sulfite, lithium sulfate, calcium bicarbonate, sodium 7 sulfate, calcium sulfate, potassium acid phosphate, calcium 8 lactate, magnesium succinate, tartaric acid, soluble carbo-9 hydrates such as sorbitol, mannitol, raffinose, glucose, sucrose, lactose, mixtures thereof; and the like.
11 The solute will usually also be substantially inert physi-12 ologically and pharmacologically. This means that it is non-13 toxic, provides no therapy, and creates no significant un-14 desirable side effects. However, ionic therapeutic agents 15 ~ may be used as the solute, in which case the nonionic drug 16 ¦ and the ionic therapeutic agent will be administered concomi-17 1 tantly. The solute component of the device may also comprise 18 ¦ a mixture o~ a nontherapeutic solute and an ionic therapeutic agent if desired.
20 ¦ The number and size of the solute depots is important.
21 ¦ In order to achieve a significant increase in the effective 22 1 surface area of the device, there must be a large number of 23 ¦ depots. If the depots are too large or too small, they may not be easily dispersed in the mixture with a high'degree of ~S ¦ discreteness ~i.e., individual encapsulation) or they may 26 ¦ not be able to imbibe su~ficient water to rupture the layers 271 . , .
:2~1 . ' ' . ' ' .
2~ ~ ~~
''' : . ' ~
. . ' . -' . ' - ' , ' . -., ~ , . . . , -- . , . ~ ., , ~ . . .
~ ~0~3~ A~C 49'A
,' I .
1 1 of polymer surrounding them. In this regard, depot size may 2 ¦ vary depending on osmotic ef~ectiveness of the solute, the 3 1 thickness of the surroundin~ polymer layers, and the physical 4 ¦ properties of the polymer. Depots in the range of l to 250 S I microns, number average diameter, will normally be employed.
6 1 More usually, they will be in the range of l to 50 microns, 7 ¦ number average diameter.
8 ¦ The polymer component of the mixture has the following 9 ¦ characteristics: substantial water insolubility; permeability
Solutes that are capable of forming saturated solutions that 2S exhibit relatively high osmotic gradients are preferred since 26 the depots will rupture more rapidly, and, correlati~elyt the 29 4_ 3~
.; , . . .
~ ~83all~L .
1 ¦ effective surface area of the device will increase in situ 2 1 more rapidly. Solutes having a ~ (osmotic pressure) in the 3 ¦ ~ange of 3000 and 30000 kPa are suitable. Examples of such 4 ¦ solutes are magnesium sulfate, magnesium chloride, sodium ¦ chloride, lithium chloride, potassium sulfate, sodium carbonate, 6 sodium sulfite, lithium sulfate, calcium bicarbonate, sodium 7 sulfate, calcium sulfate, potassium acid phosphate, calcium 8 lactate, magnesium succinate, tartaric acid, soluble carbo-9 hydrates such as sorbitol, mannitol, raffinose, glucose, sucrose, lactose, mixtures thereof; and the like.
11 The solute will usually also be substantially inert physi-12 ologically and pharmacologically. This means that it is non-13 toxic, provides no therapy, and creates no significant un-14 desirable side effects. However, ionic therapeutic agents 15 ~ may be used as the solute, in which case the nonionic drug 16 ¦ and the ionic therapeutic agent will be administered concomi-17 1 tantly. The solute component of the device may also comprise 18 ¦ a mixture o~ a nontherapeutic solute and an ionic therapeutic agent if desired.
20 ¦ The number and size of the solute depots is important.
21 ¦ In order to achieve a significant increase in the effective 22 1 surface area of the device, there must be a large number of 23 ¦ depots. If the depots are too large or too small, they may not be easily dispersed in the mixture with a high'degree of ~S ¦ discreteness ~i.e., individual encapsulation) or they may 26 ¦ not be able to imbibe su~ficient water to rupture the layers 271 . , .
:2~1 . ' ' . ' ' .
2~ ~ ~~
''' : . ' ~
. . ' . -' . ' - ' , ' . -., ~ , . . . , -- . , . ~ ., , ~ . . .
~ ~0~3~ A~C 49'A
,' I .
1 1 of polymer surrounding them. In this regard, depot size may 2 ¦ vary depending on osmotic ef~ectiveness of the solute, the 3 1 thickness of the surroundin~ polymer layers, and the physical 4 ¦ properties of the polymer. Depots in the range of l to 250 S I microns, number average diameter, will normally be employed.
6 1 More usually, they will be in the range of l to 50 microns, 7 ¦ number average diameter.
8 ¦ The polymer component of the mixture has the following 9 ¦ characteristics: substantial water insolubility; permeability
10 ¦ to water; permeability to the drug; substantial impermeability ~1 ¦ to the solute; and a tensile strength and maximum elongation 12 ¦ that enables the layers of it that encapsulate the depots to 13 ¦ be ruptured by the pressure generated by the water imbibed l4 ¦ into the depots. Water insolubility enables the polymer to 1~ ¦ function as a matrix that binds the mixture together into an 16 1 integral, intact, solid body during the drug administration 17 ¦ period~ Permeability to water is necessary to permit the l8 1 depots to imbibe water. Permeability to drug is necessary l9 ¦ to permit the drug to be released from the device by a 20 ¦ process of dissolving in the polymer and diffusing there-21 ¦ through on a molecular scale in the direction of lower 22 ¦ thermodynamic activity, that is in the direction of the 23 ¦ aqueous environment. And impermeability to the solute is 24 ¦ re~uired so that the solute depots imbibe water and burst, 25 ¦ rather than merely diffusing through the polymer as does 26 ¦ the drug. Polymers having water permeabilities of ~7 ¦ !
~ X81 . .
.
' ' ' . . , .. . . - .- . .. , ., ~ ~ ~
j1083041 ARC ~92A
1 ¦10~ to 10-12 cm2 . - sec~cm llg ~ preferably 3 I~ 5 x 1~9 to 5 x 10-1~ ~ gm cm 4 Icm sec-cm Hg 5 ¦ (as determined by vapor cup permeability tests per a 6 ¦ modified version of ASTM E 96J, tensile strengths of ?500 7 ¦ to 70,000 kPa, preferably 3500 to 20,000 kPa, and maximum ¦ elongations of from 10% to 2000%, preferably 200~ to 1700%, ¦ may be used. Examples of such polymers are commercially 10 ¦ available cellulose acetate and its derivatives, partial and ll I completely hydrolyzed ethylene-vinyl acetate copolymers, 12 ¦ highly plasticized polyvinyl chloride, homo- and copolymers 13 ¦ of polyvinyl acetate, polyesters o~ acrylic acid and meth-1~ ¦ acrylic acid, polyvinyl alkyl ethers, polyvinyl fluoride and 15 ¦ silicone polycarbonates. Ethylene-vinyl acetate copoiymers, 16 ¦ either alone or mixed with other materials, are especially 17 ¦ useful. Preferred among the ethylene-vinyl acetate copolymers 1~ ¦ are those having a melt index above about 20 g/min and a 19 ¦ vinyl acetate content above about 20%, such as from 20~ to ~0 1 45~.
~1 ¦ The proportion of each component in the mixture is also 22 ¦ important. There must be sufficient drug present to provide 23 ¦ the desired therapy with the size device permitted by the 24 particular body site involved. Enough polymer must be included to encapsulate substantially individually the 26 depots and bind the mixture into an integral mass. And, ~8 29 -7_ ~- . ' .
~ . - . . ~. .
08 3!041 I ~RC 492A
1 ¦ there must be enough solute depots to create a significant 2 I ln situ increase in the effective surface area of the device.
3 ¦ In most instances, the mixture wiil comprise 4% t~ 75% drug, 4 ¦ 20~ to 95~ polymer, and 0~1% to 10~ solute. Minor amounts of 5 ¦ other materials such as surfactants, pigments, stabilizers, and ¦ the like may be included in the mixture if necessary. Prefer-7 ¦ ably, the mixture will comprise 5~ to 65% drug, 30~ to 90 8 ¦ polymer, and 0.5% to 5% solute.
I The drug, polymer, and solute may be mixed by conventional 10 ¦ blending and mixing techniques employed in the pharmaceutical,
~ X81 . .
.
' ' ' . . , .. . . - .- . .. , ., ~ ~ ~
j1083041 ARC ~92A
1 ¦10~ to 10-12 cm2 . - sec~cm llg ~ preferably 3 I~ 5 x 1~9 to 5 x 10-1~ ~ gm cm 4 Icm sec-cm Hg 5 ¦ (as determined by vapor cup permeability tests per a 6 ¦ modified version of ASTM E 96J, tensile strengths of ?500 7 ¦ to 70,000 kPa, preferably 3500 to 20,000 kPa, and maximum ¦ elongations of from 10% to 2000%, preferably 200~ to 1700%, ¦ may be used. Examples of such polymers are commercially 10 ¦ available cellulose acetate and its derivatives, partial and ll I completely hydrolyzed ethylene-vinyl acetate copolymers, 12 ¦ highly plasticized polyvinyl chloride, homo- and copolymers 13 ¦ of polyvinyl acetate, polyesters o~ acrylic acid and meth-1~ ¦ acrylic acid, polyvinyl alkyl ethers, polyvinyl fluoride and 15 ¦ silicone polycarbonates. Ethylene-vinyl acetate copoiymers, 16 ¦ either alone or mixed with other materials, are especially 17 ¦ useful. Preferred among the ethylene-vinyl acetate copolymers 1~ ¦ are those having a melt index above about 20 g/min and a 19 ¦ vinyl acetate content above about 20%, such as from 20~ to ~0 1 45~.
~1 ¦ The proportion of each component in the mixture is also 22 ¦ important. There must be sufficient drug present to provide 23 ¦ the desired therapy with the size device permitted by the 24 particular body site involved. Enough polymer must be included to encapsulate substantially individually the 26 depots and bind the mixture into an integral mass. And, ~8 29 -7_ ~- . ' .
~ . - . . ~. .
08 3!041 I ~RC 492A
1 ¦ there must be enough solute depots to create a significant 2 I ln situ increase in the effective surface area of the device.
3 ¦ In most instances, the mixture wiil comprise 4% t~ 75% drug, 4 ¦ 20~ to 95~ polymer, and 0~1% to 10~ solute. Minor amounts of 5 ¦ other materials such as surfactants, pigments, stabilizers, and ¦ the like may be included in the mixture if necessary. Prefer-7 ¦ ably, the mixture will comprise 5~ to 65% drug, 30~ to 90 8 ¦ polymer, and 0.5% to 5% solute.
I The drug, polymer, and solute may be mixed by conventional 10 ¦ blending and mixing techniques employed in the pharmaceutical,
11 ¦ finè chemicals, and polymer arts. These components wil'
12 ¦ usually be blended in solid form and cast or milled into an
13 ¦ appropriate form. When the mixture is first formed into an 1~ ¦ integral mass in bulk (such as a sheet or film) rather than in I a finished form, it may be formed into its final configuration 16 ¦ by punching, cutting, or other conventional techniques. The 1'7 ¦ final size and shape of the device will usually be dictated by 1~ ¦ the body site at which the device is to be placed and the 19 ¦ therapy for which the device is intended. For instance, 20 ¦ devices that are to be placed in the cul-de-sac of the eye 21 to dispense ophthalmic drugs ~or periods of 1 to 7 days will 22 be sized and shaped for insertion and retention in the eye.
23 Such devices will usually be in the form of thin wa~er-like 24 elliptical bodies 6-25 mm x 4-10 mm x 0.1-1 mm.
2~ The environment in which the device is placed may be any 26 body tissue or body cavityl internal or external, that contains 2~ -8-.
, . . ~i.
. . . ~ , . . .
~ 3~ ARC ~92A
1 ¦ an agueous medium. Such environments include the eye, 2 ¦ vagina, uterus, gastrointestinal tract, circ~latory system 3 ¦ and muscle tissue. Once the device is placed in one of those ~ ¦ environments, the following occurs. Release of the drug from S ¦ the device commences. As mentioned above, such release 6 ¦ involves the dissolving of the drug in the polymer and ¦ diffusion therethrough to a surface of the device that is ¦ exposed to the environment. The distance the drug must 9 1 travel through the polymer before reaching such a surface, 10 ¦ affects the rate of drug release. Imbibition of water by 11 ¦ the solute depots also commences in a serially inward manner `
12 ¦ beginning with the depots at or nearest the exterior surface 13 1 of the clevice. As water is imbibed by a depot, the sur-
23 Such devices will usually be in the form of thin wa~er-like 24 elliptical bodies 6-25 mm x 4-10 mm x 0.1-1 mm.
2~ The environment in which the device is placed may be any 26 body tissue or body cavityl internal or external, that contains 2~ -8-.
, . . ~i.
. . . ~ , . . .
~ 3~ ARC ~92A
1 ¦ an agueous medium. Such environments include the eye, 2 ¦ vagina, uterus, gastrointestinal tract, circ~latory system 3 ¦ and muscle tissue. Once the device is placed in one of those ~ ¦ environments, the following occurs. Release of the drug from S ¦ the device commences. As mentioned above, such release 6 ¦ involves the dissolving of the drug in the polymer and ¦ diffusion therethrough to a surface of the device that is ¦ exposed to the environment. The distance the drug must 9 1 travel through the polymer before reaching such a surface, 10 ¦ affects the rate of drug release. Imbibition of water by 11 ¦ the solute depots also commences in a serially inward manner `
12 ¦ beginning with the depots at or nearest the exterior surface 13 1 of the clevice. As water is imbibed by a depot, the sur-
14 ¦ rounding layer of polymer first swells and then ruptures as
15 ¦ its cohesive strength is exceeded by the pressure generated
16 ¦ by the imbibed water. ~pon rupture, the solute is quickly
17 ¦ released from the device leaving a void at the depot site.
l8 ¦ This ~oid is also quickl~ filled by the aqueous medium which 19 ¦ is then imbibed by the next adjacent depot and so forth.
20 ¦ Water uptake by a depot is not entirely dependent upon the 21 ¦ rupture o~ outwardly adjacent depots and it is possible f~r 22 ¦ water to be imbibed into a depot before outwardly adjacent 23 ¦ depots rupture. The effect of such serial rupturing is that 24 ¦ interior pores and channels are formed in the device whose 25 ¦ surfaces are sites from which drug may be released from the 261 polymer to the medium. Thus the distance the dru~ must ~ ~71 281 ' . ' ~9 ~,`
.
.. ..
~ 1 08 30 41 AI~C 492A
1 ¦ travel through the polymer before it is released is 2 ¦ generally shortened. The formation of the interior pores 3 ¦ and channels is desirably rapid relative to the total period 4 ¦ of drug release. Preferably, such formation will be sub-¦ stantially complete in the first 1~ to 20% of the therapeutic ¦ lifetime of the device.
7 ¦ As used herein "effective surface area" means that 8 ¦ surface area of the device from which drug may be released I from the polymer to the aqueous medium. When the device is 10 ¦ first placed in the environment, its effective surface area 11 ¦ is equdl to the area of the surfaçes that def-ine its exterior.
12 ¦ However, as-described above, the serial rupturing of the 13 ¦ solute depots create additional surfaces from which the drug 1~ ¦ may be released. Thus, during the rùpturing period, that is 15 ¦ until all the depots have ruptured, the effective sur~ace area 16 ¦ is increaslng continuously. And, at any given time, t, during 17 ¦ that period, the effective surface is approximately equal to ¦ the area of the surfaces that define the device's exterior ¦ and the area of the surfaces defined by the interconnected 20¦ voids formed by the rupturing. The difference between the 21 ¦ initial and final effective surface areas will depend upon 22¦ the depot size, the number of depots and the nature of the 231 polymer.
24 ¦ Such in situ increase in the effective surface area 25 ¦ affects the relèase of drug in three ways: it increases 26¦ the release rate; it shortens the release period for a given 271 .
' 2SI .
` 31 108 30 4l ARC ~92 1 ¦ total amount of drug; and it may increase the constancy ¦ of the drug release rate. These effects are advantageous ~ ¦ in instances in which higher drug release rates are desired 4 I than may be achieved with a simple monolithic diffusional 5 ¦ device. It may also be more economical to achieve higher 6 ¦ release rates in this manner than by increasing the concen-7 ¦ tration of drug. In the latter instance, significant 8 ¦ quantities o~ drug may be left in the device at the end of I the therapy period and thus wasted.
101 . .
13 ¦ The following examples are intended to illustrate the 14 ¦ invention and not to limit it in any manner. Unless indi-15 ¦ cated otherwise, parts and percentages are by weight.
161 . ' 17 ¦ Example 1
l8 ¦ This ~oid is also quickl~ filled by the aqueous medium which 19 ¦ is then imbibed by the next adjacent depot and so forth.
20 ¦ Water uptake by a depot is not entirely dependent upon the 21 ¦ rupture o~ outwardly adjacent depots and it is possible f~r 22 ¦ water to be imbibed into a depot before outwardly adjacent 23 ¦ depots rupture. The effect of such serial rupturing is that 24 ¦ interior pores and channels are formed in the device whose 25 ¦ surfaces are sites from which drug may be released from the 261 polymer to the medium. Thus the distance the dru~ must ~ ~71 281 ' . ' ~9 ~,`
.
.. ..
~ 1 08 30 41 AI~C 492A
1 ¦ travel through the polymer before it is released is 2 ¦ generally shortened. The formation of the interior pores 3 ¦ and channels is desirably rapid relative to the total period 4 ¦ of drug release. Preferably, such formation will be sub-¦ stantially complete in the first 1~ to 20% of the therapeutic ¦ lifetime of the device.
7 ¦ As used herein "effective surface area" means that 8 ¦ surface area of the device from which drug may be released I from the polymer to the aqueous medium. When the device is 10 ¦ first placed in the environment, its effective surface area 11 ¦ is equdl to the area of the surfaçes that def-ine its exterior.
12 ¦ However, as-described above, the serial rupturing of the 13 ¦ solute depots create additional surfaces from which the drug 1~ ¦ may be released. Thus, during the rùpturing period, that is 15 ¦ until all the depots have ruptured, the effective sur~ace area 16 ¦ is increaslng continuously. And, at any given time, t, during 17 ¦ that period, the effective surface is approximately equal to ¦ the area of the surfaces that define the device's exterior ¦ and the area of the surfaces defined by the interconnected 20¦ voids formed by the rupturing. The difference between the 21 ¦ initial and final effective surface areas will depend upon 22¦ the depot size, the number of depots and the nature of the 231 polymer.
24 ¦ Such in situ increase in the effective surface area 25 ¦ affects the relèase of drug in three ways: it increases 26¦ the release rate; it shortens the release period for a given 271 .
' 2SI .
` 31 108 30 4l ARC ~92 1 ¦ total amount of drug; and it may increase the constancy ¦ of the drug release rate. These effects are advantageous ~ ¦ in instances in which higher drug release rates are desired 4 I than may be achieved with a simple monolithic diffusional 5 ¦ device. It may also be more economical to achieve higher 6 ¦ release rates in this manner than by increasing the concen-7 ¦ tration of drug. In the latter instance, significant 8 ¦ quantities o~ drug may be left in the device at the end of I the therapy period and thus wasted.
101 . .
13 ¦ The following examples are intended to illustrate the 14 ¦ invention and not to limit it in any manner. Unless indi-15 ¦ cated otherwise, parts and percentages are by weight.
161 . ' 17 ¦ Example 1
18 A. Preparation o~ drug-polymer-solute mix~ures.
19 Hydrocortisone (sold under the trade designation Cortisol), ethylene-vinyl acetate copolymer ~40% vinyl 21 acetate, melt index ca 45-70, sold under the trade designa-~2 tion Elvax 40), and sodium chloride (number average diameter ~3 particle size 40 microns) were blended on a rubber mill in 24 the proportions indicated below.
2s ~ Tr~d~/har :~7 .
. ,;Ll- ~ .
` 30 321j , . . , ~ - ..
.1 I ~= .
2 ¦ Mix No. ~ Hydrocortisone ~ Polymer ~ NaCl 3 I l(a) 10 90 0 4 ¦ l(b~ 10 87.5 2.5 l(c) 10 85 5 6 l 7 ¦ These mixes were each then passed through the cooled rolls of ¦ a small rubber mill to form rough 0.75 mm thick sheets. The ¦ sheets were compression molded in a hydraulic press at 57C
10 ¦ for 5 min to form 0.4 mm thick films.
11 ¦ B. Preparation and testing of ocular inserts.
12 ¦ Replicate elliptical ocular inserts (13.5 x 5.8 x 13 ¦ 0.4 mm) were punched from the films o~ part A. Each insert 14 ¦ contained approximately 2 mg hydrocortisone. These inserts ¦ were placed in a simulated ocular aqueous environment and the 16 ¦ amount of hydrocortisone released was determined at various 17 ¦ time intervals by a UV spectometer set at 248 nanometers.
18 ¦ From these determinations, release rates in ~g/hr were calcu-1~ ¦ lated. The release rates are plotted in Figure 1.
2s ~ Tr~d~/har :~7 .
. ,;Ll- ~ .
` 30 321j , . . , ~ - ..
.1 I ~= .
2 ¦ Mix No. ~ Hydrocortisone ~ Polymer ~ NaCl 3 I l(a) 10 90 0 4 ¦ l(b~ 10 87.5 2.5 l(c) 10 85 5 6 l 7 ¦ These mixes were each then passed through the cooled rolls of ¦ a small rubber mill to form rough 0.75 mm thick sheets. The ¦ sheets were compression molded in a hydraulic press at 57C
10 ¦ for 5 min to form 0.4 mm thick films.
11 ¦ B. Preparation and testing of ocular inserts.
12 ¦ Replicate elliptical ocular inserts (13.5 x 5.8 x 13 ¦ 0.4 mm) were punched from the films o~ part A. Each insert 14 ¦ contained approximately 2 mg hydrocortisone. These inserts ¦ were placed in a simulated ocular aqueous environment and the 16 ¦ amount of hydrocortisone released was determined at various 17 ¦ time intervals by a UV spectometer set at 248 nanometers.
18 ¦ From these determinations, release rates in ~g/hr were calcu-1~ ¦ lated. The release rates are plotted in Figure 1.
20 ¦ The inserts made from mixes Nos. l(h) and l(c) were 2~ ¦ determined to have increased their effective surface area ~2 ¦ over the first 5 hr of testing by the water imbibition-23 ¦ burstin~ mechanism described above. By that time, NaC1 I release ~rom the inserts had dropped to ~100 ~g/hr.
: 2~1 261 .
,271 . ' .
~; 28 1 29 1 -12- `
I
. . .
,, .
. .
~ 1083041 ARC ~92A
1 I ~xam~le 2 I . ~ . .
2 ¦ A. Preparation of drug-polymer-solute mixtures.
3 ¦ ~ixes o~ hydrocortisone, ethylene-vinyl acetate 4 ¦ copolymer, and sodium chloride were prepared as in Example 1 S ¦ in the proportions indicated below. These mixes were formed 6 ¦ into films as in Example 1.
8 I Proportions 9 I Mix No. ~ Hydrocortisone ~ Polymer % NaCl 10 ¦ 2(a) 30 70 0 2~b) 30 68.75 1.25 2(c) 30 ~ 67.5 2.5 3 1 2(d) 30 65 5 14 1 2te) 30 60 10 IS I 2(f) . 30 55 15 1~6 ¦ B. Preparation and testing of ocular inserts.
17 ¦ Replicate inserts of the films of part A were made lB ¦ and tested by the procedure of Example 1. The release rates 19 ¦ for these inserts are plotted in Figure 2. As with the 20 ¦ inserts of Figure 1, these inser~s also increased their 22 ~ effective surface area over about the first 5 hr of testing.
: 2sl .
'. 261 .
I .
. , 2~1 . , ..
~9 1 -13-3l ¦
.
., . ..
. ~ 10~04~L I
~ ~RC ~92A
1 ¦ Example_3 ¦ A. Preparation of drug-polymer-solute mixtures.
, 3 ¦ Idoxuridine ~number a~erage particle size ~15 4 ¦ microns), the copolymer of Example 1, and sodium chloride 5 ¦ ~number average particle size 40 microns~ were blended by -6 ¦ the procedure of Example 1 in the proportions indicated 7 ¦ below. These mixtures were formed into 0.3 mm thick films 8 ¦ by the procedure of Example 1.`
I
10 I Proportions 11 ¦ Mix No~~ Idoxuridine % Polymer % NaCl 12 1 3(a) 65 35 0 13 1 3(b~ 65 34.$ 0.5 14 1 3(c) 65 34 1.0 ls ¦ 3~d) 65 - 33 2.`0 16 ¦ 3(e) 65 31 4.0 I 3(O 65 29 6.0 18 ¦ B. Preparation and testing of ocular inserts.
19 ¦ Quadruplicate ocular elliptical inserts (13.5 x 5.8 ¦ x 0.3 mm) each weiy~ing about 22 mg were prepared and tested
: 2~1 261 .
,271 . ' .
~; 28 1 29 1 -12- `
I
. . .
,, .
. .
~ 1083041 ARC ~92A
1 I ~xam~le 2 I . ~ . .
2 ¦ A. Preparation of drug-polymer-solute mixtures.
3 ¦ ~ixes o~ hydrocortisone, ethylene-vinyl acetate 4 ¦ copolymer, and sodium chloride were prepared as in Example 1 S ¦ in the proportions indicated below. These mixes were formed 6 ¦ into films as in Example 1.
8 I Proportions 9 I Mix No. ~ Hydrocortisone ~ Polymer % NaCl 10 ¦ 2(a) 30 70 0 2~b) 30 68.75 1.25 2(c) 30 ~ 67.5 2.5 3 1 2(d) 30 65 5 14 1 2te) 30 60 10 IS I 2(f) . 30 55 15 1~6 ¦ B. Preparation and testing of ocular inserts.
17 ¦ Replicate inserts of the films of part A were made lB ¦ and tested by the procedure of Example 1. The release rates 19 ¦ for these inserts are plotted in Figure 2. As with the 20 ¦ inserts of Figure 1, these inser~s also increased their 22 ~ effective surface area over about the first 5 hr of testing.
: 2sl .
'. 261 .
I .
. , 2~1 . , ..
~9 1 -13-3l ¦
.
., . ..
. ~ 10~04~L I
~ ~RC ~92A
1 ¦ Example_3 ¦ A. Preparation of drug-polymer-solute mixtures.
, 3 ¦ Idoxuridine ~number a~erage particle size ~15 4 ¦ microns), the copolymer of Example 1, and sodium chloride 5 ¦ ~number average particle size 40 microns~ were blended by -6 ¦ the procedure of Example 1 in the proportions indicated 7 ¦ below. These mixtures were formed into 0.3 mm thick films 8 ¦ by the procedure of Example 1.`
I
10 I Proportions 11 ¦ Mix No~~ Idoxuridine % Polymer % NaCl 12 1 3(a) 65 35 0 13 1 3(b~ 65 34.$ 0.5 14 1 3(c) 65 34 1.0 ls ¦ 3~d) 65 - 33 2.`0 16 ¦ 3(e) 65 31 4.0 I 3(O 65 29 6.0 18 ¦ B. Preparation and testing of ocular inserts.
19 ¦ Quadruplicate ocular elliptical inserts (13.5 x 5.8 ¦ x 0.3 mm) each weiy~ing about 22 mg were prepared and tested
21¦ by the general procedure of Example 1. Idoxuridine release
22 ¦ was monitored at 288 nanometers. The release rates for these
23 ¦ devices are plotted in Figure 3. As with the inserts of
24 ¦ Figure 1, these inserts also increased thelr efective surface
25 ¦ area over about the first 5 hr of testing.
~6 The effects of the addition of small amounts of sodium ~7 28 . .
. . ' ,.,.
~ ' .
- ~ .
¦ 1083041. ARC ~92~
1 ¦ chloride to .the inserts of Examples 1-3 is shown in Figures .
2 ¦ 1-3. The release rate of drug from the sodium chloride-3 ¦ containing inserts is significantly greater than the release 4 I rate of drug from inserts containing no sodium chloride. And, ¦ in the case of higher sodium chloride loadings, the period of 9 rel~ase is ecreased significan y.
, ,~
,61 . .
18 . .
:`' 201 . , .
21,1 ., ` 22 ~ . . ~:
24 ~ . .
261 .
,'` 271 .
,' 281 . ' 29 1 ~ .
.. 301 . .
3~1 .
. 32 , . . .. ~,,
~6 The effects of the addition of small amounts of sodium ~7 28 . .
. . ' ,.,.
~ ' .
- ~ .
¦ 1083041. ARC ~92~
1 ¦ chloride to .the inserts of Examples 1-3 is shown in Figures .
2 ¦ 1-3. The release rate of drug from the sodium chloride-3 ¦ containing inserts is significantly greater than the release 4 I rate of drug from inserts containing no sodium chloride. And, ¦ in the case of higher sodium chloride loadings, the period of 9 rel~ase is ecreased significan y.
, ,~
,61 . .
18 . .
:`' 201 . , .
21,1 ., ` 22 ~ . . ~:
24 ~ . .
261 .
,'` 271 .
,' 281 . ' 29 1 ~ .
.. 301 . .
3~1 .
. 32 , . . .. ~,,
Claims (20)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINlED AS FOLLOWS:
1. A sustained release delivery device, for use in an aqueous body environment, that releases drug substantially by diffusion, said device:
being in the form of an integral solid body that is sized and shaped for placement and retention in said environment; and being made from a mixture of a) about 4% to about 75% by weight of a nonionic drug having a solubility in water from about 200 to about 10,000 ppm, and heing in the form of particles 1 to 250 microns,number average diameter, in size, b) about 0.1% to about 10% by weight of an osmotically effective solute in the form of discrete depots about 1 to about 250 microns, number average diameter, in size and, c) about 20% to about 95% by weight of a polymer that is permeable to the drug and to water, is impermeable to the solute, is substantially insoluble in the environment at least during the time that drug is being released and has a tensile strength of about 2,500 to 70,000 kPa, wherein the depots of said solute are dispersed in the polymer such that said depots are surrounded substantially individually by a layer of polymer, whereby when the device is placed in the environment the depots imbibe water causing the respective polymer layer surrounding the depots to rupture, thereby forming a network of interconnected pores in the solid body and increasing in situ the effective surface area of the solid body, said device being a physiologically and pharmacologically acceptable device.
being in the form of an integral solid body that is sized and shaped for placement and retention in said environment; and being made from a mixture of a) about 4% to about 75% by weight of a nonionic drug having a solubility in water from about 200 to about 10,000 ppm, and heing in the form of particles 1 to 250 microns,number average diameter, in size, b) about 0.1% to about 10% by weight of an osmotically effective solute in the form of discrete depots about 1 to about 250 microns, number average diameter, in size and, c) about 20% to about 95% by weight of a polymer that is permeable to the drug and to water, is impermeable to the solute, is substantially insoluble in the environment at least during the time that drug is being released and has a tensile strength of about 2,500 to 70,000 kPa, wherein the depots of said solute are dispersed in the polymer such that said depots are surrounded substantially individually by a layer of polymer, whereby when the device is placed in the environment the depots imbibe water causing the respective polymer layer surrounding the depots to rupture, thereby forming a network of interconnected pores in the solid body and increasing in situ the effective surface area of the solid body, said device being a physiologically and pharmacologically acceptable device.
2. The device of claim 1 characterized in that the solute constitutes 0.5% to 5% of the mixture.
3. The device of claim 1 characterized in that the solute is capable of generating an osmotic pressure in the range of 3,000 to 30,000 kPa.
4. The device of claim 1 characterized in that the size of the depots is in the range of 1 to 50 microns, number average diameter, in size.
5. The device of claim 1 characterized in that the solute is sodium chloride.
6. The device of claim 1 characterized in that the polymer is an ethylene-vinyl acetate copolymer.
7. The device of claim 1 characterized in that the drug is hydro-cortisone or idoxuridine.
8. The device of claim 1 characterized in that the polymer is an ethylene-vinyl acetate copolymer, the solute is sodium chloride, the size of the depots of the solute is in the range of 1 to 50 microns, number average diameter, in size, and the drug is hydrocortisone or idoxuridine.
9. The device of claim 1 characterized in that the nonionic drug constitutes 5% to 65% of the mixture, the polymer constitutes 30% to 90%
of the mixture and the solute constitutes 0.5% to 5% of the mixture.
of the mixture and the solute constitutes 0.5% to 5% of the mixture.
10. The device of claim 8 characterized in that the nonionic drug constitutes 5% to 65% of the mixture, the polymer constitutes 30% to 90%
of the mixture and the solute constitutes 0.5% to 5% of the mixture.
of the mixture and the solute constitutes 0.5% to 5% of the mixture.
11. A process for preparing a sustained release delivery device, for use in an aqueous body environment, that releases drug substantially by diffusion, said process comprising forming a mixture of a) about 4% to about 75% by weight of a nonionic drug having a solubility in water from about 200 to about 10,000 ppm, and being in the form of particles 1 to 250 microns, number average diameter, in size, b) about 0.1% to about 10% by weight of an osmotically effective solute in the form of discrete depots about 1 to about 250 microns, number average diameter, in size and c) about 20% to about 95% by weight of a polymer that is permeable to the drug and to water, is impermeable to the solute, is substantially insoluble in the environment at least during the time that drug is being released and has a tensile strength of about 2500 to 70,000 kPa and forming said mixture into an integral solid body that is sized and shaped for placement and retention in said environment, said process being characterized in that before the mixture is formed into said body, said solute is dispersed in the polymer such that the depots of solute are substantially individually surrounded by a layer of polymer, whereby when the device is placed in the environment the depots imbibe water causing the respective polymer layer surrounding the depots to rupture, thereby forming a network of interconnected pores in the solid body and increasing in situ the effective surface area of the solid body, said device being a physiologically and pharmacologically acceptable device.
12. A process according to claim 11 characterized in that the solute constitutes 0.5% to 5% of the mixture.
13. A process according to claim 11 characterized in that the solute is capable of generating an osmotic pressure in the range of 3,000 to 30,000 kPa.
14. A process according to claim 11 characterized in that the size of the depots is in the range of 1 to 50 microns, number average diameter, in size.
15. A process according to claim 11 characterized in that the solute is sodium chloride.
16. A process according to claim 11 characterized in that the polymer is an ethylene-vinyl acetate copolymer.
17. A process according to claim 11 characterized in that the drug is hydrocortisone or idoxuridine.
18. A process according to claim 11 characterized in that the polymer Is an ethylene-vinyl acetate copolymer, the solute is sodium chloride, the size of the depots of the solute is in the range of 1 to 50 microns, number average diameter, in size and the drug is hydrocortisone or idoxuridine.
19. A process according to claim 11 characterized in that the nonionic drug constitutes 5% to 65% of the mixture, the polymer constitutes 30% to 90% of the mixture and the solute constitutes 0.5% to 5% of the mixture.
20. A process according to claim 18 characterized in that the nonionic drug constitutes 5% to 65% of the mixture, the polymer constitutes 30% to 90% of the mixture and the solute constitutes 0,5% to 5% of the mixture.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US59979575A | 1975-07-28 | 1975-07-28 | |
| US599,795 | 1975-07-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1083041A true CA1083041A (en) | 1980-08-05 |
Family
ID=24401120
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA257,322A Expired CA1083041A (en) | 1975-07-28 | 1976-07-20 | Sustained release drug delivery device and process for making same |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS5215810A (en) |
| CA (1) | CA1083041A (en) |
| CH (1) | CH623232A5 (en) |
| DE (1) | DE2633987A1 (en) |
| FR (1) | FR2319380A1 (en) |
| GB (1) | GB1503116A (en) |
| IT (1) | IT1069521B (en) |
| SE (1) | SE7608161L (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2048710B (en) * | 1979-05-07 | 1983-03-09 | Alza Corp | Osmotically driven fluid dispenser |
| GB2109237B (en) * | 1981-11-18 | 1985-12-18 | Standard Telephones Cables Ltd | Composite materials |
| JPS60139222U (en) * | 1984-02-28 | 1985-09-14 | 株式会社東芝 | foldable recorder |
| DE19537090A1 (en) * | 1995-10-05 | 1997-04-10 | Lohmann Therapie Syst Lts | Osmotic device for the continuous release of active substances into the fluids of the gastrointestinal tract |
| ZA97976B (en) * | 1996-04-05 | 1997-08-18 | Alza Corp | Uniform drug delivery theraphy. |
| US6096339A (en) * | 1997-04-04 | 2000-08-01 | Alza Corporation | Dosage form, process of making and using same |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3892842A (en) * | 1971-09-01 | 1975-07-01 | Alza Corp | Intrauterine contraceptive device for releasing steroid having double bond functionality |
| GB1425550A (en) * | 1973-04-25 | 1976-02-18 | Alza Corp | Device for releasing active agent and process for producing the same |
-
1976
- 1976-07-06 GB GB2809376A patent/GB1503116A/en not_active Expired
- 1976-07-16 SE SE7608161A patent/SE7608161L/en not_active Application Discontinuation
- 1976-07-20 CA CA257,322A patent/CA1083041A/en not_active Expired
- 1976-07-27 FR FR7622829A patent/FR2319380A1/en active Granted
- 1976-07-27 IT IT6887676A patent/IT1069521B/en active
- 1976-07-27 JP JP8960076A patent/JPS5215810A/en active Pending
- 1976-07-28 DE DE19762633987 patent/DE2633987A1/en not_active Withdrawn
- 1976-07-28 CH CH967576A patent/CH623232A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IT1069521B (en) | 1985-03-25 |
| GB1503116A (en) | 1978-03-08 |
| JPS5215810A (en) | 1977-02-05 |
| FR2319380A1 (en) | 1977-02-25 |
| SE7608161L (en) | 1977-01-29 |
| FR2319380B1 (en) | 1978-11-17 |
| DE2633987A1 (en) | 1977-02-10 |
| CH623232A5 (en) | 1981-05-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0669129B1 (en) | Expandable release controlled medicaments | |
| CA1318825C (en) | Plurality of tiny pills in liquid dosage form | |
| US4127127A (en) | Therapeutic systems made from certain segmented copolyesters | |
| JP2527713B2 (en) | Drug controlled release formulation | |
| US5004614A (en) | Controlled release device with an impermeable coating having an orifice for release of drug | |
| CA1265449A (en) | Devices for the controlled release of active substances, as well as process for the preparation thereof | |
| US4911707A (en) | Monolithic user-activated transdermal therapeutic system | |
| EP0010876B1 (en) | Osmotically driven active agent dispenser | |
| CA1189754A (en) | Simultaneous delivery of two drugs from unit delivery device | |
| US4439196A (en) | Osmotic drug delivery system | |
| EP1499289B1 (en) | Volume efficient controlled release dosage form | |
| US4917676A (en) | User-activated transdermal therapeutic system | |
| DE69531216T2 (en) | ADMINISTRATION SYSTEM WITH CONTROLLED RELEASE OF A DRUG SUSPENSION | |
| US4475916A (en) | Osmotic drug delivery system | |
| JP3973684B2 (en) | Oral administration and methods for treating oral pain conditions | |
| US6534089B1 (en) | Uniform drug delivery therapy | |
| EP0089548B1 (en) | Osmotic drug delivery system | |
| US4439194A (en) | Water and drug delivery system for suppository use | |
| JPS596843B2 (en) | Manufacturing method of drug supply body | |
| IL92966A (en) | Dispensing devices powered by hydrogel | |
| JPS6043327B2 (en) | Manufacturing method of drug releaser | |
| EP0100424A2 (en) | Acid anhydrides as rate controlling agent for the erosion of polymers which latter polymers have beneficial substances dispersed throughout their matrix or where the polymer matrix surrounds the beneficial substance | |
| SK49389A3 (en) | Floating system for oral therapy | |
| NZ239033A (en) | Semipermeable capsule with a hole containing a nicotine salt which reacts with water to release nicotine base | |
| CA1083041A (en) | Sustained release drug delivery device and process for making same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |