US3851648A - Zero-order release device - Google Patents

Zero-order release device Download PDF

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Publication number
US3851648A
US3851648A US00405616A US40561673A US3851648A US 3851648 A US3851648 A US 3851648A US 00405616 A US00405616 A US 00405616A US 40561673 A US40561673 A US 40561673A US 3851648 A US3851648 A US 3851648A
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United States
Prior art keywords
solid
cavity
slot
medium
container
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Expired - Lifetime
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US00405616A
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English (en)
Inventor
D Brooke
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mead Johnson and Co LLC
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Mead Johnson and Co LLC
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Filing date
Publication date
Application filed by Mead Johnson and Co LLC filed Critical Mead Johnson and Co LLC
Priority to US00405616A priority Critical patent/US3851648A/en
Priority to ZA00746099A priority patent/ZA746099B/xx
Priority to FR7433012A priority patent/FR2247398B3/fr
Priority to AU73933/74A priority patent/AU7393374A/en
Priority to BE149285A priority patent/BE820784A/xx
Priority to NL7413243A priority patent/NL7413243A/xx
Priority to JP49115703A priority patent/JPS584574B2/ja
Priority to SE7412787A priority patent/SE7412787L/xx
Priority to DK533074A priority patent/DK533074A/da
Priority to DE19742448631 priority patent/DE2448631A1/de
Priority to US527477A priority patent/US3924622A/en
Application granted granted Critical
Publication of US3851648A publication Critical patent/US3851648A/en
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Expired - Lifetime legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/08—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of suppositories or sticks
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01M—CATCHING, TRAPPING OR SCARING OF ANIMALS; APPARATUS FOR THE DESTRUCTION OF NOXIOUS ANIMALS OR NOXIOUS PLANTS
    • A01M7/00—Special adaptations or arrangements of liquid-spraying apparatus for purposes covered by this subclass
    • A01M7/0089—Regulating or controlling systems
    • A01M7/0092—Adding active material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F6/00—Contraceptive devices; Pessaries; Applicators therefor
    • A61F6/06—Contraceptive devices; Pessaries; Applicators therefor for use by females
    • A61F6/14—Contraceptive devices; Pessaries; Applicators therefor for use by females intra-uterine type
    • 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
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin

Definitions

  • ABSTRACT A diffusible solid is released by diffusion into a fluid medium from a cavity within a container through an opening therein at a rate which is independent of the amount of solid present in the container. Zero-order release is effected by the shape of the cavity and the opening. The rate is related to the solubility and to the diffusion constant of the solid in the fluid medium.
  • the rate of release is determined by cavity shape and dimensions of the diffusion opening.
  • the device is adapted for use in both liquid and gaseous media and can be used for thezero-order release .of drug substances into the system of a living organism, and for non-medical uses.
  • This invention provides a device comprised of a container of rigid material which is impermeable to the fluid medium into which it is desired to dispense a diffusible solid which is contained within the device.
  • the container may be of any convenient size and shape to fit the particular application under consideration.
  • Housed within the container is a cavity communicating through a slot in the surface of the container with the exterior medium through which the contained solid is dispensed.
  • the solid is dispensed by the processes of dissolution of vaporization within the container into the fluid medium which enters through the slot, and diffusion of the dissolved or vaporized solid outwardly through the slot into the surrounding medium.
  • Zeroorder release results from the configuration of the cavity and slot which is such as to provide an increasing surface area of diffusible solid exposed to the fluid medium within the container as the length of the path through which the dissolved or sublimed solid must diffuse to reach the exterior increases. A constant ratio of area of dissolution or sublimation surface to diffusion distance is maintained.
  • the device is applicable to various drug delivery systems, and to non-medical uses such as the dispensing of insecticides, pesticides, perfumes, and water treatment with germicides in swimming pools, toilets, etc.
  • FIG. 1 is a perspective view of a device of the present invention which is cylindrical in form and contains a rectangular slot lengthwise on one side thereof which communicates with a cavity within the cylindrical container the cross-section of which is shaped like a slice of pie.
  • FIG. 3 is a perspective view of a device of the present invention in which the container is ring-shaped and the diffusion slot is arranged concentrically upon the upper surface thereof.
  • FIG. 4 is a view in cross-section of the device shown in FIG. 3 along line 4--4.
  • FIG. 5 is a collection of graphs in which the rate of release of a diffusible solid from the device of FIG. 1 is related to its solubility, and the dimensions of the cavity and the slot.
  • FIG. 6 is a perspective view of a device of the present invention which is comprised of a hollow container in the form of a right circular cylinder bisected along the axis thereof and having an elongated diffusion slot located on the bisecting surface along the axis.
  • the cavity is illustrated by broken lines and the slot through which it communicates with the exterior is indicated by 20.
  • the slot is of uniform length and width.
  • the narrower dimension or width is situated at the ends 21 and 24 of the slot.
  • the elongated dimension is located at the sides of the slot represented by 22 and 23.
  • Drug substance or other active ingredient to be dispensed 25 is contained within cavity 15 and is outlined by a broken line in the drawing.
  • the cavity fill should be a solid under ambient conditions.
  • the end walls of cavity 15 are represented by and 31. End walls 30 and 31 lie in parallel planes which are at right angles to slot 20, adjacent to the ends thereof, and are congruent in shape.
  • FIG. 2 is a cross-section of the device of FIG. 1 taken along line 22 of FIG. 1 in a plane parallel with the planes of end walls 30 and 31 of cavity 15. Like numbers in FIG. 2 refer to like features of FIG. 1. Cavity 15 of the device shown in FIGS. 1 and 2 is only partially filled with drug substance 25, 26 representing the surface of drug substance 25 which is opposite slot 20.
  • the release of drug 25 from carrier 10 is controlled by dissolution and diffusion processes. This includes dissolution of drug 25 into fluid medium 51 at surface 26 thereof, and diffusion therefrom in solution to slot 20 and thence into the surrounding medium 50.
  • the release rate of drug 25 through slot 20 into the surrounding medium 50 is a function not only of the solubility and diffusion coefficient of the drug in the receiving fluid 50 but also of the dimensions of slot 20 and of the angle between side walls 45 and 46 of cavity 15.
  • Initially cavity may be filled flush with slot with a single pellet of drug substance 25.
  • fluid 50 from the surrounding medium diffuses into the cavity as shown by 51 in FIG. 2 to replace the drug which has dissolved and diffused out.
  • FIG. 2 represents the cross-section of a carrier from which about 50 percent of the initial drug fill has been released.
  • the arcuate drug surface 26 shown in FIG. 2 is naturally formed as a result of the dissolution and diffusion processes. If it is desired to prepare a drug carrier which is only partially filled with drug substance at the outset as shown in FIG. 2, then the surface of the drug substance should be provided with an arcuate contour as shown at 26 in FIG. 2.
  • the reason for the arcuate contour of drug surface 26 is that the rate of diffusion of drug substance through medium 51 to slot 20 is inversely proportional to the distance d separating drug surface 26 from slot 20 and directly proportional to the area A of drug surface 26.
  • the ratio of A to d remains constant so long as slot 20 lies along the axis of a section ofa cylindrical surface 26 formed by drug substance 25.
  • the rate of release R of drug substance 25 from slot 20 is governed by the expression shown in Equation I.
  • Equation I 6 is the angle (expressed in radians, l radian 57.3") between side walls 45-and 46 of cavity 15.
  • D is the diffusion coefficient of drug 25 in medium 50 and Cs is the solubility thereof.
  • the symbol a is the width of slot 20 and L is the length of slot 20.
  • the symbol h is the distance from slot 20 to that closest hypothetical point in medium 50 where the concentration of drug substance 25 is zero.
  • Equation I shows that since a, L, and 0 are fixed by the dimensions of cavity 15, then the rate of release R depends upon D, h, and Cs, all constants for any specific drug substance. Thus as long as drug is present and the arcuate surface 26 thereof is exposed to medium 51, the rate of release will be constant.
  • Equation 1 further dictates that an increase in L will cause a proportionate increase in the release rate R. An increase in a will cause an increase in rate R but as a is made larger, its influence on rate declines. The rate R can be increased by increasing 6 but like a and unlike L the effect is not linear.
  • the release rates of various members from devices having the same dimensions are substantially proportional to their solubilities Cs. If the values for D and h have not been previously determined as above, a trial and error approach to construction of the device to provide the desired release rate may be used.
  • rear wall 40 of cavity 15 have arcuate configuration as shown in FIGS. 1 and 2 similar to that of drug surface 26 such that rear wall 40 forms the wall of a cylinder the axis of which lies within slot 20.
  • a steady state of release of drug substance 25 will be maintained until the drug is entirely exhausted from the device.
  • rear wall 40 is-flat or has another configuration other than the arcuate form shown, a constant rate of drug release will be maintained only until drug surface 26 intercepts wall 40 and exposes a portion thereof. From that time until all of the drug is exhausted, the release rate R from slot 20 will be less than the steady state zero-order condition.
  • drug substance 25 may be filled into cavity 15 in the molten state and then permitted to solidify. This is particularly suitable if the drug substance is stable at its melting point and solidifies in a form such that the dissolution properties are isotropic.
  • a compressed solid may also be used as cavity fill.
  • Another means of using the device of the present invention is to fill cavity 15 with a suspension of drug substancein a thixotropic gel or liquid monomer. In the latter instance, the monomer is caused to polymerize in place. In the former, a firm gel forms on allowing the fill to stand in the quiescent state.
  • the diffusion coefficient of the drug substance through the polymer or gel matrix and the partitioning of drug between matrix and fluid is taken into account in calculating the release rate.
  • the release rate may be greater under these circumstances than when a solid pellet 25 of drug substance is used as illustrated in FIG. 1.
  • FIG. 6 is a drawing of another embodiment of the invention in which the container 75 is in the form of a right circular cylinder which is bisected lengthwise by a plane in which the axis of the cylinder lies.
  • the planar bisecting face is represented by the numeral 80.
  • Diffusion slot 85 lies along the axis of the bisected cylinder on the planar face of the container.
  • the inner side of the arcuate cylinder wall 81 constitutes the rear wall of cavity 90 which is the interior of the container.
  • Rear wall 81 thus has the arcuate concave configuration as is preferred for zero-order release during the entire residence time of diffusible solid within the container while it is immersed in the medium into which it is desired to dispense the solid.
  • the angle 0 between side walls 45 and 46 of cavity 15 may vary from about to about 140.
  • the angle employed is selected to afford the desired release rate.
  • Release rates can be further manipulated by the use of wax, polymer, or gel matrices such as petroleum wax, cholesterol, silicone rubber, polymeric hydrophilic hydrogels, and thixotropic gels prepared from polyethylene glycol, carboxymethylcellulose, or carboxyvinyl polymer as the continuous phase of a suspension of crystalline diffusible solid to be dispensed within the cavity.
  • wax, polymer, or gel matrices such as petroleum wax, cholesterol, silicone rubber, polymeric hydrophilic hydrogels, and thixotropic gels prepared from polyethylene glycol, carboxymethylcellulose, or carboxyvinyl polymer as the continuous phase of a suspension of crystalline diffusible solid to be dispensed within the cavity.
  • FIG. 5 is a collection of graphs in which the rate of release R expressed in micrograms per day is plotted as ordinate and solubility Cs in micrograms per milliliter is plotted as abscissa for delivery of a drug substance from a cylindrical intrauterine device similar to that of FIG. 1 having radius 0.12 cm and slot length 3.2 cm. Each of the lines plotted on these coordinates is for a different device having the values for the angle 0 and slot width a shown at the right hand side of the graph. The values of Roseman and Higuchi (loc. cit.) for medroxyprogesterone acetate of D 0.6 cm /day and h 0.058 cm were used for these calculations.
  • the system was tested experimentally by measuring the amount of stearic acid released from a device fabricated from stainless steel and immersed in USP alcohol.
  • the prism-shaped device was 2.5 inches long, 1.0 inches wide at the base, and 0.63 inches high from the base to the slot.
  • the sides, base, and one end were made of 18 gauge stainless steel.
  • the other end was cut from three-sixteenths inch stainless steel and was drilled to provide a filling port which could be closed with a stainless steel bolt. All of the joints were silver soldered.
  • a larger filling port was made in the base of the prism-like device by cutting a hole of appropriate size and soldering in place a stainless steel nut to be closed with a stainless steel bolt. Solvent resistant gaskets were used at both filling ports.
  • the slot width (a) was 0.030 inches and the effective slot length (L) was 2.263 inches.
  • the angle 6 was For filling, the slot was covered with a sheet of polyethylene and the device was inverted. Molten stearic acid was added through the large port in increments. The device was rocked back and forth and the portions allowed to solidify after each addition. The device held approximately 9.5 g. of stearic acid. After the port was closed, the polyethylene was carefully removed from the slot The release of stearic acid from the device into USP alcohol was measured by placing the device in the bottom of a double-walled beaker with an inside diameter of 11.0 cm. containing 1,000 ml. of alcohol. The bolt used to close the port in the base served as a pedestal for the device.
  • the beaker was kept at 30C. and its contents were stirred with a three bladed propeller (radius 2 cm., blade pitch 30) rotated at 50 rpm 2.5 cm. below the solvent surface.
  • the distance between the top of the device and the propeller was 4.9 cm.
  • a cover with a hole for the stirrer and one for the sampling port was kept on the beaker.
  • Solvent samples were withdrawn periodically. Alcohol at 30C was added to the beaker to maintain volume. The stearic acid concentration in the samples was estimated colorimetrically after extraction from the sample. A 10 ml. aliquot of the ethanolic solution conanol and the density of blue color was estimated photo- 10 metrically at 640 nm against an appropriate standard. The blue color was stable after approximately 30 minutes. The absorbance was linearly dependent on the concentration of stearic acid in the sample. The complete data for three trials according to this procedure are listed in Table I.
  • the white wax is melted and the megestrol acetate is added with mixing.
  • the molten mixture is then poured into the cavity of a device such as is illustrated in FIG. 1, and rapidly solidified by cooling to ensure uniform drug dispersion.
  • the amount of megestrol acetate employed in Composition 1 may be varied, and the white wax may be substituted by cholesterol.
  • composition 2 Silicone Rubber Matrix Silicone rubber elastomer 10.0 g. i99 !y QZQWJQQQQ 92. 4
  • Composition 1 Wax Matrix White Wax. USP 10.0 2 0 g. Mcgcstrol Acetate. microfinc g.
  • Composition 3 Carboxvpolvmethvlene Gel What is claimed is: y
  • a device for the automatic release at a substantially constantpredetermined rate of a diffusible solid into a fluid medium into which said solid has a propensity to diffuse when said device is immersed in said medium which comprises,
  • said container having a slot in the surface thereof defining an elongated opening of uniform length and width having two ends and two sides with the narrower dimension at the ends and the longer dimension at the sides, said slot communicating in its entirety with an internal cavity within said container said cavity being defined by an accuate wall and a pair of parallel congruent planar end walls arranged at right angles to said slot and adjacent the ends thereof,
  • a means for diffusing said solid from within said cavity into the immersing medium including a diffusible solid housed within said cavity as a homogenous mass in bonded relation to the inner wall surface of the cavity and having a surface thereof facing and opposing said slot opening to expose the diffusable solid surface to said fluid medium when said device is immersed therein.
  • arcuate concave configuration defining a segment of a cylinder wall the axis of which lies within said slot.
  • the device of claim 1 adapted for use in a gaseous medium and said solid possesses a vapor pressure such that sublimation thereof occurs under ambient conditrons.
  • the device of claim 8 wherein said solid is a suspension or a dispersion of a particulate pure drug substance in an'inert carrier solid wherein said carrier solid is substantially insoluble in said medium but permeable to diffusion of said drug substance.
  • said device is sized and shaped for placement and retention within the uterine cavity of a mammal and said solid is a biologically active substance.
  • said container is a ring adapted for placement and retention within the vagina of a mammal, said solid is a biologically active substance, and said slot and cavity are positioned concentrically on said ring.
  • a device for the automatic release at a substantially constant predetermined rate of a diffusible solid into a fluid medium into which said solid has a propensity to diffuse when said device is immersed in said medium which comprises a ring-shaped container which is insoluble in said medium, impermeable Q thereto, and impermeable to said solid,
  • said container having a slot in the surface thereof defining an elongated opening of uniform width having two opposing sides concentrically positioned and traversing the longer dimension of said opening, said slot communicating in its entirety with an internal concentrically positioned cavity within said Q container said cavity being defined in cross-section by a rear wall, and
  • a means for diffusing said solid from within said cavity into the immersing medium including a diffusible solid substance housed within said cavity as a homogenous mass in bonded relation to the inner wall surfaces of the cavity and having a surface thereof facing and opposing said slot opening to expose the diffusable solid surface to said fluid medium when said device is immersed therein,
  • said diffusible solid is a biologically active substance and said ring-shaped container is adapted for placement and retention within the vagina of a mammal.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Anesthesiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Vascular Medicine (AREA)
  • Dermatology (AREA)
  • Reproductive Health (AREA)
  • Medical Informatics (AREA)
  • Insects & Arthropods (AREA)
  • Pest Control & Pesticides (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Medicinal Preparation (AREA)
  • Feeding, Discharge, Calcimining, Fusing, And Gas-Generation Devices (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
US00405616A 1973-10-11 1973-10-11 Zero-order release device Expired - Lifetime US3851648A (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
US00405616A US3851648A (en) 1973-10-11 1973-10-11 Zero-order release device
ZA00746099A ZA746099B (en) 1973-10-11 1974-09-25 Zero-order release device
FR7433012A FR2247398B3 (ja) 1973-10-11 1974-10-01
AU73933/74A AU7393374A (en) 1973-10-11 1974-10-03 Release device
BE149285A BE820784A (fr) 1973-10-11 1974-10-07 Dispositif de liberation de produit a vitesse constante
NL7413243A NL7413243A (nl) 1973-10-11 1974-10-08 Inrichting voor het verdelen van een vaste stof n vloeistof of een gas.
JP49115703A JPS584574B2 (ja) 1973-10-11 1974-10-09 固体のゼロオ−ダ−放出装置
SE7412787A SE7412787L (ja) 1973-10-11 1974-10-10
DK533074A DK533074A (ja) 1973-10-11 1974-10-11
DE19742448631 DE2448631A1 (de) 1973-10-11 1974-10-11 Vorrichtung fuer eine nach nullter ordnung verlaufende freisetzung eines mittels
US527477A US3924622A (en) 1973-10-11 1974-11-26 Zero-order release method

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US00405616A US3851648A (en) 1973-10-11 1973-10-11 Zero-order release device

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US3851648A true US3851648A (en) 1974-12-03

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US00405616A Expired - Lifetime US3851648A (en) 1973-10-11 1973-10-11 Zero-order release device

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US (1) US3851648A (ja)
JP (1) JPS584574B2 (ja)
AU (1) AU7393374A (ja)
BE (1) BE820784A (ja)
DE (1) DE2448631A1 (ja)
DK (1) DK533074A (ja)
FR (1) FR2247398B3 (ja)
NL (1) NL7413243A (ja)
SE (1) SE7412787L (ja)
ZA (1) ZA746099B (ja)

Cited By (25)

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Publication number Priority date Publication date Assignee Title
US3924622A (en) * 1973-10-11 1975-12-09 Mead Johnson & Co Zero-order release method
US3926188A (en) * 1974-11-14 1975-12-16 Alza Corp Laminated drug dispenser
US3977404A (en) * 1975-09-08 1976-08-31 Alza Corporation Osmotic device having microporous reservoir
US4034758A (en) * 1975-09-08 1977-07-12 Alza Corporation Osmotic therapeutic system for administering medicament
US4290426A (en) * 1978-05-04 1981-09-22 Alza Corporation Dispenser for dispensing beneficial agent
EP0259113A2 (en) * 1986-09-04 1988-03-09 Pfizer Inc. Controlled release device for an active substance
EP0294993A1 (en) * 1987-06-11 1988-12-14 Pfizer Inc. A generic zero order controlled drug delivery system
US4863445A (en) * 1984-07-30 1989-09-05 Baxter Travenol Laboratories, Inc. Assembly for inhibiting microbial growth in collected fluid
US4948592A (en) * 1986-05-09 1990-08-14 Alza Corporation Pulsed drug delivery
US4986987A (en) * 1986-05-09 1991-01-22 Alza Corporation Pulsed drug delivery
US5114719A (en) * 1987-04-29 1992-05-19 Sabel Bernhard A Extended drug delivery of small, water-soluble molecules
US5200196A (en) * 1986-05-09 1993-04-06 Alza Corporation Improvement in pulsed drug therapy
US5256440A (en) * 1992-06-22 1993-10-26 Merck & Co., Inc. Process for producing a tablet core aperture
US5342627A (en) * 1991-11-13 1994-08-30 Glaxo Canada Inc. Controlled release device
US6264985B1 (en) * 1994-09-06 2001-07-24 Lts Lohmann Therapie-Systeme Gmbh Laminated tablet with pointed core
US6440445B1 (en) 1996-09-30 2002-08-27 Brigham & Women's Hospital Methods and compounds for treatment of abnormal uterine bleeding
US6569152B2 (en) 2000-03-21 2003-05-27 Farrington Pharmaceuticals, Llc Sustained release delivery systems for solutes
US20030133982A1 (en) * 2001-12-20 2003-07-17 Heimlich John M. Zero-order sustained release dosage forms and method of making same
US20030215510A1 (en) * 1991-06-27 2003-11-20 Frank Jao System for delaying drug delivery up to seven hours
US6960357B2 (en) 2001-05-25 2005-11-01 Mistral Pharma Inc. Chemical delivery device
US20060185678A1 (en) * 2005-02-03 2006-08-24 Bronnenkant Lance J Devices for delivering agents to a vaginal tract
US20070190144A1 (en) * 2005-12-30 2007-08-16 Zerbe Horst G Multilayer tablet
US9717682B2 (en) 2009-12-08 2017-08-01 Intelgenx Corporation Solid oral film dosage forms and methods for making same
US10058092B2 (en) 2012-04-13 2018-08-28 Sumatics, Llc Apparatus and method for controlled release of botanical fumigant pesticides
US10610528B2 (en) 2009-12-08 2020-04-07 Intelgenx Corp. Solid oral film dosage forms and methods for making same

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS603286B2 (ja) * 1977-03-03 1985-01-26 日本化薬株式会社 定速溶出性製剤
GB2077586A (en) * 1980-06-12 1981-12-23 Standard Telephones Cables Ltd Sustained-release device
DE3040978A1 (de) * 1980-10-28 1982-05-27 Schering Ag, 1000 Berlin Und 4619 Bergkamen Vaginalring
FR2599624B2 (fr) * 1986-06-09 1990-06-29 Virbac Dispositif a liberation programmee
DE4341442C2 (de) * 1993-12-04 1998-11-05 Lohmann Therapie Syst Lts Vorrichtung zur kontrollierten Freisetzung von Wirkstoffen sowie ihre Verwendung

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US827706A (en) * 1906-01-02 1906-08-07 John R Callahan Combined roost and nest-support.
US2045941A (en) * 1935-03-11 1936-06-30 Samuel C Brody Support and dispensing device
US2139404A (en) * 1937-05-21 1938-12-06 Sidney J Evans Chemical receptacle for attachment to garment hangers
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US3926188A (en) * 1974-11-14 1975-12-16 Alza Corp Laminated drug dispenser
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US4290426A (en) * 1978-05-04 1981-09-22 Alza Corporation Dispenser for dispensing beneficial agent
US4863445A (en) * 1984-07-30 1989-09-05 Baxter Travenol Laboratories, Inc. Assembly for inhibiting microbial growth in collected fluid
US4986987A (en) * 1986-05-09 1991-01-22 Alza Corporation Pulsed drug delivery
US4948592A (en) * 1986-05-09 1990-08-14 Alza Corporation Pulsed drug delivery
US5200196A (en) * 1986-05-09 1993-04-06 Alza Corporation Improvement in pulsed drug therapy
EP0259113A3 (en) * 1986-09-04 1988-05-18 Pfizer Inc. Controlled release device for an active substance
US4803076A (en) * 1986-09-04 1989-02-07 Pfizer Inc. Controlled release device for an active substance
EP0259113A2 (en) * 1986-09-04 1988-03-09 Pfizer Inc. Controlled release device for an active substance
US5114719A (en) * 1987-04-29 1992-05-19 Sabel Bernhard A Extended drug delivery of small, water-soluble molecules
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US4792448A (en) * 1987-06-11 1988-12-20 Pfizer Inc. Generic zero order controlled drug delivery system
US7736668B2 (en) 1991-06-27 2010-06-15 Janssen Pharmaceutica Nv System for delaying drug delivery up to seven hours
US6764697B1 (en) 1991-06-27 2004-07-20 Alza Corporation System for delaying drug delivery up to seven hours
US20030215510A1 (en) * 1991-06-27 2003-11-20 Frank Jao System for delaying drug delivery up to seven hours
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US6440445B1 (en) 1996-09-30 2002-08-27 Brigham & Women's Hospital Methods and compounds for treatment of abnormal uterine bleeding
US6569152B2 (en) 2000-03-21 2003-05-27 Farrington Pharmaceuticals, Llc Sustained release delivery systems for solutes
US6960357B2 (en) 2001-05-25 2005-11-01 Mistral Pharma Inc. Chemical delivery device
US20030133982A1 (en) * 2001-12-20 2003-07-17 Heimlich John M. Zero-order sustained release dosage forms and method of making same
US20060185678A1 (en) * 2005-02-03 2006-08-24 Bronnenkant Lance J Devices for delivering agents to a vaginal tract
US20070190144A1 (en) * 2005-12-30 2007-08-16 Zerbe Horst G Multilayer tablet
US8691272B2 (en) 2005-12-30 2014-04-08 Intelgenx Corp. Multilayer tablet
US9717682B2 (en) 2009-12-08 2017-08-01 Intelgenx Corporation Solid oral film dosage forms and methods for making same
US10610528B2 (en) 2009-12-08 2020-04-07 Intelgenx Corp. Solid oral film dosage forms and methods for making same
US10058092B2 (en) 2012-04-13 2018-08-28 Sumatics, Llc Apparatus and method for controlled release of botanical fumigant pesticides

Also Published As

Publication number Publication date
JPS5066475A (ja) 1975-06-04
FR2247398A1 (ja) 1975-05-09
ZA746099B (en) 1975-11-26
BE820784A (fr) 1975-04-07
JPS584574B2 (ja) 1983-01-27
AU7393374A (en) 1976-04-08
NL7413243A (nl) 1975-04-15
DK533074A (ja) 1975-06-16
FR2247398B3 (ja) 1977-07-08
DE2448631A1 (de) 1975-04-17
SE7412787L (ja) 1975-04-14

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