US3923939A - Process for improving release kinetics of a monolithic drug delivery device - Google Patents

Process for improving release kinetics of a monolithic drug delivery device Download PDF

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US3923939A
US3923939A US477297A US47729774A US3923939A US 3923939 A US3923939 A US 3923939A US 477297 A US477297 A US 477297A US 47729774 A US47729774 A US 47729774A US 3923939 A US3923939 A US 3923939A
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active agent
drug
polymer matrix
washing
agent
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Richard W Baker
Alan S Michaels
Felix Theeuwes
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Alza Corp
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Alza Corp
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Priority to US477297A priority Critical patent/US3923939A/en
Priority to GB2165075A priority patent/GB1477545A/en
Priority to SE7506099A priority patent/SE405803B/xx
Priority to CH714475A priority patent/CH611160A5/xx
Priority to DE2525061A priority patent/DE2525061C2/de
Priority to MX001433U priority patent/MX3007E/es
Priority to JP50068485A priority patent/JPS6043327B2/ja
Priority to FR7517693A priority patent/FR2273515A1/fr
Priority to IT68466/75A priority patent/IT1036192B/it
Priority to CA228,740A priority patent/CA1047403A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0039—Devices retained in the uterus for a prolonged period, e.g. intrauterine devices for contraception
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system

Definitions

  • ABSTRACT A process for improving the release kinetics of a monolithic active agent delivery device comprising a shaped body of a dispersion of particulate active agent, such as a drug, with a polymer matrix, such as ethylene/vinylacetate copolymer, by substantially reducing the initial burst of active agent from the device when it is placed in its'cnvironment of use.
  • the process involves prior to placing the body in its use environment removing, such as by water washing, the par ticulate drug from the exterior surface of the body to form an agent depleted layer of polymer matrix voided by the removal of the agent, the thickness of the layer being at least 571 of the overall body thickness.
  • 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 uniformly in a polymer matrix permeable to the drug by diffusion.
  • the polymer matrix may be substantially imperforate and homogeneous in which case the drug dissolves in and permeates through the polymer material itself.
  • the matrix may be microporous, the pores of which contain a drug-permeable liquid or gel medium, in which case the drug will preferentially dissolve in and permeate through the medium in the pores. It is of course possible to use a polymer matrix which is both microporous and made of a polymer permeable to the drug in which case movement of the drug through the matrix is via a combination of the above described modes.
  • Another type of monolithic device for use in releasing active agents into aqueous environments, such as drugs into the various cavities of the human body consists of a shaped body of discrete particulate osmotic solute/active agent depots dispersed in and surrounded by an active agent impermeable but water permeable polymer matrix whose cohesive strength is exceeded by the osmotic pressure generating ability of the individual depots.
  • Such devices release their active agent by an osmotic bursting mechanism in which water is imbibed osmotically into the depots nearest the exterior surfaces of the device, thereby dissolving those depots contents and generating pressure therewithin sufficient to cause the surrounding polymer matrix to rupture thus allowing release of the agent therefrom and access by the environment to the next nearest depots and serially so forth.
  • osmotic bursting monolithic osmotic bursting
  • a monolithic device is attractive commercially because they are inexpensive and easily fabricated relative to other devices such as laminated devices or capsule devices. Also, in the case of some drugs, a monolithic device is the only type of device capable of practically and sustainedly releasing the drug at a therapeutically effective rate.
  • the active agent release kinetics of these monolithic devices exhibit a feature which is often undesirable, namely the release begins at a high rate--called an initial burst-which rapidly decreases to a significantly lower rate.
  • the kinetics of monolithic diffusion for a device having a thin rectangular cross sectional shape i.e., the device is shaped as a flat slab
  • this initial burst of active agent may be undesirable because it results in overdosing, toxicity or side reactions, or may not conform to the optimal dosage regimen for a particular active agent.
  • the initial high level or burst in the release rate of active agent from a monolithic device may be reduced by coating the body with a layer of pure polymer ma trix.
  • a coated device is taught (the coating is used for a different purpose) in US. Pat. No. 3,577,512 issued May 4, 1971 to T. H. Shepherd et al.
  • this coating procedure has the disadvantage of lowering the entire release rate profile (i.e., the entire dM /dt vs. 2 plot) of the device. Such lowering may result in release rates below those required for efficacy.
  • the device has an irregular shape, it is usually quite difficult to devise a manufacturing procedure to make a continuous, uniform coating on the device in a reproducible manner.
  • This invention is a process for improving the release kinetics of the above described monolithic active agent delivery devices by substantially eliminating the initial burst of active agent release without significantly lowering the entire release rate profile of the device.
  • This novel process comprises, prior to placing the device in its intended environment of use, removing the particulate agent from the exterior surface of the device to form an agent depleted layer of polymer matrix voided by the removal of the particulate agent.
  • the removal of particulate agent from the surface of the device is done by washing the device in a liquid which does not deleteriously affect the polymer matrix at a temperature which enhances the removal of agent from the matrix.
  • the devices made by the invention process are placed in fluid containing environments into which the agent is released by diffusion or by osmotic bursting.
  • the environment may be a body cavity, a stream, an aquarium, soil, a chemical reactor or the like.
  • Embodiments intended to release drug within body cavities may be placed within the gastrointestinal tract, mouth, eye,
  • FIG. 1 is a vertical, sectional view of a disc-shaped monolithic diffusion type drug delivery device made in accordance with the invention process
  • FIG. 2 is an enlarged view of a portion of the section of FIG. 1 taken along line 2-2 of FIG. 1;
  • FIG. 3 is a graphic representation of the release kinetics of a prior art monolithic diffusion drug delivery device
  • FIG. 4 is a graphic representation of the improvements in the release kinetics of the device represented in FIG. 3 which may be realized by subjecting that device to the process of this invention;
  • FIG. 5 is a graphic representation of several prior art devices of the same geometry as the device of FIG. 3 but having different loadings of active agent;
  • FIG. 6 is a graphic representation of the improvements in the release kinetics of the devices of FIG. 5 which may be realized by subjecting those devices to the process of this invention;
  • FIG. 7 is a vertical, sectional view of a disc-shaped monolithic osmotic bursting drug delivery device made by the invention process
  • FIG. 8 is an enlarged view of a portion of a section of FIG. 7 taken along line 8-8 of FIG. 7;
  • FIG. 9 is a graphic representation of the release kinetics of a prior art monolithic osmotic bursting drug delivery device.
  • FIG. 10 is a graphic representation of the improvement in the release kinetics of the device of FIG. 9 which may be realized by treating that device in accordance with the process of this invention.
  • FIG. 1 depicts a disc-shaped monolithic diffusion type active agent delivery device, generally designated 10, comprising a particulate active agent 11, such as drug, dispersed in a polymer matrix 12.
  • the particles of agent 11 may be liquid, semi-solid or solid but are preferably solid.
  • Active agents as used herein include those compositions of matter which when dispensed in their environment of use produce a predetermined, beneficial and useful result.
  • agents include for example pesticides, herbicides, germicides, biocides, algicides, rodenticides, fungicides, insecticides, anti-oxidants, plant growth promotors and inhibitors, preservatives, surfactants, disinfectants, catalysts, fermentation agents, nutrients, drugs, plant minerals, sex sterilants, plant hormones, air purifiers, micro-organism attenuators and the like.
  • Drug as used herein broadly includes physiologically or pharmacologically active substances for producing a localized effect at the administration site or a systemic effect at a site remote from the administration site.
  • drugs include inorganic and organic compounds, for example, drugs which act on the central nervous system such as hypnotics and sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle relaxants and anti-parkinson agents, antipyretics and anti-inflammatory agents, local anesthetics, anti-spasmodics and antiulcer agents, prostaglandins, antimicrobials, hormonal agents, estrogenic steroids, progestational steroids, such as for contraceptive purposes, sympathomimetic drugs, cardiovascular drugs,
  • the active agent In the osmotic bursting devices the active agent must either itself be water soluble to the extent that the osmotic pressure of a saturated solution thereof exceeds the osmotic pressure of the external environment of use or it must be mixed with a compatible osmotically effective solute such as an inorganic or organic salt capable of generating such an osmotic pressure. Such pressure provides the necessary driving force by which the osmotic bursting mechanism is effected. Methods of calculating or measuring osmotic pressure are well known. See for example, S. Glasstone, Textbook of Physical Chemistry, MacMillan & Co., London (1960).
  • the polymer forming the polymer matrix may be substantially imperforate and homogeneous or microporous.
  • substantially imperforate polymers which may be used are poly(methylmethacrylate), poly(butylmethacrylate), plasticized poly(vinylchloride), plasticized soft nylon, natural rubber, poly(isoprene), poly(isobutylene), poly(butadiene), poly(ethylene), poly(vinylidene chloride), cross-linked poly(vinylpyrrolidone), chlorinated poly(ethylene) poly(4,4-isopropylidene diphenylene carbonate), ethylene-vinylacetate copolymer, plasticized ethylene-vinylacetate copolymer, vinylidene chloride-acrylonitrile copolymer, vinyl chloride-diethyl fumerate copolymer, silicone rubbers, especially the medical grade poly(- dimethylsiloxanes), ethylene-propylene rubber, silicone-carbonate
  • Microporous materials which may be used in making monolithic devices have pores which range in size from at least about IOA to several hundred microns, but usually not more than about I00 microns.
  • materials from which microporous structures may be made are regenerated, insoluble, nonerodible cellulose, acylated cellulose, esterified cellulose, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate diethylamino-acetate, poly(urethanes), poly(carbonates), modified insoluble collagen, cross-linked poly(vinyl alcohol), epoxy resins and poly(olefins) or poly(vinylchlorides). These materials may be made microporous by well known procedures such as coprecipitation or leaching out incorporated salts, soap micelles, starch or like materials. See, for example, J. D. Ferry, Chemical Reviews, 18, 373 (I935).
  • Diffusive media which may be used to fill the pores of the porous materials should be compatible with the environment of use. Also the active agent should leave only limited solubility in the medium (10 ppm to 10,000 ppm on a weight basis) so that the active agent is released by diffusion rather than by simple dissolutron.
  • Representative media are saline, glycerin, ethylene glycol, propylene glycol, water, emulsifying and suspending agents such as methyl cellulose mixed with water, mixtures of propylene glycol monostearate and oils, gum tragacanth, sodium alginate, poly(vinyl pyrrolidone), poly(oxyethylene stearate), fatty acids such as linoleic, and silicone oil.
  • Other representative media are set forth in Remingtons Pharmaceutical Sciences, pages 24 to 269 and 1338 to 1380, 1970, published by Mack Publishing Co., Easton, Pas.
  • the polymers used to make the osmotic bursting devices may be defined in terms of their permeabilities to active agent and water and their tensile strength and maximum elongation (which delimit their cohesive and rupture strength). Normally these materials will have water permeabilities of about g m "1 -24 hr- 100% rel. humidity a tensile strength of about 14 to 700 kg/cm (preferably 35 to 210 kglcm and a maximum elongation of IO% to 2000% (preferably 200% to l700%). They also should'have a high degree of impermeability to the active agent i.e., active agent permeabilities less than cm /sec.
  • Typical polymers for forming the osmotic bursting devices include unplasticized cellulose acetate, cellulose nitrate with 1 1% nitrogen, cellulose diacetate, cellulose triacetate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, cellulose acetate, acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethaminoacetate, cellulose acetate ethyl carbonate, cellulose acetate chloroacetate, cellulose acetate ethyl oxatate, cellulose acetate methyl sulfonate, cellulose acetate butyl sulfonate, cellulose acetate propionate, cellulose acetate butyl sulfonate, cellulose acetate propionate
  • Ethylene-vinyl acetate copolymers are especially useful for forming the osmotic bursting device.
  • Preferred among the ethylene-vinyl acetate copolymers are those having a melt index above about g/min and a vinyl acetate content above about 20%, such as from 20-45%.
  • the concentration of active agent dispersed in the polymer matrix will primarily depend upon the desired dosage level for the device. Normally the concentration of active agent will be in the range of 5 to 70 weight percent based on the polymer matrix. Its particle size will usually be in the range of 0.1 to 100 microns.
  • the active agent depot loading (which depends on the size and number of depots percent volume) is important.
  • the depots will usually comprise 5% to 70% by weight of the device. In this range sufficient polymer is present to adequately encapsulate the depots and maintain the devices integrity after a substantial amount of the agent depots have been released.
  • the depot size will usually range between 0.l and 100 microns in diameter.
  • the shape of the device made from the above described active agent/polymer dispersions will depend on the intended environment of use. In most environments complex shapes will be unnecessary and thus for convenience and economy the device will have a sim ple shape such as flat disc, a cylindrical rod, or a sphere. For specific embodiments such as an embodiment intended for use in the eye to release an ophthalmic drug therein, the device will usually be in the shape of a flat disc, oval, ellipse or kidney.
  • the device will be sized according to the environment and desired dosage.
  • Drug delivery devices for implanting in the body will be sized in accordance with the dimensions of the implant size. For instance for ocular inserts for inserting in a cul-de-sac of the eye the device will normally have a length of 4 to 20 mm, a width of l to 15 mm and a thickness of 0.1 to 4 mm and will usually contain 1 to 200 mg ophthalmic drug.
  • the active agent/polymer dispersions may be formed by mixing the two components by conventional techniques. Likewise, the dispersions may be formed into shaped bodies by conventional techniques such as solvent casting, extruding, roll milling, melt pressing, cutting, punching and the like.
  • the particles of active agent are removed from the exterior surface layer of the body in accordance with the process of this invention. This may be done by washing the body with a liquid which is inert relative to the polymer matrix (in other words the liquid should not deleteriously affect the polymer matrix either physically or chemically such as by dissolving, disintegrating, or chemically reacting with the matrix).
  • a liquid which is inert relative to the polymer matrix in other words the liquid should not deleteriously affect the polymer matrix either physically or chemically such as by dissolving, disintegrating, or chemically reacting with the matrix.
  • the wash liquid will usually be aqueous, with water being preferred.
  • the washing of the device causes active agent which is dissolved in the polymer matrix at the surface to diffuse into the wash liquid which in turn causes agent particles located at or nearthe surface to dissolve into the polymer and be diffused therefrom.
  • the washing causes any agent at the surface to be dissolved and water to be imbibed by the encapsulated agent depots causing them to burst and release their contents.
  • this washing ultimately results in the active agent being depleted from a surface layer of desired thickness.
  • the drug has been depleted from a layer, designated A, at the exterior surface of the device leaving voids 14.
  • the number and size of the voids in the matrix will depend on the concentration and particle size of the dispersed active agent. In this regard it has been observed that the voids tend to irreversibly shrink, i.e., the porosity of the layer decreases, if the device is permitted to dry after the washing. This phenomenon is believed to make the layer of a dried device act more like a coating of pure matrix in that it may be less permeable to the agent than the remainder of the matrix. In any event voids l4 affect the release kinetics of device 10 because they form preferred pathways (indicated by small arrows) for the active agent to diffuse along.
  • FIGS. 7 and 8 illustrate a monolithic osmotic bursting active agent delivery device, generally designated 15, which has been prewashed in accordance with the invention process.
  • Device 15 comprises discrete active agent/osmotic solute depots l6 encapsulated within a polymer matrix 17.
  • the prewashing 7 has depleted the active agent depots from a layer, designated B, at the surface of the device leaving voids l8.
  • Voids 18 are similar to voids 14 of device 10 except that voids 18 are substantially interconnected due to the bursting mechanism by which the active agent was released.
  • the process conditions of the wash e.g., time and temperature, will be selected to provide an agent depleted layer of predetermined thickness. Given a desired layer thickness the wash temperature and time will depend on the particular polymer and active agent involved.
  • wash times may be shortened by employing temperatures at which diffusion is enhanced.
  • osmotic bursting device wash times may be shortened by using temperatures at which water inhibition by the depots is enhanced. In almost all instances this means that elevated temperatures (above ambient temperature) below the matrix melt temperature and below that which might adversely affect the agent in any manner will shorten the wash time.
  • elevated temperatures above ambient temperature
  • agent wash temperatures in the range of about 50C to about 60C may be used advantageously.
  • any degree of prewashing will improve the release kinetics of the device, it is desirable to remove active agent from a layer which represents at least about of the total thickness or diameter of the device.
  • the thickness of the layer will comprise about 5% to about 25% of the overall thickness or diameter. It should be understood that in most devices the layer appears at both sides or both edges of the device and that the above percentages relate to only a single appearance of the layer. In other words in a spherical device the layer would appear at both ends of a diameter and thus the total diametrical drug depleted portion of the device would represent at least about of the entire diameter.
  • Example 1 A A monolithic diffusion device such as might be used to dispense a drug intrauterinely is made by mixing 20 parts progesterone (5-10 micron particle size) into a methylene chloride solution of 80 parts ethylenevinyl acetate copolymer (the drug loading is approximately 20% by volume). This mixture is cast into a 0.2 cm thick sheet from which a rectangular body having a total surface area of 1 cm is cut. This rectangular body is placed in a simulated uterine environment where it releases progesterone by diffusion. This release is monitored, the plot of which is shown in FIG. 3. As seen in FIG. 3 the initial release rate of progesterone is in the neighborhood of 150 ,ug/day and drops off rapidly during the first 100 days to about 40 ,ug/day after which the release curve slowly and continuously declines until the solid progesterone is exhausted.
  • A Three rectangular bodies of a progesterone/ethylene-vinyl acetate copolymer dispersion are prepared as in A. Each is washed in water at 50C; the first until a drug free surface layer 0.020 cm thick is formed; the second until a drug free layer 0.033 cm thick is formed;
  • each device is then placed in the simulated uterine environment as described in A and the progesterone release therefrom is monitored and plotted, the plots of which are shown in FIG. 4. As shown by these plots the initial release rate relative to the unwashed device is decreased respectively by about 30%, 60% and in the washed devices. Also the release rate during the major portion of the devices lifetime (ca. days to 500 days) is not significantly decreased by the washing.
  • Example 2 A A device identical with that of Example 1A and two other devices identical to the same except in drug loading (one contained half the amount of progesterone and the other contained double the amount of progesterone) are prepared and tested as in Example lA. Their release plots are illustrated in FIG. 5.
  • Example lA Three devices identical to those ofA are prepared and prewashed in water at 50C until a 0.047 cm thick drug-free layer is formed in each. These washed devices are then tested as in Example lA. Their release plots are shown in FIG. 6.
  • Example 3 A An osmotic bursting device such as might be used to dispense drug to the eye is made by mixing 30 parts pilocarpine nitrate with 70 parts of ethylene/vinyl acetate copolymer on a laboratory rubber mill. The well dispersed mixture which contains pilocarpine nitrate particles with an average diameter of between 1 and 10 microns is then pressed into a flat film 500 microns thick from which an ellipse shaped body 13.5 mm by 6.5 mm is cut. This body is placed in simulated lachrymal fluid at 37C where it releases pilocarpine nitrate by an osmotic bursting mechanism. This release is monitored, the plot of which is shown in FIG. 9. As seen in FIG. 9 the initial pilocarpine nitrate release rate is about 175pg/hour and drops off rapidly during the first 25 hours to about 25 ug/hour.
  • Example 4 Osmotic bursting ocular inserts are made by dispersing 30 parts tetracycline hycrochloride in 70 parts ethylene/vinyl acetate copolymer (Elvax 220) on a rubber mill, melt pressing the dispersion into a flat film 500 microns thick and cutting 13.5 mm X 5.8 mm ellipses therefrom. Individual ellipses are washed, 0, 15, 30, 60 and 120 minutes respectively, in water at 50C, dried and then placed in simulated lachrymal fluid. The average tetracycline hydrochloride release over the first-7 hours of release is respectively 26, l8, l7, l2 and 9 ug/hour.
  • Example inserts were made and tested as in Example 4 except that a different ethylene/vinyl acetate copolymer (Elvax 40) was used.
  • the average tetracycline hydrochloride release over the first 7 hours is, respectively, 25,15, 12, 9 and 6 ug/hour.
  • Method for substantially reducing the initial burst of active agent release from a monolithic active agent delivery device when said device is placed in its environment of use said device comprising a shaped body of a dispersion of particulate active agent within a polymer matrix comprising prior to placing said shaped body in said environment, removing the particulate agent from the exterior surface of said body to form an agent depleted layer of polymer matrix voided by such removal of particulate active agent, the thickness of said layer being at least about 5% of the overall thickness of the body.
  • a process for making a monolithic drug delivery device comprising a dispersion of solid particulate drug in a polymer matrix comprising the steps of forming a dispersion of the solid particulate drug within said matrix and forming the dispersion into a shaped body adapted for placement in the environment of use of the device, the improvement comprising the additional step of removing the solid particulate drug from the surface of said body to form a drug depleted layer of polymer matrix voided by the removal of the particulate solid drug therefrom, the thickness of said layer being at least about 5% of the overall thickness of said body.

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US477297A 1974-06-07 1974-06-07 Process for improving release kinetics of a monolithic drug delivery device Expired - Lifetime US3923939A (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
US477297A US3923939A (en) 1974-06-07 1974-06-07 Process for improving release kinetics of a monolithic drug delivery device
GB2165075A GB1477545A (en) 1974-06-07 1975-05-20 Drug delivery devices
SE7506099A SE405803B (sv) 1974-06-07 1975-05-28 Forfarande for framstellning av en anordning for avgivande av ett aktivt medel
CH714475A CH611160A5 (enrdf_load_stackoverflow) 1974-06-07 1975-06-03
DE2525061A DE2525061C2 (de) 1974-06-07 1975-06-05 Formkörper zur Abgabe eines Wirkstoffs und Verfahren zu dessen Herstellung
MX001433U MX3007E (es) 1974-06-07 1975-06-06 Procedimiento mejorado para hacer un dispensador monolitico de agente activo
JP50068485A JPS6043327B2 (ja) 1974-06-07 1975-06-06 薬品放出体の製造法
FR7517693A FR2273515A1 (fr) 1974-06-07 1975-06-06 Procede de fabrication d'un corps monolithique pour la liberation continue d'agents actifs, notamment de medicaments
IT68466/75A IT1036192B (it) 1974-06-07 1975-06-06 Procedimento per la fabbricazione di un dispositivo monolitico erogatore di un farmaco
CA228,740A CA1047403A (en) 1974-06-07 1975-06-06 Process for making a monolithic drug delivery device

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JP (1) JPS6043327B2 (enrdf_load_stackoverflow)
CA (1) CA1047403A (enrdf_load_stackoverflow)
CH (1) CH611160A5 (enrdf_load_stackoverflow)
DE (1) DE2525061C2 (enrdf_load_stackoverflow)
FR (1) FR2273515A1 (enrdf_load_stackoverflow)
GB (1) GB1477545A (enrdf_load_stackoverflow)
IT (1) IT1036192B (enrdf_load_stackoverflow)
MX (1) MX3007E (enrdf_load_stackoverflow)
SE (1) SE405803B (enrdf_load_stackoverflow)

Cited By (70)

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US4145408A (en) * 1976-08-16 1979-03-20 The Procter & Gamble Company Controlled release article
US4156604A (en) * 1978-09-15 1979-05-29 Minnesota Mining And Manufacturing Company Controlled delivery of corrosion inhibitors for silver recovery cartridges
US4177256A (en) * 1973-04-25 1979-12-04 Alza Corporation Osmotic bursting drug delivery device
US4190642A (en) * 1978-04-17 1980-02-26 Alza Corporation Ocular therapeutic system for dispensing a medication formulation
US4267138A (en) * 1976-09-17 1981-05-12 Richter Gedeon Vegyeszeti Gyar Rt. Coating ensuring a controlled release of active ingredients of biologically active compositions, particularly pharmaceutical compositions and a process for preparation of biologically active compositions ensuring controlled release of active ingredients
US4304765A (en) * 1980-10-14 1981-12-08 Alza Corporation Ocular insert housing steroid in two different therapeutic forms
US4333850A (en) * 1979-06-15 1982-06-08 Borg-Warner Corporation Filled polymer composition for automatic addition of a corrosion inhibitor to a coolant system
US4432964A (en) * 1981-08-24 1984-02-21 Alza Corporation Topical composition containing steroid in two forms released independently from polymeric carrier
US4478818A (en) * 1982-12-27 1984-10-23 Alza Corporation Ocular preparation housing steroid in two different therapeutic forms
WO1985002408A1 (en) * 1983-11-25 1985-06-06 Exxon Research & Engineering Company Polymer article of manufacture
US4557925A (en) * 1982-07-08 1985-12-10 Ab Ferrosan Membrane-coated sustained-release tablets and method
US4564364A (en) * 1983-05-26 1986-01-14 Alza Corporation Active agent dispenser
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US4156604A (en) * 1978-09-15 1979-05-29 Minnesota Mining And Manufacturing Company Controlled delivery of corrosion inhibitors for silver recovery cartridges
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US4478818A (en) * 1982-12-27 1984-10-23 Alza Corporation Ocular preparation housing steroid in two different therapeutic forms
US4564364A (en) * 1983-05-26 1986-01-14 Alza Corporation Active agent dispenser
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US4704282A (en) * 1984-06-29 1987-11-03 Alza Corporation Transdermal therapeutic system having improved delivery characteristics
US4725439A (en) * 1984-06-29 1988-02-16 Alza Corporation Transdermal drug delivery device
US4629620A (en) * 1984-09-05 1986-12-16 Ab Ferrosan Membrane-coated sustained-release tablets and method
US4629619A (en) * 1984-09-05 1986-12-16 Ab Ferrosan Membrane-coated sustained-release tablets and method
US4874366A (en) * 1984-12-03 1989-10-17 Baxter Internatiional Inc. Housing enabling passive mixing of a beneficial agent with a diluent
WO1986003416A1 (en) * 1984-12-03 1986-06-19 Baxter Travenol Laboratories, Inc. Drug delivery apparatus preventing local and systemic toxicity
US5024657A (en) * 1984-12-03 1991-06-18 Baxter International Inc. Drug delivery apparatus and method preventing local and systemic toxicity
US4898733A (en) * 1985-11-04 1990-02-06 International Minerals & Chemical Corp. Layered, compression molded device for the sustained release of a beneficial agent
US5141750A (en) * 1986-06-13 1992-08-25 Alza Corporation Delayed onset transdermal delivery device
EP0249343A1 (en) * 1986-06-13 1987-12-16 Alza Corporation Moisture activation of transdermal drug delivery system
US5284660A (en) * 1986-06-13 1994-02-08 Alza Corporation Delayed onset transdermal delivery device
US4908027A (en) * 1986-09-12 1990-03-13 Alza Corporation Subsaturated transdermal therapeutic system having improved release characteristics
US5342623A (en) * 1986-09-12 1994-08-30 Alza Corporation Subsaturated transdermal therapeutic system having improved release characteristics
US4761289A (en) * 1986-10-10 1988-08-02 International Minerals & Chemical Corp. Sustained release implant and method for preparing same
US5071656A (en) * 1987-03-05 1991-12-10 Alza Corporation Delayed onset transdermal delivery device
DE3743945A1 (de) * 1987-09-01 1989-03-09 Lohmann Gmbh & Co Kg Vorrichtung zur abgabe von stoffen, verfahren zu ihrer herstellung sowie ihre verwendung
US4917895A (en) * 1987-11-02 1990-04-17 Alza Corporation Transdermal drug delivery device
US4837027A (en) * 1987-11-09 1989-06-06 Alza Corporation Transdermal drug delivery device
USRE39588E1 (en) * 1987-11-09 2007-04-24 Alza Corporation Transdermal drug delivery device
US4781924A (en) * 1987-11-09 1988-11-01 Alza Corporation Transdermal drug delivery device
US5108762A (en) * 1989-04-19 1992-04-28 Wm. Wrigley Jr. Company Gradual release structures for chewing gum
US5154939A (en) * 1989-04-19 1992-10-13 Wm. Wrigley Jr. Company Use of salt to improve extrusion encapsulation of chewing gum ingredients
US5165944A (en) * 1989-04-19 1992-11-24 Wm. Wrigley Jr. Company Gradual release structures for chewing gum
US5198251A (en) * 1989-04-19 1993-03-30 Wm. Wrigley Jr. Company Gradual release structures for chewing gum
US5229148A (en) * 1989-04-19 1993-07-20 Wm. Wrigley Jr. Company Method of combining active ingredients with polyvinyl acetates
US4978537A (en) * 1989-04-19 1990-12-18 Wm. Wrigley Jr. Company Gradual release structures for chewing gum
WO1990012511A1 (en) * 1989-04-19 1990-11-01 Wm. Wrigley Jr. Company Gradual release structures for chewing gum
US5091186A (en) * 1989-08-15 1992-02-25 Cygnus Therapeutic Systems Biphasic transdermal drug delivery device
US5124157A (en) * 1989-08-18 1992-06-23 Cygnus Therapeutic Systems Method and device for administering dexmedetomidine transdermally
LT3753B (en) 1989-08-18 1996-03-25 Cygnus Therapeutic System Device for administering dexmedetomidine transdermally
US5364627A (en) * 1989-10-10 1994-11-15 Wm. Wrigley Jr. Company Gradual release structures made from fiber spinning techniques
US5508038A (en) * 1990-04-16 1996-04-16 Alza Corporation Polyisobutylene adhesives for transdermal devices
US5128155A (en) * 1990-12-20 1992-07-07 Wm. Wrigley Jr. Company Flavor releasing structures for chewing gum
US5706807A (en) * 1991-05-13 1998-01-13 Applied Medical Research Sensor device covered with foam membrane
US5798065A (en) * 1991-05-13 1998-08-25 George J. Picha Collagen disruptive surface morphology for implants
US5564439A (en) * 1991-05-13 1996-10-15 George J. Picha Infusion device for soft tissue
US5853758A (en) * 1992-01-13 1998-12-29 Pfizer Inc. Preparation of tablets of increased strength
EP0729324A4 (en) * 1993-11-15 1997-09-03 Oculex Pharm Inc BIOCOMPATIBLE EYE IMPLANTS
US5962011A (en) * 1993-12-06 1999-10-05 Schering-Plough Healthcare Products, Inc. Device for delivery of dermatological ingredients
US6126956A (en) * 1994-06-23 2000-10-03 Axxia Technologies Subcutaneous implant
US5819742A (en) * 1996-11-06 1998-10-13 Family Health International Vaginal device for preventing conception or the transmission of sexually transmitted diseases, or both
US6331311B1 (en) 1996-12-20 2001-12-18 Alza Corporation Injectable depot gel composition and method of preparing the composition
US6130200A (en) * 1996-12-20 2000-10-10 Alza Corporation Gel composition and methods
US6673767B1 (en) 1996-12-20 2004-01-06 Alza Corporation Gel composition and methods
US6468961B1 (en) 1996-12-20 2002-10-22 Alza Corporation Gel composition and methods
US20030044467A1 (en) * 1996-12-20 2003-03-06 Brodbeck Kevin J. Gel composition and methods
US20060013879A9 (en) * 1996-12-20 2006-01-19 Brodbeck Kevin J Gel composition and methods
EP0887074A3 (en) * 1997-06-24 1999-01-07 Hoechst Marion Roussel Intravaginal drug delivery device
US6110500A (en) * 1998-03-25 2000-08-29 Temple University Coated tablet with long term parabolic and zero-order release kinetics
US7118376B2 (en) * 2000-03-14 2006-10-10 Coll Partners Ltd. System for the controlled delivery of an active material to a dental site
US20050175959A1 (en) * 2000-03-14 2005-08-11 Coll Partners Ltd. System for the controlled delivery of an active material to a dental site
US20030165792A1 (en) * 2000-03-14 2003-09-04 Ahron Jodaikin System for the controlled delivery of an active material to a dental site
US20030211974A1 (en) * 2000-03-21 2003-11-13 Brodbeck Kevin J. Gel composition and methods
US8303609B2 (en) * 2000-09-29 2012-11-06 Cordis Corporation Coated medical devices
US7829109B2 (en) 2001-11-14 2010-11-09 Durect Corporation Catheter injectable depot compositions and uses thereof
US20030157178A1 (en) * 2001-11-14 2003-08-21 Guohua Chen Injectable depot composition
US20080026031A1 (en) * 2002-05-31 2008-01-31 Titan Pharmaceuticals, Inc. Implantable polymeric device for sustained release of buprenorphine
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US8252303B2 (en) 2002-07-31 2012-08-28 Durect Corporation Injectable depot compositions and uses thereof
US8501215B2 (en) 2002-07-31 2013-08-06 Guohua Chen Injectable multimodal polymer depot compositions and uses thereof
US20080311171A1 (en) * 2003-03-31 2008-12-18 Patel Rajesh A Implantable polymeric device for sustained release of dopamine agonist
US20120258161A1 (en) * 2003-03-31 2012-10-11 Patel Rajesh A Implantable polymeric device for sustained release of dopamine agonist
US8852623B2 (en) * 2003-03-31 2014-10-07 Titan Pharmaceuticals, Inc. Implantable polymeric device for sustained release of dopamine agonist
US9278163B2 (en) 2003-03-31 2016-03-08 Titan Pharmaceuticals, Inc. Implantable polymeric device for sustained release of dopamine agonist
US8287277B2 (en) 2007-08-08 2012-10-16 Colldent V.A. Ltd. Reshapable device for fixation at a dental site
US20110104635A1 (en) * 2007-08-08 2011-05-05 Coll Partners Ltd. Reshapable device for fixation at a dental site
USRE48948E1 (en) * 2008-04-18 2022-03-01 Warsaw Orthopedic, Inc. Clonidine compounds in a biodegradable polymer
US11712370B2 (en) * 2009-02-23 2023-08-01 Mati Therapeutics Inc. Lacrimal implants and related methods
US20110129516A1 (en) * 2009-10-30 2011-06-02 Aton Pharma, Inc. Ocular drug delivery devices
US9138308B2 (en) 2010-02-03 2015-09-22 Apollo Endosurgery, Inc. Mucosal tissue adhesion via textured surface
US9205577B2 (en) * 2010-02-05 2015-12-08 Allergan, Inc. Porogen compositions, methods of making and uses
US20130032962A1 (en) * 2010-02-05 2013-02-07 Allergan, Inc. Porogen compositions, methods of making and uses
US8685296B2 (en) * 2010-05-11 2014-04-01 Allergan, Inc. Porogen compositions, method of making and uses
US20110278755A1 (en) * 2010-05-11 2011-11-17 Allergan, Inc. Porogen compositions, method of making and uses
US9668844B2 (en) 2013-11-06 2017-06-06 Colldent Y.A Ltd Device for fixation at a dental site
US10758623B2 (en) 2013-12-09 2020-09-01 Durect Corporation Pharmaceutically active agent complexes, polymer complexes, and compositions and methods involving the same
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Also Published As

Publication number Publication date
SE405803B (sv) 1979-01-08
DE2525061A1 (de) 1976-01-02
JPS6043327B2 (ja) 1985-09-27
CA1047403A (en) 1979-01-30
MX3007E (es) 1980-01-28
DE2525061C2 (de) 1985-08-22
JPS5112920A (enrdf_load_stackoverflow) 1976-01-31
SE7506099L (sv) 1975-12-08
FR2273515A1 (fr) 1976-01-02
IT1036192B (it) 1979-10-30
CH611160A5 (enrdf_load_stackoverflow) 1979-05-31
FR2273515B1 (enrdf_load_stackoverflow) 1980-02-15
GB1477545A (en) 1977-06-22

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