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Número de publicaciónUS3923939 A
Tipo de publicaciónConcesión
Fecha de publicación2 Dic 1975
Fecha de presentación7 Jun 1974
Fecha de prioridad7 Jun 1974
También publicado comoCA1047403A1, DE2525061A1, DE2525061C2
Número de publicaciónUS 3923939 A, US 3923939A, US-A-3923939, US3923939 A, US3923939A
InventoresBaker Richard W, Michaels Alan S, Theeuwes Felix
Cesionario originalAlza Corp
Exportar citaBiBTeX, EndNote, RefMan
Enlaces externos: USPTO, Cesión de USPTO, Espacenet
Process for improving release kinetics of a monolithic drug delivery device
US 3923939 A
Resumen
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 environment of use. The process involves prior to placing the body in its use environment removing, such as by water washing, the particulate 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 5% of the overall body thickness.
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United States Patent Baker et al.

Dec. 2, 1975 PROCESS FOR IMPROVING RELEASE KINETICS OF A MONOLlTHlC DRUG DELIVERY DEVICE [75] Inventors: Richard W. Baker, Mountain View;

Alan S. Michaels, Atherton; Felix 'lheeuwes, Los Altos, all of Calif.

[73] Assignee: Alza Corporation, Palo Alto, Calif.

[22] Filed: June 7, 1974 [21] Appl. No.: 477,297

I52] US. Cl. 264/49; 264/109; 264/233;

[51] Int. Cl. B29D 27/00 [58] Field of Search 264/233, 344, 49, 10);

[56] References Cited UNITED STATES PATENTS 3,402,240 9/1968 Cain et al. 424/22 3,700,380 l0/l972 Kitrilakis 264/49 UX R27,l07 3/1971 Levesque 424/22 FOREIGN PATENTS OR APPLICATIONS 808,014 1/1959 United Kingdom 424/22 Primary E.\'aminerPhilip Anderson Atl0rn0y,Agenl, 0r FirmThomas E. Ciotti; Paul L. Sabatine; Edward L. Mandell [57] 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.

14 Claims, 10 Drawing Figures US. Patent Dec. 2. 1975 Sheet of} 3,923,939

DEVICE 0F EXAMPLE IA TIME (DAYS) Dec. 2, 1975 shw 2 0f 3 3,923,939

DEVICESOF EXAMPLE IB 0.04? CM. do 560 US. Patent 600 760 800 TIME (DAYS TIME (DAYS) DEVICESOF EXAMPLE 2A E DEVICES 0F EXAMPLE 2B 0 4'00 TIM E (ms) US. Patent Dec. 2, 1975 DEVICE 0F EXAMPLE 3A 0 (m /HOUR) PILOCAPIRE RELEASE RATE TIME (HOURS) Sheet 3 of 3 PIL QCAPINE RELEASE RATE (mcg/ HOUR) DEVICES OFEXAMPLE TIME (HOURS) PROCESS FOR IMPROVING RELEASE KINETICS OF A MONOLITI-IIC DRUG DELIVERY DEVICE BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to a process for improving the active agent release kinetics of a monolithic active agent delivery device.

2. Description of the Prior Art 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. Alternatively, 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. These monolithic osmotic bursting" devices are the subject matter of commonly assigned, copending application Ser. No. 354,359 filed Apr. 25, 1973 and now abandoned, the disclosure of which is incorporated by reference herein.

These monolithic devices are 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) may be expressed by the equation:

(dMJd!) A (DC, C.,/2 in which M, is the agent released at time, t, C is the agent solubility in the polymer matrix, C, is the total concentration of agent in the polymer matrix, C, being and a sphere are also known T. Higuchi, J. Pharm. Soil, 50, 874 (196i).

T. J. Roseman et al.. J. Pharm. SCI., 59. 353 (1970); T. J. Roseman, J. Pharm. Sci., 6i, 46 (1972); and H. K. Lonsdale, R. W. Baker, Controlled Release of Biologically Active Agents", Ed. C. Tanquery, Plenum Press, New York (1974).

In a plot of the above equation with dMJdt plotted against 1, the release rate in the initial stage of release is extremely high and drops off very quickly to a level markedly below the rate in the initial stage. Corresponding plots for monolithic diffusion devices of other simple geometry, such as a rod-like cylinder or sphere, follow the same general release rate pattern as the simple slab described above.

The release kinetics for monolithic osmotic bursting devices have been found empirically to also exhibit an initial burst which decreases rapidly to a significantly lower rate. However the release rate plateaus after the initial decrease in the osmotic bursting devices whereas it continuously decreases in the diffusion devices.

In both types of devices 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. Such 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. However 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. Also, if 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.

SUMMARY OF THE INVENTION 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.

In a preferred embodiment of this process 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. Depending on the particular active agent involved 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,

uterus, vagina and other cavities.

BRIEF DESCRIPTION OF THE DRAWINGS In the drawings:

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; and

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; and

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.

DETAILED DESCRIPTION OF THE 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. Such 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. Such 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,

4 diuretics, antiparasitic agents, hypoglycemic drugs and ophthalmic drugs.

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).

As indicated above, in the monolithic diffusion devices the polymer forming the polymer matrix may be substantially imperforate and homogeneous or microporous. Examples of 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 copolymers, vinylidene chloride-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer and vinylidene chloride-acrylonitrile copolymer.

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. Examples of 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, cellulose acetate p-toluene sulfonate, triacetate of locust gum bean, cellulose acetate with acetylated hydroxy-ethyl cellulose, hydroxylated and unhydroxylated ethylene-vinyl acetate copolymers, highly plasticized polyvinyl chloride, homoand copolymers of polyvinyl acetate, polymers of acrylic acid and methacrylic acid, polyvinyl alkyl ethers, polyvinyl fluoride, polycarbonates, polymeric epoxides, copolymers of an alkylene oxide and alkyl glycidyl ether, semi-permeable polyurethanes, semipermeable polyglycolic or polylactic acid and derivatives thereof and derivatives of polystyrene such as poly(sodium styrenesulfonate) and poly(vinylbenzyl trimethylammonium chloride). Ethylene-vinyl acetate copolymers, either alone or mixed with other materials, 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%.

In the diffusion devices 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.

In the osmotic bursting devices 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.

After the dispersion is formed into the desired shape (this may be its final form for introducing into the use environment or some intermediate form such as a large sheet or roll) but before it is placed in the environment of use, 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). For convenience and economy the wash liquid will usually be aqueous, with water being preferred.

In a diffusion device 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. In the case of the osmotic bursting devices 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. In both types of devices this washing ultimately results in the active agent being depleted from a surface layer of desired thickness. In the device shown in FIGS. 1 and 2 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. As shown in FIG. 8 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. In a diffusion device wash times may be shortened by employing temperatures at which diffusion is enhanced. In an 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. For most polymers and agent wash temperatures in the range of about 50C to about 60C may be used advantageously. For both types of devices it is desirable to carry out the wash with agitation to ensure good clearance of the released agent from the exterior of the device.

Although 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. Usually 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.

EXAMPLES The invention process and the improvement in release kinetics realized by using it are further illustrated by the following examples.

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.

B. 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;

and the third until a drug free layer 0.047 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.

B. 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.

As is readily seen by comparing FIGS. 5 and 6 the washing eliminated the initial burst in the progesterone release while not significantly affecting the release rate over the bulk of each devices lifetime.

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.

B. Five devices identical to those of A are prepared and soaked in water at 37C for 15, 30, 60 and minutes and 24 hours respectively. Each device is then tested as in A. Their pilocarpine nitrate release plots are shown in FIG. 10. As shown by these plots the washing decreases the initial release rate by about 20%, 40%, 50%, and 90% respectively. Also, there is little variation in release rate between the unwashed and washed devices after 25 hours.

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 hoursis, respectively, 25,15, 12, 9 and 6 ug/hour.

Various modifications of the invention process will be obvious to those of ordinary skill in the active agent formulations art. Such modifications are intended to be within the scope and spirit of the following claims.

We claim:

1. 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.

2. The method of claim 1 wherein said removing is done by washing the body in a liquid which is inert relative to said polymer matrix.

3. The method of claim 2 wherein said liquid is water.

4. The method of claim 2 wherein said device is a diffusion type device and said washing is carried out at an elevated temperature at which diffusion of the agent from the matrix is enhanced.

5. The method of claim 2 wherein the polymer matrix is an ethylene/vinyl acetate copolymer and the washing is carried out at about 50C to about 60C.

6. The method of claim 2 wherein the device is an osmotic bursting type device and the washing is carried out at an elevated temperature at which imbibition of said liquid by the active agent is enhanced.

7. The method of claim 1 wherein the thickness of the layer is about 5% to 25% of the overall thickness of the body.

8. In 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.

9. The improvement of claim 8 in which the thickness of said layer is about 5% to about 25% of the overall thickness of the body.

10. The improvement of claim 8 wherein said removing is done by washing the body in a liquid which is inert relative to the polymer matrix.

11. The improvement of claim 10 wherein the liquid is water.

12. The improvement of claim 10 wherein the device is a diffusion type device and said washing is carried out at an elevated temperatureat which diffusion of the drug from the matrix is enhanced.

13. The improvement of claim 12 wherein the polymer matrix is made of an ethylene/vinyl acetate copolymer and the elevated temperature is from about 50C to about C.

14. The improvement of claim 10 wherein the device is an osmotic bursting type device and the washing is carried out at an elevated temperature at which the imbibition of liquid by the active agent is enhanced.

Citas de patentes
Patente citada Fecha de presentación Fecha de publicación Solicitante Título
US3402240 *25 Jun 195717 Sep 1968Pfizer & Co CMedicinal tablet and process of making same
US3700380 *1 Oct 197024 Oct 1972Tecna CorpSurface or lining compatible with blood or other tissue
Citada por
Patente citante Fecha de presentación Fecha de publicación Solicitante Título
US4145408 *31 Oct 197720 Mar 1979The Procter & Gamble CompanySpermicidal, micelle-forming non-ionic surfactant, microporous membrane
US4156604 *15 Sep 197829 May 1979Minnesota Mining And Manufacturing CompanyMetallic filler coated with polyurethane foam for ion exchanging
US4177256 *29 Nov 19774 Dic 1979Alza CorporationPolymers, sustained release
US4190642 *11 May 197926 Feb 1980Alza CorporationOcular therapeutic system for dispensing a medication formulation
US4267138 *19 Sep 197712 May 1981Richter 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
US4304765 *14 Oct 19808 Dic 1981Alza CorporationSolubility; antiinflammatory agents; vision defects
US4333850 *15 Jun 19798 Jun 1982Borg-Warner CorporationFilled polymer composition for automatic addition of a corrosion inhibitor to a coolant system
US4432964 *27 Dic 198221 Feb 1984Alza CorporationTopical composition containing steroid in two forms released independently from polymeric carrier
US4478818 *5 Ene 198423 Oct 1984Alza CorporationOcular preparation housing steroid in two different therapeutic forms
US4557925 *5 Sep 198410 Dic 1985Ab FerrosanMembrane-coated sustained-release tablets and method
US4564364 *26 May 198314 Ene 1986Alza CorporationActive agent dispenser
US4629619 *19 Sep 198516 Dic 1986Ab FerrosanConstant dissolution rate
US4629620 *19 Sep 198516 Dic 1986Ab FerrosanPolyvinyl chloride, polyvinyl acetate, polyvinyl alcohol terpolymer
US4704282 *29 Jun 19843 Nov 1987Alza CorporationSustained release
US4725439 *13 Ene 198616 Feb 1988Alza CorporationReinforced matrix containing drug reservoir
US4761289 *10 Oct 19862 Ago 1988International Minerals & Chemical Corp.Sustained release implant and method for preparing same
US4781924 *9 Nov 19871 Nov 1988Alza CorporationRelease by moisture activator
US4837027 *9 Ago 19886 Jun 1989Alza CorporationTherapeutic agent stored as salt, moisture activates
US4874366 *19 Dic 198817 Oct 1989Baxter Internatiional Inc.Housing enabling passive mixing of a beneficial agent with a diluent
US4898733 *4 Nov 19856 Feb 1990International Minerals & Chemical Corp.Layered, compression molded device for the sustained release of a beneficial agent
US4908027 *12 Sep 198613 Mar 1990Alza CorporationSubsaturated transdermal therapeutic system having improved release characteristics
US4917895 *14 Jul 198817 Abr 1990Alza CorporationTransdermal drug delivery device
US4923607 *30 Nov 19878 May 1990Nitto Denko CorporationMembrane containing a liquid active substance and process for the production of same
US4978537 *19 Abr 198918 Dic 1990Wm. Wrigley Jr. CompanyGradual release structures for chewing gum
US5024657 *4 May 199018 Jun 1991Baxter International Inc.Drug delivery apparatus and method preventing local and systemic toxicity
US5071656 *14 Nov 198810 Dic 1991Alza CorporationNitroglycerin delivery to skin or mucosa
US5091186 *15 Ago 198925 Feb 1992Cygnus Therapeutic SystemsDelivers drug at therapeutic rate in initial phase, no drug in secondary phase
US5108762 *30 Oct 199028 Abr 1992Wm. Wrigley Jr. CompanyMelt spinning blend of gum base, water soluble bulk portion, and active agent which is formed by an artificial sweetener and polymeric wall material into fibers
US5124157 *18 Ago 198923 Jun 1992Cygnus Therapeutic SystemsUsing adhesive skin patch
US5128155 *20 Dic 19907 Jul 1992Wm. Wrigley Jr. CompanyCellulose and silicon dioxide
US5141750 *14 Nov 198825 Ago 1992Alza CorporationDelayed onset transdermal delivery device
US5154939 *8 Nov 199113 Oct 1992Wm. Wrigley Jr. CompanyComprising polyvinyl acetate, salt and sweetener
US5165944 *18 Oct 199124 Nov 1992Wm. Wrigley Jr. CompanySustained release by mixing a gum, extrusion and cutting
US5198251 *16 Dic 199130 Mar 1993Wm. Wrigley Jr. CompanyRelease agents and active agents for gum
US5229148 *20 Feb 199220 Jul 1993Wm. Wrigley Jr. CompanyChewing gum with encapsulation mixture
US5284660 *21 Ago 19928 Feb 1994Alza CorporationDelayed onset transdermal delivery device
US5342623 *18 Jun 199330 Ago 1994Alza CorporationSubsaturated transdermal therapeutic system having improved release characteristics
US5364627 *21 Jul 199215 Nov 1994Wm. Wrigley Jr. CompanyGradual release structures made from fiber spinning techniques
US5508038 *16 Abr 199016 Abr 1996Alza CorporationDrug delivery patches having mixture of high and low molecular weight polymers as adhesives which dissolve active agents, free of plasticizers and tackifiers
US5564439 *27 Dic 199415 Oct 1996George J. PichaInfusion device for soft tissue
US5706807 *11 Oct 199613 Ene 1998Applied Medical ResearchSensor device covered with foam membrane
US5798065 *2 Oct 199725 Ago 1998George J. PichaCollagen disruptive surface morphology for implants
US5819742 *30 Oct 199713 Oct 1998Family Health InternationalVaginal device for preventing conception or the transmission of sexually transmitted diseases, or both
US5853758 *10 Jul 199629 Dic 1998Pfizer Inc.Preparation of tablets of increased strength
US5962011 *24 Jun 19975 Oct 1999Schering-Plough Healthcare Products, Inc.The device is useful for treating lesions or abnormal skin features such as corns, warts, calluses, bunions, actinic keratoses and hard hyperkeratotic skin as is often found on the face, arms, legs or feet.
US6110500 *25 Mar 199829 Ago 2000Temple UniversityCoated tablet with long term parabolic and zero-order release kinetics
US6126956 *22 Dic 19983 Oct 2000Axxia TechnologiesSubcutaneous implant
US6130200 *18 Dic 199710 Oct 2000Alza CorporationGel composition and methods
US633131118 Dic 199718 Dic 2001Alza CorporationInjectable depot gel composition and method of preparing the composition
US646896113 Jul 200022 Oct 2002Alza CorporationGel composition and methods
US667376721 Mar 20006 Ene 2004Alza CorporationGel composition and methods
US7118376 *14 Mar 200110 Oct 2006Coll Partners Ltd.System for the controlled delivery of an active material to a dental site
US782910914 Nov 20029 Nov 2010Durect CorporationCatheter injectable depot compositions and uses thereof
US825230314 Nov 200228 Ago 2012Durect CorporationA biodegradable, biocompatible polymer, a water-immiscible solvent to plasticize the polymer and form a gel, a thixotropic agent and a beneficial agent; drug delivery; improved shear thinning and reduced injection
US827833027 Sep 20102 Oct 2012Durect CorporationShort duration depot formulations
US82872773 Nov 201016 Oct 2012Colldent V.A. Ltd.Reshapable device for fixation at a dental site
US8303609 *28 Sep 20016 Nov 2012Cordis CorporationCoated medical devices
US850121528 Jul 20036 Ago 2013Guohua ChenHaving a solvent with a miscibility in water of less than or equal to 7 wt. % at 25 degrees C., to plasticize the polymer and form a gel therewith; improved shear thinning behavior and reduced injection force
US8685296 *10 May 20111 Abr 2014Allergan, Inc.Porogen compositions, method of making and uses
US20080311171 *12 May 200818 Dic 2008Patel Rajesh AImplantable polymeric device for sustained release of dopamine agonist
US20110129516 *29 Oct 20102 Jun 2011Aton Pharma, Inc.Ocular drug delivery devices
US20110278755 *10 May 201117 Nov 2011Allergan, Inc.Porogen compositions, method of making and uses
US20120258161 *15 Jun 201211 Oct 2012Patel Rajesh AImplantable polymeric device for sustained release of dopamine agonist
USRE39588 *31 Oct 199024 Abr 2007Alza CorporationDelays onset of drug administration; does not deliver an initial burst of drug, less likely to cause irritation; stabilizes an active drug by storing it within a transdermal therapeutic system, in form suitable for storage
DE3743945A1 *23 Dic 19879 Mar 1989Lohmann Gmbh & Co KgVorrichtung zur abgabe von stoffen, verfahren zu ihrer herstellung sowie ihre verwendung
EP0127282A2 *26 Mar 19845 Dic 1984Alza CorporationImproved active agent dispenser
EP0249343A1 *14 May 198716 Dic 1987Alza CorporationMoisture activation of transdermal drug delivery system
EP0729324A1 *9 Nov 19944 Sep 1996Oculex Pharmaceuticals, Inc.Biocompatible ocular implants
EP0887074A2 *23 Jun 199830 Dic 1998Hoechst Marion RousselIntravaginal drug delivery device
WO1985002408A1 *20 Nov 19846 Jun 1985Exxon Research Engineering CoPolymer article of manufacture
WO1986003416A1 *29 Nov 198519 Jun 1986Baxter Travenol LabDrug delivery apparatus preventing local and systemic toxicity
WO1990012511A1 *26 Ene 19901 Nov 1990Wrigley W M Jun CoGradual release structures for chewing gum
Clasificaciones
Clasificación de EE.UU.264/49, 264/233, 604/57, 264/109, 424/486, 604/523, 128/832, 264/344, 424/469
Clasificación internacionalA61P31/00, A61K47/32, A61K9/00, A61K31/65, A61P5/00, A61K9/70, A61K9/26, A61K38/22
Clasificación cooperativaA61K9/0039, A61K9/0051, A61K9/0004
Clasificación europeaA61K9/00L4, A61K9/00M8D, A61K9/00M16B