Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS3732865 A
Publication typeGrant
Publication dateMay 15, 1973
Filing dateJan 13, 1971
Priority dateJan 13, 1971
Publication numberUS 3732865 A, US 3732865A, US-A-3732865, US3732865 A, US3732865A
InventorsHiguchi T, Leeper H
Original AssigneeAlza Corp
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Osmotic dispenser
US 3732865 A
Abstract
An osmotic active agent dispenser is comprised of (1) a first compartment of relatively impervious material containing an active agent and provided with an aperture for releasing said active agent to the exterior of the dispenser; (2) a second compartment of controlled permeability to water containing a solution of an osmotically effective solute which exhibits an osmotic pressure gradient against water; and (3) a movable barrier member separating the first from the second compartment. The barrier member is slidably responsive to an increase in volume in the second compartment via absorption of water therein; whereby as water flows by osmosis into the compartment (2) of the dispenser in a tendency towards osmotic equilibrium with its environment, corresponding pressure is exerted behind the barrier (3) driving it into and diminishing the volume of the compartment (1), in turn continuously ejecting active agent thereout at an osmotically controlled rate over a prolonged period of time. In a specific embodiment, the dispenser is comprised of a plurality of capsule half shells one of which compartmentalizing and being free to move within the device, thereby defining a closure for both the active agent compartment and the solution compartment.
Images(2)
Previous page
Next page
Claims  available in
Description  (OCR text may contain errors)

Elite tates atf: r 91 iguchi et all.

[ May 15, R973 OSMOTIC DISPENSER [75] Inventors: Takeru Higuchi; Harold M. Leeper,

both of Lawrence, Kans.

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

[22] Filed: Jan. 13, 1971 [2]] Appl. No.: 106,130

[52] U.S. Cl. ..l28/260, 128/272, 128/213 [51] Int. Cl. ..A61m 7/00, A6lm 31/00 [58] Field of Search. ..l28/l27l3l,

Primary Examiner-Richard A. Gaudet Assistant Examiner.l. C. McGowan A ttorney-Steven D. Goldby and Paul L. Sabatine [57] ABSTRACT An osmotic active agent dispenser is comprised of l) a first compartment of relatively impervious material containing an active agent and provided with an aperture for releasing said active agent to the exterior of the dispenser; (2) a second compartment of controlled permeability to water containing a solution of an osmotically effective solute which exhibits an osmotic pressure gradient against water; and (3) a movable barrier member separating the first from the second compartment. The barrier member is slidably respon sive to an increase in volume in the second compartment via absorption of water therein; whereby as water flows by osmosis into the compartment (2) of the dispenser in a tendency towards osmotic equilibrium with its environment, corresponding pressure is exerted behind the barrier (3) driving it into and diminishing the volume of the compartment (1), in turn continuously ejecting active agent thereout at an osmotically controlled rate over a prolonged period of time. In a specific embodiment, the dispenser is comprised of a plurality of capsule half shells one of which compartmentalizing and being free to move within the device, thereby defining a closure for both the active agent compartment and the solution compartment.

9 Claims, 7 Drawing Figures 'PATENTEDHAY 1 51915 SHEET 1 OF 2 murrrnii INV ENTORS TAKERU HIGUCHI HAROLD M. LEEPER ATTOR Y mvzmons ATTO sum 2 or 2 PATENIEDMAH 5 ms FIG. 4

TAKERU H|GUCHI HAROLD M. LEEPER ()SMOTIC DISPENSER Takeru I-Iiguchi copending application, Ser. No. 106,131 filed Jan. 13, 1971, assigned to the assignee of the present invention.

FIELD OF THE INVENTION This invention relates to an osmotic dispenser, and, more especially, to an osmotic dispenser, simple in construction, capable of releasing to its outside environment concentrations of active agent at an osmotically controlled rate over a prolonged period of time.

DEFINITION OF TERMS The expression active agent as used herein denotes any drug (as defined, infra); composition in any way affecting any biological entity; substance having a nutrient or stimulating action, or growth inhibiting, destroying or any regulating action on plant growth, controlled or otherwise; substance to be assimilated by any organism, e.g., human being, animal, or lower order organism, for its nourishment or for regulating its growth;

' substance exhibiting any of the above activities to be directly applied to the habitat, surroundings or environment of any of the above organisms; and substance having any other effect on any other environment, especially any aqueous environment.

Therefore, suitable active agents for use with the dispenser of this invention include, without limitation, those which are generally capable of:

1. Preventing, alleviating, treating or curing abnormal and pathological conditions of the living body of such means as destroying a parasitic organism or limiting the effect of the disease or abnormality by chemically altering the physiology of the host or parasite;

2. Maintaining, increasing, decreasing, limiting or destroying a physiologic body or plant function, e.g., vitamin compositions, sex sterilants, fertility inhibitors, fertility promoters, growth promoters, and the like;

3. Diagnosing a physiological condition or state;

4. Controlling or protecting an environment or living body by attracting, disabling, inhibiting, killing, modifying, repelling or retarding an animal or microorganism, such as food and non-food baits, attractants and lures, biocides, pesticides, algicides, parasiticides, rodenticides, insecticides, fungicides, and the like;

5. Preserving, disinfecting or sterilizing; and

6. Controlling or affecting generically an environment, as by introducing a catalyst or metering a reactant into a reacting chemical system, or by effecting any chemical process therein, such as a fermentation, including propagation and/or attenuation of a microorganism.

The terms environment," surroundings" and habitat as used hereinabove and herein denote any prospective situs for the osmotic dispenser of this invention which is comprised of or will provide sufficient water for absorption into the device to develop the needed osmotic pressure on which its motive force depends; and implicit in the foregoing definition of active agent" one that will develop its action in the presence of such environment, surroundings or habitat, or one that will develop its action on a remote and/or another environment, which need not be aqueous. as hereinafter described and illustrated.

BACKGROUND OF THE INVENTION Many and varied compositions, products, appliances, depositors, applicators, dispensers, injectors and devices are well known in the art in which the timing or spacing of administration or absorption of an active agent is regulated by the structure or physical arrangement of elements so that a single administration provides a gradual but continuous or sustained feeding of the active agent to a system by slow or differential release. All of such prior art devices and the like, however, are characterized by at least one feature which adversely affects control over their rate of sustained or differential release or which detracts from the practical benefits attendant the long-term continuous administration of various active agents both to humans, animals, and into other environments.

An osmotic dispenser too has been proposed which is capable of delivering drug solution at a relatively constant rate. See Rose and Nelson, Austral. J. Exp. BioL, 33 pp. 415 420 (1955). The Rose et al. injector consists of three compartments and a clamp to hold a semi-permeable membrane. The motive force of the injector depends on the osmotic pressure developed by a saturated aqueous solution of Congo red against water. This solution is contained in a partially collapsed rubber compartment and is separated from a second water compartment by the semi-permeable cellophane membrane. The partially collapsed bag is placed in a glass ampoule, with the drug compartment of the device being defined by the space between the Congo red bag and the glass ampoule. The ampoule is also provided with drugrelease means and when the drug compartment is charged with a drug solution by osmosis water will move into the Congo red solution thus expanding the rubber compartment and providing the mechanical force to eject the drug out of the apparatus.

The Rose et al. device, however, has substantial inherent disadvantages which has prevented its wide acceptance by the medical community. In the first place, the use of a solution as the drug vehicle l will not permit high concentration of drug to be embodied within the device; (2) such solutions exhibit the deleterious tendency to be released from the device by simple leaching; and (3) many chemical substances on prolonged storage in a dissolved state undergo chemical deterioration. The reference injector is moreover cumbersome in that it depends for its motive force on a separate water compartment rather than its environment. In addition, the Rose et al. device is essentially only a research or experimentation tool, is complex in construction and is at least literally restricted to a Congo red solution to produce the osmotic driving force and to a cellophane osmotic membrane. See also Rose and Nelson, Austral. J. Exp. BioL, 33 pp. 41 l 414 (1955).

SUMMARY OF THE INVENTION Accordingly, it is a primary object of this invention to provide an osmotic dispenser, simple in construction, which exhibits all of the practical benefits of longterrn continuous administration of various active agents both to animals, humans, and into other environments.

Another object of this invention is to provide an improved osmotic dispenser which overcomes problems inherent in related devices heretofore proposed.

Another object of this invention is to provide an improved osmotic dispenser which will permit high concentrations of active agent to be embodied therein, and which high concentrations of active agent will not exhibit the tendency to be leached from the device nor be decreased in potency by chemical breakdown.

Another object of this invention is to provide an osmotic active agent dispenser which depends for its motive force on its environment.

Still another object of this invention is to provide an osmotic dispenser, the osmotic membrane of which can be fabricated from many and varied suitable materials, and which is capable of using a variety of solutions of osmotically effective solutes to produce the osmotic driving force.

Yet another object of this invention is to provide an osmotic dispenser of simple design which will release active agent solution, or gel, or semisolid active agent formulation, at a controlled rate over a prolonged period of time.

In attaining the objects of this invention, one feature resides in an osmotic dispenser comprised of a first compartment of relatively impervious material containing an active agent and a second compartment containing a solution of an osmotically effective solute which exhibits an osmotic pressure gradient against water. Separating the said first from the said second compartment, and defining a wall member common to each of said compartments, is a sliding or movable barrier of impervious material. The enclosure, whether of integral construction or not, defining the remainder of the second compartment, wherein the osmotic motive force of the dispenser is developed, is at least in part comprised of membrane which exhibits controlled permeability to water. When placed in a hypotonic aqueous environment, water, by osmosis, is absorbed therefrom through the membrane and diffuses into the solution contained in the said second compartment. As the water flows into the second compartment, the solution contained therein increases in volume exerting corresponding pressure behind the movable barrier divider. Such pressure serves to drive the said barrier forward and into the active agent compartment thus diminishing the volume of same and which sliding barrier in turn ejects the active agent out of the apparatus at an osmotically controlled rate over a prolonged period of time. For purposes of permitting the active agent to be squeezed out of the first compartment, same is provided with any suitable dispensing head or active agent release means to the exterior of the device, for example, capillary ducts therethrough.

A further feature of this invention resides in an osmotic active agent dispenser comprised of a plurality of capsule half shells, similar in shape to pharmaceutical hard gelatin half shells, with a first and a second half shell being securedly affixed in capsular configuration, and a third half shell frictionally disposed in such capsule but free to slidably move therein. The said capsule is thereby divided into the two compartments with the third half shell defining the wall member common to each of same. Optionally, a fourth half shell defines capping means for the dispensing head of the capsule.

Other objects, features and advantages of this invention will become more apparent from the following description when taken in conjunction with the accompanying drawings and wherein like reference numerals are used to indicate like or equivalent parts.

BRIEF DESCRIPTION OF THE DRAWINGS In the drawings:

FIG. 1 is a cross-sectional view of an osmotic dispenser of this invention;

FIG. la is a fragmentary cross-sectional view of a modification in the dispensing head of the osmotic dispenser of FIG. 1;

FIG. 1b is a fragmentary cross-sectional view of another modification in the dispensing head of the osmotic dispenser of FIG. 1;

FIG. 2 is a cross-sectional view of another osmotic dispenser of this invention;

FIG. 3 is a cross-sectional view of yet another osmotic dispenser of this invention;

FIG. 4 is a cross-sectional view of still another osmotic dispenser of this invention; and

FIG. 5 is an exploded view of the dispenser of FIG. 4.

DETAILED DESCRIPTION OF THE INVENTION In one embodiment in accordance with this invention as illustrated in FIG. 1 an osmotic dispenser 10 is comprised of a rigid, impervious housing member or plastic shell 12, capsule-shaped and having a thickened rounded end and bored with one or more capillary ducts or openings 14 approximately 0.5 mm in diameter. The open end of the plastic shell 12 is sealed or closed off with a membrane 16 which exhibits controlled permeability to water, advantageously a semipermeable, anisotropic cellulose acetate membrane of the type used in reverse osmosis water desalination. The membrane 16 is backed up by and supported by a stiff water-porous disc 18 which is advantageously cemented in place in the said shell 12 and is fabricated from such materials as, for example,.a ceramic frit. A sliding barrier plug, disc or seal 20, of impermeable barrier material compartmentalizes the shell 12 into an active agent compartment 22 and a compartment 24 wherein the motive force of the dispenser is developed. The said first compartment 22 contains the active agent, advantageously a drug, in a gel, paste or other semisolid state (albeit a solution or concentrated solution of active agent will sometimes suffice), and the active agent, if a drug, is preferably normally carried in an oil phase, such as cocoa butter. The said compartment 24 contains a solution of an osmotically effective solute which exhibits an osmotic pressure gradient against water; and the sliding barrier plug 20 is so constructed as to movably provide and maintain a tight barrier between the active agent phase in the first compartment and the osmotic fluid in the second. Without this tight barrier undesirable contamination could take place. The capillary ducts or active agent release means 14 provide communication from the interior of the compartment 22 to the exterior of the device 10, in this instance the said means being comprised of one or more of said capillary ducts 14 drilled in the thickened rounded end or dispensing head of the said shell 12. The plug 20 is frictionally disposed but is free to move within the device by sliding while at the same time maintaining an impenetrable or contamination preventing barrier between the active agent phase and the osmotic fluid.

To use the osmotic active agent dispenser of FIG. 1, the device, when the active agent is a drug or other agent for treating, etc., a living organism, is either physically inserted or surgically implanted in the body of the organism, typically a mammal, or is administered via the gastrointestinal tract. Once in place, water will be absorbed therein from either body tissues or body fluids through the stiff porous support 18 and through the water permeable membrane 16 in an effort to reach osmotic equilibrium, i.e., a transition from hypertonicity to isotonicity. As the water flows by osmosis into the compartment 24 tending to increase the volume of same corresponding pressure is built up behind the sliding barrier plug 20. Such pressure serves to drive the said barrier plug forward at a constant rate thus forcing the drug through the capillaries 14 at an osmotically controlled and constant rate into the external environment. There is accordingly provided the gradual and controlled constant release of drug or similar agent directly to the body or affected organ thereof over a prolonged period of time. Moreover, the use of any semisolid drug vehicle will reduce the tendency to release the drug, or any other active agent for that matter, by leaching and will permit high concentrations thereof to be embodied within the device.

In some instances, the dispenser is of insufficient specific gravity to maintain placement at the desired location. For example, for use in the rumen of polygastric animals, the weight should be sufficient to provide a specific gravity of at least 1.5. In those instances of insufficient specific gravity, therefore, a weight or ballast can be placed in the device, such as the steel ball 26 of FIG. 1. Other suitable weights comprise iron plugs, iron ore tablets, brass plugs, ceramic plugs, or the like.

When the active agent is other than a drug or similar agent, or is intended for use other than in a living organism, the device is introduced into the desired aqueous environment to produce the desired effect exactly as would be any of the known means for accomplishing a like result. And this is generally a mere physical insertion, such as by placing a pesticide containing device in a river or stream, or a catalyst containing device in an aqueous reaction medium.

If desired, long flexible tubing of polythene or the like can be extended from the dispensing head of the device of FIG. 1. See FIG. la. In such manner the device can be deposited at a site remote from the desired point of application and still release its active agent contents through the dispensing head and then through the tube directly to said point. This permits placement of the dispenser in an aqueous environment and release of the active agent into another environment which need not be aqueous. The dispensing head can also be provided with a check valve, for example, a one way ball valve (see FIG. 1b), to prevent back flow of active agent or other materials from the external environment into the device.

The design of the FIG. 1 device is moreover unique in that it requires a membrane of but limited surface area. This because of the ready availability of the highly water-permeable cellulose acetate membranes designed for use in reverse osmosis processes for water desalination. These membranes, typically and preferably anisotropic membranes, are highly permeable to water (allow relatively rapid rates of water transmission) but are relatively impermeable to salt, thus permitting their use in relatively small exposure area devices.

In FIG. 2 there is depicted an osmotic active agent dispenser 10 which allows for higher available exposure area of the membrane 16 and, accordingly, which design takes advantage of the availability of a far greater number of membranes than the semi-permeable, anisotropic cellulose acetate membranes of the type used in reverse osmosis water desalination. In this embodiment, both the membrane 16 and the stiff water porous support 18 are cup shaped rather than a flat disc, with the former being adhered or cemented to the latter. The designs of both FIG. 1 and FIG. 2 are also such that the porous disc or cup 18/membrane l6 assembly can alternatively merely be snapped or press-fit into the porous shell 12 and be there secured without the need for added adhesive or cement, and in such manner this mechanical lock in and of itself prevents any leakage. Optionally, in another alternative embodiment, a separator of porous paper, fabric or the like can conveniently be disposed between the support 18 and membrane 16. This prevents the membrane from being punctured or drawn into too tight a contact with the casing, thereby assuring that the entire membrane is exposed to the aqueous environment. Also in FIG. 2 it is depicted that the separator 20 may take the configuration of a capsule half shell, rather than a plug or disc (as in, for example, the design of FIG. 3).

FIG. 3 illustrates another embodiment of this invention wherein an osmotic active agent dispenser 30, similar to that of FIG. 1, is comprised of three, and optionally four capsule half shells, similar in shape to pharmaceutical hard gelatin half shells. The shell 32 is optional and designed to rapidly dissolve in the aqueous environment in which the device is intended to be placed, for example, is designed to rapidly dissolve in body fluids (when the active agent is a drug or other agent for treating, etc., a living organism). Shell 32 thus provides a capping means for the release port 44 of the capsule. Contran'wise, the shells 34 and 36 are rigid and resistant to dissolution and degradation in the aqueous environment or body fluids, but exhibit controlled permeability to moisture. The shells 34 and 38 are cemented tightly on manufacture, in capsular configuration, with shell 36 being free to move or slide in response to water flowing into the compartment 40, which compartment contains the solution of the osmotically effective solute exhibiting an osmotic pressure gradient against water, and said compartment 40 being defined by the walls of the said shells 36 and 38 and to some extent by the walls of the said shell 34. The active agent, advantageously a drug, is contained in the compartment 42 which is defined by the space between the walls of the shells 34 and 36. Shell 34 is provided with an aperture or orifice 4-4 from which the active agent or drug exits upon expansion of the solution compartment 40 which forces the shell 36 further into the active agent compartment 42, thus diminishing the active volume of the latter. The shell 36 is frictionally set into the shells 34 and 38 to such an extent (1) that it is free to move in response to absorption of water through the permeable shell 38 and concomitant increase in volume of the said compartment 40 but (2) the fit is tight enough as to prevent commingling and contamination of the contents of the several compartments 40 and 42 by leakage. It can be seen that, in use, as water flows into the solution compartment in a tendency towards osmotic equilibrium with the environment, the said solution compartment expands or increases in volume by forcing the interior shell further into the active agent compartment, thus continuously ejecting or squeezing active agent thereout at an osmotically controlled rate over a prolonged period of time. Thus, it will be appreciated that, mechanism-wise, the dispenser of FIG. 3 is functionally equivalent to those of .FIGS. I and 2. The shell 38 most preferably is a composite comprised of a rigid, highly porous half shell 46 lined with membrane 48 which is controlledly permeable to water. Such composite is readily fabricated by either lining or laminating the membrane 48 to the porous half shell 46, or by casting a film of the said membrane 48 onto and preferably within the said shell 46. The aforementioned casting about the porous shell is advantageously perfected by depositing the film from a solution of membrane forming material in a solvent, e.g., a 20 percent solution of cellulose acetate in an acetone-ethanolethyl lactate mixed solvent, 65 percent 20 percent 15 percent. In casting the film, care should be taken that the pores of the shell 46 do not become clogged.

Moreover, a device of either FIG. 1, FIG. 2 or FIG. 3 type is admirably suited for the continuous administration of the antibiotic oxytetracycline to beef cattle from the rumen. This because such devices can easily be fabricated of a size, weight and shape as to be retained in the rumen of polygastric animals to release drug or similar agent thereto at a carefully controlled rate. Other variations on the basic theme would be readily apparent to the skilled artisan. Although particular configurations may be designed for specific body uses, each of these configurations is applicable to use in other environments.

The membrane 16 of FIGS. 1 and 2 and the half shell lining 48 of FIG. 3 can be formed from a wide variety of materials permeable or semi-permeable to solvent (water) but not to solute, i.e., those suitable for the construction of an osmotic cell. For best results, the membrane should be substantially impermeable to passage of the osmotically effective solute so as to prevent loss thereof. Typical membranes are isotropic membranes such as unplasticized cellulose acetate, plasticized cellulose acetate, reinforced cellulose acetate, cellulose diand triacetate, ethyl cellulose; anisotropic reverse osmosis membranes which typically are made of cellulose acetate; silicone rubbers, polyurethanes, natural rubber, and hydrolyzed ethylene/vinyl acetate copolymers. Isotropic membranes have less water permeability than do the anisotropic membranes. Also, with both types of membranes, increasing the acetate content of the cellulose acetate polymer decreases the water permeability. Since, as previously described, the surface area of the membrane is relatively limited in a device of FIG. 1 type, it will be preferred to use semipermeable membranes allowing relatively rapid water transmission in this general category of dispensers. Thus, in such embodiments the anisotropic membranes are the preferred. A cellulose acetate membrane suitable for this limited surface area application is Eastman Chemical Products Type R 97, which is rated to be permeable to 1.5 to 2 cc/cm /day at atmospheric pressure, against a saturated solution of K 80 at 39 C. A specific example of the design of FIG. 1 constructed with polymethylmethacrylate dispensing head, separator and tubing having an inner diameter of 1.9 cm, is capable of delivering 4 to 6 cc of active agent, advantageously a drug, per day. In one specific embodiment of a dispenser of FIG. 2 type, the membrane used was an isotropic cellulose acetate membrane, with no plasticizer, having an acetate substitution of 2.4, being 3 mils thick, and passing water at the rate of mg/cm per day against a saturated magnesium sulfate solution at 39 C. The membranes too are insoluble, and chemically compatible with the salt solution and any excess solute therein. For drug depot applications as heretofore described, the membranes are also biologically inert, non-irritating to body tissues and non-allergenic. For devices designed to deliver active agents relatively rapidly for a limited period, membranes of controlled high water permeability are indicated; membranes of lower water permeability are used to provide slower and more prolonged delivery.

The impermeable plastic shell 12 of FIGS. 1 and 2 and the half shell 34 of FIG. 3 too are insoluble and can be formed of polystyrene, polyethylene, polypropylene, polyvinyl chloride, reinforced epoxy resin, polymethylmethacrylate, etc., sheet metal (e.g., aluminum, cop per, steel, etc.), galvanized pipe, or styrene/acrylonitrile copolymer. It is of course intended that such casing or shell act as a barrier to the transport of water. Again, for drug depot applications the same are advantageously biologically inert, non-irritating to body tissues and non-allergenic. The barrier plug 20 and the half shell 36 can be formed of materials identical to those used for fabricating the shells 12 and 34. Espe cially preferred of the above are the impermeable or refractory plastics. Likewise with respect to thevporous disc or cup 18 of FIGS. 1 and 2, and the half shell 46 of FIG. 3, except in this instance the materials would be highly porous since it is not intended that the member 18 and the half shell 46 in any way act as a barrier to or restrict the transport of water.

l-Ialf shell 32 of the FIG. 3 dispenser can be formed from any material which will rapidly dissolve in the aqueous environment in which the device is intended to be placed, such as gelatin and such material again being biologically inert, non-irritating to body tissues and non-allergenic when the device is designed for placement in the body.

Many other materials including those which are biologically acceptable are suitable for fabrication of the several component parts of the device of this invention. While the said several component parts of the device of the invention have previously been described as being insoluble under the conditions and in the environment of intended use, it is also within the scope of the invention that such materials be insoluble only during the period of said intended use; thereafter dissolving away in the environment of the device. Thus, a dis penser is here contemplated which is unaffected by its environment, solubility-wise, at the situs of use, or which is only slightly soluble during the period of intended use, such that once its active agent content has been discharged it will then dissolve or erode away leaving no objectionable residue or empty container at the said situs of use.

It is further within the scope of the invention to optionally provide the subject dispenser with a selfcontained water supply or separate water compartment, as in the first mentioned Rose and Nelson publication, supra.

The relative thicknesses of the various membranes comprising the dispensers of the invention, as well as the relative thickness of the various shells and half shells can vary widely and are not limitations on the invention. Typically, however, each shell and half shell has a wall thickness of 0.5 to 50 mils, preferably of 5 to 50 mils, and the water permeable membranes have a wall thickness of 1 to 10 mils.

One specific embodiment of a dispenser fabricated in accordance with the invention, and as illustrated in FIG. 4 and 5, fitted witha 3 mils thick semi-permeable membrane 16, and having the following dimensions and specifications:

Outer diameter of dispenser 1.125 inch Wall thickness of shell 12 0.125 inch Inner diameter of dispenser 0.875 inch Overall length 2.5 inch External volume 2.45 inch lntemal volume 1.24 inch Overall dispenser density 1.5

Available membrane area 0.44 inch Active agent volume 0.94 inch Active agent density 1.2

Active agent: Approximately 60 percent tetracycline hydrochloride dispersed in 40 percent cocoa butter medium;

Osmotic solution: Saturated aqueous solution of K 80 containing sufficient excess solute in solid form to maintain solution saturated over a period of at least 3 days; Water permeable membrane: Cellulose diacetate, with a degree of acetyl substitution of 2.4;

Shell 12: Soft polyethylene; Threaded end cap 50: Soft polyethylene; Delivery cap 52: Soft polyethylene; Barrier member 20: Soft polyethylene; Chamfered ring 54: Polycarbonate; Membrane support 18: Polystyrene; Diameter of delivery port 14: 0.0625 inch; Diameter of orifices in cap 50: 0.0625 inch; Diameter of orifices in support 18: 0.1250 inch; is capable of delivering gm of the active drug per day, over a period of 3 days, when administered to the rumen of a 500 pound calf, whereat it is retained, via the gastrointestinal tract. It will be appreciated that the design of the FIG. 4 and FIG. 5 device is quite similar to that of FIG. 1, with the most salient distinctions therebetween residing, in the FIGS. 4 and 5 device, in the separate rather than integral delivery cap 52; the chamfered polycarbonate retaining ring 54 which aids in maintaining a tight seal between the shell 12 and cap 52; and the perforated end cap construction 50 which is threaded onto the shell 12 and fitted with a rubber O-ring 56 to prevent leakage at the point of the thread fit. The cap 50 houses the membrane 16 and the membrane support 18. Of course, the greater the free space or total open surface area of the plurality of ducts bored into the end cap 50, the greater the amount of the membrane 16 which is exposed to the aqueous environment. Likewise, the greater the open surface area of the plurality of ducts bored into the membrane support 18, the more readily the water difi'uses into the compartment 24. As in the designs of FIGS. 1 and 2, it is again optional that a separator of porous paper, fabric or the like can be placed between either or both of the membrane support 18 and end cap 50 and the semipermeable membrane 16. Same, as heretofore mentioned, prevents the membrane from being punctured or drawn into too tight a contact with its housing, thereby additionally assuring that the entire membrane is exposed to the aqueous environment.

Any of the drugs used to treat the body, both topical and systemic, can be compartmentalized as the active agent in any of the osmotic dispensers of this invention. Drug is used herein in its broadest sense as including any composition of substance that will produce a pharmacological or biological response.

Suitable drugs for use in therapy with the dispenser of the invention include without limitation:

1. Protein drugs such as insulin;

2. Desensitizing agents such as ragweed pollen antigens, hay fever pollen antigens, dust antigen and milk antigen;

3. Vaccines such as small pox, yellow fever, distemper, hog cholera, fowl pox, antivenom, scarlet fever, diphtheria toxoid, tetanus toxoid, pigeon pox, whooping cough, influenza, rabies, mumps, measles, poliomyelitis, Newcastle disease, etc.;

4. Anti-infectives, such as antibiotics, including penicillin, tetracycline, chlortetracycline, bacitracin, nystatin, streptomycin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, and erythromycin; sulfonamides, including sulfacetamide, sulfamethizole, sulfamethazine, sulfadiazine, sulfamerazine, and sulfisoxazole; anti-virals including idoxuridine; and other anti-infectives including nitrofurazone and sodium propionate;

5. Anti-allergenics such as antazoline, methapyrilene,

chlorpheniramine, pyrilamine and prophenpyridamine;

6. Anti-inflammatories such as hydrocortisone; cortisone, hydrocortisone acetate, dexamethasone, dexamethasone 2 l-phosphate, fluocinolone, triamcinolone, medrysone, prednisolone, prednisolone 21-phosphate, and prednisolone acetate;

7. Decongestants such as phenylephrine, naphazoline, and tetrahydrozoline;

8. Miotics and anticholinesterases such as pilocarpine, eserine salicylate, carbachol, di-isopropyl fluorophosphate, phospholine iodide, and demecarium bromide;

9. Mydriatics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine, and hydroxy-amphetamine;

10. Sympathomimetics such as epinephrine;

11. Sedatives and Hypnotics such as pentobarbital sodium, phenobarbital, secobarbital sodium, codeine, (a-bromoisovaleryl) urea, carbromal;

l2. Psychic Energizers such as 3-( 2-aminopropyl) indole acetate and 3-(2-aminobutyl) indole acetate;

13. Tranquilizers such as reserpine, chlorpromazine,

and thiopropazate;

14. Androgenic steroids such as methyltestosterone and fluoxymesterone;

15. Estrogens such as estrone, 17 B -estradiol, ethinyl estradiol, and diethyl stilbesterol;

l6. Progestational agents such as progesterone, megestrol, melengestrol, chlormadinone, ethisterone, norethynodrel, l9-nor-progesterone, norethindrone, medroxyprogesterone and l 7 a-hydroxy-progesterone;

17. Humoral agents such as the prostaglandins, for

example, PGE P05 and PGF 18. Antipyretics such as aspirin, sodium salicylate,

and salicylamide;

19. Antispasmodics such as atropine, methantheline,

papaverine, and methscopolamine bromide;

20. Anti-malarials such as the 4-aminoquinolines, 8-

aminoquinolines, chloroquine, and pyrimethamine;

21. Antihistamines such as diphenhydramine, dimenhydrinate, tripelennamine, perphenazine, and carphenazine;

22. Cardioactive agents such as hydrochlorothiazide,

flumethiazide, chlorothiazide, and aminotrate;

23. Nutritional agents such as vitamins, essential amino acids and essential fats;

24. Anti-Parkinsonism agents such as L-dopa, (L-

3,4-dihydroxyphenylalanine);

25. Investigative antihypotensive agents such as dopamine, 4-(2-aminoethyl) pyrocatechol.

Other drugs having the same or different physiological activity as those recited above can be employed in osmotic dispensers within the scope of the present invention; Suitable mixtures of drugs can, of course, be dispensed with equal facility as with single component systems.

Drugs can be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating pharmacologically acceptable salts such as hydrochloride, hydrobromide, sulphate, phosphate, nitrate, borate, acetate, maleate, tartrate, salicylate, etc. For acidic drugs, salts of metals, amines, or organic cations (e.g., quaternary ammonium) can be employed. Furthermore, simple derivatives of the drugs (such as ethers, esters, amides, etc.) which have desirable retention and release characteristics but which are easily hydrolyzed by body pH, enzymes, etc., can be employed.

The amount of drug incorporated in the osmotic dispenser varies widely depending on the particular drug, the desired therapeutic effect, and the time span for which it takes the drug to be released. Since a variety of dispensers in a variety of sizes and shapes are intended to provide complete dosage regimes for therapy for a variety of maladies, there is no critical upper limit on the amount of drug incorporated in the dispenser. The lower limit too will depend on the activity of the drug and the time span of its release from the dispenser. Thus it is not practical to define a range for the therapeutically effective amount of drug to be released by the dispenser.

The motive force of the dispenser of this invention depends on the osmotic pressure generated by the solution of the osmotically effective solute contained in the compartments 24 and 40, which solution exhibits an osmotic pressure gradient against water. Said solution is most preferably a saturated aqueous salt solution. To maintain the solution saturated and therefore to achieve a constant osmotic pressure throughout operation of the dispenser, the compartment containing the solution also contains excess solute in solid form. Various osmotically effective solutes can be used. These include magnesium sulphate, magnesium chloride, sodium chloride, potassium sulphate, sodium carbonate, sodium sulphite, sodium sulphate, sodium bicarbonate, potassium acid phthalate, calcium bicarbonate, potassium acid phosphate, raffinose, tartaric acid, succinic acid, calcium succinate, calcium lactate, and magnesium succinate. The excess solid solute can be in the form of dispersed particles or preferably in the form of a pellet. The solution can initially be a solution of the same or of a osmotically effective solute difi'erent than the solid excess solute.

The osmotic dispenser can be fabricated in any con-- venient shape for either physical insertion or implantation in the body, or for administration via the gastrointestinal tract, or for introduction into any desired aqueous environment. Dimensions of the device can thus vary widely and are not of controlling importance. The lower limit of the size of the device is governed by the amount of the particular active agent to be supplied to the aqueous environment to elicit the desired response, as well as by the form the dosage unit takes, for example, in cases of specific body uses, implantate, bolus, IUD, IVD, vaginal ring, uterine capsule for fertility suppression, artificial gland, pessary, prosthesis, suppository, and the like. Likewise with respect to the upper limit on the size of the device. In one specific embodiment, the dispenser can be of such size as to deliver 1 to 2 0c of drug formulation per day and to deliver a total of 5 to 10 cc of drug formulation over a 5 to 10 day period. With alternate choice of slower permeation membranes, the pump can deliver drug more slowly up to and in excess of 1 year. It is preferred that the construction of the several compartments and of the active agent release means be such that the osmotic driving pressure developed is at least 10 times greater than the back pressure generated by the active agent formulation.

Thus, the invention provides, in an osmotic dispenser, a reliable means for releasing effective concentrations of active agent contained therein to the body of a living organism, or to any other aqueous environment, at an osmotically controlled rate and over a prolonged period of time. In addition, prime advantages of the dispenser of the invention are thatit is simple in construction and exhibits all of the practical advantages of the long-term continuous administration of various active agents both to humans, animals, and into other environments, and that the active agent contained therein will not exhibit the tendency to be leached therefrom.

While the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various modifications, changes, omissions, and substitutions can be made without departing from the spirit of the invention. It is intended, therefore, that the invention be limited only by the scope of the following claims.

What is claimed is:

1. An osmotic active agent dispenser, comprised of a plurality of capsule half shells, with a first and a second half shell securedly afiixed in capsular configuration, and a third half shell frictionally disposed in such capsule but free to slidably move therein, the said capsule being thereby divided into two compartments, an active agent compartment containing active agent and provided with release means therefor to the exterior of the dispenser and a second compartment containing a solution of an osmotically effective solute which exhibits an osmotic pressure gradient against water; the shell of the capsule comprising the solution compartment is rigid, resistant and water pervious; the shell of the capsule comprising the active agent compartment is rigid, resistant and water impervious; and the interior half shell is rigid, resistant and water impervious, the open end of which is in communicating relationship with the said second compartment; whereby as water flows by osmosis into the solution compartment in a tendency towards osmotic equilibrium with its environment the said solution compartment expands by forcing the interior shell further into and diminishing the volume of the active agent compartment, thus continuously squeezing active agent thereout at an osmotically controlled rate over a prolonged period of time.

2. The osmotic dispenser as defined by claim 1, further comprising a rapidly soluble fourth half shell capping the active agent release means of the capsule.

3. The osmotic dispenser as defined by claim 1, wherein the active agent is selected from the group consisting of a drug and a bio-affecting composition.

4. The osmotic dispenser as defined by claim 1, wherein the active agent contained therein is in the form of a semisolid formulation.

5. The osmotic dispenser as defined by claim 1, wherein the solution of an osmotically effective solute exhibiting an osmotic pressure gradient against water is a saturated aqueous salt solution.

6. The osmotic dispenser as defined by claim wherein the saturated salt solution contains excess solute in solid form.

7. The osmotic dispenser as defined by claim 1, wherein the said second compartment is comprised of a membrane selected from the group consisting of cellulose acetate, silicone rubber, polyurethane, natural rubber and hydrolyzed ethylene/vinyl acetate copolymet.

8. The osmotic dispenser as defined by claim 7, wherein the membrane is anisotropic.

9. The osmotic dispenser as defined by claim 1, wherein the osmotically effective solute is selected from the group consisting of magnesium sulphate, magnesium chloride, sodium chloride, potassium sulphate, sodium carbonate, sodium sulphite, sodium sulphate, sodium bicarbonate, potassium acid phthalate, calcium bicarbonate, potassium acid phosphate, raffin0se,'tartan'c acid, succinic acid, calcium succinate, calcium lactate and magnesium succinate.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US2962023 *Oct 22, 1956Nov 29, 1960Gaston ChappazMedicator
US3118439 *Mar 19, 1958Jan 21, 1964Jean-Pierre PerrenoudDiagnostic and medicating capsule and the method of use
US3247066 *Sep 12, 1962Apr 19, 1966Parke Davis & CoControlled release dosage form containing water-swellable beadlet
US3415249 *Jan 7, 1966Dec 10, 1968Stanley Drug Products IncSuppository
US3604417 *Mar 31, 1970Sep 14, 1971American Cyanamid CoOsmotic fluid reservoir for osmotically activated long-term continuous injector device
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3880164 *May 22, 1972Apr 29, 1975Alza CorpOsmotic wound drain
US3894538 *Aug 6, 1973Jul 15, 1975Siemens AgDevice for supplying medicines
US3995631 *Sep 25, 1972Dec 7, 1976Alza CorporationOsmotic dispenser with means for dispensing active agent responsive to osmotic gradient
US4111201 *Nov 22, 1976Sep 5, 1978Alza CorporationOsmotic system for delivering selected beneficial agents having varying degrees of solubility
US4111202 *Nov 22, 1976Sep 5, 1978Alza CorporationOsmotic system for the controlled and delivery of agent over time
US4111203 *Nov 22, 1976Sep 5, 1978Alza CorporationOsmotic system with means for improving delivery kinetics of system
US4136250 *Jul 20, 1977Jan 23, 1979Ciba-Geigy CorporationCrosslinked, addition monomer or polymer
US4177256 *Nov 29, 1977Dec 4, 1979Alza CorporationPolymers, sustained release
US4180073 *Aug 29, 1977Dec 25, 1979Alza CorporationDevice for delivering drug to biological environment
US4203442 *Jan 4, 1979May 20, 1980Alza CorporationDevice for delivering drug to a fluid environment
US4207890 *Sep 21, 1978Jun 17, 1980Mcneilab, Inc.Drug-dispensing device and method
US4210139 *Jan 17, 1979Jul 1, 1980Alza CorporationOsmotic device with compartment for governing concentration of agent dispensed from device
US4217894 *May 4, 1978Aug 19, 1980Siemens AktiengesellschaftApparatus for supplying medication to the human or animal body
US4277582 *Jun 22, 1979Jul 7, 1981Ciba-Geigy CorporationWater-insoluble hydrophilic copolymers
US4298003 *May 12, 1980Nov 3, 1981Alza CorporationSystem for delivering agent at zero order rate with emerging agent below saturation
US4320758 *Dec 8, 1980Mar 23, 1982Alza CorporationOsmotically driven fluid dispenser
US4548990 *Aug 15, 1983Oct 22, 1985Ciba-Geigy CorporationCrosslinked, porous polymers for controlled drug delivery
US4595583 *Mar 19, 1984Jun 17, 1986Alza CorporationDelivery system controlled administration of beneficial agent to ruminants
US4612186 *Sep 27, 1985Sep 16, 1986Alza CorporationAvermectin
US4624945 *Aug 9, 1985Nov 25, 1986Alza CorporationDispensing system with means for increasing delivery of beneficial agent from the system
US4643731 *Aug 16, 1985Feb 17, 1987Alza CorporationMeans for providing instant agent from agent dispensing system
US4675174 *Aug 16, 1985Jun 23, 1987Alza CorporationSustained release; administering by mouth to a ruminant
US4684524 *Aug 8, 1985Aug 4, 1987Alza CorporationRate controlled dispenser for administering beneficial agent
US4692336 *Aug 7, 1985Sep 8, 1987Alza CorporationSelf controlled release device for administering beneficial agent to recipient
US4704118 *Aug 16, 1985Nov 3, 1987Alza CorporationRuminant dispensing device with thermo-activated memory
US4717566 *Jun 23, 1986Jan 5, 1988Alza CorporationDosage system and method of using same
US4717568 *Aug 11, 1986Jan 5, 1988Alza CorporationThermo-responsive device for administering drugs at a controlled rate
US4717718 *Aug 11, 1986Jan 5, 1988Alza CorporationAvermectin layer, heat sensitive layer for pushing, veterinary medicine
US4723958 *May 23, 1986Feb 9, 1988Merck & Co., Inc.Pulsatile drug delivery system
US4729793 *Sep 2, 1986Mar 8, 1988Alza CorporationCellulose acetates and trialkyl citrates
US4772474 *Aug 11, 1986Sep 20, 1988Alza CorporationDispenser for medical and veterinary agents, insoluble agents or nutrients; controllable rate over prolonged time
US4832690 *Jan 23, 1987May 23, 1989Baxter International Inc.Needle-pierceable cartridge for drug delivery
US4844984 *Mar 24, 1988Jul 4, 1989Alza CorporationFor ruminants, semipermeable walls
US4863456 *Feb 8, 1988Sep 5, 1989Alza CorporationDosage form with improved delivery capability
US4865598 *Feb 2, 1988Sep 12, 1989Alza CorporationDispensing system for administering beneficial agent
US4871544 *Nov 27, 1987Oct 3, 1989Alza CorporationRuminant dispensing device
US4872873 *Dec 14, 1987Oct 10, 1989Merck & Co., Inc.Controlled release bolus device
US4883667 *Nov 27, 1987Nov 28, 1989Alza CorporationThermosensitive for drug delivery, ruminants
US4927633 *Jun 24, 1987May 22, 1990Alza CorporationDispenser for delivering drug to livestock
US4955881 *Jul 25, 1989Sep 11, 1990Alza CorporationRuminant dispensing device
US4960416 *Jul 10, 1989Oct 2, 1990Alza CorporationDosage form with improved delivery capability
US4963141 *Jul 17, 1989Oct 16, 1990Alza CorporationDispensing system for administering beneficial agent formulation to ruminants
US4966767 *Mar 23, 1989Oct 30, 1990Alza CorporationA housing containing a beneficial agent and means for urging it through exit for delivery and a density member; drugs paracitides
US4976966 *Dec 29, 1988Dec 11, 1990Alza CorporationDelayed release osmotically driven fluid dispenser
US5000957 *Mar 28, 1989Mar 19, 1991Alza CorporationDispenser comprising hydrophilic osmopolymer
US5021053 *Jul 14, 1989Jun 4, 1991Alza CorporationFor delvering drug into mouth of patient
US5030216 *Dec 15, 1989Jul 9, 1991Alza CorporationOsmotically driven syringe
US5053032 *Dec 21, 1990Oct 1, 1991Barclay Brian LOsmotic device for controlled drug delivery into mouth
US5098425 *Jun 15, 1990Mar 24, 1992Alza CorporationMethod of administering a ruminant dispensing device comprising density member dispersed in hydrogel member
US5147654 *Nov 15, 1991Sep 15, 1992Alza CorporationStop smoking
US5180591 *Jul 11, 1990Jan 19, 1993Alza CorporationDelivery device with a protective sleeve
US5234692 *Sep 2, 1992Aug 10, 1993Alza CorporationDelivery device with a protective sleeve
US5234693 *Sep 2, 1992Aug 10, 1993Alza CorporationVeterinary medical use, durability
US5234694 *Sep 2, 1992Aug 10, 1993Alza CorporationImplanting somatotropin dispenser with protective sleeve
US5238687 *Sep 2, 1992Aug 24, 1993Alza CorporationTubular dispenser surrounded by strong rigid sleeve, for livestock implants to supply drugs or growth regulating agents
US5248310 *Mar 27, 1992Sep 28, 1993Alza CorporationOral osmotic device with hydrogel driving member
US5312390 *Jan 14, 1993May 17, 1994Alza CorporationFluid imbibation; reversibly sliding, telescoped housings
US5443459 *Aug 19, 1993Aug 22, 1995Alza CorporationOsmotic device for delayed delivery of agent
US5474985 *Dec 22, 1993Dec 12, 1995The Regents Of The University Of CaliforniaPreventing and treating elevated intraocular pressure associated with administered or endogenous steroids using non-steroidal cyclooxygenase inhibitors
US5498255 *May 15, 1995Mar 12, 1996Alza CorporationOsmotic device for protracted pulsatile delivery of agent
US5512299 *Jul 14, 1993Apr 30, 1996Alza CorporationControlled delivering of beclomethasone dipropionate by means of an osmotic delivery device
US5540665 *Jan 31, 1994Jul 30, 1996Alza CorporationGas driven dispensing device and gas generating engine therefor
US5573776 *Sep 8, 1994Nov 12, 1996Alza CorporationDelivery of ergot alkaloids to mouths
US5599535 *Jun 7, 1995Feb 4, 1997Regents Of The University Of CaliforniaAdministering a non-steroidal antiinflammatory agent preventing cell lose in eye disorders
US5674888 *Jun 7, 1995Oct 7, 1997University Of CaliforniaMethod for the treatment of a trabecular meshwork whose cells are subject to inhibition of cell division
US5728088 *Jul 1, 1994Mar 17, 1998Alza CorporationOsmotic system for delivery of fluid-sensitive somatotropins to bovine animals
US5776493 *Dec 22, 1993Jul 7, 1998Alza CorporationOral osmotic device for delivery of nystatin with hydrogel driving member
US5869096 *Dec 9, 1994Feb 9, 1999Alza CorporationOral osmotic device with hydrogel driving member
US5879716 *Jun 14, 1993Mar 9, 1999Advanced Polymer Systems, Inc.Solid particles composed of a cross-linked copolymer of monoethylenically unsaturated monomers and polyethylenically unsaturated monomers
US5904935 *Jun 7, 1995May 18, 1999Alza CorporationDelivery of drugs with peptides and proteins
US5938654 *Feb 1, 1995Aug 17, 1999Alza CorporationOsmotic device for delayed delivery of agent
US5955109 *Jun 17, 1993Sep 21, 1999Advanced Polymer Systems, Inc.Delivery of retinoic acid to skin
US5972370 *Jan 28, 1999Oct 26, 1999Alza CorporationPeptide/protein suspending formulations
US5980509 *Nov 24, 1997Nov 9, 1999Alza CorporationOsmotic system for delivery of fluid-sensitive somatotropins to bovine animals
US5997527 *Mar 23, 1998Dec 7, 1999Alza CorporationSelf adjustable exit port
US6113938 *Jul 24, 1998Sep 5, 2000Alza CorporationBeneficial agent delivery system with membrane plug and method for controlling delivery of beneficial agents
US6180129 *Oct 23, 1997Jan 30, 2001Alza CorporationProtecting a fluid sensitive biological agent in the device from fluid; for delivering beneficial fulids such as hormones to animals
US6217906Sep 17, 1999Apr 17, 2001Alza CorporationDrug delivery
US6270787Dec 22, 1998Aug 7, 2001Alza CorporationOsmotic delivery system with membrane plug retention mechanism
US6283953Dec 22, 1998Sep 4, 2001Alza CorporationOsmotic drug delivery monitoring system and method
US6287295Jul 24, 1998Sep 11, 2001Alza CorporationOsmotic delivery system, osmotic delivery system semimpermeable body assembly, and method for controlling delivery rate of beneficial agents from osmotic delivery systems
US6361552 *Sep 27, 1999Mar 26, 2002Michael J. BadalamentiTeething gel applicator with cutter, and burstable ampule and method of making the same
US6436091 *Nov 16, 1999Aug 20, 2002Microsolutions, Inc.Methods and implantable devices and systems for long term delivery of a pharmaceutical agent
US6508808Dec 21, 2000Jan 21, 2003Alza CorporationImplant capsule; drug delivery; time release; valve preventscontamination and/or expulsion of the drug
US6524305Jul 24, 1998Feb 25, 2003Alza CorporationLess air is within
US6544252 *Dec 27, 1999Apr 8, 2003Alza CorporationOsmotic delivery system having space efficient piston
US6575961 *Feb 20, 2001Jun 10, 2003Microlin, L.C.Fluid delivery device and associated method
US6629950 *Feb 3, 1999Oct 7, 2003John M. LevinFluid delivery system
US6682522Dec 4, 2002Jan 27, 2004Alza CorporationFor controlled delivery of a beneficial agent(such as drugs)
US6740077 *Aug 20, 2001May 25, 2004Alcove Surfaces GmbhImplant with permeable element
US6840931Oct 25, 2002Jan 11, 2005Alza CorporationOsmotic pump; flow modulator lessens the chance that air or gas pockets will form in the enclosures of the system during assembly; time to start-up of delivery of the drug/beneficial agent is enhanced and less drug will be wasted
US6872201Jan 30, 2003Mar 29, 2005Bonnie Burdett DennisOsmotic agent imbibes liquid from a surrounding environment through a semipermeable body to cause the piston to move and in turn causing drug delivery
US6899887May 17, 2001May 31, 2005Micron Technology, Inc.Controlling supply; insert capsules
US6923800May 18, 2001Aug 2, 2005Alza CorporationOsmotic delivery system, osmotic delivery system semipermeable body assembly, and method for controlling delivery rate of beneficial agents from osmotic delivery systems
US6976981May 17, 2001Dec 20, 2005Alza CorporationOsmotic delivery system with membrane plug retention mechanism
US6977074Feb 2, 2001Dec 20, 2005Mannkind Corporationto an antigen by sustained release to the lymphatic system; cytotoxic T lymphocytes; immunization; drug delivery
US6994851Jul 10, 1998Feb 7, 2006Mannkind Corporationcytotoxic T-lymphocyte (CTL) response; comprises placing a physiologically-acceptable, antigen-containing composition in a reservoir having a pump for delivering the composition at a defined rate through a transmission line
US6997922Oct 5, 2004Feb 14, 2006Alza CorporationOsmotic delivery system having space efficient piston
US7094230 *Dec 16, 2003Aug 22, 2006Medtronic Vascular, Inc.Systems and methods for delivering drugs to selected locations within the body
US7163688 *Jun 18, 2002Jan 16, 2007Alza CorporationOsmotic implant with membrane and membrane retention means
US7235068Feb 14, 2006Jun 26, 2007Alza CorporationHaving recess and rib for effecting a movable seal with the enclosure; osmotic agent imbibes liquid from a surrounding environment through a semipermeable body to cause the piston to move and in turn causing drug delivery
US7364729Dec 19, 2005Apr 29, 2008Mannkind CorporationMethod of inducing a CTL response
US7407500Nov 22, 2004Aug 5, 2008Alza CorporationOsmotic delivery system flow modulator apparatus and method
US7655257Aug 20, 2003Feb 2, 2010Intarcia Therapeutics, Inc.Impermeable reservoir divided into water-swellable agent/drug chambers; fluid from environment imbibed through semipermeable plug into the water-swellable agent chamber releasing drug through a back-diffusion regulating outlet; delivering leuprolide acetate for advanced prostate cancer for 2 years
US7670329Aug 15, 2006Mar 2, 2010Medtronic Vascular, Inc.Systems and methods for delivering drugs to selected locations within the body
US8080259Dec 29, 2009Dec 20, 2011Intarcia Therapeutics, Inc.Sustained delivery of an active agent using an implantable system
US8083708Mar 1, 2010Dec 27, 2011Medtronic Vascular, Inc.Systems and methods for delivering drugs to selected locations within the body
US8298562May 26, 2011Oct 30, 2012Intarcia Therapeutics, Inc.Sustained delivery of an active agent using an implantable system
US8372393May 3, 2006Feb 12, 2013Mannkind CorporationMethod of inducing a CTL response
US8535701Oct 4, 2012Sep 17, 2013Intarcia Therapeutics, Inc.Sustained delivery of an active agent using an implantable system
US8540694Dec 27, 2011Sep 24, 2013Medtronic Vascular, Inc.Systems and methods for delivering drugs to selected locations within the body
DE2201357A1 *Jan 12, 1972Sep 7, 1972Alza CorpOsmotische Wirkstoffabgabevorrichtung
EP0089548A1 *Mar 8, 1983Sep 28, 1983Merck & Co., Inc.Osmotic drug delivery system
EP0373867A1 *Dec 12, 1989Jun 20, 1990Alza CorporationDelivery system comprising means for governing fluid ingress into the system
WO1981001794A1 *Dec 24, 1980Jul 9, 1981S AshSystem for demand-based administration of insulin
WO1990012567A1 *Apr 21, 1989Nov 1, 1990Mo Avtomobilestroitelny I VtuzDevice for controlled dosing of active substances into an operative medium
WO1990012568A1 *Apr 21, 1989Nov 1, 1990Mo Avtomobilestroitelny I VtuzDevice for controlled dosed feeding of active substances into an operative medium
WO1992000728A1 *Jul 8, 1991Jan 23, 1992Alza CorpDelivery device with a protective sleeve
WO1999004768A2Jul 24, 1998Feb 4, 1999Alza CorpOsmotic delivery system flow modulator apparatus
WO2000028976A1 *Nov 15, 1999May 25, 2000Schmidt William JMulti chamber soft capsules and method of making the same
Classifications
U.S. Classification604/892.1, 424/436, 424/453, 424/455, 424/433
International ClassificationA61F6/14, A61K9/00, A61F6/00
Cooperative ClassificationA61K9/0004, A61F6/14
European ClassificationA61F6/14, A61K9/00L4