CA2089738C - Dispensing device containing a hydrophobic medium - Google Patents

Abstract

A device for the controlled delivery of an insoluble or partially aqueous insoluble beneficial agent to an aqueous contain-ing environment. The device comprises a shaped wall that surrounds and defines an internal reservoir. The wall is formed at least in part of a material, permeable to a beneficial agent-containing hydrophobic medium, when the wall is present in the aqueous containing environment. The reservoir contains a mixture of a hydrophilic swellable composition and a beneficial agent-contain-ing hydrophobic medium.

Description

WO 92J0577S ~ PCr/US91/05018 I~ISPENSING DEVICE CONTATNTNG A HYDROPIIOBIC ~nIUM
This invention relates to devices pa,rticularly adapted for the delivery of a benef icial aglent to an environment of use and methods for using the same.
Ba~ h~.,u.. d of the Invention The desirability of controlled release of be!neficial agents to an environment of use, such as the physiological fluid of animals (e.g. mammals) is known.
Controlled delivery of beneficial agents such as drugs 10 cAn, for example, result in a relatively constant concentration of such agents in the physiological fluids of an animal instead of the more dramatic rises arld subsequent decreases in concentration of such a~ents usually associated with periodic dosing.
15 Furthermore, controlled delivery of drugs can eliminate c~rtain deleterious effects sometimes associated with a sudden, substantial rise in the co~lc~ ,tion of certain drugs.
A variety of devices for the controlled delivery 20 of beneficial agents have been described. Certain of t~lose devises employ the physical rh~n~ enon of diffusion for their operation. Examples of such diffusion driven devices are disclosed in U.S. Patent 4,217,898. Other devices have been described which 25 ol?erate with the principle of colloidal osmotic pLessu-e. Examples of such osmotically driven devices are disclosed in U.S. Patents 3,845770; 3,995,631;
4,111,202; 4,160,020; 4,439,196 and 4,615,598. Devices .' ~

77~ - PCrJUS91/0~018 2 ~ 2089738 whicb employ a swellable hydrophilic polymer which exerts pressure on a container forcing drug therefrom is disclosed in U.S. Patent 4,180,073. U.S. Patent 4,327,725 discloses a device which employs a layer of 5 fluid swellable hydrogel to force beneficial agent out of the device through a specified and defined . Other hydrogel powered devices containing such a p~Cc~q~ay for delivery of beneficial agents are d~cclcsed in GB 2,140,687A.
U.S. Patent 4,350,271 teaches a fluid disp~ncDr that operates by absorbing water. The 1 i sp~nc-~r includes a rigid water permeable housing, a water insoluble, water swellable composition that fills a segmellt of the space within the housing, a lipophilic fluid charge that fills the remainder of the space withill the housing and that is i~miscible in the water-swellable composition, and an outlet throuqh the housilng that communicates with the fluid charge. In opera~ion the water swellable composition absorbs water, expands, and in piston-like fashion displaces the fluid charge from the dispenser via the outlet.
Finally U.S. Patent 4,434,153 discloses a delivery device comprising a hydrogel reservoir containing tiny pills which include a drug core surrounded by a wall.
Although the aboYe inventions have advanced the art significantly there is a continuing search for other delivery devices particularly those which deliver water insoluble agents.
Summarv of the I]nvention This invention is directed to a device for the controlled delivery of an insoluble or partially aqueous insoluble benef icial agent to an aqueous containi~g enviro_ent. The device comprises a shaped -WO 92/05775 - PCI/l~S91/05018 .

3 2089~38 wall ~hat ~iuL-ou;-ds and defines an internal reservoir.
The w~all is formed at least in p~rt of a materi~l, permeable to a beneficial-agent containing hydrophobic medium, when the wall i5 present in the aqueous containing environment. The reservoir contains a mixture of a hydrophilic swellable composition and a beneficial agent containing hydrophobic medium.
~ther features and advantages will be apparent from the ~pecification and claims and ~rom the accompanying drawings which illustrate an Dmho~i- - t of this invention.
E~rief Description of Drawinas Figure 1 illustrates a cross-section view of an exemplary dispensing device of this invention.
Figure 2 illustrates the beneficial agent release profile of an exemplary device of this invention.
Figure 3 illustrates the effect of initial benef iciil agent concentration on the release prof ile for modified devices of Figure 2.
Figure 4 illustrates the beneficial agent release rate ~plotted as a function of initial benef icial agent, concentration for modified devices of Figure 2.
Figure 5 illustrates the beneficial agent release profile as a function of the beneficial agent-containing hydrophobic medium permeable memhrane area for modified devices of Figure 2.
Figure 6 illustrates the beneficial release rate plotted as a function of beneficial agent-containing hydrophobic medium permeable membrane area for modified devices of Figure 2.
Figure 7 illustrates the release profile for modified devices of Figure 2 having holes drilled through the membranes.

~ ~ PCr~US91~050~8 Figure 8 illustrates the release profile for modif ied devices of Figure 2 .
Figure 9 illustrates the release profile for modified devices of Figure 2 for different hydrophobic 5 mediu~s .
Figure 10 illustrates the release proflle for modi~ied devices of Figure 2 for different hydrogels.
Figure 11 illustrates the release prof ile for modified devices of Figure 2 at different temperatures.
Detailed DescriDtion of the Invention According to Figure 1, dispensing device 3 comprises a wall 6 that surrounds and defines an internal reservoir 9. At least some portion 12 of the wall 6 i5 permeable to the beneficial agent-containing 15 hydrophobic medium (described below~ and, if desired, to an aqueous medium. By permeable is meant that the benef iLcial agent either as a suspension or as solutiion in the hydrophobic medium may pass through the wall 6. A variety of other wall portions (having 20 diffe~-ent permeabilities to various c -nts) ~ay be combilled with the beneficial agent permeable portion 12 28 desired. For example part 15 of the wall 6 may be impermeable to the beneficial agent-containing hydropobic medium but is permeable to an aqueous 25 mediu~. In addition, a portion 18 of wall 6 may be impermeable. Incorporation of these last two wall types are advantageous since if the whole wall is perme~ble to the benef icial agent then it typically must have other characteristics such as the appropriate 30 water permeability and the appropriate mechanical strength. Incorporation of different wall portions facilitates achieving the different desired characteristics described above. For example the ~ WO 92/0~775 PCr/US91/O~nl8 5 208~38 impermeable wall portion 18 can afford structural rigidity and robustness. In addition for a device designed to be retained in the rumen of an animal, the impermeable wall portion 18 may provide the required 5 densi ty so that the device i~ not regurgitated. Also for example, for hydrophobic beneficial agents, it is easi~r to have a separate wall portion permeable to water than to have a single wall portion pP -hle to a ~ Lup~lobic medium and water.
The wall 6 thickness may be any dimension that provides the desired structural stability, effective resistance, and partitioning characteristics offered by the wall to transport of the desired species for the parti cular wall material chosen. For human health applications typical wall 6 thiclrnpcses are from about 100 micrometers to about 2500 micrometers. Below about 100 micrometers a stagnant water film will control the transport properties instead of the membrane controlling them. Preferably the wall thickness is from about 100 micrometers to about 1000 micrometers because above about 1000 micrometers production may be more difficult. For wall portion 15 the flux of water through a water permeable wall is flepPndPnt on the gradient of chemical potential of water across the wall and on the resistance offered by the wall. The resistance offered by the wall, in turn, is a function of the effective mass transport coefficient, or, effective diffusivity of water through the wall, and its thickness and area.
The dispensing device 3 will vary based on the particular application (e.g. tablet). The shape may be modified (in conjunction with the desired wall portion characteristics) to change the diff~sion rate of the W0 92/0~77~
~ Pcr/us9l/05018 4 device as different shapes are associated with different diffusion rates. Common exemplary shapes are cylindrical, tablet-shape, and c~rs~ r-shape. The dispensing device dimensions may vary with the desired 5 application (e.g. cattle tablets, human tablets). The shape and size may also Yary d~QpQnAin~ on the appllcation so that for example the tablet is suitable for oral administration. The device dimensions vary dQrQn~7ing on the quantity and rate of beneficial agent 10 delivery which vary based on the application. However, typical dimensions range from about 0. 4 inch to about 1 inch in length and about 0 .1 inch to about 0. 4 inch in dia~eter for human health appplications. For animal applications such as ruminal delivery to cattle typical 15 dimensions range from about 3 inches to about 4 inches in length and about 0 . 8 inch to about 1. 2 inches in diameter .
The wall 6 defines a reservoir 9 which contains a mixture of beneficial aqent 21 in a hydrophobic medium 20 22, a swellable composition 24, and any other desired ingredients including for ex2mple, air 27. By mixture is meallt two or more intermingled substances with each ,- t essentially retaining its original properties. Thus, for example, the swellable 25 composition retains its hydrophilic properties and the beneficial agent-containing hydrophobic medium (solution or suspension) remains hydrophobic.
Tlle swellable composition 24 may be any composition that upon contact with an aqueous medium 30 increases in size. By aqueous medium (i.e. aqueous contai~ling environment) is meant a composition contailling water as the principal liquid component (e.g. ph~siological flui~s, solutions of organic or inorganic substances, particularly electrolytes, and mixture of substances in water). Preferably hydrogels are used becau~e of their desirable phy6ical, chemical and mechanical properties. For example their solubility and extent of swelling ~i.e. equilibrium water uptake), can be tailored by a varlety of methods (e.g. (a) by modifying the chemical groups (alcoholic portion of pHEMA), (b) by copolymerization (HE~lA and polystyrene or IIEMA and poly (ethylene oxide), (c) by selecting the appropriate degree of crosslinking (the 10 greater the degree of crosslinking the lower the solubility), and (d) by selecting the appropriate molecular weight and molecular weight distribution). However other swellable materials 3uch as water-soluble polymers which hydrate, swell, and form gels before ultimately forming a solution may also be used te.g. cellulose derivatives such as methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethycellulose and salts thereof; polyacrylic esters and polymethacrylic esters and copolymers; gelatin;
20 copolymers of polyacrylic and polymethacrylic acid;
polyethyleneoxide; and polyvinyl alcohol ) .
Hydrogels are known, for example, U.S. Patent 4,327,7~5 de3cribes various hydrogels. The term hydrogel, as used herein, means at least one water swellable polymer that doe~ no~ dissolve when exposed to water. Such hydrogels comprise polymeric materials which, when in contact with 7a 2089738 aqueou~ medium, absorb such water~medium and swell. Such absorption can be reversiole or irreversible. Synthetic hydroqels are compatible with body f luids and have been WO 92/0577~
~ = PCI~US91~0~018 investigated as biomaterials (e.g. contact lenses) and for controlled release applications.
The particular molecular weight of hydrogels employed in the devices of this invention are ~uch that 5 in co~njunction with the a~ount of hydrogel the desired release rate through the coating is achieved.
Preferably the polymers are no..- L-,sslinked, although crosslinked polymers may be u6ed, as this can obviate variation in the degree of crosslinking for different lO batches. In addition, as the crosslinking increases the swelling capacity reduces and the solubility reduces .
In addition it is preferred that the water swellable polymer is pelletized (in contrast to fine 15 particles). By pelletized is meant increasing the size or g1-anulating the swellable composition. This is because the gel, which results from the interaction between the pelletized polymer and water, inhibits transport to the portion of the device which is 20 permeable to the beneficial agent formulation. If this transport occurs the permeability may be altered. For example, the gelled material can block the porous portion of the membrane and make it impermeable to the drug formulation (but permeable to water). However it 25 is believed that the potential of altering the permeability of the membrane to the beneficial agent solution is critical only during the period immediately foll~wing the exposure of the device to an aqueous mediulm, (i.e. before the steady convective flow of the 30 beneficial agent formulation through the appropriate portion of the device has been established). As the beneficial agent formulation is being delivered, the convective flow of the hydrophobic formulation may ~ WO92~ 5775 PCr~US91/05018 .

prevent transport of hydrophyllic materials Lnto the beneficial agent permeable membrane. The gel may also inhibit transport of the swellable composition to the water p~ Ahl e membrane wall portion and change its 5 prc~perties undesirably.
Thus, preferably the hydrogel phase (e.g. pellets) are of a size such that before or soon after gelling, they do not diffuse/migrate to the benefici~l agent membrane. For animal health applications (e.g. ruminal 10 delivery) pellets are typically from abut 0.125 inch to about 0 . 5 inch in diameter. For human health application pellets are typically from about 500 micrometers to about 2 . 5 millimeters or larger.
Preferably for human health applications the pellets or 15 granules are in the range from about 0.125 micrometers to about 1000 nicrometers in d i ~ - t~r . The larger the 6ize of the hydrogel phase, the lower will be its tendency to inhibit the n~ of the benef icial agent formulation, and thus the phase is preferably 20 larger than the pores available for beneficial agent permeab i 1 ity .
Exemplary hydrogels include gelled cellulose triacetate, polyvinyl alcohol, cellulose acetate, cellulose acetate butyrate, ethylcellulose, poly 25 thydroxyethyl methacrylate), poly (vinyl alcohol), poly (ethylene oxide), poly (N-vinyl-2-pyrrolidone), naturally occurring resins such as polysaccharides (e. g. dextrans) and water-soluble gums, starches, ch~mically modified starches, and chemically modified 30 ce~Llulose. A preferred hydrogel is polyethylene oxide (PE0) because of its relatively large capacity to absorb water and swell, its availability in a variety of different molecular weights in commercial W~ 92/~577~ ~ PCr/US9~05018 ~
--- 10 20sg73s quantities, its biocompatibility, and its ~afety and favourable toxicity properties. PE0 is commercially available and can be obtained having a variety of different molecular weights. For example, PE0 can be 5 obtained with nominal molecular weights of 8R, 14R, lOOg, 400K, 600K, l,OOOR, lOOOX or 5,000X. A preferred molecular weight i5 about 400X to about 1, OOOX and an ~peci~l ly preferred molecular weight is about 500K to about 700K because of its advantages in providing a 10 three $o four week ruminal delivery device for cattle.
Another preferred hydrogel is polyvinyl alcohol (PVA1 because of its relatively lower equilibrium swelling, and rate of swelling, which enables a long delivery duration of beneficial agent release. PVA is 15 commercially available and can be obtained having a variety of different molecular weights and degrees of hydrolysis. For example, PVA can be obtained with molecular weights of 8K, 14K, lOOK, 400R, 600R, l,OOOR
or 5, OOOR. A preferred mo1ecular weight is about lOOR
20 to ~bout 200R as this facilitates ruminal delivery for a duration of 100 to 150 days. In other applications where the delivery duration is shorter, other molecular weights will be preferred. A preferred degree of hydrolysis is about 75% to about 99.7%
25 because of their ready availability.
The hydrogel employed can be a blend of, for example, two or more polymers. For example, different hydrogels comprising blends of PE0 polymers of different molecular weights can be prepared and 30 employed. Such blends can be adjusted to assist in achieving the desired delivery rates for the beneficial agents .

PCr~US91/05018 1l 2089~38 In addition to the hydrogel the delivery device contains a carrier for the benericial agent Idescribed belo~). The carrier is a hydrophobic medium. By hydrophobic is meant a substance which has a low 5 affinity for water, (i.e. it is ~lightly soluble to insoluble in water, therefore it is not miscible in water or in an aqueous ~nedium) . The hydrophobic medium is critical to this invention as it is the carrier that allows delivery in contrast to an aqueous carrier).
10 The ]hydrophobic medium viscosity is important since the average fluid velocity is inversely related to the ~luid viscosity. Any hydrophobic medium viscosity may be used that in conjunction with the swellable composition, other c . ^ntS and membrane permeability 15 pumps the benef icial agent at the desired rate . The viscosity may be varied as desired by the addition of additives (e.g. beeswax).
Hydrophobic mediums include all hydrophobic liquids and semisolids or solids. The active agent may 20 be insoluble or soluble in the medium. It is preferred to use a hydrophobic medium that is a solvent for the desired beneficial agent in order to reduce settling of the suspended beneficial agent particles and thus causing variation in the drug concentration pumped out 25 of the device. In contrast if beneficial agent solution stability is a problem, formulation of the beneficial agent as a suspension may be warranted. The consistency of the drug formulation can for example ran,ge from a low viscous liquid (e.g. up to 10 cp) to 30 a "thick paste or semi-solid" at ambient temperature.
Even a solid which becomes a flowable semi-solid or liquid at the temperature of the use environment may be used. Pref~ably the substance is a solid under WO 9~/0577S PCr/US9]JO~;D18 lz 2089738 ambient storage conditions and which becomes a flowable fluid at the temperature of the use environment as this facilil:ates formulation stability and desired shelf-life. Exemplary hydrophobic mediums include alcohols, 5 soybean oils, isopropyl myristate, mineral oils, ~ilicone oils, fatty alcohols, fatty acids, their esters, mono, di, and tri glycerides, and their mixtures, etc. Preferred hydrophobic mediums include silicorle oils or polydimethylsiloxanes because they are 10 physiologically inert, biocompatible, and available in a range of physical and chemical properties. Other preferred hydrophobic mediums include mineral oils te-g- C1~ to C2~), refined or unrefined oils from plant or animal origin (e.g. soybean oil, coconut oil, olive 15 oil), siaturated or unsaturated fatty alcohols and their mixtures (e . g octyl alcohol, lauryl alcohol, oleyl alcohol, etc.), esters of fatty acids (e.g. isopropyl myristate), fatty acids (e.g. oleic acid), esters of monohydric alcohols and fatty acids. In addition the 20 hydrophobic Dedium may include other ingredients such as viscosity modifying agents (e.g. beeswax).
The above described carrier is used as a medium for the beneficial agents. The term beneficial agents includes for example any physiologically or 25 pharmac~logically active substance that produces a localized or systemic effect in animals. The term animals is ~eant to include ~ammals (e.g. human beings). The physiologically or pharmacologically active substances are sparingly soluble to insoluble in 30 water. Indeed, an advantage of these devices is that such insoluble or partially insoluble substances can be delivered to the environment of use in a controlled fashion by the devices hereof. By insoluble is meant wo g2/05775 PCr~US91/0~;018 13 2089~38 less than one part solute for 10, 000 parts solvent.
This invention is particularly adapted for delivering beneficial asents that are partially insoluble (i.e. a solubility less than one part solute to 30 parts S solvent) and especially adapted for delivering beneficial agents that have a solubLlity range of about less l:han one part solute to 30 parts solvent and more than one part solute to 1000 parts solvent.
~xamples of active substances include inorganic 10 and organic ~ lo~n~lC such as drugs that ~ct on the perip~leral nerves, adrenergic receptors, cholinergic recepl:ors, nervous system, skeletal muscles, cardiovascular smooth muscles, blood circulatory system, synaptic sites, neuroeffector junctional sites, 15 endoci~ine and hormone systems, immunological system, reproductive system, autocoid systems, alimentary and excrel:ary systems, inhibitors of autocoids and hista~ine systems. The pharmaceutical agent that can be delivered ~or acting on these systems includes anti-20 depressants, hypnotics, sedatives, psychic energizers,tranguilizers, anti-convulsants, muscle relaxants, antisecretories, anti-parkinson agents, analgesics, anti-inflammatory agents, lDcal anesthetics, muscle contractants, antibiotics, anti-microbials, 25 anthelmintics, anti-malarials, hormonal agents, contraceptives, histamines, antihistamines, adrenergic agents, diuretics, antiscabiosis, anti-pediculars, anti-parasitics, anti-neoplastic agents, hypoglycemics, electrolytes, vitamins, diagnostic agents and 30 cardiovascular pharmaceuticals.
Also included in such active substances are prodrugs of the above-described drugs. Such drugs or prodrugs can be in a variety of forms such as the WO 9'L/05775 PCI'~US91~05018 , 14 2089~8 pharmaceutically acceptable salts thereof. However, a partil:ular advantage of the devices of this invention iç that such beneficial agents, such as the drugs and prodrllgs described above may be delivered at the 5 desir~d rate (e.g. controlled ~anner) in spite of poor sol ub L 1 ity in water .
Devices of this invention are particularly advantageous for delivering two or more drugs cimul~nDollcly. The rate of drug release is controlled 10 primarily by the rate of water influx into the device which is a function of the permeability of the device to water and the affinity of the composition within the device to water and is relatively i~ er~ nt of the solubility of the incorporated drugs.
Thus two or more incorporated drugs c:an be released at absolute rates which depend upon their individual loadings in the device. For example, such devices can be used to co-deliver a sustained dose of an a Lpha-blocker, such as prazosin, and a diuretic, 20 such as polythiazide, for the treatment o~
hypertension. For the treatment of cold symptoms, these devices can be used to deliver a combination of a decongestant, such as pseudephedrine hydrochloride, and an antihistamine, such as chlorpheniramine maleate 25 or cetirizine hydrochloride. For treatment of coug~/cold symptoms, three or more drugs can be released in a controlled fashion from such devices; for example a combination of an analgeslc, a decongestant, and antihistamine, and an antitussive can be delivered.
30 In addition the devices can provide controlled and sustained delivery of a wide variety of combination of drugs .

PCr/US91/05018 The term beneficial agent is also meant to include other substances for which it is desirable and/or advantageous to control delivery into an environment of use. Examples of such substances include, fertilizers, 5 algacides, reaction catalysts and enzymes.
In addition other additives such as viscosity modifiers, antioxidants, 6tabilizers, pH controlling sgents, f lavoring agents, agents to improve the f low characteristics of the other components, s1~p~ ir7 10 agents, lubricants, fillers, etc. may be added as desired to the mixture contained within the reservoir 9. Even gases (e.g. air) may be added to the reservoir for example to serve as a ~eans of deliberately introducing a time-lag before beneficial agent deliverv 15 begins. ~hen a device containing air is placed in the aqueous use environment, water influx into the device is initiated in response to the lower thermodymanic activi ty of water within the device . Because of the swellable composition, there is an expansion in the 20 volume of the device contents. However, beneficial agent delivery does not substantially begin until there is a compressible component present within the interior of the device. Hence the volumetric expansion is partl~r "used" by the device to compress/expel the air 25 but not the beneficial agent formulation resulting in a time-lag. The amount of air present in the device can be controlled by selecting the appropriate level of nongaseous material in the interior of the device. The duration of the time-lag can be used in may beneficial 30 ways. Por example, it can be used to release the drug in the lower gastrointestinal tract similar to enteric dosage forms. It can also be used to deliver drugs in the jejunum, ileum, or even the colon, depending on the PCrtUS91/050~8 `~16 2089738 magnitude of the time-lag fro= the device, and the transit time of the device through the gastrointestinal tract .
Although any mixture of the above ingredients may S be used that satisfactorily delivers (in conjunction with the device wall~ the beneficial a~ent, typically the proportion of liquid to solid is determined from the eguilibrium swelling properties of the swellable composition. Preferably the aDount of swellable 10 composition is such that ~ 50% of the internal space within the device is filled by the swelled composition 60 that at least about 50~ of the beneficial agent formulation is released from the device by the pumping n jSm VS. other moch~nismc (e.g. diffusion). The 15 amount of beneficial agent is the amount that is sufficient to achieve the desired therapeutic effect.
In addition the amount of air is such as to achieve the desired time lag. Thus in human health applications an amount of air sufficient to achieve a 1-3 hour time laq 20 for starting drug delivery in the jejenum and a 4-6 hour time lag for starting drug delivery in the colon is desired.
Al~y wall that is permeable to the beneficial agent contail~ing hydrophobic medium and provides, or aids in 25 providing, tbe desired beneficial agent release rate may be used. However it is preferred to use a wall that has a pore size of about 1 micron to about 100 microns because above about 1 micron the drug may be in solution or suspension and pass through the pores but 30 below about 1 micron the drug must be in solution (because of particle size) to pass through the pores.
Above about 100 microns there may be a large diffusive component, the mechanical strength of the mem.brane may WO 92~0S775 PCr/US91/050~8 ` 17 2089738 be _ .~ i5ed, and, the internal pressure required for drug delivery may not be generated leading to uncontrolled release- The pores can be relatively nontortuous, uniform, and cylindrical; or, like a 5 sponge or swiss-cheese, having an interconnected network of voids. This network can be complex with tortuc~us paths and with dead-end pores and occluded void spaces.
Suitable materials for this beneficial agent-10 containing ~y-l~Ol~hObic medium permeable wall include microporous membranes such as sintered polymers, organic polymers, porous metals, and porous ceramics.
Sintered polymers refers to thermally fused polymer particles. Typically sintered polymers have about 50 15 to about 99~ porosity.
Exemplary sintered polymers include sintered polyethylene (PE~, sintered polypropylene (Pp), sintered polytetrafluoroethylene (PTFE), sintered polyvinylchloride (PVC) and sintered polystyrene tPS).
20 Exemplary nonsintered film-forming polymers include cellulose acetate, ethylcellulose, silicone rubber, cellulose nitrate, polyvinyl alcohols, cellulose acetate butyrate, cellulose succinate, cellulose laurate, cellulose palmitate. Polymers which do not 25 degrade significantly (i.e., break or burst) during the delivery period may also be used. Examples of such biode~radable polymers include polylactic acid, polyglycolic acid and poly (lactide-co-glycolide).
Preferred beneficial agent permeable layers for animal 30 health applications are sintered polymers such as PE, pP and PTFE used as a substrate (e . g . for impregnation as described below). For human health applications preferred beneficial agent perm~ble layers are W0 g2/05775 L .. PCI`~US91/0501~ ~
-l8 2089~38 nonsintered film forming cellulosic polymers.
In addition the benef icial agent-containing hydrophobic medium permeable wall portion may be impregnated with a variety of other ~dditiYes as 5 desired. For example the porous barrier may be impregnated with a low vapor pressure hydrophobic medium such as those described above. This aids in providing control of the rate of transport of species such as the benef icial agent-containing hydrophobic 10 medium. All or part of the porous barrier may be treated .
Alternatively the pores may be impregnated with a hydrophilic hydrogei such as the hydrogels described above (e.g. gelled cellulose triacetate) which 15 facilitates tailoring of the wall properties (e.g.
diffusion rates1, provides mechanical strength to prevent pore collapse, prevents leakage of beneficial agent formulation etc. In order to facilitate diffusion of beneficial agent-containing hydrophobic 20 medium the hydrogel may be wetted with a low vapor pressure hydrophobic medium such as those described above (e.g. lauryl alcohol). In addition instead of wetting the hydrogel with a hydrophobic medium it may be wetted with z hydrophilic medium (described 25 hereafter) and at least one hole provided therethrough to all~w beneficial agent-containing hydrophobic medium diffusion. This facilitates for example the further tailoring of the diffusion rate. Any hydrophilic medium that facilitates the diffusion of the beneficial 30 agent may be used. Typically the hydrophilic medium is a low to moderate molecular weight, high viscosity, low vapor pressure liquid. Exemplary polymers are the polyethylene glycols, propylene glycols and glycerols.

WO 92/D~77~
- PCl~l~S91J05018 Tlle agueous permeable membrane typically comprises the s~me structures as described above ( for the benefi~ial agent-containing hydrophobic medium permeable wall (e.g. pore size, composition of sintered 5 polymers, nonsintered polymers)). In contrast however the aqueous permeable ~embrane is impregnated with different materials to achieve the desired aqueou6 permeability. Thus, the aqueous permeable membrane may be fi],led with ~ hydrophilic medium such as those lO described above (e.g. Polyethylene glycol).
Alternatively, the pores may be impregnated with a hydrogel such as those described above and wetted with a hydrophilic medium such as those described above to prevent drying out of the hydrogel in order to make the 15 barrier permeable to water. The rate of transport of an aqueous medium through the membrane barrier depends on thl~ difference in the ~ yl,amic activity of water on either side of the barrier, and the resistance offered by the barrier (i.e. the effective barrier 20 thickness, the area available for transport, etc. ) .
The gel in the pores is not released from the device because it is present in a swollen state. Alternately, it ca~ be crosslinked, in order to prevent its release.
The polymer can be incorporated as the polymer or as 25 the monomer and then polymerized in situ. A wetting agent imparts stability to the incorporated hydrogel.
Thus for example PEG-400 prevents the drying out of gelled cellulose triacetate and imparts stability and shelf--life. Generally the wetting agent should be of 30 a viscosity and volatility that is not lost during the maxim~lm shelf-life of the product.
The above permeable layers can also comprise one or more porosigens such that, when the devices are PCI/US9~05018 -` -20 2089738 placed in an environment of use, the porosigens dissolve and effect the formation of a plurality of pores in and through the desired coating.
As stated above, the porosigens can be employed s Illone c~r in combination to effect formation of the pores Ln and through the coating. The ratio of porosigen to coating polymer can be varied as well ~s the choice of porosigens to be employed. Such vari~tions are known and will be determinrd by such 10 factors as the solubility of the beneficial agents, the particle size of the agents, the molecular weight of the hydrogel and the desired rate of-release. Examples of porosigens which will function to form the pores in and through the cQating include inorganic salts such as 15 sodium chloride, potassium chloride, potassium phosphate. Other effective porosigens are particulate organic - -c and salts thereof such as glucose, sucrose, lactose, succinic acid, sodium succinate, sodium carbonate. Also effective porosigens are water-20 soluble polymers such as polyethyleneglycol (PEG),hydroxypropyl cellulose (HPC), and polyethylene oxide (PEO). Preferably such pore-forming polymers have the ability to form a phase-separated coating when mixed with the coating forming polymer of this invention.
25 That is to say, preferably the porosigen polymer and the coating polymer are not totally miscible.
Combinations of porosigens such as particulate organic compounds and salts thereof with inorganic salts and/or water-soluble polymers can also be employed.
30 Similarly, inorganic salts with water-soluble polymers can be employed as porosigens. ~Ihen the devices are to . _ ~ ~ 21 2089738 be used to deliver beneficial agents to an animal, the porosigl~n or porosigens employed must be pharmac~eutically acceptable.
In addition to the formation of pores upon 5 placement of the devices of this invention into an environ]Dent of use through dissolution of one or more porosiglens, the pores can be preformed. Such preformed pores can be produced by known methods such as by gas generation in the coating during formation of the lO coating; etched nuclear tracking: laser, sonic or mechanical drilling; or electric discharge. It is preferred, however, that such pores result from dissolution of porosigen as described above.
The devices of this invention may also utilize an 15 ; - --hle wall portion which is typically comprised of high strength, corrosion resistant metals such as stainless steel in order to impart the desired density for ruminal delivery applications.
In addition to the above-mentioned ingredients of 20 the devices of this invention, other common pharmaceutical excipients may be present. Examples of such excipients include, binders such as microcrystalline cellulose, plasticizers such as polyethyleneglycol-600, and buffers such as sodium 2 5 phosphate .
The devices of this invention can also be administered within a capsule comprising a water soluble wall. For example, the devices can be manufactured to be of suitable size for inclusion 30 either singly or multiply within a gelatin capsule such that when the capsule dissolves the device(s) are released into the environment of use. While the devices to be included within a capsule can be of a WO 92/0577~; `
PCr~VS92~D5018 22 2089~38 variet~ of shapes, a preferred shape for such devices is spherical or substantially spherical. The exact number and size of such devices can and will be determined according to a variety of well known 5 factors. For example, the environment of use, the benef icial agent or agents, the amount of benef icial agent and the rate of release are all factors to be considlered in determini~g the size, shape, and number of de~ ices to be included in such capsules as well as 10 the composition of the capsule.
~ ?he devices of this invention having the above described desired characteristics may be made using the above described materials using conventional methods.
For example, in general capsules may be produced by 15 forming a cap and body of sintered polymers. Typically the desired polymers are molded into the desired shapes and sintered. Either the cap or the body is made permeable to water and the other i5 made permeable to the beneficial agent-containing hydrophobic medium. A
20 solution of the desired impregnating material ~e.g.
cell~lose triacetate) is imbibed into the porous sintered structure by differential pressure appl ication . The impregnated sintered structure is wetted if appropriate by for example equilibriating in 25 a bath of the wetting agent. If appropriate a hole is drilled through the wetted gelled impregnated structure by mechanical or lazer drilling. The beneficial agent, swellable composition and other ingredients are placed into the structure as a mixture or in succession 30 leaving room for the desired amount of air. Then the capsule is assembled and if desired joined by conventional methods used for gelatin capsules.
Preferably water insoluble ~oining methods are used - PCr/US91/DSU18 = ~

since if the capsule comes apart it may not function in the desired manner. For ruminal ~pplications an impermeable wall portion may be joined between the cap ~nd body portions.
Tablets ~ay be made for example by compressing blends (using conventional tabletting methods) o~ the beneficial agent-containing hydrophobic medium, swellable composition and other additives to form a tablet core. This tablet core is coated with the desired porous polymeric barrier using conventional pan or fluidized-bed coating techniques. Alternatively by dipping a suitably shaped tablet core partly in a hydrophobic polymer solution and partly in a hydrophilic polymer solution a tablet having a benef icial agent-containing hydrophobic medium permeable wall portion and an aqueous mediu~ permeable wall portion may be made.
Granules may be made by forming the desired composition by extrusion-spheronization or fluid-bed granulation. The thus formed particles are coated with the desired porous polymeric barrier by conventional pan or fluidized-bed granulation.
Methods for using the devices of this invention include administration of the appropriate devices to animals via oral administration or by insertion of the appropriate devices into a body cavity of the animal.
Devices of this invention can also be used to deliver aqents to such environments of use as ~ish tanks, soil and aqueous chemical and/or enzymatic reaction systems.
In such cases, the devices are placed into the desired environn~ent of use. The de~ic~s of this invention _ . . PCI/US91~0~018 - 2-4-- 2089~38 ~
reguire that such environment of use be either agueous or provide for contact of the device with water or other aqueous medium.
In ~pite of the many advA-- ~rts m~de in the s design and manufacture of drug delivery devices, the development of a device for ruminants such as cattle, and for humans, which is able to deliver a relatively poorly water-soluble t 1 to 50 ug/mL) drug of moderate molecular weight (up to 500 daltons~ remain a challenge 10 to the delivery device designer. Utilizing the diffusion-dissolution of the drug through a polymeric membrane or matrix as a ~me^h~ni~m to control the drug release rate is limited by the relatively low flux of drug that can be achieved using commonly available and 15 pharmaceutically acceptable polymers. This eliminates an important class of drug delivery devices. Devices based on the chemical or physical erosion of polymers are not suitable, particularly for drugs with a narrow therapeutic index, if the erosion cannot be restricted 20 to the surface of the device. Thus, the choices of drug delivery technologies available for a large number of therapeutic agents which are poorly water soluble are limited. The device of this invention will be primarily useful for delivering drugs that fall into 25 this category, and in particular, drugs which can be dissolved/dispersed in an oily vehicle, mixed with the second phase consisting of a water-swellable composition, and surrounded by a bal-rier with suitable permeability characteristics.

WO 92~a~77~
PCr/US91~DS018 Construction of the Delivery Device and Characterization of th~ Druq Release Prof ile Prototype delivery devices were made from a stainless steel cylinder of nominal diameter 21.8 mm and nominal length 77 mm- Each device contained 6 grams ]poly (ethylene oxide) having an average molecular weight of 600,000 daltons tpolysciences) and about 28 ml of a 5% solution of the ionophore CP-53,607 in octyl alcoho~l. The total drug load in the device was 1380 mg. Ihe poly (ethylene oxide) polymer was present in the device in the form of pellets made by ~ SSing 60 mg of the polymer on a type "F" tabletting machine with S/32" flat-face tooling. The device was capped at lS one elld with sintered polyethylene disc impregnated with cellulose acetate and wetted with PEG-400. The other end of the device was capped with a porous (unimpregnated) sintered polyethylene disc. The release medium (dissolute medium) consisted of 300 mi of o.~ M phosphate buffer at pH 9.0 and 100 mi of octyl alcohol in a 1000 mi flask. The organic phase (octyl alcohol) was present as a distinct layer above the aqueous phase (phosphate buffer). The device was lowered gently into the flask kept on a laboratory shaker at room temperature. The device was completely immersed in the aqueous layer throughout the release rate testing period. Every six to seven days, the media in the dissolution ~lask were replaced with fresh solutions. The drug released into the aqueous and organic layers was assayed by W spectrophotometry.
~he average cumulative amount of the drug released from three prototype devices made as described above is shown i~ Figure 2, The drug release prof ile showed :- 26- ~ 2089738 ~' . =
three distinc'c phases. The first phase consisted of a relatively rapid drug release rate which can be considered as initial "burst" of druq. In the second phase, about 70% of the initial drug load was released 5 over a period of about 3 weeks at a relatively constant rate~ The third phase was a period of decreasinq release rate in which the la5t 20% of the initial drug load was released. During the constant release period, a drug release rate of 36 . 5 mg/day was calculated by 10 linear regression.

Effect of the Initial Druq 3Load on the Druq Release Rate 3?rototype devices were made by the procedure 15 described in Example 2 to study the effect o~ the initial drug load on the release rate. Thus, the concentration of drug dissolved in the octyl alcohol vehicle ranged from 25 mg/ml to 200 mg/ml. The cumulative drug released from the devices was 20 determined by the procedure described in Example 1.
The release rate p~ofiles for three values of the initial drug concentration are shown in Figure 3. The drug release rates increased with the initial drug concentration in the device. A plot of the drug 25 release rate calculated from the slope of the release profile during the constant release rate or zero-order phas~ as function of the initial concentration of the drug solution is shown in Figure 4. The release rates were linearly proportional to the drug concentration 30 and the slope of the regressed straight line was 0.34 ml/day. These observations support the conclusion the drug is releasel at a volumetric rate of 0.34 ml/day as ~ WO 92~05775 _ PCr/US91/0~018 ~ 27 208~738 z~ soll~tion. Increasing release rates over ~ desired deliv~ry-period can be achieved by lncreasing the drug load in the deliver device.
EXAMP3~E 3 Effect of PE/CTA Membrane Area on the Drua Release Rate 3?rototype devices were made a5 in Example l except that the sintered polyethylene membrane impregnated with cellulose triacetate and wetted with PEG-400 (PE/CTA) present ~t one end of the device was sandwiched in aluminu~ discs with hole5 in the center.
These aluminum discs served to occlude some of the disc area ~hich was exposed to the release medium and the drug formulation within the device. Thus, the ef fective diameter of the PE/CTA membrane disc was varied by using aluminum discs with central holes of an appro~,~riate diameter.
Pigure 5 shows that the drug release rates are decrei~sed as the effective diameter of the PE/CTA disc is decreased. The total drug load in all cases was 1430 mg. The drug release rates during the constant delivery period were c~lculated as before and plotte~
as a function of the exposed (effective) area of the PE/CTA membrane (Figure 5). The intercept of the best fitting straight line in Figure 5 was 13.5 mg/day which represents the release rate expected from a hypothetical device with a permeable membrane only at one end.

Effect of PE 3Yembrane Area on the Druq Release Rate Prototype devices were made as in example 3 except that instead of occluding the sintered polyethylene membrane impregnated with cellulose triacetate and wetted with PEG-400, the other membrane which was made WO 92/~5775 _ ,~?8~ Pcr~usgl~o~Olg from sintered polyethylene (PE), was occluded on both side!. with the aluminurl discs. The release profiles of the ionophore CP-S3, 607 from thQse devices were i nrlel?~n~nt of the area of the PE membrane and no diffQrences in the release were 8een attributed to a chanqe in the PE membrane area. These observations supp~ort the conclusion that tbe PE membrane is not rate-limiting for the drug release kinetics.

Ef fect of Havinq PE/CTA~PEG-400 Membranes at Both T~n-lc Prototype devices wére made as in Example 1 except that both end membranes of the device consisted of sintered polyethylene discs impregnated with cellulose triacetate and wetted with PEG-400. Drug was not lS released from these devices. It was concluded from this experimental observation that the PE~CTA/PEG-400 membrane is not permeable to a hydrophobic formulation of the ionophore CP-53, 607 .
EXAMPT~ 6 E~fect of T~rillinq Multi~le Hol~s in the Membrane Prototype devices were made as in Example S except that three, five, or nine holes in a symmetric pattern were drilled in one of the end membranes. The drug release profile for the case in which five holes were 2S dri~ led in the PE/CTA/PEG-400 membrane is shown in Figure 7. The average release rate during the constant release rate portion of the delivery prof ile was 41 mg/day which is consistent with the 36. 5 mg/day release rate obtained from devices described in Example 1. It was also concluded that puncturing the PE/CTA/PEG-400 disc with holes made this menbrane permeable to the drug solution .

wo s2/as77s PCr/l~S9l/05018 EXAMpLE 7 2(~89738 a~ptionS for End-Membrane Penn~hle to Drua Ill the previous examples, it was shown that a sintered polyethylene disc without impregnated hydrogel 5 was pe~rmeable to the drug formulation and suitable for use in this invention. It was also shown that a ~intered polyethylene disc impregnated with a hydrogel such as cellulose triacetate and wetted with PEG-400 was not pe --hl e to the drug solution but could be 10 made permeable by drilling ~a~-- Los.c,~ic holes through the me~brane. This example presents yet another option for the portion of the delivery device which must be permeable to the hydrophobic drug formulation.
Sintered polyethylene discs which were iDpregnated 15 with cellulose triacetate were hwetted" with a ~IydI~hobic liquid such as lauryl alcohol by immersing the discs into a reservoir of lauryl alcohol and applying suction (negative pressure) to entrap lauryl alcohol in the membrane disc. Prototype devices were 20 made as in Example 1 and capped with sintered polyethylene disc impregnated with cellulose triacetate and wetted with PEG-400 (PE/CTA/PEG-400) on the end.
The other end was capped with a sintered polyethylene disc impregnated with cPllulose triacetate and wetted 25 with lauryl alcohol tpE/cTA/LA). Figure 8 compares the norma~ized drug release profiles from prototype devices with a PE/CTA/PEG-400 membrane disc at one end and various different membranes, all of which are permeable to the hydrophobic drug formulation, at the other end.
30 The n~rmalized drug release rates were independent of the ~arious membrane types. Since it is highly unlikely that all the different hydrophobic membranes have the same permeability, thes-- data support our WO 92/0~77~ ~ Pcr~US9l~OSO18 - --~ 30 2089738 conclusion that the membrane permeable to the drug formu].ation does not directly influence the drug release rate.
ExAMpT~
Carriers for Hvdrol~hobic Druqs-Solutions Devices were made as in Example l using isopropyl myristate, octyl alcohol, lauryl alcohol, or soybean oil as the solvent for the ionophore CP-53-607. The normalized drug release profiles (% of initial drug load released) as a function of time are shown in Figure 9. The assay pro~eduLe for the drug released was either a W assay or a specific reverse phase HPLC
assay flerP~1ing on our choice of the solvent carrier.
It was concluded from the data presented in Figure 9 that there were no differences in the normalized release rate which could be attributed to the specific solYent carrier used to formulate the drug solution.
The actual release rate was d~rPnfl~nt on the initial drug ~oncentration (or drug load) as described in Example 2.
EXAMPLE g Carriers for Hvdrophobic ~ruqs-Sus~ension Prototype devices were made as in Example l wherein the drug formulation consisted of a suspension of the drug ionophore CP-53, 607 in silicone oil, liqht mineral oil, or heavy mineral oil, and the swellable polymer was present in the devices as a granular material as opposed to compressed pellets. Although drug was released from these devices, the release rates were erratic and there was a large device-to-device variability. This was attributed to clogging of the membrane with the swellable polymer, or settling of the drug within the suspension, or both. These experiments wo 92/as77s ~ PCT/US91/05018 ~~ 31 ~ 2~89738 did demonstrate th~t the device of the present invention is capable of deliYering a suspension of drug .

o~tions for the Swellable Polymer ~?rototype devices were made as described in ExampLe 1 with a PE/CTA/PEG-400 membrane at one end of the device and a PE/CTA/L~ membrane at the other end containing a ~olution of the drug in lauryl alcohol and io 6 grams of a swellable polymer. Devices with polymers haYing a range of equilibrium swelling capacity were chose~n for this experiment. The normalized drug relea~se profiles for poly (ethylene oxide) and poly(vinyl alcohol) are shown in Figure 9 and indicate that lche drug release rates are affected by the nature of the swellable polymer incorporated into the device, and that it is possible to get drug delivery over several months from devices containing poly (vinyl alcohol) as the swellable polymer.

Effect of External TemPerature Prototype devices were made as described in Example 1 and the drug solution was formulated as a solution in isopropyl myristate or in lauryl alcohol.
The external release medium was kept at a 40-C compared to ambient temperature (22 C~. Since the shape of the release profile was not altered, it was concluded that the mechanism of the drug release was unchanged as a - function of temperature.

_ PCr~US91/050~8 12 ~89738 E~:AMPLE 1 2 Effect of External Hvdrodvnamics Prototype devices were made and the release experiments were carried out in flask5 as described 5 before . A comparison of the release rate prof ile with devices shaken using a laboratory shaker versus devices stirred with a magnetic stir-bar revealed that the external hydrodynamiCs did not effect the release prof iles .
FX~MpJ~ 13 Effect of External ~H and Aqueous Dissolution Media Drug release experiments were conducted using phosphate buffer at pH 9.0, volatile fatty acid buffer at pH 9.0, and volatile fatty acid buffer at pH 5.5.
In all cases, the drug release profiles from the prototype device5 were not affected by the external pH
of the aqueous dissolution medium.

Release From a Device Made From Clear Plastic In order to further understand the release me-hAn~ devices were constructed as described in Example 1 with the following exceptions: (1) The tube containing the swellable polymer and the drug formulation was made from clear plastic which was transparent as opposed to stainless steel, which was opaque, (2) Instead of the unimpregnated disc at one end of the device, a small hole was made in the plastic tube, (3) A small amount of red dye (FD & C #3) was added to the drug solution.
The drug release rate from the device made from clear plastic was the same as that from the equivalent steel prototype. From the observed swelling of the poly(ethylene oxi~e) placed in the device, it appeared WO 92/~S775 PCr/US91~0~018 33 2~189738 that w~ater fro~m~the external medium first entered the device througll the hole. The oil 601uble dye was not seen being pu~ped through the hole. This was followed by 6welling of the polymer on the membrane-side of the device indicating that water ~lux was through the PE/CTA/PEG-400 membrane. Withirl the first day of drug release, the polymer pellets were 6wollen.
~MPLE 1 5 A device for human health llpplications based on this inventior~ is made as follows: A two piece capsule shell is constructed of sintered polymer, and either the body or the cap is impregnated with CTA and wetted with PEG-400 while the other is made 50 that it is p~rmeable to the drug formulation in a hydrophobic medium. The solid polymer and the liquid drug formulation are simultaneously or sequentially filled into the capsule body, the cap is attached and sealed with one of the standard gelatin capsule sealing technologies .
It should be understood that the invention is not 1 imited to the particular embodiments shown and described herein, but that various changes and modif ications may be made without departing from the spirit and scope of this novel concept as defined by the ~ollowing claims.

Claims (23)

34

1. A device for controlled delivery of a beneficial agent to an aqueous containing environment, said device comprising: a shaped wall that surrounds and defines an internal reservoir;said wall formed at least in part of a material, permeable to a beneficial agent-containing hydrophobic medium, when the wall is present in the aqueous containing environment; and said reservoir containing a mixture of a hydrophilic swellable composition and said beneficial agent-containing hydrophobic medium, said beneficial agent being insoluble or partially insoluble in said aqueous containing environment.

2. The device as recited in claim 1 wherein said wall is formed at least in part of a material permeable to the aqueous containing environment.

3. The device as recited in claim 1 wherein said material permeable to said beneficial agent-containing hydrophobic medium is a microporous membrane.

4. The device as recited in claim 3 wherein said microporous membrane is a sintered polymer.

5. The device as recited in claim 3 wherein said beneficial agent-containing hydrophobic medium permeable wall is a nonsintered film forming polymer that is porous in the aqueous environment.

6. The device as recited in claim 4 wherein said sintered polymer is impregnated with a low vapor pressure hydrophobic medium.

7. The device as recited in claim 4 wherein said sintered polymer is impregnated with hydrogel and wetted with a low vapor pressure hydrophobic medium.

8. The device as recited in claim 4 wherein said sintered polymer is impregnated with a hydrophilic hydrogel, wetted with 2 hydrophilic medium, and said wetted hydrogel is provided with holes therethrough.

9. The device as recited in claim 2 wherein said material permeable to said aqueous containing environment is a micro-porous membrane.

10. The device as recited in claim 9 wherein said material permeable to said aqueous containing environment is a sintered polymer.

11. The device as recited in claim 10 wherein said sintered polymer is impregnated with a low vapor pressure hydrophilic medium.

12. The device as recited in claim 10 wherein said sintered polymer is impregnated with a hydrogel and wetted with a low vapor pressure hydrophilic medium.

13. The device as recited in claim 1 wherein a portion of said wall is impermeable to an aqueous medium and to a beneficial agent-containing hydrophobic medium.

14. The device as recited in claim 1 wherein said wall is impermeable to said swellable composition.

15. The device as recited in claim 1 wherein said beneficial agent has an aqueous solubility less than about one part solute to 30 parts aqueous solvent.

16. The device as recited in claim 15 wherein said beneficial agent has a solubility more than about one part solute to 1000 parts aqueous solvent.

17. The device as recited in claim 14 wherein said hydrogel comprises pellets having a size of about 0.125 inch to about 0.5 inch in diameter.

18. The device as recited in claim 16 wherein said beneficial agent is soluble in said hydrophobic medium.

19. The device as recited in claim 18 wherein the reservoir contains sufficient hydrogel such that the swelled hydrogel fills at least about 50% of the reservoir.

20. The device as recited in claim 19 wherein the reservoir contains sufficient air to achieve a predetermined time lag release.

21. A device in the form of a tablet or capsule for controlled delivery of a drug into an aqueous physiological fluid in a mammal, wherein the drug is insoluble or partially insoluble in the aqueous physiological fluid, the device comprising:
a shaped wall that surrounds and defines an internal reservoir, and in the reservoir, a mixture of a hydrophilic biocompatible hydrogel which upon contact with the aqueous physiological fluid, absorbs the fluid and increases its size and a hydrophobic biocompatible medium which contains therein the drug and is liquid or semiliquid or is solid under ambient conditions but becomes a flowable fluid at body temperature, wherein the wall is formed at least in part of such a material that the drug either as a suspension or solution in the hydrophobic medium may pass through that part of the wall, and the hydrophobic medium has such a viscosity that in conjunction with the hydrogel, the drug is delivered through the said part of the wall at a desired rate.

22. The device as recited in claim 21, wherein the hydrophobic medium is selected from the group consisting of silicone oils, mineral oils, plant or animal oils, saturated or unsaturated fatty alcohols, fatty acid esters and fatty acids.

23. The device as recited in claim 22, wherein the hydrogel is in the form of pellets of such a size that before or soon after gelling of the hydrogel, the hydrogel does not diffuse or migrate to the said part of the wall through which the drug passes.