United States Patent (19) 11 4,111,203 Theeuwes (45) "Sep

United States Patent (19) 11 4,111,203 Theeuwes (45) "Sep. 5, 1978

54) OSMOTIC SYSTEM WITH MEANS FOR Primary Examiner-Benjamin R. Padgett MPROVING DELVERY KNETCS OF Assistant Examiner-T. S. Gron SYSTEM Attorney, Agent, or Firm-Paul L. Sabatine; Thomas E. 75 Inventor: Felix Theeuwes, Los Altos, Calif. Ciotti; Edward L. Mandell 73) Assignee: Alza Corporation, Palo Alto, Calif. 57 ABSTRACT * Notice: The portion of the term of this patent An osmotic system for delivering a beneficial agent is subsequent to Sep. 5, 1995, has been disclosed. The system comprises a wall surrounding a disclaimed. compartment and has a passageway through the wall for delivering agent from the compartment. The wall is (21) Appl. No.: 744,089 formed of a material permeable to the passage of an (22 Filed: Nov. 22, 1976 external fluid and impermeable to the passage of agent. 51) Int. Cl’...... A61M31/00 The compartment contains an agent that is soluble in 52 U.S. C...... 128/260; 206/0.5; the fluid and exhibits an osmotic pressure gradient 222/130; 222/193; 222/389; 222/395; 222/491; across the wall against the fluid, or the compartment 424/19 contains an agent that has limited solubility in the fluid 58) Field of Search ...... 128/260, 261,268, 272; and exhibits a limited osmotic pressure gradient across 424/15, 19-22, 33, 37; 222/491,395, 193,389, the wall against the fluid. The compartment also con 130; 206/0.5 tains means for increasing the amount of agent deliv ered from the system. The means comprises a film sur (56) References Cited rounding an osmagent with the film formed of a mate U.S. PATENT DOCUMENTS rial permeable to fluid, impermeable to osmagent and 3,247,066 4/1966 Milosovich, Jr...... 128/260 movable from an initial to an expanded state. In opera 3,732,865 5/1973 Higuchi et al...... 128/260 tion, agent is delivered from the system through the 3,760,805 9/1973 Higuchi...... 128/260 passageway at a controlled rate by fluid being imbibed 3,760,984 9/1973 Theeuwes ...... 128/260 through the wall into the compartment to produce a 3,828,777 8/1974 Ness ...... 128/260 solution or suspension containing agent, and for imbibi 3,916,899 11/1975 Theeuwes et al...... 128/260 3,948,254 4/1976 Zaffaroni...... 128/260 tion by the means causing it to concentrate the solution 3,952,741 4/1976 Baker ...... 128/260 or suspension, expand and fill the compartment, 3,977,404 8/1976 Theeuwes ... 128/260 whereby agent is released at a rate controlled by the 3,993,073 11/1976 Zaffaroni ...... 128/260 permeability of the wall, the oosmotic pressure gradient 4,008,719 2/1977 Theeuwes et al. . ... 128/260 across the wall, and the rate of imbibition and expansion 4,014,334 3/1977 Theeuwes et al. . ... 128/260 of the means over a prolonged period of time. 4,016,880 4/1977 Theeuwes et al. . ... 128/260 4,036,227 7/1977 Zaffaroni et al...... 128/260 4,036,228 7/1977 Theeuwes ...... 128/260 13 Claims, 11 Drawing Figures

U.S. Patent Sept. 5, 1978 sheet 1 of 2 4,111,203

U.S. Patent Sept. 5, 1978 Sheet 2 of 2 4,111,203

Lif m al O2 - Lut 2 C. CH - - C o SS ed C Co

Fl G. s TIME, HOURS

; 2 3 4 5 6 7 8 9 TO 2 3 4 5 TIME, HOURS

-H 4,111,203 1. 2 hances the amount of these latter agents delivered at a OSMOTC SYSTEM WITH MEANS FOR controlled rate and continuously over a prolonged per IMPROVING DELVERY KINETCS OF SYSTEM iod of time by using means to improve the delivery kinetics and the amount of agent delivered from the CROSS-REFERENCE TO RELATED osmotic system. The osmotic system with the means APPLICATION also can optionally deliver increased amounts of very This application is copending with my application soluble or practically insoluble agents as pure agents U.S. Ser. No. 743,760 filed on Nov. 22, 1976. This appli substantially free of any osmotically effective com cation and application Ser. No. 743,760 are both as pounds being mixed therewith. A mathematical presen signed to the ALZA Corporation of Palo Alto, Calif. 10 tation pertaining to the instant subject matter is known in J. Pharm. Sci, Vol. 64, No. 12, pages 1987 to 1991, FIELD OF THE INVENTION 1975. This invention pertains to an osmotic delivery sys tem. More particularly, the invention relates to an os OBJECTS OF THE INVENTION motic system manufactured in the form of an osmotic 15 Accordingly, it is an immediate object of this inven device comprising a semipermeable wall surrounding a tion to provide an improved osmotic system for the compartment containing an agent and a means for im controlled and continuous delivery of an active agent proving the delivery kinetics of the system over a pro over a prolonged period of time which system over longed period of time. comes the problems known to the prior art. 20 Another object of the invention is to provide an os BACKGROUND OF THE INVENTION motic system that can deliver essentially all of its agent Osmotic delivery systems manufactured in the form at a controlled and constant rate continuously over a of osmotic devices for delivering a beneficial agent to prolonged period of time. an environment of use are known to the art in U.S. Pat. Another object of the invention is to provide an os Nos. 3,845,770 and 3,916,899. The systems disclosed in 25 motic system for the delivery of a beneficial agent com these patents comprise a semipermeable wall that sur prising means that improves the delivery kinetics of the rounds a compartment containing an agent. The wall is system. permeable to an external fluid, substantially imperme Still another object of the invention is to provide an able to agent, and there is a passageway through the osmotic system housing a delivery means useful for wall for delivering the agent from the system. These 30 increasing the amount of all kinds of agents delivered systems release agent by fluid being continuously in from the system. bibed through the wall into the compartment at a rate Still yet another object of the invention is to provide determined by the permeability of the wall and the an osmotic system comprising a delivery means for osmotic pressure gradient across the wall to produce a increasing the amount of both very soluble or practi solution of soluble agent, or a solution of an osmotic 35 cally insoluble agents delivered from the system. attractant containing an agent that has limited solubility Yet another object of the invention is to provide an in the fluid, which solution in either operation is dis osmotic system having means for continuously chang pensed from the system. These systems are extraordi ing the internal volume of the system thereby maintain narily effective for delivering both an agent that is solu ing the solution or suspension in the system saturated ble in the fluid and exhibits an osmotic pressure gradient with agent for constant release over time. across the wall against the fluid, and for delivering an Still another object of the invention is to provide an agent that has limited solubility in the fluid and is ad osmotic system having means for uptaking fluid for mixed with an osmotically effective compound that is maintaining excess solid agent in the solution or suspen soluble in the fluid and exhibits an osmotic pressure sion for the controlled release of the agent over time. gradient across the wall against the fluid. While the 45 Still a further object of the invention is to provide an above systems are outstanding and represent a pioneer osmotic system that can maintain the major amount of advancement in the delivery art, and while they are agent inside the system present as a saturated solution or endowed with ideal delivery kinetics useful for deliver saturated suspension with excess solid dispersed therein ing numerous beneficial agents at a controlled rate and throughout the time agent is released from the system. continuously to environments of use, there is an occa 50 Yet still a further object of the invention is to provide sional instance where the delivery kinetics of the system an osmotic therapeutic system that can administer a can be unexpectedly improved to lead to more desirable complete pharmaceutical regimen comprising soluble to results. For example, the rate of agent delivered by the very soluble or limited soluble to practically insoluble system is constant for most agents as long as excess solid agents at a constant rate to animals including warm agent is present in the system with its rate declining 55 blooded animals and humans for a particular time per parabolically towards zero as the agent's concentration iod, the use of which requires intervention only for decreases below saturation. That is, both the solubility initiation and possibly termination of the regimen. and the density of the agent influence the amount of Other objects, features and advantages of the inven agent delivered at a constant rate, and that amount tion will be more apparent to those skilled in the art delivered at a declining rate is proportional to the solu 60 from the following detailed specification, take in con bility of the agent and inversely proportional to its den junction with the drawings and the accompanying sity. These actions often make it difficult to deliver claims. substantially all of the agent and thereby obtain the full benefit of the agent's specific therapeutic effect, particu SUMMARY OF THE INVENTION larly when the agent is very soluble or practically insol 65 This invention concerns an osmotic system for dis uble in the fluid and concomitantly a portion of the pensing a beneficial agent to an environment of use. The agent cannot be delivered at a constant rate over a system is comprised of a semipermeable wall surround prolonged period of time. The present invention en ing a compartment and has a passageway through the 4,111,203 3 4. wall communicating with the compartment and the invention, and which examples are not to be considered exterior of the system. The compartment in a presently as limiting, one example of an osmotic delivery system preferred embodiment contains an agent that is very manufactured in the form of an osmotic device is indi soluble in an external fluid and exhibits an osmotic pres cated in FIGS. 1A, 1B and 1C, considered together, by sure gradient across the wall against the fluid, or in the numeral 10. The phrases "osmotic delivery system' another presently preferred embodiment, it contains an and "osmotic delivery system in the form of an osmotic agent having limited solubility in the fluid that exhibits device' as used for the purpose of this invention are a limited osmotic pressure gradient across the wall used as functional equivalents and they also embrace the against the fluid. The compartment additionally con expressions "osmotic therapeutic system', "osmotic tains means for delivering substantially most of the 10 device', and "system'. agent at essentially zero order from the compartment. In FIGS. 1A, 1B and 1C, system 10 is seen comprised Optionally, the compartment can contain an osmoti of a body 11 having a wall 12 that surrounds a compart cally effective compound that exhibits an osmotic pres ment 13, illustrated in FIGS. Band 1C in opened sec sure gradient across the wall against the fluid as an aid tion, and a passageway 14 that communicates with com to deliver agent. In operation, agent is released from the 15 partment 13 and the exterior of system i0. Compart system by the combined physico-chemical actions of ment 13, as seen in FIG. 1B, in one embodiment con the system and the means comprising fluid being im tains an agent 15 that is soluble in an external fluid and bibed through the semipermeable wall into the com in a presently preferred embodiment is very soluble in partment at a rate controlled by the permeability of the the external fluid and exhibits an osmotic pressure gra wall and the osmotic pressure gradient across the wall 20 dient across wall 12 against an external fluid. Compart to produce a solution or suspension containing agent ment 13 in another presently preferred embodiment, and to activate the means to imbibe fluid and expand in contains an agent 15 which has limited solubility or is volume, whereby the combined actions cause the sys substantially insoluble in the external fluid and exhibits tem to release agent at a controlled rate and continu a limited or it does not exhibit any osmotic pressure ously over a prolonged period of time. 25 gradient across wall 12 against said fluid. In another embodiment, compartment 13 optionally contains a BRIEF DESCRIPTION OF THE DRAWINGS mixture comprising agent 15 which has limited solubil In the drawings, which are not drawn to scale, but are ity or is substantially insoluble in the fluid mixed with an set forth to illustrate various embodiments of the inven osmotically effective compound 16 that is soluble in the tion, the figures are as follows: 30 fluid, and exhibits an osmotic pressure gradient across FIG. 1A is a view of an osmotic therapeutic system wall 12 against the fluid, and which compound further designed for orally delivering a beneficial agent; aids in delivering agent 13 from system 10. FIG. 1B is a view of the osmotic therapeutic system System 10 also contains in compartment 13 means 17, of FIG. 1A in opened section illustrating the compart seen in FIGS. 1B and 1C, for improving the zero order ment of the system housing means for increasing the 35 delivery kinetics of the system and increasing the amount of the beneficial agent delivered from the sys amount of agent 15 delivered from system 10. Means 17, tem; also identifiable as component 17, comprises a film 18 FIG. 1C is a view of the osmotic system of FIG. 1B encapsulating an osmotically effective compound 16, showing the means in operation as it continuously ex seen in FIG. 1B, that is soluble or swells in fluid imbibed pands to fill the compartment; into means 17 from fluid in compartment 13. Film 18 is FIG. 2A is another osmotic system in opened section free of any passageways and it is formed of a material showing the system housing a pluralty of delivery that can move from an initial or rested position, seen in means; FIG. 1C at 18, through sequential changes as repre FIG. 2B is a view of FIG. 2A showing the means sented by elliptical dotted lines to form means 17 with expanding in the compartment; 45 its film in expanded state 18a, Means 17 of the invention FIG.3 shows an osmotic therapeutic system designed is placed in compartment 13 free of any attachment to for releasing drug in the vaginal cavity of an adult; wall 12, and means 17 can contain one, or a plurality of FIG. 4 is a front view of the human eye illustrating an osmotically effective compounds 16 with each exhibit osmotic therapeutic system in operative position in the ing the same or different osmotic pressure gradients environment of use; 50 across film 18 against the fluid. FIG. 5 shows an opened osmotic delivery system Means 17 operates in cooperation with system 10 to illustrating the cooperative relationship between the release increased amount of agent 15 to the environment parts of the system; and of use. System 10 releases agent 15 housed in compart FIGS. 6, 7 and 8 are graphs recording the cummula ment 13, which agent is soluble or very soluble in the tive release, the rate of release for osmotic systems 55 external fluid, or has limited solubility or is practically made with and without the delivery means, and the insoluble in the fluid, by fluid being imbibed into com improvement in the percent of agent delivered over partment 13, in a tendency towards osmotic equilibrium time. at a rate controlled by the permeability of wall 12 and In the drawings and specification, like parts in related the osmotic pressure gradient across wall 12 to continu figures are identified by like numbers. The terms ap ously dissolve or form a suspension agent 15 which is pearing earlier in the specification and in the description osmotically pumped from system 10 through passage of the drawings, as well as embodiments thereof, are way 14 over a prolonged period of time. Means 17 further detailed elsewhere in the disclosure. operates to substantially insure that delivery of agent 15 is constant from system 10 by two methods. First, DETAILED DESCRIPTION OF THE 65 means 17 operates to concentrate agent 15 by imbibing DRAWINGS fluid from compartment 13 into means 17 to keep the Turning now to the drawings in detail, which are concentration of agent 15 from falling below saturation; examples of various osmotic delivery systems of the and secondly, means 17 continuously expands in size as 4,111,203 5 6 the hydrostatic pressure in 17 increases generated by Referring to FIG. 4, an ocular therapeutic system 10 osmotic imbibition into means 17 thereby reducing the is seen in an eye 25 for administering drug at an osmoti volume of compartment 13 and consequently dispens cally metered dosage rate thereto. In FIG. 4, eye 25 is ing agent 15 in solution or suspension from compart comprised of an upper eyelid 26 with eyelashes 27 and ment 13. System 10, in another embodiment, releases lower eyelid 28 with eyelashes 29. Eye 25 anatomically agent 15 that has limited solubility or is practically is comprised of an eyeball 30 covered for the greater insoluble in the fluid and is mixed with an osmotically part by sclera 31 and at its center area by cornea 32. effective compound by fluid being imbibed through Eyelids 26 and 28 are lined with an epithelial membrane wall 12 into compartment 13 in a tendency towards or palpebral conjunctiva, and sclera 31 is lined with a osmotic equilibrium at a rate controlled by the permea O bulbar conjunctiva that covers the exposed surface of bility of wall 12 and the osmotic pressure gradient eyeball 30. Cornea 30 is covered with a transparent across wall 12 to continuously dissolve the osmotically epithelial membrane. The portion of the palpebral con effective compound and form a solution containing junctiva which lines upper eyelid 26 and the underlying agent in suspension that is pumped from system 10 portion of the bulbar conjunctiva defines an upper cul 15 de-sac, while that portion of the palpebral conjunctiva through passageway 14. In this latter embodiment, de which lines lower eyelid 28 and the underlying portion livery means 17 operates as described supra. A detailed of the bulbar conjunctiva defines a lower cul-de-sac. mathematical discussion of the operation of means 17 Ocular osmotic system 10, seen in broken lines, is de appears later in the specification. signed for placement in the upper or lower cul-de-sac. Wall 12 of system 10 is comprised in total or in at least System 10 is seen in the lower cul-de-sac and it is held a part of a semipermeable material that is permeable to in place by the natural pressure of lower eyelid 28. an external fluid essentially impermeable to agent 15, System 10 contains an ophthalmic drug for release to and ingredients in compartment 13. When wall 12 is eye 25 at a controlled rate and continuously over a formed in part of a semipermeable material, the remain prolonged period of time. der is formed of an impermeable material. Film 18 of 25 Ocular system 10 can have any geometric shape that means 17 is formed of a material that is deformable and fits comfortably in the eye or in the cul-de-sac. Typical can undergo expansion over a period of time. Wall 12 shapes include, ellipsoid, bean, banana, circular, ring, and film 18 can be formed of synthetic or naturally rectangular, doughnut, crescent and half-ring shaped occurring materials and a detailed description of these systems. In cross-section, the systems can be doubly materials appears later in the specification. 30 convex, concavo-convex, rectangular and the like, as System 10 of FIGS. 1A, 1B and 1C can be made into the device in use will tend to conform to the shape of many embodiments including the presently preferred the eye. The dimensions of an ocular system can vary embodiments for oral use, that is, for releasing either a widely with the lower limit governed by the amount of locally or systemically acting therapeutic agent in the drug to be administered to the eye as well as the smallest gastrointestinal tract over a prolonged period of time. 35 sized system that can be placed and positioned in the Oral system 10 can have various conventional shapes eye. The upper limit on the size of the system is gov ... and sizes such as round with a diameter of 3/16 inch to erned by the space limitation in the eye consistent with inch, or it can be shaped like a capsule having a range comfortable retention in the eye. Satisfactory systems of sizes from triple zero to zero, and from 1 to 8. have a length of 4 to 20 millimeters, a width of 1 to 15 FIGS. 2A and 2B represent another system 10 manu millimeters. The ocular system can contain from 0.15 factured according to the invention and designed for micrograms to 100 milligrams of drug, or more, and it is administering agent 15 to an environment of use. In made from materials non-toxic to the eye. FIGS. 2A and 2B, system 10 is seen in opened section While FIGS. 1 through 4 are illustrative of various and it is similar to system 10 of FIGS. 1A, 1B and 1C, as osmotic delivery systems that can be made according to it comprises a body 11 having a wall 12 that surrounds 45 the invention, it is to be understood these systems are a compartment 13 having a passageway 14 that commu not to be construed as limited, as the system can take a nicates with the exterior of the system 10. Compartment wide variety of shapes, sizes and forms for delivering 13 of system 10 contains a multiplicity of driving com agent to different environments of use. For example, the ponents 17 or means comprising a film 18 encasing an system includes buccal, implant, anal, rectal, artificial osmotically effective compound 16 and they operate as SO gland, cervical, intrauterine, ear, nose, dermal, subcuta described supra to maintain a concentrated solution or neous, and blood systems. The systems also can be suspension containing excess solid agent 15 for substan adapted for delivering an active agentin streams, aquar tially zero order release of agent 15 over a prolonged iums, fields, factories, reservoirs, laboratory facilities, period of time. hot houses, transportation means, naval means, military FIG. 3 shows an osmotic system 10 designed for 55 means, hospitals, veterinary clinics, nursing homes, placement in a vagina or other body opening. System 10 farms, zoos, chemical reactions, and other environments has an elongated, cylindrical, self-sustaining shape with of use. a rounded lead end 19 and it is equipped with a manu ally controlled cord 20 for easily removing system 10 DETAILED DESCRIPTION OF THE from the vagina. System 10 is structurally identical with INVENTION system 10 as described above and it has a means 17 that In accordance with the practice of the invention, it operates in a like manner by being capable of increasing has now been found that osmotic delivery system 10 can in volume from a through h. System 10 of FIG.3 in one be manufactured with a wall 12 formed of a material embodiment contains a drug designed for absorption by that does not adversely affect the agent, an animal body, the vaginal mucosa to produce a local or systemic ef 65 or other host, and is permeable to an external fluid such fect, and in another embodiment it contains an odor as water and biological fluids while essentially imper reductant that emits an odor counteracting scent or meable to agents, drugs and the like. The selectively fragrance in the vagina. permeable materials forming wall 12 are insoluble in 4,111,203 7 8 body fluids, and they are non-erodible, or they can be ene glycol with maleic acid and polyester of triethylene bioerodible after a predetermined period with bioero glycol with adipic acid. sion corresponding to the end of the agent release per Exemplary film expansion agents suitable for the iod. Typical materials for forming wall 12 include mate present purpose generically include agents that lower rials known to the art as semipermeable membranes the temperature of the second-order phase transition or including osmosis and reverse osmosis membranes such the glass transition temperature of the film forming as cellulose acetate, cellulose triacetate, agar acetate, materials or the elastic modulus thereof, increase the amylose triacetate, beta glucan acetate, cellulose diace workability of the film, its flexibility, and its permeabil tate, acetaldehyde dimethyl acetate, cellulose acetate ity to fluid. Agents operable for the present purpose ethyl carbamate, polyamides, polyurethane, sulfonated 10 include both cyclic and acyclic agents. Typical agents polystyrenes, cellulose acetate phthalate, cellulose ace are those selected from the group consisting of phthal tate methyl carbamate, cellulose acetate succinate, cel ates, phosphates, citrates, adipates, tartrates, sebacates, lulose acetate dimethylaminoacetate, cellulose acetate succinates, glycolates, glycerolate, benzoates, myris ethyl carbamate, cellulose acetate chloroacetate, cellu tates, sulfonamides, and halogenated phenyls. lose dipalmitate, cellulose dioctanoate, cellulose dicap 15 Exemplary agents further include dialkyl phthalates, rylate, cellulose dipentanlate, cellulose acetate valerate, dicycloalkyl phthalates, diaryl phthalates and mixed cellulose acetate succinate, cellulose propionate succi alkyl-aryl phthalates as represented by dimethyl phthal nate, methyl cellulose, cellulose acetate p-toluene sulfo ate, dipropyl phthalate, di(2-ethylhexyl)-phthalate, di nate, cellulose acetate butyrate, selectively permeable isopropyl phthalate, diamyl phthalate and dicapryl polymers formed by the coprecipitation of a polycation 20 phthalate; alkyl and aryl phosphates such as tributyl and a polyanion as disclosed in U.S. Pat. Nos. 3,173,876; phosphate, trioctyl phosphate, tricresyl phosphate, tri 3,276,586; 3,541,005; 3,541,006; and 3,546,142. Gener octyl phosphate, tricresyl phosphate and triphenyl ally, semipermeable materials useful for forming wall 12 phosphate; alkyl citrate and citrate esters such as tribu will have a fluid permeability of 10 to 10 (cc.mil/c- tyl citrate, triethyl citrate, and acetyl triethyl citrate; m.hr-atm) expressed per atmosphere of hydrostatic or 25 alkyl adipates such as dioctyl adipate, diethyl adipate osmotic pressure difference across wall 12 at the tem and di(2-methoxyethyl)-adipate; dialkyl tartrates such perature of use. Suitable materials are known to the art as diethyl tartrate and dibutyl tartrate; alkyl sebacates in U.S. Pat. Nos. 3,845,770 and 3,916,899. such as diethyl sebacate, dipropyl sebacate and dinonyl Film 18 of means 17 is formed of the above materials sebacate; alkyl succinates such as diethyl succinate and and it additionally contains from 0.01% to 40% of a film 30 dibutyl succinate; alkyl glycolates, alkyl glycerolates, expansion agent that imparts flexibility, deformability glycol esters and glycerol esters such as glycerol diace and expansion properties to the film. Suitable agents in tate, glycerol triacetate, glycerol monolactate diacetate, one embodiment include polyhydric alcohols and deriv methyl phthalyl ethyl glycolate, butyl phthalyl butyl atives thereof, such as polyalkylene glycols of the for glycolate, ethylene glycol diacetate, ethylene glycol mula H-(O-alkylene)-OH wherein the bivalent al 35 dibutyrate, triethylene glycol diacetate, triethylene gly kylene radical is straight or branched chain and has col dibutyrate and triethylene glycol dipropionate. from 1 to 10 carbon atoms and n is 1 to 500 or higher. Also, camphor, N-ethyl-(o- and p-toluene) sulfonamide, Typical glycols include polyethylene glycols 300, 400, chlorinated biphenyl, benzophenone, N-cyclohexyl-p- 600, 1500, 1540, 4000 and 6000 of the formula H toluene sulfonamide, and substituted epoxides. (OCH2CH2)-OH wherein n is respectively 5, 5.7, 8.2 Suitable agents can be selected for blending with the to 9.1, 12.5 to 13.9, 29 to 36, 29.8 to 37, 68 to 84, and 158 film forming materials by selecting agents that have a to 204. Other polyglycols include low molecular weight high degree of solvent power for the materials, are glycols such as polypropylene, polybutylene and polya compatible with the materials over both the processing mylene. and use temperature range, exhibit permanence as seen The film expansion agents in another embodiment 45 by a strong tendency to remain in the film, impart the include poly(a,a)-alkylenediols wherein the alkylene is desired properties, and are non-toxic to animals, hu straight or branched chain of from 2 to 10 carbon atoms 'mans, avians, fishes and reptiles when the osmotic sys such as poly(1,3)-propanediol, poly(1,4)-butanediol, tem is used for dispensing drugs. Procedures for select poly(1,5)-pentanediol and poly(1,6)-hexanediol. The ing an agent having the described characteristics are diols also include aliphatic diols of the formula HOCH 50 disclosed in the Encyclopedia of Polymer Science and OH wherein n is from 2 to 10 and the diols are option Technology, Vol. 10, pages 228 to 306, 1969, published ally bonded to a non-terminal carbon atom such as by John Wiley & Sons, Inc. 1,3-butylene glycol, 1,4-pentamethylene glycol, 1,5- The expression "passageway” as used herein com hexamethylene glycol and 1,8-decamethylene glycol; prises means and methods suitable for releasing the and alkylenetriols having 3 to 6 carbons atoms such as 55 agent from the system. The expression includes apera glycerine, 1,2,3-butanetriol, 1,2,3-pentanetriol, 1,2,4- ture, orifice or bore through wall 12 formed by mechan hexanetriol and 1,3,6-hexanetriol. ical procedures, or by eroding an erodible element, such Other film expansion agents include esters and poly as a gelatin plug, in the environment of use. A detailed esters of alkylene glycols of the formula HO-(alky description of osmotic passageways and the maximum lene-O)-H wherein the divalent alkylene radical in and minimum dimensions for a passageway are dis cludes the straight chain groups and the isomeric forms closed in U.S. Pat. Nos. 3,845,770 and 3,916,899. These thereof having from 2 to 6 carbons and n is 1 to 14. The patents are assigned to the Alza Corporation of Palo esters and polyesters are formed by reacting the glycol Alto, Calif., the assignee of this application. with either a monobasic or dibasic acid. Exemplary The osmotically effective compounds that can be agents are ethylene glycol dipropionate, ethylene gly 65 used for the purpose of the invention include inorganic col butyrate, ethylene glycol diacetate, triethylene gly and organic compounds that exhibit an osmotic pressure col diacetate, butylene glycol dipropionate, polyester of gradient against an external fluid across wall 12 and ethylene glycol with succinic acid, polyester of diethyl across film 18. These compounds are known as osma

H 4,111,203 10 gents. The osmagents when present in compartment 13 inorganic and organic compounds without limitation, are mixed with an agent that has limited solubility in those materials that act on the central nervous system external fluid with the osmagent forming a saturated such as hypnotics and sedatives, psychic energizers, solution containing agent that is osmotically delivered tranquilizers, antidepressants, anticonvulsants, muscle from the system. The osmagents are present in means 17 relaxants, antiparkinson agents, analgesics, anti-inflam for: (a) imbibing fluid from compartment 13 to concen matory, local anesthetics, muscle contractants, anti trate a solution or a suspension in compartment 13; and infectives, anti-microbials, anti-malarials, hormonal (b) for means 17 to expand and fill the volume of com agents, sympathomimetics, metabolic aberration cor partment 13. The osmagents are used in compartment recting agents, diuretics, anti-parasitics, neoplastics, 13 by homogenously or heterogenously mixing it or a 10 hypoglycemics, nutritionals, fats, ophthalmic, electro mixture of osmagents with an agent, either before they lytes, cardiacs, and diagnostic agents. are charged into the compartment, or by self-mixing Exemplary of drugs that are very soluble in water after they are charged into the compartment. In opera and can be delivered by the systems of this invention tion, these osmagents attract fluid into the compartment include prochlorperazine edisylate, ferrous sulfate, ami producing a solution or suspension of osmagents which 15 nocaproic acid, potassium chloride, mecamylamine is delivered from the system concomitantly transporting hydrochloride, procainamide hydrochloride, ampheta undissolved and dissolved agent to the exterior of the mine sulfate, benzphetamine hydrochloride, isoproter system. The osmagents are present in the means 17 nol sulfate, methamphetamine hydrochloride, phenmet independent of the presence of any other agent. Osmoti razine hydrochloride, bethanechol chloride, methacho cally effective compounds useful as osmagents for the 20 line chloride, pilocarpine hydrochloride, atropine sul present purpose in 13 and 17 include salts such as mag fate, methscopolamine bromide, isopropamide iodide, nesium sulfate, magnesium chloride, sodium chloride, tridihexethyl chloride, phenformin hydrochloride, and lithium chloride, potassium sulfate, sodium carbonate, methylphenidate hydrochloride. sodium sulfite, lithium sulfate, potassium chloride, am Exemplary of agents that are very slightly soluble or monium chloride, calcium carbonate, sodium sulfate, 25 practically insoluble in water that can be delivered by calcium sulfate, potassium acid phosphate, calcium lac the system of this invention include diphenidol, mecli tate, mannitol, urea, inositol, magnesium succinate, tar zine hydrochloride, prochlorperazine maleate, thie taric acid, carbohydrates such as raffinose, sorbitol, thylperazine maleate, anisindione, diphenadione, eryth succrose, fructose, glycose, and mixtures thereof. The rity tetranitrate, dizoxin, isoflurophate, reserpine, acet osmagent suitable for housing in 17 also includes algin, 30 azolamide, methazolamide, bendroflumethiazide, chlor sodium alginate, potassium alginate, carrageenan, propamide, tolazamide, chlormadinone acetate, phena fucoridan, furcellaran, laminaran, hypnea, pectin, and glycodol, allopurinol, aluminum aspirin, methotrexate, the like. The osmagent is usually present in an excess acetyl sulfisoxazole, erythromycin, steroids, including amount, and it can be in any physical form such as corticosteroids such as hydrocortisone, desoxycortico particle, crystal, pellet, tablet, strip, powder, film or 35 sterone acetate, cortisone acetate, triancinolone, andro granule. The osmotic pressure ar, in atmospheres ATM, gens such as methyltesterone, estrogenic steroids such of the osmagents suitable for the invention will be as 17.6-estradiol, and ethinyl estradiol, progestational greater than zero ATM, generally from zero ATM up steroids such as 17a-hydroxyprogesterone acetate, 19 to 500 ATM, or higher. nor-progesterone, prednisolone, norethindrone acetate, The expression “active agent” as used herein broadly progesterone, norethynodrel, and the like. includes any compound, composition of matter or mix The drug also can be in various forms, such as un ture thereof, that can be delivered from the system to charged molecules, molecular complexes, pharmaco produce a beneficial and useful result. The agent can be logically acceptable acid or base addition salts such as soluble in a fluid that enters the compartment and func hydrochlorides, hydrobromides, sulfate, laurylate, pal tions as its own osmotically effective solute, or it can 45 mitate, phosphate, nitrate, borate, acetate, maleate, tar have limited solubility in the fluid and be mixed with an trate, oleate, and salicylate, For acidic drugs, salts of osmotically effective compound soluble in fluid that is metals, amines or organic cations, for example quater delivered from the system, or the agent can be delivered nary ammonium can be used. Derivatives of drugs such from system 10 by means 17. The active agent includes as esters, ethers and amides can be used alone or mixed pesticides, herbicides, germicides, biocides, algicides, 50 with other drugs. Also, a drug that is water insoluble rodenticides, fungicides, insecticides, anti-oxidants, can be used in a form that on its release from the device, plant growth promoters, plant growth inhibitors, pre is converted by enzymes, hydrolyzed by body pH or servatives, anti-preservatives, disinfectants, sterilization other metabolic processes to the original form, or to a agents, catalysts, chemical reactants, fermentation biologically active form. The agent can be in the reser agents, foods, food supplements, nutrients, cosmetics, 55 voir as a dispersion, paste, cream, particle, granule, drugs, vitamins, sex sterilants, fertility inhibitors, fertil emulsion, suspension or powder. Also, the agent can be ity promoters, air purifiers, micro-organism attenuators, mixed with a binder, diluent, dispersant, stabilizer, and other agents that benefit the environment of use. emulsifier or wetting agent and dyes. In the specification and the accompanying claims, the The amount of agent present in the system is initially term "drug' includes any physiologically or pharmaco in excess of the amount that can be dissolved in or logically active substance that produces a localized or mixed with the fluid that enters the compartment. systemic effect or effects in animals, including warm Under this physical state when the agent is soluble and blooded animals, mammals, humans, primates, avians, in excess, or if the agent is mixed with an osmagent, the domestic household animals, sport and farm animals. system will osmotically operate to give a substantially such as sheep, goats, cattle, horses and pigs, for adminis 65 constant rate of release. The rate of agent release pat tering to laboratory animals such as mice, rats and tern can also be varied by having different amounts of guinea pigs, and to fishes, reptiles, jungle and Zoo ani agent in the compartment to form solutions, suspensions mals. The active drug that can be delivered includes or mixtures containing different concentrations of

sets. 4,111,203 11. 12 agent, and optionally, osmagents for delivery of agents means, and then closed. The system also can be manu from the system. Generally, the system can house from factured with an empty compartment that is filled 0.05 ng to 5 grams or more of agent, with individual through the passageway. Walls forming the system also systems containing for example, 25 ng, 1 mg, 5 mg, 250 can be joined by various joining techniques such as high mg, 500 mg, 1.5 g, of agent or mixtures thereof, and the frequency electronic sealing that provides clean edges like. The beneficial drugs are known to the art in Phar and firmly formed walls. Another, and presently pre maceutical Sciences, by Remington, 15th Ed., 1975, pub ferred technique that can be used is the air suspension lished by Mack Publishing Co., Easton, Penna; The procedure. This procedure consists in suspending and Drug, The Nurse, The Patient, Including Current Drug tumbling the agent and means in a current of air and a Handbook, 1974-1976, by Falconer, et al, published by 10 wall forming composition until the wall is applied to the Saunder Company, Philadelphia, Penna; and, Medicinal agent. The means comprising the film surrounding the Chemistry, 3rd Ed., Vol. I & II, by Burger, A., pub osmagent can be manufactured by the above tech lished by Wiley-Interscience, New York. niques. Also, the air suspension procedure is well-suited The solubility or insolubility of an agent in an exter for independently forming the means by applying a film nal fluid can be determined by various art known tech 15 to an osmagent. The air suspension procedure is de niques. One method consists in preparing a saturated scribed in U.S. Pat. No. 2,799,241; in J. Am. Pharm. solution or suspension comprising the external fluid plus Assoc, Vol. 48, pages 451 to 459, 1959; and ibid., Vol. the agent and ascertaining by analyzing the amount of 49, pages 82 to 84, 1960. Other wall forming and film agent present in a definite quantity of the fluid. A simple forming techniques such as pan coating can be used in apparatus for this purpose consists of a test tube of me 20 which the materials are deposited by successive spray dium size fastened upright in a water bath maintained at ing of the polymer solution on the agent or osmagent constant temperature and pressure in which the fluid tumbling in a rotating pan. Other standard manufactur and agent are placed and stirred by a motor driven ing procedures are described in Modern Plastics Encyclo rotating glass spiral. After a given period of stirring, a pedia, Vol. 46, pages 62 to 70, 1969; and in Pharmaceuti definite weight of the fluid is analyzed and the stirring 25 cal Sciences, by Remington, 14th Ed., pages 1626 to continued for an additional period of time. If the analy 1678, 1970, published by Mack Publishing Company, sis shows no increase of dissolved or suspended agent Easton, Penna. after successive periods of stirrings, in the presence of Exemplary solvents suitable for manufacturing the excess solid agent in the fluid, the solution or suspension wall, or the film include inert inorganic and organic is saturated and the results are taken as the solubility of 30 solvents that do not adversely harm the wall forming the product in the fluid. Optionally, if the agent is solu materials, the film forming materials, and the final sys ble an osmagent is not needed; if the agent has limited tem. The solvents broadly include members selected solubility or if it is insoluble in the fluid, then an osma from the group consisting of aqueous solvents, and gent can optionally be incorporated into the compart organic solvents, such as alcohols, ketones, esters, ment already housing the delivery component. Numer 35 ethers, aliphatic hydrocarbons, halogenated solvents, ous other methods are available for determining the cycloaliphatics, aromatics, heterocyclic solvents and solubility of an agent in a fluid. Typical methods used mixtures thereof. Typical solvents include acetone, for measuring solubility include chemical analysis, ultra diacetone alcohol, methanol, ethanol, isopropyl alco violet spectrometry, density, refractive index and elec hol, butyl alcohol, methyl acetate, ethyl acetate, isopro trical conductivity. Generally, for the purpose of this 40 pyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, invention soluble to very soluble agents will dissolve in isopropyl acetate, n-butyl acetate, methyl isobutyl ke the range of from 175 mg to 900 mg of agent or higher tone, methyl propyl ketone, n-hexane, n-heptane, ethyl per milliter of fluid, and limited soluble to insoluble ene glycol monoethyl ether, ethylene glycol monoethyl agents will dissolve in the range of 0.001 mg to 125 mg acetate, methylene dichloride, ethylene dichloride, of agent per milliter of fluid. While the invention has 45 propylene dichloride, carbon tetrachloride, nitroethane, been described with particular reference to presently nitropropane, tetrachloroethane, ethyl ether, isopropyl preferred embodiments including soluble and insoluble, ether, cyclohexane, cyclo-octane, benzene, toluene, it is understood the system of the invention can be used naphtha, 1,4-dioxane, tetrahydrofuran, diglyme, water, to deliver other agents having other degrees of solubili and mixtures thereof such as acetone and water, acetone ties. Details of various methods for determining solubili 50 and methanol, acetone and ethyl alcohol, methylene ties are described in United States Public Health Service dichloride and methanol, and ethylene dichloride and Bulletin, No. 67 of the Hygienic Laboratory; Encyclope methanol. dia of Science and Technology, Vol. 12, pages 542 to 556, 1971, published by McGraw-Hill, Inc.; and Encyclopae DESCRIPTION OF EXAMPLES OF THE dic Dictionary of Physics, Vol. 6, pages 547 to 557, 1962, 55 INVENTION published by Pergamon Press, Inc. The following examples are merely illustrative of the The systems of the invention are manufactured by present invention and they should not be considered as standard techniques. For example, in one embodiment, limiting the scope of the invention in any way, as these the agent, the delivery means, and other ingredients that examples and other equivalents thereof will become may be housed in the compartment and a solvent are apparent to those versed in the art in the light of the mixed into a solid, semi-solid or gel by conventional present disclosure, the drawings and the accompanying methods such as ball milling, calendering, stirring or claims. rollmilling and then pressed into a preselected shape. The wall forming the system can be applied by molding, EXAMPLE 1 spraying or dipping the pressed shape into wall forming 65 An osmotic delivery device for the controlled and materials. In another embodiment, a wall can be cast, continuous release of a beneficial agent to an environ shaped to the desired dimensions to define a wall that ment of use is constructed as follows: first, a delivery surrounds a compartment that is filled with agent and means is formed by encapsulating a given amount of an 4,111,203 13 14 osmagent with a film consisting of a semipermeable material and a film expansion agent in an air suspension dy A. (6) machine. Next, the means is mixed and compressed with # = k it, a a water soluble agent that can exhibit an osmotic pres (7) sure gradient across a wall and then they are sur d a rounded with a semipermeable polymeric wall forming ------(n-1)-ar material. A passageway is drilled in the wall to form a do -dy (8) system having a compartment housing the agent and the -- = - component. The system of this example is illustrated in FIG. 5, 10 By selecting films having sufficient flexible or expansion and it releases agent at a zero order rate over a pro properties for the means, AP in Relation 7 can be ne longed period of time. In FIG. 5the agent compartment glected. The mass of agent is solution in the compart is identified by (1), the means is identified as (0), and the ment after all excess solid is delivered is given by Rela delivery from the system 10 is governed by the osmotic 15 tion 9: pressure of the agent at the volume flow rate (dv/dt) as given by Relation 1: m1 = c V (9) wherein mi is the mass of agent in solution in the com A. (1) partment, cis the concentration of agent in solution and --dy = K..K --.h 7 20 y is the volume of the compartment. The mass changes in the compartment are related to volume and concen wherein Kis the fluid (water in this example) permeabil tration as set forth in Relation 10: ity of the wall of the system, aris the osmotic pressure of the agent at saturation, A1 is the area of the wall, and 25 dm dy de (10) his the thickness of the wall, and the mass zero order - = c-- + v - delivery rate is given by Relation 2:

(2) with the mass change dm/dt given by Relation 11 as --dm = --dy Cls 30 related to the systems delivery rate: dm k All (11) wherein C is the concentration of agent at saturation. - dr = cR11 "1at m The volume flow rate from the system dv/dt is given by Relation 3, indicating that the volume flow rate from 35 By substituting Relation 11 and Relation 7 into Rela the system is equal to the volume of liquid imbibed into tion 10, the general differential equation evolves as set compartment (1): forth in Relation 12: ----- (3) (12) The differential Relation 11 can be solved to obtain It is practical to assume nois equal to a constant, or that cas a function of time, and also to give the delivery rate sufficient osmagent is available in the means. The effec 45 from the system as a function of time. After the initial tive osmotic pressure of the osmagent in the means can zero order delivery rate is obtained from the system as be selected as shown by Relation 4: described by Relation 2, a second zero order state can be programmed during which the concentration change 7to S ar. (4) in the compartment is zero as shown by Relation 13: such that delivery promoted by the means is temporar 50 ily delayed until all solid agent in the compartment is de (13) delivered from the system. When all the agent is deliv - = 0 ered, the means starts to imbibe water from the comi partment at a rate (dv/dt) which is equal to the volume The equilibrium osmotic pressure at which develops in changedy/dt of the means and also equal to the volume 55 the compartment under this condition is obtained from change of the compartment dy/dt. The total volume Relation 12 and 13 and gives Relation 14: flow from the system is given by Relation 5: (14) (5) dy - dr - - d. dy at T at dt 0 dt mua is 0.

The volume flow terms in Relation 5 can be expressed 65 as they relate to their individual wall and film perme With the new or second zero order steady state concen abilities, and dimensions as given by Relations 6, 7 and tration c can be calculated by Van' Hoff Law accord 8: ing to Relation 15:

15 4,111,203 6 film allows it to stretch such that back pressure is small C (15) compared to the osmotic pressure of the osmagent and the means therefore will increase in volume at a con stant rate according to Relation 22: The new second zero order rate is expressed by Rela 5 tion 16 which is analagous to Relation 11, wherein aris (22) given by Relation 14, and c is given by Relation 15:

dm k wherein Aois the area of the component, his the thick a = 1 a A ness of the film of the means A1 is the area of the system k-i- and his the thickness of the wall of the system. 1 + For a system of size A s 3 cm and his 10 mils then ko the ratio of A1 to his given by Relation 23: 15 --A as 4.6 x 10' mils (23)23 This new steady state expressed by Relation 16 can be l selected to be equal to the initial agent delivery rate expressed by Relation 2 if the means has the same os and for a means having a spherical shape and a radius ro motic pressure as the agent as expressed by Relation 17 20 and a film thickness ho the ratio of Aoto hois given by when the conditions of Relation 18 hold. Relation 24: fo = 7ts (17) Ao 4 x n x ro (24) Ao A1 (18) 2- = n x ho o K. He 25 k-->>O Ki wherein n is the number of means in the compartment. Conditions 17 and 18 are then sufficient criteria to ar Relation 24 also can be expressed as Relation 25: rive at a zero order rate from the system for the total lifetime of the device if sufficient driving agent is in 30 (25) cluded to keep no substantially constant. The minimum mass of driving agent Moneeded to sustain zero order is obtained from the driving agent's solubility, So in mass per unit volume solution and the system total inside and for an area to thickness ratio selecting ro/hoequal to volume, Vio + Voo is given by Relation 19: 35 10, and for a film thickness of hegual to 1 mill, Relation 26 holds as follows: Mo 2 So (Yo - Vo) (19) wherein Vo and Woo are the initial agent and driving Ao = n x 1.2 x 10mil (26) agent volumes, and for a driving agent with a density po ho Relation 20 holds as follows: with the number of means needed to satisfy Relation 22, po Vo2. So (Vo + Vo) (20) taking Ao/hoas a factor 100 times larger, is then obtained from Relations 23 and 26 and now expressed by Rela tion 27: and for convenience is expressed as Relation 21: 45 n = 4 x 10 (27) 1 (21) The weight of 4,000 means with a radius roequal to 10 mill with a density poequal 1 g/cmis expressed by Rela tion 28: 50 for all agents and driving agents of the same density M = (4/3) Iroix n x pogram (28) M/M = V/Vol. The above discussion is illustrated in FIG. 5 which shows the relationship between the vol resulting in Relation 29: ume of fluid being imbibed into the compartment in unit time expressed as (dv/dt), the volume of fluid being 55 M = 65 pug x n = 260 mg (29) imbibed into the means in unit time expressed as Thus, to keep a constant driving action with this mass (dv/dt) and the volume of fluid leaving the system in of means Mo as expressed by Relation 29, Mo must be unit time dy/dt. larger than Mo expressed by Relation 19, and for a sys EXAMPLE 2 ten containing 500 mg of agent, 260 mg of means is The procedure employed in this example uses the required to satisfy Relation 21 if the solubility of the relations of Example 1. In this example it is assumed the osmagent So does not exceed 650 mg/ml. osmotic pressure generated by the osmagent in the means is substantially equal to the osmotic pressure EXAMPLE 3 generated by the agent in the compartment, and that the 65 Repeating the relations of Examples 1 and 2, and permeability of the film encapsulating the means is sub using an osmagent having a solubility So, the minimum stantially equal to the permeability of the wall of the amount of osmagent, mass Mo can be calculated from system koski. The use of the expansion agent in the Relation 19 for delivering an amount of agent Mo, with 4,111,203 17 18 Mohaving a radius ro, the amount is obtained from Rela osmagent sodium chloride coated with a film of cellu tion 28 expressed as Relation 30: lose acetate. The release for this system is identified by the curve with the squares. In FIG. 7 the release rate in -- 3 - W -o- -- mg/hr is plotted against time for two systems. The line ro = X X with the circles represents an osmotic system that con tains 235 mg of procainamide hydrochloride, and the The quantities rand n are further defined by Relation line with the squares represents a system containing in 22, quantitively expressed by Relation 31 in which F the compartment 235 mg of procainamide hydrochlo expresses the closeness of the second zero order rate to ride and 350 mg of osmagent sodium chloride sur first zero order rate: O rounded with a semipermeable film of cellulose acetate. FIG. 8 illustrates improvement attributed to a compo ment. al (31) . 4 x x .x: - F - EXAMPLE 6 15 The procedures of Examples 4 and 5 are repeated in with rand n two viables which simultaneously have to this example with all conditions as previously described satisfy Relations 30 and 31 as given by Relations 32 and except that the agent in compartment 13 is replaced 33: with a member selected from the group consisting of hypnotics, sedatives, psychic energizers, tranquilizers, 3 Mo (32) 20 anticonvulsants, muscle relaxants, antiparkinson agents, fo = hoto A1 analgesics, antiinflammatory, anesthetics, muscle con tractants, anti-microbials, anti-malarials, hormones, f(4) sympathomimetics, diuretics, hypoglycemics, and nutri (33) A. 3 tional agents, and component 17 in the compartment 13 P(4- h 25 comprises an osmagent selected from the group consist n = 8.8 x 10 M. Y2 ing of sodium fluoride, ammonium chloride, a mixture of sodium chloride and ammonium chloride with the (-) osmagent surrounded with a semipermeable film of cellulose acetate containing the film expansion agent The above presentation demonstrates that film encap 30 polyethylene glycol. sulating osmagents substantially increases the Zero order delivery rate of a given osmotic system even EXAMPLE 7 when F equals 10, which would in Example 2 corre The procedures of Examples 4, 5 and 6 are repeated spond to a driving mass Mo equal to 26 mg for a final in this example, with all conditions as described except zero rate being 90% of the original zero order rate. 35 that the drug in compartment 13 is replaced with a EXAMPLE 4 member selected from the group consisting of prochlor An osmotic therapeutic system manufactured in the perazine edisylate, ferrous sulfate, aminocaproic acid, form of an oral, osmotic device for delivering procaina potassium chloride, mecamylamine hydrochloride, an mide hydrochloride to the gastrointestinal tract is man phetamine sulfate, benzphetamine hydrochloride, iso ufactured as follows: first, 350 mg of discrete, sodium proternol sulfate, methamphetamine hydrochloride, chloride osmagent particles are coated in an air suspen phenmetrazine hydrochloride, bethanechol chloride, sion machine with a film forming composition compris methacholine chloride, atropine sulfate, methscopola ing (1) 70% cellulose acetate having an acetyl content mine bromide, isopropamide iodide, tridihexethyl chlo of 32% mixed with (2) 30% polyethylene glycol having 45 ride, phenformin hydrochloride, and methylphenidate a molecular weight of 400 dissolved in (3) methylene hydrochloride, and the osmagent in component 17 is chloride-methanol, 80:20, until each particle is encapsu selected from the group consisting of potassium sulfate, lated with the film to form component 17. Next, 235 mg sodium sulfite, potassium chloride and a mixture of of agent procainamide hydrochloride having a molecu potassium chloride and sodium chloride. lar weight of 271.79 is mixed with the delivery compo 50 nent 17, compressed and coated in an air suspension . EXAMPLE 8 with a wall of semipermeable polymeric cellulose ace The procedures of Examples 4 and 5 are repeated in tate having an acetyl content of 32%. The cellulose this example with all conditions as previously described acetate is intimately applied from a 5% w/w solution in except that the system is designed as an ocular, osmotic acetone:water in the proportion of 89:11 wit:wt. Finally, 55 therapeutic system and compartment 13 contains an an osmotic passageway is drilled through the wall and it ophthalmic drug that is a member selected from the had a diameter of 7.5 mils to yield the osmotic system. group consisting of idoxuridine, phenylephrine, pilocar pine hydrochloride, eserine, carbachol, phospholine EXAMPLE 5 iodine, demecarium bromide, cyclopentolate, homatro The procedure of Example 4 is repeated in this exam pine, scopolamine and epinephrine. ple, with all conditions as described, except that the osmotic system is manufactured with the compartment EXAMPLE 9 containing only 235 mg of the agent procainamide hy An osmotic system designed for delivering an agent drochloride. The cummulative rate released expressed having limited solubility is designed by governing the as percent of the total is plotted in FIG. 6 and identified 65 flux of fluid into the delivery component 17 as the os by the curves with the circles. Also in FIG. 6the release motic pressure To across the composite structure of the rate is plotted for a system having in its compartment film of component 17 and the wall of the osmotic sys 235 mg of procainamide hydrochloride and 350 mg of tem. The increase in size of component 17 and the rate 4,111,203 2 of agent delivery from the system is given by Relation vention as applied to presently preferred embodiments, 34: those skilled in the art will appreciate that various modi fications, changes, additions and omissions in the sys 4- = r (34) tems illustrated and described can be made without at "0 h. s h 5 departing from the spirit of the invention. Aoko A ki I claim: 1. An osmotic system for the controlled dispensing of wherein h, k, and A, with subscripts (0) and subscripts a beneficial agent to an environment of use, said system (1) and (0) have the meanings set forth above. From comprising: Relation 34 it is obvious a controlled and constant rate O (a) a wall formed of a material that is permeable to the of release is obtained from the system when Relations passage of an external fluid in the environment of 35 and 36 hold as follows: use and substantially impermeable to the passage of agent, the wall surrounding and forming; ho h (35) (b) a compartment containing a beneficial agent; 4, << 4 15 (c) means in the compartment comprising a film per Aoko A ki (36) meable to the passage of fluid, substantially imper a >> -t; meable to the passage of agents and surrounding an osmotically effective agent that exhibits an osmotic with controlled delivery obtained for the system as A. pressure gradient across the film against fluid in the K, and h are constant throughout the lifetime of the 20 compartment, said means changeable from a rested system. Hence, following Relations 34, 35 and 36, and to a dispensing state on imbibition of fluid for in by manufacturing systems according to the procedure creasing the amount of beneficial agent dispensed set forth in Examples 4 and 5, drugs having limited from the compartment; solubility that can be delivered by the systems are a (d) a passageway in the wall communicating with the member selected from the group consisting of di 25 compartment and the exterior of the system for phenidol, meclizine hydrochloride, prochlorperazine dispensing beneficial agent from the compartment; maleate, thiethylperazine maleate, anisindione, ethinyl and estradiol, progesterone, diphenadione, erythrityl tetra (e) wherein in operation, when the system is in the nitrate, digoxin, isoflurophate, reserpine, acetazolam environment of use, fluid from the environment is ide, methazolamide, bendroflumethrazide, allopurinol 30 imbibed through the wall into the compartment in and aspirin. The drugs delivered by the osmotic system a tendency towards osmotic equilibrium at a rate manufactured according to the example are in one em determined by the permeability of the wall and the bodiment present in the compartment in a formulation osmotic pressure gradient across the wall thereby consisting of 20% drug, 79% sorbitol and 1% magne 35 forming a liquid formulation containing beneficial sium stearate. agent, and causing the means to imbibe fluid from EXAMPLE 10 within the compartment and change to a dispensing state, whereby beneficial agent is dispensed from An osmotic delivery system manufactured in the form of an osmotic device is made as follows: first, a the system at a volume flow rate dv/dt, wherein dy delivery component 17 shaped like a tablet and weigh 40 is the volume of formulation transported through ing 205 mg comprising a combination of 98% sorbitol, the passageway per unit time dt, over a prolonged 2% magnesium and a trace of yellow dye is pressed in a period of time. conventional Manesty press and then coated with a film 2. The osmotic system for the controlled dispensing forming composition consisting of 70% cellulose ace of a beneficial agent according to claim 1 wherein the tate having an acetyl content of 32% and 30% polyeth 45 environment of use is the gastrointestinal tract and the ylene glycol having a molecular weight of 400. Compo system is sized, shaped and adapted as a dosage form for nent 17 had a diameter of 5/16 inch, an area of 1.52 cm, dispensing the beneficial agent to the gastrointestinal the semipermeable film had a thickness of 4.0 mils and a tract, and the wall of the system is formed of a material volume of 0.137 cm. Next, 225 mg of a composition selected from the group consisting of osmosis and re comprising 210 mg of procainamide hydrochloride, 11 SO verse osmosis semipermeable materials. mg of poly(vinyl pyrrolidone) and 4 mg of magnesium 3. The osmotic system for the controlled dispensing stearate are tableted around component 17 until the of a beneficial agent according to claim 1 wherein the tableted mass had a diameter of 7/16 inch, a thickness of beneficial agent is a drug and the compartment contains 4.82 mm, a final volume of 0.355 cm with the procaina an osmotically effective compound that exhibits an mide hydrochloride having a volume of 0.218 cm. 55 osmotic pressure gradient across the wall against the Next, the procainamide hydrochloride delivery compo external fluid. nent 17 is coated with a 2.0 mill thick wall of a wall 4. The osmotic system for the controlled dispensing forming composition consisting of 90% cellulose ace of a beneficial agent according to claim 1 wherein the tate having an acetyl content of 38.3% and 10% poly beneficial agent is soluble to very soluble in fluid that is ethylene glycol having a molecular weight of 400. Fi imbibed into the compartment, and the wall of the sys nally, a passageway having a diameter of 10 mils is tem is formed of a member selected from the semiper drilled through the wall to yield the osmotic delivery meable group consisting of cellulose acetate, cellulose system. - diacetate, cellulose triacetate, polyamide, polyurethane, The novel osmotic systems of this invention use a sulfonated polystyrene, cellulose acetate valerate and means for the obtainment of precise release rates in the 65 cellulose acetate succinate. environment of use while simultaneously. maintaining 5. The osmotic system for the controlled dispensing the integrity and character of the system. While there of a beneficial agent according to claim 1 wherein the has been described and pointed out features of the in beneficial agent has limited solubility in the fluid that is 4,111,203 21 22 imbibed into the compartment, and it is a member se chlorperazine maleate, thiethylperazine maleate, pro lected from the group consisting of corticosteroids, gesterone, anisindine, diphenadione, and allopurinol. androgens, estrogens, and progestational steroids. 13. An osmotic system for the controlled and continu 6. The osmotic system for the controlled dispensing ous delivery of a beneficial agent to an environment of of a beneficial agent according to claim 1 wherein the use(a) said a shaped system wall crprising: formed of a semipermeable material wall has a fluid permeability of 10 to 10 that is permeable to the passage of an external fluid cc/mil/cm/hr/atm in the environment of use, and the in the environment of use and substantially imper means comprises a film formed of an expandable semi meable to the passage of agent and osmagent, the permeable film that contains from 0.01 to 40% of a film 10 wall surrounding and forming; expansion agent that imparts flexibility and expandabil (b) a compartment containing a beneficial agent se ity to the film and surrounds the osmotically effective lected from the group consisting of a soluble bene solute. ficial agent that exhibits an osmotic pressure gradi 7. The osmotic system for the controlled dispensing ent across the wall against the fluid, and a benefi of a beneficial agent according to claim 1 wherein the 15 cial agent that has limited solubility in the fluid and compartment contains at least one osmotically effective is mixed with an osmagent which osmagent is solu compound that is a member selected from the group ble in the fluid and exhibits an osmotic pressure consisting of salts, carbohydrates and mixtures thereof gradient across the wall against the fluid; along with the beneficial agent. (c) a delivery means for improving the delivery kinet 20 ics of the system in the compartment comprising an 8. The osmotic system for the controlled dispensing expandable material movable from a rested to a of a beneficial agent according to claim 1 wherein the delivery position on imbibition of fluid present in means moves from a collapsed rested state to an ex the compartment by said means; panded dispensing state in the compartment when the (d) a passageway in the wall communicating with the system is in the environment of use, and the film form 25 compartment and the exterior of the system for ing the means contains a member selected from the delivering beneficial agent from the compartment group consisting of polyalkylene glycol, preferably to the exterior of the system; and, polyethylene glycol having a molecular weight of 300 (e) wherein in operation, when the system is in the to 6,000 of the formula H-(OCHCH)-OH wherein environment of use, fluid from the environment is n is 5 to 204; poly (a,c)-alkylenediols; polyester alkyl 30 imbibed through the wall into the compartment in ene glycol; and mixtures thereof. a tendency towards osmotic equilibrium at a rate 9. The osmotic system for the controlled dispensing determined by the permeability of the wall and the of a beneficial agent according to claim 1 wherein the osmotic pressure gradient across the wall, thereby osmotically effective compound in the means is a mem forming a member selected from the group consist ber selected from the group consisting of magnesium 35 ing of a solution of soluble beneficial agent and a sulfate, magnesium chloride, sodium chloride, lithium solution of osmagent containing beneficial agent, chloride, potassium chloride, ammonium chloride, po and for activating the means causing it to move tassium sulfate, sodium carbonate, sodium sulfite, urea, from a rested position to an expanded delivery mannitol, sorbitol and calcium lactate, and the film of position whereby beneficial agent is delivered the means contains an expansion agent selected from the through the passageway at a rate expressed by group consisting of phthalates, phosphates, citrates, relation: adipates, tartrates, sebacates, succinates, glycolates, dm A1 aro C. glycerolates, benzoates and myristates. - a - - - - - 10. The osmotic system for the controlled dispensing 45 of a beneficial agent according to claim 1 wherein the means imbibes fluid from within the compartment, is accompanied by an expansion in volume to continu ously fill the compartment, and the system houses a wherein dim/dt is the mass of agent delivered per plurality of means. 50 unit time, k is the fluid permeability of the wall, A 11. The osmotic system for the controlled dispensing is the area of the wall, his the thickness of the wall, of a beneficial agent according to claim 1 wherein the C is the concentration of the beneficial agent at system is sized, shaped, and adapted for dispensing ben saturation, 7T is the osmotic pressure of the osmoti eficial agent to an anal system. cally active agent in the compartment at saturation, 12. The osmotic system for the controlled dispensing 55 kois the fluid permeability of the film, Aois the area of a beneficial agent according to claim 1 wherein the of the film, hois the thickness of the film and Tois beneficial agent is a member selected from the group the osmotic pressure in the means. consisting of diphenidol, meclizine hydrochloride, pro k . . . .