AU602221B2 - Multi-unit delivery system - Google Patents

Description

COMJMONWEALTH OF AUSTRALI 0 222 PATENTS ACT 1952 CO0M PLET E __SP ECIFCAIN FORPFFICE--USiE Class Int.Class Applica~tion Number,- Lodged.: Complete Specification Loc~ged: Accepted: Published., Priority: Related Art: Name of Applicant: Address of Applicant: Actual Inveyntws: ALZA CORPORATION 950 Mill Road, Palo Alto, California, United States of America Patrick S.L. Wong, Felix Theeliwes and James B. Eckenhoff Address for Service: SHELSTON WATERS, 55 Clarence Street, Sydney Complete Specification for the Invention entitled:* "MULTI-UNIT DELIVERY SYSTEM" The following statement is a full descriptioni of this invention, including the best method of performing it known to me:- I A 1ydrogens such as methyltesterone, esterogenic steroids such as 2 17 -3 estradi ol ethinvi estradiol. ethinvl estradiol 3-inethyll *kI" "~Jgd~ 1 ABSTRACT OF THE DISCLOSURE 2 3 4 6.

7 8 9 0000 o O S0 12 0 0 0 13 13 0 0 16 S C 17 18 19 21 22 23 24 26 27 28 A dispen-er for use in a fluid environment which is capable of delivery of plurality of discrete drug containing units in any desired delivery pattern or profile.

1 MULTI-UNIT DELIVERY SYSTEM 2 3 Field of the Invention This invention relates to patterned drug delivery. More particularly, this invention relates to patterned drug delivery 6 by means of a plurality of individual drug delivery units or 7 tablets. Still more particularly, but without limitation thereto, 8 this invention relates to delivery of multi-agents orally or in .other media in a pre-programmed delivery profile.

0 o0 C G c 11 S 0 C ac: 12 a C a C 13 S 14 e C 0C CC Definition of Terms i; o, 16 C 17 The expressions "active agent" and "drug" are used i t 18 I interchangeably and as used herein broadly include any compound, Scomposition of matter or mixture thereof, that can be delivered from the system to produce a beneficial and useful result. This 21 includes pesticides, herbicides, germicides, biocides, algicides, 22 rodenticides, fungicides, insecticides, anti-oxidants, plant 23 growth promoters, plant growth inhibitors, preservatives, Santipreservatives, disinfectants, sterilization agents, catalysts, chemical reactants, fermentation agents, foods, food .26 supplements, nutrients, cosmetics, drugs, vitamins, sex 27 sterilants, fertility inhibitors, fertility promoters, air 28 1 purifiers, micro-organism attenuators and other agents that 2 benefit the environment of use.

3 The terms "active agent" and "drug" as used herein further 4 includes any physiologically or pharmnacol ogically active substance that produces a localized or systemic effect or effects 6 in animals, including warm blooded mammals, humans and primates, 7 avians, domestic household, sport or farm animals such as sheep, 8 goats, cattle, horses and pi or is administered to laboratory 9 animals such as mice, rat. adnd guinea pigs, to fish, reptiles, c a 10 zoo and wild animals. The active drug which can be delivered S 11 includes inorganic and organic compounds including without 12 limitation, those materials that act upon the central nervous 13 system such as hypnotics and sedatives, psychic energizers, 14 tranquilizers, anticonvulsants, muscle relaxants, antiparkinson 1 agents, analgesics, anti-inflammatory, local anesthetics, muscle c 16 contractants, anti-microbials, anti -malarials, hormonal agents 17 including contraceptives, sympathomimetrics, diuretics, anti- 18 parasites, neoplastics, hypoglycemics, nutritional, fats, 19 ophthalmic, electrolytes and diagnostic agents.

The term "drug unit" as used herein includes units that are 21 capable of maintaining their physical and chemical integrity 22 while housed within the dispenser. This includes, without S23 limitation, tablets with or without a density element; matrix 24 tablets; capsules; elementary osmotic pumps, such as that described in U.S.Pat.No. 3,845,770; mini osmotic pumps such as 26 those described in U.S.Pat.Nos. 3,995,631, 4,034,756 and 27 4,111,202; and multichamber osmotic systems referred to as push- 28 pull and push-melt osmotic pumps such as those described in I

I

U.S.Pat.Nos. 4,320,759 and 4,449,983, all of which are incorporated herein by reference.

As used herein the expression "external fluid" includes water and other biological fluids.

Background of the Invention 7 8 9 11 12 13 14 i 16 17 18 19 21 22 23 24 ,26 27 28 The concept-of patterned drug delivery covers a broad ,ange of systems from time release capsules whose cc,.iponents have coatings which erode at different rates, to controlled release rate tablets which operate by osmosis.

Despite the development of the art however, there remains a continuing need for improved methods and systems for providing -ntrolled drug release profiles.

Summary of the Invention An object of this invention is to provide sequential timing and dispensing of delivery units containing the same or different active agents.

Another object of this invention is to provide both a novel and useful agent formulation delivery system that is selfcontained, self-powered, and also represents an improvement in the delivery art.

These and other objects are demonstrated by the present invention wherein a drug dispenser for use in a fluid containing environment comprises a rigid housing, a plurality of movable drug units filling a portion of the housing, a fluid activated driving member for dispensing the drug units filling the 1 remainder of the housing and a drug unit outlet means.

2 Brief Description of the Drawings 3 4 The invention will be described in further detail with reference to the accompanying drawings wherein: 6 Figure 1 is a partial cross-sectional view of the dispenser 7 of this invention, illustrating one embodiment of the dispensing 8 configuration; 9 Figure 2 is a partial cross-sectional view of the dispenser of this invention, illustrating a second embodiment of the 11 dispensii,g configuration; 12 rigure 3 is a partial cross-sectional view of the dispenser 13 of this invention, illustrating still another embodiment of the 14 dispensing configuration; Figure 4 is a partial cross-sectional view of one embodiment 16 of the driving member for the dispenser of this invention, S, 17 utilizing a hydrophilic expandable member; i18 Figure 5 is a partial cross-sectional view of a second i 19 embodiment of the driving member for the dispenser of this i 20 imvention, utilizing an osmotically effective solute; i 21 Figure 6 is a partial cross-sectional view of another 22 embodiment of the driving member for the dispenser of this 23 invention, utilizing an elementary osmotic pump; 24 Figure 7 is a partial cross-sectional view of another embodiment of the driving member for the dispenser of this 26 invention, utilizing a gas generating composition; and 27 Figure 8 is a partial cross-sectional view of the dispenser 28 of this invention, illustrating another embodiment of the II I dispensing configuration.

2 3 Description of the Preferred Embodiment This invention can provide a variety of drug delivery profiles including, but not limited to, pulsed delivery of a 6 single drug or drug formulation, pulsed delivery of a sequence if different drugs or drug formulations, pulsed delivery of one drug 8 or drug formulation superimposed on continuous delivery of a 9 different drug or drug formulation, and simultaneous continuous fw. 10 0 delivery of several drugs or drug formulations.

1.r The drug dispenser of this invention is designed to deliver 12 a plurality of discrete longitudinally aligned individual drug 13 units by the linear expansion of a fluid activated driving 14 1 member. The drug units are such that they retain their physical and chemical integrity while contained within the system and do s 6 16 16 not substantially commence delivery of active agent until after a 17 1 they have been dispensed into the environment. It is comprised of 18 18 a dispensing component and a driving component, representative 19 embodiments of which are disclosed herein. Figures 1, 2, 3 and 8 illustrate various embodiments of the dispensing component 21 suitable for use in the dispenser of this iv-;ntion. These 22 configurations can be combined with variouis c,;odiments of the 23 driving component, representative embodiments of which are 24 illustrated in Figures 4-7.

The dispensing and driving component designs are for use in a 26 fluid-containing environment and are merely exemplary of the 27 numerous embodiments suitable for use in this invention. The 28 IC I 1 ;i IL V LI1E-~ihlii I 1 portion of the housing adjacent to the dispenser component is 2 of a material which may be either semipermeable or impermeable to 3 the passage of external fluid. Typical suitable impermeable 4 materials include without limitation, polyethylene, polyethylene terephthalate (Mylar), plasticized polyvinyl chloride, metal-foil 6 polyethylene laminates, neoprene rubber, natural gum rubber and 7 Pliofilm (rubber hydrochloride). These materials are 8 additionally flexible, insoluble and chemically compatible with 9 the active agent contained in the units positioned therein, and, 10 in the instance of providing a drug or like depot within the body 11 of a living organism, are biologically inert, non-irritating to 12 body tissues and non-allergenic. Additional suitable materials 13 include polystyrene, polypropylene, polyvinyl chloride, 14 reinforced epoxy resin, polymethylmethacrylate, etc., sheet metal aluminum, copper, steel, etc.), galvanized pipe, or 16 styren.e/acrylonitri e copolymer. Again, for drug depot 17 applications the same are advantageously biologically inert, non- 18 irritating to body tissue and non-allergenic. Suitable 19 semipermeable materials include without limitation, all cellulosic polymers such as cellulose acetates, ethylcellulose, 21 methylcellulose, cellulose acetate butyrate, cellulose acetate 22 propionate, etc., or impermeabte material blended with a 23 hydrophilic polymer or a low molecular weight water soluble 24 enhancer to render the material semipermeable.

Many other materials including those which are biologically .26 acceptable are suitable for fabrication of the impermeable 27 component of the device of this invention. While the impermeable 28 portion of the housing has previously been described as being 1 insoluble under the conditions and in the environment of intended use, it is also within the scope of the invention that such materials be insoluble only during the period of said intended use; thereafter dissolving or otherwise degrading into the environment of the device. Thus, a dispenser is here contemplated which is unaffected by its environment, solubility-wise, at the 7 situs of use, or which is only slightly soluble during the period of intended use, such that once all the units have been dispensed, it will then dissolve or erode away, leaving no 11 objectionable residue or empty container at the said situs of 12 use.

i 12 S13 The portion of the housing adjacent to the driving component 13 14..must be semipermeable so as to allow for passage of external B 14 fluid, since the driving member is fluid activated. Suitable 4, materials will be discussed at length with regards to specific i 16 17t embodiments of the driving member.

Q 17 The dispensing cor )onent shown in Figure 1 is comprised of a eti rigid housing member 20. Housing 20 is also designed with an outlet mean, exit port 22. A plurality of movable discrete units 24, 26, 28, 30 and 32 are aligned within the housing 20. This 21 configuration is merely illustrative and the dispenser may have 22 numerous drug units in excess of the number shown in Fig. 1.

23 The drug units are in the form of a solid core, matrix 24 tablet or in any of a variety of forms which are capable of maintaining their physical and dhemical integrity, i.e do not ,26 erode. The driving member 34 operates to displace the units 27 towards the exit port 22. As unit 24 comes into contact with the 28 9 1 exit, it is dispensed into the environment and begins to deliver

S

2 drug in a controlled or semi-controlled fashion. Once unit 24 is 3 dispensed, linear displacement pushes unit 30 through the housing 4 20 so that it then comes into contact with exit 22 and is likewise dispensed. This continues until the dispenser is 6 depleted of drug units.

7 The units can provide a variety of drug delivery profiles 8 depending upon their composition. They can all contain the same 9 drug(s) at the same concentration(s) to deliver identical pulses 1, 0 of drug over time as each unit is dispensed or they can contain oo, 11 the same drug(s) at different concentrations to give different 12 pulses of drug. Alternately, the units may contain a different 13 drug or drug formulation.

!4 In the preferred embodiment, units 24, 26 and 28 contain a drug or drug formulation and alternate units 30 and 32 contain no 16 drug, .such that when they are dispensed, an "off" period is 17 provided, during which time no drug is being delivered. The 18 additional advantage of this "alternating" configuration is that 19 once unit 24 is dispensed, the surface of unit 30 is exposed and may begin the erode. Having 30 as a non-drug containing unit 21 guarantees that the drug being delivered to the environment comes 22 from the dispensed unit rather-than from the units still retained S23 within the housing.

24 The dispensing configuration shown in Figure 2 is Ialso designed to deliver a plurality of discrete units to the ,26 environment, and operates similar to the embodiment of Fig. 1.

27 In Fig. 1, the geometry of the units permits close alignment so 28 as not to have any space between adjacent units. This aspect is L 1-I i 1 not critical to the effectiveness of the invention as is shown by 2 Fig. 2 where the units are curved and therefore do not fit S3 closely together within the housing.

4 The dispensing configuration of Fig. 2 is comprised of a rigid housing 38 and a plurality of discrete drug units 40, 42 6 and 44, aligned therein. Three drug units are shown but in actual application, any number of units may be used. The driving member 8 46 displaces the units at the desired rate and dispenses them 9 individually through the exit port 48.

o i The units, 40 for example, can be elementary osmotic pumps o 11 or mini-osmotic pumps, for example. They can also be coated with *o 12 a degradable coating to delay delivery until the units are 13 actually dispensed into the environment, S 14 The dispensing configuration shown in Figure 3 is comprised of a housing member 50 and a plurality of discrete drug units 52, S 16 "c,54, 56 and 58 aligned therein. As with Figs. 1 and 2, the numher 17 of units shown is merely illustrative and is not intended to 18 limit the invention in any manner.

19 The driving member 60 operates to linearly displace the units and dispense them through the exit port 62. The units, 52 21 for example, are comprised of a plastic or polyethylene cap 64 22 I 212 o lsi rpoytyeecp6 with a drug mixture 66 compressed within. The units may be bowl- 23 shaped as shown or they may be box-shaped to hold a larger 24 quantity of drug.The units are separated by partitions 68, 70, 72 and 74, which can be a rigid solid or a gel. As the unit 52 is ,26 dispensed, the drug mixture 66 is exposed to tis, ;nvironment 27 (external fluid) and is thus delivered. Subsequently the 28 iI 1 partition 68 is dispensed through the exit port 62.

V 2 This dispensing configuration provides pulsed drug delivery.

i 3 As unit 52 is dispensed, a burst of drug is delivered which is 4 followed by another pulse when unit 54 is dispensed and so forth.

The units may contain the same drug in the same or different 6 concentrations, or different drugs. In this manner, any pattern I 7 of delivery may be fashioned.

8 Example I 9 The dispenser of Fig. 3 is especially suited for treatment 10 of helminth infections in ruminants, specifically cattle.

11 Depending upon the nature of delivery desired, several drug Ioi 12 formulations can be used in this dispenser.

13 A suitable drug formulation is comprised of about 80 weight 14 percent Hapadex* which is an anthelmintic agent for cattle sold by Schering-Plough Corporation. About 0.5 grams of the S9 16 formulation 66 is compressed into cap 64. Units 54, 56 and 58 are 17 also filled with the drug formulation. However, if an off period I 18 is desired, units 52 and 56 can contain drug and the alternate 19 units 54 and 58 can be empty.

For fast pulse delivery of Hapadex®, the drug formulation is 21 100% drug. However, this system can be designed to provide a 22 short duration pulse where the drug formulation has a gas 23 generator contained therein. Especially suitable is a formulation 24 comprised of about 80% Hapadex® and 20% citric acid/sodium bicarbonate.

.26 If a longer period of delivery is desired, a disintegrating 27 agent such as Ac-Di-Sol (FMC Corporation), otherwise known as 28 croscarmellose sodium, can be incorporated into the drug 44 4 4 4 .4 4 4 4 Q 44 4 4 4, 44 formulation in an amount up to 20 weight percent.

For evzn longer duration of drug delivery, jg formulation can be 80% Hapadexe and 20% polymer, such as Polyoxe or hydroxypropyl methylcellulose.

For rumenal systems, an important criteria is that the system remain in the rumen of an animal over a prolonged period of time. This is accomplished by placement of a density element within the dispenser. The housing 50 itself, may be the density element. Alternately, one of the partitions, 74 for example, can act as the density element. In still another embodiment, unit 58 can be a density element, placed so as to remain within the housing 50 after all of the drug containing units have been dispensed.

The density element suitable for use in the dispenser of this invention must be dense enough to retain the dispenser in the rumen-reticular sac of a ruminant. The presence of a density element allows the dispenser to remain in the rumen over a prolonged period of time rather than letting it pass into the alimentary tract and be eliminated therefrom. As the dispenser remuains in the rumen, a beneficial agent can be delivered to the ruminant at a controlled rate over an extended period of time.

GeneFrlly, b density element will have a density of from about 0.8 to 8, or higher, with the density in a presently preferred embodiment exhibiting a specific gravity of from about 2.2 to 7.6. For the ruminants cattle- and sheep, it is presently preferred that the density element exhibit a density such that there is a resulting dispenser density of about 3. Materials that J_ I Ilq '-psl YX 2 3 4 6 7 8 9 St 11 12 13 4 4 14 9! 4 2 2 2 16 S 17 18 19 2Q 21 22 23 24 ,.26 27 28 have a density that can be used for forming a suitable density element include iron, iron shot, iron shot coated with iron oxide, iron shot magnesium alloy, steel, stainless stee copper oxide, a mixture of cobalt oxide and iron powder, and the like.

Exemplary of drugs that are soluble or very soluble in water and can be delivered by the dispenser systems of this invention include prochlorperazine edisylate, ferrous sulfate, aminocaproic =cid, potassium chloride, mecamylamine hydrochloride, procainamide hydrochloride, amphetamine sulfate, benzphetamine hydrochloride, isoproterenol sulfate, met'amphetami ne hydrochloride, phenmetrazi ne hydrochloride, bethanechol chloride, metacholirce chloride, pilocarpine hydrochl oride, atropine sulfate, methscopolamine bromide, isopropamide iodide, tridihexethyl chloride, phenformin hydrochloride rt thyl pheni date hydrochl ori de, and mixtures thereo.f.

Exemplary of agents that have limited solubility or are very slightly soluble, or insoluble in water vnd biological fluids that can be delivered by the dispenser systems of this invention include diphenidol, meclizine hydro loride, prochlorperazine maleate, thiethylperazine maleate, anisindione, diphenadione, erythrityl tetranitrate, digoxin, isoflurophate, reserpine, azetazolamide, methazolamide, bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetyl sulfis,,azolh, erythroiycin, and mixtures thereof, steroids including corticosteroids such as hydrocortisone, hydrocorticosterone acetate, cortisone acetate and triamcinolone, -1 ydrogens such as methyltesterone, esterogenic steroids such as 2 17 -estradiol, ethinyl estradiol, ethinyl estradiol 3-amethyl 3 ether and estradiol, progestational steroids such as 4 prednisolone, 17 o -hydroxy-progesterone acetate, 19-nor- S progesterone, norethindrone, progesterone, norethynodrel, and the 6 like.

7 The drug can also be {n the various chemical and physical 8 forms such as uncharged molecules, molecular complexes, i 9 9 ,.pharmacologically acceptable acid addition and base addition salts such as hydrochlorides, hydrobromides, sulfate, laurylate, S palmitate, phosphate, nitrate, borate, acetate, maleate, 12 tartrate, oleate and salicylate. For acidic drugs, salts of 13 1 metals, amines or organic cations, for example quaternary S ammonium can be used. Derivatives of drugs such as esters, ethers 1 and amides can 'e used alone or mixed with other drugs. Also, a 16 drug Which is water insoluble can be used in a form that on its 17 release from the dispenser, is converted by enzymes, hydrolyzed 18 by body pH or other metabolic processes to the original form, or 19 to a biologically active form.

The dispensing configuration of Figures 1, 2 and 3, can be 21 combined with any of the driving members illustrated in Figures 22 4, 5, 6, and 7, to provide a tailored drug delivery system.

23 Figure 4 illustrates a driving member system 76 utilizing an 24 expandable driving member 78 comprised of an external fluid insoluble, external fluid swellable composition. Member 78 is ,26 encased in housing 80 which is a semipermeable membrane 27 substantially permeable to the passage of an external fluid and 28 CP P Yll~^lsrBC9sXel DII IVIBFI-~C~-eaL~~ S substantially impermeable to the passage of any ingredients 2 contained in member 78. The driving member 78 is positioned 3 adjacent to one of the drug units at interface 82.

4, External fluid is imbibed through the housing 80 by the B expandable hydrophilic member 78 in a tendency toward osmotic S equilibrium, to continuously ,well and expand rn, e) 78. Member S.78 expands while maintaining an intact immiscible bouindary at 3 interface 82, defined by the surface of drug unit 86 and 9 expandable member 78.

Expandable member 78 has a shape that corresponds to 11 internal shape of housing 80 and is preferably made from a 12 hydrogel composition. The hydrogel composition is noncross-linked 13 or optionally cross-linked and it possesses osmotic properties, 1 such as the ability to imbibe an external fluid through 5 semipermeable housing 80, and exhibit an osmotic pressure 16 gradient across senipermeable housing 80 against a fluid outside 7 the dispenser system. The materials used for forming the 13 swellable, expandable member 78 are polymeric materials neat, and 19 polymeric materials blended with osmotic agents that interact with water or a biological fluid, absorb the fluid and swell or 21 expand to an equilibrium state. The polymer exhibits the ability 22 to retain a significant fraction of imbibed fluid in the polymer 23 molecular structure. The polymers in a preferred embodiment are 24 gel polymers that can swel' or expand to a very high degree, usually exhibiting a 2 to 50 fold volume increase. The swellable, .26 hydrophilic polyr rs, also known as osmopolymers, can be 27 noncross-linked or lightly cross-linked. The cross-links can be 28 covalent, ionic or tydrogen bonds with the polymer possessing the 1 2 3 4 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28 ability to swell in the presence of fluid, and when cross-linked 't will not dissolve in the fluid. The polymer can be of plant, animal, or synthetic origin. Polymeric materials useful for the present purpose include poly(hydroxyalkyl methacrylate) having a molecular weight of from 5,000 to 5,000,000; poly(vinylpyrrolidone) having a molecular weight of from 10,000 to 360,000; anionic and cationic hydrogels; poly(electrolyte) complexes; poly(vinyl alcohol) having a low acetate residual; a swellable mixture of agar and carboxymethyl cellulose; a swellable composition comprising methyl cellulose mixed with a sparingly cross-linked agar; a water swellable copolymer produced by a dispersion of finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, or isobutylene; a water swellawle polymer of N-vinyl lactams; swellable scdium salts of carboxyl methyl cellulose; and the like.

Other gelable, fluid imbibing and retaining polymers useful for forming tne hydrophilic, expandable driving member 78 include pectin having a molecular weight ranging from 30,000 to 300,000; polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar; Carbopol® acidic carboxy polymer and its salt derivatives; polyacrylamides; water swellable indene maleic anhydride polymers; Good-rites polyacrylic acid having a molecular weight of 80,000 t- 200,000; Polyox® polyethylene oxide polymers having a molecular weight of 100,000 to 5,000,000; starch graft copolymers; Aqua-Keep® acrylate polymers with water absorbability of about 400 times its original weight; diesters of polyglucan; a mixture of cross-linked polyvinyl alcohol and i 1 i ~r 2 3 4 6 7 8 9 11 12 13 14 16 17 18 19 21 22 23 24 26 27 28 poly(N-vinyl-2-pyrrolidone); poly(ethylene glycol) having a molecular weight of 4,000 to 100,000; ard the like. In a preferred embodiment, the expandable member 78 is formed from polymers and polymeric compositions that are thermoformable.

Representative polymers possessing hydrophilic properties are known in U.S.Pat.Nos. 3,865,108, 4,002,173, 4,207,893, 4,220,152, 4,327,725, 4,350,271, all of which are incorporated herein by reference and in Scott et al, "Handbook of Common Polymers", CRC Press, Cleveland, Ohio (1971).

The osmotically effective compound that can be blended homogeneously or heterogeneously with the swellable polymer, to form a driving member, arc the osmotically effective solutes that are soluble in fluid imbibed into the swellable polymer, and exhibit an osmotic pressure gradient across the semipermeable housing 80 against an external fluid. Osmotically effective compounds are known also as osmagents. Osmotically effective osmagents useful for the present purpose include magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, inositol, sucrose, glucose and the like. The osmotic pressure in atmospheres, atm, of the osmagents suitable for the invention will be greater than zero atm, generally from 8 atm up to 500 atm, or higher.

Representative materials for forming the semipermeable housing include without limitation, semipermeable homopolymers, semipermeable copolymers, and the like. In one embodiment typical materials include cellulose esters, cellulose monoesters, cellulose diesters, cellulose triesters, cellulose ethers, and C *I1~L*nr~-rrr~ll---auuaaEl~ -aarriluo~~,~, 1 cellulose ester-ethers, mixtures thereof, and the like. These 2 cellulose polymers have a degree of substitution, on their 3 anhydroglucose unit form greater than 0 up to 3 inclusive. By 4 "degree of substitution" is meant the average number of hydroxyl groups originally present on the anhydroglucose unit that are replaced by a substituting group, or converted into another 7 1 group. The anhydroglucose unit can be partially or completely 8 substituted with groups such as acyl, alkanoyl, aroyl, alkyl, 9 -alkenyl, alkoxy, halogen, carboalky!, alkylcarbamate, alkylcarbonate, alkylsulfonate, alkylsulfamate, and like 11 semipermeable polymer forming groups.

12 The semipermeable materials typically include a member 13 selected from the group consisting of cellulose acylate, 14 cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tri- 16 cellulose alkanylates, mono-, di- and tri-alkenylates, mono-, di- 17 and tri-aroylates, and the like. Exemplary polymers including 18 cellulose acetate having a D.S. of 1.8 to 2.3 and an acetyl 19 content oi' 32 to 39.9%; cellulose diacetate having a D.S. of 1 to 2 and an acetyl content of 21 to 35%; cellulose triacetate having 21 a D.S. of 2 to 3 and an acetyl content of 34 to 44.8% and the 22 S like. More specific cel7ulosic polymers include cellulose 23 propionate having a D.S. of 1.8 and a propionyl content of 38.5%; 24 cellulose acetate propionate having an acetyl content of 1.5 to 7% and a propionyl content of 39 to 42%; cellulose acetate .26 propionate having an acetyl content of 2.5 to an average 27 propionyl content of 39.2 to 45% and a hydroxyl content of 2.8 to 28 1 cellulose acetate butyrate having a D.S. of 1.8, and acetyl 2 content of 13 to 15%, and a butyryl content of 34 to 39%; 3 cellulose acetate butyrate having an acetyl content of 2 to 4, 29.5%, a butyryl content of 17 to 53%, and a hydroxyl content of 0.5 to cellulose triacylates having a D.S. of 2.9 to 3 such 6 as cellulose trivalerate, cellulose trilaurate, cellulose 7 tripalmitate, cellulose trioctanoate, and cellulose 8 tripropionate; cellulose diesters having a D.S. of 2.2 to 2.6 9 such as cellulose disuccinate cellulose dipalmitate, cellulose 4a,.

S 10 dioctanoate, cellulose dicarpylate; cellulose propionate 11 morpholinobutyrate; cellulose acetate butyrate; cellulose acetate 12 phthalate; and the like; mixed cellulose esters such as cellulose 13 acetate valerate, cellulose acetate succinate, cellulose S 14 propionate succinate, cellulose acetate octanoate, cellulose 4 15 valerate palmitate, cellulose acetate heptonate, and the like.

16 Semipermeable polymers are known in U.S.Pat.No. 4,077,407, and 17 they can be made by procedures described in "Encyclopedia of 18 Polymer Science and Technology", Vol. 3, pages 325-354, 19 Interscience Publishers, Inc., New York, (1964).

Additional semipermeable polymers include cellulose 21 acetaldehyde; dimethyl cellulose acetate; cellulose acetate 22 ethylcarbamate; cellulose acetate methylcarbamate; cellulose 23 dimethylaminoacetate; a cellulose composition comprising 24 cellulose acetate and hydroxypropyl methylcellulose; a composition comprising cellulose acetate and cellulose acetate .26 butyrate; a cellulose composition comprising cellulose acetate 27 butyrate and hydroxypropyl methylcellulose; semipermeable 28 polyamides; semipermeable polyurethanes; semipermeable S polysulfanes; semipermeable sulfonated polystyrenes; crosslinked, S selectively semipermeable polymers formed by the coprecipitation of a polyanion and a polycation as disclosed in U.S.Pat.Nos, 4 3,173,876, 3,276,586, 3,541,005, 3,541,006 and 3,546,142, all of which. -are incorporated herein by reference; selectively 6 semipermeable silicon rubbers; semipermeable polymers as disclosed by Loeb and Sourirajan in U.S.Pat.No. 3,133,132, 8 incorporated herein by reference; semipermeable polystyrene 'derivatives; semipermeable (polysodiumstyrenesulfonate); semipermeable poly(vinylbenzyltrimethyl) ammonium chloride; 11 semipermeable polymers exhibiting a fluid permeability of 10" to 12 -7 2 7 (cc.mil/cm2hr-atm) expressed as per atmosphere of 13 hydrostatic or osmotic pressure difference across a semipermeable 14 wall. The polymers are known to the art in U.S.Pat.Nos.

3,845,770, 3,916,899 and 4,,160,020, all of which are incorporated 16 herein by reference; and in J.R. Scott and W.J. Roff, "Handbook 17 of Common Polymers", CRC Press, Cleveland, Ohio (1971).

18 Other materials that can be used to form the semipermeable 19 S housing for imparting flexibility and elongation properties to the wall, for making the housing less to non-brittle and to 21 2 render tear strength include phthalate plasticizers such as 22 dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, 23 straight chain phthalates of six to eleven carbons, diisononyl 24 phthalate, diisodecyl phthalate, and the like. The plasticizers include nonphthalates such as citric acid esters, triacetin, .26 dioctyl azelte, epoxidized tallate, triisoctyl trimellitate, 27 triisononyl trimellitate, sucrose acetate isobutyrate, epoxidized 28 -n a I CE 4 I: I S.E I I C Ella 1 soybean oil, and the like. The amount of plasticizer in the 2 housing when incorporated therein, is about 0.01 to 20% by 3 weight, or higher.

4 Figure 5 illustrates a driving member 88 utilizing an osmotically effective solute. The osmotically effective solute is 6 in solution 90 which is retained within a rigid housing 92 7 comprised of a semipermeable membrane substantially permeable to 8 the passage of an external fluid and substantially impermeable to 9 the passage of the osmotically effective solute contained in solution 90. The solution 90 is separated from the drug units 94 11 for example, by means of a flexible membrane 96.

12 The ability of driving member 88 to displace the drug units, 13 94 for example, housed within a dispenser depends upon the 14 osmotic pressure geiarated by the solution 90 of the osmotically 15 effective solute confined within housing 92. This solution 16 exhibits an osmotic pressure gradient against fluid in the 17 environment into which the dispenser is placed, and is preferably 18 a saturated aqueous salt solution. To maintain the solution 19 saturated and therefore to achieve a constant osmotic pressure throughout operation of the dispenser, the housing containing the 21 solution also contains excess solute in solid form. Various 22 osmotically effective solutes can be used. These include 23 magnesium sulfate, magnesium chloride, sodium chloride, potassium 24 sulfate, sodium carbonate, sodim sulfite, sodium sulfate, sodium bicarbonate, potassium acid phthalate, calcium bicarbonate, .26 potassium acid phosphate, raffinose, tartaric acid, succinic 27 acid, calcium succirate, calcium lactate and magnesium succinate.

28 The excess solid solute can be in the form of dispersed particles 1or preferably in the form of i pellet. The solution can initially be a solution of the same or of an osmotically effective solute 3 dif(ferent than the solid excess solute.

Figure 6 illustrates a driving member 98 which is similar in operation to that of Fig. 5. An elementary osmotic pump 100, such as that disclosed in U.S.Pat.No. 3,845,770 is held rigidly in 7 place in the impermeable housing 102, being exposed to the S3 environment at surface 104. External fluid is imbibed through the 9 I semipermeable wall 106 by the osmotically effective solute 108 contained within the pump 100. As the osmotic pressure within the 11 pump 100 increases, solution (external fluid and osmotic solute) 12 is forced through the orifice 110 intO chamber 112, thereby 13 exerting pressure on piston 114 wihich subsequently moves through the housing 102 to dispense the drug units 116 contained therein.

In order for this; driving member to be operable, the wall of the V 16 housing 102 imvimediatelY surrounding the pump 100, must be 17 impermeable to the passage of fluid so that external fluid does 18 not enter chamber 112. Therefore, use of driving member 98 19 mandates that the housing be at least in part of an impermeable composition. In this manner, the housing in contact with the drug 21 units can be semipermeable or impermeable.

22 Figure 7 illustrates a driving member 118 which operates by 23 means of a gas generating composition 120. Housing 122 is made of 24 a isemipermeable material which is substantially impermeable to the passage of gas generating -composition 120, has a low permeability to the passage of an internally generated gas and is 27 substantially permeable to the passage of an external fluid.

28

I

I Membrane 124 is made n emipermeable material which is 2 substantially impermeable he passage of gas generating 3 composition 120 and substantially permeable to the passage of a 4 generated gas. Its main function is to keep the gas generating composition 120 apart from the drug units contained in the 6 dispenser.

7 In operation, external fluid is imbibed through housing 122 8 to continuously wet and dissolve the gas generating composition 9 1,0, causing it to react and produce a large volume of gas. This gas expands and passes through membrane 124, filling the area 11 126. This action correspondingly causes pressure to be exerted on 12 the drug unit 128 which thereby pushes this and the other units 13 contained therein, through the housing 122.

14 Gas generating composition 120 consists essentially of a dry compound or an anhydrous mixture of compounds that when 16 intimately contacted by an external fluid that enters the housing 17 122, generates a gas that exerts a pressure to drive the 18 dispensing system. The composition 120 comprises a preferably 19 solid acidic material, and a preferably solid basic material that dissolve and react in the presence of fluid that enters the 21 housing 122. This composition may be in powder, crystalline, 22 granular or layered form. -Alternately, the gas generating 23 composition may be present homogeneously or heterogeneously 24 dispersed in a matrix. The matrix is a polymer permeable to the passage of external fluid and permeable to the passage of the 26 generated gas. The rate o' gas generated in this embodiment is 27 governed by the rate of fluid passage through the polymer coupled 18 with the rate of fluid passage through the housing 122. Suitable

I

materials are disclosed in Theeuwes, U.S.Pat.No. 4,203,441, 2 incorporated herein by reference.

3 3 Another embodiment of the dispensing configuration of this 4 4 invention is illustrated in Figure 8. This embodiment is 5 especially suited for delivery of units which all contain drug, 6 6 where it is desired to prevent delivery from units which are still contained within the housing. The dispenser of Fig. 8 is 8 comprised of a rigid housing member 130 which is designed with an 9 outlet means, exit port 132. A plurality of movable discrete units 134, 136, 138, 140 and 142 are aligned within the housing 11 130, and are displaced towards the exit port 132 by means of 12 12 driving member 144. The drug units are similar in form to those 13 described in reference to Fig. 1 but are all drug containing 14 14 units rater then drug- alternating with non-drug containing units.

16 Ih Fig. 8, while the units are contained within the housing 17 they are protected from exposure to the environmental fluid by 18 18 means of a plurality of plastic or polyethylene partitions 146, 19 148, 150, 152 and 154. When the dispenser is placed in the fluid 20 environment of use, the driving member 144 becomes fluid 21 Sactivated and linearly displaces the units, first dispelling the 22 partition 146 and then unit 134. As unit 134 is delivering drug, 23 unit 136 is gradually being displaced towards the exit 132 and in 24 the meantime is protected from the environment by partition 148.

The amount of drug incorporated in the units of the 126 dispenser of this invention varies widely depending on the 27 particular drug, the desired therapeutic effect, and the time 28 1 span for which it takes the drug to be released. Since a variety 2 of units in a variety of sizes, shapes and compositions are 3 intended to provide complete dosage regimes for therapy for a 4 variety of maladies, there is no critical upper limit on the amount of drug incorporated in the units of the dispenser. The 6 lower limit too will depend on the activity of the drug and the 7 time span of its release from the units. Thus, it is not 8 practical 6o define a range for the therapeutically effective 9 amo ut of drug to be released by the individual units, or the dispenser as a whole.

ii This invention has been described in detail with particular 12 reference to certain preferred embodiments thereof, but it will 13 be understood that variations and modifications can be effected 14 within the spirit and scope of the invention.

16 17 18 19 21 22 23 24 126 27 28

Claims (7)

1. A drug dispenser for use in a fluid-containing environment comprising in combination: 6 a rigid housing; 7 a fluid activated driving member filling a portion of the 8 space within said housing and being in contact with the housing; 4 9 a plurality of discrete drug units longitudinally aligned S and contained within said housing, said units -aintaining thc'r 11 physical and chemical integr 4 ty while contained within said 12 housing; and 13 a drug unit out.it means in said housing that communicates 14 with the units. 16

2. The dispenser of claim 1 wherein said purality of drug units S 17 contain the same drug. 18 19 3, The dispenser of cla' m 2 wherein said drug units are separated by non-drug containing units. 21 22 4, The dispenser of claim 1 wherein said plurality of drug units 23 contain different drugs. 24 The dispenser of claim 4 wherein said drug units are separated by non-drug containing units. 27 28

6. The dispenser of claim 1 wherein the portion of said housing A 1 2 in contact with said driving member is permeable to the passage 3 of fluid. 4

7. The dispenser of claim 6 wherein seid driving member comprises 6 a fluid swellable composition. 7 8 8. The dispenser of claim 6 wherein said driving member comprises 9 an osmotically effective solute. 11 9. The dispenser of claim 8 wherein said solute and said drug 12 units are separated by a flexible membrane. 13 14 10. The dispe:nser of claim 6 wherein said driving 'ember is a gas generating composition. '16 17 11. The dispenser of claim 10 wherein said gas generating 18 composition and said drug units are separated by a semipermeable 19 membrane. i 21 12. The dispenser of claim 1 wherein the portion of said housing 22 in contact with said driving member is impermeable to the passage 23 of fluid. 24

13. The dispenser of claim 12 wherein said driving member 26 comprises an elementary osmotic pump. 27 28 14. The dispenser of claim 13 wherein said elementary osmotic pump and said drug units are separated by a movable piston. The dispenser of claim 1 which further comprises a coensity element.

16. A dispenser sIubstantia11y as herein described with reference to any one of the accompanying drawings. DATED this 20th Day of Juane, 1988 ALZA CORPORATION MA'Lurney: \ViI IAM S. 1. 1:0110\ 111Slitt nOi PLut('I I\1(0torne\! 01~Aulru1 ut SiIUSI ON \\ATIARS

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