IIlIlIllllllllIllllllllIlIlllllllllllIlllllllllllllllllllllllllllllllllllll US005200194A United States Patent [191 [11] Patent Number: 5,200,194 Edgren et a1. [45] Date of Patent: Apr. 6, 1993

[54] ORAL OSMOTIC DEVICE _ Primary Examiner-Thurman K. Page Assistant Examiner—-Leon R. Home [75] Inventors: David E. Edgren, El Granada; Attorney, Agent, or Firm-Jean M. Duvall; D. Byron Gui-dish K. Bhatti, Fremont, both of Miller; Steven F. Stone Calif. [73] Assignee: ALZA Corporation, Palo Alto, Calif. [57] ABSTRACT [21] Appl. No.: 809,741 An osmotic device (10) for delivering a bene?cial drug, such as an anti-microbial drug, into the mouth of a [22] Filed: Dec. 18, 1991 human patient is disclosed. The device (10) has a size [51] Int. Cl.5 ...... A61K 9/24 and shape adapting it to be comfortably retained in the [52] US. Cl...... 424/473; 424/468; mouth for extended periods of time. The device com 424/472 prises a thin semipermeable membrane wall (12) sur [58] Field of Search ...... 424/473, 472, 468 rounding a compartment (13) housing a bene?cial agent [56] References Cited (14) that has at least some degree of solubility in aque ous biological ?uids, e.g., saliva, and a ?brous support U.S. PATENT DOCUMENTS material (15) composed of hydrophilic water-insoluble 2,799,241 7/1957 Wurster ...... 118/24 ?bers. A passageway (17) in the wall (12) connects the 3,133,132 5/1964 Loeb et a1...... 264/49 agent 14) with the exterior of the device (10). The wall 3,173,876 3/1965 Zobrist ...... 252/137 (12) is permeable to the passage of aqueous biological 3,276,586 10/1966 Rosaen ...... 210/90 ?uid but substantially impermeable to the passage of the 3,541,005 11/1970 Strathmann et a1...... 210/ 19 ?brous support material (15). The ?brous support mate 3,541,006 11/1970 Bixler et al ...... 210/23 3,546,142 12/1970 Michaels et a1. . 260/21 rial (15), once hydrated, provides a rigid support for the 3,845,770 11/1974 Theeuwes et a1. . . 128/260 thin semipermeable wall (12) and prevents the device 3,916,899 11/1975 Thecuwes et a1. 128/260 (10) from prematurely releasing the bene?cial agent (14) 4,111,202 9/1978 Theeuwes ...... 128/260 even when the device (10) is subjected to patient suck 4,160,020 7/1979 Ayer et a1. 424/15 mg. 4,327,725 5/1982 Cortese et al. 123/260 4,568,535 2/1986 Locsche 428/435 5,021,053 6/1991 Barclay et a1...... 604/8901 19 Claims, 1 Drawing Sheet US. Patent Apr. 6, 1993 5,200,194

9.0 FIG. 4 0“trims: ._

0. I I I 0.0111L111 1.0 2.0 3.0 TIME (HR)

16.0 '1 FIG 5

mmchlormadinone acetate, phe'naglycodol, allo cording to the mode of the invention where the bene? purinol, aluminum aspirin, methotrexate, acetyl sul? cial agent has poor aqueous solubility, are osmotically soxazole, erythromycin, progestins, esterogenic proges 55 e?‘ective compounds soluble in the ?uid that enters the tational hormones, corticosteroids, hydrocortisone, device, and exhibits an osmotic pressure gradient across hydrocorticosterone acetate, cortisone acetate, triam the semipermeable wall against the exterior ?uid. Os cinolone, testosterone, testosterone esters, methyltester motically effective osmagents useful for the present one, WAS-estradiol, ethinyl estradiol, ethinyl estradiol purpose include magnesium sulfate, magnesium chlo 3~methyl ether, prednisolone, 17B-hydroxyprogester~ 60 ride, sodium chloride, lithium chloride, potassium sul one acetate, l9-nor-progesterone, norgestrel, norethin fate, sodium carbonate, sodium sul?te, lithium sulfate, done, norethiderone, progesterone, norgesterone, nore potassium chloride, sodium sulfate, d-mannitol, urea, thynodrel, isosorbide dinitrate, and the like. sorbitol, xylitol, inositol, raf?nose, sucrose, glycose, Examples of other drugs that can be delivered by the hydrophilic polymers such as cellulose polymers, mix osmotic device include aspirin, indomethacin, na 65 tures thereof, and the like. The osmagent is usually proxen, fenoprofen, sulidac, diclofenac, indoprofen, present in an excess amount, and it can be in any physi nitroglycerin, propranolol, metoprolol, valproate, ox cal form, such as particle, powder, granule, and the like. prenolol, timolol, atenolol, alprenolol, cimetidine, cloni The osmotic pressure in atmospheres of the osmagents 5,200,194 11 12 suitable for the invention will be greater than zero and agent from the device. The expression includes one or generally up to about 500 atm, or higher. more aperture, ori?ce or bore through wall 12 formed For the purpose of the invention, the phrase agents by mechanical procedures, or by eroding an erodible with degrees of solubility as used herein indicates agents element, such as a gelatin plug, in the oral cavity. In that have at least some degree of solubility in aqueous cases where the semipermeable membrane is suf?ciently biological ?uids present in the oral cavity, such as sa permeable to the passage of bene?cial agent/drug, the liva. Further for this purpose, an agent having a low pores in the membrane may be sufficient to release the degree of solubility is one that dissolves in the range of agent/drug in therapeutically effective amounts. In about 25 mg to 150 mg of agent per ml of ?uid, whereas such cases, the expression “passageway” refers to the an agent having a high degree of solubility dissolves pores within the membrane wall even though no bore or greater than about 150 mg of agent per ml of ?uid. other ori?ce has been drilled therethrough. A detailed Typical methods used for the measurement of solubil description of osmotic passageways and the maximum ity are chemical and electrical conductivity. Details of and minimum dimensions for a passageway are dis various methods for determining solubilities are de closed in U.S. Pat. Nos. 3,845,770 and 3,916,899, the scribed in United States Public Health Service Bulletin, 15 disclosures of which are incorporated herein by refer No. 67 of the Hygienic Laboratory; Encyclopedia of ence. Preferably, l to 2 passageways 17 are provided in Science and Technology, Vol. 12, pages 542 to 556, 1971, device 10 as shown in the Figures. published by McGraw-Hill, Inc,; and Encyclopedia Dic The expressions “extended period of time” and “ex tionary of Physics, Vol. 6, pages 547 to 557, 1962, pub tended delivery period” as used herein generally refers lished in Pergamon Press, Inc. to periods greater than about 0.5 hours, preferably The device of the invention is manufactured by stan about 0.5 to 12 hours, more preferably about 0.5 to 6 dard techniques. For example, in one embodiment, the hours, most preferably about l-4 hours. agent, the ?brous support material, and other optional The following examples are merely illustrative of the ingredients can be simply mixed into a solid or semisolid present invention and should not be considered as limit form by conventional methods such as ballmilling, cal 25 ing the scope of the invention in any way. endering, stirring or rollmilling, and then pressed into a preselected shape using a conventional tableting press. EXAMPLE 1 The wall 12 can be applied by molding, spraying or An osmotic therapeutic device was made for the dipping the pressed shapes into a wall forming material. controlled and continuous release into the oral cavity of Another and presently preferred technique that can be 30 the bene?cial antimicrobial drug cetylpyridinium chlo use for applying the wall is the air suspension proce dure. This procedure consists of suspending and tum ride (CPC) sold by Spectrum Chemical Manufacturing bling the pressed agent and dry hydrophilic polymer in Corp., Gardena, Calif. The following components were a current of air and a wall forming composition until the pre-sieved #40 mesh and dry mixed: 37 g sorbitol, 5 g wall is applied to the agent ?brous support material low-substituted hydroxypropyl cellulose ?bers having a composite. The air suspension procedure is described in nominal length of 50 microns (LHPC ll sold by Shin US. Pat. No. 2,799,241; J. Am. Pharm. Assoc, vol. 48, Etsu Chemical Co., Ltd.of Tokyo, Japan) and 5 g mi pages 451 to 459, 1979; and ibid. Vol. 49, pages 82 to 84, crocrystalline cellulose ?bers having a nominal length 1960. Other standard manufacturing procedures are of 200 microns (Avicel® PH 102 sold by FMC of described in Modern Plastics Encyclopedia, Vol. 46, 40 Philadelphia, Pa.). Then 1.5 g CPC was dissolved in 30 pages 62 to 70, 1969; and in Pharmaceutical Sciences, by ml ethanol SDA, anhydrous. The drug solution was Remington, Fourteenth Edition, pages 1626 to 1678, stirred into the pre-mix to form a uniform, doughy mass. 1970, published by Mack Publishing Company, Easton, The resulting dough was passed through a #20 mesh Pa. sieve, forming damp granules. These granules were air Exemplary solvents suitable for manufacturing the 45 dried overnight, then re-passed through the #20 mesh wall include inorganic and organic solvents that do not sieve. Then 1.5 g TWEEN 80 was blended into the adversely harm the wall forming material, and the ?nal granulation. device. The solvents broadly include members selected 200 mg portions of this granulation were compressed from the group consisting of aqueous solvents, alcohols, in a i inch oval tablet tooling at 2 tons pressure. The ketones, esters, ethers, aliphatic hydrocarbons, haloge 50 resulting compressed cores were then coated with nated solvents, cycloaliphatic, aromatics, heterocyclic about 50 mg of a 50/50 wt % mixture of cellulose ace solvents, and mixtures thereof. Typical solvents include tate (cellulose acetate 398-10 sold by Eastman Chemical acetone, diacetone alcohol, methanol, ethanol, isopro Products, Inc. of Kingsport, Tenn.) and polyethylene pyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, glycol (Carbowax @ PEG 3350 sold by Union Carbide isopropyl acetate, n-butyl acetate, methyl isobutyl ke Corp. of Danbury, Conn.) deposited from a 95/5 wt. % tone, methyl propyl ketone, n-hexane, n-heptane, ethyl acetone and water solution. The coated systems were ene glycol monoethyl ether, ethelene glycol monoethyl air dried overnight. Then, two 15 mil diameter exit acetate, methylene dichloride, ethylene dichloride, ports were drilled, one port per side. propylene dichloride, carbon tetrachloride, nitroethane, The systems were immersed in arti?cial intestinal nitropropane, tetrachloroethane, ethyl ether, isopropyl 60 ?uid for three hours to determine their in vitro release ether, cyclohexane, cyclooctane, benzene, toluene, rate. The systems uniformly released their contents as naphtha, 1,4-dioxane, tetrahydrofuran, diglycol methyl shown by the gradually declining bar graph in FIG. 4. ether, water and mixtures thereof such as acetone and When tested in the oral cavity, the systems released water, acetone and methanol, acetone and ethyl alco similarly to this in vitro release pattern, i.e., the duration hol, methylene dichloride and methanol, and ethylene 65 of drug delivery was also about three hours. dichloride and methanol, and mixtures thereof. The arti?cial intestinal ?uid was made by dissolving The expression “passageway” as used herein com 6.8 g of monobasic potassium phosphate in 150 ml water prises means and methods suitable for releasing the and adding 190 ml of 0.2N sodium hydroxide. The pH 5,200,194 13 14 of the arti?cial intestinal ?uid was adjusted to 7.5 using dispersed in water for 30 minutes. Then, TWEEN 80 the sodium hydroxide. was mixed in for 5 minutes, followed by the sodium The buckling pressure of spent, hydrated systems was saccharin, mixed for another 5 minutes. The CPC was measured as follows. Four vent holes were mechani added, and the mixture is stirred another 5 minutes. The cally pierced through the lateral edge of the membrane PEG was added, mixed for 5 minutes, then the HPMC with a 22 gauge needle. The outside diameter of the was added and the resulting blend was stirred for 1 needle was 0.028 inch. The holes were spaced evenly at hour. The ?nal blend consisted of l4%/86% solids/ 90 degree intervals around the lateral edge of the mem puri?ed water on a weight basis. brane. The system was then wrapped in a single layer of This coating ?uid was applied to the drilled, mem nylon mesh netting (20 holes per inch of mesh). A small brane coated systems in a pharmaceutical coater using a vent tube (inside diameter of 0.027 inch, outside diame stream of warmed air. The inlet temperature was ap ter of 0.42 inch) was placed near one of the vent holes proximately 70°-75' C. and the outlet temperature was through a slit in the mesh. The resulting assembly was approximately 38'-42‘ C. The resulting drug-over then sandwiched between two latex sheets (0.002 inch coated systems were dried to constant weight. thick) which were mounted in a bi-chamber pressure The average release rates for these systems is illus cell. The vent tube was oriented such that it was ex trated in FIG. 5. The release rates were determined by posed to ambient atmospheric pressure. The chambers immersing the systems in arti?cial intestinal ?uid in shared a common source of pressurized air and the air accordance with the procedures described in Example pressure within the chambers was monitored with a 1. The high release rates recorded for the ?rst 30 min manometer. 20 utes of operation was due primarily to the CPC-contain Compressed air was forced into the chambers causing ing overcoat layer, which dissolved very rapidly. The pressure on the latex sheets. This pressure in turn systems exhibited a relatively uniform pumping rate squeezed the spent system. As the air pressure in the from 30 minutes until 3.0 hours following immersion in chambers was gradually increased, the ?uid within the the intestinal ?uid. 25 spent system was squeezed from the system through the EXAMPLE 3 vent tube to the atmosphere. The pressure at which the membrane shell could no longer retain its shape and The following components were pre-sieved #40 collapsed was recorded in millimeters of mercury. The mesh and dry mixed: 15 grams captopril, 64 grams sor buckling pressure of the spent systems consistently ex bitol, 10 grams low-substituted hydroxypropyl cellulose ceeded 400 mm Hg. ?bers (hydroxypropoxy content 11 weight percent), and 10 grams cellulose ?ber Solka-?oc BW 40. After a COMPARATIVE EXAMPLE 1 uniform mixture was obtained, 1 gram of stearic acid When comparable systems to those described in Ex sized to minus #80 mesh, was tumble mixed into the ample 1, but without any low substituted hydroxypro blend. Portions of the blend weighing 167 mg were pyl cellulose or microcrystalline cellulose ?bers in the 35 compressed with a 5 inch by 3/16 inch oval tablet press. core, were tested in the oral cavity, release of a drug The resulting tablets were coated with a membrane was prone to uncontrolled mechanical pumping and composition consisting of 50% cellulose acetate having convective losses with the CPC being completely re an acetyl content of 39.8 weight percent and 50% poly leased within 30 minutes. The buckling pressures of the ethylene glycol molecular weight 8.000 grams per mole. spent systems of Comparative Example 1 were less than 40 This membrane was sprayed from a solvent system of 199 mm Hg. 95/5 acetone/water weight by weight in a pharmaceuti cal coating pan. After coating, the systems were dried EXAMPLE 2 to remove residual solvent. Then two 15 mil ports, one An osmotic, therapeutic device for continuous deliv on each side of the system, were drilled. The resulting ery of cetyl pyridinium chloride (CPC) and having a 45 systems were given to patients who were asked to keep drug overcoating for instantaneous release of CPC in the system beneath their tongue (i.e., sublingual deliv the oral cavity, was made as follows. The following ery). The systems provided controlled delivery and components were pre-sieved on a #40 mesh sieve and absorption of 25 milligrams captopril at an average rate dry mixed: 68.5 g sorbitol, 10 g LHPC ll, 10 g Avicel of delivery of 6 mg captopril/hr. for a period about 4 PH 102. Then, 3.3 g CPC was dissolved in ethanol and hours for treatment of hypertension. the solution was stirred into the pre-mix to form a uni While there have been described and pointed out form doughy mass. The resulting mass was passed features of the invention as applied to the presently through a #20 mesh sieve forming damp granules. preferred embodiments, those skilled in the art will These granules were air dried overnight, then repassed appreciate that various modifications, changes, addi through the #20 mesh sieve. Then, 3.0 g TWEEN 80 55 tions and omissions in the systems illustrated and de and 5.0 g of a mint ?avoring agent, was stirred into the scribed can be made without departing from the spirit granulation. and scope of the invention as de?ned in the appended 250 mg portions of this granulation were compressed claims. with i inch oval tablet tooling and then coated with a We claim: 50/50 wt. % mixture of cellulose acetate 398-10 and 1. An osmotic device for the controlled delivery of a PEG 3350 following the same procedure as described in bene?cial agent to an oral cavity of an animal over an Example 1. Then, two 15 mil diameter exit ports were extended delivery period, the device having a size and drilled, one port per side. The systems were then each shape suitable for comfortably retaining the device in overcoated with 34 mg of an instant release overcoat the oral cavity for the extended delivery period, the layer. The overcoat layer was comprised of 13 wt. % 65 device including a wall surrounding a solid dose of the CPC, 52 wt. % HPMC 603, 7 wt. % PEG 3350, 13 wt bene?cial agent, the bene?cial agent exhibiting at least % TWEEN 80 and 14 wt. % of ?avoring agents, e.g., some degree of solubility in an aqueous ?uid present in mint ?avor and sodium saccharin. The mint ?avor was the oral cavity, and a ?brous support material com 5,200,194 15 16 prised of hydrophilic water-insoluble ?bers selected range of about 1.2:1 to about 3:1, a height of about 0.5 to from the group consisting of cellulose ?bers, microcrys about 10 mm, and a volume of less than about 2 cm3. talline cellulose ?bers, cellulose ester ?bers, cross 10. The osmotic device of claim 1, wherein the bene linked sodium carboxymethyl cellulose ?ber, low-sub ?cial agent has a low degree of solubility in the aqueous stituted hydroxypropyl cellulose ?bers, seaweed ?bers, ?uid and the compartment also contains an osmagent. chitin ?bers, chitsan ?bers, and blends thereof, the wall 11. The osmotic device of claim 1, wherein the device having a passageway communicating the solid dose is substantially free of any gelling agent. with the exterior of the device, the wall being formed of 12. The osmotic device of claim 1, wherein the bene a semipermeable material which is (i) permeable to the ?cial agent is a member selected from the group consist passage of the aqueous ?uid and (ii) substantially imper ing of anti-plaque agents, antifungal agents, antiviral meable to the passage of the ?brous support material. agents, antimicrobial agents, antibiotics, non-steroidal 2. The osmotic device of claim 1, wherein the solid anti-in?ammatory agents, anti-dental caries agents, sali dose contains an amount of the ?brous support material va-enhancing agents, smoking cessation agents, oral suf?cient to impart a buckling pressure of at least about ulcer healing agents and breath fresheners. 100 mm Hg during use. 15 13. The osmotic device of claim 12, wherein the bene 3. The osmotic device of claim 1, wherein the solid ?cial agent comprises an anti-plaque agent selected dose contains about 5 to 70 vol % of the ?brous support from the group consisting of clorhexidine digluconate, material. chlorhexidine dichloride, chlorhexidine diacetate, ce 4. A method for controlled delivery of a bene?cial tylpyridinium chloride, ethanol, sanguinarine, sanguina agent into an oral cavity of an animal over an extended rine chloride, sodium salicylate, sodium borate, sodium delivery period, comprising: benzoate, dequalinium chloride, benzalkonium chlo a) placing in the oral cavity of the animal an osmotic ride, aminacridine hydrochloride, mepacrine hydro device having a size and shape suitable for comfort chloride, hydrogen peroxide, potassium peroxidiphos ably retaining the device in the oral cavity for the phate, proguanil hydrochloride, dibromopropamidine 25 diisothionate, hexidine, alexidine, octenidine, zinc ci extended delivery period, the device including a trate, thymol, triclosan, mutanases, amylogycosidase, shaped semipermeable wall surrounding a solid glucose-oxidase, xylitol, mannitol, stannous ?uoride, dose of a bene?cial agent that exhibits at least some sodium ?uoride, decapinol, sodium polyvinylphos degree of solubility in an aqueous ?uid present in phonic acid, per?uoroalkyl surfactants and cetyl the oral cavity, a ?brous support material compris dimethylbenzyl ammonium chloride. ing hydrophilic water-insoluble ?bers, and a pas 14. The method of claim 4, wherein the extended sageway in the semipermeable wall connecting the delivery period is about 0.5 to 12 hours. exterior of the device and the agent for delivering 15. The method of claim 4, wherein the extended the agent from the device into the oral cavity at a delivery period is about 1 to 6 hours. controlled rate over the extended delivery period, 16. The method of claim 4, wherein the extended the wall being permeable to the passage of the delivery period is about 1 to 4 hours. aqueous ?uid and substantially impermeable to the 17. The method of claim 4, wherein the bene?cial passage of the ?brous support material; agent is an anti-plaque agent which is administered to b) allowing the aqueous ?uid present in the oral cav suppress the formation of plaque on teeth. ity to permeate through the semipermeable wall to 40 18. The method of claim 17, wherein the anti-plaque form a liquid solution of the bene?cial agent; and agent is selected from the group consisting of clorhexi c) delivering the solution of the bene?cial agent into dine digluconate, chlorhexidine dichloride, chlorhexi the oral cavity over the extended delivery period. dine diacetate, cetylpyridinium chloride, ethanol, san 5. The osmotic device of claim 1, wherein the device guinarine, sanguinarine chloride, sodium salicylate, exhibits a buckling pressure of greater than about 200 sodium borate, sodium benzoate, dequalinium chloride, mm Hg during use. benzalkonium chloride, aminacridine hydrochloride, 6. The osmotic device of claim 1, wherein the semi mepacrine hydrochloride, hydrogen peroxide, potas permeable wall has a ?uid permeability of greater than sium peroxidiphosphate, proguanil hydrochloride, di about 2 X 10-4 cm.mil/atm.hr. bromopropamidine diisothionate, hexidine, alexidine, 7. The osmotic device of claim 1, wherein the semi octenidine, zinc citrate, thymol, triclosan, mutanases, permeable wall has a thickness in the range of about 1 to amylogycosidase, glucose-oxidase, xylitol, mannitol, 10 mils and a porosity of about 40 to 70 vol. %. stannous ?uoride, sodium fluoride, decapinol, sodium 8. The osmotic device of claim 1, wherein the semi polyvinylphosphonic acid, per?uoroalkyl surfactants permeable wall has an overcoating containing bene?cial and cetyldimethylbenzyl ammonium chloride. agent. 55 19. The method of claim 17, wherein the anti-plaque 9. The osmotic device of claim 1, wherein the device agent comprises cetylpyridinium chloride. has a smooth oval shape with an aspect ratio in the

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