United States Patent [19]
`Edgren et al.
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`US005160743A
`5,160,743
`Patent Number:
`* Nov. 3, 1992
`Date of Patent:
`
`[II]
`[45]
`
`[75]
`
`[54] ANNEALED COMPOSITION FOR
`PHARMACEUTICALLY ACCEPTABLE
`DRUG
`Inventors: David E. Edgren, El Granada; Felix
`Theeuwes, Los Altos, both of Calif.
`[73] Assignee: Alza Corporation, Palo Alto, Calif.
`[ *] Notice:
`The portion of the term of this patent
`subsequent to Apr. 9, 2008 has been
`disclaimed.
`[21] Appl. No.: 647,321
`[22] Filed:
`Jan. 28, 1991
`
`Related U.S. Application Data
`[60] Continuation-in-part of Ser. No. 350,482, May II,
`1989, Pat. No. 5,006,346, which is a division ofSer. No.
`187,621, Apr. 28, 1988, Pat. No. 4,931,285.
`Int. Cl.5 ................................................ A61K 9/24
`[51]
`[52] U.S. Cl. ........................................ 424/473; 427/3;
`427/214; 424/468; 424/472
`[58] Field of Search ....................... 424/473, 472, 468;
`427/3, 214
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`2,779,241
`
`
`1/1957 Wurster ·······························-··· 89/1
`
`3,845,770 11/1974 Theeuwes et al. .................. 128/260
`3,865,108 2/1975 Hartop ................................ 128/260
`3,916,899 11/1975 Theeuwes eta!. .................. 128/260
`4,002,173 1/1977 Manning ............................. 128/296
`4,063,064 12/1977 Saunders et al. ............... 219/121 L
`4,088,864 5/1978 Theeuwes et al. .......... 219/121 LM
`4,160,020 7/1979 Ayer et al. ............................ 424/15
`4,200,098 4/1980 Ayer et a!. .......................... 128/260
`4,207,893 6/1980 Michaels ............................. 128/260
`4,285,987 8/1981 Ayer eta!. .............................. 427/3
`4,369,172 1/1983 Schor eta!. ........................... 424/19
`4,716,041 12/1987 Kjornaes et al. ................... 424/468
`4,783,337 11/1988 Wong eta!. ........................ 424/468
`4,786,505 11/1988 Lovgren .............................. 424/468
`4,816,264 3/1989 Phillips eta! ....................... 424/468
`4,853,230 3/1989 Lovgren eta!. .................... 424/466
`5,006,346 4/1991 Edgren eta!. ...................... 421/473
`Primary Examiner-Thurman K. Page
`Assistant Examiner-Leon R. Horne
`Attorney, Agent, or Firm-Paul L. Sabatine; Jacqueline
`S. Larson; Jean M. Duvall
`ABSTRACT
`[57]
`A dosage form is disclosed comprising a coat that sur-
`rounds a drug. The coat comprises a subcoat and an
`overcoat thermally annealed to provide a single unit
`coat around the drug.
`
`1 Claim, 2 Drawing Sheets
`
`10
`
`I I
`12
`
`KASHIV1062
`IPR of Patent No. 9,492,392
`
`

`

`U.S. Patent
`
`Nov. 3, 1992
`
`Sheet 1 of 2
`
`5,160,743
`
`FIG.I
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`21
`2
`24
`25
`
`KASHIV1062
`IPR of Patent No. 9,492,392
`
`

`

`U.S. Patent
`
`Nov. 3, 1992
`
`Sheet 2 of 2
`
`5,160,743
`
`FIG_?
`
`...,_
`U-1
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`c:::: -c::::
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`24.00
`
`KASHIV1062
`IPR of Patent No. 9,492,392
`
`

`

`1
`ANNEALED COMPOSITION FOR
`PHARMACEUTICALLY ACCEPTABLE DRUG
`
`5,160,743
`
`I 5
`
`2
`that if a coating is provided that is substantially-free of
`organic solvents for coating drugs, drug granules, drug
`powders, drug delivery devices, and the like, such a
`coating would have an immediate positive value and,
`5 concomitantly, represent an advancement in the drug
`coating art. Likewise, it will be appreciated by those
`versed in the dispensing art that if a delivery device is
`made available comprising a coating applied from a
`non-organic solvent, and which delivery device pos-
`sesses the thermodynamic ability to deliver a beneficial
`drug at a controlled rate, such a delivery device would
`have a practical application in the fields of human and
`veterinary medicine.
`OBJECTS OF THE INVENTION
`Accordingly, in view of the above presentation, it is
`an immediate object of this invention to provide a novel
`and useful coating composition for dosage forms and
`20 which coating overcomes the disadvantages associated
`with the prior art.
`Another object of this invention is to provide a new
`coating composition comprising pharmaceutically ac-
`ceptable ingredients, and which coating composition is
`25 innocuous and useful for manufacturing dosage forms.
`Another object of this invention is to provide a non-
`toxic coating composition free of organic solvents and
`which coating composition is useful for making dosage
`forms by standard manufacturing techniques.
`Another object of the invention is to provide an aque-
`ous coating composition which is relatively uncompli-
`cated, capable of application without difficulty, and is
`applied at a relatively low cost.
`Another object of the invention is to provide an aque-
`ous polymeric coating that exhibits stability and resis-
`tance to sedimentation.
`Another object of the invention is to provide an aque-
`ous coating composition useful for manufacturing a
`drug delivery device possessing drug release rate con-
`trolling properties.
`Another object of this invention is to provide a drug
`delivery device that can be manufactured by standard
`manufacturing techniques into various sizes, shapes and
`forms that comprise an improvement in the dispensing
`art, which comprises a non-toxic, aqueous coated wall
`that surrounds a drug.
`Another object of this invention is to provide an
`aqueous-solvent coating composition that is non-flamm-
`able and is not an environmental hazard during formula-
`tion and not a hazard when applied to a drug core.
`Another object of the invention is to provide a novel
`coating composition comprising a water carrier useful
`for coating a drug.
`Other objects, features and advantages of this inven-
`tion will be more apparent to those versed in the dis-
`pensing art from the following detailed specification
`taken in conjunction with the drawings and the accom-
`panying claims.
`BRIEF DESCRIPTION OF THE DRAWINGS
`In the drawing figures, which are not drawn to scale
`but are set forth to illustrate various embodiments of the
`invention, the drawing figures are as foliows:
`FIG.l is an opened view depicting a powdered drug
`coated with the coating composition provided by this
`invention;
`
`10
`
`CROSS-REFERENCE TO RELATED
`APPLICATON
`This application is a continuation-in-part of U.S.
`Appln. Ser. No. 07/350,482 filed on May 11, 1989, now
`U.S. Pat. No. 5,006,346 issued Apr. 9, 1991 which appli-
`cation Ser. No. 07/350,482 is a division of U.S. Pat.
`Appln. Ser. No. 07/187,621, filed Apr. 28, 1988 now
`U.S. Pat. No. 4,931,285 issued Jun. 5, 1990, which appli-
`cations are incorporated herein by reference and benefit
`is claimed of its filing date. These applications are as-
`signed to the ALZA Corporation of Palo Alto, Calif.
`FIELD OF THE INVENTION
`This invention pertains to both a novel and useful
`pharmaceutical coating composition. More particu-
`larly, the invention relates to a pharmaceutically ac-
`ceptable coating composition on dosage forms such as
`delivery devices comprising a core comprising a thera-
`peutically active drug; osmotic delivery systems; tab-
`lets; capsules; powders; granules; and beads.
`BACKGROUND OF THE INVENTION
`In Remington's Pharmaceutical Sciences, 14th Ed., p
`1681, published in 1970, it is reported that pill coating
`has been a pharmaceutical technique for well over ten
`centuries. For example, Rhazes (850-932 A.D.) used a 30
`mucilage for coating pills in the ninth century and A vi-
`cenna (980-1037 A.D.) is credited with the introduction
`of silver and gold pill coatings into medicine. The coat-
`ing of pills with finely powdered talcum, called pearl
`coating, was popular at one time. Gelatin coating of 35
`pills was introduced by Garot in 1838. The first sugar-
`coated pills in the United States were imported from
`France in about 1842. The first sugar-coated pill manu-
`factured in the United States was in 1856 by Warner, a
`Philadelphia pharmacist. The coating of pills with tolu 40
`was done in about 1860, and twenty-four years later
`Unna introduced enteric coated pills.
`Various pharmaceutically indicated articles of manu-
`facture have been coated by the drug dispensing art.
`For example, tablets were coated to provide a more 45
`attractive dosage form, to protect its drug content from
`moisture and to enhance its taste. Then too, tablets were
`provided with a coat for releasing a drug by enteric
`dissolution in the intestine of a warm-blooded animal.
`Recently osmotic dosage forms were coated with a 50
`semipermeable rate controlling walJ for delivering a
`drug at a known rate per unit time.
`While the above mentioned dosage forms are useful
`in the management of health and disease, serious disad-
`vantages are associated with them. That is, usualJy or- 55
`ganic solvents are used for applying the coating to the
`drug and drawbacks accompany the use of organic
`solvents. For example, organic solvents generally are
`toxic and they must be substantially removed, usualJy
`by vacuum or by air ciruclation, from the dosage form 60
`to avoid hazard to health the dosage form's recipient.
`Another drawback is that most organic solvents are
`flammable thereby possibly providing the danger of fire
`to the manufacturer. Also, organic solvents present an
`environmental problem and they require complicated 65
`recovery systems to avoid contaminating the environ-
`ment, which systems are expensive to operate. It will be
`appreciated by those skilled in the drug dispensing art
`
`KASHIV1062
`IPR of Patent No. 9,492,392
`
`

`

`5,160,743
`
`3
`FIG. 2 is an opened view illustrating granules of a
`beneficial drug coated with a coating composition pro-
`vided by this invention;
`FIG. 3 is a view of an osmotic device designed and
`shaped for orally administering a beneficial drug to the 5
`gastrointestinal tract;
`FIG. 4 is an opened view of the osmotic device of
`FIG. 3 depicting the wall of the osmotic device com-
`prising the wall-forming coating composition of this
`im ention;
`FIG. 5 is a view of another embodiment of an osmotic
`device provided by this invention, which osmotic de-
`vice is adapted and sized for oral admittance into the
`gastrointestinal tract of a host;
`FIG. 6 is an opened view of the osmotic system of 15
`FIG. 5 for illustrating a wall formed from the coating
`composition provided by this invention;
`FIG. 7 is a graph that depicts the drug delivery rate
`per unit time from a device comprising a wall coated by
`the process of the invention; and,
`FIG. 8 is a graph that depicts the cumulative amount
`of drug released per unit time by the delivery device of
`FIG. 7.
`In the drawings and in the specification like parts in 25
`related figures are identified by like numbers. The terms
`appearing earlier in the specification and in the descrip-
`tion of the drawings, as well as embodiments thereof,
`are further described elsewhere in the disclosure.
`DETAILED DESCRIPTION OF THE
`DRAWINGS
`Turning now to the drawing figures in detail, which
`figures are examples of a dosage form comprising a
`coating composition provided by this invention and 35
`which examples are not to be considered as limiting the
`invention, one example of a dosage form is illustrated in
`FIG. 1. In FIG. 1, a dosage form 10 is seen in opened
`section. Dosage form 10 comprises a powdered drug 11,
`generally exhibiting a powder size that passes through a 40
`sieve having an opening of from 0.074 mm to 0.250 mm,
`surrounded by coating composition 12. Coating compo-
`sition 12 comprises a subcoat and an overcoat. The
`subcoat comprises a finely divided membrane forming
`polymer dispersed in an oil-in-water emulsion, wherein 45
`the oil, generally present as an oily plasticizer, lowers
`the glass transition temperature of the membrane form-
`ing polymer. The overcoat comprises a water soluble
`composition wherein the glass transition temperature of
`the overcoat is higher than that of the subcoat. The 50
`subcoat and the overcoat are annealed, with the subcoat
`forming an insoluble membrane that surrounds pow-
`dered drug 11. The annealed overcoat forms a mem-
`brane that dissolves in an aqueous environment of use,
`leaving a continuous, insoluble membrane coating 12.
`In FIG. 2, another embodiment of dosage form 10 is
`seen in opened view. In FIG. 2 dosage form 10 com-
`prises granules of drug 13. The drug granules generally
`exhibit a granule size that passes through a sieve having
`an opening from greater than 0.250 mm to 9.50 mm. 60
`Drug granules 13 are surrounded by aqueous-applied
`coating composition 14. Coating composition 14 is ap-
`plied in two steps, first a subcoat followed by an over-
`coat. The two coats are annealed, which annealing
`process coalesces the polymer in the subcoat thereby 65
`providing a continuous membrane or film. The over-
`coat protects the subcoat during the annealing process
`and the overcoat additionally prevents the subcoat of
`
`4
`one dosage form from fusing with the subcoat of a
`neighboring dosage form.
`In FIG. 3, another embodiment of dosage form 10 is
`illustrated manufactured as an osmotic drug delivery
`device. In FIG. 3 osmotic dosage form 10 comprises a
`body 15 comprising a wall 16 that surrounds and forms
`an internal compartment, not seen in FIG. 3. Osmotic
`dosage form 10 comprises at least one passageway 17
`10 for connecting the interior of osmotic dosage form 10
`with the exterior of osmotic dosage form 10 when in a
`biological environment of use.
`In FIG. 4 osmotic dosage form 10 of FIG. 3 is seen in
`opened view. In FIG. 4 osmotic dosage form 10 com-
`prises body member 15, aqueous coated wall16 and exit
`passageway 17. Wall16 surrounds and forms an internal
`compartment 18. Internal compartment 18 comprises a
`dispensable drug 19, represented by dots, and an op-
`tional osmagent, represented by dashes. Wall 16 is per-
`meable to the passage of an exterior fluid present in the
`environment of use, and wall 16 is substantially imper-
`meable to the passage of drug 19 and osmagent 20.
`In FIG. 5 another embodiment of dosage form 10 is
`illustrated and made as an osmotic drug delivery device.
`In FIG. 5 osmotic dosage form 10 comprises a body
`member 21 comprising a wall 22 that surrounds and
`forms an internal compartment, not seen in FIG. 5.
`Dosage form 10 comprises at least one passageway 23,
`30 formed during the manufacture of dosage form 10 or,
`optionally, formed when dosage form 10 is in a fluid
`environment of use. Passageway 23 connects the inte-
`rior of dosage form 10 with its exterior for delivering a
`drug to an environment of use.
`In FIG. 6 dosage form 10 of FIG. 5 is seen in opened
`view. In FIG. 6 dosage form 10 comprises body mem-
`ber 21, aqueous coated annealed wall 22 and exit pas-
`sageway 23. Wall 22 surrounds, forms and defines an
`internal compartment 24. Internal compartment 24
`comprises a first composition identified by dots 25, and
`a second composition 26 identified by vertical lines.
`First composition 25 comprises a beneficial drug and
`second composition 26 comprises an expandable hydro-
`gel. First composition 25 and second composition 26 are
`in laminar arrangement and they cooperate with wall 22
`for the effective delivery of a drug through exit passage-
`way 23 to an environment of use.
`FIG. 7 and FIG. 8 exemplify the release of an active
`agent from a delivery system made according to this
`invention. The release rate per unit time and the cumu-
`lative amount release of the drug potassium chloride are
`depicted, respectively, for a delivery system made ac-
`cording to this invention.
`While FIGS. 1 through 8 illustrate different embodi-
`ments of dosage forms that can be coated with the coat-
`ing composition of this invention, it is to be understood
`that the coating composition can be applied to a wide
`variety of dosage forms, which dosage forms comprise
`various shapes, sizes and forms. The coating composi-
`tion can be applied to devices not limited to but includ-
`ing uses for buccal, implant, artificial gland, cervical,
`intrauterine, nose, and the like. In these forms the de-
`vice coated with the coat of this invention can be
`adapted for administering a beneficial medicine to ani-
`mals, warmblooded mammals, humans, farm and zoo
`animals, avians and reptiles.
`
`20
`
`55
`
`KASHIV1062
`IPR of Patent No. 9,492,392
`
`

`

`5
`DETAILED DESCRIPTION OF THE
`INVENTION
`In accordance with the practice of this invention a
`drug or the like is first coated with a subcoat followed 5
`by an overcoat. The subcoat comprises a membrane
`forming polymer, a plasticizer, an emulsifier, an op-
`tional hydrophilic enhancer, and an aqueous carrier.
`The overcoat comprises a membrane or film forming
`polymer, an optional plasticizer and an optional carrier. 10
`The polymeric material used for forming the subcoat,
`which subcoat when the dosage form is in operation in
`a fluid environment of use, comprises the sole coat on
`the form and is a polymer that is nontoxic and does not
`adversely affect a beneficial drug and an animal host, 15
`including humans. In a presently preferred embodi-
`ment, polymeric materials useful for providing the sub-
`coat comprise polymeric members selected from the
`group consisting of a cellulose ester, cellulose ether,
`cellulose ester-ether, cellulose acylate, cellulose diacy- 20
`late, cellulose triacylate, cellulose acetate, cellulose
`diacetate and cellulose triacetate. More specific exam-
`ples of polymeric materials comprise a member selected
`from the group consisting of cellulose acetaldehyde
`methyl carbamate, cellulose acetate succinate, cellulose 25
`acetate dimethylaminoacetate, cellulose acetate ethyl-
`carbamate, cellulose acetate dipalmate, cellulose acetate
`dioctanoate, cellulose acetate dicaprylate, cellulose
`acetate pentylate, cellulose acetate valerate, cellulose
`acetate succinate, cellulose acetate propionate, cellulose 30
`acetate p-toluene sulfonate, cellulose acetate butyrate,
`cellulose propionate butyrate, and the like. Generally
`the polymer used for forming the composition will have
`a particle size of less than about 2 to 15 microns and
`more, preferably less than about 2 to 10 microns. The 35
`amount of polymer on a weight basis of the coating in a
`final, dry coated dosage form generally is about 15 to
`95%.
`The subcoating additionally comprises a non-toxic
`plasticizer or blends of plasticizers. The plasticizers 40
`presently preferred are highboiling softening agents,
`which are often liquids, pastes, or waxes at room tem-
`perature, that are added to the subcoat composition to
`facilitate processing, and to increase flexibility and
`toughness. The plasticizers generally comprise, in a 45
`presently preferred embodiment, a member selected
`from the group consisting of monoglycerides, diglycer-
`ides, triglycerides, alkyl phthalyl alkyl glycolates, trial-
`kyl esters of acyl citric acid, dialkyl adipates, dialkyl
`phthalates, dialkyl sebacates, fatty acid ester deriva- 50
`tives, akyl-aryl phosphates, fatty acid esters of polysac-
`charides, triethyl citrate, acetyltriethyl citrate, diethyl
`phthalate, diethyl tartrate, dibutyl phthalate, dibutyl
`sebacate, dibutyl tartrate, dibutyl maleate, dibutyl succi-
`nate, diethyl succinate, propylene glycol, glycerin, 55
`monoacetin, diacetin, triacetin, polyethylene glycol,
`di(methoxyethyl) phthalate, methyl and ethyl phthalate
`ethyl glycolate, butyl phthalyl butyl glycolate, benzyl
`phthalate, ethylene glycol diacetate, methylglycol
`phthalate, ethylene glycol monoacetate, trimethyl phos- 60
`phate,
`triethyl phosphate, dioctyl adipate, dioctyl
`phthalate, dibutyloxyethyl phthalate, epoxidized natu-
`ral glyceride of unsaturated fatty· acids, soybean oil
`epoxide, di-n-hexyl azelate, dimethyl phthalate, di-
`phenyl phthalate butyl stearate, diethyl oxalate, di- 65
`isodecyl adipate, dicyclohexyl phthalate, di(2-ethyl-
`hexyl) adipate, cresyldiphenyl phosphate, tributyl ci-
`trate, acetyl tributyl citrate, trimethyl citrate, acetyltri-
`
`5,160,743
`6
`tricy-
`n-hexyl citrate, n-butyryltri-n-hexyl citrate,
`clohexyl citrate, acetyltri-n-(hexyl!octyl!decyl) citrate,
`acetyltri-n-( octyl! decyl) citrate, acetyltri-n-(decyl!-
`dodecyl)citrate, tristearyl citrate, stearyl citrate-mono,
`methylglycol stearate, butyl phthalyl butyl glycolate,
`tri(n-octyl!n-decyl) trimellitate, triisodecyl trimellitate,
`tri-n-hexyl trimellitate, di(2-ethylhexyl) isophthalate,
`butyl ricinoleate, polymeric plasticizer acetylated, citric
`acid esters, natural oils and derivatives of natural oils,
`fish oils, lard oils, vegetable oils, babassu oil, castor oil,
`coconut oil, cottonseed oil, corn oil, linseed oil olive oil,
`palm oil, peanut oil, safflower oil, seasme oil, soybean
`oil, tall oil, acetyl tri-2-ethylhexyl citrate, linoleic acid,
`oleic acid, butyl sterate, benzyl benzoate, polysiloxanes,
`silcone oils, mineral oils, hydrogenated oils, methyl
`ester of rosin, stearic acid, cetyl alcohol, acetylated
`glycerides, glycerol esters, polyethylene glycol, and the
`like. The amount of plasticizing agent in a final subcoat
`on a drug delivery dosage form is about 2% to 75%.
`The subcoat comprises also an emulsifying agent or
`blends of emulsifying agents. The emulsifying agents
`generally are surface active agents comprising anionic,
`polar, nonpolar, amphoteric, zwitterionic and cationic
`active emulsifying agents. The amount of emulsifying
`agents in an aqueous coating composition usually is
`about 0.1% to 20%, and more preferably about 0.01%
`to 4%, by weight, of water in the aqueous phase. Repre-
`sentatives of general classes of emulsifying agents com-
`prise a member selected from the group consisting es-
`sentially of alkanolmides, alkyl sulfonates, amines and
`amides sulfonated, betaine emulsifiers, diphenyl sulfo-
`nates, ethoxylated alcohols, ethoxylated alkyl phenols,
`ethoxylated amines, ethoxylated amides, ethoxylated
`fatty acids and oils, fatty esters, florocarbons, glycerl
`esters, glycol esters, heterocyclic emulsifiers, isethion-
`ates, lanolin based emulsifiers, lecithin based emulsifiers,
`phospholipids, lignin emulsifiers, monoglycerides, ole-
`fin sulfonates, phosphate emulsifiers, phosphate esters
`emulsifiers, polyamino carboxylic emulsifiers, protein
`emulsifiers, quaternary emulsifiers, sarcosine emulsifi-
`ers, silicone emulsifiers, siloxane emulsifiers, sorbitan
`emulsifiers, sulfo succinate emulsifiers, sucrose esters,
`ethoxylated alcohol sulfates, ethoxylated alcohol sul-
`fates, sulfates and sulfonates of ethoxylated alkyl phe-
`nols, sulfates of fatty acids, sulfates of oils, sulfonates of
`oils, sulfates of fatty acids, sulfonates of fatty acids,
`sulfonates of alkyl aryls, sulfonates of naphtholenes,
`sulfonates of dodecyl and tridecylbenzenes, sulfonates
`of petroleum, tridecyl and dodecyl benezene sulfonic
`acids, taurates, tertiary amine oxides, and thio and mer-
`capto emulsifiers. Representatives of nonionic emulsify-
`ing agents include polyoxyethylene sorbitan tristearate,
`polyoxyethylene sorbitan mono-oleate, polyoxyethyl-
`ene sorbitan monopalmitate, sorbitan monopalmitate,
`polyoxyethylene sorbitan tri-oleate, polyoxyethylene
`sorbitan monostearate, polyoxyethylene alkyl phenol,
`polyoxyethylene sorbitan monolaurate, polyoxyethyl-
`ene oxypropylene stearate, glycerol monostearate,
`propylene glycol fatty acid ester, and the like. Repre-
`sentatives of anionic emulsifying agents include trietha-
`nolamine oleate, sodium oleate, calcium stearoxyl-2-lac-
`tylate, calcium dodecylbenzene sulfonate, ammonium
`Iaury] sulfate, sodium alkyl sulfate, triethanolamine
`Iaury! sulfate, sodium dodecylsolfate, and the like. Ex-
`emplary cationic emulsifiers include high molecular
`weight fatty amine blends, polyoxyethylene fatty
`amines, polyoxyethylene tallow amines, N-cetyl-N-
`ethyl morpholinium ethyl sulfate, and the like. The
`
`KASHIV1062
`IPR of Patent No. 9,492,392
`
`

`

`5,160,743
`7
`8
`"at least one passageway," embraces aperature, orifice,
`emulsifiers are known in McCutcheon's Detergents and
`bore, pore, porous element, and the like, through which
`Emulsifiers, North American Edition (1979) and Inter-
`national Edition (1979), in the Encyclopedia of Chemical
`pores a drug can travel, hollow fiber, capillary tube,
`porous overlay, porous insert, and the like. The expres-
`Technology, by Kirk-Othmer, 3rd Ed. Vol. 8, pp 900-30,
`(1984), and in the Cosmetic, Toiletry, and Fragrance 5
`sion also includes a material that erodes, or is leached
`from a wall in a fluid environment of use to produce at
`Association Cosmetic Ingredient Dictionary 3rd Ed.,
`(1982) and 3rd Ed., Supplement (1985).
`least one passageway of controlled releasing dimen-
`sions. Representative materials for forming a passage-
`The subcoat comprises an optional hydrophilic en-
`way or two passageways, or a multiplicity of passage-
`hancer or blends of hydrophilic enhancers that aid in
`ways in an environment of use include an erodible,
`transportili.g fluid from the environment of use into a 10
`innocuous poly(glycolic) acid, or poly(lactic) acid
`dosage form. The hydrophilic enhancers in one embodi-
`member in the wall; a gelatinous filament; a particle of
`ment are polyhydric alcohols and derivatives thereof,
`polyvinyl alcohol; leachable materials such as a fluid
`such as polyalkylene glycols of the formula H-(0-
`removable pore forming polysaccharide, salt, oxide,
`alkylene)nOH, wherein the bivalent alkylene radical is a
`polyhydric alcohols, and the like. A passageway or a
`straight or branched chain of from 1 to 10 carbons and 15
`plurality of passageways of governed dimensions for
`n is 1 to 500 or higher. Typical glycols comprise poly-
`the controlled release of a drug can be formed by leach-
`ethylene glycols 300, 400, 600, 1500, 3350, 4000 and
`ing a passageway former such as sorbitol from a wall.
`6000 of the formulae H(OCH2CH2)nOH wherein n is,
`The passageway can have any shape such as round,
`respectively, 5 to 5.7, 8.2 to 9.1, 12.5 to 13.9, 29 to 36,
`29.8 to 37, 68 to 84, and 158 to 204. Other polyglycols 20
`triangular, square, elliptical, irregular, and the like, for
`assisting in the metered release of a drug from a dosage
`comprise the low molecular weight glycols such as
`form. A dosage form can comprise one or more than
`polypropylene glycol, polybutylene glycol and polya-
`one passageways in spaced apart relations or, option-
`mylene glycol. Other hydrophilic enhancers include
`ally, on more than a single surface of a dosage form.
`polyvinyl pyrrolidone, hydroxypropyl methylcellulose,
`hydroxypropyl cellulose, sorbitol, fructose, mannitol, 25
`Passageways and equipments for forming passageways
`are disclosed in U.S. Pat. Nos. 3,845,770; 3,916,889;
`citric acid, sodium citrate or entirely active materials
`such as finely divided cellulose acette trimellitate, cellu-
`4,063,064; and 4,088,864. Representative passageways
`lose acetate phthalate, hydroxypropyl methylcellulose
`formed by the governed leaching of a pore former to
`produce a pore of precontrolled rate releasing size are
`phthalate, acrylic copolymers, polyvinyl acetae phthal-
`30 disclosed in U.S. Pat. Nos. 4,200,098 and 4,285,987.
`ate. The amount of hydrophilic enhancer in the aqueous
`emulsion is 0% to 70%, with water and the concentra-
`The expression, "therapeutically active drug," as
`tion of oil ingredients in the aqueous coating composi-
`used herein, denotes a beneficial medicine neat, or a
`tion equal to 100%. Hydrophilic enhancers are known
`composition comprising a beneficial drug and other
`in U.S. Pat. No. 4,160,020.
`composition forming ingredients. In the specification
`The overcoat annealing composition comprises a 35
`and the accompanying claims the terms, "medicine and
`water soluble polymer such as, in a presently preferred
`drugs," are used as equivalents, and the term, "drug,"
`includes any physiologically or pharmacologically ac-
`manufacture, a member selected from the group consist-
`ing of hydroxypropyl cellulose, methyl cellulose, meth-
`tive substance that produces a local or a systemic effect
`in animals, including warm-blooded mammals, primates
`ylethyl cellulose, polyvinylpyrrolidone, sodium carbox-
`ymethylcellulose, hydroxypropylmethyl cellulose, and 40
`and humans. The terms, "physiologically and pharma-
`cologically," are defined in Stedman's Medical Dictio-
`the like. Other optional annealing agents comprise gums
`such as pectin, acacia, tragacanth, karaya, locust, bean
`nary, published by Williams and Wilkins, (1966),
`gum, chondrus and alginic acid. The overcoat can com-
`Baltimore, MD. The active drug that can be coated
`with a composition provided by this invention includes
`prise from 10% to 100% of the final dosage form when
`applied by compression coating. In an optional embodi- 45
`inorganic and organic drugs, without limitations, com-
`ment the overcoat can comprise from 0% to 60% of a
`prising drugs that act on the central nervous system,
`plasticizer such as glycerin, propylene glycol glyceryl
`depressants, hypnotics, sedatives, psychic energizers,
`triacetate, polyethylene glycol, and the like, and water
`tranquilizers, anticonvulsants, muscle relaxants, anti-
`to 100%. The overcoat comprising the water soluble
`Parkinsons, analgesics, anti-inflammatories, local anes-
`ingredients can be coated by spraying, dipping, and the 50
`thetics, muscle contractants, antimicrobials, antimaleri-
`like. The overcoat and the subcoat are annealed in a
`als, hormones, contraceptives, sympathomimetics, di-
`presently preferred embodiment at about 35° c. to 85°
`uretics, antiparasitics, neoplastics, hypoglycemics, oph-
`C., for 10 to 72 hours in a forced air oven. As an option
`thalmics, electrolytes, and cardiovascular drugs. These
`the annealing process can result in causing the plasti-
`drugs and their daily dosage are known in the art in
`cizer in the overcoat to partition from the overcoat into 55
`Pharmaceutical Sciences, by Remington, 16th Ed.,
`the subcoat. The subcoat, overcoat, or both subcoat and
`(1980), published by Mack Publishing Co., Easton, PA.
`overcoats can, optionally, contain finely divided insolu-
`The drug can be in various pharmaceutically accept-
`ble material. These are useful for reducing tackiness or
`able forms, such as uncharged molecules, molecular
`for enhancing mechanical integrity of the layers. Typi-
`complexes, pharmacologically acceptable salts such as
`cal materials for this application wold be microcrystal- 60
`hydrochloride, hydrobromide, sulfate, laurylate, palmi-
`line cellulose, titanium dioxide or fumed silicon dioxide.
`tate, phosphate, nitrate, borate, acetate, maleate, tar-
`The expression, "exit passageway," as used herein for
`trate, oleate and salicylate. For acidic medicines salts of
`a drug delivery device coated with the composition of
`metals, amines or organic cations; for example quater-
`this invention, comprises means and methods suitable
`nary ammonium can be used. Derivatives of medicines,
`for the controlled, metered release of a drug from a 65
`such as an ester, ether and amides, can be used. Also, a
`drug delivery device or dosage form. The exit means
`medicine that is water insoluble can be used in a form
`comprise at least one passageway, orifice, or the like,
`that is a water soluble derivative thereof to serve as a
`through the wall of the dosage form. The expression,
`solute, and on its release from a dosage form it is con-
`
`KASHIV1062
`IPR of Patent No. 9,492,392
`
`

`

`5,160,743
`10
`9
`verted by enzymes, hydrolyzed by the body pH, or
`ethyl cellulose, melting it and dispersing the melt in
`water with high shear and elevated temperature.
`other metabolic process to the original biologically
`active form.
`DETAILED DESCRIPTION OF THE EXAMPLES
`Hydrophilic polymers that exhibit an osmotic pres-
`The following examples are merely illustrative of the
`sure gradient, imbibe fluid and expand, that are useful 5
`present invention and they should not be considered as
`for manufacturing as coated osmotic dosage forms com-
`limiting the scope of the invention in any way, as these
`prise noncross-linked hydrogels, and lightly cross-
`examples and other equivalents thereof will become
`linked hydrogels, such as cross-linked by covalent or
`more apparent to those skilled in the drug delivery art in
`ionic bonds. The hydrophilic hydrogels usually exhibit
`the light of the present disclosure, the drawings and the
`a 2 to 50 fold volume increase comprising acidic car- 10
`accompanying claims.
`bo