Aqueous Emulsion Coating for Pharmaceutical Dosage Form

Europaisches Patentamt 0 347 024 3> European Patent Office J) Publication number: Dffice europeen des brevets

3) EUROPEAN PATENT APPLICATION

The title of the invention has been amended © Applicant: ALZA CORPORATION (Guidelines for Examination in the EPO, A-lll, 950 Page Mill Road P.O. Box 10950 7.3). Palo Alto California 94303-0802(US)

© Inventor: Wong, Patrick S.-L. © Priority: 21.04.88 US 184478 2030 Cornell Street Palo Alto California 94306(US) © Date of publication of application: Inventor: Theeuwes, Felix 20.12.89 Bulletin 89/51 1634 Fallen Leaf Lane Los Altos California 94022(US) © Designated Contracting States: AT BE CH DE ES FR GB GR IT LI LU NL SE © Representative: Evans, David Charles et al F.J. CLEVELAND & COMPANY 40-43, Chancery Lane London, WC2A UQ(GB)

© A dosage form is disclosed comprising a cured emulsion coat that surrounds a drug. The emulsion comprises a lower alkyl acrylate-lower alkyl methacrylate copolymer and ethyl cellulose. The emulsion optionally comprises a hydrophilic polymer.

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AQUEOUS EMULSION FOR PHARMACEUTICAL DOSAGE FORM

This invention pertains to a pharmaceutical final dosage form. dosage form comprising an aqueous emulsion coat It will be appreciated by those skilled in the and to an aqueous emulsion coat. drug dispensing art that if a coating is provided that is substantially free of organic solvents when coat- 5 ing drugs, drug granules, drug powders, drug dis- BACKGROUND OF THE INVENTION pensers, and the like, such a coating would have an immediate positive value and, concomitantly, represent an advancement in the drug coating art. In Remington's Pharmaceutical Sciences, 14th Likewise, it will be appreciated by those versed in Ed., p 1681. (1970), it is reported that pill coating w the dispensing art that if a coating that is applied has been a pharmaceutically accepted technique from a non-organic solvent, and the coated delivery for well over ten centuries. For instance, Rhazes device possesses the thermodynamic ability to de- (850-932 A. D.) in the ninth century used a mu- liver a beneficial drug at a controlled rate, such a cilage for coating pills, and Avicenna (980-1037 A. delivery device would have a practical application D.) is credited with the introduction of silver and 15 in the field of human and veterinary medicine. gold pill coatings into medicine. At one time the coating of pills with finely powdered talcum, called pearl coating, was very popular. The gelatin coating OBJECTS OF THE INVENTION of pills was introduced by Garot in 1838. The first sugar coated pills in the United States were im- 20 ported from France in about 1842. The first sugar In view of the above presentation it is an imme- coated pills manufactured in the United States was diate object of this invention to provide a novel and in 1856 by Warner, a Philadelphia pharmacist. The useful coating composition for dosage forms, which coating of pills with tolu was done in about 1860 coating composition overcomes the disadvantages and twenty-four years later Unna introduced the 25 associated with the prior art. enteric coated pill. Another object of this invention is to provide a Various pharmaceutical articles of manufacture new coating composition comprising pharmaceuti- have been coated by the drug dispensing art. For cally acceptable ingredients, and which coating example, tablets were coated to provide a more composition is innocuous and useful for manufac- attractive dosage form, to protect the drug content 30 turing dosage forms. from moisture and to enhance its taste. Then too, Another object of this invention is to provide a tablets were provided with a coat for releasing a non-toxic coating composition that is substantially drug by enteric dissolution in the intestine of a free of organic solvents, and which coating com- warm-blooded animal. Recently, in 1972, Theeuwes position is useful for making dosage forms by and Higuchi coated osmotic dosage forms with a 35 standard manufacturing techniques. semipermeable rate controlling wall for delivering a Another object of this invention is to provide a drug at a known rate per unit time. aqueous based coating composition, which com- While the above-mentioned dosage forms are position is relatively uncomplicated, is capable of useful in the management of health and disease application without difficulty, and has a relatively serious disadvantages are associated with them. 40 low cost. That is, usually organic solvents are used for ap- Another object of the invention is to provide an plying the coating to the drug and serious, unwan- aqueous polymeric coating composition that exhib- ted drawbacks accompany the use of organic sol- its long term stability and is resistant to sedimenta- vents. For example, organic solvents generally are tion in a fluid environment of use. toxic to living tissue and they must be substantially 45 Another object of this invention is to provide an pulled from the dosage form to avoid a hazard to aqueous coating composition that is useful for the dosage form's recipient. Another serious manufacturing a drug delivery device possessing drawback with the use of organic solvents is that drug release rate controlling properties. they are flammable thereby possibly providing the Another object of this invention is to provide a danger of fire during the manufacturing process. so drug delivery device that can be manufactured by Also, organic solvents present an environmental conventional manufacturing procedures into various problem and the use of such solvents requires sizes, shapes and designs that comprise an im- complicated recovery systems to avoid contaminat- provement in the dispensing art characterized by ing the environment. The recovery systems are coating the device with a non-toxic, aqueous coat expensive to operate and adds to the cost of the that surrounds a drug.

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Another object of this invention is to provide an dosage form is illustrated in Figure 1. In Figure 1 a aqueous-solvent coating composition that is non- dosage form 10 comprises a powdered drug 11, :lammable. is not an environmental hazard during generally exhibiting a powder size that passes ermuiation and when applied to a drug core. through a sieve having an opening from 0.074 mm Another object of this invention is to provide a 5 to 0.250 mm, surrounded by a coating composition Drocess for applying an aqueous coating onto a 12. Coating composition 12 comprises an aqueous jrug core thereby providing an orally administrable emulsion of ethylacrylatemethyl methacrylate and jrug dosage form an aqueous latex of ethylcellulose. Coating com- Other objects, features and advantages of this position 12 optionally comprises a hydrophilic poly- nvention will be more apparent to those versed in 70 mer such as polyvinyl alcohol, and the like. tie drug dispensing art from the following detailed In Figure 2 another embodiment of dosage specification taken in conjunction with the drawings form 10 is seen in opened view. In Figure 2 dosage and the accompanying claims. form 10 comprises granules 13 of drug. The drug granules generally exhibit a granule size that 15 passes through a sieve having an opening from BRIEF DESCRIPTION OF THE DRAWINGS greater than 0.250 mm to 9.50 mm. Drug granules 13 are surrounded by aqueous applied coating composition 14. Coating composition 14, in a pres- In the drawing figures, which are not drawn to ently preferred embodiment, comprises an aque- scale but are set forth to illustrate various embodi- 20 ous emulsion of an acrylate-methacrylate polymer ments of the invention, the drawing figures are as exhibiting a glass transition temperature of about follows: 10° C, an aqueous latex that is partially miscible Figure 1 is an opened view depicting a pow- with the aqueous emulsion of the acrylate and dered drug coated with the coating composition which latex imports mechanical stability to the ac- provided by this invention; 25 rylate emulsion, and an optional hydrophilic poly- Figure 2 is an opened view illustrating gran- mer that regulates the water permeability of the ules of a beneficial drug coated with the aqueous- aqueous acrylate-latex composition. The wall, or carrier based composition provided by this inven- the membrane composition, is formed by coales- tion. cence of the latex particles that are intermingled Figure 3 is a view of an osmotic device 30 with the water soluble polymer during a low tem- designed and shaped for orally administering a perature curing cycle, in a presently preferred em- dosage amount of a drug to the gastrointestinal bodiment at least one com ponent of the ingre- tract of a warm-blooded animal; dients comprising the blended emulsion exhibits a Figure 4 is an opened view of the osmotic glass transition temperature lower than the curing device of Figure 3 depicting the wall of the osmotic 35 temperature so that coalescence occurs during the device comprising a wall-forming coating composi- drying period. tion provided by the invention; In Figure 3 another embodiment of dosage Figure 5 is a view of the osmotic device of form 10 is illustrated manufactured as an osmotic Figure 3 in opened section illustrating the osmotic drug delivery device 10. In Figure 3 osmotic dos- device comprising another embodiment of the wall- 40 age form 10 comprises a body 15 comprising a forming coating composition provided by the inven- wall 16 that surrounds and forms an internal com- tion; partment, not seen in Figure 3. Osmotic dosage form 10 comprises at least one passageway 17 for In the drawings and in the specification like connecting the interior of dosage form 10 with the parts in related figures are identified by like num- 45 exterior of osmotic dosage form 10. ber. The terms appearing earlier in the description In Figure 4 osmotic dosage form 10 is seen in of the drawings, as well as embodiments thereof, opened section. In Figure 4 osmotic dosage form are further described elsewhere in the disclosure. 10 comprises body member 15, aqueous applied coat wall 16, and exit passageway 17. Wall 16 so surrounds and forms an internal compartment 18. DETAILED DESCRIPTION OF THE DRAWINGS Internal compartment 18 comprises a dispensable drug 19 identified by dots, and an optional osmagent 20 represented by dashes. Wall 16 is per- Turning now to the drawing figures in detail, meable to the passage of an exterior fluid present which figures are examples of dosage forms com- 55 in the environment of use, and wall 16 is substan- prising a coating composition provided by this in- tially impermeable to the passage of drug 19. In vention, and which examples are not to be consid- Figure 4 wall 16 comprises (a) an aqueous emul- ered as limiting the invention, one example of a sion of ethylacrylatemethyl methacrylate, a 70/30

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% copolymer having a molecular weight of about tion a drug, or a drug delivery device, is provided 800,000 and a glass transition temperature of about by coating or forming a wall with the coating com- 10° C, and (b) an aqueous latex of ethyl cellulose position provided by this invention. The coating having a particle size of 0.1 to 0.3 microns aver- composition comprises an aqueous emulsion of an age. 5 alkyl-acrylate-alkyl methacrylate. This aqueous In Figure 5 another embodiment of dosage synthetic polymer emulsion is made by emulsion form 10 is illustrated made as an osmotic drug polymerization. In an emulsion polymerization pro- delivery device 10. In Figure 5 osmotic dosage cess the monomers are finely distributed by the form 10 comprises a body member 21 comprising addition of an emulsifier in water. The emulsifier a wall 22 that surrounds and forms an internal w accumulate at the boundary between the monomer compartment, not seen in Figure 5. Dosage for 10 droplets and the water, but they also form miscel- comprises at least one or more passageways 23 les in the aqueous phase, in which the monomer formed during the manufacture of dosage form 10, molecules are solubilized. Before the start of the or passageway 23 optionally is formed when dos- polymerization one milliliter of such an emulsion age form 10 is in a fluid environment of use. 15 contains, in addition to the monomers in solution, Passageway 23 connects the interior of dosage about 10ia miscelles with solubilized monomers form 10 with the exterior for delivering a drug to a and 1010 monomer droplets stabilized by the emul- biological environment of use. sifier. In Figure 6, dosage form 10 is an opened view Polymerization is started by the addition of of dosage form 10 of Figure 5. In Figure 6 dosage 20 water soluble initiator, generally a radical initiator to form 10 comprises body member 21, aqueous be dissolved in the monomers reaction vessel first. coated annealed wall 22 and exit ports 23. Wall 22 The activated monomers or oligomers migrate into surrounds and forms an internal compartment 24. the miscelles and lead to the polymerization of the Internal compartment 24 comprises a first composi- solubilized monomers. As a latex particle is formed tion comprising a drug identified by dots 25, and 25 from the miscelle, this particle then swells and an optional osmagent or optional dispensable os- takes up more monomer from the aqueous phase. mopolymer identified by dashes 26. Compartment Monomer molecules migrate from the monomer 24 comprises a second composition identified by droplets through the water phase into the latex vertical lines 27, comprising an expandable particles until ail monomer droplets are dissolved hydrogel. First composition 25 and second com- 30 and all the monomer is converted to macromole- position 27 are in laminar arrangement, and they cules. In this process the latex particles gradually cooperate with wall 22 for the effective delivery of increase in size until the polymerization is com- drug 25 through exit passageway 23. In Figure 6, plete. A milliliter of the final dispersion generally wall 22 is a three component composition compris- contains 101* latex particles, each consisting of ing (a) an aqueous emulsion of ethylacrylate meth- 35 several hundred monomolecules. The macromole- yl methacrylate, (b) an aqueous latex of ethyl cel- cules comprise 103 to 104 monomer structural units lulose and (c) a hydrophilic polymer such as poly- resulting in a molecular weight of 10s to 10s. The vinyl alcohol. emulsion comprises polyacrylates-methacrylates of While Figures 1 through 6 illustrate various the following structure: embodiments of dosage form 10 that can be coat- 40 ed with the coatings of this invention, it is to be R R understood the coating composition can be applied I \ to a wide variety of dosage forms that have various C CH, C — shapes and sizes. The coating composition can be 2 I I applied to devices including buccal, implant, ar- 45 c=o c=o tifical gland, cervical, intrauterine, nasal, vaginal, I I anal-rectal, osmotic, diffusion, elastomeric, and the OR' OR' like. In these forms the dosage form is coated with the coat of the invention and it can be adapted for administering a beneficial medicine to animals, 50 wherein R is the hydrogen or a lower alkyl of 1 to 7 warm-blooded mammals, humans, farm and zoo carbons such as methyl, ethyl, and the like, and R animals, avians, reptiles, and the like. is a lower alkyl radical of 1 to 7 carbons such as methyl, ethyl, and the like. Procedures for manufacturing polyacrylate-methacrylate emulsions are DETAILED DESCRIPTION OF THE INVENTION 55 described in Drugs Made in Germany, Vol. 16, No. 4, pp 126-36, (1973). The emulsions are commercially available as Eudragit8 from Rohm Pharma, In accordance with the practice of this inven- Weiterstadt, West Germany, and from Rohm Tech,

4 IP 0 347 024 A2 nc, Maiden, MA. The emulsions are available as weight percent (wt u/o) or an aqueous emuision or Eudragits-E30D, a copolymerization product based the alkylacrylate methacrylate, (b) from 10 to 60 wt )n polyacrylic and methacrylic acid esters, and as % of the aqueous emuision of ethyl cellulose and, Eudragit3-L30D a copolymerization product based optionally, (c) from 0 to 60 wt % of a hydrophilic jn methacrylic and acrylic acid esters. 5 polymer, with the amount of all ingredients equal to The coating composition comprises also an 100 wt %. For example, in more specific embodi- aqueous polymeric dispersion of ethyl cellulose. An ments a coating composition comprises (d) 40 wt aqueous emulsion comprising ethyl cellulose is % of an aqueous emulsion of ethylacrylate methyl prepared by a polymer emulsification process. The methacrylate wherein the monomers are present in xocess comprises dispersing a liquified water in- w a 70/30 ratio in the copolymer, 40 wt % of an soluble polymer phase in an aqueous liquid me- aqueous emulsion of ethyl cellulose, and 20 wt % jium phase containing at least one nonionic, an- of polyvinyl pyrrolidone; a coating comprising (e) onic or cationic emulsifying agent in the presence 36 wt % of the emulsion of ethylacrylate methyl Df a compound selected from the group consisting methacrylate, 24 wt % of the emulsion of ethyl jf hydrocarbons, hydrocarbyl alcohols, ethers, al- 15 cellulose and 40 wt % of hydroxypropylmethylcel- ;ohol esters, amines, halides and carboxylic acid lulose exhibiting a molecular weight of 9,200; a asters that are inert, non-volatile, water insoluble, coating composition comprising (f) 36 wt % of the iquid and contain a terminal aliphatic hydrocarbyl emulsion of .ethylacrylate methyl methacrylate, 24 group of at least 8 carbons, and mixtures thereof, wt % of the aqueous emulsion of ethyl cellulose, and subjecting the resulting emulsion to a com- so and 40 wt % polyethylene oxide having a molecu- ninuting force sufficient to enable the production of lar weight of about 50,000; a composition compris- an aqueous emulsion containing polymer particles ing (g) 31 wt % of an aqueous emulsion of averaging less than about 0.5 micron in size. methylacrylate ethyl methacrylate, 29 wt % of an An aqueous latex of ethyl cellulose having a aqueous emulsion of ethyl cellulose and 40 wt % D.1 to 0.3 micron particle size is prepared as fol- 25 of an acidic carboxyvinyl polymer; and a com- ows: first, sodium lauryl sulfate and cetyl alcohol postion comprising (h) 36 wt % of an aqueous are dissolved in deionized water. Then a solution of emulsion of ethylacrylate methyl methacrylate, 24 sthyl cellulose comprising ethyl cellulose in wt % of an aqueous emulsion of ethylcellulose and toluene.-methyl alcohol-methylene chloride is added 40 wt % of polyvinyl alcohol having a molecular to the sodium lauryl siilfate-cetyl alcohol water 30 weight of 4,000,000. phase to form an emulsion. The emulsion is next The coating composition can be applied to a homogenized by passing it through a submicron drug or to a compressed drug core by standard dispenser operated at about 6000 psi. The homog- manufacturing procedures. For example, one man- snized emulsion next is placed into a rotating flask ufacturing procedure that can be used for coating a and the solvents evaporated by slowly rotating the 35 drug substrate is the air suspension technique. The flask at about 50 "C and at 100 mmHg vacuum to air suspension technique consists in suspending remove all the solvent and to concentrate the poly- and tumbling a drug, or a compressed drug core to mer emulsion. The evaporation is continued for be coated, in a current of air comprising the coat- about three hours to provide a stable ethyl cel- ing composition until a coat is applied to the drug lulose latex comprising 18% solids. Procedures for 40 or to the drug core. The air suspension procedure preparing ethyl cellulose emulsions are disclosed is known in U. S. Patent No. 3,207,824; in J. Am. in U. S. Patent No. 4,177,177. Emulsions compris- Pharm. Assoc., Vol. 48, pp 451-59, (1959); and in ing ethyl cellulose are commercially available from ibid, Vol 49, pp 82-84, (1960). A drug or a drug FMC Corporation, Philadelphia, PA. core can be coated or surrounded with the wall The coating composition provided by the in- 45 forming composition in a Wurster3 air suspension vention also comprises a hydrophilic polymer. Re- coater, or in an Aeromatic® air suspension coater. presentative polymers include polyvinyl alcohol that Other coating procedures such as pan coating can is 99% hydrolyzed and has a molecular weight of be used for applying the coat. Generally the coat about 100,000; polyvinyl pyrrolidone having a mo- that surrounds a drug, or a drug core, will have a lecular weight of about 100,000 to 360,000; hydrox- so thickness of 1 to 25 mils, usually 4 to 12 mils thick. ypropylmethylcellulose having a molecular weight The drug coated product generally is annealed of 9,200 to 5,000,000; hydroxypropylceliulose, acid- or cured at a temperature of about 35° C to 65° C, ic carboxy polymers having a molecular weight of usually for 24 to 72 hours. More specifically, in a 450,000 to 4,000,000; polyethylene oxide having a preferred embodiment, the coated manufacture is molecular weight of 100,000 to 5,000,000, and the 55 dried at 50° C for 30 hours in a forced air oven to like. yield the final product. The coating composition provided by the in- The expression, "exit passageway," as used in vention generally comprises (a) about 10 to 60 Figures 3 through 6, for a drug delivery device 9 EP 0 347 024 A2 10 comprising a coated composition as provided by sedatives, psychic energizers, tranquilizers, anti- this invention, denotes means and methods suit- convulsants, muscle relaxants, anti-Parkinsons, an- able for the controlled, metered release of a drug algesics, anti-inflammatories, local anesthetics, from a drug delivery device or from a drug dosage muscle contractants, anti-microbials, anti-malarials, form. The exit means comprises at least one pas- 5 hormones, contraceptives, sympathomimetics, sageway, orifice, or the like, through the coated diuretics, paraciticides, neoplastics, hypoglycemics, wall of a dosage form. The expression, "at least ophthalmics, electrolytes and cardiovascular drugs. one passageway," embraces aperture, orifice, bore, These drugs and the daily dosage is known to the pore, porous element, through which pores a drug art in Pharmaceutical Sciences, edited by Reming- can travel, a hollow fiber, capillary tube, porous ;o ton, 16th Ed., (1980), published by Mack Publish- overlay, porous insert, and the like. The expression ing Company, Easton, PA. also includes a material that erodes or is leached The drug can be in various pharmaceutically from a wall in a fluid environment of use to produce acceptable forms, such as uncharged molecules, at least one passageway of controlled releasing molecular complexes, pharmacologically accept- dimensions. Representative materials for forming a 75 able salts such as hydrochloride, hydrobromide, passageway or two passageways, or a multiplicity sulfate, laurylate, palmitate, phosphate, nitrate, bo- of passageways in an environment of use, include rate, acetate, maleate, tartrate, oleate and salicy- an erodible innocuous poly(glycolic acid), or poly- late; for acidic medicines such as salts of metals, (lactic acid) member in the wall, a gelatinous fila- amines or organic cations, for example quaternary ment, a particle of polyvinyl alcohol leachable ma- 20 ammonium can be used. Derivatives of medicine terials such as fluid removable pore forming poly- such as an ester, ether and amides can be used saccharide, salt, oxide, polyhydric alcohol, and the for the purpose of this invention. Also, a medicine like. A passageway or a plurality of passageways of that is water insoluble can be used in a form that is governed dimensions for the controlled release of a water soluble derivative thereof to serve as a drug can be formed by leaching a passageway 25 solute, and on its release from a dosage form it is forming material, such as sorbitol, from the wall. converted by enzymes, hydrolyzed by the body The passageway can have any shape such as pH, or by other metabolic process, to the originally round, triangular, square, elliptical, irregular, and biologically active form. the like, for assisting in the metered release of a The osmopolymer 27 used for making the os- drug from a dosage form. A dosage form can 30 motic device of Figure 6 comprises a homo- comprise one or more than one passageway in polymer that exhibits an osmotic pressure gradient spaced apart relations which are, optionally, on across a fluid permeable wall, imbibes fluid into more than a single surface of a dosage form. The dosage form 10, expands and pushes drug 25 passageways and equipment for forming a pas- through passageway 23 to the exterior of device sageway are disclosed in U. S. Patents No. 35 10. The osmopolymers are hydrophilic polymers 3,845,770; 3,916,889; 4,063,064; and in 4,088,864. comprising noncross-linked hydrogels and lightly Representative passageways formed by the gov- cross-linked hydrogels, such as cross-linked by erned leaching of a pore former to produce a pore covalent or ionic bonds. Tne hydrophilic hydrogels of precontrolled rate releasing size are disclosed in usually exhibit a 2 to 50 fold volume increase U. S. Patents No. 4,200,098 and 4,285,987. 40 comprising acidic carboxy polymers having a mo- The expression, "therapeutically active drug," lecular weight of 450,000 to 4,000,000; poly- as used herein, denotes a beneficial medicine neat, (hydroxyalkyl methacrylate) polymers having a mo- or a composition comprising a beneficial drug. In lecular weight of 30,000 to 5,000,000; poly- the specification and in the accompanying claims, vinylpyrrolidone) having a molecular weight of the term, "medicine and drug," are used as equiv- 45 10,000 to 360,000; polyacrylic acid having a molec- alents, and these terms include any physiologically ular weight of 80,000 to 200,000; polyethylene ox- or pharmacologically active substance that pro- ide polymers having a molecular weight of 100,000 duces a local or a systemic effect in animals, to 5,000,000, and the like. Representative polymers including warm-bloode^ mammals, primates and that form hydrogels are known to the prior art in U. humans. The terms, "physiologically and pharma- so S. Patent Nos. 3,865,108 issued to Hartop; cologically," are defined in Stedman's Medical Dic- 4,002,173 issued to Manning; 4,207,893 issued to tionary, (1966), published by Williams and Wilkins, Michaels; 4,327,725 issued to Cortese et al, and in Baltimore, MD. The active drug that can be coated, Handbook of Common Polymers, by Scott and or the drug that can be placed into a drug delivery Roff, published by Chemical Rubber Company, device coated with the composition of this inven- 55 Cleveland, OH. tion, comprise inorganic and organic drugs that Osmagent 20 as seen in Figure 4, and os- include, without limitation, drugs that act on the magent 26 as seen in Figure 6, are osmotically central nervous system, depressants, hypnotics, effective compounds that exhibit an osmotic pres-

6 iP 0 347 024 A2 ure gradient across a wall against a fluid. Os- wt % methylacrylate ethyl metnacryiate copolymer, nagents are known also as osmotically effective pigment, lactose and water and blending with (b) ;olutes. Representative osmagents include magne- 40 wt % ethyl cellulose, sodium lauryl sulfate and ;ium sulfate, magnesium chloride, sodium chloride, water, and blending all ingredients with 20 wt % thium chloride, potassium sulfate, sodium sulfate, 5 polyvinyl alcohol with vigorous stirring for 40 min- thium sulfate, potassium chloride, sodium sulfate, utes to yield the blended emulsion. The emulsion nannitol, urea, sorbitol, inositol, raffinose, sucrose, is applied as an external wall to a drug core for jlycose, and the like. The osmagents are known in providing osmotic dosage forms. J. S. Patent No. 4,327.725. The osmotic dosage forms are manufactured '0 for oral administration and comprise the following: a first composition is prepared by passing through )ETAILED DESCRIPTION OF THE EXAMPLES a 40 mesh screen 74.40 wt % polyethylene oxide having a molecular weight of 200,000. Then 20.10 wt % of nifedipine and 5.00 wt % of hydrox- The following examples are merely illustrative ys ypropylmethylcellulose having an average molecu- )f the present invention and they should not be lar weight of 11,200 is added to the polyethylene ;onsidered as limiting the scope of the invention in oxide and the three ingredients mixed for about 10 three any way, as these examples and other equivalents minutes in a conventional mixer. While the hereof will become more apparent to those skilled ingredients are mixing, 300 ml of denatured anhy- n the drug delivery art in the light of the present 20 drous ethanol is added slowly to the mixer and the jisclosure. the drawings and the accompanying mixing continued for an additional five minutes. ;laims. The wet granulation is passed through a 20 mesh screen, dried at room temperature for 16 hours and passed again through a 20 mesh screen. Finally, EXAMPLE 1 25 1.5 wt % of magnesium stearate is added to the granulation and all the ingredients mixed on a roller mill for one to three minutes. A drug delivery dosage form adapted, de- A second composition is prepared by mixing signed and shaped as an osmotic delivery system 64.30 wt % of polyethylene oxide having a molecu- s manufactured as follows: first, 98.7 wt % potas- 30 lar weight of 5,000,000 with 29.20 wt % sodium sium chloride, 1.2 wt % silicon dioxide and 0.1 wt chloride and the mix passed through a 40 mesh % stearic acid are added to a blender to produce a screen. The just prepared mixture is mixed with lomogeneous blend. Then the blend is com- 5.00 wt % hydroxypropylmethylcellulose having a pressed into potassium chloride drug cores. number average molecular weight of 9,200 and The drug cores are coated with an aqueous 35 with 1.00 wt % of ferric oxide for 10 minutes in the emulsion. The cores weigh 500 mg and they are mixer. Then, 300 ml of denatured anhydrous added to an Aeromatic coater. The coating com- ethanol is added slowly to the blending mixture and position comprises 36 wt % of aqueous emulsion all the ingredients mixed for an additional five min- ethylacrylate methyl methacrylate copolymer, 24 wt utes. The freshly prepared wet granulation is % aqueous emulsion of ethyl cellulose and 40 wt 40 passed through a 20 mesh screen, allowed to dry % polyvinyl alcohol. at room temperature for 16 hours, and again The aqueous emulsion coat is applied in an passed through a 20 mesh screen. The screened Aeromatic air suspension coater at a process air granulation is mixed with 0.50 wt % magnesium temperature of 42° C, an atomizing air pressure of stearate in a roller mill for 10 minutes. 2.4 atm, a coating solution pumping rate of 15 45 A drug core is prepared by adding 328 mg of milliliters per minute, and possessing a solid con- the first composition to a tablet press and tamped, tent of copolymer of about 10 wt %. then 164 mg of the second composition is added The coated systems next were cured in a to the press and the two compositions pressed into forced air oven for 30 hours at 50° C. The systems a two-layered drug core. The compressed two- were cooled to room temperature and a 0.037 mm 50 layered drug core is coated with a coating com- exit port was laser drilled through the dry coated position and the coat cured with the aid of heat as wall that surrounds the core of potassium chloride. des cribed in Example 1. Finally, a 20 mil orifice is drilled through the coated wall to provide the final dosage form. EXAMPLE 2 55

EXAMPLE 3 An emulsion coat is prepared by taking (a) 40

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An emulsion coat is prepared by blending 60 Claims wt % of an aqueous emulsion of ethyl acrylate methyl methacrylate titanium, lactose and water, 1. A coating composition for a drug comprising: known also as Eudragit3-E30D, with 40% of an an emulsion comprising a lower alkylacrylate-lower aqueous emulsion of ethyl cellulose, dibutyl 5 alkyl methacrylate copolymer wherein the lower sebacate, hydroxypropylmethylcellulose and water, alkyl group comprises 1 to 7 carbon atoms, and also known as Aquacoat3 coat, to produce a uni- ethyl cellulose. form homogeneous emulsion. 2. The coating composition according to claim Next, a drug core weighing 323.23 mg is pre- 1, wherein the coating composition comprises a pared comprising 5.96 wt % salbutamol hemisul- w hydrophilic polymer. fate, 89.01 wt % sodium chloride, 20 wt % poly- 3. A therapeutic composition comprising: vinyl pyrrolidone, 2 wt % cross-linked sodium car- (a) a drug; and, boxymethylcellu lose and 1.0 wt % magnesium (b) an emulsion coat surrounding the drug, stearate. The drug core is coated with the emul- said emulsion coat comprising a lower sion, annealed, and a 20 mil passageway drilled /5 alkylacrylate-lower alkyl methacrylate copolymer through the freshly prepared wall of the dosage and ethyl cellulose. form to provide an osmotic delivery device. An embodiment of the invention pertains to a 4. The therapeutic composition according to method for administering a drug to the gastrointes- claim 3, wherein the emulsion coat comprises a tinal tract to establish a drug blood level. The 20 hydrophilic polymer. method comprises the steps of: (A) admitting into 5. An osmotic device comprising: the gastrointestinal tract an osmotic dosage form (a) a wall comprising a cured emulsion, said comprising: (1) a wall comprising a non-toxic emul- emulsion comprising a lower alkylacrylate-lower sion that is permeable to the passage of fluid and methacrylate wherein the lower alkyl comprises 1 substantially impermeable to the passage of drug, 25 to 7 carbon atoms and ethylcellulose, which wall which wall forms: (2) a compartment comprising a surrounds; gastrointestinal administrable drug; and (3) at least (b) a compartment; one exit passageway in the emulsion-based wall (c) a therapeutically effective amount of drug that connects the exterior of the dosage form with in the compartment; and, the interior of the dosage form; (B) imbibing fluid 30 (d) at least one passageway in the wall con- through the wall into the compartment at a rate necting the exterior with the interior of the device determined by the permeability of the wall and the for delivering the drug over time. osmotic pressure gradient across the wall to form, in the compartment, a dispensable composition 6. The osmotic device according to claim 5, that is hydrodynamically and osmotically pumped 35 wherein the emulsion comprises a hydrogel. through the passageway from the dosage form; (C) thereby delivering the drug in a therapeutically effective amount to the gastrointestinal tract for passing into the blood circulation for established a blood level over a prolonged period of time from 4 40 hours to 24 hours. The invention pertains to an dosage form comprising an emulsion coat or wall for delivering a drug at a controlled rate over time. While there has been described and pointed out the novel features 45 of the invention as applied to presently preferred embodiments, those skilled in the art will appre- ciate that various modifications, changes and omis- sions in the invention disclosed and claimed can be made without departing from the spirit of the 50 invention.

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