Aqueous emulsion coating for pharmaceutical dosage form

DESCRIPTION

GIVES

PATENT OF INVENTION

No. 90 343

APPLICANT: ALZA CORPORATION, North American, headquartered at 950 Page Mill Road, Palo Alto, California 94303-0802, United States of America.

EPIGRAPH: PROCESS FOR PREPARING A COMPOSITION

COATING FOR AN OSMOTIC MEDICINAL PRODUCT AND RESPECT.

INVENTORS:

Claim of right of priority under Article 4 of the Paris Convention of 20 March 1883. United States of America, 21 April 1988, under the paragraph. 07 / 184,478.

INPI MOD. 113 RF 16732 * ~ I <y and yo '

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RESUME

PROCESS FOR PREPARATION OF A COATING COMPOSITION FOR A MEDICINAL PRODUCT AND ITS DEVICE 0SM0TIC0

This invention relates to a process of preparing a therapeutic composition comprising a treated emulsion coating which surrounds the medicament. The emulsion comprises a lower alkyl lower alkyl methacrylate alkyl acrylate copolymer, and ethyl cellulose. The emulsion optionally comprises a hydrophilic polymer.

FlG.l FIG.2

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HOLDER: ALZA CORPORATION

EPIGRAPH: PROCESS FOR PREPARATION OF A COATING COMPOSITION FOR AN OSMOTIC DEVICE AND MEDICINAL PRODUCT

DESCRIPTIVE MEMORY

FIELD OF INVENTION

This invention relates to a pharmaceutical dosage form containing an aqueous emulsion coating, and an aqueous emulsion coating.

BACKGROUND OF THE INVENTION

In Remington's Pharmaceutical Sciences, 14th Ed., P. 1681 (1970) it is stated that pill coating has been a pharmaceutically accepted technique for well over ten centuries. For example, Rhazes (850 - 932 AD) in the ninth century used a pill coating mucilage, and Avicenna (980 - 1037 AD) was given the introduction of silver and gold pill coatings in medicine. There was a time when the coating of fine powdered talcum pills, called pearl coating, was very popular. The coating1

Gelatin pills were introduced by Garot in 1838. The first sugar-coated pills that appeared in the United States were imported from France around 1842. The first sugar-coated pills were made in the United States in 1856 by Warner, a Philadelphia pharmacist. Coating of tolu pills was done around 1860 and, twenty-four years later, Unna introduced the enteric pill coated.

Various pharmaceutical articles of manufacture have been coated by the drug industry. For example, tablets were coated to a more attractive form, to protect the drug content from moisture, and to improve its taste. The tablets also had an enteric dissolving drug release coating in the intestine of a warm-blooded animal. Recently, in 1972, Theeuwes and Higuchi coated osmotic dosage forms with a rate-controlling semipermeable membrane for drug release at a known rate per unit time.

While the above mentioned dosage forms are useful in controlling health and disease, they are associated with serious disadvantages. That is, organic solvents are usually used to apply the coating to the medicament, serious, undesirable disadvantages accompany the use of organic solvents. For example, organic solvents are generally toxic to

They are living tissues and must be substantially withdrawn from the dosage form to avoid a danger to their recipient. Another major disadvantage with the use of organic solvents is that they are flammable, thus the danger of fire during the manufacturing process is possible. Organic solvents also represent an environmental problem and the use of such solvents requires complicated recovery systems to avoid environmental contamination. Recovery systems are expensive, which increases the costs of the final dosage form.

Those skilled in the pharmaceutical industry will agree that if a coating that is substantially free of organic solvents is provided by coating drugs, granules and powders, drug dispensers and the like, such a coating would have immediate positive value and, concomitantly, would represent a breakthrough in drug coating industry. Similarly, pharmaceutical industry experts will appreciate that if a coating that is applied from a non-organic solvent, and having the coated release device, the thermodynamic ability to release a beneficial drug at a controlled rate, such a device release would have practical application in the field of human and veterinary medicine.

OBJECTIVES OF THE INVENTION

In view of the foregoing, it is an immediate object of this invention to provide a novel and useful dosage form coating composition which overcomes the disadvantages related to the above process.

Another object of this invention is to provide a novel coating composition including pharmaceutically acceptable ingredients which is innocuous and useful for the manufacture of dosage forms.

Another object of this invention is to provide a non-toxic coating composition that is substantially free of organic solvents which is useful in the manufacture of dosage forms by standard manufacturing techniques.

Another object of this invention is to provide an aqueous based coating composition which is relatively uncomplicated, easy to apply and relatively inexpensive.

Another object of this invention is to provide an aqueous polymeric coating composition that has long term stability and is sedimentation resistant in a liquid medium.

Another object of this invention is to provide an aqueous coating composition that is useful in the manufacture of a drug delivery device having drug release rate control qualities.

Another object of this invention is to provide a medicament delivery device which can be manufactured by conventional processes in various sizes, shapes and shapes which includes an improvement characterized by coating the device with a non-toxic aqueous coating that surrounds the device. medicine.

Another object of this invention is to provide an aqueous solvent coating composition that is not flammable, is not a threat to the environment during its production, and when applied to a core of a medicament.

Another object of this invention is to provide a process for applying an aqueous coating to a drug core, thereby creating an orally administrable drug dosage form.

Other objects, features and advantages of this invention will become more apparent to those skilled in the drug industry from the following detailed description, together with the accompanying drawings and claims.

BRIEF DESCRIPTION OF DRAWINGS

In the drawn figures, which are not drawn to scale but are published to illustrate various embodiments of the invention, the drawn figures are as follows:

Figure 1 is an open view showing a powdered medicine coated with the coating composition provided by this invention;

Figure 2 is an open view illustrating granules of a medicament coated with the aqueous-based composition provided by this invention.

Figure 3 is a view of a designed and shaped osmotic device for oral administration of a metered amount of medicament to the gastrointestinal tract of a warm-blooded animal;

Figure 4 is an open view of the osmotic device of Figure 3 depicting the device wall. osmotic composition, including a wall-forming coating composition provided by this invention;

Figure 5 is a view of the osmotic device of Figure 3, in open section, illustrating it in eluding another embodiment of the wall forming coating composition provided by this invention;

In the drawings and description, like parts in the related figures are identified by like numbers. The terms which appear earlier in the description of the drawings, as well as their modalities are later described elsewhere in the specification.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now in detail to the drawings which are examples of dosage, including a coating composition provided by this invention, and which examples are not to be construed as limiting the invention, an example of a dosage form is illustrated in the following. Figure 1.

In Figure 1 a dosage form 10 includes a powdered medicament 11 generally having a size for the powder passing through a sieve having an aperture of 0.074mm by 0.250mm surrounded by a coating composition 12. coating 12 includes an aqueous methyl methacrylate - ethyl acrylate emulsion, ^{and unite} Aqueous ethyl cellulose IStex. The coating composition 12 may further include a hydrophilic polymer such as polyvinyl alcohol and the like.

In Figure 2 another embodiment of dosage form 10 is shown in open view. In Figure 2 the dosage form 10 includes drug granules 13. The granules of the medicament are generally of a size that passes through a sieve with an opening larger than 0.250mm by 9.50mm. The drug granules 13 are surrounded by the applied aqueous coating composition 14. Coated position 14 in a presently preferred embodiment includes an aqueous emulsion of a acrylate methacrylate polymer having a phase transition temperature of about 10 ° C, an aqueous latex which is partially miscible with the aqueous acrylate emulsion, and whose latex imparts mechanical stability to the acrylate emulsion, and an optional hydrophilic polymer that regulates the water permeability of the aqueous acrylate composition.

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latex. The wall or membrane composition is formed by the coalescence of latex particles which are interlaced with the water-soluble polymer during a low temperature treatment cycle. In a presently preferred embodiment, at least one component of the ingredients included in the blended emulsion has a glazing phase transition temperature less than the treatment temperature, so that coalescence occurs during the drying period.

In Figure 3 another embodiment of dosage form 10, manufactured as an osinotic drug delivery device 10 is illustrated. In Figure 3 the osmotic dosage form 10 comprises a body 15, including a wall 16 surrounding and forming an internal compartment. , which is not seen in Figure 3. Osmotic dosage form 10 includes at least one passageway 17 for connecting the interior of dosage form 10 with the exterior of osmotic dosage form 10.

Figure 4 shows the osmotic dosage form 10 in open section. In Figure 4 the osmotic dosage form 10 contains a body member 15, an applied aqueous coating wall 16, an outlet passage 17.

Wall 16 surrounds and forms an inner compartment 18.

The inner compartment 18 comprises a dot-distributable medicament 19 and an optional osmotic agent 20, represented by dashes. Wall 16 is permeable to the passage of an external liquid present in the environment of use, and wall 16 is substantially impermeable to the passage of medicament 19. In Figure 4 wall 16 comprises (a) an aqueous methylmethacrylate-ethylacrylate emulsion, a 70/30% copolymer with a molecular weight of about 800,000, and an aerca vitrification phase transition temperature of 10 ° C, and (b) an ethyl cellulose aqueous latex with particle sizes of from 0.1 to 0.3 micron on average.

In Figure 5 another embodiment of dosage form 10, manufactured as an osmotic drug delivery device is illustrated. In Figure 5 the osmotic dosage form 10 comprises a body member 21 including a wall 22 which surrounds and forms an inner compartment, which is not seen in Figure 5. The dosage form 10 contains at least one or more passageways 23 formed during the manufacture of dosage form 10, or the passageway 23 is optionally formed when the dosage form 10 is in a liquid use medium. The passageway 23 connects the interior of the dosage form 10 with the exterior for releasing a medicament to a biological environment.

In Figure 6, the dosage form 10 is an open view of the dosage form 10 of Figure 5. In Figure 6 the form 10 comprises a body member 21, an aqueous lining pliable wall 22 and outlet holes 23. A wall 22 surrounds and forms an inner compartment 24. Inner compartment 24 includes a first composition including a dot-identified medicament 25, an optional osmotic agent, or a distributable optional trace-identified osmopolymer 26. 0 Compartment 24 comprises a second composition identified by vertical lines 27, including an expandable hydrogel. First composition 25 and second composition 27 are in laminar arrangement and collaborate with wall 22 for effective release of medicament 25 through the exit passageway.

23 In Figure 6, wall 22 is a composite composition comprising (a) an aqueous methyl methacrylate-ethylacrylate emulsion, (b) an aqueous ethyl cellulose latex and (c) a hydrophilic polymer such as polyvinyl alcohol.

While Figures 1 to 6 illustrate various embodiments of dosage form 10 which may be coated with the coatings of this invention, it is to be understood that the coating composition may be applied to a wide variety of dosage forms having various shapes and sizes. sizes. The coating composition may be applied to devices including buccal, implants, artificial, cervical, intrauterine, nasal, rectal, osmotic, elastomeric diffusion, and other glands; In such forms, the dosage form is coated with the coating of the invention and may be adapted to administer medicaments to animals, warm-blooded mammals, humans, farm and zoo animals, birds, reptiles and animals. others.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of this invention, a medicament or medicament delivery device is prepared by coating or forming a wall with the coating composition provided by this invention. The coating composition comprises an aqueous emulsion of an alkyl^andtacrilate alkylacrylate. . This polymeric synthetic aqueous emulsion is made by emulsion polymerization. In an emulsion polymerization process the monomers are finely divided by the addition of an emulsifier in water. Emulsifiers accumulate at the boundary between the monomer droplets and water, but also form micelles in the aqueous phase, in which the monomer molecules are solubilized. Prior to the commencement of polymerization one milliliter of such an emulsion contains, in addition to the monomers in solution, about elas micelles with solubilized monomers and ΙΟ micrometer droplets stabilized by the emulsifier.

Polymerization is initiated by the addition of a water-soluble initiator, generally a radical to be dissolved first in the monomer reaction vessel. Activated monomers or oligomers migrate within micelles and lead to polymerization of solubilized monomers. As a latex particle is formed from the micelle, this particle swells and absorbs more monomer from the aqueous phase. Monomer molecules migrate from monomer droplets through the aqueous phase to ί

latex particles until all monomer droplets are dissolved and all monomer is converted to macromolecules. In this process the latex particles gradually increase in size until polymerization is complete. One milliliter of the final dispersion contains generally 10 latex particles, each consisting of several hundred monomolecules. The macromolecules 34 comprise from 10 to 10 monomer structural units, resulting in a molecular weight of from 10 to 1θ. The emulsion comprising polyacrylates-methacrylates of the following structure.

IR

-C-CH

I

C-0

I

0R '

C-0 (Ir 'where R is hydrogen or lower alkyl of 1 to 7 carbon atoms, such as methyl, ethyl and the like, and R' is a lower alkyl radical of 1 to 7 carbon atoms, such as methyl, ethyl and the like Polyacrylate-methacrylate emulsion manufacturing processes are described in Drugs Made in Germany, Vol. 16, No. 4, pp. 126-36, (1973).

Eudragit from Rohm Pharma, Weiterstadt, West Germany, and Rohm Tech, Inc., Malden, Ma.

are marketed as Eudragit-E30D, a copolymerization product based on polyacrylic and methacrylic acid esters, and as Eudragit '-L30D a copolymerization product based on netacrylic and acrylic acid esters.

The coating composition also comprises an aqueous polymeric dispersion of ethyl cellulose. An aqueous emulsion including ethyl cellulose is prepared by a polymer emulsification process. The process comprises dispersing a phase of a water-insoluble polymer, disrupted, into an aqueous liquid phase phase containing at least one nonionic, anionic or cationic emulsifying agent in the presence of a compound selected from hydrocarbons, hydrocarbyl alcohols. , ethers, alcohol-esters, amines, halides and esters of carboxylic acids which are inert, non-volatile, water-insoluble, liquid and contain a terminal aliphatic hydrocarbyl group of, at least 8 carbon atoms and mixtures thereof subjecting the resulting emulsion to a sufficient crushing force to enable the production of an aqueous emulsion containing the polymer particles having an average size of less than 0.5 micron.

An aqueous ethyl cellulose latex with 0.1 to 0.3 micron particles is prepared as follows: first sodium lauryl sulfate and cetyl alcohol are dissolved in deionized water. Then, an ethyl cellulose solution containing ethyl cellulose in netylene chloride and toluene methyl alcohol joins the aqueous phase of sodium lauryl sulfate-cetyl alcohol to form an emulsion. The emulsion is then homogenized by passing through a submicron distributor operating at about 6000 psi. The homogenized emulsion is then placed in a rotating vessel and the solvents are evaporated by slowly rotating the vessel at about 50 ° C and at a vacuum of 100mm.

Hg to remove all solvent and concentrate the polymer emulsion. Evaporation is continued for about three hours to obtain a stable 18% solids ethyl cellulose latex. Processes for preparing ethyl cellulose emulsions are disclosed in US Pat.

No. 4,177,177. Ethyl cellulose containing emulsions are marketed by FMC Corporation, Philadelphia, PA.

The coating composition provided by the invention also contains a hydrophilic polymer. The most important polymers include polyvinyl alcohol which is 99% hydrolyzed and has a molecular weight of about 100,000. polyvinyl pyrrolidone with molecular weight from about 100,000 to 360,000; hydroxypropyl methylcellulose having a molecular weight of 9,200 to 5,000,000; hydroxypropylcellulose carboxylic acid polymers having a molecular weight of 450,000 to 4,000,000; polyethylene oxide with a molecular weight of 100,000 to 5,000,000 and others.

The coating composition provided by the invention generally contains (a) about 10 to 60 weight percent (wt%) of an aqueous methacrylate alkylacrylate emulsion, (b) 10 to 60 wt% of the aqueous ethyl cellulose emulsion and optionally (c) from 0 to 60 wt% of a hydrophilic polymer, with the total of all ingredients being 100 wt%. For example, in more specific embodiments, a coating composition comprises (d) wt% of an aqueous methylmethacrylate-ethylacrylate emulsion, wherein the monomers are present in a ratio of 70/30 in the copolymer, 40 wt% of an aqueous emulsion. of ethylcellulose, and 20 wt% polyvinyl pyrroiidone; a cladding (e) containing 36 wt% methyl methacrylate-ethylacrylate emulsion, 24 wt% ethylcellulose emulsion and 40 wt% hydroxypropyl methylcellulose having a molecular weight of 9,200; a coating composition containing (f) 36 wt% methyl methacrylate-ethylacrylate emulsion, wt% ethyl cellulose aqueous emulsion and 40 wt% polyethylene oxide having a molecular weight of about 50,000; a composition containing (g) 31 wt% of an aqueous ethyl methacrylate methylacrylate emulsion, 29 wt% of an aqueous ethylcellulose emulsion and 40 wt% of a carboxyvinyl acid polymer; and a composition including (h) wt% of an aqueous methyl methacrylate-ethylacrylate emulsion, 24 wt% of an aqueous ethylcellulose emulsion and 40 wt% polyvinyl alcohol having a molecular weight of

4.000.000

The coating composition may be applied to a medicament or a compressed medicament core by standard manufacturing processes. For example, a manufacturing process that can be used to coat a drug substrate is the air suspension technique. The air suspension technique is to suspend and turn a drug, or the core of a compressed drug to be coated in an air stream containing the coating composition, until a coating is applied to the drug or to the drug core. The air suspension process is known from U.S. Patent No. 3,207,824; in J. Am.

Pharm. Assoe., Vol 48, pp. 451-59, (1959) and in ibid, vol.

49, pp. 82-84, (1960). A medicament or the core of a medicament may be coated or enveloped with the wall-forming composition in a Wurster air suspension coater, or an Aeromatic air suspension coater. Other coating processes such as autoclave coating may be used for coating application. Generally, the coating surrounding a medicament or the interior of a medicament will have a thickness of 1 to 25 mils, usually 4 to 12 mils.

The coated form is generally subjected to a temperature of 35 ° C to 65 ° C, usually for 24 to 72 hours. More specifically, in one embodiment the coated product is dried at 50 ° C for 30 hours in a forced air oven to produce the final product.

The term exit passage as used in Figures 3 to 6 for a drug release mechanism containing a coated composition as provided by this invention means appropriate means and methods for the controlled, controlled release of a drug from a drug delivery device or a drug dosage form. The outlet means comprises at least one passage, orifice or the like, through the coated wall of a dosage form. The term at least one passageway encompasses the opening, orifice, hole, pore, porous member through which pores may pass a medicament, a hollow filament, capillary tube, porous cover, porous insert and the like. The term also includes a material which crumbles or is degradable from a wall in a liquid medium of use to produce at least one passage of such dimensions as to permit controlled release. Materials most commonly used to form a passageway or two passages or a multiplicity of passages in a medium of use include a harmless, corrosive member of polyglycolic acid or polylactic acid in the wall, a gelatinous filament, a polyvinyl alcohol particle / degradable materials such as a removable pore-forming polysaccharide, salts, oxides, polyhydric alcohol and others. A passageway or a plurality of passageways of regulated size for controlled release of medicament may be formed by degradation of a passageway-forming material, such as sorbitol, from the wall.

The passageway can be any shape: round, triangular, square, elliptical, irregular and the like to assist in the measured release of a drug from the dosage form. A dosage form may contain one or more than one passage in spaced, spaced apart, optionally structured relationships, on more than one surface of a dosage form. The passages and the equipment for forming a passage are patented in U.S. Patent No. 3,845,770; 3,916,889; 4,063,064 and 4,088,864.

Representative passages formed by the regular degradation of a pore former to produce a pre-controlled rate release pore are patented in U.S. Pat. Nos. 4,200,098 and

4.285.987 .

The term therapeutically active medicament as used herein means a pure beneficial medicament or a composition containing a beneficial drug. In the description and appended claims the terms medicament and drug are used as equivalents and these terms include any physiological or pharmacologically active substance producing a local or systematic effect. in animals, including warm-blooded mammals, primates and humans. The terms physiologically and pharmacologically are defined in the Stedman's Medical Dictionary, (1966) published by Williams and Wilkins, Baltimore, MD. The active medicament which may be coated or the medicament which may be placed in a medicament delivery mechanism coated with the composition of this invention comprises inorganic and organic medicaments which include, without limitation, central nervous system drugs, antidepressants, hypnotics, sedatives, psychic stimulants, tranquilizers, anti-convulsants, muscle relaxants, anti-Parkinson's, analgesics, anti-inflammatories, local anesthetics, muscle contractors, antimicrobials, antimalarials, hormones, contraceptives, sympathomimetics, diuretics, parasiticides, antineoplastics, hypoglycemic agents, ophthalmic agents, electrolytes and cardiovascular drugs. These medications and the daily dosage are disclosed in Pharmaceutical Sciences, edited by Remington,

16th ed. , (1980), published by Mack Publishing Company,

Easton, PA.

The medicament may be used in various pharmaceutically acceptable forms such as support molecules, molecular complexes, (pharmacologically acceptable) salts such as hydrochloride, hydrobromide, sulfate, laurylate, palmitate, phosphate, nitrate, borate, acetate, maleate, tartrate, oleate and salicylate; for acidic medicines such as metal salts, amines or organic cations. For example, quaternary ammonium may be used. Derivatives of medicaments such as an ester, ether and amides may be used for the purpose of this invention. In addition, a water-insoluble medicament may be used in a form that is a water-soluble derivative thereof to serve as a solute and in its release from the dosage form it is converted by enzymes to hydrolyzate. by the body's PH or other metabolic processes to its original biologically active form.

The osmopolymer 27 used to make the osmotic mechanism of Figure 6 contains a homopolymer that has an osmotic pressure gradient through a fluid permeable wall, soaks liquid into the dosage form 10, raises and pushes the medicament 25 through. passage 23 to the exterior of the device 10. Osmopolymers are hydrophilic polymers containing non-cross-linked and slightly cross-linked hydrogels such as

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πιο crosslinked by covalent or ionic bonds. Hydrophilic hydrogels typically have a 2- to 50-fold swelling containing carboxylic acid polymers with a molecular weight of 450,000 to 4,000,000; hydroxyalkyl polymethacrylate polymers having a molecular weight of 30,000 to 5,000,000; polyvinylpyrrolidones having a molecular weight of 10,000 to 360,000; polyacrylic acid having a molecular weight of 80,000 to 200,000; polyethylene oxide polymers with a molecular weight of 100,000 to 5,000,000, e.g. Representative hydrogel-forming polymers are already known in the industry in U.S. Pat. 3,865,108 to Hartop, - 4,002,173 to Manning; 4,207,893 to Michaels;

No. 4,327,725 to Cortese et al, and in Scott and Roff's Handbook of Common Polymers, published by the Chemical Rubber Company, Cleveland, OH.

Osmotic agent 20, as seen in Figure 4 and osmotic agent 26, as seen in Figure 6, are osmotically effective compounds that present an osmotic pressure gradient through a wall against a liquid. Osmotic agents are also known as osmotically effective solutes. The most representative osmotic agents include magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium chloride, sodium sulfate, mannitol, urea, sorbitol, inositol. , raffinose, sucrose, glucose and others. Osmotic agents are known from U.S. Patent No. 4,327,725.

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DETAILED DESCRIPTION OF EXAMPLES

The following examples are merely illustrative of this invention and should not be construed as limiting the scope of the invention at all, as these examples and other equivalents will be more apparent to those skilled in the art of drug delivery in light of this disclosure. , of the drawings and chs revinvin indications together.

Example 1

An adapted drug release dosage form designed and arranged as an osmotic release system is manufactured as follows: first, 98.7 wt% potassium chloride, 1.2 wt% dioxide are added. of silica and 0.1 wt% stearic acid in a mixer to produce a homogeneous mixture. Then the mixture is compressed into the core of the potassium chloride drug.

The drug cores are coated with an aqueous emulsion. The cores weigh 500 mg and are placed in an Aeromatic Coater. The coating composition contains 36 wt% methyl methacrylate-ethylacrylate copolymer aqueous emulsion, 24 wt% ethylcellulose aqueous emulsion and 40 wt% polyvinyl alcohol.

The aqueous emulsion coating is applied in an Aeromatic air suspension coater at a temperature

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ambient temperature of 42 ° C, an atmospheric pressure of 2.4 atm, a pumping speed coating solution of 15 milliliters per minute and having a solid copolymer content of about 10 wt%.

The coated systems were then treated in a forced air oven for 30 hours at 50 ° C. The systems were cooled to room temperature and a 0.037 mm exit hole was drilled through the dry coated wall surrounding the potassium chloride core with laser.

Example 2

An emulsion coating is prepared by taking (a) 40 wt% methyl methacrylate ethylacrylate, pigment, lactose and water copolymer and mixing with (b) 40 wt% ethyl cellulose, sodium lauryl sulfate and water, and mixing all ingredients with 20 wt% polyvinyl alcohol, stirring vigorously for 40 minutes to produce a well bonded emulsion. Emulsion applies as an outer wall to a drug core for making osmotic dosage forms.

Osmotic dosage forms are manufactured for oral administration and contain the following: A first composition is prepared by passing through a 40 mesh screen, 74.40 wt% polyethylene oxide with a molecular weight of 200,000. Then, 20.10 wt% nifedipin * and 5.00 wt% hydroxypropilloatylcellulose, by weight, are added.

average 11,200 to polyethylene oxide and the three ingredients are mixed for about ten minutes in a conventional mixer. While mixing the three ingredients, 300 ml of denatured anhydrous ethanol are slowly added to the mixer, and stirring is continued for a further five minutes. The wet granulation is passed through a 20 mesh screen, dried at room temperature for 16 hours and again passed through a 20 mesh screen. Finally 1.5 p% magnesium stearate is added to the granulation, and all ingredients are stirred in a roller mill for one to three minutes.

A second composition is prepared by mixing 64.30 wt% polyethylene oxide with a molecular weight of 5,000,000 with 29.20 wt% sodium chloride and the mixture is passed through a 40 mesh screen. The freshly prepared mixture is mixed with 5.00 wt% hydroxypropyl methylcellulose having an average molecular weight of 9,200 and 1.00 wt% ferric oxide for 10 minutes in the blender. Then 300 ml of denatured anhydrous ethanol is slowly added to the mixture being formed and all the ingredients are stirred for a further five minutes. The freshly prepared wet granulation is passed through a 20 mesh screen, allowed to dry at room temperature for 16 hours and again passed through a 20 mesh screen. The granulation that was sieved through is mixed with 0.5 wt% magnesium stearate in a roller mill for 10 minutes.

A medicament core is prepared by adding 328 mg of the first composition in a tablet press and calcining, then 164 mg of the second composition is added and the two compositions compressed into a two-layer medicament core. The compressed two-layer medicament core is coated with a coating composition and the coating is heat treated as described in Example 1. Finally, a 20 mil hole is drilled through the coated wall to form the final dosage form.

Example 3

An emulsion coating is prepared by mixing 60 wt.% Of an aqueous methylmethacrylate-ethylacrylate, titanium, lactose and water emulsion also known as Eudragit-E30D with 40% of an aqueous emulsion of ethylcellulose, dibutyl cebacate, hydroxypropyl methylcellulose and water. , also known as Aguacoat coating, to produce a homogeneous and uniform emulsion.

A core of drug weighing 323.23 mg, including 5.96 wt% salbutamol hemisulfate, 89.01 wt% sodium chloride, 20 wt% polyvinylpyrridone, 2 wt% sodium carboxymethylcellulose, is then prepared. cross-linked and 1.0 wt% magnesium stearate. The medicament core is coated with the emulsion, strengthened and a 20 mils passage is drilled through the freshly prepared wall of the dosage form to provide an osmotic delivery device.

One embodiment of the invention relates to

a method for administering a medicament for the gastrointestinal tract to achieve a therapeutic level of the medicament in the blood. 0 The method comprises the following steps: (A) admitting into the gastrointestinal tract an osmotic dosage form containing: (1) a wall containing a non-toxic liquid-permeable emulsion substantially impermeable to the passage of the medicament, which wall forms: (2) a compartment containing a gastrointestinally administrable medicament and (3) at least one emulsion-based wall outlet passage that connects the exterior of the dosage form with the interior of the dosage form; (B) soaking liquid through the wall into the compartment, the rate determined by the wall permeability and the osmotic pressure gradient across the wall, to form in the compartment a distributable composition that is hydrodynamically and osmotically pumped through the passageway. from the dosage form; (C) thereby releasing a medicament in a therapeutically effective amount to the gastrointestinal tract to pass into the bloodstream establishing a blood level over an extended period of 4 to 24 hours.

The invention relates to a dosage form containing an emulsion coating or wall for releasing a medicament at a controlled rate over time.

While the novel features of the invention have been described and highlighted as applied to the presently preferred embodiments, those skilled in the art will appreciate that various modifications, changes, and omissions may be made to the patented and claimed invention without departing from the spirit of the invention.