HK1021886B - Dosage form for providing ascending dose of drug - Google Patents

Description

Dosage form with escalating drug dose

Technical Field

The present invention relates to dosage forms for administering a drug in progressively increasing doses. The invention also relates to dosage forms containing different concentrations of drug for administration of the treatment at a slowly increasing rate. The present invention also relates to a layered formulation for use in dosage form comprising a first layer and a second layer and each layer comprising a drug at a first concentration and a second concentration. The invention also relates to a method for obtaining a therapeutic effect by administering a dosage form which first gives an initial dose and then gives a dose of drug which continuously increases with time.

Background

For a long time, every social class has benefited from medicine using drugs for pain relief, mood, thought, emotion, behavior and mental personality. Representative drugs for these treatments are opioids, barbiturates, hypnotics, central nervous system stimulants, psychostimulants, alcohols, cannabinoids and catecholamines. Although these drugs are beneficial, there are also serious problems associated with their use, known as drug resistance. MedicineThe development of drug resistance can cause adaptation in affected patients, and thus the efficacy is reduced in the presence of equivalent concentrations of drug. Resistance to certain drugs, such as opioids, is characterized by a shortened duration of action and a reduced intensity of the therapeutic effect. The resistance observed in many drugs is due to adaptation of nervous system cells to the action of the drug, as in Goodman and GilmanTherapeutic pharmacology foundation (The Pharmacological Basis of Therapeutics)7 th edition, page 534 (1940).

In current medical practice, one common class of drugs among these that has become a management of behavior and personality, including attention deficit disorders, is central nervous system stimulants. Although the present invention has been described in detail with respect to central nervous system drugs, it is to be understood that the invention is broad and encompasses drugs administered by the dosage forms of the invention as well as the modes and modes of the invention.

A benefit observed by physicians, psychiatrists, sociologists and clinicians is the rapidity of central nervous system drugs, which has led to the widespread acceptance of central nervous system drugs for the treatment of attention deficit disorders. From recently collected data, it was observed that there were about 2% school-age girls and about 6% school-age boys, totaling about 2 million patients treated with medication for attention deficit.

Prior to the present invention, opioids, barbiturates, hypnotics, central data system stimulants, neurostimulants, alcohols, cannabinoids and catecholamines were all administered in the form of conventional medicaments. For example, one known method of administration involves the use of immediate release drug-containing tablets. The immediate release form releases the drug by dumping it immediately, producing non-equilibrium blood levels characterized by peaks and troughs. Immediate release dosage forms containing the drug have a fast action and a short half-life, and the drug needs to be administered several times a day, resulting in fluctuations in blood levels and thus loss of therapeutic effect. Such dosage forms fail to provide the desired treatment over an extended period of time.

Another known form of administration is a sustained release form. Sustained release dosage forms release drug in a curvilinear manner that does not gradually increase in (drug concentration) over time. Such dosage forms, however, do not provide the desired treatment and proper blood concentration profile. When a drug, such as a centrally acting drug, is released from a sustained release dosage form in which the dosage is not gradually increased, patients often develop rapid or slow resistance to the drug, which is manifested by a shortened duration of action and a reduced intensity required for acceptable treatment. Known sustained release dosage forms do not overcome their inherent deficiencies.

Disclosure of Invention

Based on the above, it is a direct object of the present invention to provide a new and unique dosage form that provides a gradual increase in the dosage of drug over time.

It is another object of the present invention to provide a dosage form that releases the drug in a controlled incremental manner over an extended period of time to maintain therapeutic efficacy.

It is another object of the present invention to provide a dosage form for maintaining the therapeutic effect of a drug in a patient who has acquired drug resistance, wherein the dosage form releases the drug to the patient in a manner that the dosage is controlled to increase over time.

It is another object of the present invention to provide a dosage form for maintaining the therapeutic effect of a drug in a patient who has acquired rapid drug resistance, wherein the dosage form releases the drug to the patient in a manner that the dosage increases controllably over time.

It is another object of the present invention to provide a dosage form for maintaining the therapeutic effect of a drug in a patient who has acquired a slow drug resistance, wherein the dosage form releases the drug to the patient in a controlled increase in the dose over time.

It is another object of the present invention to reduce the incidence of drug resistance in patients to whom drugs are administered, said drugs developing drug resistance in the patients, using a dosage form characterized by being administered in a manner such that the dosage is slow and gradual increasing over time to produce a prolonged effect.

It is another object of the present invention to provide a dosage form for administration of opioids, barbiturates, hypnotics (sedatives), central nervous system stimulants, psychiatric system stimulants, alcohols, cannabinoids and catecholamines which overcomes the disadvantages known in the prior art.

It is another object of the present invention to provide a dosage form comprising a dosage form that substantially reduces the deleterious side effects of drug resistance by orally administering the drug in a slowly increasing dose, which reduces the development of drug resistance associated with drugs having the ability to develop resistance in a patient.

It is another object of the present invention to provide a method of reducing the incidence of acquired resistance in a patient to whom a drug has been administered, said drug developing resistance in the patient, wherein the method comprises administering a dosage form which releases the drug in a manner such that the dosage slowly increases over time to produce the desired effect.

It is another object of the present invention to provide a method of administering a drug in a manner that the dose is slowly increasing over time by administering a dosage form that releases the drug in a manner that the dose is slowly increasing over time.

It is another object of the present invention to provide a dosage form comprising a first layer comprising a first concentration of drug and a second layer comprising a second and higher concentration of drug, the dosage form releasing the first layer followed by the second layer to provide a slow and gradual increase in drug release.

It is another object of the present invention to provide a method of administering a drug in a slow and gradual increasing dose manner by administering a dosage form comprising a first concentration of the drug and a second, higher concentration of the drug, the dosage form releasing the first concentration of the drug first and then the second, higher concentration of the drug to slowly and gradually increase the release of the drug.

It is another object of the present invention to provide a dosage form for administering a drug in a slow and gradual increasing pattern over time (dose), characterized in that the first drug layer contains a lower concentration of drug than the second drug layer, which are continuously released to provide the gradual increasing pattern.

It is another object of the present invention to provide a pharmaceutical oral tablet manufactured in the form of a solid dosage form comprising a first layer containing 10ng to 300mg of a drug and a pharmaceutically acceptable carrier, and a second layer containing 50ng to 500mg of a drug and a pharmaceutically acceptable carrier, said first and second layers releasing the drug in a sequential manner to administer a slow and increasing dose of the drug.

It is another object of the present invention to provide an osmotic pharmaceutical tablet manufactured in the form of an osmotic dosage form, comprising a first layer containing 10ng to 300mg of drug and a pharmaceutically acceptable carrier, a second layer containing 50ng to 500mg of drug and a pharmaceutically acceptable carrier, and a third layer sequentially displacing (dispplaying) the first and second layers from the dosage form, for administration of a slow and increasing dose of the drug.

It is another object of the present invention to provide an osmotic dosage form comprising a first layer containing a first dose of drug, a second layer containing a higher dose of drug than the first layer, a third layer formed from the dosage form to aid the first layer and then the second layer, and a semi-permeable wall layer surrounding the inner layer and having an exit orifice for releasing an increasing dose of drug over a period of 16 hours or more.

It is another object of the present invention to provide a bilayer arrangement dosage form comprising a first drug layer containing a lower concentration of drug than a second drug layer.

It is another object of the present invention to provide a tri-layer dosage form comprising a first drug layer comprising a drug layer at a lower concentration than a second drug layer, and a third layer providing physical support to the first and second layers to facilitate release of the first and second layers into an environment of use.

It is another object of the present invention to provide a composition comprising: (1) an agent selected from the group consisting of opioids, barbiturates, central nervous system stimulants, psychostimulants, alcohols, cannabinoids, and catecholamines; (2) a pharmaceutically acceptable hydrophilic polymeric carrier; and (3) hydrophobic compounds that help control the hydration rate of the composition.

It is another object of the present invention to provide an osmotic dosage form comprising an immediate release dose of drug on the exterior of the dosage form and a delayed escalating dose of drug on the interior of the dosage form, the combination of the two doses of drug providing the escalating dose of drug to attenuate acquired and ongoing resistance.

It is another object of the present invention to provide an oral tablet comprising a first layer comprising a drug at a first concentration and a pharmaceutically acceptable carrier and a second layer comprising a drug at a second concentration and a pharmaceutically acceptable carrier, wherein the second layer of the tablet comprises a higher dose of the drug.

These and other objects, features and advantages of the present invention will become more fully apparent from the following detailed disclosure of the invention and appended claims.

Drawings

FIG. 1 depicts the increasing release rate of the drug methylphenidate in the dosage form provided by the present invention.

FIG. 2 depicts the increasing release rate of the drug pseudoephedrine in the dosage forms provided by the present invention.

In accordance with the practice of the present invention, it has now been found that the present invention provides a dosage form having a drug release rate that gradually increases over time. The dosage form of the present invention comprises a wall layer surrounding a cavity (component). The wall layer of the dosage form is permeable to fluids present in the environment of use, such as aqueous biological fluids of the gastrointestinal tract, but is impermeable to the drug. The wall layer comprises a semipermeable component capable of maintaining its physical and chemical integrity during the delivery of the drug from the dosage form. The semipermeable wall layer comprises a polymer selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate and cellulose triacetate. The wall layer may contain from 65 wt% (weight percent) to 100 wt% of the polymer. The wall layer may contain 0-35 wt% of polyethylene glycol having a number average molecular weight of 190-20000, 0-35 wt% of hydroxypropyl alkylcellulose selected from the group consisting of hydroxypropyl methylcellulose having a number average molecular weight of 9000-250000, hydroxypropyl ethylcellulose, hydroxypropyl butylcellulose and hydroxypropyl amylcellulose, and 0-35 wt% of hydroxyalkyl cellulose including hydroxymethyl cellulose having a number average molecular weight of 7500-200000, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose. The total amount of all components including the wall layers is equal to 100 wt%. Wall-forming polymers are well known from us patents 3845770, 3916899, 4036228, 4111202 and 5178899.

The dosage form includes at least one exit port connecting the exterior to the interior of the dosage form. The term "outlet" as used herein includes passages, pores, bores, pores, micropores, hollow fibers, capillaries, apertured patches, apertured inserts and the like for the delivery of a drug from a dosage form. The exit passageway may comprise an erodible material or may leach out of the parietal layer in a fluid environment of use, such as the gastrointestinal tract. Representative materials for forming the one or more passageways include erodible poly (glycolic) acid, erodible poly (lactic acid), erodible poly (orthoester), erodible poly (orthocarbonate), gelated silk, poly (vinyl alcohol), leachable materials including liquid removable pore-forming polysaccharides, salts and oxides. The outlet may be formed by leaching compounds such as sorbitol, lactose or glucose. The outlet may be of any shape, such as circular, triangular, square or oval. The dosage form may have one or more spaced pathways on a common surface. Passageways and instruments formed thereby are disclosed in U.S. patents 3845770, 3916899, 4036064, 4088864, 4200098, 4285987 and 5178866.

The compartment of the dosage form includes a first layer containing a dose of drug and a second layer containing a higher dose of drug. The first and second layers are released sequentially. The first layer is adjacent the exit orifice to facilitate first release from the dosage form, and the second layer is released to provide a gradual increase in the profile of the released drug. The first layer comprises from 10ng (nanogram) to 250mg (milligram) of the drug and a pharmaceutically acceptable carrier; the second layer contains between 50ng (nanogram) and 500mg (milligram) of drug and a pharmaceutically acceptable carrier. Administration of the first dose followed by the second dose provides a controlled increase in dosage while reducing or eliminating the frequency of daily administration or reducing drug resistance. The first layer releases its drug within 30 minutes to 5 hours and the second layer releases its drug within 1.5 hours to 9 hours.

The present invention provides a first layer comprising: (a)10ng-250mg of the drug; (b)5mg to 250mg of a pharmaceutically acceptable carrier comprising a hydrophilic polymer comprising a poly (alkylene oxide) having a number average molecular weight of 40000-1000000, a viscosity of 12 to 17600cps (centipoise) in 5% aqueous solution at 25 ℃, representative members selected from the group consisting of poly (methane oxide), poly (ethylene oxide), poly (propylene oxide), poly (butylene oxide), poly (ethylene oxide) poly (propylene oxide) copolymers and mixtures of two different poly (alkylene oxides), such as poly (ethylene oxide) having a number average molecular weight of 100000 and two different pharmaceutically acceptable carrier mixtures comprising (polyethylene oxide) having a number average molecular weight of 200000, and poly (ethylene oxide) having a number average molecular weight of 200000-300000, the poly (alkylene oxide) polymer being obtainable from Union Carbide Corporation; from 0mg to 100mg of a hydrophilic pharmaceutically acceptable carboxyvinyl polymer (also known as a carboxypolyalkylene polymer) having a number average molecular weight of 7500-3000000, including a carboxyvinyl polymer having a number average molecular weight of 450000, a carboxyvinyl polymer having a number average molecular weight of 1250000 having a number average molecular weight of 750000 and a carboxyvinyl polymer having a number average molecular weight of 3000000, as disclosed in U.S. Pat. Nos. 2798053, 2909462 and 3825068, Carbopol may be usedPolymer commercially available from b.f. goodrich Company; and 0mg to 250mg of a pharmaceutically acceptable alkali metal salt of carboxymethylcellulose wherein the alkali metal is sodium or potassium, typically sodium carboxymethylcellulose having a viscosity average molecular weight of 10000-7000000 available from Hercules Corporation, the term "pharmaceutically acceptable" means not orally administrable to a human patientToxic and acceptable; (c)0.05mg to 7.5mg of a surfactant selected from the group consisting of amphoteric, anionic, cationic and nonionic surfactants, and representative are sorbitan trioleate, sorbitan tristearate, ethylene glycol fatty acid esters, polyethylene glycol monostearate, sorbitan sesquioleate, glycerol monostearate, sorbitan monooleate, propylene glycol monolaurate, sorbitan monostearate, diethylene glycol monolaurate, sorbitan monopalmitate, polyethylene oxide mannitol dioleate, sorbitan monolaurate, polyethylene oxide lauryl ether, polyethylene oxide monostearate, polyethylene glycol 400 monostearate, triethanolamine oleate, polyethylene oxide alkylphenols, polyethylene oxide alkylaryl ethers, polyethylene oxide sorbitan monolaurate, polyethylene oxide sorbitan monostearate, amphoteric surfactants, sorbitan monolaurate, polyethylene oxide monostearate, sorbitan monolaurate, Polyethylene oxide sorbitan monooleate, polyethylene oxide monostearate, polyethylene oxide sorbitan monopalmitate, polyethylene oxide monostearate, polyethylene oxide sorbitan monolaurate, polyethylene oxide lauryl ether, polyethylene oxide monostearate, sodium oleate and sodium lauryl sulfate, these surfactants being those of RemingtonScience of medicine17 th edition, 1305-1306 (1985); (d)0.5mg to 20mg of a hydroxypropyl alkylcellulose binder polymer selected from the group consisting of hydroxypropyl methylcellulose having a number average molecular weight of 9000-; and 0.0mg to 20mg of a hydroxyalkyl cellulose selected from the group consisting of hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose and hydroxypentyl cellulose having a number average molecular weight of 7500 and 750000, available from Aqualon Company; (e)0.01mg-5mg of a lubricant, such as stearic acid, magnesium stearate, calcium stearate, potassium oleate, magnesium laurate or calcium palmitate.

A second layer in contact with the first layer contains from 50ng to 500mg of the drug, the second layer having a higher concentration of drug than the first layer in order to achieve a gradually increasing release profile of the released drug. The second layer includes: (a) 50ng-500mg of the drug; (b)25mg to 450mg of the pharmaceutically acceptable carrier for the hydrophilic hydrogel polymer exemplified, e.g., a poly (alkylene oxide) having a number average molecular weight of 40000-1000000; 0mg to 100mg of a carboxyvinyl polymer having a number average molecular weight of 7500-3000000; 0ng-250mg of carboxymethyl cellulose alkali metal salt with viscosity average molecular weight of 10000-700000; (c)0.05mg to 7.5mg of a surfactant; (d)0.5mg to 20mg of hydroxypropyl alkylcellulose with a number average molecular weight of 9000-750000 and 0.0mg to 20mg of hydroxyalkyl cellulose with a number average molecular weight of 7500-750000; and (e)0.01mg to 5mg of a lubricant. The polymer, surfactant and lubricant are the same as disclosed in the first layer.

The dosage form includes a third layer that sequentially displaces or propels the first or second layer through the exit orifice. The second layer includes: (a)15ng-450mg of a hydrophilic osmopolymer selected from poly (alkylene oxide) having a number average molecular weight of 2000000-10000000 or alkali metal salt of carboxymethylcellulose having a viscosity average molecular weight of 2000000-10000000; (b)2mg to 50mg of an osmotic agent, also referred to as an osmotically effective solute, osmotically effective compound, and osmotic agent, including inorganic and organic compounds, representative osmotic agents being selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium chloride, sodium sulfate, magnesium succinate, tartaric acid, sugars, rhamnose, sucrose, glucose, and lactose; (c)0.01mg to 10.0mg of a surfactant, including amphoteric, anionic, cationic and nonionic surfactants, as shown in the first layer; (d)0mg to 20mg of a carboxyvinyl polymer having a number average molecular weight of 7500-10000000, as shown in the first layer; (e)0.1mg to 30mg of a hydroxypropyl alkylcellulose having a number average molecular weight of 9200-750000, including a hydroxypropyl alkylcellulose polymer shown in the first layer; (f)0.0mg to 5mg of a colorant compound to distinguish the dosage form, e.g., red iron oxide; and (g)0.0mg to 5mg of a lubricant, including those shown in the first layer.

The drugs present in the first and second layers include opioids, barbiturates, hypnotics, CNS-acting drugs, psychostimulants, alcohols, cannabinoids and catecholamines. Examples of drugs are central nervous system acting drugs for the treatment of attention deficit disorders, including catecholamines and drugs that can mimic their action. The drug for this treatment is selected from amphetamine, dextroamphetamine, methamphetamine, methylphenidate, racemic methylphenidate, hydroxymethyl methylphenidate, ethyl methylphenidate, amphetamine, and phenytoin. The medicaments also include their pharmaceutically acceptable salts, for example selected from the hydrochloride, sulfate, phosphate, acetate, hydrobromide, pamoate and maleate salts.

The present invention also includes coating the outer surface of the dosage form. The coating is the outer coating provided by the dosage form. An outer coating on the wall layer of the dosage form contains a dose of drug, the coating releasing the drug in conjunction with the chamber containing the dose of drug to provide an unexpected gradual ascending drug release profile. The cover layer provides an initial dose of drug, while a larger dose of drug is then released from the cavity of the dosage form giving a gradual rising drug release profile. The cover layer contains 100ng-100mg of drug which is released within up to 2 hours, followed by a larger dose of drug released from the dosage form. The coating contains a drug selected from the group consisting of opioids, barbiturates, hypnotics, CNS-acting drugs, and catecholamines. Various representative drugs present in the cover layer include drugs selected from the group consisting of: amphetamine, dextroamphetamine, methamphetamine, methylphenidate, racemic methylphenidate, hydroxymethyl methylphenidate, ethyl methylphenidate, alkyl methylphenidate, amphetamine, and phenytoin. These medicaments also include their pharmaceutically acceptable salts, for example selected from the hydrochloride, sulfate, phosphate, acetate, hydrobromide, pamoate and maleate salts. Representative examples of drugs present in the cover layer are alkyl piperazinolates, including 10ng-20mg methylphenidate.

The covering layer contains the drug mixed with a pharmaceutically acceptable carrier, wherein the carrier comprises an aqueous release carrier, alkyl cellulose, methyl cellulose and ethyl cellulose; hydroxyalkyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxybutyl cellulose; hydroxypropyl alkylcellulose, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, hydroxypropyl butylcellulose; methyl dextrose, gum arabic, guar gum (acacia guar gum), pregelatinized starch, propylene glycol alginate and cyclodextrin, a coating containing 0-5 wt% (in one possible embodiment 0.01-5 wt%) polyethylene glycol, polypropylene glycol, polyvinylpyrrolidone and acetylated triglycerides. The cover layer provides the desired therapeutic effect of the drug, e.g., methylphenidate, and dissolves in the presence of the fluids in the gastrointestinal tract of the patient. Thus, the cover layer provides a therapeutic effect of the drug by oral administration into the drug-receiving environment of the patient, the gastrointestinal tract.

The wall layers of the dosage form are formed during manufacture by an aerosol process. The method comprises suspending and tumbling the compressed three-layer article in an air stream and applying the wall layer-forming composition until a wall layer is formed over the chamber containing the three-layer core. The air-suspension method is particularly suitable for forming the wall layers independently. The air suspension method is disclosed in us patents 2799241 and 5082668. The wall layer can be formed in an air-suspension coater using 2.5-5% solids in a co-solvent, such as a methylene chloride-methanol (80:20, wt: wt) or acetone-water co-solvent (85:15, 90:10, or 95:5, wt: wt). Other wall layer forming techniques, such as coating pans, may also be used to deposit the wall layer forming composition by continuously spraying it while tumbling in a rotating pan. Thicker wall layers can be produced using a coating pan. The use of a larger volume of solvent, such as methanol, in the co-solvent system produces thinner wall layers. Finally, the chamber coated with the wall layer is dried in an oven at 30-50 ℃ for one week or at 50 ℃ with humidity controlled to 50RH (relative humidity) for 18 hours to 3 days.

The first and second layers of the present invention can be fabricated using conventional techniques. For example, one method of manufacture is to mix and compress the drug and other ingredients into a solid layer. The drug and other ingredients may also be mixed with the solvent by conventional means such as ball milling, calendering, stirring or roller compaction to form a semi-solid or solid, which is then pressed into a preselected shape. The laminate should be of a size to conform to the internal dimensions of the area of the laminate occupied by the dosage form and should also be of a size to conform to the second and third layers in contact therewith. The transmitting or boosting layer comprising the osmopolymer is in contact with the second drug layer. The displacement layer is manufactured using a technique for manufacturing the first layer and the second layer. Lamination of the first drug layer, the second drug layer and the displacement layer may be made using conventional lamination techniques. The three-layered chamber forms a core surrounded and encapsulated by an outer semi-permeable wall layer. Laser drilling is used to open the exit port into contact with the first drug layer, and the dosage form is optionally oriented with a laser to form an exit passageway.

In another method of manufacture, the dosage form is prepared by wet granulation techniques. In wet granulation techniques, for example, the ingredients contained in the drug and drug layers are mixed with an organic solvent such as isopropanol-dichloromethane (80:20, v: v) (vol: vol) or methanol-dichloromethane as the granulation liquid. Other granulation liquids, such as denatured alcohol (100%) may also be used for this purpose. The ingredients forming the drug layer are separately sieved and then thoroughly mixed in a blender. Thereafter, the other ingredients contained in the drug layer are dissolved in a portion of the granulation liquid, such as the above-mentioned co-solvent. The wet mixture, which was prepared later, was then slowly added to the drug mixture and mixing continued in a blender. The granulation liquid was added until a wet mix was obtained, and then the wet mass was pressure sieved into a pan. The mixture is dried at 30-50 ℃ for 18-24 hours. The dried granules are then sieved to size. Next, the lubricant is sieved and added to the dry sieved granulation mixture. The particles were added to a ball mill jar and mixed in a porcelain ball mill jar for 1-15 minutes. Other drug layers and displacement layers were also prepared using the same wet granulation technique. The compositions were pressed into the respective laminates in a laminator.

Another manufacturing method that may be used to provide the chamber forming composition layer includes separately mixing the powdered ingredients of each layer in a fluid bed granulator. After the powdered ingredients are dry mixed in the granulator, a granulation liquid, such as an aqueous solution of poly (vinyl-pyrrolidone), a denatured alcohol solution of poly (vinyl-pyrrolidone), a solution of poly (vinyl-pyrrolidone) in 95:5 ethanol/water, or a solution of poly (vinyl-pyrrolidone) in a mixture of ethanol and water, is sprayed onto the powder. The ingredients may optionally be dissolved or suspended in the granulation liquid. The coated powder is then dried in a granulator. The process granulates all the ingredients present therein while adding the granulation liquid. After the granules are dried, a lubricant, such as stearic acid or magnesium stearate, is added to the granulator. The granules of each layer are then freed from compaction by the method described above.

The continuation of the invention can also be prepared by another method, mixing a known dose of the drug with the layer forming ingredients of the composition, and then compressing the composition into a solid layer article having dimensions corresponding to the internal dimensions of the cavity. The other layer of the contact containing the increased dose of drug is made in a similar manner. In another method of manufacture, the layers are independently manufactured by mixing the drug, other drug composition-forming ingredients, and solvent using conventional laboratory methods such as ball milling, calendaring, stirring, or roll compaction to form a semi-solid or solid, which is then pressed into a laminate. Next, a first layer and a second, different layer are discharged adjacent to a displacement composition comprising an osmopolymer and optionally an osmotic agent. The three-layered core is then surrounded by a semi-permeable wall layer. Lamination of the first, second, intermediate and third layers may be accomplished by conventional ply lamination techniques. The wall layer may be formed by casting, spraying or dipping the three-layer core formed by pressure into the wall layer forming material. Another technique for forming the wall layer is air-suspension coating. The process comprises suspending and tumbling the compressed three-layer article in an air stream until the wall layer-forming composition surrounds the core of the three layers. The air suspension method is described in us patent 2799241; journal of the American society for pharmacy (J.am.pharm.Assoc.), Vol.48, pp 451-; and Vol.49, pp.83-84(1960), supra. Other methods of manufacture are described inModern plastic encyclopedia (Modern) Plastic Encyclopedia)Vol., 46, pp.62-70 (1969); and RemingtonScience of medicine14 th edition, page 626-.

Examples of solvents suitable for making the wall layer, first layer and second layer include inert inorganic and organic solvents. Solvents broadly include aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, aromatic, heterocyclic solvents, and mixtures thereof. Representative solvents include acetone, diacetone alcohol, methanol, ethanol, isopropanol, butanol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene chloride, ethylene dichloride, propylene dichloride, carbon tetrachloride, chloroform, nitroethane, nitropropane, tetrachloroethane, diethyl ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, tetrahydrofuran, diethylene glycol dimethyl ether, aqueous or non-aqueous mixtures thereof, such as acetone and water, acetone and methanol, acetone and ethanol, methylene chloride and methanol, ethylene dichloride and methanol, and methylene chloride and ethanol. Solvents are disclosed in us patent 5030456.

Detailed Description

The following examples illustrate the invention and should not be construed as limiting the scope of the invention in any way, as it will be apparent to those skilled in the art in view of the description and claims of the invention and their equivalents.

Example 1

A dosage form designed and adapted for administration with a gradual increase in release rate profile was prepared according to this example.

First, a first layer composition containing a drug dose is prepared as follows. 157.8g of polyethylene oxide having a number average molecular weight of 200000 were passed through a 40 mesh U.S. sieve and placed in the drum of a conventional planetary mixer. Next, 31.2g of methylphenidate drug was added to the blender. Then, 10g of hydroxypropylmethylcellulose having a number average molecular weight of 9200 was passed through a 40 mesh sieve and added to a blender containing methylphenidate and polyethylene oxide. Thereafter, 0.5g of FD & C blue dye No.1 for identification was added to the drum of the mixer. This component was stirred in a blender for 10 minutes to obtain a homogeneous composition. Next, about 100ml of denatured anhydrous ethanol was gradually added to the blender over 5 to 10 minutes under continuous stirring to turn the hard dry ingredients into wet granules. The wet granules were passed through a 20 mesh sieve, dried at room temperature for 16 hours, and then passed through a 20 mesh sieve. Then, 0.5g of magnesium stearate was passed through a 40 mesh screen, added to the homogeneous composition and all components were mixed for a few more minutes.

Next, a second composition providing a second layer was prepared as follows. First, 112.6g of polyethylene oxide having a number average molecular weight of 200000 were passed through a 40 mesh U.S. sieve and placed in the drum of a conventional planetary mixer. Next, 76.4g of methylphenidate drug was added to the blender. Then, 10g of hydroxypropylmethylcellulose having a number average molecular weight of 9200 was passed through a 40 mesh sieve and added to a blender containing methylphenidate and polyethylene oxide. Thereafter, 0.5g of FD & C blue dye No.1 or a different FD & C dye, providing a different color between layers, was added to the blender. This component was stirred in a blender for 10 minutes to obtain a homogeneous composition. Next, about 100ml of denatured anhydrous ethanol was gradually added to the blender over 5 to 10 minutes under continuous stirring to turn the hard dry ingredients into wet granules. The wet granulation was passed through a 20 mesh screen, dried at room temperature (72 ℃ F., 22.2 ℃) for 16 hours, and passed through a 20 mesh screen. Then, 0.5g of magnesium stearate was passed through a 40 mesh screen, added to the homogeneous composition and all components were mixed for an additional 1 minute.

Next, a displacement layer, i.e., a third layer was prepared as follows. First, 107g of polyethylene oxide of number average molecular weight 7000000, 80g of sodium chloride as a penetrant, 10g of hydroxypropylmethylcellulose of number average molecular weight 9200, and 2g of red iron oxide were passed through a 40 mesh sieve, and then added to a drum of a blender. These components are stirred together to form a homogeneous mixture. Next, 50ml of denatured anhydrous ethanol was added to the mixer while continuously stirring for 7 to 10 minutes to prepare wet granules. The wet granules were passed through a 20 mesh sieve, dried at room temperature for 16 hours and then passed through a 20 mesh sieve. Next, 1g of magnesium stearate was passed through a 40 mesh screen, added to the granules, and all components were mixed for several minutes.

Next, the first composition and the second composition were pressed together into a contact layer by the following method. First, 33mg of the first composition was added to 7/32' (0.55cm) of the mold cavity and lightly tamped. Next, 24mg of the second composition was added to the mold and lightly tamped to provide two drug layers. Then, 57mg of the displacement composition was added to the mold and the three layers were compressed together with 1/2 tons of pressure to form a three-layer tablet. The weight of the three-layer tablet is 114 mg.

The three layers were then coated with a semipermeable membrane as follows. First, a semipermeable membrane composition was prepared containing 95% cellulose acetate and 5% polyethylene glycol (supplied by Union Carbide co., inc.) having a number average molecular weight of 3350, wherein the cellulose had an acetyl group content of 39.8%. The process is carried out by dissolving the components in a mixture of acetone and water (90:10, wt.: wt.) to obtain a composition having a solids content of 5%. The trilayer tablets were placed in a coating pan and 15mg of the semipermeable membrane composition was sprayed onto the trilayer tablets. Next, a 30 mil (0.76mm) hole was drilled in one side of the drug to connect the first layer to the exterior of the dosage form. The tablets were dried at 50 ℃ and 50% relative humidity to remove residual solvent.

The first layer of the dosage form contained 5.2mg of methylphenidate, 26mg of polyethylene oxide having a number average molecular weight of 200000, 1.65mg of hydroxypropylmethylcellulose having a number average molecular weight of 9200, 0.083mg of magnesium stearate and 0.083mg of dye. The second layer of the dosage form contained 9.17mg methylphenidate, 13.52mg polyethylene oxide having a number average molecular weight of 200000, 1.2mg hydroxypropylmethylcellulose having a number average molecular weight of 9200, 0.06mg magnesium stearate and 0.06mg dye. The third displacement layer contained 30.5mg of polyethylene oxide having a number average molecular weight of 7000000, 22.8mg of sodium chloride as a penetrant, 2.85mg of hydroxypropylmethylcellulose having a number average molecular weight of 9200, 0.57mg of iron oxide, and 0.285mg of magnesium stearate as a lubricant. The semipermeable membrane contained 14.25mg of cellulose acetate having an acetyl content of 39.8% and 0.75mg of polyethylene glycol having a number average molecular weight of 3350. The dosage form exhibited a gradual increase in release rate profile of 0.03mg at 1 hour, 0.4mg at 2 hours, 1.08mg at 3 hours, 0.95mg at 4 hours, 1.06mg at 5 hours, 1.31mg at 6 hours, and 1.72mg at 7 hours, as shown in figure 1.

Example 2

This example was prepared according to the method of example 1 except that the first and second layers were selected from amphetamine, dextroamphetamine, methamphetamine, etoposide, amphetamine, and phenytoin, wherein the drug dose in the second layer was greater than the same drug dose in the first layer, the first layer contained between 10ng and 300mg of drug and the second layer contained between 50mg and 500mg of drug.

Example 3

In accordance with this example, a dosage form was prepared which was designed and adapted for the administration of pseudoephedrine hydrochloride with a gradually increasing release rate profile,

first, a first layer of the pharmaceutical composition was prepared by passing 139g of a 300000 number average molecular weight polyethylene oxide through a 40 mesh screen and placing the first screened hydrophilic polymer into the drum of a blender. Next, 40g of pseudoephedrine hydrochloride was added to the blender and the composition was stirred for 5 minutes. Then, 10g of hydroxypropylmethylcellulose having a number average molecular weight of 9200 and 10g of polyoxyethylene stearate 40 were passed through a 40-mesh sieve and charged into a blender filled with the above components. Thereafter, all components were stirred together for 10 minutes to obtain a homogeneous composition. Next, about 100ml of denatured anhydrous ethanol was gradually added to the blender over 5 to 10 minutes under continuous stirring to turn the hard dry ingredients into wet granules. The wet granules were passed through a 20 mesh sieve, dried at room temperature for 16 hours, and then passed through a 20 mesh sieve. Then, 1g of magnesium stearate was passed through a 40 mesh screen and added to the blender, and all components were blended for a few more minutes.

Next, a second drug layer is provided and prepared as follows. 28.8g of polyethylene oxide having a number average molecular weight of 300000 was passed through a 40 mesh sieve, and the hydrophilic polymer after sieving was put into a blender. Next, 150g of pseudoephedrine hydrochloride was added to the mixer and the composition was stirred for 3 minutes. Then, 10g of hydroxypropylmethylcellulose having a number average molecular weight of 9200, 10g of polyoxyethylene stearate 40 and 0.2g of red iron oxide were passed through a 40-mesh sieve and charged into a blender. Thereafter, this component was stirred for 10 minutes to obtain a uniform composition. Next, 100ml of denatured anhydrous ethanol was added to the stirrer and stirred continuously for 10 minutes to obtain wet granules. The wet granulation was then passed through a 20 mesh screen, dried at room temperature for 16 hours, and then passed through a 20 mesh screen. Then, 1g of magnesium stearate was passed through a 40 mesh screen, added to the granules and stirred for several minutes.

Next, a displacement layer, i.e., a third drug-free layer, is prepared as follows. First, 111g of polyethylene oxide having a number average molecular weight of 7000000, 60g of sodium chloride, 10g of hydroxypropylmethylcellulose having a number average molecular weight of 9200, 10g of polyoxyethylene stearate 40, 6g of a crosslinked acrylic acid polymer having a number average molecular weight of 3000000 and 2g of red iron oxide were passed through a 40-mesh sieve and charged into a blender. These components are stirred together until a homogeneous mixture is formed. Next, 25ml of denatured anhydrous ethanol was added to the mixer while continuously stirring for 10 minutes to prepare wet granules. The wet granules were passed through a 20 mesh sieve, dried at room temperature for 16 hours and then passed through a 20 mesh sieve. Next, 1g of magnesium stearate was passed through a 40 mesh screen, added to the granules, and all components were mixed for several minutes.

The three layers are then compressed into three-layer tablet cores. First, 22mg of the first pharmaceutical composition is added to a mold and lightly tamped. Next, 18mg of the second pharmaceutical composition was added to the mold and lightly tamped. Then, 40g of the third drug free displacement composition was added to the mold and the three layers were compressed together with 1/2 tons of pressure to form a three layer tablet.

The three layers were then coated with a semipermeable membrane as follows. First, a semipermeable membrane composition containing 95% cellulose acetate and 5% polyethylene glycol having a number average molecular weight of 3350, in which the acetyl group content of cellulose was 39.8%, was prepared. The process is carried out by dissolving the components in a mixture of acetone and water (90:10, wt.: wt.) to obtain a composition having a solids content of 5%. The trilayer tablets were placed in a standard coating pan and coated with 12mg of semipermeable membrane composition. Next, a 30 mil (0.76mm) hole was drilled in one side of the drug to connect the first layer to the exterior of the dosage form. The tablets were dried at 50 ℃ and 50% relative humidity for 48 hours to remove residual solvent.

The first layer of the dosage form contained 4.4mg pseudoephedrine hydrochloride, 15.3mg polyethylene oxide of number average molecular weight 300000, 1.1mg hydroxypropylmethylcellulose of number average molecular weight 9200, 1.1mg polyoxyethylene stearate 40 and 0.11mg magnesium stearate. The second layer of the dosage form contained 13.5mg pseudoephedrine hydrochloride, 2.59mg polyethylene oxide of number average molecular weight 300000, 0.9mg hydroxypropylmethylcellulose of number average molecular weight 9200, 0.9mg polyoxyethylene stearate 40, 0.018mg red iron oxide and 0.09mg magnesium stearate. The third layer contained 22.2mg of polyethylene oxide having a number average molecular weight of 7000000, 12mg of sodium chloride, 2mg of hydroxypropylmethylcellulose having a number average molecular weight of 9200, 2mg of polyoxyethylene stearate 40, 1.2mg of crosslinked acrylic acid polymer, 0.4mg of red iron oxide and 0.2mg of magnesium stearate. The semipermeable membrane contained 11.4mg of cellulose acetate and 0.6mg of polyethylene glycol having a number average molecular weight of 3350, wherein the acetyl content was 39.8%. The dosage form exhibited increasing release rate profiles of 0.13mg at 1 hour, 0.65mg at 2 hours, 2.2mg at 3 hours, 2.78mg at 4 hours, 3.24mg at 5 hours, 3.14mg at 6 hours, and 3.43mg at 7 hours, as shown in figure 2.

Example 4

The dosage forms of this example were prepared in accordance with the examples described above. In this example, the displacement or third layer and the semipermeable membrane are prepared as above, with the first and second layers being different.

First, the first drug layer is prepared as follows. First, 139g of polyethylene oxide having a number average molecular weight of approximately 100000 are passed through a 40-mesh sieve and placed in the drum of a conventional planetary mixer. Subsequently, 40g of pseudoephedrine hydrochloride were added to a drum containing polyethylene oxide. Then, 10g of hydroxypropylmethylcellulose having a number average molecular weight of 9200 and 10g of polyoxyethylene stearate 40 were passed through a 40-mesh sieve and charged into a blender containing polyethylene oxide and pseudoephedrine hydrochloride. The four components were stirred together in a planetary mixer for 10 minutes. Next, about 100ml of denatured anhydrous ethanol was gradually added to the blender over 5 to 10 minutes under continuous stirring to turn the hard dry ingredients into wet granules. The wet granules were passed through a 20 mesh sieve, dried at room temperature for 16 hours, and then passed through a 20 mesh sieve. Then, 1g of magnesium stearate was passed through a 40 mesh screen and added to the blender, and all components were blended for a few more minutes.

The second drug layer was prepared as follows: first, 28.8g of polyethylene oxide having a number average molecular weight of about 200000 was passed through a 40 mesh sieve and placed in the drum of a planetary mixer. Subsequently, 150g of pseudoephedrine hydrochloride was weighed and added to a blender filled with polyethylene oxide. Then, 10g of hydroxypropylmethylcellulose having a number average molecular weight of 9200, 10g of polyoxyethylene stearate 40 and 0.2g of red iron oxide were passed through a 40-mesh sieve and added to a drum containing polyethylene oxide and pseudoephedrine hydrochloride. This component was stirred in a planetary mixer for 10 minutes. Next, 100ml of denatured anhydrous ethanol was gradually added to the mixer over 5 to 10 minutes under continuous stirring to convert the hard dry powder into granules. The wet granulation was then passed through a 20 mesh screen, dried at room temperature for 16 hours, and then passed through a 20 mesh screen. Then, 1g of magnesium stearate was passed through a 40 mesh screen, added to the granules and stirred for an additional 1 minute.

The dosage form prepared in this example included the following components: the first drug layer contained 20.0% pseudoephedrine hydrochloride, 69.5% polyethylene oxide with number average molecular weight of 100000, 5% hydroxypropylmethylcellulose with number average molecular weight of 9200, 5% polyoxyethylene stearate 40, and 0.5% magnesium stearate. The second layer of the dosage form contains 75% pseudoephedrine hydrochloride, 14.4% polyethylene oxide with number average molecular weight of 200000, 5% hydroxypropylmethylcellulose with number average molecular weight of 9200, 5% polyoxyethylene stearate 40, 0.1% red iron oxide and 5% magnesium stearate. The third layer contained 55.5% polyethylene oxide having a number average molecular weight of 7000000, 30% sodium chloride, 5% hydroxypropyl methylcellulose, 5% polyoxyethylene stearate 40, 3% cross-linked acrylic acid polymer, 1% red iron oxide, and 0.5% magnesium stearate. The semipermeable membrane contained 11.4mg of cellulose acetate and 0.6mg of polyethylene glycol having a number average molecular weight of 3350, wherein the acetyl content was 39.8%. The dosage form was compressed into a three layer system and a 30 mil hole was drilled in the first layer as the exit port. The final system was able to complete the administration of 18mg of pseudoephedrine hydrochloride at a gradually increasing release rate over a period of time.

Example 5

The dosage forms of this example were prepared in accordance with the examples described above. In this example, the displacement or third layer and the semipermeable membrane are prepared as above, with the first and second layers being different.

The first drug layer is prepared as follows. First, 139g of polyethylene oxide having a number average molecular weight of about 200000 were passed through a 40 mesh sieve and placed in the drum of a conventional planetary mixer. Then, 40g of pseudoephedrine hydrochloride was weighed and added to a drum containing polyethylene oxide. Then, 10g of hydroxypropylmethylcellulose having a number average molecular weight of 9200 and 10g of polyoxyethylene stearate 40(Myrj 52S) were passed through a 40-mesh sieve and charged into a blender containing polyethylene oxide and pseudoephedrine hydrochloride. The four components were stirred together in a planetary mixer for 10 minutes. Next, about 100ml of denatured anhydrous ethanol was gradually added to the blender over 5 to 10 minutes under continuous stirring to turn the hard dry ingredients into wet granules. The wet granules were passed through a 20 mesh sieve, dried at room temperature for 16 hours, and then passed through a 20 mesh sieve. Then, 1g of magnesium stearate was passed through a 40 mesh screen and added to the blender, and all components were blended for an additional 1 minute.

The second drug layer was prepared as follows: first, 28.8g of polyethylene oxide having a number average molecular weight of about 300000 was passed through a 40 mesh sieve and placed in the drum of a planetary mixer. Subsequently, 150g of pseudoephedrine hydrochloride was weighed and added to a blender filled with polyethylene oxide. Then, 10g of hydroxypropylmethylcellulose having a number average molecular weight of 9200, 10g of polyoxyethylene stearate 40(Myrj 52S) and 0.2g of red iron oxide were passed through a 40-mesh sieve and added to a drum containing polyethylene oxide and pseudoephedrine hydrochloride. This component was stirred in a planetary mixer for 10 minutes. Next, 100ml of denatured anhydrous ethanol was gradually added to the mixer over 5 to 10 minutes under continuous stirring to convert the hard dry powder into granules. The wet granulation was then passed through a 20 mesh screen, dried at room temperature for 16 hours, and then passed through a 20 mesh screen. Then, 1g of magnesium stearate was passed through a 40 mesh screen, added to the granules and stirred for an additional 1 minute.

The dosage form prepared in this example included the following components: the first drug layer contained 20.0% pseudoephedrine hydrochloride, 69.5% polyethylene oxide with number average molecular weight of 200000, 5% hydroxypropylmethylcellulose with number average molecular weight of 9200, 5% polyoxyethylene stearate 40, and 0.5% magnesium stearate. The second layer of the dosage form contained 75% pseudoephedrine hydrochloride, 14.4% polyethylene oxide of number average molecular weight 300000, 5% hydroxypropylmethylcellulose of number average molecular weight 9200, 5% polyoxyethylene stearate 40, 0.1% red iron oxide and 5% magnesium stearate. The third layer contained 55.5% polyethylene oxide with a number average molecular weight of 7000000, 30% sodium chloride, 5% hydroxypropylmethylcellulose, 5% polyoxyethylene stearate 40(Myrj 52S), 3% cross-linked acrylic acid polymer, 1% red iron oxide and 0.5% magnesium stearate. A12 mg semipermeable membrane comprised 95% cellulose acetate and 5% polyethylene glycol having a number average molecular weight of 3350 and an acetyl content of 39.8%. The semipermeable membrane was coated on a compressed trilayer system and a 30 mil hole was drilled in the first layer as the exit port. The final system was able to complete the administration of 18mg of pseudoephedrine hydrochloride at a gradually increasing release rate over a period of time.

Examples 6&7

The following formulations were prepared according to the above method: (a) the first layer weighed 350mg and contained 12% by weight of nicardipine, 52.80% by weight of sorbitol and 35.20% by weight of polyethylene oxide having a number average molecular weight of 200000; a second layer weighing 136mg comprising 55% by weight nicardipine, 42% by weight polyethylene oxide of number average molecular weight 300000 and 3% by weight hydroxypropylmethylcellulose of number average molecular weight 9200; a third layer weighing 350mg comprising 68.75% by weight polyethylene oxide having a number average molecular weight of 7000000, 20% by weight sodium chloride, 5% by weight hydroxypropylmethylcellulose having a number average molecular weight of 9200, 1% by weight iron oxide, 0.25% by weight magnesium stearate and 5% by weight acrylic polymer having a number average molecular weight of 3000000; the semipermeable membrane comprised 90% by weight cellulose acetate and 10% by weight polyethylene glycol having a number average molecular weight of 3350, wherein the acetyl group content was 39.8%, and the first layer was attached to the exterior of the dosage form providing 25 mil (0.64mm) pores, which dosage form had a gradually increasing release profile over 16 hours. (b) The first layer weighed 350mg and contained 8.6% by weight of nicardipine, 54.8% by weight of sorbitol and 36.80% by weight of polyethylene oxide having a number average molecular weight of 200000; a second layer weighing 120mg and comprising 45% by weight nicardipine, 50% by weight polyethylene oxide having a number average molecular weight of 300000 and 5% by weight hydroxypropylmethylcellulose having a number average molecular weight of 11200; the third drug-free layer weighed 350mg and contained 68.75% by weight polyethylene oxide having a number average molecular weight of 7000000, 20% by weight sodium chloride, 0.25% by weight magnesium stearate lubricant, 5% by weight hydroxypropylmethylcellulose having a number average molecular weight of 9200, 1% by weight iron oxide, and 5% by weight acrylic polymer having a number average molecular weight of 3000000; a semipermeable membrane weighing 43.50mg comprised 95% by weight cellulose acetate and 5% by weight polyethylene glycol having a number average molecular weight of 3350, wherein the acetyl group content was 39.8%, the first layer was attached to the exterior of the dosage form providing a 25 mil (0.64mm) pore opening, and the dosage form was sustained release in increasing doses over a 16 hour period. The dosage form provided by the present invention is characterized by being comprised of two drug layers and associated displacement or boosting layers, wherein the drug concentration in the second layer is greater than the drug concentration in the first layer, the viscosity in the third layer is greater than the viscosity in the second layer, and the viscosity in the second layer is greater than the viscosity in the first layer. Viscosity can be measured by standard methods, see Remington, Pharmacology, 17 th edition, p.342-345 (1985), and by using a standard viscometer, such as a Brookfield viscometer, model RVF, supplied by Brookfield Engineering Laboratories, Inc., Stoughton, Mass.

Example 8

The osmotic dosage form is designed and adapted for administration of methylphenidate with a gradually increasing release profile and is prepared as follows: 1) first drug layer composition: a first drug layer composition weighing 200g was prepared by the following method: 157.8g of polyethylene oxide having a number average molecular weight of 200000 were passed through a 40 mesh U.S. sieve and placed in the drum of a conventional planetary mixer. Next, 31.2g of methylphenidate were weighed and added to a blender containing polyethylene oxide. Then, 10g of hydroxypropylmethylcellulose (HPMC-USP grade 2910, number average molecular weight 9200) was passed through a 40 mesh sieve and added to a blender containing methylphenidate and polyethylene oxide. Thereafter, 0.5g of FD & C blue dye No.1 was added to the drum of the mixer. The four components were stirred in a blender for 10 minutes. Next, about 100ml of denatured anhydrous ethanol was gradually added to the blender over 5 to 10 minutes under continuous stirring to turn the hard dry ingredients into wet granules. The wet granules were passed through a 20 mesh sieve, dried at room temperature for 16 hours, and then passed through a 20 mesh sieve. Then, 0.5g of magnesium stearate was passed through a 40 mesh screen, added to the granules and all components were mixed for a few more minutes. 2) The second layer comprises the following components: a second drug layer composition weighing 200g was prepared as follows: 112.6g of polyethylene oxide having a number average molecular weight of approximately 200000 are passed through a 40 mesh sieve and placed in the drum of a conventional planetary mixer. Next, 76.4g of methylphenidate drug was weighed and added to a blender containing polyethylene oxide. Then, 10g of hydroxypropylmethylcellulose (HPMC-USP grade 2910, number average molecular weight 9200) was passed through a 40 mesh sieve and added to a blender containing methylphenidate and polyethylene oxide. Thereafter, 0.5g of FD & C blue dye No.1 or any other dye providing different colors between layers was added to the drum of the blender. The four components were stirred in a blender for 10 minutes. Next, about 100ml of denatured anhydrous ethanol was gradually added to the blender over 5 to 10 minutes under continuous stirring to turn the hard dry ingredients into wet granules. The wet granulation was passed through a 20 mesh screen, dried at room temperature (72 ℃ F., 22.2 ℃) for 16 hours, and passed through a 20 mesh screen. Then, 0.5g of magnesium stearate was passed through a 40 mesh screen, added to the granules and all components mixed for an additional few 1 minutes. 3) A third layer of components: a third or booster layer weighing 200g was prepared as follows: 107g of polyethylene oxide of number-average molecular weight 7000000, 80g of sodium chloride (45%) as a penetrant, 10g of hydroxypropylmethylcellulose (USP grade 2910, number-average molecular weight 9200) and 2g of red iron oxide were passed through a 40-mesh sieve and then added to the drum of a planetary mixer. These components are stirred together to form a homogeneous mixture. Next, 50ml of denatured anhydrous ethanol was added to the mixer with continuous stirring over 5 to 10 minutes to change the hard dry powder into wet granules. The wet granules were passed through a 20 mesh sieve, dried at room temperature for 16 hours and then passed through a 20 mesh sieve. Next, 1g of magnesium stearate was passed through a 40 mesh screen, added to the granules, and all components were mixed for 1 minute.

Lamination is the compression of two layers together to form a tablet. First, 33mg of the first layer was added to 7/32' (0.55cm) of the mold cavity and lightly tamped. Next, 24mg of the second layer was added to the mold and lightly tamped. Then, 57mg of the third layer was added to the mold and the three layers were compressed together with 1/2 tons of pressure to form a three-layer tablet.

The semipermeable membrane composition providing the coating for the dosage form comprises 95% cellulose acetate (39.8% acetyl content) and 5% polyethylene glycol having a number average molecular weight of 3350. The semipermeable membrane composition was dissolved in a mixture of acetone and water (90:10, wt: wt) to a solids content of 5%. The trilayer tablets were placed in a coating pan and 15mg of the semipermeable membrane composition was sprayed onto the trilayer tablets. Next, a 30 mil (0.76mm) hole was drilled in one side of the drug to connect the first layer to the exterior of the dosage form. The tablets were dried at 50 ℃ and 50% relative humidity for 48 hours to remove residual solvent. Next, an outer drug-containing coating and a flavor coating are applied to the outer surface of the membrane. The drug-containing outer coating was composed of 60% hydroxypropylmethylcellulose having a number average molecular weight of 9200 and 40% methylphenidate. The hydroxypropyl methylcellulose is added to water and mixed until a homogeneous solution is obtained. Then, methylphenidate was added to this solution and mixed until a clear solution was obtained. The final solution contained 10% solids. The film coating system was placed in a coating machine and 10mg of the drug overcoat solution was sprayed onto the bilayer tablets. For flavor coatings, preparation(commercially available from Colorcon, which is a film forming concentrate consisting of hydroxypropylmethylcellulose, titanium dioxide, polyethylene glycol, Tween 80, and a product identification dye) in an aqueous suspension having a solids content of 10%. The system with the outer coating containing the drug was placed in a coating machine and 9mg of the flavor solution was sprayed into the system. The system was then dried in a 40 ℃ coating pan for 10 to 15 minutes.

This example describes a methylphenidate dosage form containing a first drug-containing layer weighing 33mg consisting of 15.6% methylphenidate, 78.9% polyethylene oxide of number average molecular weight 200000, and 5% hydroxypropylmethylCellulose (USP-2910, number average molecular weight 9200), 025% magnesium stearate and 0.25% FD&C blue dye No. 1. The dosage form further comprises a 24mg second drug-containing layer comprising 38.2% methylphenidate, 53.32% polyethylene oxide having a number average molecular weight of 200000, 5% hydroxypropylmethylcellulose (USP-2910, number average molecular weight of 9200), 0.25% magnesium stearate and 0.25FD&C blue dye No.1 or any other dye. The third layer of the dosage form consisted of 53.5% polyethylene oxide with a number average molecular weight of 7000000, 40% sodium chloride, 5% hydroxypropylmethylcellulose, 1% iron oxide, and 0.5% magnesium stearate. The 15mg semipermeable membrane consisted of 95% cellulose acetate containing 39.8% acetyl groups and 5% polyethylene glycol with a number average molecular weight of 3350. The semipermeable membrane was added to the compressed trilayer system and a 30 mil hole was drilled on one side of the drug layer as the exit port. 1omg drug overcoat the application was made on a film coating system consisting of 6mg hydroxypropylmethylcellulose and 4mg methylphenidate. Coating 9mg by 100%The final taste corrective coating of the composition. The final system released 18mg of methylphenidate, with 4mg released immediately from the outer coating and 14mg released from the interior of the dosage form at a gradually increasing release rate.

The invention also relates to a method for delivering a dose of a pharmaceutical agent that gradually increases over time to a warm-blooded animal in need of such treatment. The method comprises the following steps: (A) administering to a patient a dosage form comprising: (1) a wall layer surrounding the chamber, the wall layer containing a semipermeable component that is permeable to fluids, including aqueous biological fluids of the gastrointestinal tract, but impermeable to the passage of drugs; (2) the three layers of the chamber comprise a first layer containing a dose of the drug, a second layer containing a higher dose of the drug, a third layer containing a drawing and absorbing fluid of an osmotic composition (formulation) and serving to assist in the propulsion of the first and second layers from the dosage form, thereby providing an increased dose of the drug per unit time; and (3) at least one outlet in the wall layer connected to the first layer; (B) drawing liquid through the semi-permeable wall layer at a rate determined by the permeability of the semi-permeable wall layer and the permeability gradient through the semi-permeable wall layer to distend and expand the third layer; and (C) delivering the drug from the first layer and then from the second layer through the outlet passageway to provide the patient with an increasing dose of the drug.

In conclusion, it will be apparent from the prior art that unexpected dosage forms of the present invention that provide useful administration of a drug at a metered release rate with a slowly increasing dosage over time, while the present invention has been described and illustrated in detail with respect to its operative embodiments, it will be apparent to those skilled in the art that various changes, modifications, substitutions and deletions can be made therein without departing from the spirit of the invention. That is, the scope of the present invention covers the scope equivalent to the claims.

Claims (31)

1. A drug tablet for delivering an increased dose of a drug to a use environment, comprising a chambered core comprising:

a) a first layer comprising a drug in a dose of 10ng to 300mg and a hydrophilic polymer in a dose of 5mg to 250 mg;

b) a second layer comprising a drug in a dose of 50ng to 500mg and 25ng to 450mg of a hydrophilic polymer, said second layer comprising a higher dose of the drug than the first layer; and

c) a third layer containing 15ng to 450mg of a hydrophilic polymer, the third layer providing support for the first and second layers for sequential drug release;

a semipermeable wall surrounding said chambered core, wherein said wall is permeable to liquid but impermeable to the drug; and

an outlet formed in the semipermeable wall that opens into the chamber-shaped core at a location proximate the first layer to allow release of the drug from the tablet into an environment of use;

wherein the drug is released from the tablet at a sustained rate of increase per unit time over an extended period of time.

2. The tablet of claim 1, wherein the first layer and the second layer comprise the same drug.

3. The tablet of claim 1 wherein the first and second layers contain the same drug and the third layer does not contain a drug.

4. The tablet of claim 1 wherein the first and second layers comprise the same drug selected from the group consisting of amphetamine, dextroamphetamine, methamphetamine, methylphenidate, racemic methylphenidate, hydroxymethyl methylphenidate, ethyl methylphenidate, amphetamine, and phenytoin.

5. The tablet according to claim 1, wherein the hydrophilic polymer in the first and second layers comprises a poly (alkylene oxide) having an average molecular weight of 40000-1000000 and the hydrophilic polymer in the third layer comprises a poly (alkylene oxide) having an average molecular weight of 2000000-10000000.

6. The tablet according to claim 1, wherein the hydrophilic polymer in the first and second layers comprises a poly (alkylene oxide) having an average molecular weight of 40000-1000000, the hydrophilic polymer in the third layer comprises a poly (alkylene oxide) having an average molecular weight of 2000000-10000000, and the first and second layers further comprise a hydroxypropylmethylcellulose having an average molecular weight of 9000-750000.

7. A dosage form comprising

a) A first layer containing 10ng-300mg of the drug;

b) a second layer containing 50ng to 500mg of a drug, the second layer having a higher drug content than the first layer;

c) a third layer comprising 15ng to 450mg of a hydrophilic polymer for displacing the first layer, then the second layer in the dosage form;

d) a wall layer surrounding the three layers, wherein the wall layer is permeable to liquid but impermeable to the drug; and

e) the passageways in the wall layers associated with the first drug layer serve to release the first drug layer followed by the second drug layer of the dosage form, thereby releasing the drug from the dosage form at a sustained rate of increase per unit time.

8. The dosage form of claim 7, wherein the drugs in the first and second layers are the same and the drugs are selected from the group consisting of central nervous system acting drugs, stimulants, and catecholamines.

9. The dosage form of claim 7, wherein the three layers each contain a poly (alkylene oxide).

10. The dosage form of claim 7, wherein the first and second layers comprise hydroxypropyl alkylcellulose.

11. The dosage form of claim 7 wherein the first layer comprises a hydroxyalkyl cellulose.

12. The dosage form of claim 7 wherein the second layer comprises a hydroxyalkyl cellulose.

13. The dosage form of claim 7, wherein the first layer comprises carboxymethyl cellulose.

14. The dosage form of claim 7, wherein the second layer comprises carboxymethyl cellulose.

15. The dosage form of claim 7, wherein the third layer comprises carboxymethyl cellulose.

16. The dosage form of claim 7, wherein the first layer comprises a carboxyvinyl polymer.

17. The dosage form of claim 7, wherein the second layer comprises a carboxyvinyl polymer.

18. The dosage form of claim 7, wherein the third layer comprises a carboxyvinyl polymer.

19. A dosage form comprises

a) A first layer containing from 10ng to 300mg methylphenidate;

b) a second layer comprising 50ng to 500mg of methylphenidate, said second layer having a higher methylphenidate content than the first layer;

c) a third layer comprising a composition that expands and displaces the first layer, followed by the second layer, from the dosage form;

d) a wall layer surrounding the three layers; said wall layer being permeable to liquid but impermeable to methylphenidate; and

e) the passageways in the wall layers associated with the first drug layer serve to release the first drug layer followed by the second drug layer of the dosage form whereby the drug is released from the tablet at a sustained rate of increase per unit time over an extended period of time.

20. The dosage form of claim 19, wherein the first layer comprises 1mg to 250mg of poly (ethylene oxide).

21. The dosage form of claim 19, wherein the second layer comprises 1mg to 450mg of poly (ethylene oxide).

22. The dosage form of claim 19, wherein at least one of the first layer and the second layer comprises 0.05 to 7.5mg of surfactant.

23. The dosage form of claim 19, wherein at least one of the first layer and the second layer comprises 0.5-20mg of hydroxypropyl methylcellulose.

24. The dosage form of claim 19, wherein at least one of the first layer and the second layer comprises up to 20mg of hydroxypropyl cellulose.

25. The dosage form of claim 19, wherein at least one of the first layer and the second layer comprises up to 100mg of carboxyvinyl polymer.

26. The dosage form of claim 19, wherein at least one of the first layer and the second layer comprises up to 250mg of carboxymethyl cellulose.

27. The dosage form of claim 19 wherein the third layer comprises poly (ethylene oxide) having an average molecular weight of 2000000-.

28. The dosage form of claim 19 wherein the third layer comprises a carboxymethylcellulose having an average molecular weight of 2000000-.

29. The dosage form of claim 19 wherein the third layer comprises a carboxyvinyl polymer having a molecular weight of 750000-.

30. The dosage form of claim 19 wherein the third layer comprises a hydroxypropyl alkylcellulose having an average molecular weight of 9200 and 750000.

31. A tablet for oral administration of methylphenidate to humans, wherein the tablet comprises:

a) a first layer containing from 10ng to 300mg methylphenidate;

b) a second layer comprising between 10ng and 500mg methylphenidate, wherein the second layer comprises a greater dosage of methylphenidate than the first layer;

c) a third layer comprising 15ng to 450mg of a hydrophilic polymer;

d) a wall layer comprising a semipermeable component surrounding the first layer, the second layer, and the third layer, wherein the wall layer is permeable to liquid and impermeable to the drug;

e) (ii) a passageway in the wall layer associated with the first drug layer for release of the first drug layer followed by the second drug layer of the tablet whereby the drug is released from the tablet at a sustained rate of increase per unit time for an extended period of time; and

f) a covering layer on the outer surface of the wall layer containing 10ng to 20mg methylphenidate.