KR20070020022A - Controlled release dosage for gaba receptor agonist - Google Patents

Abstract

The present invention relates generally to pharmaceutical dosage forms having immediate release and controlled release properties that contain a gamma-aminobutyric acid (GABAB) receptor agonist, e.g., baclofen, for the treatment of medical conditions, which includes spasms, cramping, and tightness of muscles, associated with ailments such as multiple sclerosis or certain spinal injuries. ® KIPO & WIPO 2007

Description

Controlled Release Formulation for BAA Receptor Agonists {CONTROLLED RELEASE DOSAGE FOR GABA RECEPTOR AGONIST}

The present invention generally relates to γ-aminobutyric acid (GABA _B ) receptor agonists for the treatment of medical conditions associated with diseases such as multiple sclerosis, spinal cord diseases or certain spinal cord injuries, such as spasms, convulsions, muscle strains, or stiffness. For example, it relates to pharmaceutical dosage forms containing baclofen, having immediate release and controlled release properties.

Multiple sclerosis is considered to be an autoimmune disease. In this aspect, an individual's immune system can attack myelin sheaths that surround nerve cells. This damage results in muscle weakness, paralysis, coordination weakness, balance problems, fatigue, and the possibility of blindness. GABA _B agonist baclofen can be used to treat these symptoms. Baclofen can also facilitate adjuvant medical treatments, such as physiotherapy, to improve the condition of patients with multiple sclerosis or certain spinal cord injuries. Baclofen is also used to reduce the number and severity of trigeminal neuralgia development in patients who cannot tolerate or do not respond to the effects of carbamazepine.

Baclofen, or 4-amino-3- (4-chlorophenyl) -butanoic acid, is a muscle relaxant and anticonvulsant. The mechanism of this action is unclear. Although baclofen appears to be able to inhibit both monosynaptic and multisynaptic reflexes, perhaps by hyperpolarization at the apical end, at the spinal cord level, the action at the superficial site causes and contributes to its clinical effect. In animal studies, baclofen appears to have general central nervous system (CNS) compression properties that are manifested by sedation, such as tolerance, narcolepsy, dyspnea, and breathing and cardiovascular compression.

Absorption of baclofen is site specific. Baclofen is mainly absorbed in the upper part of the gastrointestinal GI, and in the lower part of the gastrointestinal tract, the amount of baclofen absorption is substantially reduced. Baclofen is rapidly and widely absorbed. Absorption depends on the dosage, and as the dosage increases, the absorption may decrease. An improved method of administering baclofen to a patient includes delivering an effective amount of drug over the gastrointestinal tract for an extended period of time.

Several side effects are probably associated with the administration of baclofen to mammals. These problems include nausea, vomiting, diarrhea, dizziness, daytime sedation, and rarely mental illness conditions such as depressive mood disorders. In addition, if frequent administration is required, such as three or four times daily, patient compliance with the dosing regimen may be suboptimal. Thus, less frequent administration, such as pharmaceutical dosage forms, which are administered once or twice a day, would be desirable. In addition, pharmaceutical dosage forms capable of establishing and maintaining stable plasma levels of baclofen for sustained time may benefit the patient by requiring a reduced number of doses and minimizing side effects.

Baclofen tablets 10/20 mg (Watson Pharmaceuticals, Inc., Corona, Calif.) And KEMSTRO ™ (Schwarz Pharma, Monheim, Germany) Certain baclofen pharmaceutical formulations are commercially available, including oral disintegrating tablets sold in Germany), but do not provide controlled release of baclofen. For example, upon single 20 mg oral administration of KEMSTRO ™, the peak plasma concentration reaches about 1.5 hours after administration.

Baclofen has a serum half-life of 2.5-4 hours. (Drug Monograph: Bethesda, MD, American Hospital Pharmacist Association 2003, Baclofen American Hospital Regulation Service: American Hospital Formulary Service ( AHFS ) ) Following oral administration of current immediate release baclofen formulations, the minimum therapeutic plasma level is Typically about 4 to 8 hours after administration. Therefore, current immediate-release preparations typically require three to four administrations per day.

Various controlled release baclofen compositions have been reported. For example, Khanna, US Pat. No. 5,091,184, issued February 25, 1992, describes a tablet that attaches to the oral mucosa and delivers the drug through the mucosa. These compositions have several problems with adherent tablets and deliver the drug to sites that are less optimal for GABA related drugs. Additionally, US Pat. No. 5,651,985 to Penners et al., Issued July 29, 1997, refers to matrix dosage forms with extended intragastric residence time. Dosage forms prepared according to the references of Penus are described as having excellent swellability and high dimensional stability in the expanded state. In addition, osmotic pump dosage forms for delivering biclofen are described in U.S. Pat. No. 4,764,380 to Urquhart et al., Issued August 16, 1988, which describes the continuous administration of a drug over an extended period of time. Described in the heading.

Nevertheless, GABA _B receptor agonists for treating medical conditions, such as multiple sclerosis or certain spinal cord injury, which reduce the number of doses and minimize side effects by achieving and maintaining stable plasma levels of the drug for a prolonged period of time, There remains a significant and lasting need for pharmaceutical dosage forms with controlled release properties containing, for example, baclofen. These and other objects are achieved by the present invention.

Summary of the Invention

The present invention generally relates to pharmaceutical dosage forms with controlled release properties containing GABA _B receptor agonists such as baclofen. These dosage forms can be used for the treatment of medical conditions associated with diseases such as multiple sclerosis or certain spinal cord injury, such as spasms, convulsions, and muscle tension.

For example, a pharmaceutical dosage form of the invention may comprise a controlled release dosage form, wherein the controlled release dosage form comprises a GABA _B agonist and a pharmaceutically acceptable excipient, wherein the dosage form is in an artificial serous medium, An in vitro dissolution profile comprising less than about 70% GABA _B agonist release after 1 hour, at least about 20% GABA _B agonist release after 4 hours, and at least about 30% GABA _B agonist release after 6 hours. Indicates. In such embodiments, the controlled release dosage form comprises less than about 80% GABA _B agonist release after 1 hour, at least about 30% after 4 hours in artificial gastric juice / artificial intestinal fluid (1 hour switchover) medium. GABA _B shows the effect the release, and at least in vitro dissolution profile comprising a GABA _B agonist release of about 40% after 6 hours.

In a preferred embodiment, the controlled release dosage form comprising a GABA _B agonist and a pharmaceutically acceptable excipient is less than about 50% GABA _B agonist release after 1 hour, at least about 40% after 4 hours in artificial serous medium. GABA _B shows the effect the release, and at least in vitro dissolution profile comprising a GABA _B agonist release of about 50% after 6 hours. In a preferred embodiment, the controlled release dosage form comprises less than about 70% GABA _B agonist release after 1 hour, at least about 40% GABA _B agonist after 4 hours in artificial gastric juice / artificial serous (1 hour switchover) medium. Release, and an in vitro dissolution profile comprising at least about 50% GABA _B agonist release after 6 hours.

In other embodiments, the controlled-release GABA _B agonist dosage form is combined with an immediate release GABA _B agonist component. In such embodiments, the immediate release component exhibits an in vitro dissolution profile comprising at least about 80% GABA _B agonist release after one hour in artificial gastric juice. The ratio of the immediate-release component to the controlled-release component is about 1:10 to about 10: 1, preferably about 1: 4 to about 4: 1, more preferably about 1: 3 to about 3: 1, and Most preferably from about 1: 2 to about 2: 1.

In another embodiment, a pharmaceutical dosage form of the invention contains an enteric coating controlled release component, wherein the enteric coating controlled release component comprises a GABA _B agonist and a pharmaceutically acceptable excipient, wherein the enteric coating controlled release component is an artificial gastric juice In artificial serous (2 hour switchover) medium, less than about 10% GABA _B agonist release after 2 hours, at least about 40% GABA _B agonist release after 3 hours, and at least about 70% GABA after 6 hours _In vitro dissolution profile including _B agonist release. Preferably, the enteric coating controlled release component is less than about 10% GABA _B agonist release after 2 hours, at least about 50% GABA _B agonist after 3 hours in artificial gastric juice / artificial intestinal fluid (2 hour switchover) medium Release, and an in vitro dissolution profile comprising at least about 80% GABA _B agonist release after 6 hours. Most preferably, the enteric coating controlled release component is less than about 10% GABAB agonist release after 2 hours and at least about 60% GABA _B agonist after 3 hours in artificial gastric juice / artificial intestinal fluid (2 hour switchover) medium. In vitro dissolution profile comprising at least about 90% GABA _B agonist release after 6 hours of release.

In a further preferred embodiment, the dosage form also contains an immediate release component in combination with an enteric coating controlled release component. For example, GABA _B agonists can be formulated as a combination of immediate-release beads and control-release beads compressed into tablets or contained in capsule dosage forms. The ratio of the immediate-release component to the controlled-release component is about 1:10 to about 10: 1, preferably about 1: 4 to about 4: 1, more preferably about 1: 3 to about 3: 1, and Most preferably from about 1: 2 to about 2: 1.

The present invention includes pharmaceutical dosage forms that have both immediate release and extended release properties. In such embodiments, the pharmaceutical dosage form comprising a GABA _B agonist and a pharmaceutically acceptable excipient releases less than about 75% of the GABA _B agonist after 2 hours in artificial gastric juice / artificial serous (2 hour switchover) medium. , In vitro dissolution profile comprising at least about 80% GABA _B agonist release after 3 hours. Preferably, the pharmaceutical dosage form is less than about 65% GABA _B agonist release after 2 hours, and at least about 90% GABA _B agonist after 3 hours, in artificial gastric juice / artificial intestinal fluid (2 hour switchover) medium In vitro dissolution profile including release.

The pharmaceutical dosage forms of the invention are suitable for twice daily administration to patients in need of chronic baclofen therapy. As such, in vivo absorption is delayed compared to immediate release baclofen formulations, so that the median time for which 80% or more baclofen is absorbed under fasting conditions in vivo is longer than 2.5 hours. Dosage forms of the present invention exhibit an in vivo plasma profile that typically includes an average maximum baclofen level (C _max ) between about 30 minutes to about 7 hours after administration, usually between 2.5 and 5.5 hours after administration.

1A is a graph of an in vitro dissolution profile of baclofen tablet formulation prepared according to Example 8, prepared according to Example 8, as measured by USP paddle method at 50 rpm in 900 ml of artificial gastric juice (pH 1.2) at 37 ° C. to be.

1B is a graph of an in vitro dissolution profile of baclofen tablet formulation prepared according to Example 11, 20 mg, as measured by USP paddle method at 50 rpm in 900 ml artificial intestinal fluid (pH 6.8) at 37 ° C. .

FIG. 2 is a baclo prepared according to Example 11, switched over to artificial intestinal fluid (pH 6.8) and measured by USP paddle method at 50 rpm in 900 ml of artificial gastric juice (pH 1.2) for 1 hour at 37 ° C. Pen tablet formulation, graph of 20 mg in vitro dissolution profile.

3 is a graph of in vitro dissolution profile of baclofen capsule formulation prepared according to Example 2, measured according to USP paddle method at 75 rpm in 900 ml of artificial gastric juice (pH 1.2) at 37 ° C., 20 mg .

FIG. 4 is a baclo prepared according to Example 12, switched over to artificial intestinal fluid (pH 6.8) and measured by USP paddle method at 75 rpm in 900 ml of artificial gastric juice (pH 1.2) for 2 hours at 37 ° C. Pen capsule formulation, graph of 20 mg in vitro dissolution profile.

FIG. 5 is prepared according to Examples 13 and 14, switched over to artificial intestinal fluid (pH 6.8) and measured by USP paddle method at 75 rpm in 900 ml of artificial gastric juice (pH 1.2) for 2 hours at 37 ° C. Baclofen capsule formulation, 30 mg, is a graph of in vitro dissolution profile.

FIG. 6 is a graph of the in vivo plasma profile of baclofen tablet formulation measured as described in Example 16.

FIG. 7 is a simulated graph of steady state baclofen plasma levels measured as described in Example 17, where (C) represents a 40 mg dosage form of the invention, and (D) is a reference 20 mg immediate Indicate the release dosage form.

The present invention provides controlled-release GABA _B agonists (preferably baclofen, baclofen prodrug, baclofen analogs, or mixtures thereof, and racemic baclofen mixtures or substantially pure L-baclocene mirror images). Isomeric product) formulations. Controlled-release GABA _B agonist formulations may be in the form of enteric coating control-release formulations. In addition, controlled-release GABA _B agonist formulations, including enteric coating control-release formulations, can be combined with immediate release GABA _B agonist formulations in the final pharmaceutical dosage form.

With the present invention, the formulations of the present invention enable a reduction in the number of doses compared to current immediate release formulations. For example, in patients in need of chronic GABA _B agonist therapy, twice daily administration of a formulation of the present invention is biologically equivalent to three times daily administration of an existing immediate release formulation. This reduced frequency of administration is more convenient for the patient and typically makes the patient better to follow. It also reduces the number of plasma peaks and troughs, which are typically associated with improved efficacy and reduced side effects.

As used herein and in the claims, the singular forms “a,” “an” and “the” include plural unless the context clearly dictates otherwise. Thus, for example, reference to a profile is a reference to one or more such profiles, including their equivalents known in the art. In the examples, or unless stated otherwise, all values indicative of the amount of component or reaction conditions used herein are to be understood to be in all instances varied by the term “about”. The term "about" as used in connection with a percentage may mean ± 1%.

All patents and other publications mentioned are hereby incorporated by reference for the purpose of describing and disclosing the methodology described in, for example, the publications that may be used in combination with the present invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any known methods, devices, and materials can be used in the practice or testing of the present invention, preferred methods, devices, and materials of this aspect are described herein.

The baclofen of the present invention, also known as butanoic acid or 4-amino-3- (4-chlorophenyl) butanoic acid, includes racemic baclofen, enantiomerically pure L-baclocene, and analogs, Derivatives, prodrugs, metabolites thereof, and any pharmaceutically acceptable salts thereof.

Baclofen is a GABA _B receptor agonist and therefore other GABA _B receptor agonists are intended to be within the scope of the present invention. These are 4-aminobutanoic acid (GABA); (3-aminopropyl) methylphosphinic acid; 4-amino-3-phenylbutanoic acid; 4-amino-3-hydroxybutanoic acid; 4-Amino-3- (4-chlorophenyl) -3-hydroxyphenylbutanoic acid; 4-amino-3- (thien-2-yl) butanoic acid; 4-amino-3- (5-chlorothien-2-yl) butanoic acid; 4-amino-3- (5-bromothien-2-yl) butanoic acid; 4-amino-3- (5-methylthien-2-yl) butanoic acid; 4-amino-3- (2-imidazolyl) butanoic acid; 4-guanidino-3- (4-chlorophenyl) butanoic acid; 3-amino-2- (4-chlorophenyl) -1-nitropropane; (3-aminopropyl) aphosphonic acid; (4-aminobut-2-yl) aphosphonic acid; (3-amino-2-methylpropyl) aphosphonic acid; (3-aminobutyl) aphosphonic acid; (3-amino-2- (4-chlorophenyl) propyl) aphosphonic acid; (3-amino-2- (4-chlorophenyl) -2- (hydroxypropyl) aphosphonic acid; (3-amino-2- (4-fluorophenyl) propyl) aphosphonic acid; (3-amino- 2-phenylpropyl) aphosphonic acid; (3-amino-2-hydroxypropyl) aphosphonic acid; (E)-(3-aminopropen-1-yl) aphosphonic acid; (3-amino-2- Cyclohexylpropyl) aphosphonic acid; (3-amino-2-benzylpropyl) aphosphonic acid; [3-amino-2- (4-methylphenyl) propyl] aphosphonic acid; [3-amino-2- (4- Trifluoromethylphenyl) propyl] aphosphonic acid; [3-amino-2- (4-methoxyphenyl) propyl] aphosphonic acid; [3-amino-2- (4-chlorophenyl) -2-hydroxypropyl ] Aphosphonic acid; (3-aminopropyl) methylphosphinic acid; (3-amino-2-hydroxypropyl) methylphosphinic acid; (3-aminopropyl) (difluoromethyl) phosphinic acid; (4-aminobut -2-yl) methylphosphinic acid; (3-amino-1-hydroxypropyl) methylphosphinic acid; (3-amino-2-hydroxypropyl) (difluoromethyl) phosphinic acid (E)-(3-aminopropen-1-yl) methylphosphinic acid; (3-amino-2-oxo-propyl) methylphosphinic acid; (3-aminopropyl) hydroxymethylphosphinic acid; (5- Aminopent-3-yl) methylphosphinic acid; (4-amino-1,1,1-trifluorobut-2-yl) methylphosphinic acid; (3-amino-2- (4-chlorophenyl) propyl) Sulfinic acid, 3-aminopropylsulfinic acid, 1- (aminomethyl) cyclohexaneacetic acid, etc. See, eg, US Pat. No. 6,664,069.

The term “analogue” means a compound that includes a chemically modified form of a particular compound or class thereof and retains the pharmaceutical and / or pharmacologically active characteristics of that compound or class. For example, baclofen analogs include 3-thienyl- and 3-furylaminobutyric acid.

The term "derivative" refers to a chemical, such as an ester or amide of an acid, a protecting group such as a benzyl group for an alcohol or thiol, and a tert-butoxycarbonyl group for an amine, with modifications that are commonly considered routine by a skilled practitioner. It means a compound modified with.

As used herein, the term "prodrug" is meant to include a covalently bound carrier which, when administered to a patient, releases the active parent drug of the invention in vivo. Since prodrugs are known to enhance various desired properties of the drug (ie, solubility, bioavailability, manufacture, etc.), the compounds of the present invention can be delivered in prodrug form. Prodrugs of the present invention may be prepared by modifying functional groups present in the compounds in a routine manner or in a manner that causes degradation to the parent compound in vivo. In vivo modifications may be the result of, for example, some metabolic processes of chemical or enzymatic hydrolysis of carboxylic acids, phosphoric acid or sulfuric acid esters, or reduction or oxidation of sensitive functional groups. Prodrugs within the scope of the present invention have a hydroxy, amino or sulfhydryl group attached to any group, and when the prodrug of the present invention is administered to a mammalian subject, it is broken down to free hydroxyl, free amino, or Compounds that form free sulfhydryl groups. Functional groups that can be rapidly modified by metabolic degradation form a class of groups reactive in vivo with the carboxyl groups of the compounds of the invention. These include alkanoyls (eg acetyl, propionyl, butyryl, etc.), unsubstituted and substituted aroyl (eg benzoyl and substituted benzoyl), alkoxycarbonyls (eg ethoxycarbonyl), trialkylsilyl ( Such as, but not limited to, trimethyl- and triethylsilyl), monoesters formed by dicarboxylic acids (eg succinyl), and the like. Since the metabolically degradable groups of the compounds useful according to the invention are readily degraded in vivo, compounds having such groups act as prodrugs. Compounds with metabolically degradable groups have the advantage that due to the presence of metabolically degradable groups, they may exhibit improved bioavailability as a result of the enhanced solubility and / or absorption rates imparted to the parent compound.

Details of prodrugs can be found in DESIGN OF PRODRUGS, H. Bundgaard, ed., (Elsevier, 1985); METHODS IN ENZYMOLOGY, K. Widder et al., Eds., Vol. 42, 309-96 Academic Press, 1985; A TEXTBOOK OF DRUG DESIGN AND DEVELOPMENT, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; Design and Applications of Pro-drugs 113-191, (1991); Bundgard, Advanced Drug Delivery Reviews , 1-38, (1992); J. PHARM. SCIENCES 285, (1988); N. Nakeya et al., 32, CHEM.PHARM.BULL., 692, ( 1984)]; T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems , 14 ACS SYMPOSIUM SERIES; and BIOREVERSIBLE CARRIERS IN DRUG DESIGN, Edward B. Roche, ed. (Am. Pharm. Assoc. & Pergamon Press, 1987), which are incorporated herein by reference.

Accordingly, the present invention is intended to include the use of prodrugs of GABA _B receptor agonists (including baclofen), methods of delivering them, and compositions containing them. For example, baclofen prodrugs are described in Leisen et al., Lipophilicities of Baclofen Ester Prodrugs Correlate with Affinities to the ATP-dependent Efflux Pump P- glycoprotein , 20 PHARM. RES. 772-78 (2003).

The term "metabolite" refers to a methylated compound in the form of a compound obtained by the action of the human or animal body on the dosage form of the compound in the human or animal body, for example as a result of the action of the body on the methylated compound. Demethylated analogs of the compounds having methyl groups obtained in the body after administration are shown. Metabolites can themselves have biological activity.

As used herein, the phrase "pharmaceutically acceptable" is intended to be used in humans and animals without excessive toxicity, irritation, allergic reactions or other problems or complications, corresponding to reasonable benefit / risk ratios within the scope of normal medical judgment. A compound, material, composition and / or dosage form suitable for use in contact with tissue is meant.

For example, “pharmaceutically acceptable salts” means derivatives of the described compounds, in which certain compounds are converted into their acid or base salts. Pharmaceutically acceptable salts include inorganic or organic acid salts of basic residues such as amines; Acidic residues such as alkali or organic salts of carboxylic acids, and the like. Pharmaceutically acceptable salts include, for example, conventional nontoxic salts or quaternary ammonium salts of the parent compound, formed from nontoxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; And organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanoic acid, Salts prepared from 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isetionic acid and the like.

For the purposes of the present invention, the term “controlled release” releases one or more pharmaceutically active agents by prolonging the release of the active agent over an extended period of time (eg, 1 hour or longer), or for an extended period of time. Partial or all dosage forms are shown. The properties of controlled release (CR) may also be called sustained release (SR), prolonged release (PR), modified release (MR), delayed release (DR) or prolonged release (ER). When used in connection with the dissolution profile referred to herein, the term “controlled release” means a portion of a dosage form according to the invention that delivers the active agent over a period of one hour or more.

"Immediate release" means a partial or total dosage form that releases the active agent substantially immediately upon contact with gastric fluid and exhibits substantially complete dissolution within about 1 hour. Immediate release (IR) characteristics can also be expressed as instantaneous release. When used in connection with the dissolution profile referred to herein, the term “immediate release” refers to a portion of a dosage form according to the invention that delivers an active agent over a period of less than one hour.

The term "C _max " is the peak plasma concentration exhibited by the composition of the present invention. "T _max " means the time at which C _max appears in the plasma concentration-time profile. "C _MIN " is the minimum plasma concentration. "C" stands for concentration, "T" means time, "max" means maximum, and "min" means minimum. Initial peak plasma level means a primary increase in the plasma level of the active agent, followed by one or more additional peaks, one of which may be C _max . As used herein, “average maximum GABA _B agonist level” means mean GABA _B agonist C _max . Plasma concentrations described herein are typically measured in at least 12 subject populations.

The plasma concentrations described above may indicate plasma levels after a single oral administration of the dosage form, or may indicate levels obtained at steady state. As used herein, “steady state” plasma concentrations refer to the plasma levels obtained by repeated administration of drugs until the rate of absorption and clearance reaches a stable level and the amount of drug in the body is substantially constant.

As used herein, the term “patient” refers to any mammal, including humans.

The term "effective amount" means the amount of the compound / composition according to the invention that is effective to produce the desired therapeutic effect.

The term "excipient" refers to a pharmacologically inactive ingredient that is not active in the body. See Handbook of Pharmaceutical Excipients , (Am. Pharm. Ass'n 1986). Those skilled in the art will recognize that many different excipients may be used in the formulations according to the invention and that the list provided herein is incomplete.

The active ingredients of the present invention, depending on the mode of administration and the nature of the dosage form, can be used as pharmaceutically acceptable pharmaceutically acceptable carriers, diluents, adjuvants, excipients or vehicles such as preservatives, fillers, polymers, disintegrants, glidants, wetting agents, emulsifiers. , Suspending agents, sweetening agents, flavoring agents, fragrances, lubricants, acidifying agents and dispersants. Some ingredients, including pharmaceutically acceptable carriers and excipients, can be used to formulate oral dosage forms. Pharmaceutically acceptable carriers include water, ethanol, polyols, vegetable oils, fats, waxes, polymers including gel-forming and non-gel-forming polymers, and suitable mixtures thereof. Examples of excipients include starch, pregelatinized starch, Avicel, lactose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate, and lake blends. Examples of disintegrants include starch, alginic acid, and certain complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycols.

"Administration under fasting conditions" is defined as when the subject is fasted overnight for at least 10 hours and then the formulation is orally administered with 240 ml of room temperature water. No liquids are allowed from 1 hour before administration to 1 hour after administration except when drug is administered. Two hours after administration, the subject may drink 240 ml of room temperature water.

Pharmaceutical dosage forms of the invention may comprise a controlled release dosage form comprising a GABA _B agonist and a pharmaceutically acceptable excipient, wherein the dosage form has a GABA _B efficacy of less than about 70% after 1 hour in an artificial serous medium. An in vitro dissolution profile comprising the first release, at least about 20% GABA _B agonist release after 4 hours, and at least about 30% GABA _B agonist release after 6 hours. In such embodiments, the controlled release dosage form comprises less than about 80% GABA _B agonist release after 1 hour, at least about 30% GABA _B agonist after 4 hours, in artificial gastric juice / artificial serous (1 hour switchover) medium. Release, and an in vitro dissolution profile comprising at least about 40% GABA _B agonist release after 6 hours.

Preferably, the controlled release dosage form comprises less than about 50% GABA _B agonist release after 1 hour, at least about 40% GABA _B agonist release after 4 hours, and at least about 50% after 6 hours. An in vitro dissolution profile comprising GABA _B agonist release. In a preferred embodiment, the controlled release dosage form is less than about 70% GABA _B agonist release after 1 hour, at least about 40% GABA _B efficacy after 4 hours in artificial gastric juice / artificial intestinal fluid (1 hour switchover) medium. And an in vitro dissolution profile comprising at least about 50% GABA _B agonist release after the first release and 6 hours.

In other embodiments, the controlled-release GABA _B agonist dosage form is combined with an immediate release GABA _B agonist component. In such embodiments, the immediate release component exhibits an in vitro dissolution profile comprising at least about 80% GABA _B agonist release after one hour in artificial gastric juice.

In another embodiment, the pharmaceutical dosage form of the present invention contains an enteric coating controlled release component, wherein the enteric coating controlled release component comprises a GABA _B agonist and a pharmaceutically acceptable excipient and comprises artificial gastric fluid / artificial sera (2 hour switch Over) in a medium comprising less than about 10% GABA _B agonist release after 2 hours, at least about 40% GABA _B agonist release after 3 hours, and at least about 70% GABA _B agonist release after 6 hours In vitro dissolution profile. Preferably, the enteric coating controlled release component is less than about 10% GABA _B agonist release after 2 hours, at least about 50% GABA _B agonist after 3 hours in artificial gastric juice / artificial intestinal fluid (2 hour switchover) medium Release, and an in vitro dissolution profile comprising at least about 80% GABA _B agonist release after 6 hours. Most preferably, the enteric coating controlled release component has less than about 10% GABA _B agonist release after 2 hours and at least about 60% GABA _B efficacy after 3 hours in artificial gastric juice / artificial intestinal fluid (2 hour switchover) medium. And an in vitro dissolution profile comprising at least about 90% GABA _B agonist release after the first release and 6 hours.

In a more preferred embodiment, the dosage form also contains an immediate release component in combination with an enteric coating controlled release component.

The present invention includes pharmaceutical dosage forms that have both immediate release and extended release properties. In this embodiment, the pharmaceutical dosage form comprising a GABA _B agonist and a pharmaceutically acceptable excipient releases less than about 75% of the GABA _B agonist after 2 hours in artificial gastric juice / artificial serous (2 hour switchover) medium. And an in vitro dissolution profile comprising at least about 80% GABA _B agonist release after 3 hours. Preferably, the pharmaceutical dosage form is less than about 65% GABA _B agonist release after 2 hours, and at least about 90% GABA _B agonist after 3 hours, in artificial gastric juice / artificial intestinal fluid (2 hour switchover) medium In vitro dissolution profile including release.

Suitable in vitro dissolution test methods for the dosage forms of the invention are known to those skilled in the art and include those described in the Examples herein. The USP Paddle Method refers to the Paddle and Basket Method described in US Pharmacopoeia XXII (1990). In particular, the USP paddle method at 50 rpm or 75 rpm at 900 ° C. at 37 ° C., artificial gastric juice (SGF) (pH 1.2) or artificial intestinal fluid (SIF) (pH 6.8) may be used to measure the in vitro dissolution profile according to the invention. Can be.

When the dosage forms of the invention comprise not only an immediate release component but also a controlled release component comprising an enteric coating controlled release, the ratio of the immediate release component to the controlled release component is from about 1:10 to about 10: 1, preferably about 1: 4 to about 4: 1, more preferably about 1: 3 to about 3: 1, and most preferably about 1: 2 to about 2: 1.

The pharmaceutical dosage forms of the invention are suitable for delayed absorption of the active agent, which allows for a reduction in the number of administrations compared to conventional immediate-release preparations. As used herein, “long term absorption” means that the active agent is absorbed in vivo over an extended period of time under fasting conditions. In particular, the time at which most of the uptake (ie, 80-90%) occurs is extended to about 7 or 8 hours after administration of the dosage form. Specifically, the time at which 80% or more of the active agent is absorbed from the dosage forms of the present invention is greater than 2.5 hours after administration, and typically 3 to 4.5 hours after administration. In comparison, the median time that at least 80% of the active agent is absorbed from the current immediate-release preparation is 1.5 to 2 hours after administration. The time for which the active agent is absorbed from the dosage form can be calculated by deconvolution using mathematical methods known in the art.

Dosage forms of the invention will exhibit an in vivo plasma profile that includes an average maximum GABA _B agonist level at about 30 minutes to about 7 hours, usually about 2.5 hours to about 5.5 hours, after a single dose to a fasting patient. In the steady state, the pharmaceutical dosage form of the present invention will reach a C _MIN equivalent to that obtained in the rectified state from the immediate-release dosage form at a later point in time, which allows for a reduction in the number of doses. In particular, when administered twice daily, the 40 mg dosage form of the invention is the average steady state area (AUC) under the plasma concentration-time curve, maximum plasma concentration, similar to the immediate-release tablet formulation administered three times daily. (C _MAX ), and minimum plasma concentration (C _MIN ).

These dosage forms (preferably tablets or capsules which may contain beads, granules, particles, or mixtures thereof) contain about 2 mg to about 150 mg (preferably between about 2.5 mg and about 100 mg) baclofen. And may be used in the treatment of medical conditions associated with diseases such as multiple sclerosis or certain spinal cord injury, such as spasms, convulsions, muscle tension.

The total daily dosage of the useful compounds according to the invention administered to the host in single or divided doses is generally in an amount of about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day, preferably about 0.05 mg Weight / kg / day to about 50 mg / kg / day. However, the specific dosage level for any particular patient depends on several factors, including body weight, general health, sex, diet, time and route of administration, rate of absorption and excretion, combination with other drugs, and the severity of the particular disease being treated. It is to be understood that it depends. The actual dosage level of the active ingredient in the compositions of the invention can be varied to obtain an active ingredient in an amount effective to obtain the desired therapeutic response for the particular composition and method of administration.

The total daily dosage of the said useful compounds according to the invention administered to a host in single or divided doses is for example from about 0.01 mg / kg body weight / day to about 20 mg / kg body weight / day, and preferably It may be an amount of 0.02 to 10 mg / kg body weight / day. The preferred dosage range of baclofen is 2.5 mg to 100 mg per dosage form. Dosage forms according to the invention may contain amounts or fractions thereof that can be used to make up the daily dosage.

Preferred dosage strengths for the formulation of the present invention include those having baclofen 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg. Typically, the optimal dosage for a patient is determined by titration so that the patient is initially dosed in small quantities and subsequently dosed until reaching a dosage level that achieves maximum therapeutic efficacy with minimal side effects. Incrementally increases.

One embodiment of the present invention provides a controlled release solid oral dosage form with immediate release of baclofen and delayed or delayed-sustained release of baclofen. Dosages according to the invention may comprise immediate release components and delayed or delayed-release components. Combinations of these two components can release the drug in pulsed or continuous form upon oral administration of the dosage form.

In one aspect, the present invention relates to a controlled release baclofen solid oral dosage form comprising an immediate release baclofen component and a delayed or delayed-sustained or sustained release baclofen component. The immediate release baclofen component comprises baclofen formulated with one or more pharmaceutically acceptable excipients that allow immediate release of baclofen, and the delayed or delayed-sustained or sustained release baclofen component is baclofen. Baclofen formulated with one or more excipients that allow delayed, or delayed-sustained, or sustained release of the pen. See, for example, US Pat. No. 6,372,254, which refers to a formulation, such as a tablet, having both immediate and extended release components.

Among other dosage forms apparent to those skilled in the art, the solid oral dosage form according to the invention may be a tablet formulation, or a separate unit-filled capsule formulation, or a sachet formulation. Separation units of the present invention include beads, granules, pellets, spheroids, particles, tablets, pills, and the like.

Specifically, the immediate release, delayed release, delayed-sustained, and sustained release components of the dosage forms are pending in US Pat. No. 6,372,254, filed on April 16, 2002, filed September 12,2002. US Patent Application No. 10 / 241,837, and International Patent Publication No. WO 03/101432, filed December 11, 2003, each of which is assigned to Impax Laboratories, Inc. It may take any form known to those of ordinary skill in the art, including one component of a multi-component tablet as described in. Controlled release baclofen formulations according to the invention may be in the form of a core comprising baclofen.

Dosage forms may be prepared according to methods known in the art. Some preferred methods are described below.

Matrix dosage forms

The term matrix, as used herein, refers to a solid having an active agent incorporated therein. Upon exposure to the dissolution medium, channels are formed in the solid to allow the active agent to flow out. Dosage forms according to the invention may be in the form of a coated or uncoated matrix. The coating may, for example, contain immediate release baclofen, or alternatively the matrix itself may contain controlled release baclofen. Drug release from delayed or delayed- or sustained release components ensures effective absorption of the drug immediately or continuously, for example within 7 hours after oral dosage administration.

The controlled release baclofen component may include baclofen coated with at least one delayed release layer. The delayed-sustained release baclofen component may comprise a sustained-release-coated baclofen coated with at least one delayed release layer. The sustained release baclofen component can include baclofen coated with at least one sustained-release polymer, or matrix-controlled release polymer.

The skilled practitioner should appreciate that the matrix material may be selected from a variety of materials that can provide the desired dissolution profile. This material is for example one or more gel-forming polymers such as polyvinyl alcohol, cellulose ethers such as hydroxyl propyl alkyl celluloses such as hydroxypropyl methylcellulose, hydroxy alkyl celluloses such as hydroxy propyl cellulose Natural or synthetic gums such as guar gum, xanthum gum, and alginates, and ethyl cellulose, polyethylene oxide, polyvinyl pyrrolidone, fats, waxes, polycarboxylic acids or esters such as Carbopol; Polymers), methacrylic acid copolymers, and methacrylate polymers.

Methods of preparing matrix dosage forms are well known in the art, and the methods which may include the desired dissolution profile and / or plasma profile may depend on the present invention. One such method includes mixing baclofen with a solid polymeric material and one or more pharmaceutically acceptable excipients, then blending and compressing them into a controlled release tablet core. Such tablet cores can be used for further processing into bilayer tablets, compression coated tablets or film coated tablets.

A coating containing immediate release baclofen may be added to the outside of the controlled release tablet core to produce the final dosage form. Such coatings can be prepared by mixing baclofen with polyvinylpyrrolidone (PVP) 29/32 or hydroxypropyl methylcellulose (HPMC) and water / isopropyl alcohol and triethyl acetate. This immediate release coating can be spray coated onto the tablet core. Immediate release coatings can also be applied in blends consisting of 80 wt% baclofen and 20 wt% lactose and hydroxypropyl methylcellulose type 2910 using the compression coating method. Compression coating techniques are known in the art and are described in US Pat. No. 6,372,254 to Ting et al., Which is incorporated herein by reference in its entirety.

In addition, the formulation of each release component can take place by any suitable granulation method which is well known in the art. In wet granulation, a solution of binder (polymer) is added to the mixed powder with stirring. The powdered mass is wetted with the binding solution until the mass has a consistency of moist eye or brown sugar. The wet granulated material is pushed through a sieving device. The wet material obtained from the milling step is placed in a temperature controlled vessel and dried. After drying, the granulated material is reduced in particle size by passing through a beating device. After the lubricant is added, the final blend is compressed into a matrix dosage form.

In fluid bed granulation, the particles of inert material and / or active agent are suspended in a vertical column with a cleaning air stream. While the particles are suspended, the conventional granulating material in solution is sprayed into the column. Gradual particle production is performed under controlled set of conditions to result in tablet granulation. After drying and adding lubricant, the granulated material is prepared to compact.

In dry-granulation, the actives, binders, diluents and lubricants are blended and compressed into tablets. The compressed large tablets are ground through the desired mesh screen by a beating device. Additional lubricant is added to the granulated material and blended gently. This material is then compressed into tablets.

Particle Based Dosage Forms, Immediate Release Particles

Immediate release / controlled release dosage forms of the invention may also take the form of pharmaceutical particles. Dosage forms may comprise immediate release particles in combination with controlled release particles in a ratio sufficient to deliver the desired release amount of the active agent. Controlled release particles can be produced by coating the released particles immediately.

The term "particle" as used herein refers to granules having a diameter of about 0.01 mm to about 5.0 mm, preferably about 0.1 mm to about 2.5 mm, and more preferably about 0.5 mm to about 2 mm. The skilled practitioner can assume that the particles according to the invention can have any geometric shape within this size range, and as long as the average of the statistical distribution of the particles is within the particle sizes listed above, they are the intended scope of the invention. It will be considered to exist within. The particles can be inferred to any standard structure known in the pharmaceutical art. The structure includes, for example, matrix particles, non-pareil cores with drug layers, and active or inactive cores with several layers therein. Controlled release coatings can be added to any of these structures to produce controlled release particles.

The particles can be prepared according to any of a number of known methods for producing the particles. Immediate release particles contain an active agent combination and a disintegrant. Suitable disintegrants include, for example, starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, calcium carboxymethylcellulose, hydroxypropyl starch, sodium starch glycolate and microcrystalline cellulose.

In addition to the components mentioned above, the matrix may also contain suitable amounts of other materials, for example diluents, lubricants, binders, granulation aids, colorants, flavors and glidants conventional in the pharmaceutical arts. The amount of these additional substances is sufficient to provide the desired effect on the desired formulation. The matrix incorporating the particles may also contain other materials customary in the pharmaceutical art, such as diluents, lubricants, binders, granulation aids, colorants, flavors, and glidants, if necessary in amounts of up to about 75% by weight of the granules. It may contain a suitable amount.

In one preferred embodiment, the oral dosage form is prepared to contain an effective amount of particles as described above in a capsule. For example, the melt-extruded particles can be placed in gelatin capsules in an amount sufficient to provide an effective controlled release dose when ingested and in contact with gastric juice. In another preferred embodiment, conventional tableting devices using standard techniques are used to compress the appropriate amount of particles into oral tablets. Techniques and compositions for the manufacture of tablets (compressed and shaped), capsules (hard and soft gelatin) and pills are also described in REMINGTON'S PHARMACEUTICAL SCIENCES , Arthur Osol, ed., 1553-1593 (1980). )). The particles can be prepared by mixing the components and granulating the mixture. The resulting particles are dried and screened to use particles with the desired size for drug formulation.

Controlled release particles

The controlled release particles of the present invention slowly release baclofen when ingested, exposed to gastric juice and then exposed to intestinal fluid. The controlled release profile of the formulations of the present invention can be altered by varying the amount of overcoating, for example by increasing or decreasing the thickness of the retardant coating. The resulting solid controlled release particles can then be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and in contact with an environmental emulsion, such as gastric juice, intestinal fluid or dissolution medium. The particles can be overcoated with an aqueous dispersion of hydrophobic or hydrophilic material to modify the release profile. The aqueous dispersion of hydrophobic material preferably further comprises an effective amount of plasticizer, for example triethyl citrate. Preformulated aqueous dispersions of ethyl cellulose may also be used, such as Aquacoat® or Shurelease®. If Shreeliz® is used, it is not necessary to add a plasticizer separately.

The release of the therapeutically active agent from the controlled release formulation of the present invention can be further affected by adding one or more release-modifying agents, ie can be adjusted to the desired release rate. Release-controlling agents can be organic or inorganic materials and include materials that can be dissolved, extracted or leached from the coating in the environment of use. The pore-former may contain one or more hydrophilic materials such as hydroxypropyl methylcellulose. Release-modulating agents may also include semi-permeable polymers. In certain preferred embodiments, the release-modifying agent is selected from hydroxypropyl methylcellulose, lactose, metal stearate and mixtures thereof.

Controlled release components may also include combinations of hydrophilic and hydrophobic polymers. In such embodiments, once administered, the hydrophilic polymer dissolves to weaken the structure of the controlled release component, and the hydrophobic polymer helps to delay water penetration and maintain the shape of the drug delivery system.

The hydrophobic material may be selected from the group consisting of alkylcellulose, acrylic acid and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, or mixtures thereof. In certain preferred embodiments, the hydrophobic material is an acrylic and methacrylic acid copolymer, methyl methacrylate, methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer , Poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamine copolymer, poly (methyl methacrylate), poly (methacrylic anhydride), polymethacrylate, polyacrylamide, poly (methacryl Acid anhydrides), and glycidyl methacrylate copolymers. In an alternative embodiment, the hydrophobic material is selected from one or more hydroxyalkyl celluloses, such as hydroxypropyl methylcellulose. Hydroxyalkyl cellulose is preferably hydroxy (C ₁ to C ₆ ) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose or preferably hydroxyethylcellulose. The amount of hydroxyalkyl cellulose in this oral dosage form is determined in particular by the exact proportion of the active agent desired and can vary from about 1% to about 80%.

In embodiments of the present invention, where the coating comprises an aqueous dispersion of hydrophobic polymer, incorporating an effective amount of plasticizer in the aqueous dispersion of hydrophobic polymer may further improve the physical properties of the film. For example, since ethylcellulose has a relatively high glass transition temperature and does not form a flexible film under conventional coating conditions, it is necessary to plasticize it before use as a coating material. Generally, the amount of plasticizer included in the coating solution is based on the concentration of the film-forming agent, for example most often from about 1% to about 50% by weight of the film-forming agent. However, the concentration of the plasticizer is preferably determined after careful experiments with the particular coating solution and application method.

Examples of suitable plasticizers for ethylcellulose include water-insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, but other water-insoluble plasticizers (eg, acetylation). Monoglycerides, phthalate esters, castor oil, etc.) may also be used. Triethyl citrate is a particularly preferred plasticizer for the aqueous dispersion of ethyl cellulose of the present invention.

Examples of plasticizers suitable for the acrylic polymer of the present invention include, but are not limited to, citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol. . Other plasticizers that have been shown to be suitable for enhancing the elasticity of films formed from acrylic films, such as Eudragit® RL / RS lacquer solutions, include polyethylene glycol, propylene glycol, diethyl phthalate, castor oil and triacetin. Include. Triethyl citrate is a particularly preferred plasticizer for aqueous dispersions of ethyl cellulose. In addition, the addition of small amounts of talc has been found to act as an abrasive and reduce the tendency of the aqueous dispersion to stick during processing.

Commercially available aqueous dispersions of ethylcellulose are Aquacoat® prepared by dissolving ethyl cellulose in a water-immiscible organic solvent and then emulsifying ethylcellulose in water in the presence of surfactants and stabilizers. After the homogenization step to produce submicron droplets, the organic solvent is evaporated under vacuum to form pseudolatex. The plasticizer is not incorporated into the pseudolatex during the manufacturing step. Thus, prior to using Pseudolates as a coating, Aquacoat® is mixed with a suitable plasticizer.

Another aqueous dispersion of ethylcellulose is commercially available from Shreliz® (Colorcon, Inc., West Point, PA., U.S.A.), West Point, Pennsylvania. This product is prepared by incorporating plasticizer into the dispersion during the manufacturing process. A thermal melt of the polymer, plasticizer (dibutyl sebacate) and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to give an aqueous dispersion which can be applied directly onto the substrate.

In one preferred embodiment, the acrylic coating is an acrylic resin lacquer used in the form of an aqueous dispersion, such as those sold under the tradename Eudragit® from Rohm Pharma. In a further preferred embodiment, the acrylic coating comprises a mixture of two acrylic resin lacquers sold under the tradename Eudragit® RL 30 D and Eudragit® RS 30 D. Eudragit® RL 30 D and Eudragit® RS 30 D are copolymers of acrylic and methacrylic esters with low content of quaternary ammonium groups, wherein the remainder of the neutral (meth) acrylic ester The molar ratio of ammonium groups is 1:20 in Eudragit® RL 30 and 1:40 in Eudragit® RS 30 D. The average molecular weight is about 150,000 Daltons. Code designations RL (high permeability) and RS (low permeability) refer to the permeation properties of these agents. Eudragit® RL / RS mixtures are insoluble in water and digestive fluids, but the coatings formed from them are swellable and permeable in aqueous and digestive fluids.

Eudragit® RL / RS dispersions can be mixed together in any desired ratio to obtain a controlled release formulation that ultimately has a desired dissolution profile. Preferred controlled release formulations are, for example, various coating combinations, such as 100% Eudragit® RL; 50% Eudragit® RL and 50% Eudragit® RS; Or from a delayed coating derived from one of 10% Eudragit® RL and 90% Eudragit® RS. Those skilled in the art will appreciate that other acrylic polymers, such as Eudragit® L, may also be used. In addition to modifying the dissolution profile by changing the relative amounts of different acrylic resin lacquers, the dissolution profile of the final product can also be modified, for example by increasing or decreasing the thickness of the retardant coating.

In a preferred embodiment of the invention, the stabilized product is obtained by oven curing the coated substrate at a temperature above the Tg of the plasticized acrylic polymer for the required period, and the optimum values of temperature and time for the particular formulation are determined experimentally. . In certain embodiments of the invention, the stabilized product is obtained through oven curing performed at a temperature of about 45 ° C. for a period of about 1 to about 48 hours. In addition, certain products coated with the controlled release coating of the present invention are expected to require a curing time of more than 24 to 48 hours, such as about 48 to about 60 hours or more.

The coating solution preferably contains, in addition to film-forming agents, plasticizers and solvent systems (ie water) colorants which provide solidity and product identification. The pigment may be added to the solution of the therapeutically active agent instead of, or in addition to, an aqueous dispersion of hydrophobic material. For example, the pigment can be added to the water-soluble polymer solution under shear, followed by the use of low shear for plasticized Aquacoat®, thereby dispersing alcohol or propylene glycol based pigment dispersions, crushed aluminum lakes, and milky whites. Agents, such as titanium dioxide, may be added to the Aquacoat®. Alternatively, any suitable method of providing a pigment to the formulation of the present invention can be used. When aqueous dispersions of acrylic polymers are used, suitable components for providing a pigment in the formulation include titanium dioxide, and pigment pigments such as iron oxide pigments. However, incorporation of pigments can increase the delaying effect of the coating.

Spheres or beads coated with a therapeutically active agent, for example, dissolve the therapeutically active agent in water and then spray the solution onto a substrate, such as Bipareil 18/20 beads, using a Worcester insert. It can manufacture by doing. Optionally, additional ingredients may also be added prior to coating the beads to help bind the active agent to the beads and / or to color the solution. For example, a solution comprising hydroxypropyl methylcellulose in the presence or absence of a colorant (e.g., Opadry (R) available from Coloron, Inc.) The solution can be mixed (eg, for about 1 hour) before application to the beads. The beads, the coating substrate produced in this example, can then be optionally overcoated with a barrier agent to separate the therapeutically active agent from the hydrophobic controlled release coating. Examples of suitable barrier agents are those comprising hydroxypropylmethylcellulose. However, any film-forming agent known in the art can be used. The barrier agent preferably does not affect the dissolution rate of the final product.

Compression Coated Pulsating Dosage Form

In another embodiment of the invention, baclofen contains a compressed blend of the active agent and one or more polymers substantially enclosed by an immediate release component containing a compressed blend of the active agent and a hydrophilic and hydrophobic polymer. It is administered via a compression coated pulsatile drug delivery system suitable for oral administration with the release component. The immediate release component preferably comprises a compressed blend of one or more polymers and an active agent with disintegrating properties, allowing the polymer to disintegrate quickly when exposed to an aqueous medium.

The controlled release component preferably contains a combination of hydrophilic and hydrophobic polymers. In such embodiments, once administered, the hydrophilic polymer dissolves to weaken the structure of the controlled release component, and the hydrophobic polymer helps to delay water penetration and maintain the shape of the drug delivery system.

According to the present invention, the term “polymer” includes a single or multiple polymer components that can swell, gel, decompose or erode when in contact with an aqueous environment (eg water). Examples include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polyacrylic potassium, powdered Cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate, starch, ethylcellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polymethacrylate, povidone, pregelatinized starch , Shellac, and zein, combinations thereof.

The term "hydrophilic polymer" as used herein refers to one or more carboxymethylcellulose, natural gums such as guar gum or acacia gum, tragacanth gum or xanthan gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methyl Cellulose, methylcellulose, and povidone, with hydroxypropyl methylcellulose being more preferred. The term “hydrophilic polymer” also refers to sodium carboxymethylcellulose, hydroxymethylcellulose, polyethylene oxide, hydroxyethyl methylcellulose, carboxypolymethylene, polyethylene glycol, alginic acid, gelatin, polyvinyl alcohol, polyvinylpyrroli Don, polyacrylamide, polymethacrylamide, polyphosphazine, polyoxazolidine, poly (hydroxyalkylcarboxylic acid), alkali metal or alkaline earth metal, carrageate alginate, ammonium alginate, sodium alganate, Or mixtures thereof.

The “hydrophobic polymer” of the drug delivery system includes carbomer, carnauba wax, ethylcellulose, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type 1, microcrystalline wax, polyacrylic potassium, polyethylene jade It may be any hydrophobic polymer that achieves the object of the present invention, including but not limited to one or more polymers selected from seeds, polymethacrylates, or stearic acid, wherein hydrogenated vegetable oil type 1 is preferred. Hydrophobic polymers are, for example, pharmaceutically acceptable acrylic copolymers such as acrylic and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylates, aminoalkyl methacrylates. Copolymer, poly (acrylic acid), poly (methacrylic acid), methacrylic acid alkylamide copolymer, poly (methyl methacrylate), poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate Copolymers, poly (methacrylic anhydride), and glycidyl methacrylate copolymers, but are not limited thereto. The acrylic copolymer may also be a cationic, anionic, or nonionic polymer, and may be an acrylate, methacrylate formed from methacrylic acid or methacrylic acid esters. The polymer may also be pH dependent.

Jang Sung  Coating controlled release

In one embodiment, the delayed or delayed-release coating is an enteric coating. All commercially available pH-sensitive polymers can be used to form enteric coatings. Drugs coated with enteric coatings are minimal or rarely released in an acidic gastric environment of about pH less than 4.5. The drug may be used at a higher pH at which the intestinal layer is present in the intestine; After a suitable delay time; Or dissolve after the unit passage time through the stomach. The preferred duration of drug release time is in the range of 7 hours or less after administration under fasting conditions.

Enteric polymers include cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, copolymerized methacrylic acid / methacrylic acid methyl esters, for example trade name Eudragit Substance known as L12.5, Eudragit® L100, or Eudragit® S 12.5, S 100 (Romm GmbH, Darmstadt, Germany: Rohm GmbH, Darmstadt, Germany Or similar compounds used to form enteric coatings. Aqueous colloidal polymer dispersions or redispersions include, for example, Eudragit® L 30D-55, Eudragit® L100-55, Eudragit® S100, Eudragit (registered). Trademark) Formulation 4110D c; Aquateric®, Aquacoat® CPD 30 (FMC Corporation); Kollicoat MAE® 30D and Colicoat MAE® 30DP (BASF); Eastacryl® 30D (Eastman Chemical, Kingsport, TN), Tennessee.

The enteric polymer used in the present invention can be modified by mixing with other known coating products that are not sensitive to pH. Examples of such coating products are currently marketed under the trade names E Eudragit®, Eudragit® RL, Eudragit® RS, and small amounts of trimethylammonioethyl methacrylate chloride Neutral methacrylic acid esters; Neutral ester dispersions sold under the trade names Eudragit® NE30D and Eudragit® NE30, without any functional groups; And other pH independent coating products.

The enteric coating will substantially enclose the controlled-release component. The term "substantially enclosed" is defined as encapsulating all or almost all of the components. Such inclusions preferably include at least about 80% inclusions, more preferably at least about 90% inclusions, and most preferably at least about 99% inclusions.

One embodiment of the present invention provides a free flowing formulation comprising baclofen. As used herein, the term “free flow” refers to a dosage form that passes through the patient's digestive system without the mechanism of hindrance or slow passage. Thus, for example, the term “free flow” excludes a dosage form of the splint type defined as remaining in the stomach for an extended period of time, such as in US Pat. No. 5,651,985.

Dosage forms according to the invention may also include combinations of baclofen and one or more additional active agents, such as tizanidine, dantrolene, nonsteroidal anti-inflammatory agents (NSAIDs), opioids, and COX-2 inhibitors. Other active agents can be co-formulated in immediate-release or delayed-release, delayed-release, or sustained-release components to achieve the desired therapeutic effect.

Dosage forms according to the invention may also be applied to pure racemic, L-baclocene, and other GABA related active agents as shown in US Pat. No. 6,350,769 to Kaufman et al., Issued February 26, 2002. Can be.

The dosages of any active agent and baclofen (racemic or L-baclofen) used in combination with baclofen in the composition, when used in the amount and combination product of baclofen, are specified in the composition and method of administration. It may be varied to obtain an amount of the active ingredient effective to obtain the desired therapeutic response to.

It is an object of the present invention to provide a controlled bioavailability of baclofen required by a health provider. Bioavailability refers to the extent to which a therapeutically active medicament becomes available in vivo after administration. Typically, bioavailability is measured in patients fasting overnight prior to administration with the test formulation. Plasma samples are then taken and analyzed for plasma concentrations of the parent compound and / or its active metabolites. This data can be expressed as C _MAX , the maximum amount of active ingredient found in plasma, or AUC, the area under the plasma concentration time curve. See Shargel & Yu, APPLIED BIOPHARMACEUTICS AND PHARMACOKINETICS ch. 10 (3d ed. 1996), and also in APPLIED PHARMACOKINETICS: PRINCIPLES OF THERAPEUTIC DRUG MONITORING, Evans et al., Eds. (3d ed. 1992).

For example, baclofen formulations can be used for comparative bioavailability studies in a subject. Subjects are fasted overnight before drug administration. Plasma samples are then collected at the time of dosing, every hour for 12 hours after dosing, and at 16 and 24 hours post dosing, and analyzed for ng / ml concentrations of baclofen or baclofen metabolite.

Without further work, those skilled in the art having the benefit of the above technology can utilize the present invention to its fullest extent. The following examples are merely illustrative and are not intended to limit the remaining disclosure in any way.

Example 1. Active Baclofen-Coated Seeds.

Povidone (Plasdon K-29 / 32®) was added to purified water and mixed until the povidone was sufficiently dissolved. The baclofen was mixed in the solution until uniformly dispersed. The spherical sugar was then coated with baclofen suspension using a fluidized bed coating apparatus to obtain an active coated seed.

Example 2. Active Baclofen-Coated Seeds.

Hypromellose, Type 2910®, USP (Pharmacote 606, 6 cps) was added to a suitable amount of purified water and mixed until the hypromellose was sufficiently dissolved. The baclofen was mixed in the solution until uniformly dispersed. The spherical sugar was then coated with baclofen suspension using a fluidized bed coating apparatus to obtain an active coated seed.

The dissolution profile of this formulation is shown in FIG. 3.

Example 3. Active Baclofen-Containing Granules.

Baclofen, starch 1500 (pregelatinized starch) and Avicel PH-102 (microcrystalline cellulose) are mixed. The baclofen mixture was placed in a Hobart mixer and blended to form a uniform mixture. The mixture was granulated with purified water to form granules. The granules were dried in an oven at 60 ° C. to form granules. Granulators were screened using a # 30 mesh screen. It was mixed with magnesium stearate to form active granules.

Example 4 Enteric-Coated Seed-Containing Baclofen

Purified water is poured into a stainless steel container and mixed in hypromellose until completely dissolved. Purified water and acetone were then introduced into another stainless steel vessel and then mixed in acetyltributyl citrate to form an acetyltributyl citrate solution. To this, hypromellose phthalate was added to form an enteric coating solution.

Baclofen active coated seeds prepared in any of Examples 1-3 were film coated with a seal coating solution to form sealed baclofen beads. The sealed baclofen beads were then film coated with an enteric coating solution to prepare an enteric coating seed.

Example 5 Enteric-Coated Seed-Containing Baclofen

Isopropyl alcohol and purified water were placed in a stainless steel vessel and then mixed in triethyl citrate. Added to methacrylic acid copolymer type A, NF (Eudragit® L 100) or methacrylic acid copolymer type C, NF (Eudragit ® L 100-55) ® suspension was formed. Talc was dispersed in Eudragit® suspension. The baclofen active coated seeds of Example 4 were film coated with Eudragit® suspension to form an enteric coated seed.

Example 6. Baclofen active coating and enteric coating seed containing compositions.

Designated doses of the active coated seeds and the enteric coated seeds were mixed together to form a dosage form. In the case of capsules, the seeds were mixed and added to gelatin capsules. In the case of tablets, the seeds were compressed to form tablets. In the case of Sachet, the seeds were mixed and filled into pouches.

Example 7. Enteric-Coated Seed-Containing Baclofen

Pharmacote 606 was dissolved in purified water and then baclofen was dispersed in this aqueous solution to prepare an aqueous suspension. Spherical sugars were coated with baclofen suspension using a fluidized bed coating apparatus and active coated seeds were prepared.

Eudragit® RL 100, RS 100, and dibutyl sebacate were dissolved in a mixture of acetone and isopropyl alcohol. Talc and magnesium stearate were then dispersed in the solution. A fluidized bed coating apparatus was used to coat the active coated seeds with the suspension to prepare sustained-release coated seeds.

HPMCP and triethyl citrate were dissolved in a mixture of acetone and purified water. An enteric coated seed was prepared by using a fluidized bed coating apparatus to coat the sustained-release coated seed with the solution.

Example 8. Baclofen Tablets.

Baclofen, sodium starch glycolate, anhydrous dicalcium phosphate, and lactose anhydride were mixed in a high shear granulator. The mixture was wet granulated with purified water and the granules were dried in an oven at 60 ° C. for at least 16 hours. Granulators were screened using a # 25 mesh screen. Oversize granules were milled using a Fitzpatric grinder equipped with a # 18 mesh screen. Screened and milled granules were blended with magnesium stearate and the blend was compressed into tablets using a rotary tablet compressor.

Example 9. Baclofen Tablets.

In a high shear granulator, baclofen, hydroxypropyl methylcellulose, lactose monohydrate or mannitol, and microcrystalline cellulose are mixed. The mixture was wet granulated with purified water and the granules were dried in an oven for at least 16 hours at a temperature of 60 ° C. Granulators were screened using a # 25 mesh screen. Oversize granules were milled using a Fitzpatrick mill equipped with a # 18 mesh screen. Screened and milled granules were blended with magnesium stearate and the blend was compressed into tablets using a rotary tablet compressor.

Example 10. Baclofen active coating and enteric coating seed containing compositions.

Hypromellose, type 2910, USP was added to a suitable amount of purified water and mixed until the hypromellose was sufficiently dissolved. The baclofen was then mixed in the solution until uniformly dispersed. The suspension was passed through a # 40 mesh beating into a stainless steel vessel. Spherical sugar was charged into a flow-bed coater equipped with a Worster inserter and heated until the discharge atmospheric temperature reached 50 ± 5 ° C. The active suspension was sprayed to coat the spherical sugars and then dried at a temperature of 60 ± 10 ° C. for 5 minutes. IR seeds were passed through a # 16 mesh stainless steel screen. Acceptable IR seeds were collected and mixed with talc, USP for 1 minute in an inclined cone blender.

Enteric solution was prepared by mixing purified water and acetone. Triethyl citrate and methacrylic acid copolymers, type C, were stirred in the mixture until complete dissolution. Mix until talc is completely dispersed in the solution. Subsequently, the IR seeds prepared previously were coated with the enteric solution using an assimilated bed coating apparatus to prepare an enteric coating seed. The enteric coated seeds were passed through a # 14 mesh stainless steel screen. Acceptable enteric coated seeds were collected and mixed with talc, USP for 1 minute in an inclined cone blender.

Appropriate amount of IR seed and appropriate amount of enteric coated seed were encapsulated to yield baclofen ER capsule.

Example 11. Baclofen Tablets

Tablets with the following compositions were prepared according to the method described in Example 9.

Dissolution profiles of the formulations are shown in FIG. 1B (in SIF) and FIG. 2 (SGF / SIF switchover method).

Example 12 Baclofen ER Capsule

Using the method described in Example 7, baclofen extended release capsules (20 mg) were prepared having the following formulation.

The dissolution profile of the formulation is shown in FIG. 4.

Example 13. Baclofen ER Capsule.

According to the method described in Example 10, baclofen ER capsules were prepared having the following formulations.

The dissolution profile of the formulation is shown in FIG. 5.

Example 14. Baclofen ER Capsule.

Bark of the following composition according to the method described in Example 10, except that the enteric material is triethyl citrate and methacrylic acid copolymer, acetyltributyl citrate and hypromellose phthalate instead of type C Lofen ER capsules were prepared.

The dissolution profile of the formulation is shown in FIG. 5.

Example 15. Baclofen ER Capsule.

Baclofen ER capsule having the following composition was prepared according to the method described in Example 10. Capsules with baclofen 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg, which are directly proportional to the different dosage strengths, were prepared.

Example 16 Determination of Plasma Profiles for Baclofen-Containing Formulations.

Example 15 except that 12 mg baclofen with the immediate-release component and 24 mg baclofen with the enteric coating controlled release component, and the remaining excipients were proportionally controlled. Bioavailability studies were performed in 20 healthy volunteers comparing 36 mg baclofen formulations prepared accordingly. Under fasting conditions, the formulations were compared to 20 mg immediate release reference tablets (Watson Laboratories, Inc.). After subjects fasted for at least 10 hours overnight, test samples were administered orally with 240 ml of room temperature water. Except at the time of drug administration, no liquid was allowed from 1 hour before administration to 1 hour after administration. At 2, 6, 8 and 12 hours after dosing, subjects were allowed to drink 240 ml of room temperature water. The subjects were also drunk 480 ml of liquid with lunch and dinner. Blood samples were taken at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16 and 24 hours after administration. The results are shown in FIG. 6 also shows the plasma levels of the simulations for 30 mg immediate-release baclofen, based on data obtained from administration of 20 mg dose intensity.

Example 17 Determination of the steady state plasma profile for baclofen-containing formulations.

Based on single dose bioavailability data, steady-state averages for 40 mg baclofen formulations prepared according to Example 15 administered every 12 hours and immediate-release 20 mg baclofen formulations administered every 8 hours Baclofen plasma levels were calculated. The results are shown in FIG. 7 where (C) represents the 40 mg dosage form of the present invention and (D) represents the reference 20 mg immediate-release dosage form. The results, 40 mg dosage form of the present invention shows that it reaches the C _MIN, similar to a C _MIN obtained with an immediate release formulation eight hours after administration in, the steady state in 12 hours after administration.

As will be described fully herein, those skilled in the art will understand that the methods of the present invention may be carried out in various and equivalent ranges of conditions, formulations, and other conditions or any embodiment thereof without departing from the scope of the present invention.

Claims (36)

Includes GABA _B agonists and pharmaceutically acceptable excipients, In artificial serous medium, comprising less than about 70% GABA _B agonist release after 1 hour, at least about 20% GABA _B agonist release after 4 hours, and at least about 30% GABA _B agonist release after 6 hours Indicating in vitro dissolution profile Pharmaceutical dosage forms comprising a controlled release component. The method of claim 1, wherein the controlled release component is less than about 80% GABA _B agonist release after 1 hour, at least about 30% GABA after 1 hour in artificial gastric juice / artificial intestinal fluid (1 hour switchover) medium. _B agonist released, after 6 hours, and the one that represents the in vitro dissolution profile, including at least GABA _B agonist release of about 40% of the pharmaceutical dosage form. The method of claim 1, wherein the controlled release component is less than about 50% GABA _B agonist release after 1 hour, at least about 40% GABA _B agonist release after 4 hours, and at least about 50 after 6 hours. A pharmaceutical dosage form exhibiting an in vitro dissolution profile comprising% GABA _B agonist release. 4. The GABA _B agonist of claim 3, wherein the controlled release component is less than about 70% GABA _B agonist release after 1 hour, at least about 40% GABA _B agonist after 4 hours in artificial gastric juice / artificial intestinal fluid (1 hour switchover) medium. Pharmaceutical dosage form comprising a release and an in vitro dissolution profile comprising at least about 50% GABA _B agonist release after 6 hours. The method of claim 1, comprising a GABA _B agonist and a pharmaceutically acceptable excipient, In artificial gastric juice, further comprising an immediate release component exhibiting an in vitro dissolution profile comprising at least about 80% GABA _B agonist release after one hour, A pharmaceutical dosage form wherein the ratio of the immediate release component to the controlled release component is from about 1:10 to about 10: 1. The pharmaceutical dosage form of claim 5 wherein the GABA _B agonist is baclofen. The pharmaceutical dosage form of claim 6 wherein the ratio of the immediate release component to the controlled release component is from about 1: 4 to about 4: 1. The pharmaceutical dosage form of claim 7 wherein the ratio of the immediate release component to the controlled release component is from about 1: 2 to about 2: 1. Includes GABA _B agonists and pharmaceutically acceptable excipients, In artificial gastric juice / artificial serous (2 hour switchover) medium, less than about 10% GABA _B agonist release after 2 hours, at least about 40% GABA _B agonist release after 3 hours, and at least about 70% after 6 hours Exhibiting an in vitro dissolution profile comprising the GABA _B agonist release of A pharmaceutical dosage form comprising an enteric coating controlled release component. 10. The method of claim 9, wherein the enteric coating controlled release component is less than about 10% GABA _B agonist release after 2 hours, at least about 50% GABA after 2 hours in artificial gastric juice / artificial intestinal fluid (2 hour switchover) medium. _B agonist released, after 6 hours, and the one that represents the in vitro dissolution profile, including at least GABA _B agonists released about 80% of the pharmaceutical dosage form. The method of claim 10, wherein the enteric coating controlled release component is less than about 10% GABA _B agonist release after 2 hours, at least about 60% GABA after 2 hours in artificial gastric juice / artificial intestinal fluid (2 hour switchover) medium. _B agonist released, after 6 hours, and the one that represents the in vitro dissolution profile comprising a GABA _B agonist release of at least about 90% of the pharmaceutical dosage form. The method of claim 9, comprising a GABA _B agonist and a pharmaceutically acceptable excipient, In artificial gastric juice, further comprising an immediate release component exhibiting an in vitro dissolution profile comprising at least about 80% GABA _B agonist release after one hour, A pharmaceutical dosage form wherein the ratio of the immediate release component to the controlled release component is from about 1:10 to about 10: 1. The pharmaceutical dosage form of claim 12 wherein the GABA _B agonist is baclofen. The pharmaceutical dosage form of claim 13 wherein the ratio of the immediate release component to the controlled release component is from about 1: 4 to about 4: 1. The pharmaceutical dosage form of claim 14 wherein the ratio of the immediate release component to the controlled release component is from about 1: 2 to about 2: 1. A GABA _B agonist and a pharmaceutically acceptable excipient, in an artificial gastric juice / artificial serous (2-hour switchover) medium, less than about 75% GABA _B agonist release after 2 hours, and at least about 80% after 3 hours A pharmaceutical dosage form exhibiting an in vitro dissolution profile comprising a GABA _B agonist release. The method of claim 16, comprising less than about 65% GABA _B agonist release after 2 hours and at least about 90% GABA _B agonist release after 3 hours in artificial gastric juice / artificial serous (2 hour switchover) medium. A pharmaceutical dosage form exhibiting an in vitro dissolution profile. The pharmaceutical dosage form of claim 16, wherein the GABA _B agonist is baclofen. A pharmaceutical dosage form comprising baclofen and a pharmaceutically acceptable excipient and wherein the median time of the period at which at least 80% of baclofen is absorbed in vivo upon oral administration under fasting conditions is greater than 2.5 hours. The pharmaceutical dosage form of claim 19 wherein the median time period of at least 80% baclofen in vivo absorption upon oral administration under fasting conditions is from about 3 hours to about 4.5 hours. The pharmaceutical dosage form of claim 20 comprising an enteric coating controlled release component and an immediate release component. The method of claim 21 wherein the enteric coating controlled release component is cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, copolymerized methacrylic acid, methacrylic acid A pharmaceutical dosage form comprising a polymer selected from the group consisting of methyl esters, and mixtures thereof. The pharmaceutical dosage form of claim 21 exhibiting an in vivo plasma profile comprising an average maximum baclofen level upon oral administration under fasting conditions from about 2.5 hours to about 5.5 hours after administration. The pharmaceutical dosage form of claim 21, wherein said pharmaceutical dosage form provides a steady-state in vivo plasma profile exhibiting C _MIN at about 12 hours after administration. The pharmaceutical dosage form according to any one of claims 6, 13, 18 or 19, wherein the baclofen is present in an amount from about 2 mg to about 150 mg. The pharmaceutical dosage form of claim 25, wherein said baclofen is present in an amount of about 20 mg. The pharmaceutical dosage form of claim 25, wherein said baclofen is present in an amount of about 25 mg. The pharmaceutical dosage form of claim 25, wherein said baclofen is present in an amount of about 30 mg. The pharmaceutical dosage form of claim 25, wherein said baclofen is present in an amount of about 35 mg. The pharmaceutical dosage form of claim 25, wherein said baclofen is present in an amount of about 40 mg. The pharmaceutical dosage form according to any one of claims 6, 13, 18 or 19, wherein baclofen is formulated as a combination of immediate-release beads and control-release beads. The pharmaceutical dosage form of claim 31 which is a tablet. The pharmaceutical dosage form of claim 31 which is a capsule. Includes baclofen in the immediate release component and the enteric coating controlled release component, The enteric coating controlled release component comprises cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, copolymerized methacrylic acid, methacrylic acid methyl ester, and mixtures thereof. Selected from the group consisting of A pharmaceutical dosage form wherein the median time of the period at which at least 80% of baclofen is absorbed in vivo upon oral administration under fasting conditions is from about 3 hours to about 4.5 hours. The pharmaceutical dosage form of claim 34 wherein said polymer is copolymerized methacrylic acid. Includes baclofen in the immediate release component and the controlled release component, The controlled release component comprises a matrix dosage form, A pharmaceutical dosage form wherein the median time of the period at which at least 80% of baclofen is absorbed in vivo upon oral administration under fasting conditions is from about 3 hours to about 4.5 hours.

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