JP2007531727A - Pharmaceutical dosage form with immediate and / or controlled release properties containing a GABAB receptor agonist - Google Patents

Abstract

The present invention generally relates to gamma-aminobutyric acid (GABA) for treating medical conditions, including convulsions, painful spasms, and muscle tone, associated with diseases such as multiple sclerosis or certain types of spinal cord injury. _B ) relates to pharmaceutical dosage forms with immediate release and controlled release properties, containing receptor agonists such as baclofen.

Description

BACKGROUND OF THE INVENTION The present invention generally treats medical conditions including convulsions, painful spasms, muscle tone, or spasticity associated with diseases such as multiple sclerosis, spinal cord disease, or certain types of spinal cord injury. In particular, it relates to a pharmaceutical dosage form containing immediate release and controlled release properties, comprising a γ-aminobutyric acid (GABA _B ) receptor agonist such as baclofen.

Multiple sclerosis is considered an autoimmune disease. In this regard, the individual's immune system can attack the myelin sheath that surrounds the nerve cells. This damage leads to muscle weakness, paralysis, coordination failure, balance function problems, fatigue, and the possibility of blindness. The GABA _B agonist baclofen can be used to treat these symptoms. Baclofen can also facilitate ancillary medical treatment, such as physical therapy, to improve the condition of patients with multiple sclerosis or certain types of spinal cord injury. Baclofen is also used to reduce the number and severity of trigeminal neuralgia attacks in patients who cannot tolerate or become refractory to the effects of carbamazepine.

  Baclofen, or 4-amino-3- (4-chlorophenyl) -butanoic acid, is a muscle relaxant and antispasmodic. Its mechanism of action appears unclear. Baclofen can also act at the upper spinal sites and contribute to its clinical effects, but suppresses both monosynaptic and polysynaptic reflexes at the spinal level, possibly by hyperpolarization of afferent nerve terminals Seems to be able to. In animal studies, baclofen has systemic central nervous system (CNS) inhibitory properties as indicated by the occurrence of tolerance sedation, somnolence, ataxia, and respiratory and cardiovascular hypofunction It was shown that.

  The absorption of baclofen is site specific. Baclofen is absorbed primarily in the upper digestive (GI) tract, and the degree of baclofen absorption is substantially reduced in the lower GI tract. Baclofen is absorbed quickly and extensively. Absorption is dose-dependent and may decrease with increasing dose. An improved method of administering baclofen to patients involves the delivery of an effective amount of the drug to the upper GI tract over an extended period of time.

  Several side effects may be associated with the administration of baclofen to mammals. These problems include nausea, vomiting, diarrhea, dizziness, daytime sedation, and less frequently psychotic conditions such as depressive mood disorders. In addition, if frequent dosing is required, such as the need to administer a dosage form three or four times a day, patient compliance with the dosing regimen may be suboptimal. Accordingly, pharmaceutical dosage forms that require less frequent dosing, such as once or twice daily, may be preferred. In addition, pharmaceutical dosage forms that can establish and maintain stable plasma levels of baclofen over time benefit patients by requiring less frequent dosing and minimizing side effects. Can bring

  Several baclofen pharmaceutical formulations are available, including orally disintegrating tablets marketed as Baclofen Tablet, 10/20 mg (Watson Pharmaceuticals, Inc., Corona, CA) and KEMSTRO (TM) (Schwarz Pharma, Monheim, Germany). Although commercially available, they do not provide controlled release of baclofen. For example, a single oral dose of KEMSTRO ™ 20 mg reaches a maximum plasma concentration approximately 1.5 hours after administration.

Baclofen has a serum half-life of 2.5-4 hours. (Drug Monograph: Baclofen American Hospital Formulary Service (AHFS) American Society of Hospital Pharmacists, Inc., Bethesda, MD 2003). Oral administration of conventional immediate release baclofen formulations typically reaches a therapeutically minimal plasma concentration approximately 4-8 hours after administration. Thus, conventional immediate release formulations typically require 3-4 doses per day.

  Various controlled release baclofen compositions have been reported. For example, US Pat. No. 5,091,184 issued to Khanna on February 25, 1992 describes an adhesive tablet that adheres to the oral mucosa and delivers the drug through the mucosa. These compositions have one or more of the problems associated with adhesive tablets and deliver drugs to sites that are not optimal for GABA related drugs. In addition, US Pat. No. 5,651,985 issued to Penners et al. On July 29, 1997 relates to a matrix dosage form having an extended gastric residence time. Dosage forms made according to the Penners reference are described as having significant swelling and high dimensional stability in the expanded state. In addition, an osmotic pump-type dosage form for delivering baclofen describes U.S. Pat. No. 4,764,380 issued to Urquhart et al. On Aug. 16, 1988, which describes sustained administration of drugs over a long period of time. ).

Nonetheless, like multiple sclerosis or certain types of spinal cord injury, by establishing and maintaining stable plasma concentrations of the drug over time to achieve less frequent medication and minimize side effects There is still a significant and continuing need for pharmaceutical dosage forms with controlled release properties that contain GABA _B receptor agonists such as baclofen to treat various medical conditions. These and other objects are achieved by the present invention.

U.S. Pat.No. 5,091,184 U.S. Pat.No. 5,651,985 U.S. Pat.No. 4,764,380

SUMMARY OF THE INVENTION The present invention relates generally to pharmaceutical dosage forms with controlled release properties that contain GABA _B receptor agonists such as baclofen. These dosage forms can be used in the treatment of medical conditions such as convulsions, painful convulsions, and muscle tone associated with diseases such as multiple sclerosis or certain types of spinal cord injury.

For example, a pharmaceutical dosage form of the invention may comprise a controlled release dosage form comprising a GABA _B agonist and a pharmaceutically acceptable excipient, which dosage form is about 1 hour after in a simulated intestinal fluid medium. 2 shows an in vitro dissolution profile comprising less than 70% GABA _B agonist 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 this embodiment, the controlled release dosage form is less than about 80% GABA _B agonist release after 1 hour, at least about 30% GABA _B agonist after 4 hours in simulated gastric / simulated intestinal fluid (switched in 1 hour) media. FIG. 5 shows an in vitro dissolution profile including release and at least about 40% GABA _B agonist release after 6 hours.

In a preferred embodiment, a controlled release dosage form comprising a GABA _B agonist and a pharmaceutically acceptable excipient has a GABA _B agonist release of less than about 50% after 1 hour, at least about 4 hours after in a simulated intestinal fluid medium. FIG. 5 shows an in vitro dissolution profile including 40% GABA _B agonist release and at least about 50% GABA _B agonist release after 6 hours. In this 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 after 4 hours in simulated gastric / simulated intestinal fluid (switched in 1 hour) media. FIG. 5 shows an in vitro dissolution profile including agonist release and at least about 50% GABA _B agonist release after 6 hours.

In another embodiment, the controlled release GABA _B agonist dosage form is combined with an immediate release GABA _B agonist component. In this embodiment, the immediate release component exhibits an in vitro dissolution profile comprising at least about 80% GABA _B agonist release after 1 hour in simulated gastric fluid. The ratio of immediate release component to 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, most preferably about 1: 2 to about 2: 1.

In another embodiment, the pharmaceutical dosage form of the invention contains an enteric coated controlled release component comprising a GABA _B agonist and a pharmaceutically acceptable excipient, the enteric coated controlled release component. 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 after 6 hours in simulated gastric fluid / simulated intestinal fluid (switched at 2 hours) medium FIG. 5 shows an in vitro dissolution profile with about 70% GABA _B agonist release. Preferably, the enteric coated controlled release component is less than about 10% GABA _B agonist release after 2 hours, at least about 50% after 3 hours in simulated gastric fluid / simulated intestinal fluid (switched at 2 hours) medium. GABA _B agonists release, and after 6 hours shows the in vitro dissolution profile comprises at least about 80% of the GABA _B agonist release. Most preferably, the enteric coated controlled release component is less than about 10% GABA _B agonist release after 2 hours, at least about 60% after 3 hours in simulated gastric fluid / simulated intestinal fluid (switched at 2 hours) medium. shows the in vitro dissolution profile comprises at least about 90% of the GABA _B agonists release of GABA _B agonists release, and after 6 hours.

In a further preferred embodiment, the dosage form also contains an immediate release component in combination with an enteric coated controlled release component. For example, GABA _B agonists may be prepared as a combination of immediate release and controlled release beads, compressed into tablets, or encapsulated. The ratio of immediate release component to controlled release component is from about 1:10 to about 10: 1, preferably from about 1: 4 to about 4: 1, more preferably from about 1: 3 to about 3: 1, and most preferably It will be about 1: 2 to about 2: 1.

The present invention includes pharmaceutical dosage forms that have both immediate release and sustained release characteristics. In this embodiment, a pharmaceutical dosage form comprising a GABA _B agonist and a pharmaceutically acceptable excipient is less than about 75% GABA _B after 2 hours in simulated gastric / simulated intestinal fluid (switched in 2 hours) medium. FIG. 5 shows an in vitro dissolution profile including agonist release and at least about 80% GABA _B agonist release after 3 hours. Preferably, the pharmaceutical dosage form provides less than about 65% GABA _B agonist release after 2 hours, at least 90% GABA _B agonist release after 3 hours in simulated gastric / simulated intestinal fluid (switched in 2 hours) media. In vitro dissolution profiles are shown.

The pharmaceutical dosage forms of the invention are adapted to be administered twice daily to patients in need of long-term baclofen therapy. Thus, in vivo absorption is prolonged compared to immediate release baclofen formulations, with a median time over which at least 80% of the baclofen is absorbed in vivo under fasting conditions is greater than 2.5 hours. The dosage forms of the present invention typically have an in vivo plasma profile comprising an average maximum baclofen level (C _max ) of about 30 minutes to about 7 hours after administration to a fasting patient, often between 2.5 and 5.5 hours after administration. It is thought that shows.

Detailed Description of the Invention The present invention relates to controlled release GABA _B agonists (preferably baclofen, baclofen prodrugs, baclofen analogs, or mixtures thereof, as well as racemic mixtures or substantially pure L-baclofen enantiomeric products of baclofen. ) Relates to pharmaceutical dosage forms including formulations. The controlled release GABA _B agonist formulation may be in the form of an enteric coated controlled release formulation. In addition, controlled release GABA _B agonist formulations, including enteric coated controlled release formulations, may be combined with immediate release GABA _B agonist formulations in the final pharmaceutical dosage form.

It has been found that the formulations of the present invention allow less frequent dosing compared to conventional immediate release formulations. For example, for patients in need of long-term GABA _B agonist therapy, twice daily administration of the formulations of the present invention is bioequivalent to three times daily administration of conventional immediate release formulations. This reduction in dosing frequency is more convenient for the patient and typically leads to better patient compliance. In addition, it reduces the number of plasma peak and trough values, which are typically associated with improved efficacy and reduced side effects.

  As used in this specification and the claims, the singular forms “a”, “an”, and “the” include reference to the plural unless the context clearly dictates otherwise. Thus, for example, a reference to a profile is a reference to one or more such profiles, including equivalents thereof known to those skilled in the art. It is understood that all numbers representing the amounts of ingredients or reaction conditions used herein are modified in all cases by the term “about”, except in the examples practiced or unless otherwise indicated. It should be. The term “about” when used in connection with percentages can mean ± 1%.

  All patents and other publications identified are hereby incorporated by reference for the purpose of describing and disclosing the methodology described in such publications that may be used, for example, in connection with the present invention. Incorporated into the book.

  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 may be used in the practice and testing of the present invention, the preferred methods, devices, and materials are described herein in this regard.

  Baclofen of the present invention, also known as butanoic acid or 4-amino-3- (4-chlorophenyl) butanoic acid, includes racemic baclofen, enantiomerically pure L-baclofen, and analogs, derivatives thereof, Prodrugs, metabolites, and any pharmaceutically acceptable salts thereof are included.

Baclofen is a GABA _B receptor agonist, therefore other GABA _B receptor agonists are contemplated within the scope of the present invention. These include 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) phosphonous acid; (4-aminobut-2-yl) phosphonous acid; -Amino-2-methylpropyl) phosphonous acid; (3-aminobutyl) phosphonous acid; (3-amino-2- (4-chlorophenyl) propyl) phosphonous acid; (3-amino-2- (4- Chlorophenyl) -2-hydride Xylpropyl) phosphonous acid; (3-amino-2- (4-fluorophenyl) propyl) phosphonous acid; (3-amino-2-phenylpropyl) phosphonous acid; (3-amino-2-hydroxypropyl) (E)-(3-aminopropen-1-yl) phosphonous acid; (3-amino-2-cyclohexylpropyl) phosphonous acid; (3-amino-2-benzylpropyl) phosphonous acid; 3-amino-2- (4-methylphenyl) propyl] phosphonous acid; [3-amino-2- (4-trifluoromethylphenyl) propyl] phosphonous acid; [3-amino-2- (4-methoxy Phenyl) propyl] phosphonic acid; [3-amino-2- (4-chlorophenyl) -2-hydroxypropyl] phosphonous acid; (3-aminopropyl) methylphosphinic acid; (3-amino-2-hydroxypropyl) (3-aminopropyl) (difluoromethyl) phosphinic acid; (4-aminobut-2-yl) (3-amino-1-hydroxypropyl) methylphosphinic acid; (3-amino-2-hydroxypropyl) (difluoromethyl) phosphinic acid; (E)-(3-aminopropen-1-yl) methyl (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. It is. See, for example, US Pat. No. 6,664,069.

  The term “analog” refers to a compound that includes a chemically modified form of a particular compound or class thereof and that retains the pharmacological and / or pharmacological activity characteristic of said compound or class. means. For example, baclofen analogs include 3-thienyl- and 3-furylaminobutyric acid.

  The term “derivative” refers to modifications that are considered routine by skilled chemists, such as protecting groups such as esters or amides of acids, benzyl groups for alcohols or thiols, and tert-butoxycarbonyl groups for amines, Means a chemically modified compound.

  As used herein, the term “prodrug” refers to any covalently bonded carrier that releases the active parent drug of the invention in vivo when such prodrug is administered to a patient. Including. Since prodrugs are known to enhance a number of desirable attributes of a drug (i.e., solubility, bioavailability, manufacturing, etc.), the compounds of the invention may be delivered in the form of a prodrug. . Prodrugs of the invention can be prepared by modifying functional groups present in the compound such that the modification is cleaved to the parent compound, either routinely or in vivo. In vivo conversion can occur as a result of several metabolic processes such as, for example, chemical or enzymatic hydrolysis of esters of carboxylic acid, phosphoric acid, or sulfuric acid, or reduction or oxidation of sensitive functional groups. Prodrugs within the scope of the present invention are cleaved to give a free hydroxyl group, a free amino group, or a free sulfhydryl group, respectively, when the prodrug of the present invention is administered to a mammalian subject. Any group that is formed includes compounds having a hydroxy, amino, or sulfhydryl group attached thereto. Functional groups that can be rapidly transformed in vivo by metabolic cleavage form a class of groups that react with the carboxyl groups of the compounds of the invention. These include, but are not limited to, alkanoyl (such as acetyl, propionyl, butyryl), unsubstituted and substituted aroyl (such as benzoyl and substituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl), trialkylsilyl (such as trimethylsilyl and triethyl). Groups such as silyl), monoesters formed with dicarboxylic acids (such as succinyl), and the like. Since metabolically cleavable groups of useful compounds according to the present invention are readily cleaved in vivo, compounds having such groups act as prodrugs. Compounds with metabolically cleavable groups have improved as a result of the increased solubility and / or absorption rate they have been given to the parent compound due to the presence of the metabolically cleavable group It has the advantage that it can exhibit bioavailability.

  A discussion of prodrugs is provided in the following literature: 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 & H. Bundgaard, ed., Chapter 5; Design and Applications of Prodrugs, 113-91 (1991); H. Bundgard, Advanced Drug Delivery Reviews, 1-38 (1992); 8 J. PHARM. SCIENCES 285 (1988); N. Nakeya et al., 32 CHEM. PHARM. BULL. 692 (1984); T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems , 14 ACS SYMPOSIUM SERIES: BIOREVERSIBLE CARRIERS IN DRUG DESIGN, Edward B. Roche, ed. (Am. Pharm. Assoc. & Pergamon Press 1987). Each of these documents is incorporated herein by reference.

Thus, the present invention contemplates the use of prodrugs of GABA _B receptor agonists (including baclofen), methods of delivering it, and compositions containing the same. 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 the form of a compound obtained in the human or animal body by the action of the body on the administered form of the compound, eg, after administration of the methylated compound, of the action by the body on the methylated compound. It means a demethylated analog of a compound having a methyl group, obtained as a result in the body. The metabolite itself may have biological activity.

  The phrase “pharmaceutically acceptable” as used herein is suitable for use in contact with human and animal tissues, within the limits of reasonable medical judgment, and is associated with excessive toxicity, irritation Sexual, allergic responses are also used to mean compounds, substances, compositions, and / or dosage forms without other problems or complications commensurate with a reasonable benefit / risk ratio.

  For example, “pharmaceutically acceptable salt” means a derivative of a disclosed compound wherein the specified compound has been converted to its acid or base salt. Such pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids. Etc. are included. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid; and 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, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid And salts prepared from organic acids such as toluene sulfonic acid, methane sulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid and the like.

  For the purposes of the present invention, the term “controlled release” is capable of releasing one or more active pharmaceutical substances over a long period of time (ie over a period of 1 hour or more) or over a long period of time. Mean part or all of a dosage form that delays the release of the active substance. Controlled release (CR) characteristics may be referred to as sustained release (SR), extended release (PR), modified release (MR), delayed release (DR), or sustained release (ER). As used herein in connection with the dissolution profile discussed herein, the term “controlled release” means that portion of the dosage form according to the invention that delivers the active agent over a period of more than one hour.

  By “immediate release” is meant a part or the whole of the dosage form that releases the active substance substantially immediately upon contact with gastric juice and dissolves substantially completely within about one hour. The feature of immediate release (IR) may be referred to as instant release (IR). The term “immediate release” when used in connection with the dissolution profile discussed herein means that part of the dosage form according to the invention that delivers the active substance during a period of less than 1 hour. .

The term “C _MAX ” is the highest plasma concentration exhibited by the composition of the present invention. “T _MAX ” means the time at which C _MAX occurs in the plasma concentration-time profile. “C _MIN ” is the lowest plasma concentration. “C” is the concentration, “T” is the time, “max” is the maximum, and “min” is the minimum. An initial peak in plasma level means the first increase in plasma level of the active substance, which may be followed by one or more additional peaks, one of which can be C _MAX . As used herein, the term "mean maximum level of GABA _B agonist" refers to the average C _MAX of GABA _B agonists. Plasma concentrations as described herein are typically measured using a population of at least 12 subjects.

  The aforementioned plasma concentration may mean the plasma level after a single oral administration of the dosage form, or may mean the level obtained at steady state. As used herein, “steady-state” plasma concentration refers to repeated dosing of a drug until a stable level of absorption and excretion is reached such that the amount of drug in the body is substantially constant. It means the plasma level obtained at that time.

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

  The term “effective amount” means an amount of a compound / composition according to the present invention effective to produce the desired therapeutic effect.

  The term “excipient” means a pharmacologically inactive ingredient that is not active in the body. See HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (Am. Pharm. Ass'n 1986). One skilled in the art will recognize that many different excipients can be used in the formulations according to the present invention and the list provided herein is not exhaustive.

  The active ingredient of the present invention may contain preservatives, extenders, polymers, disintegrants, glidants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, dressings, depending on the mode of administration and the nature of the dosage form. It may be mixed with pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles such as flavoring agents, lubricants, acidifying agents, and dispensing agents. Such ingredients, including pharmaceutically acceptable carriers and excipients, can be used to prepare oral dosage forms. Pharmaceutically acceptable carriers include water, ethanol, polyols, vegetable oils, fats, waxes, polymers including gel-forming polymers 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 mixtures. 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.

  “Dosing under fasting conditions” is defined as when a subject is fasted overnight for at least 10 hours and then dosed orally with 240 ml of room temperature water. Except for those given with drug administration, no liquid is given from 1 hour before dose administration to 1 hour after dosing. Two hours after administration, the subject may receive 240 ml of room temperature water.

The pharmaceutical dosage form of the present invention may comprise a controlled release dosage form comprising a GABA _B agonist and a pharmaceutically acceptable excipient, the dosage form being about 70% after 1 hour in a simulated intestinal fluid medium. 2 shows an in vitro dissolution profile comprising less than GABA _B agonist 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 this embodiment, the controlled release dosage form is less than about 80% GABA _B agonist release after 1 hour, at least about 30% GABA _B agonist after 4 hours in simulated gastric / simulated intestinal fluid (switched in 1 hour) media. FIG. 5 shows an in vitro dissolution profile including release and at least about 40% GABA _B agonist release after 6 hours.

Preferably, the controlled release dosage form has 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 in the simulated intestinal fluid medium. FIG. 5 shows an in vitro dissolution profile with% GABA _B agonist release. In this 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 after 4 hours in simulated gastric / simulated intestinal fluid (switched in 1 hour) media. FIG. 5 shows an in vitro dissolution profile including agonist release and at least about 50% GABA _B agonist release after 6 hours.

In another embodiment, the controlled release GABA _B agonist dosage form is combined with an immediate release GABA _B agonist component. In this embodiment, the immediate release component exhibits an in vitro dissolution profile comprising at least about 80% GABA _B agonist release after 1 hour in simulated gastric fluid.

In another embodiment, the pharmaceutical dosage form of the invention contains an enteric coated controlled release component comprising a GABA _B agonist and a pharmaceutically acceptable excipient, the enteric coated controlled release component. 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 after 6 hours in simulated gastric fluid / simulated intestinal fluid (switched at 2 hours) medium Figure 5 shows an in vitro dissolution profile with about 70% GABA _B agonist release. Preferably, the enteric coated controlled release component is less than about 10% GABA _B agonist release after 2 hours, at least about 50% after 3 hours in simulated gastric fluid / simulated intestinal fluid (switched at 2 hours) medium. GABA _B agonists release, and after 6 hours shows the in vitro dissolution profile comprises at least about 80% of the GABA _B agonist release. Most preferably, the enteric coated controlled release component is less than about 10% GABA _B agonist release after 2 hours, at least about 60% after 3 hours in simulated gastric fluid / simulated intestinal fluid (switched at 2 hours) medium. shows the in vitro dissolution profile comprises at least about 90% of the GABA _B agonists release of GABA _B agonists release, and after 6 hours.

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

The present invention includes pharmaceutical dosage forms that have both immediate release and sustained release characteristics. In this embodiment, the pharmaceutical dosage form comprising a GABA _B agonist and a pharmaceutically acceptable excipient is less than about 75% GABA _B after 2 hours in simulated gastric / simulated intestinal fluid (switched in 2 hours) medium. FIG. 5 shows an in vitro dissolution profile including agonist release and 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 90% GABA _B agonist release after 3 hours in simulated gastric / simulated intestinal fluid (switched at 2 hours) medium. In vitro dissolution profile comprising

  In vitro dissolution testing methods suitable for the dosage forms of the present invention are known to those skilled in the art and include those described herein in the Examples. USP paddle method refers to the Paddle and Basket Method described in United States Pharmacopoeia, Edition XXII (1990). In particular, the in vitro dissolution profile according to the present invention was measured using USP paddle method at 50 rpm or 75 rpm in simulated gastric fluid (SGF) (pH 1.2) or simulated intestinal fluid (SIF) (pH 6.8) at 37 ° C. and 900 ml. Can be done.

  Where the dosage form of the present invention comprises a controlled release component comprising enteric coated controlled release, as well as an immediate release component, the ratio of immediate release component to controlled release component is from about 1:10 to about 10: 1, preferably Is from about 1: 4 to about 4: 1, more preferably from about 1: 3 to about 3: 1, and most preferably from about 1: 2 to about 2: 1.

  The pharmaceutical dosage forms of the invention are adapted to allow sustained absorption of the active substance, allowing for less frequent administration compared to conventional immediate release formulations. As used herein, “sustained absorption” means that the active substance is absorbed over a long period of time in vivo under fasting conditions. In particular, the period during which the majority of absorption occurs (ie 80-90%) extends to about 7 or 8 hours after administration of the dosage form. Specifically, the median period of time when at least 80% of the active substance is absorbed from the dosage form of the present invention is longer than 2.5 hours after administration, typically 3 to 4.5 hours after administration. By comparison, the median time period during which at least 80% of the active substance is absorbed from conventional immediate release formulations is 1.5-2 hours after administration. The time period during which the active substance is absorbed from a dosage form can be calculated by deconvolution using mathematical methods known to those skilled in the art.

The dosage form of the present invention exhibits an in vivo plasma profile comprising an average highest GABA _B agonist level of about 30 minutes to about 7 hours, often about 2.5 to about 5.5 hours after administration of a single dose to a fasted patient. Conceivable. At steady state, the pharmaceutical dosage forms of the present invention are expected to reach C _MIN at a later point in time, comparable to that obtained at steady state from immediate release dosage forms, which allows less frequent dosing It is thought to be. In particular, the 40 mg dosage form of the present invention is below the mean plasma concentration-time curve at steady state, similar to the value of an immediate release tablet administered three times a day when administered twice a day. It is believed to give the area (AUC), the highest plasma concentration (C _MAX ), and the lowest plasma concentration (C _MIN ).

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

  The total daily dose of the compounds useful according to the invention administered to the host in a single dose or divided dose will generally be from about 0.01 mg / kg body weight to about 100 mg / kg body weight per day, preferably about 0.05 per day. The amount is from mg / kg body weight to about 50 mg / kg body weight. However, the particular dose level for any particular patient will depend on body weight, overall health, sex, diet, time and route of administration, rate of absorption and excretion, combinations with other drugs, and the individual being treated It should be understood that it depends on various factors including the severity of the disease. The actual dosage level of the active ingredients in the compositions of the present invention may be varied in order to obtain an amount of the active ingredient effective to obtain the desired therapeutic response to the particular composition and method of administration.

  The total daily dose of the compounds useful according to the invention administered to the host in single or divided doses is, for example, from about 0.01 mg / kg body weight to about 20 mg / kg body weight per day, and preferably about 0.02 mg. The amount may be from / kg / day to about 10 mg / kg / day. A preferred dosage range for baclofen is 2.5 mg to 100 mg per dosage form. The dosage form according to the invention may contain such an amount or a part thereof that it can be used to constitute a daily dose.

  Preferred dosage strengths of the formulations of the present invention include those having 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, and 40 mg baclofen. Typically, the optimal dosage for a patient is that patient is first given a small dose and then that dose is reached until the patient reaches a dosage level that achieves maximum therapeutic efficacy with minimal side effects. Determined by titration to gradually increase.

  One embodiment of the present invention provides a controlled release solid oral dosage form that includes immediate release of baclofen and delayed or delayed release of baclofen. The dosage form according to the invention may comprise an immediate release component and a delayed release or delayed sustained release component. The combination of these two ingredients can release the drug in an intermittent or continuous manner when the dosage form is administered orally.

  In one aspect, the invention relates to a controlled release baclofen solid oral dosage form comprising an immediate release baclofen component and a delayed release or delayed sustained release or sustained release baclofen component. Immediate release baclofen component includes baclofen formulated with one or more pharmaceutically acceptable excipients that allow immediate release of baclofen, a delayed release or delayed sustained release or sustained release baclofen component Includes baclofen formulated with one or more excipients that allow delayed or delayed sustained release of baclofen, or sustained release. See, for example, US Pat. No. 6,372,254 for formulations such as tablets having both immediate release and sustained release components.

  Among other dosage forms that will be apparent to those skilled in the art, the solid oral dosage form according to the invention may be a tablet formulation, or a capsule formulation packed with individual units, or a sachet formulation. Individual units of the present invention include beads, granules, pellets, spheroids, particles, tablets, pills and the like.

  Specifically, the immediate release, delayed release, delayed sustained release, and sustained release components of the dosage form are each assigned to Impax Laboratories, Inc., U.S. Pat. No. 6,372,254, pending US patent application 10 / 241,837 filed on September 12, 2002, and published international patent application WO 03/101432 filed on December 11, 2003. Can take any form known to a skilled pharmaceutical formulator including one component of a multi-component tablet. Controlled release baclofen dosage forms according to the present invention may be in the form of nuclei containing baclofen.

  The dosage forms can be made by methods known in the art. Some preferred methods are described below.

The term matrix dosage form matrix, as used herein, means a solid material in which the active agent is incorporated. When exposed to the dissolution medium, a channel is formed in the solid material so that the active material can flow out. The dosage form 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. Delayed release or delayed sustained release, or drug release from a sustained release component, can be immediate or sustained, e.g. 7 hours after oral administration of an oral dosage form to ensure effective absorption of the drug Is within.

  The controlled release baclofen component may consist of baclofen coated with at least one release-retarding layer. The delayed-type sustained release baclofen component may consist of baclofen coated for sustained release coated with at least one delayed release layer. The sustained release baclofen component may consist of at least one sustained release polymer, or baclofen coated with a matrix controlled release polymer.

  One skilled in the art should understand that the matrix material can be selected from a wide variety of materials that can achieve the desired dissolution profile. Materials include, for example, one or more gel-forming polymers such as polyvinyl alcohol, for example, hydroxypropylalkylcelluloses such as hydroxypropylmethylcellulose, cellulose ethers including hydroxyalkylcelluloses such as hydroxypropylcellulose, guar gum, xanthum Natural and synthetic rubbers such as rubber and alginate, and esters, methacrylic acid copolymers, and methacrylic acid polymers such as ethyl cellulose, polyethylene oxide, polyvinylpyrrolidone, fat, wax, polycarboxylic acid, or Carbopol® series of polymers Can be included.

  Methods for producing matrix dosage forms are known in the art and may be relied upon in any manner that can produce a desired dissolution profile and / or plasma profile in accordance with the present invention. One such method involves baclofen together with a solid polymeric material and one or more pharmaceutically acceptable excipients that are then mixed and compressed into the core of a controlled release tablet. Such tablet cores can be used for further processing as bilayer tablets, compression-coated tablets, or film-coated tablets.

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

  In addition, the formulation of the individual release components can occur by suitable granulation methods that are well known in the art. In the wet granulation method, a solution of a binder (polymer) is added to the mixed powder while stirring. The powder mass is moistened with the binding solution until the mass has a damp snow or brown sugar hardness. The wet granulated material is pushed through a sieving device. Dry the moist material resulting from the grinding process by placing it in a temperature controlled container. After drying, the particle size of the granular material is reduced by passing through a sieving device. Lubricant is added and the final mixture is then compressed into a matrix dosage form.

  In fluidized bed granulation, an ascending air stream is used to suspend particles of inert material and / or active material in a vertical tube. While the particles are suspended, normal granulated material in solution is sprayed into the tube. Particles gradually accumulate under a set of controlled conditions that result in tablet granulation. After drying and addition of lubricant, the granular material can be compressed as it is.

  In the dry granulation method, the active substance, binder, diluent, and lubricant are mixed and compressed into tablets. The compressed large tablet is crushed through a desired mesh sieve by a sieving machine. Add additional lubricant to the granular material and mix gently. This material is then compressed into tablets.

Particle-Based Dosage Form, Immediate Release Particle The immediate release / controlled release dosage form of the present invention may take the form of pharmaceutical particles. This dosage form may contain immediate release particles in combination with controlled release particles in a ratio sufficient to provide the desired release of the active agent. Controlled release particles can be made by coating immediate release particles.

  As used herein, the term “particle” means a granule 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. . Those skilled in the art will appreciate that the particles according to the present invention may be of any geometric shape within this size range, as long as the average value of the statistical distribution of the particles falls within the particle size range listed above. It should be understood that they are considered to fall within the intended scope of the present invention. The particles may exhibit any standard structure known in the pharmaceutical art. Such structures include, for example, matrix particles, non-pareil nuclei with drug layers, and active or inactive nuclei with multiple layers thereon. Controlled release coatings can be added to any of these structures to create controlled release particles.

  These particles can be made according to any of several known methods for making particles. Immediate release particles comprise a combination of active substances and a disintegrant. Suitable disintegrants include, for example, starch, low substituted hydroxypropyl cellulose, croscarmellose sodium, calcium carboxymethyl cellulose, hydroxypropyl starch, sodium starch glycolate, and crystalline cellulose.

  In addition to the above components, the matrix may contain other materials in appropriate amounts, such as diluents, lubricants, binders, granulating aids, colorants, flavoring agents, and glidants commonly used in the pharmaceutical field. An agent may be contained. The amount of these additional substances is sufficient to give the desired effect to the desired formulation. The matrix that incorporates the particles, if desired, in amounts up to about 75% by weight of the particles, diluents, lubricants, binders, granulating aids, colorants, flavoring agents, and fluids commonly used in the pharmaceutical field. Appropriate amounts of these other substances, such as accelerators, may be included.

  In one preferred embodiment, the oral dosage form is prepared to contain an effective amount of the aforementioned particles in the capsule. For example, a quantity of melt-extruded particles sufficient to achieve an effective controlled release dose when ingested and contacted with gastric juice may be placed in a gelatin capsule. In another preferred embodiment, an appropriate amount of particles are compressed into an oral tablet by standard techniques using conventional tableting equipment. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin), and pills are described in REMINGTON'S PHARMACEUTICAL SCIENCES, Arthur Osol, ed., 1553-, incorporated herein by reference. 93 (1980). Particles can be made by mixing the appropriate ingredients and granulating the mixture. The resulting particles are dried and screened and the particles with the desired size are used for drug preparation.

Controlled Release Particles The controlled release particles of the present invention slowly release baclofen when ingested and exposed to gastric fluid and then to intestinal fluid. For example, the controlled release profile of the formulations of the present invention can be altered by increasing or decreasing the thickness of the delay coating, ie, by changing the amount of overcoat. The resulting solid controlled release particles are then ingested and gelatin capsules in an amount sufficient to achieve an effective controlled release dose when in contact with the surrounding liquid, such as gastric juice, intestinal fluid, or dissolution medium. It may be placed inside. To alter the release profile, the particles may be overcoated with an aqueous dispersion of a hydrophobic or hydrophilic material. The aqueous dispersion of hydrophobic material preferably further comprises an effective amount of a plasticizer, such as triethyl citrate. A pre-prepared aqueous dispersion of ethyl cellulose such as Aquacoat® or Surelease® may be used. When using Surelease (registered trademark), it is not necessary to add a plasticizer separately.

  Add one or more release-modifying agents to further influence the release of the therapeutically active substance from the controlled release formulation of the present invention, ie, adjust to the desired rate can do. Release modifiers can be organic or inorganic and include materials that can be dissolved, extracted, or leached from the coating in the environment of use. The pore-former may comprise one or more hydrophilic substances such as hydroxypropylmethylcellulose. These release modifiers may also include semipermeable polymers. In certain preferred embodiments, the release modifier is selected from hydroxypropyl methylcellulose, lactose, metal stearate, and mixtures thereof.

  The controlled release component may also include a combination of hydrophilic and hydrophobic polymers. In this embodiment, once administered, the hydrophilic polymer dissolves away, the structure of the controlled release component is weakened, and the hydrophobic polymer retards water penetration and helps maintain the shape of the drug delivery system.

The hydrophobic material may be selected from the group consisting of alkyl cellulose, polymers and copolymers of acrylic acid and methacrylic acid, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, or mixtures thereof. In certain preferred embodiments, the hydrophobic material is, but is not limited to, a copolymer of acrylic acid and methacrylic acid, methyl methacrylate, methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer. , Poly (acrylic acid), poly (methacrylic acid), alkylamine methacrylate copolymer, poly (methyl methacrylate), poly (methacrylic anhydride), polymethacrylate, polyacrylamide, poly (methacrylic anhydride), and methacrylic acid A pharmaceutically acceptable acrylic polymer, including an acid glycidyl copolymer. In an alternative embodiment, the hydrophobic material is selected from materials such as one or more hydroxyalkylcelluloses such as hydroxypropylmethylcellulose. The hydroxyalkyl cellulose is preferably a hydroxy (C ₁ -C ₆ ) alkyl cellulose such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, or preferably hydroxyethylcellulose. The amount of hydroxyalkylcellulose in the oral dosage form of the present invention is determined, inter alia, by the exact rate of the desired active substance and can vary from about 1% to about 80%.

  In embodiments of the invention where the coating comprises an aqueous dispersion of a hydrophobic polymer, the physical properties of the film can be further improved by including an effective amount of a plasticizer in the aqueous dispersion of hydrophobic polymer. For example, ethylcellulose has a relatively high glass transition temperature and does not form a flexible film under normal coating conditions, so it must be plasticized before it can be used as a coating material. Generally, the amount of plasticizer included in the coating solution is based on the concentration of the film former, for example, in most cases from about 1 weight percent to about 50 weight percent of the film former. Preferably, however, the concentration of plasticizer is determined after careful experimentation with the individual coating solutions and application methods.

  Examples of plasticizers suitable for ethylcellulose include water-insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, but other water-insoluble plasticizers (acetylated monoglycerides). Phthalates, castor oil, etc.). 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 polymers of the present invention include, but are not limited to, triethyl citrate NF XVI, citrate esters such as tributyl citrate, dibutyl phthalate, and optionally 1,2- Propylene glycol is included. Other plasticizers found 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 are included. Triethyl citrate is a particularly preferred plasticizer for aqueous dispersions of ethyl cellulose. It has further been found that the addition of a small amount of talc reduces the tendency of the aqueous dispersion to stick during processing and behaves like an abrasive.

  One commercially available aqueous dispersion of ethyl cellulose is Aquacoat®, which dissolves ethyl cellulose in a water-immiscible organic solvent and then in water in the presence of surfactants and stabilizers. It is prepared by emulsifying ethyl cellulose. After homogenization to produce submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. No plasticizer is incorporated into the pseudolatex during the manufacturing phase. Therefore, before using the pseudolatex as a coating, Aquacoat® is mixed with a suitable plasticizer.

  Another aqueous dispersion of ethylcellulose is commercially available as Surelease® (Colorcon, Inc., West Point, PA, USA). This product is prepared by incorporating a plasticizer into the dispersion during the course of the manufacturing process. A water melt that can be applied directly onto a substrate by preparing a hot melt of polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) as a homogeneous mixture, which is then diluted with an alkaline solution Get a system.

  In one preferred embodiment, the acrylic coating is an acrylic resin lacquer used in the form of an aqueous dispersion, such as that marketed by Rohm Pharma under the trade name Eudragit®. In an additional preferred embodiment, the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the trade names Eudragit® RL30D and Eudragit® RS30D. Eudragit® RL30D and Eudragit® RS30 are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the moles of ammonium groups and residual neutral (meth) acrylic esters. The ratio is 1:20 for Eudragit® RL30 and 1:40 for Eudragit® RS30D. The average molecular weight is about 150,000 daltons. The symbols RL (high permeability) and RS (low permeability) relate to the transmission properties of these substances. Eudragit® RL / RS mixtures are insoluble in water and digestive fluids, but the coatings formed from them are swellable and permeable in aqueous solutions and digestive fluids.

  Eudragit® RL / RS dispersions may be mixed in any desired ratio to ultimately obtain a controlled release formulation with the desired dissolution profile. For example, Eudragit (R) RL 100%, Eudragit (R) RL 50%, Eudragit (R) RS 50%, or Eudragit (R) RL 10% and Eudragit (R) RS 90% Desired controlled release formulations can be obtained from delayed coatings derived from one of the various coating combinations. One skilled in the art should recognize that other acrylic polymers, such as Eudragit® L, may be used. In addition to changing the dissolution profile by changing the relative amounts of the various acrylic lacquers, the dissolution profile of the final product can also be changed, for example, by increasing or decreasing the thickness of the delayed coating.

In a preferred embodiment of the present invention, at a temperature above the T _g of the plasticized acrylic polymer, for periods of time necessary, by subjecting the coated substrate to oven curing, products that are stabilized can be obtained, this time, the individual Optimum temperature and time values for these formulations are determined empirically. In certain embodiments of the invention, a stabilized product is obtained by oven curing performed at a temperature of about 45 ° C. for a period of about 1 to about 48 hours. It is also contemplated that certain products coated with the controlled release coating of the present invention may require a cure time of longer than 24-48 hours, for example, from about 48 to about 60 hours or longer.

  The coating solution preferably also contains, in addition to the film former, plasticizer, and solvent system (ie water), a colorant that improves the appearance and allows product differentiation. The colorant may be added to a solution of the therapeutically active substance instead of or in addition to the aqueous dispersion of the hydrophobic substance. For example, through the use of an alcohol or propylene glycol based colorant dispersion, milled aluminum lake, and opacifiers such as titanium dioxide, the colorant is added while applying shear to the water soluble polymer solution and then plasticized Colorant can be added to Aquacoat® by using a low shear force against the modified Aquacoat®. Alternatively, any suitable method of supplying a colorant to the formulation of the present invention may be used. Suitable ingredients for supplying the colorant to the formulation when using an aqueous dispersion of acrylic polymer include colored pigments such as titanium dioxide and iron oxide pigments. However, the mixing of pigments can increase the retardation effect of the coating.

  For example, a therapeutically active substance is coated in a therapeutically active substance by dissolving it in water and then spraying the solution onto a substrate, such as non-parrel 18/20 beads, using a Wuster insert. Spheroids or beads can be prepared. Optionally, additional components are also added prior to coating the beads, such as to aid binding of the active agent to the beads and / or to color the solution. For example, before applying a product containing hydroxypropyl methylcellulose with or without a colorant (e.g., Opadry®, commercially available from Colorcon, Inc.) on the beads (e.g., about 1 hour) May be added to the solution and the mixed solution. The resulting coated substrate, in this example beads, may then optionally be overcoated with a barrier agent to separate the therapeutically active substance from the hydrophobic controlled release coating. An example of a suitable barrier agent is one that includes hydroxypropyl methylcellulose. However, any film former known in the art may be used. It is preferred that the barrier agent does not affect the dissolution rate of the final product.

Compression coated, pulsatile dosage form In another embodiment of the invention, the baclofen contains a compressed mixture of the active agent and one or more polymers, and the active agent as well as hydrophilic and hydrophobic It is administered via a compression coated pulsed drug delivery system suitable for oral administration using a controlled release component substantially encapsulated by an immediate release component containing a compressed mixture of polymers. The immediate release component preferably comprises the active substance as well as a compressed mixture of one or more polymers having disintegration properties such that the polymer rapidly disintegrates when exposed to an aqueous medium.

  The controlled release component preferably comprises a combination of hydrophilic and hydrophobic polymers. In this embodiment, once administered, the hydrophilic polymer dissolves away, the structure of the controlled release component is weakened, and the hydrophobic polymer retards water penetration and helps maintain the shape of the drug delivery system.

  According to the present invention, the term “polymer” includes single or multiple polymeric materials that can swell, gel, disintegrate, or erode upon contact with an aqueous environment (eg, water). Examples include alginic acid, carboxymethylcellulose calcium, sodium carboxymethylcellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methylcellulose, crystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, Sodium alginate, sodium starch glycolate, starch, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polymethacrylate, povidone, pregelatinized starch, shellac, zein, and combinations thereof are included.

  The term “hydrophilic polymer” as used herein refers to natural rubber such as carboxymethylcellulose, guar gum or acacia gum, tragacanth gum, or xanthan gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, and povidone. One or more of them are included, and among these, hydroxypropylmethylcellulose is more preferable. The term “hydrophilic polymer” refers to sodium carboxymethylcellulose, hydroxymethylcellulose, polyethelene oxide, hydroxyethylmethylcellulose, carboxypolymethylene, polyethylene glycol, alginic acid, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, polymethacrylamide. , Polyphosphazine, polyoxazolidine, poly (hydroxyalkyl carboxylic acid), alkali metal or alkaline earth metal, carageenate alginate, ammonium alginate, sodium alganate, or mixtures thereof.

  The “hydrophobic polymer” of the drug delivery system includes, but is not limited to, carbomer, carnauba wax, ethyl cellulose, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type 1, microcrystalline wax, polacrilin potassium, poly It can be any hydrophobic polymer that will achieve the objectives of the invention, including one or more polymers selected from ethylene oxide, polymethacrylate, or stearic acid, of which hydrogenated vegetable oil type 1 is preferred. Hydrophobic polymers include, but are not limited to, copolymers of acrylic acid and methacrylic acid, methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly (acrylic acid), Poly (methacrylic acid), alkyl methacrylate copolymer, poly (methyl methacrylate), poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), and glycidyl methacrylate copolymer A pharmaceutically acceptable acrylic polymer can be included. Furthermore, the acrylic polymer may be a cationic, anionic, or nonionic polymer, and may be an acrylate or methacrylate formed from methacrylic acid or a methacrylic ester. These polymers may be pH dependent.

Enteric coated controlled release
In one embodiment, the delayed release or delayed sustained release coating is an enteric coating. Any commercially available pH sensitive polymer may be used to form the enteric coating. Drugs coated with an enteric coating are minimally released or not released in an acidic gastric environment with a pH below about 4.5. The drug should be available if the enteric layer dissolves at the higher pH present in the intestine after an appropriate lag time or after the unit has passed through the stomach. The preferred duration of drug release time ranges from up to 7 hours after dosing under fasting conditions.

  Enteric polymers include cellulose acetate phthalate, cellulose acetate trimellitic acid, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, e.g., trade name Eudragit® L12.5, Eudragit® L100. Or similar materials used to obtain copolymerized methacrylic acid / methacrylic acid methyl ester, or enteric coatings, such as those known as Eudragit® S12.5, S100 (Rohm GmbH, Darmstadt, Germany) These compounds are included. For example, Eudragit (R) L 30D-55, Eudragit (R) L100-55, Eudragit (R) S100, Eudragit (R) preparation 4110D c; Aquateric (R), Aquacoat (R) CPD30 (FMC Corp.); aqueous colloidal dispersions or redispersions of polymers such as Kollicoat MAE® 30D and Kollicoat MAE® 30DP (BASF); Eastacryl® 30D (Eastman Chemical, Kingsport, TN) A system can also be applied.

  The enteric polymer used in the present invention can be modified by mixing with other known coating products that are not pH sensitive. Examples of such coating products include small amounts of trimethylammonioethyl methacrylate chloride, commonly sold under the trade names E Eudragit (R), Eudragit (R) RL, Eudragit (R) RS Neutral methacrylates; neutral ester dispersions with no functional groups sold under the names Eudragit® NE30D and Eudragit® NE30; and other pH-independent coatings Product included

  The enteric coating is believed to substantially enclose the controlled release component. The term “substantially enveloping” is intended to define the total or nearly total encapsulation of a component. Such encapsulation preferably includes at least about 80% encapsulation, more preferably at least about 90% encapsulation, and even more preferably at least about 99% encapsulation.

  One aspect of the present invention provides a free-flowing formulation comprising baclofen. As used herein, the term “free-flowing” refers to a dosage form that passes through the patient's digestive system without any obstruction or mechanism that delays passage. Thus, for example, the term “free-flowing” excludes intragastric raft-type dosage forms that are designed to exist in the stomach for extended periods of time, as described, for example, in US Pat. No. 5,651,985. I think that.

  The dosage form according to the invention can also comprise a combination of baclofen and at least one additional active substance such as tizanidine, dantrolene, non-steroidal anti-inflammatory drugs (NSAIDs), opioids and COX-2 inhibitors. . To achieve the desired therapeutic effect, other active agents can be formulated together in an immediate or delayed release, delayed sustained release, or sustained release component.

  The dosage form according to the present invention also applies to pure racemate, L-baclofen and other GABA related actives mentioned in US Pat. No. 6,350,769 issued to Kaufman et al. On February 26, 2002. obtain.

  In order to obtain an effective amount of baclofen to obtain the desired therapeutic response to the individual composition and method of administration, and an effective amount of active ingredient when used as a combination product, the baclofen (racemate) in the composition Or L-baclofen) as well as any active substance dose level used in combination with baclofen may be varied.

The object of the present invention provides the controlled bioavailability of baclofen desired by health care providers. Bioavailability means the extent to which a therapeutically active agent is available in the body after administration. Bioavailability is typically measured in patients who are fasted overnight before being administered a test preparation. A plasma sample is then collected and analyzed for plasma concentration of the parent compound and / or its active metabolite. These 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 also Shargel & Yu, APPLIED BIOPHARMACEUTICS AND PHARMACOKINETICS ch. 10 (3d ed. 1996); APPLIED PHARMACOKINETICS: PRINCIPLES OF THERAPEUTIC DRUG MONITORING, Evans et al., Eds. (3 d ed. 1992).

  For example, baclofen formulations may be used for bioavailability comparison studies in subjects. Subjects fast overnight before drug administration. Plasma samples are then taken and analyzed for ng / ml concentration of baclofen or baclofen metabolite at dosing, every hour for 12 hours after dosing, then at 16 and 24 hours after dosing.

  Without further elaboration, those skilled in the art who have the benefit of the above description can make the most of the invention. The following examples are illustrative only and in no way limit the remainder of the disclosure.

Examples Example 1 Active seed coated with baclofen

  Add povidone (Plasdone K-29 / 32®) to the purified water and mix until povidone is completely dissolved. Mix baclofen in the above solution until uniformly dispersed. The sugar spheres are then coated with baclofen suspension using a fluid bed coater to produce a coated active seed.

Example 2 Active seed coated with baclofen

  Hypromellose, Type 2910®, USP (Pharmacoat 606, 6 cps) is added to an appropriate amount of purified water and mixed until the Hypromellose is completely dissolved. Mix baclofen in the above solution until uniformly dispersed. The sugar spheres are then coated with baclofen suspension using a fluid bed coater to produce a coated active seed.

  The dissolution profile of this formulation is shown in FIG.

Example 3 Active Granules Containing Baclofen

  Mix baclofen, Starch 1500 (pregelatinized starch), and Avicel PH-102 (crystalline cellulose). Fill the baclofen mixture into a Hobart mixer and mix to form a homogeneous mixture. This mixture is granulated with purified water to form a granulate. The granulate is dried in an oven at a temperature of 60 degrees to form granules. Screen these granules using a # 30 mesh screen. The magnesium stearate is mixed to form active granules.

Example 4 Enteric-coated seed containing baclofen

  Fill the stainless steel container with purified water and mix in hypromellose until completely dissolved. A separate stainless steel container is then filled with purified water and acetone and then mixed in acetyl tributyl citrate to form an acetyl tributyl citrate solution. To this, hypromellose phthalate is added to form an enteric coating solution.

  The baclofen coated active seed produced in any of Examples 1-3 is film coated with a seal coat solution to form sealed baclofen beads. The sealed baclofen beads are then film coated with an enteric coating solution to produce an enteric coated seed.

Example 5 Enteric-coated seed containing baclofen

  Fill isopropyl alcohol and purified water into a stainless steel container and then mix in triethyl citrate. Methacrylic acid copolymer type A, NF (Eudragit® L100) or methacrylic acid copolymer type C, NF (Eudragit® L100-55) is added to form a Eudragit® suspension. Disperse talc in the Eudragit® suspension. The active coated seed of baclofen from Example 4 is film coated with Eudragit® suspension to form an enteric coated seed.

Example 6 Composition Containing Baclofen Coated Active Seed and Enteric Coated Seed

  A specified portion of the coated active seed and enteric coated seed are mixed together to form a dosage form. In the case of capsules, the seed is mixed and added to the gelatin capsule. In the case of tablets, the seed is compressed to form tablets. For sachets, mix seeds and pack into sachets.

Example 7 Enteric-coated seed containing baclofen

  Dissolve Pharmacoat 606 in purified water and then disperse baclofen in this aqueous solution to make an aqueous suspension. Using a fluid bed coater, sugar spheres are coated with baclofen suspension to produce coated active seeds.

  Eudragit® RL100, RS100, and dibutyl sebacate are dissolved in a mixture of acetone and isopropyl alcohol. Talc and magnesium stearate are then dispersed in this solution. Using a fluidized bed coating apparatus, the coated active seed is coated with the above suspension to produce a sustained release coated seed.

  Dissolve HPMCP and triethyl citrate in a mixture of acetone and purified water. Using a fluid bed coater, a sustained release coated seed is coated with the above solution to produce an enteric coated seed.

Example 8 Baclofen tablets

  Mix baclofen, sodium starch glycolate, anhydrous dicalcium phosphate, and anhydrous lactose in a high shear granulator. The mixture is wet granulated with purified water and the granulate is dried in an oven at a temperature of 60 degrees for at least 16 hours. Screen these granules using a # 25 mesh sieve. Grind oversized granules with a Fitzpatric grinder equipped with a # 18 mesh screen. The screened and milled granules are mixed with magnesium stearate and the mixture is compressed into tablets using a rotary tableting machine.

Example 9 Baclofen tablets

  Mix baclofen, hydroxypropylmethylcellulose, lactose monohydrate or mannitol, and crystalline cellulose in a high shear granulator. The mixture is wet granulated with purified water and the granulate is dried in an oven at a temperature of 60 degrees for at least 16 hours. Screen these granules using a # 25 mesh sieve. Grind oversized granules with a Fitzpatric grinder equipped with a # 18 mesh screen. The screened and milled granules are mixed with magnesium stearate and the mixture is compressed into tablets using a rotary tableting machine.

Example 10 A Composition Containing Baclofen Coated Active Seed and Enteric Coated Seed

  Add Hypromellose, Type 2910, USP to the appropriate amount of purified water and mix until the hypromellose is completely dissolved. The baclofen is then mixed in the above solution until uniformly dispersed. This suspension is passed through a # 40 mesh sieve into a stainless steel container. Fill the sugar spheres in a fluid bed coater equipped with a Wurster insert and heat until the exhaust temperature reaches 50 ± 5 ° C. The active suspension from above is sprayed to coat the sugar spheres, which are then dried at a temperature of 60 ± 10 ° C. for 5 minutes. Pass the IR seed through a # 16 mesh stainless steel sieve. Collect IR seeds that meet standards and mix with talc and USP for 1 minute in a tilted cone blender.

  An enteric solution is prepared by mixing purified water and acetone. Stir triethyl citrate and methacrylic acid copolymer, Type C, in this mixture until fully dispersed. Mix talc in the above solution until fully dispersed. The IR seed prepared as described above is then coated with this enteric solution using a fluid bed coater to produce an enteric coated seed. Pass the enteric coated seeds through a # 14 mesh stainless steel sieve. Collect the enteric-coated seeds that meet the standards and mix with talc and USP for 1 minute in a tilted cone blender.

  Add the appropriate amount of enteric coated seed to the appropriate amount of IR seed and encapsulate to obtain the baclofen ER capsule.

Example 11 Baclofen Tablets Tablets having the following composition were prepared according to the process described in Example 9.

  The dissolution profiles of the above formulations are shown in FIG. 1B (in SIF) and FIG. 2 (SGF / SIF switching method).

Example 12 Baclofen ER Capsules Using the process described in Example 7, baclofen sustained release capsules (20 mg) having the following formulation were prepared.

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

Example 13 Baclofen ER Capsule According to the process described in Example 10, a baclofen ER capsule having the following formulation was prepared.

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

Example 14 Baclofen ER Capsule According to the process described in Example 10, except that the enteric material is triethyl citrate and methacrylic acid copolymer, acetyl tributyl citrate and hydromellose phthalate instead of type C. Baclofen ER capsules of the following composition were prepared.

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

Example 15 Baclofen ER Capsule According to the method described in Example 10, a baclofen ER capsule having the following composition was prepared. Capsules with 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, and 40 mg baclofen were prepared, and these different dose strengths were directly proportional.

Example 16 Determination of Plasma Profile of Baclofen-Containing Formulation Immediate release component contains 12 mg baclofen, enteric-coated controlled release component contains 24 mg baclofen, and the remaining excipients are adjusted proportionally Except as described above, a bioavailability study comparing the 36 mg baclofen preparation prepared according to Example 15 was conducted in 20 healthy volunteers. This formulation was compared to a 20 mg reference immediate release tablet (Watson Laboratories, Inc.) under fasting conditions. After fasting the subject overnight for at least 10 hours, the test sample was orally administered with 240 ml of room temperature water. Except for those given with drug administration, no liquid is given from 1 hour before dose administration to 1 hour after dosing. Subjects received 240 ml of room temperature water 2 hours, 6 hours, 8 hours, and 12 hours after administration. In addition, subjects ingested 480 ml of liquid with lunch and dinner. 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, 16 hours, And blood samples were taken after 24 hours. These results are shown in FIG. Furthermore, FIG. 6 shows simulated plasma concentrations of 30 mg immediate release baclofen based on data obtained from administration of a dose strength of 20 mg.

Example 17 Determination of Steady State Plasma Profile of Baclofen-Containing Formulation 40 mg baclofen formulation prepared according to Example 15 administered every 12 hours, based on single dose bioavailability data, and 8 hours Average plasma levels of baclofen at steady state were calculated for 20 mg immediate release baclofen tablets (Watson Laboratories, Inc.) administered each time. These results are shown in FIG. 7 ((C) represents the 40 mg dosage form of the present invention and (D) represents the reference 20 mg immediate release dosage form). These results, in the steady state, the C _MIN comparable to C _MIN obtained 8 hours after administration by immediate release formulation, dosage form of 40mg of the present invention shows that thought to arrive at 12 hours after administration.

  Having fully described the invention so far, the method of the invention can be practiced using a wide range and equivalent range of conditions, formulations, and other parameters without departing from the scope of the invention or any embodiment thereof. Will be understood by those skilled in the art.

FIG. 1A is a graph of the in vitro dissolution profile of a 20 mg baclofen tablet formulation prepared according to Example 8 as measured by USP paddle method at 50 rpm in 37 ml, 900 ml simulated gastric fluid (pH 1.2). FIG. 1B is a graph of the in vitro dissolution profile of a 20 mg baclofen tablet formulation prepared according to Example 11 as measured by USP paddle method at 50 rpm in 37 ml, 900 ml simulated intestinal fluid (pH 6.8). 20 mg of baclofen tablet formulation prepared according to Example 11 measured at 50 rpm USP paddle method in 900 ml simulated gastric fluid (pH 1.2) at 37 ° C. for 1 hour with switching to simulated intestinal fluid (pH 6.8). 2 is a graph of an in vitro dissolution profile. FIG. 4 is a graph of the in vitro dissolution profile of 20 mg of baclofen capsule preparation prepared according to Example 2, measured in USP paddle method at 75 rpm in 900 ml simulated gastric fluid (pH 1.2) at 37 ° C. FIG. 20 mg of baclofen capsule formulation prepared according to Example 12 by measuring at 75 rpm USP paddle method in 900 ml simulated gastric fluid (pH 1.2) at 37 ° C. for 2 hours with switching to simulated intestinal fluid (pH 6.8). 2 is a graph of an in vitro dissolution profile. Baclofen capsule formulation prepared according to Examples 13 and 14 by measurement with USP paddle method at 75 rpm in 900 ml simulated gastric fluid (pH 1.2) at 37 ° C. for 2 hours with switching to simulated intestinal fluid (pH 6.8) Figure 2 is a graph of 30 mg in vitro dissolution profile. FIG. 6 is a graph of in vivo plasma profile of baclofen tablet formulation measured as described in Example 16. FIG. FIG. 19 is a graph simulating steady state baclofen plasma concentrations measured as described in Example 17. FIG. (C) represents the 40 mg dosage form of the present invention and (D) represents the reference 20 mg immediate release dosage form.

Claims (36)

A pharmaceutical dosage form comprising a controlled release component comprising:
The controlled release component comprises a GABA _B agonist and a pharmaceutically acceptable excipient; and
The controlled release component is 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 after 6 hours in a simulated intestinal fluid medium. _A pharmaceutical dosage form showing an in vitro dissolution profile including _B agonist release. Controlled release component is less than about 80% GABA _B agonist release after 1 hour, at least about 30% GABA _B agonist release after 4 hours, and 6 hours in simulated gastric / simulated intestinal fluid (switched in 1 hour) media 2. The pharmaceutical dosage form of claim 1, wherein the pharmaceutical dosage form exhibits an in vitro dissolution profile comprising at least about 40% GABA _B agonist release afterwards. 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% GABA _B after 6 hours in the simulated intestinal fluid medium. The pharmaceutical dosage form of claim 1, which exhibits an in vitro dissolution profile including agonist release. Controlled release component is less than about 70% GABA _B agonist release after 1 hour, at least about 40% GABA _B agonist release after 4 hours, and 6 hours in simulated gastric / simulated intestinal fluid (switched in 1 hour) medium 4. The pharmaceutical dosage form of claim 3, wherein the pharmaceutical dosage form exhibits an in vitro dissolution profile comprising at least about 50% GABA _B agonist release thereafter. Further comprising an immediate release component comprising a GABA _B agonist and a pharmaceutically acceptable excipient;
The immediate release component exhibits an in vitro dissolution profile comprising at least about 80% GABA _B agonist release after 1 hour in simulated gastric fluid;
The pharmaceutical dosage form of claim 1, wherein the ratio of the immediate release component to the controlled release component is from about 1:10 to about 10: 1. 6. The pharmaceutical dosage form according to claim 5, wherein the GABA _B agonist is baclofen.   7. The pharmaceutical dosage form of claim 6, wherein the ratio of immediate release component to controlled release component is from about 1: 4 to about 4: 1.   8. The pharmaceutical dosage form of claim 7, wherein the ratio of immediate release component to controlled release component is from about 1: 2 to about 2: 1. A pharmaceutical dosage form comprising an enteric coated controlled release component comprising:
The enteric coated controlled release component comprises a GABA _B agonist and a pharmaceutically acceptable excipient; and the enteric coated controlled release component is simulated gastric / simulated intestinal fluid (switched in 2 hours) In vitro lysis 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 the vehicle A pharmaceutical dosage form showing the profile. Enteric coated 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 simulated gastric fluid / simulated intestinal fluid (switched in 2 hours) medium 10. The pharmaceutical dosage form of claim 9, wherein the pharmaceutical dosage form exhibits an in vitro dissolution profile comprising release and at least about 80% GABA _B agonist release after 6 hours. Enteric coated controlled release component is less than about 10% GABA _B agonist release after 2 hours, at least about 60% GABA _B agonist after 3 hours in simulated gastric fluid / simulated intestinal fluid (switched in 2 hours) medium 12. The pharmaceutical dosage form of claim 10, wherein the pharmaceutical dosage form exhibits an in vitro dissolution profile comprising release and at least about 90% GABA _B agonist release after 6 hours. Further comprising an immediate release component comprising a GABA _B agonist and a pharmaceutically acceptable excipient;
The immediate release component exhibits an in vitro dissolution profile comprising at least about 80% GABA _B agonist release after 1 hour in simulated gastric fluid;
10. The pharmaceutical dosage form of claim 9, wherein the ratio of the immediate release component to the controlled release component is from about 1:10 to about 10: 1. 13. The pharmaceutical dosage form of claim 12, wherein the GABA _B agonist is baclofen.   14. The pharmaceutical dosage form of claim 13, wherein the ratio of immediate release component to controlled release component is from about 1: 4 to about 4: 1.   15. The pharmaceutical dosage form of claim 14, wherein the ratio of immediate release component to controlled release component is from about 1: 2 to about 2: 1. Shows in vitro dissolution profile with less than about 75% GABA _B agonist release after 2 hours and at least about 80% GABA _B agonist release after 3 hours in simulated gastric / simulated intestinal fluid (switched at 2 hours) medium A pharmaceutical dosage form comprising a GABA _B agonist and a pharmaceutically acceptable excipient. Shows in vitro dissolution profile with less than about 65% GABA _B agonist release after 2 hours and at least about 90% GABA _B agonist release after 3 hours in simulated gastric / simulated intestinal fluid (switched at 2 hours) medium 17. A pharmaceutical dosage form according to claim 16. 17. 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, wherein when the pharmaceutical dosage form is administered orally, at least 80% of the baclofen is absorbed in vivo under fasting conditions A pharmaceutical dosage form with a median of> 2.5 hours.   The pharmaceutical dosage form of claim 19, wherein when the pharmaceutical dosage form is administered orally, the median time that at least 80% of baclofen is absorbed in vivo under fasting conditions is from about 3 hours to about 4.5 hours. .   21. The pharmaceutical dosage form of claim 20, comprising an enteric coated controlled release component and an immediate release component.   Enteric coated controlled release ingredients include cellulose acetate phthalate, cellulose acetate trimellitic acid, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethyl ethyl cellulose, copolymerized methacrylic acid, methyl methacrylate, and their 23. The pharmaceutical dosage form of claim 21, comprising a polymer selected from the group consisting of a mixture.   24. The pharmaceutical dosage form of claim 21, wherein when the dosage form is administered orally under fasting conditions, the dosage form exhibits an in vivo plasma profile comprising an average maximum baclofen level from about 2.5 hours to about 5.5 hours after administration. . 24. The pharmaceutical dosage form of claim 21, which provides a steady state in vivo plasma profile exhibiting a _CMIN of about 12 hours after administration of the dosage form.   20. The pharmaceutical dosage form of any one of claims 6, 13, 18, or 19, wherein baclofen is in an amount of about 2 mg to about 150 mg.   26. The pharmaceutical dosage form of claim 25, wherein baclofen is in an amount of about 20 mg.   26. The pharmaceutical dosage form of claim 25, wherein baclofen is in an amount of about 25 mg.   26. The pharmaceutical dosage form of claim 25, wherein baclofen is in an amount of about 30 mg.   26. The pharmaceutical dosage form of claim 25, wherein baclofen is in an amount of about 35 mg.   26. The pharmaceutical dosage form of claim 25, wherein baclofen is in an amount of about 40 mg.   20. The pharmaceutical dosage form of any one of claims 6, 13, 18, or 19, wherein baclofen is formulated as a combination of immediate release and controlled release beads.   32. A pharmaceutical dosage form according to claim 31 which is a tablet.   32. A pharmaceutical dosage form according to claim 31 which is a capsule. A pharmaceutical dosage form comprising baclofen in an immediate release component and an enteric coated controlled release component comprising:
The enteric coated controlled release component comprises cellulose acetate phthalate, cellulose acetate trimellitic acid, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, copolymerized methacrylic acid, methyl methacrylate and the like A polymer selected from the group consisting of:
A pharmaceutical dosage form wherein the median time that at least 80% of the baclofen is absorbed in vivo under fasting conditions is from about 3 hours to about 4.5 hours when the pharmaceutical dosage form is administered orally.   35. The pharmaceutical dosage form of claim 34, wherein the polymer is copolymerized methacrylic acid. A pharmaceutical dosage form comprising baclofen in an immediate release component and a controlled release component,
The controlled release component comprises a matrix dosage form; and
A pharmaceutical dosage form wherein the median time that at least 80% of the baclofen is absorbed in vivo under fasting conditions is from about 3 hours to about 4.5 hours when the pharmaceutical dosage form is administered orally.

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