TW200536523A - Pharmaceutical dosage forms having immediate release and/or controlled release properties that contain a gabab receptor agonist - Google Patents

Abstract

The present invention relates generally to pharmaceutical dosage forms having immediate release and controlled release properties that contain a γ-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.

Description

200536523 发明, Description of the invention: [Technical field to which the invention belongs] The present invention relates to pharmaceuticals with immediate release and controlled release characteristics, including gamma-aminobutyric acid (GABΑΒ) Β such as beclofen Receptor agonists to treat physical conditions such as convulsions, cramps, and muscle tightness that accompany conditions such as multiple sclerosis (MS) or certain spinal cord injuries. [Prior art] Multiple sclerosis is considered as a disease of the autoimmune system. It refers to a body's immune system that attacks the myeHn sheath surrounding nerve cells. Fourteen types of damage cause muscle weakness, paralysis, poor coordination, balance problems, fatigue and blindness. The γ-aminobutyric acid type B receptor agonist, "Beculofen," can be used to treat the aforementioned symptoms. Becprofen can also promote adjuvant medical methods such as physical therapy to improve the condition of patients with multiple sclerosis or some spinal hearing impairment. For those patients who cannot tolerate the effect of carbamazepine or that carbamazepine has no effect, 'becprofen can also be used to reduce the number of trigeminal neuralgia episodes and the incidence of trigeminal neuralgia in these patients. The degree of pain. Becprofen, or cardioamino-aspirated phenylbutyric acid, is used as a muscle relaxant and anticonvulsant. Its mechanism of action is not yet known. OK. Beclofen seems to be able to suppress the monosynaptic and multisynaptic 3 200536523 (Poiysynaptlc) reflexes in the spinal cord by hyperpolarization of afferent terminals, although Activities that occur at supraspinal sites may also contribute to hyperpolarization clinically. In animal experiments, beclofen has been shown to exhibit properties such as financial well-being, somnolence, and ataxia. It also inhibits the sedative properties of the central nervous system (central nerv0US SyStem, CNS), such as reduced respiratory and cardiovascular function.

The absorption of beclofen is position-specific. Beclofen is mainly absorbed by the upper gastrointestinal tract (GI), while the absorption range of beclofen in the lower gastrointestinal tract is substantially reduced. Beclofen can be quickly and widely absorbed. This absorption effect is dose-dependent, and the absorption efficiency decreases as the dose increases. An improved method of administering beclofen to a patient includes delivering an effective dose of the drug to the upper gastrointestinal tract for an extended period of time. When beclofen is administered to mammals, the following side effects may be associated, including nausea, vomiting, diarrhea, dizziness, daytime sedation, and less common psychotic states such as depressive mood disorders. In addition, patients who follow the instructions may not achieve optimal results ’and therefore need to be taken more frequently, such as one to three or four times a day. Pharmaceutical agents that are taken less frequently (for example, once or twice a day) are ideal. In addition, a pharmaceutical dosage form capable of establishing and maintaining a stable plasma concentration of beclofen over an extended period of time is beneficial to patients because of its low frequency of administration and its minimization of side effects. Including 10/20 male bekeprofen bonding agent (W ats ο η Pharmaceuticals, Inc., Corona, CA) and the mouth-soluble bonding agent product KEMSTRO ™ (Schwarz Pharma, Monheim, Germany) and other Baker 4 200536523 Although already on the market, it does not provide controlled release of beloprofen. For example, after taking an oral dose of KEMSTROTM in a single tablet of 20 male silk, its maximum plasma concentration can be reached after one and a half hours.

Beclofen's serum half-life is 2.5 to 4 hours (Drug Monograph: Baclofen American Hospital Formulary Service (AHFS) American Society of Hospital Pharmacists, Inc., Bethesda, MD 2003). The current immediate release formulations of beclofen usually reach the minimum therapeutic plasma levels after about 4 to 8 hours. Therefore, the existing immediate release formulations usually require 3 to 4 administrations per day. A number of controlled release beclofen pharmaceutical compositions have been disclosed. For example, U.S. Patent No. 5,091,184 (U.S. Patent No. 5,091,184) issued to Khanna on February 25, 1992, describes a viscous tablet that can be attached to the oral mucosa to deliver drugs through the oral mucosa. Agent. These pharmaceutical compositions have one or more problems with GABA-related drugs, oral patches, and drug delivery to a poor location. In addition, U.S. Patent No. 5,651,985 issued to Penners et al. On July 29, 1997 (11.3 · Patent No. 5,6 5 1,98 5) mentions a matrix dosage form having a characteristic of prolonging the residence time of the stomach. According to Penners' reference materials, the swollen state has a significant swelling effect and high dimensional stability. In addition, U.S. Patent No. 4,764,3 80 issued to Urquhart et al. On August 16, 1988 (US Patent No. 5,651,985) mentions an osmotic pump type dosage form for delivering beclofen, which The drug can be continuously administered for an extended period of time. 5 200536523 However, ‘currently large and persistent γ-aminobutyric acid type B receptor agonists, sclerosis or certain spinal cord injuries, are established and maintained for a prolonged period of time with less frequent medication and side effects are mentioned for other purposes. There is a need for a therapeutic multi-state pharmaceutical formulation containing controlled release characteristics such as beclofen, which can be minimized by maintaining a stable plasma concentration of the drug. The present invention has been achieved. [Summary of the Invention] The present invention relates to a pharmaceutical dosage form having controlled release properties and containing a ^ aminobutyric acid type B receptor agonist such as beclofen. These dosage forms can be used for 'oral treatment' accompanied by medical symptoms such as spasms, cramps, and muscle strain caused by diseases such as multiple sclerosis or specific spinal cord injuries. For example, the pharmaceutical dosage form of the present invention may include a controlled release dosage form, wherein the controlled release dosage forms include an aminobutyric acid type B receptor agonist and a pharmaceutically acceptable excipient, wherein the dosage form is in a simulated intestinal fluid medium ( Simulated intestinal fluid medium) exhibits an in vitro batholysis profile, which includes less than 70% γ-aminobutyric acid type B stylistic agonist released after one hour, and releases at least about 2 after 4 hours. 0% of γ-aminobutyric acid type B agonist, and about 30% of γ-aminobutyric acid type B agonist was released after 6 hours. In this embodiment, the controlled release dosage form exhibits an in vitro dissolution profile in a simulated gastric / intestinal fluid (alternating time of one hour) medium including the release of less than 80% of γ-aminobutane after one hour. Acid beta receptor agonist, which releases at least about 30% of gamma-aminobutyric acid beta receptor agonist after 4 hours, and releases about 40% of gamma-aminobutyric acid after 6 hours 6 200536523 hours Acid B receptor agonist.

In a preferred embodiment, the controlled release dosage form comprises a gamma-aminobutyric acid B-type fork agonist and a pharmaceutically acceptable excipient, and the controlled release dosage form exhibits an in vitro dissolution in a simulated intestinal fluid medium The distribution pattern includes less than 50% of "aminobutyric acid beta receptor agonist" released after one hour and at least about 40% of gamma-aminobutyric acid beta receptor agonist released after 4 hours. And release about 50% of γ-aminobutyric acid type B receptor agonist after 6 hours. In this preferred embodiment, the controlled release dosage form simulates gastric / intestinal fluid (alternating time is one hour) medium It shows an in vitro dissolution profile that includes less than 70% of gamma-aminobutyric acid type B receptor agonist released after one hour, and at least about 40% of gamma-aminobutyric acid released after 4 hours. Acid beta receptor agonist, and gamma-aminobutyric acid beta receptor agonist which releases about 50% after 6 hours. In another embodiment, a controlled release aminobutyric acid beta receptor Agonist dosage form can be combined with an immediate release aminobutyric acid beta receptor The agent components are used in combination. In this embodiment, the immediate-release component exhibits an in vitro dissolution profile in simulated gastric juice, which includes at least about 80% of the gamma-aminobutyric acid beta-type receptor agonist released after one hour The ratio of the immediate-release component to the controlled-release component is from about 1:10 to about 10: 1, the preferred ratio is from about 1: 4 to about 4: 1, and the more preferred ratio is from about 1: 3 to About 3: 1, and the optimal ratio is from about 1.2 to about 2: 1. In another embodiment, the pharmaceutical dosage form of the present invention comprises an enteric-coated controlled release component, The controlled release component of the casing includes a γ-aminobutyric acid type B receptor stimulant 7 200536523 Activator and a pharmaceutically acceptable excipient, and the controlled release component of the casing is simulated in gastric / intestinal fluid (alternating time is 2 Hours) media showed an in vitro> disintegration distribution pattern, which included less than 10% release of γ-aminobutyric acid B receptor agonist after 2 hours, and released at least about 4 after 3 hours 0% γ-aminobutyric acid beta receptor agonist, And at least about 70% of the γ-aminobutyric acid type B receptor agonist is released after 6 hours. More preferably, the enteric-coated controlled release component is shown in a simulated gastric / intestinal fluid (2 hours alternation time) medium An in vitro dissolution distribution pattern is included, which includes less than 10% of the gamma-aminobutyric acid type B receptor agonist released after 2 hours, and at least about 50% of the gamma-aminobutyric acid released after 3 hours. Acid beta receptor agonist and γ-aminobutyric acid beta receptor agonist that releases at least about 80% after 6 hours. In the best case, the enteric coating controlled release component mimics gastric / intestinal fluid (alternatively The time is 2 hours) The medium shows an in vitro dissolution distribution pattern, which includes less than 10% of the γ-aminobutyric acid type B receptor agonist released after 2 hours, and at least about 60 released after 3 hours. % Γ-aminobutyric acid type B receptor agonist, and at least about 90% of γ-aminobutyric acid type B receptor agonist released after 6 hours. In yet another preferred embodiment, the dosage form also includes an immediate release type ingredient which can be used in combination with an enteric coating controlled release type ingredient. For example, the gamma-aminobutyric acid type B receptor agonist can be prepared as a combination of immediate-release type beads and controlled-release type beads, and compressed into a lozenge or contained in a capsule dosage form. The ratio of the immediate-release component to the controlled-release component is from about 1:10 to about 10: 1, the preferred ratio is from about 1: 4 to about 4: 1, and the more preferred ratio is from about 1 ... 3 to About 3: 1, and the optimal ratio is about j: 2 to about 2: j. 8

200536523 The present invention includes dosage forms having both immediate and sustained release characteristics. In this embodiment, the pharmaceutical dosage form comprises a γ-aminobutyric acid receptor agonist and a pharmaceutically acceptable excipient, and the dosage form is displayed in a simulated gastric / intestinal fluid (alternating time is 2 hours) medium Outgoing dissolution profile, which includes less than about γ-aminobutyric acid type B receptor agonist released after 2 hours, and about 80% less γ-aminobutyric acid type B receptor released after 3 hours Agonist. Preferably, the academic dosage form exhibits an in vitro dissolution distribution pattern in a simulated gastric / intestinal fluid (alternating time of 2 hours) medium, which includes about 65% release of γ-aminobutyric acid type B receptor agonism after 2 hours Agent, and γ-aminobutyric acid type B receptor agonist produced at least about 90% after 3 hours. These patients receiving long-term bekeprofen treatment are suitable for daily use of the pharmaceutical dosage form of the present invention. And compared with the immediate release beclofen formula, the in vivo absorption effect of the pharmaceutical dosage form of the present invention is prolonged, so that at least 80% of the beclofen in the fasting situation is absorbed by a median time period greater than 2.5 hour. The pharmaceutical agent of the present invention often exhibits an integrated plasma distribution pattern, which includes: after fasting patients using the pharmaceutical dosage form, between about 30 minutes to about 7 hours (usually 2.5 to 5.5 hours after use) Between) has an average highest beclofen (Cmax). [Embodiment] The present invention relates to a pharmaceutical dosage form containing a controlled-release γ-aminobutyric acid type B agonist formula, and the controlled-release γ-aminobutyric acid B pharmaceutical type B agent is 75% to the drug display The release of less than two releases compared with those in the period-type receptor makes the receptor-type receptor receptor 9 200536523 somatic agonist is preferably beclofen, a beclofenfen analog or a mixture thereof, and a baker>, The L-Baker Lomir mirror isomer aminobutyric acid type B receptor agonist formula purified on scallop may be a dosage form. In addition, a controlled-release amino group of a controlled-release formula may be incorporated in a final pharmaceutical dosage form. Compared with the existing immediate-release formula, the τ 酉 chu formula and the immediate-release γ-aminobutyric acid type B receptor have a lower frequency of administration. For example, for patients in need of long-term receptor agonist treatment, take two existing formulations three times daily and one of the existing immediate release formulations. Reducing the frequency of medication is beneficial to the patient 'and often results in better patient compliance). In addition, it also reduces the fluctuation of plasma concentration, which usually has the effect of improving drug efficacy and reducing side effects. Unless otherwise stated in the text, the singular terms "a", "an" and "the" used herein with respect to patent applications are also inclusive. Thus, for example, referring to a distribution pattern is a reference to one or more patterns, including equivalents with general knowledge in the area of expertise. Examples outside of the operating examples or indicated elsewhere. All numbers in the text that indicate the number of ingredients or reaction conditions are about "large." When used with a percentage, it can be 1%. All the patents here for the purpose of narration and disclosure as well as its Becklow 7 or a book containing honey _ 〖Release formula. There is casing: animal formula. The formula allows the butyric acid BI formula to be more convenient than the biological (patient times, , The complex in the complex type, similar distribution, well-known, need to know the value of the "indicator"> prodrugs and racemic mixtures have been confirmed. The control release casing control box and use the order B type receptor Detergent formula. Now the present invention accepts γ-ammonia J times. The present invention has the same

10 The publications of 200536523 are also incorporated by reference ' as described in the publications, which may be used with the methodology of the present invention. Unless otherwise noted, all technical and scientific terms used in the present invention have the same meanings as those of ordinary skill in the art. Although any known methods, devices, and materials can be used to implement or test the invention, related methods, devices, and materials have been described in the present invention.

Becloprofen, also known as butyric acid or 4-amino-3- (4-chlorophenyl) -butyric acid, the invention includes racemic becloprofen, mirror-isomerically purified L-becprofen, and the like Analogs, derivatives, prodrugs, metabolites, and any pharmaceutically acceptable salts. Becprofen is a γ-aminobutyric acid type B receptor agonist, so other γ-aminobutyric acid type B receptor agonists are also within the scope of the present invention. It may include 4-aminobutanoic acid (GABA); (3-aminopropyl) methyl phosphinic acid; 4-amino-3-phenyl 4-amino-3- phenylbutanoic acid; 4-amino-3-hydroxybutanoic acid; 4-amino-3- (4-aminophenyl) -3- 4-amino-3- (4-chlorophenyl) -3-hydroxyphenylbutanoic acid; 4-amino-3- (thien-2-yl) butanoic acid (4-amino-3- (thien- 2-yl) butanoic acid); 4-amino-3- (5- (5-pyridin-2-yl) butanoic acid (4-amino-3- (5-〇111〇1 * 〇1: 111611-2-; / 1) 1) 1 & 1101. & (^ (1); 4-amino-3- (5- Moss-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-methylthien-2-yl) butanoic acid; Cito) butanoic acid 11 -200536523 (4-amino-3- (2-imidazolyl) butanoic acid); 4-guanidino-3- (4-chlorophenyl) butanoic acid (4-guanidino-3- (4- chlorophenyl) butanoic acid), 3-amino-2- (4-ratyl) -1-3-amino-2- (4-chlorophenyl) -l-nitropropane; (3-aminopropyl ) (3-aminopropyl) phosphonous acid; (4-aminobut-2-yl) phosphonous acid; (3-amino-2-amidinopropyl) phosphine (3-amino-2-methylpropyl) phosphonous acid; (3-aminobutyl) phosphonous acid;

(3 -amino-2- (4- · phenylphenyl) propyl) acid ((3-amino-2- (4-chlorophenyl) propyl) phosphonous acid); (3-amino-2-(4- (Gasyl) -2-propyl) linyl acid ((3-amino-2- (4-chlorophenyl) -2-hydroxypropyl) phosphonous acid); (3-amino-2- (4-1phenyl ) (3-amino-2- (4-fluorophenyl) propyl) phosphonous acid); (3-amino-2-phenylpropyl) phenylene acid ((3-amino-2-phenylpropyl) phosphonous acid); (3-amino-2-hydroxypropyl) phosphonous acid; (E)-(3-aminopropyl-1-yl) (E)-(3-aminopropen-l-yl) phosphonous acid); (3-amino-2-cyclohexylpropyl) phosphonous acid; (3- 3-Amino-2-benzylpropyl) phosphonous acid; [3-amino-2- (4-methylphenyl) propyl] phosphonic acid ([3- amino-2- (4-methylphenyl) propyl] phosphonous acid); [3-amino-2- (4-difluorofluorenylphenyl) propyl] subacid acid ([3_ amino-2- (4-trifluoromethylphenyl) propyl] phosphonous acid); 12 200536523 [3-amino-2- (4-methoxyphenyl) propyl] phosphonous acid; [3-amino-2- (4 -[Chloroamino] -2- [3-amino-2- (4-chlorophenyl) -2-hydroxypropyl] phosphonous acid; (3-aminopropyl) methylphosphinic acid ( (3-amino propyl) methylphosphinic acid); (3-amino-2-transpropyl) methylphosphinic acid ((3-amino-2-

hydroxypropyl) methylphosphinic acid); (3-aminopropyl) (difluoromethyl) phosphinic acid); (4-aminobutyl-2-yl) methylphosphinic acid ((4-aminobut-2-yl) methylphosphinic acid); (3-amino-1-hydroxypropyl) methylphosphinic acid; (3-amino- 2-hydroxypropyl) (difluorofluorenyl) phosphinic acid ((3- & 11 ^ 11〇-2-hydroxypropyl) (difluoromethyl) phosphinic acid); (E)-(3-aminopropyl-1-yl ) Methylphosphinic acid ((E)-(3-aminopropen-l-yl) methylphosphinic acid); (3-amino-2-oxo-propyl) phosphonium phosphinic acid ((3-amino-2-oxo -propyl) methyl phosphinic acid); (3-aminopropyl) via (3-aminopropyl) hydroxymethyl phosphinic acid); (5-aminopent-3-yl) fluorenyl phosphinic acid ((5 -aminopent-3-yl) methylphosphinic acid); (4-amino-1,1,1-trifluorobut-2-yl) methylphosphinic acid ((4-amino-l, l, l-trifluorobut-2 -yl) methylphosphinic acid); (3-amino-2- (4-aminophenyl) propyl) sulfinic acid ((3-amino-2- (4-chl orophenyl) propyl) sulfinic acid); 3-aminopropylsulfinic acid; 1- (aminomethyl) cyclohexaneacetic acid and its phases 13 200536523 See U.S. Patent No. 6,664,069. The term "analog" means a compound that includes a specific compound or chemically modified form of the compound and that retains the pharmaceutically and / or pharmacologically active properties of the compound or compounds. For example, analogs of bekeprofen include 3-thienyl-aminobutyric acid and 3-furylaminobutanoic acid.

The term "derivative" means a chemical modification compound, wherein the modification method is known to those in the general chemical field, such as an acid Sester or amide, such as an Protective groups such as phenylhydrazone on alcohols or thiol, and tert-butoxycarbonyl on amines. The term "prodrug" as used herein includes any covalently bound carrier that releases an active parent drug of the present invention in vivo after the patient takes the prodrug. Because prodrugs are known to enhance a variety of desired pharmaceutical properties (i.e., solubility, bioavailability, manufacturing, etc.), the compounds of the present invention can also be delivered as prodrugs. The prodrugs of the present invention can also be prepared by modifying the functional groups present in the compound 'so that these modifications can be cleaved and separated from the parent compound in vivo or under artificial manipulation. This in vivo transformation may be the result of some metabolic processes, such as chemical or enzymatic hydrolysis reactions of Carboxyl, Phosphor or sulphate ester, or a reduction in function Or oxidation reaction. Prodrugs within the scope of the present invention include compounds in these molecules that have a hydroxyl group, an amine group, or a sulfhydryl bonded to any functional group. When the prodrug of the present invention is administered to a mammal 14 200536523 In animals, they are split into a free hydroxyl group, a free amino group, or a free hydrogenthio group. The functional group can be rapidly converted into a type of functional group which can react with the hydroxyl group in the compound of the present invention through metabolic cleavage in the body. It includes, but is not limited to, alkanoyl, such as acetyl, prOpiyl, and butyryl, benzyl, and Substituted and unsubstituted, such as benzylcarpinyl. Aroyl, alkoxycarbonyl such as ethoxycarbonyl, alkoxycarboniyl, trimethyl and triethylsilyl (Triethysilyl) and other trialkysyl groups (trialkysUyl), such as succinyl (succinyl) and the like formed by the reaction of dicarboxylic acids (monoa). Since the metabolizable functional groups of the compounds used according to the present invention can be easily cleaved and decomposed in vivo, the function of the compounds having the functional groups is equivalent to that of the prodrug. Compounds with metabolic cleavage functional groups may show advantages such as improved bioavailability due to their increased solubility and / or the absorption rate of the parent compound due to the presence of metabolic cleavage functional groups. Discussions on prodrugs are provided by the following references, each of which is incorporated herein by reference: Design of Prodrugs, H. Bundgaard, ed. (Elsevier, 1 985); Methods in Enzymology, K. Widder et al., eds., vol. 42, 3 09-96 (Academic Press 1985); A Textbook of Drug Design and Development, Krogsgaard-Larsen & H. Bundgaard, ed., Chapter 5; Design and Applications of Prodrugs, 113 -91 (19 91); H. Bundgard, Advanced Drug Delivery Reviews, 1 -3 8 (1 992); 8 J. Pharm. Sciences 285 (1 988); N. Nakeya et al., 32 15 200536523

Chem. Pharm. Bull. 692 (1 984); T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, 14 A.C.S.

Symposium Series: Bioreversible Carriers in Drug Design, Edward B. Roche, ed. (Am. Pharm. Assoc. &Amp; Pergamon

Press 1987).

Therefore, the present invention also covers the use of prodrugs of γ-aminobutyric acid type B receptor agonists (including beclofen), methods of delivery thereof, and pharmaceutical compositions thereof. For example, prodrugs of beclofen have been described in the following literature by 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 from the human or animal body after the administration of the compound. For example, a compound having a fluorenyl group can be used by the methylated compound after the action of the human body. A demethylated analog of the methylated compound is obtained in the body. Metabolites themselves can also be biologically active. As used herein, the term "pharmaceutically acceptable" means those compounds, materials, compositions and / or dosage forms which, under correct medical judgment, are suitable for use in contact with human tissues and animals without Additional toxicity, irritation, allergic reactions or other problems or complications with a reasonable benefit / risk ratio. For example, "pharmaceutically acceptable salts" means a derivative of the disclosed compound, wherein the specific compound is converted into an acid or a test salt. This pharmaceutically acceptable 16 200536523

Salts include, but are not limited to, mineral or organic acid salts such as amines and other residues; acidic residues such as carboxylic acids or organic salts. Pharmaceutically acceptable salts include traditional non-toxic salts or quaternary amine salts such as the parent compound formed from non-toxic inorganic or organic acids. For example, traditional non-toxic salts include those made of materials such as hydrogen, hydrogen bromic, hydrobromic, sulfuric, sulfamic, phosphoric, or nitric. Salts derived from inorganic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, steric acid, lactic acid, and malic acid (Malic), tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic acid (Phenylacetic), glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, tetrabutadiene Acid (fumaric), toluensulfonic acid (toluensulfonic), methyl lutein acid (methanesulfonic), ethane dislfonic acid (ethane dislfonic), oxalic acid (oxalic), carboxyethyl ethionite (isethionic) and other organic acids Out of salt. For the purposes of the present invention, the proper term "controlled re 1 ease" means that part or all of a dosage form can release one or more active drugs over a prolonged period of time (a period of more than one hour), or The release action of the drug is delayed for an extended period of time. The characteristics of controlled release (CR) also mean sustained release (SR), prolonged release (PR), modified release (17 200536523 MR), delayed release (DR) or Extended Release (ER). When used in combination with the dissolution profile discussed herein, the proper term "controlled release" means that the active dosage form is delivered by a component dosage form according to the present invention over a period of more than one hour.

"Immediate release" means that part or all of a dosage form releases the active drug substantially immediately upon contact with gastric fluid, resulting in the dosage form being substantially completely dissolved within one hour. The characteristics of immediate release (IR) can also be called instant release (IR). When used in conjunction with the dissolution profile discussed herein, "immediate release" means that part of the dosage form of the invention delivers the active drug in a period of less than one hour. The proper term "CMAX" refers to the concentration of the southernmost blood · poly as shown by the pharmaceutical composition of the present invention. "T μ A X" means the time when C M A X appears in the blood concentration-time distribution pattern. "CMIN" is the lowest plasma concentration. "C" is short for concentration, "T" is time, "max" is maximum value, and "min" is minimum value. Initial peak plasma level means the first increase in the plasma concentration of the active drug, and then there may be one or more other peaks, one of which may be CMAX . The "mean maximum GABAb agonist level" in the text means the average value of the CMAX of the γ-aminobutyric acid type B receptor agonist. The plasma concentrations described here are usually determined by a minimum of 12 subjects. The aforementioned plasma concentration may mean the plasma concentration after a single oral administration of the dosage form, or the concentration obtained in a steady state. Here, "steadystate" plasma concentration means the plasma concentration value obtained after repeated use of a drug dose from 18 200536523 to a stable concentration of absorption and discharge, at which time the amount of the drug in the body is substantially The above is fixed. The term "patient" in this context means any mammal, including humans. The proper term "effective amount" means a dose of a compound / composition made in accordance with the present invention sufficient to produce the desired therapeutic effect.

The proper term "excipient" means pharmacologically inert ingredients that are not active in the body (see Handbook of Pharmaceutical Excipients (Am. Pharm · Ass'η 1 98 6). Those of ordinary skill will appreciate that many different excipients can be used in formulations made according to the present invention, and not all of the excipients have been exhaustively listed herein. Depending on the nature of the mode of administration of the drug, the active ingredients of the present invention can also be used with preservatives Agents, fillers, polymers, disintegrating agents, slip agents, wetting agents, emulsifiers, suspensions, sweeteners, flavoring agents, flavoring agents, lubricants, acidifying agents and dispersing agents, and other pharmaceutically acceptable carriers, Diluents, adjuvants, excipients or solvents are mixed. These 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-type and non-gel-type polymers, and their appropriate blends. Exemplary excipients include dian powder, pre-gelatinized dian powder (P re ge 1 atinizedstarch), microcrystalline cellulose (Avicel), lactose, milk sugar, sodium citrate, calcium carbonate, dicalcium phosphate, and pigment mixture (lake Demonstration of disintegrating agent package 19 200536523 including powder, alginic acids and some fossilate complexes (c 0mp 1 e X si 1 icates). Demonstration lubricants include magnesium stearate (magnesium stearate), sodium 1 aury 1 sulphate, talc, and high molecular weight polyethylene glycols.

"Dosing under fasting conditions" is defined as oral administration with 240ml of warm room water after the patient has fasted for at least 10 hours overnight. Except for the water given when taking the medicine, do not drink any fluid within one hour before and after the medication. After 2 hours of taking the medication, the patient can drink 240 ml of room temperature water. The pharmaceutical dosage form of the present invention may relate to a controlled-release dosage form, wherein the controlled-release dosage form includes a gamma-aminobutyric acid type B receptor agonist and a pharmaceutically acceptable excipient, and the dosage form exhibits a Dissolution profile in vitro, which includes less than about 70% of gamma-aminobutyric acid type B receptor agonist released after one hour, and at least about 20% of gamma-aminobutyric acid beta released after 4 hours Receptor agonists, and gamma-aminobutyric acid type B receptor agonists that release at least about 30% within 6 hours. In this embodiment, the controlled release dosage form exhibits an in vitro dissolution profile in a simulated gastric / intestinal fluid (alternating time of one hour) medium, which includes less than about 80% of the gamma-amino group released after one hour. Butyric acid beta-type agonist, which releases at least about 30% of γ-aminobutyric acid beta-type agonist after 4 hours, and releases at least about 40% of γ-aminobutyric acid within 6 hours Beta receptor agonist. Preferably, the controlled release dosage form exhibits an in vitro dissolution distribution pattern in a simulated intestinal fluid agonist, which includes less than 20 200536523 and about 50% of the gamma-aminobutyric acid type B receptor agonist is released after one hour. Agent 'releases at least about 40% of a gamma-aminobutyric acid beta receptor agonist after 4 hours, and releases at least about 50% of a gamma-aminobutyric acid beta receptor agonist after 6 hours . In this preferred embodiment, the controlled release dosage form exhibits an in vitro dissolution profile in a simulated gastric / intestinal fluid (alternating time of one hour) medium, which includes less than about 70% release after one hour The γ-aminobutyryl I beta receptor agonist releases at least about 40% of the "aminobutyric acid beta receptor agonist after 4 hours, and releases at least about 50% of the gamma after 6 hours Aminobutyric acid type B receptor agonist. In another embodiment, the controlled-release gamma-aminobutyric acid type B receptor agonist dosage form and an immediate-release gamma-aminobutyric acid type B receptor agonist The ingredients are used in combination. In this embodiment, the immediate-release ingredient exhibits an in vitro dissolution distribution pattern in simulated gastric juice, including the release of at least about 80% of gamma-aminobutyric acid type B after one hour. Receptor agonist. In another embodiment, the pharmaceutical dosage form of the present invention contains an enteric-coated controlled-release ingredient, wherein the enteric-coated controlled-release ingredient includes a γ-aminobutyric acid beta agonist and a pharmaceutically acceptable agent And the casing is controlled release The components exhibit a dissolution profile in vitro in a simulated gastric / intestinal fluid (alternating time of 2 hours), including release of less than about 10 ° / ° of gamma-aminobutyric acid type B receptor agonism after 2 hours. Agent, which releases at least about 40% of the γ-aminobutyric acid β-type receptor agonist after 3 hours, and releases at least about 70 ° / 0 of the aminobutyric acid β-type receptor agonist within 6 hours. Jiazhe 'The enteric coating controlled-release component exhibits an in vitro dissolution distribution pattern in a simulated gastric / intestinal fluid (alternating time of 2 hours) medium, including 2 hours 21 200536523

Less than about 1% of γ-aminobutyric acid type B receptor agonist is released, at least about 50% of γ-aminobutyric acid type B receptor agonist is released after 3 hours, and after 6 hours At least about 80% of the gamma-aminobutyric acid type B receptor agonist is released. In the best case, the enteric-coated controlled-release component exhibits an in vitro dissolution profile in a simulated gastric / intestinal fluid (alternating time of 2 hours) medium, which includes less than about 10% of γ- Aminobutyric acid beta receptor agonist, which releases at least about 60% of gamma-aminobutyric acid beta receptor agonist after 3 hours, and releases at least about 90% of gamma-aminobutyric acid after 6 hours Acid beta receptor agonist. In still another preferred embodiment, the dosage form also contains an immediate release type ingredient for use in combination with an enteric coating controlled release type ingredient. The invention includes pharmaceutical dosage forms having both immediate and delayed release characteristics. In this embodiment, a pharmaceutical dosage form comprising a gamma-aminobutyric acid type B receptor agonist and a pharmaceutically acceptable excipient exhibits an in vitro dissolution in a simulated gastric / intestinal fluid (alternating time of 2 hours). A distribution pattern that includes less than about 75% of a gamma-aminobutyric acid type B receptor agonist released after 2 hours and at least about 80% of a gamma-aminobutyric acid type B receptor agonist released after 3 hours Agent. Preferably, the pharmaceutical dosage form exhibits an in vitro dissolution distribution pattern in a medium simulating gastric / intestinal fluid (alternating time is 2 hours), and includes less than about 65% of gamma-aminobutyric acid type B released after 2 hours. Receptor agonists, and gamma-aminobutyric acid type B receptor agonists that release at least about 90% after 3 hours. In vitro solubility testing methods suitable for use in the dosage forms of the present invention are familiar to those skilled in the art and include those described herein in the Examples. US 22 200536523 The USP paddle method refers to the Paddle and Basket test methods described in the United States Pharmacopoeia, Edition XXII, 1 99 0. To further explain, the Paddle method of the US Pharmacopoeia is based on 900ml of simulated gastric fluid (SGF, pH 1.2) or simulated intestinal fluid (SIF, pH 6.8) at 37 ° C and 50 ° C. Or 70 rpm to determine the in vitro dissolution profile according to the present invention.

When the dosage form of the present invention contains a controlled release type ingredient (including a casing controlled release type ingredient) and an immediate release type ingredient, the ratio of the immediate release type ingredient to the controlled release type ingredient is from about 1: 1 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 form of the present invention is suitable to allow prolonged absorption of the active drug, and the pharmaceutical dosage form of the present invention allows a lower frequency of administration than the existing immediate release formulation. The term "prolonged absorption (pr0nged absorption)" means that the absorption of the active drug in the body under fasting conditions is prolonged for a long period of time. Especially after using this dosage form, the time required for most active drugs (such as 8090 /.) To be absorbed will be extended to about 7 to 8 hours. In particular, the average time for at least 80% of the active drug to be absorbed from the agent of the present invention after taking the drug is greater than 2.5 hours, usually about 3 to 4.5 hours. In comparison, an average of 800 to 10,000 less active drug was absorbed from the existing immediate release formulations, 1.5 to 2 hours after serving. The average time for an active drug to be absorbed from a dosage form can be calculated by a deconvolution operation (deConvolution) by a person skilled in the art using familiar mathematical methods. 23 200536523 The dosage form of the present invention will exhibit an in-body plasma distribution pattern that includes an average maximum γ-amino group from 30 minutes to about 7 hours (typically within 2.5 to 5.5 hours) after a single dose is administered to a fasting patient Concentration of butyric acid type 3 redundant agonists. In the steady state, the pharmaceutical dosage form of the present invention will reach a CM IN, which is equivalent to the concentration value obtained from the stable state of an immediate release dosage form at a later point in time, so the pharmaceutical dosage form of the present invention may allow lower Frequency of taking. In particular, when a dosage form of the 40 male silk (mg) of the present invention is taken twice a day, the average steady state region under the plasma concentration-time curve (AUC) and the maximum blood concentration ( The maximum plasma concentration (Cmax) and the minimum plasma concentration (Cmin) will be similar to an immediate release lozenge formulation taken three times daily. These dosage forms (preferably a lozenge or capsule containing beads, granules, particles, or mixtures thereof) may include about 2 male silk to about 150 male silk 'preferably Beclofen in doses of 2.5 to 1.00 males and can be used to treat physical conditions that accompany conditions such as multiple sclerosis or a spinal cord sprain, including spasms, cramps, and muscle tension Wait. According to the invention, a single or divided dose is administered to the host's mouthpiece daily, usually from about 0.001 male silk / kg (male silk / ⑻ to about 100 male silk / kg daily). , And preferably about 0.05 mg per day, silk / kg to about 50 male silk / kg 'However, it should be understood that the specific dose for any given patient will vary with body weight, overall health, gender, diet , Time and route of taking medicine, ° and rate of collection and excretion, co-use with other drugs 24 200536523 and the severity of the disease to be treated, and other factors. The actual dosage of the active ingredient in the pharmaceutical composition of the present invention can be changed To obtain an active ingredient dose sufficient to achieve the desired therapeutic response in a particular composition and method of administration.

The total daily dose of a compound administered to a host in a single or divided dose according to this invention is usually about 0.01 male silk / kg to about 20 male silk / kg daily, and preferably about 0.0 2 daily Male silk / kg to 10 male silk / kg. The preferred range of beclofen dose in each dosage form is between about 2.5 and 100 male silk. The dosage form according to the present invention may contain the above-mentioned dose or part of the dose as a single dose. The preferred dosage strength of the formula of the present invention includes those of beclofen containing 10 male silk, 15 male silk, 20 male silk, 25 male silk, 30 male silk, 35 male silk, and 40 male silk. dose. Generally, the optimal dose for a patient can be determined by titration analysis (t i t r a t i ο η), which is initially administered to the patient in a small amount, and then the dose is gradually increased until the patient reaches the dose concentration with the least side effects and the highest therapeutic effect. An embodiment of the present invention provides a controlled-release solid oral dosage form having an immediate release type of beclofen and a delayed or delayed-sustained release type of beclofen. The dosage form according to the present invention may include an immediate release type ingredient and a delayed or delayed-sustained release type ingredient. Combining the two aforementioned ingredients allows the oral dosage form to release the drug in a pulsed or continuous form. In one aspect, the present invention relates to a controlled-release solid oral dosage form of beclofen comprising an immediate-release beclofen component and a delayed-release, or delayed-sustained, or sustained-release beclofen 25 200536523 Fragrant ingredients. The immediate release beclofen composition contains beclofen and formulated with one or more pharmaceutically acceptable excipients that allow immediate release of beclofen, and the delayed, delayed-sustained or sustained release beclofen composition contains beclofen Fennel is formulated with one or more excipients that allow delayed, delayed-sustained or sustained release beclofen. For example, reference to U.S. Patent No. 6,3 72,25 4 indicates formulations such as a tablet having both an immediate release ingredient and a delayed release type ingredient.

Among other dosage forms apparent to those skilled in the art, the solid oral dosage form according to the present invention may be a lozenge formulation, a discontinuous unit filled capsule formulation, or a drug pack formulation. The discrete units of the present invention include beads, granules, pills, spheres, microparticles, lozenges, tablets, and the like. In particular, the immediate-release, delayed-release, delayed-sustained-release, or sustained-release ingredients of the dosage form can take any form well known to those skilled in pharmaceutical synthetic formulations, including one of the ingredients of a multi-component spinner, which is described in 2 US Patent No. 6,3 72,254 granted on April 16, 2002, US Patent Application No. 1/24 1,837, filed on September 12, 2002, and published international patents filed on December 11, 2003 Each of the patent applications WO 03/101432 belongs to Impax Laboratories, Inc. The controlled release dosage form of bekeprofen made in accordance with the present invention may contain a core form of bekeprofen. Dosage forms can be prepared according to methods well known in the art. Some of the better methods are described below. Matrix dosage form 26 200536523

The proper term "matrix" as used herein means a solid material in which an active drug is incorporated. When exposed to a dissolving medium, many channels are formed inside the solid material so that the active drug can be released. The dosage form according to the invention may also be in the form of a coated or uncoated matrix. For example, a coating may contain beclofen in the immediate release type, or the matrix itself may contain beclofen in a controlled release. The drug release effect of the delayed-, sustained- or sustained-release ingredient can be immediate or sustained release, such as within 7 hours after oral administration, to ensure effective absorption of the drug. The controlled-release beclofen composition is composed of beclofen which is coated with at least one delayed-release coating. The delayed-sustained release becloprofen composition may be composed of beclofen of a sustained-release coating having at least one delayed-release coating applied thereto. The sustained-release beclofen composition may be composed of beclofen which is coated with at least one sustained-release polymer or a matrix-controlled release polymer. Those skilled in the art will appreciate that the matrix material may be selected from a variety of materials that provide the expected dissolution profile. These materials include, for example, one or more colloid-forming polymers, such as polyvinyl alcohol, cellulose ethers, including hydroxypropyl methyl cellulose, such as hydroxypropyl methyl cellulose. Hydroxyl propyl alkyl celluloses, hydroxy alkyl cellulose such as hydroxy propyl cellulose, such as natural or synthetic gums such as guar gum ), Xanthum gum and alginates, as well as ethyl cellulose, polyethylene oxide 27 200536523 polyethylene oxide, polyvinyl pyrrolidone , PVP), fats, waxes, polycarboxylic acids or esters such as Carbopol® polymers, methacrylic acid copolymers (also known as succinic acid copolymers), and methacrylic acid esters Polymer (methacrylate polymers).

The method for producing the matrix dose is well known to those having ordinary knowledge in the field of the art, and any method that can produce the desired dissolution distribution pattern and / or plasma distribution pattern can be based on the present invention. One of the foregoing methods involves beclofen, a solid polymeric material, and one or more pharmaceutically acceptable excipients, and the materials are then mixed and compressed into a controlled release tablet core. Such spinner cores can be used in subsequent manufacturing processes such as bilayer lozenges, press coated lozenges, and film coated lozenges. A coating containing immediate release beclofen can be added outside the core of the controlled release bond to produce a final dosage form. Such coatings can be prepared by mixing becprofen with polyvinylbarrolidone 29/32 or hydroxypropyl methylcellulose (HPMC) and water / isopropyl alcohol and triethyl acetate ( triethy 1 acetate). This immediate release coating can be sprayed onto the tablet core. A pressure coating process can also be used to combine the immediate release coating with 80% (weight percent) becprofen and 20% (weight percent) lactose and type 29 110 hydroxypropyl fluorenyl cellulose Of a mixture. Pressure coating technology is well known to those with ordinary knowledge in the field of expertise, and is described in US Patent No. 6,372,254 (us · patent No. 6,3 72,2 5 4 (Ting et al ·)), and here The Division incorporated all of them for reference. 28 200536523

In addition, the formulation of individual release ingredients is performed by suitable granulation methods known to those having ordinary knowledge in the field. In the wet granulation method, a binding agent (polymer) solution is stirred into the mixed powder. Run the powder agglomerate with a binder solution until the consistency of the powder agglomerates is similar to moist snow or brown sugar. An external force was applied to the wet granulated material to pass it through a sieve filter. The moist material produced by the crushing step is placed in a temperature-controlled container and dried. After drying, the particle size can be reduced by passing the granulated material through a sieve filter. After adding the lubricant, the final mixture is compressed into a matrix agent floc. In the fluid-bed granulation method, the particles of the inert material and / or the active drug are suspended in a vertical column using a rinsing air stream. . When the particles are suspended ', the general granulated material in solution is sprayed into the column. Under controlled conditions, granules are gradually formed for tablet granulation. After drying and adding the lubricant, the granulated material is ready for the pressing step. In a dry-granulation method, an active drug, a binding agent, a diluent, and a lubricant are mixed and pressed into a tablet. Pressed large lozenges can be sieved through a sieve filter through a sieve of the desired size. Add additional lubricant to the granulated material and mix gently, then press the material into a tablet. The granules are plastic and immediate release particles (Particle B, as dDL.o, SAfije Forms, Immediate Release Particles) The immediate release / controlled release dosage form of the present invention can be made into the form of pharmaceutical particles 29 200536523. The dosage form may include immediate release granules and controlled release granules

System release particles.

It is within the scope of the invention to fall within the particle size range described above. The particles can be presented in any standard structural manner well known in the pharmaceutical art. Such structures include, for example, matrix particles, non-pareil cores containing a drug layer, and active or non-active cores with multiple film layers on the core. A controlled release coating can be added to any of the foregoing structures to create a controlled release particle. This particle can be produced according to any of a number of known methods of making particles. The immediate release granule contains the active pharmaceutical composition and a disintegrant. Suitable disintegrants include, for example, starch, low-substitution hydroxypropy 1 cellulose, croscarmellose sodium, calciUm carboxymethyl cellulose, Hydroxypropyl starch, sodium starch glycolate and microcrystalline cellulose 〇In addition to the above ingredients, the matrix may also contain appropriate amounts of other materials 30 200536523 quality, such as dilution Agents, lubricants, bonding agents, granulation aids, colorants, odorants, and slip agents are generally used for materials in the field of pharmacy. The amount of these additional materials needs to be sufficient to provide the desired effect for the desired formulation. The matrix incorporating particles may also contain appropriate amounts of other materials, such as diluents, lubricants, diluents, bonding agents, granulation aids, colorants, flavoring agents, and slip agents, which are generally used in the field of pharmacy, If required, it can be used up to about 75% by weight of the granules.

In a preferred embodiment, the oral dosage form is prepared by including an effective amount of granules in a capsule as described above. For example, an effective amount of melt-extruded particles can be placed in a gelatin capsule to provide an effective controlled release dose when the capsule is in contact with and digested with gastric fluid. In another preferred embodiment, a suitable number of granules can be compressed into an oral lozenge by standard dragee equipment using standard techniques. Techniques and pharmaceutical compositions used to make lozenges (pressed and cast), capsules (hard and soft gelatin), and pills are also described in the literature: Remington's Pharmaceutical Sciences, Arthur Osol, ed., 1 5 5 3 -93 ( 1 9 8 0), and incorporated herein by reference. These granules can be produced by mixing related ingredients and granulating the mixture. The resulting granules are dried and screened, and the granules of the required size are used to formulate a pharmaceutical formulation. Controlled release particles. When the controlled release particles of the present invention are digested and exposed to gastric fluid, and then to intestinal fluid, they slowly release beclofen. It is also possible to increase or decrease the thickness of the retarder coating (ie, change the amount of the outer protective film) 31 200536523

And other ways to change the controlled release profile of the formulation of the present invention. A sufficient amount of the produced solid controlled release particles can then be placed in a gelatin capsule, which can provide an effective controlled release dose when the capsule is in contact with and digested with an environmental fluid, which can be gastric fluid, intestinal fluid, or a dissolution medium . The outer layer of the particles can be coated with an aqueous dispersant of a hydrophobic or hydrophilic material to change the release distribution pattern. The water-based dispersant of the hydrophobic material preferably further comprises an effective amount of a plasticizer, such as triethyl citrate. Pre-formulated ethylcellulose dispersants such as Aquacoat® or Surelease® can be used. With Surelease®, no additional plasticizer is required. The release effect of the therapeutically active drug in the controlled-release formulation of the present invention is influenced by the following factors, that is, adjusted to the expected release rate by adding one or more release-modifying agents. Release modifiers can be organic or inorganic materials and include materials that can be dissolved, extracted or filtered out of the coating in the environment in which they are used. Pore-formers include one or more hydrophilic materials such as propyl cellulose. The release-modifying agent may also contain a semi-permeable polymer. In some preferred embodiments, the release-modifying agent may be selected from the group consisting of hydroxypropylphosphonium cellulose, lactose, metal stearate, and mixtures thereof. The controlled release component may also include a combination of a hydrophobic and a hydrophilic polymer. In this embodiment, once taken, the hydrophilic polymer will dissolve to weaken the structure of the controlled release honey component, and the hydrophobic polymer will block the penetration of water molecules and assist in maintaining the shape of the drug delivery system. Hydrophobic materials can be selected from the group consisting of: alkyl cellulose, acrylic and methyl 32 200536523

Acrylic polymers and copolymers, sh e i1 a c, zein, hydrogenated castor oil, hydrogenated vegetable oil, or mixtures thereof. In some preferred embodiments, the hydrophobic material is a pharmaceutically acceptable acrylic polymer, which includes, but is not limited to, a copolymer of acrylic acid and methacrylic acid, methyl methacrylate, methyl methacrylate Methyl ester copolymer, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly (acrylic acid ), Poly (methyl methacrylic acid), methacrylic acid alkylamide copolymer, poly (methyl methacrylate) (p〇i (methyl methacrylate)), poly (anhydro methyl methacrylate) Dilute acid) (p〇iy (methacrylic acid anhydride)), polymethacrylate, polyacrylamide, poly (anhydrous methacrylate) and methacrylic acid, water, glycerol and vinegar (Glycidyl methacrylate copolymer). In another alternative embodiment, the hydrophobic material is selected from materials such as, for example, one or more hydroxyalkyl celluloses such as propyl fluorenyl cellulose. The preferred hydroxyalkyl cellulose is monohydroxy (Ci to C6) alkyl cellulose, such as propyl cellulose, propyl methyl cellulose or hydroxyethyl cellulose. In particular, the amount of hydroxyalkylcellulose in the oral dosage form in the present invention is determined by the exact ratio of the active drug required, and it varies from about 1% to about 80%. In the embodiment of the present invention, the coating contains an aqueous dispersant of a hydrophobic polymer. The aqueous dispersant of the hydrophobic polymer contains an effective 33 200536523 dose of a plasticizer to further improve the physical properties of the film. . For example, because ethyl cellulose has a relatively high glass transition temperature and does not form elastic films under ordinary coating conditions, it is necessary to 'plasticize ethyl cellulose before using ethyl cellulose as a coating material. Into. Generally speaking, the plasticizing amount in a coating solution is determined according to the concentration of the film forming agent, for example, it is usually about 1% to about 50% by weight of the film forming agent. However, it is preferable to carefully determine the concentration of the plasticizer after careful experiments with specific coating solutions and application methods.

Examples of plasticizers suitable for ethyl cellulose include, for example, dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate And water-insoluble plasticizers such as triacetin, although other water-insoluble plastics such as acetylated monoglycerides, phthalate esters, and castor oil can also be used化 剂。 Chemical agent. Triethyl citrate is a plasticizer particularly good for the ethyl cellulose aqueous dispersant of the present invention. Examples of plasticizers suitable for the acrylic polymer of the present invention include, but are not limited to, citric vinegar such as triethyl citrate NF XVI, tributyl citrate, and dibutyl phthalate. dibutyl phthalate) and 1,2-propylene glycol can be used. Other plasticizers that have proven to be suitable for enhancing the elasticity of films formed from acrylic films such as Eudragit® RL / RS paint solutions include polyethylene glycol, propylene glycol, diethyl phthalate, castor oil, and Three vinegar extracts. Triethyl citrate is a plasticizer particularly good for ethyl cellulose aqueous dispersants. It was further discovered that the addition of a small amount of talc can reduce the tendency of the aqueous dispersant to stick during the manufacturing process, and can be used as a polishing agent. A commercially available ethyl cellulose aqueous dispersant is Aquacoat, which is prepared by dissolving ethyl cellulose in a water-insoluble organic solvent, and then dissolving it in the presence of a surfactant and a stabilizer. This ethyl cellulose was emulsified in water. After homogenizing the reaction to produce droplets smaller than micrometers in size, the organic solvent is evaporated under vacuum to produce a pseudolatex. Plasticizers are not incorporated into the pseudo-latex during the manufacturing stage. Therefore, 'Aquacoat (g) is mixed with a suitable plasticizer before using pseudo-latex as a coating. Another commercially available aqueous dispersion of ethyl cellulose

Surelease® (Colorcon, Inc., West Point, PA, USA). This product is prepared by adding a plasticizer to a dispersant during the manufacturing process. Polymer, plasticizer (dibutyl sebacate) and stabilizer (oleic acid) are prepared into a homogeneous mixture of a hot melt 'and then diluted with an alkaline solution to obtain a matrix that can be used directly in the matrix Water-based dispersant. In a preferred embodiment, the acrylic coating is an acrylic resin lacquer used as an aqueous dispersant, for example, a product sold under the trade name of E u d r ag i t ® by Rohm Pharma. In another preferred embodiment, the propionic acid coating comprises a mixture of two acrylic resin paints, both of which are commercially available under the tradename Eudragit® RL 30 D from Rohm Pharma and Product of Eudragit® RS 30 D. Eudragit® RL 30 D and Eudragit® RS 30 D are copolymers of acrylic acid and fluorenyl acrylate with low content of quaternary ammonium groups.

The molar ratio of the ammonium group to the remaining neutral (meth) acrylate in Eudragit® RL 30 D is 1:20. The molar ratio in Eudragit® RS 30 D is 1:40. The average molecular weight is about 1 50,000 Daltons. The codes RL (high permeability) and R S (low permeability 1 o w perm e ab i 1 i t y) indicated by the household cater means the permeability of these chemicals. Eudragit® RL / RS mixtures are insoluble in water and digestive fluids. However, the coatings they form are swellable and permeable in aqueous and digestive fluids.

Eudragit® RL / RS dispersants can be mixed together in any desired ratio to optimally obtain a controlled release formulation with the desired dissolution profile. For example, a desired controlled release formulation can be obtained from a barrier coating derived from one of various coating compositions, such as 100 / O Eudragit® RL; 50% Eudragit® RL and 50% Eudragit® RS; or 10% Eudragit® RL and 90% Eudragit® RS. Those with ordinary knowledge in their field of expertise need to understand that other acrylic polymers such as Eudragit® L can also be used. In addition to changing the dissolution distribution pattern by changing the relative amount of different acrylic resin paints, the dissolution distribution pattern of the final product can also be changed by means such as increasing or decreasing the thickness of the retarder coating. In a preferred embodiment of the present invention, the coating substrate can be cured in a furnace having a temperature higher than the Tg (glass transition temperature) of the plasticized acrylic polymer for a period of time necessary to obtain a stable product. And the optimal temperature and time value of a specific formula can be determined by experiments. In some embodiments of the present invention, a hardening reaction is performed in a furnace at a temperature of about 45 ° C for about 1 to 48 hours to obtain a stable product. It is expected that certain products coated with the controlled release coating of the present invention may take more than 24 to 48 hours, such as about 48 to about 60 hours or more.

In addition to film formers, plasticizers, and solvent systems (e.g., water), the coating solution preferably includes a colorant for aesthetic and product identification purposes. In addition to adding color to the water-based dispersant of hydrophobic material, color can also be added to the active drug solution with curative effect to replace it. For example, colors can be added to Aquacoat® by using ethanol or propylene glycol-based color dispersants, for example, 'abrasion-resistant | Lu precipitation pigments (111 aluminum lakes) and titanium dioxide, such as The opacifier is added to the water-soluble polymer solution by shearing, and then it is added to the plasticized Aquacoat® by using a low shearing method. The method of formulating colors according to the present invention. When an acrylic polymer aqueous dispersant is used, ingredients suitable for providing color to the formula include titanium dioxide and pigments such as iron oxide dyes. However, mixing pigments may increase the blocking effect during coating. For example, by dissolving an active drug having a therapeutic effect in water, and then spraying the solution on a substrate such as a unique 8/20 bead substrate using a Wuster embedding machine to prepare an oblong shape coated with the active drug. Spheres or beads. Before coating the beads, additional components can be optionally added to assist the combination of the active drug with the beads and / or make the solution color, etc. For example, a product containing hydroxypropylphosphonium cellulose with or without a colorant (such as the commercial product Op adry® from Colorcon, Inc.) can be added to the solution and used before the beads ( For example, about 1 hour) the solution is mixed. Then the surface of the coated substrate (beads) produced in this example can be selectively covered with a barrier agent to make the active drug with curative effect. Hydrophobic controlled release coatings are separated. An example of a suitable barrier agent includes propyl methyl cellulose. However, any film forming agent known to those skilled in the art can also be used. Preferably, The barrier agent does not affect the dissolution rate of the final product. _ Active Coated L pulsatile Dosage Form In another embodiment of the present invention, the drug is delivered by a pressure-coated pulsatile drug suitable for oral administration with a controlled release ingredient. System to provide beclofen 'The controlled release ingredient contains a compressed mixture of an active drug and one or more polymers, and is essentially an immediate release The immediate-release ingredient contains a compressed mixture of an active drug and a hydrophilic and hydrophobic polymer. The immediate-release ingredient preferably contains an active drug and one or more Compressed mixture of polymers with disintegrating properties, so that the polymers disintegrate and disintegrate quickly when exposed to aqueous media. The controlled release component preferably comprises a hydrophilic and a hydrophobic polymer In this embodiment, once the controlled-release component is taken, the 5-hydrophilic polymer will dissolve to weaken the structure of the controlled-release component, and the hydrophobic polymer will be p and water stagnant molecules. Penetrates and helps maintain the shape of the drug delivery system. In accordance with the present invention, the term "polymer" includes one or more polymeric substances that occur after contact with a solution environment such as water. 38 200536523

Swelling, gelling, degradation or corrosion. Examples include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, cross-linked weinyl cellulose, cross-linked cellulose Crospovidone, guar gum, magnesium a 1 uminumsi 1 icate, fluorenyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose cellulose), pregelatinized powder, sodium alginate, sodium starch glycolate, starch, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose ) Via hydroxypropyl methylcellulose, polymethacrylates, povidone, pregelatinized starch, shellac, zein, and combinations thereof. As used herein, "hydrophilic polymers" include one or more carboxymethylcellulose, such as guar gum or gum acacia, gum tragacanth, or gum xanthan) and other natural gums, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and povidone, the better of which are Hydroxypropylphosphonium cellulose. The term "hydrophilic polymer" may also include sodium carboxymethycellulose, hydroxymethyl cellulose, polyethelene oxide, ethylethenyl 39 200536523

Cellulose (hydroxyethyl methyl ceiiuiose), carboxypolymethylene (polyethylene glycol), polyethylene glycol (polyethelene glycol), alginic acid, gelatine (gelatine), polyethylene ethyl alcohol (poiyvinyi aic〇hol), polyethylene Polyvinylpyrrolidones, polyacrylamides, polymethacrylamides, polyphosphazines, polyoxazolidines, poly (hydroxyalkylcarboxylic acids) )), An alkali metal or alkaline earth metal, caragenate alginates, ammonium alginate, sodium alginate or a mixture thereof. The "hydrophobic polymer" in the drug delivery system can be any hydrophobic polymer that can achieve the purpose of the present invention, including but not limited to one or more selected from the group consisting of carbomer, palm hydrazone (Carnauba wax), ethylcellulose, glyceryl p almito stearate, hydrogenated ramie oil, hydrogenated vegetable oil type 1, microcrystalline soil wax), polacrilin potassium, polyethylene oxide, polymethylpropionate, or stearic acid, with the better being the first Type hydrogenated vegetable oil. The hydrophobic polymer may include, for example, a pharmaceutically acceptable acrylic polymer, which includes but is not limited to copolymers of acrylic acid and methacrylic acid, fluorenyl acrylate copolymer, ethoxyethyl acrylate, ethyl cyanoacrylate Ester, urethane methacrylate copolymer, poly (propylene 40 200536523

Acid (poly (acrylic acid)), poly (methacrylic acid) (poly (methacrylic acid)), alkyl methacrylate copolymer, poly (methyl methacrylate), poly Poly (methyl methacrylate) copolymer, poly (methyl methacrylate) copolymer, poly (methyl methacrylate) copolymer, poly (methyl methacrylate) copolymer, poly (anhydrous methacrylic acid), and poly (methyl methacrylate) glycidyl vinegar Copolymer. In addition, hyaluronic acid polymers can be positively charged, negatively charged, or non-ionic polymers, and may be acrylates or methacrylates formed from methacrylic acid or methacrylates. Polymers may also be pH-dependent. Enteric Coated Controlled Release In one embodiment, the delayed or delayed-sustained release film coating is an enteric coating. Commercially available pH-sensitive polymers can also be used to form casings. Enteric-coated drugs have little or no solubility in acidic gastric environments with a pH below 4.5. When a suitable delay time elapses or after the unit of drug passes through the stomach, the enteric coating will dissolve in the higher pH intestine, making the drug effective. The preferred drug release time is in the range of up to 7 hours after taking the drug under fasting conditions. Casing polymers include cellulose acetate phthalate, cellulose acetate trimellitate, and propyl methylcellulose phthalate ( hydroxypropy 1 methylcellulose phthalate) '' polyvinyl acetate phthalate, carboxymethylethylcellulose, copolymerized methacrylic acid / 41 200536523 methacrylate For example, materials known under the trade names Eudragit® L12.5, Eudragit® L100, or Eudragit® S12.5, S 100 (Rohm GmbH, Darmstadt, Germany) or similar compounds that can be used to obtain casings. Hydrocolloid polymer dispersants or redispersants can also be used, for example; Aquateric®, Aquacoat® CPD 30 (FMC Corp.); Kollicoat MAE® 30D and Kollicoat MAE® 30DP (B ASF); Eastacryl® 3 0D (Eastman Chemical, Kingsport, TN).

The casing polymer used in the present invention can be adjusted by mixing with other film-coating products known to be pH insensitive. Examples of such film-coating products include neutral methyl methacrylate with a small portion of trimethylammonioethyl methacrylate chloride. The trade names are E Eudragit®, Eudragit® RL,

Eudragit® RS, trade names Eudragit® NE30D and Eudragit® NE3 0, neutral ester dispersants without any functional groups; and other pH-independent film coating products. The casing will substantially surround the controlled release ingredient. The term "substantially envelop" tends to be defined as a complete or nearly complete encirclement. Such surroundings preferably include a surrounding of at least about 80%, more preferably a surrounding of at least about 90%, and even more preferably a surrounding of at least about 99%. An embodiment of the present invention provides a free flowing formulation containing beclofen. The term "free flowing" means a dosage form that can pass through a patient's digestive system without hindering or slowing down the passage mechanism. Therefore, the term "free-flowing" will exclude gastric raft type dosage forms that are designed to prolong the residence time in the stomach, such as the gastric raft type dosage forms described in U.S. Patent No. 5,651,985 .

The dosage form according to the present invention may also include a combination of beclofen and at least one such as tizanidine, dantrolene, nonsteroidal anti-inflammatory agents (NS AIDs) , Opiates, and COX-2 inhibitors and other active drugs. Other active drugs can be co-formulated in this immediate release, delayed-release or delayed-sustained release type ingredient to provide the desired therapeutic effect. The dosage form according to the present invention can also be used to purify racemates, L-becprofen, and other gamma-aminobutyric acid related materials as described in U.S. Patent No. 6,350,769 issued to Kaufman et al. On 26 February 2002. Active drug. The dose concentration of beclofen (racemate or L-beclofen) in this composition and any active drug used in combination with beclofen can be varied to obtain an amount of beclofen 'and as a pharmaceutical combination When the product is used, an active ingredient is obtained in an amount sufficient to produce a desired therapeutic response to a particular pharmaceutical composition and method of administration. It is an object of the present invention to provide the bioavailability of beclofen based on the indications of a physician. Bioavailability means the degree to which a therapeutically active drug is available in the body after it is used. In general, patients who are measuring bioavailability need to fast overnight before taking the test preparation. 43 200536523 After that, a plasma sample was taken and the blood concentration of the parent drug and / or its active metabolite was analyzed. These data can be expressed as C M A X (the maximum activity component measured in plasma) or AUC (the area under the time curve of plasma concentration). See Shargel & Yu, Applied Biopharmaceutics and Pharmacokinetics c h. 10 (3d e d. 1 9 9 6); and Applied

Pharmacokinetics: Principles of Therapeutic Drug Monitoring, Evans et al., Eds. (3d ed. 1 992).

For example, beclofen formula can be used in a patient for comparative bioavailability studies. Patients need to fast overnight before taking the medication. Take jk pulp samples at the time of taking the drug, every hour within 12 hours after taking the drug, and at the 16th and 24th hours after taking the drug, and analyze the bekeprofen or nanometers per milligram per milliliter (ng / m 1). -The concentration of bekeprofen metabolites. Without further elaboration, a person with ordinary knowledge in a field of expertise can use the present invention to the extreme according to the foregoing description. The following examples are for illustrative purposes only and cannot be used to limit the rest of the disclosure. EXAMPLES Example 1. Core (actiVe baclofen-coated seeds) coated with active Becoprofen-coated seeds Formulation component percentage (%) male silk (mg) 250.0 sugar pellets, NF (Mesh size 20-25) 81.4 Μ granulated beclofen, US P 13.0 40.0 Povidone, USP 5.6 17.14 44 200536523 (Plasdone K-29 / 32) pure water, USP N / AN / A Total: 100.0 307.14 Add Povidone (Plasdone K-29 / 32®) to pure water and mix until Proviron is completely dissolved. Becprofen is mixed into the aforementioned solution mix until uniformly dispersed. The beclofen suspension was then applied to the sugar sphere particles using a fluidized bed coating apparatus to produce an active film-coated core.

Example 2. Core Formulation coated with active Becoprofen film coating. Percentage (%) of male green (mg) sugar pellets, NF (mesh 20-25) 81.4 250.0 Micronized Beclofen Finn, USP 13.0 40.0 Hypromellose 2910 type, USP (Pharmacoat 606, 6cps) 5.6 17.14 Pure water, USP N / AN / A Total: 100.0 307.14 Hypromellose) 2910®, USP (Pharmacoat 606, 6 cp s) is added to an appropriate amount of pure water, and mixed until the hydroxypropyl methyl cellulose is completely dissolved. Becprofen is added to the aforementioned solution and mixed until uniformly dispersed. The beclofen suspension was applied to sugar sphere particles using a first-class bed coating device to produce an active film-coated core. 45 200536523 The dissolution profile of this formulation is shown in Figure 3. Example 3. Percentage of granule formulations containing active bekeprofen (%) Male silk (mg) Bekeprofen, USP 7.4 20.0 Pregelatinized Starch, NF (Starch 1500) 21.3 57.5 Microcrystalline Cellulose, NF (Avicel PH-102) 70.8 191.3 Magnesium Stearate »NF 0.5 1.3 Pure water, USP N / AN / A Total: 100.0 270.1

Becprofen, pregelatinized starch 1 500, and Avicel PH-102 microcrystalline cellulose were mixed. The aforementioned beclofen mixture is charged into a Hobart mixer and mixed to form a homogeneous mixture. This mixture is subjected to a granulation step with pure water to form a granule. It is then dried in a furnace at 60 ° C to form granules. Use # 3 0 mesh filter for screening. Mix with magnesium stearate to form active particles. Example 4: Enteric coating core containing beclofen 46 200536523 Formulation component percentage (%) male silk (mg) active film-coated core (containing 13.02% beclofen) 76.5 153.61 hydroxypropylmethyl fiber Hypromellose 2910, USP (Pharmacoat 606, 6cps) 8.5 17.07 Hypromellose Phthalate, NF (HPMCP, HP-50) 13.5 27.11 Tributyl citrate (Acetyltributyl Citrate) »NF 1.5 3.01 Acetone, NF N / AN / A pure water, USP N / AN / A Total: 100.0 200.8

Pure water was poured into a stainless steel container and mixed with hydroxypropyl fluorenyl cellulose to its element > cereal solution. Then, pure water and propylene (a c e t 〇 n e) were injected into another non-steel trough apparatus' and mixed with Acetyltributyl Citrate to form a tributyl citrate solution. To the aforementioned solution, propylphosphonium cellulose phthalate was added to form an enteric solution. A thin layer was applied to the core of any of the Becoprofen active film coats prepared in Example 1-3 with the seal coat solution to form a sealed Becoprofen ball. Subsequently, the sealed bekeprofen beads were coated with an casing solution to produce an casing core. Example 5: Enteric coating core containing becprofen 47 200536523 Formulation (component) AB percentage (%) male silk (mg) percentage (%) male silk (mg) active film coating core (containing 13.02% beclofen (Fen) 90.0 149.4 90.0 149.4 Type A methacrylic acid copolymer (methudrylic acid) NF (Eudragit L 100) 8.0 13.28-Type C fluorenyl acrylic acid copolymer NF (Eudragit L 100-55)-8.0 13.28 Talc ( Talc), USP 1.0 1.66 1.0 1.66 Triethyl Citrate, NF 1.0 1.66 1.0 1.66 Isopropyl Alcohol, USP N / AN / AN / AN / A pure water, USP N / AN / AN / AN / A Total: 100.0 166.00 100.0 166.0

Isopropyl alcohol and pure water were poured into a stainless steel container, and then mixed with triethyl citrate. Add A-type methacrylic acid copolymer, NF (Eudragit L 100) or C-type fluorenyl acrylic copolymer, NF (Eudragit L 1 00-55) to form an Eudragit® suspension. Talcum is dispersed in this Eudragit® suspension. A thin film was applied to the bekeprofen active film coating core of Example 4 with Eudr a git® suspension to form an enteric coating core. Example 6. Pharmaceutical composition containing beclofen active film coating and casing core 48 200536523 Formulation component Immediate release component Delayed release component Total Beclofen 10 mg 20 mg 30 mg Pharmacoat 606 2 mg 4 mg 6 mg Talc 0.4 mg 12.1 mg 12.5 mg Sugar granules S 62.5 mg 12 5 mg 18 7.5 mg Eudragit L100-55 0 22.32 mg 22.32 mg Triethyl Citrate 0 3.72 mg 3.72 mg Water N / AN / AN / A Isopropyl Alcohol N / AN / AN / A Propionate n / a N / AN / A Total: 74.9 187.14 262.04 Mix the specified number of beclofen active film coatings with the core of the casing to form a dosage form. For capsules, the core is mixed and added to gelatin capsules. For tablets, the core is compressed into tablets. In the case of drug packs, the core is mixed and poured into the bag.

Example 7. The percentage of total formulation components containing beclofen enteric coating (W eight 0 / 〇) becprofen 10.56 sugar sphere particles 65.97 Pharmacoat 6 0 6-" 〇2-Eudragit® RL 100 " οΤβο-Eudragit® RS 100 'ΓΤ9' ~-49 200536523 Dibutyl Sebacate 0.20 Talc '1.39 Mono-Magnesium Stearate 0.40 Hydroxypropyl 曱Hydroxypropyl Methyl cellulose phthalate (HPMCP) HP-50 13.50 Triethyl Citrate 1.50 Total: 100.00

After P h a r m a c o a t 6 0 6 is dissolved in pure water, beclofen is dispersed in this aqueous solution to form an aqueous suspension. A fluidized bed coating equipment was used to apply the beclofen suspension to the sugar sphere particles to produce an active film-coated core. Eudragit® RL 100, RS 100 and dibutyl sebacate were dissolved in a mixture of monoacetone and isopropanol. Talcum and magnesium stearate were also dispersed in the solution. The aforementioned suspension was applied to the active film-coated core using a first-class bed coating equipment to produce a sustained-release film-coated core. HPMCP and triethyl citrate were dissolved in a mixture of monoacetone and pure water. The aforementioned suspension was applied to the sustained release film-coated core using a first-class bed coating equipment to produce an enteric-coated core. Example 8: Beclprofen tablets Formula (Formulati __ (component)) ^ ~-

$ Alcohol, Source: Sodium Starch Glycoj ^ te 50 200536523 Dicalcium Phosphate Anhydrous 26.5 Lactose Anhydrous 132.5 Magnesium Stearate 1 Total: 200 Sodium Glycolate Powder, Dicaicium Phosphate Anhydrous and Lactose Anhydr〇us; ^

s is in a high shear granulator. This mixture was wet-granulated with pure water, and the granules were dried in a furnace at a temperature of 60 t for at least 16 hours. The particles were sifted through a # 2 5 mesh screen. The oversized particles were crushed with a Fitzpatric pulverizer equipped with a # 丨 8 mesh screen. The sieved and milled granules were mixed with magnesium stearate, and the mixture was compressed into a tablet using a rotart tablet press. Example 9, Beclofen Lozenge Formula (Formulation) Component Weight (Male) (Weight (mg)) Beclofen ......... __ 2910 type hydroxypropyl fluorenyl cellulose- ------— (Hydroxypropyl Methylcellulose, type 2910), USP (Methocel K100LV) 60 Lactose Monohydrate or Mannitol H60 Micro crystal line Cellulose, NF (Avicel PH101 ) 79.40 Magnesium Stearate __ __------ Total: ~ --- 700 — ___------ 51 200536523 Add beclofen, propyl fluorenyl cellulose, monohydrate Lactose Monohydrate or Mannitol (M a η nit ο 1) and microcrystalline cellulose are mixed in a high shear rate granulator. This mixture was granulated by humidifying with pure water, and the granules were dried in an oven at a temperature of 60 ° C for at least 16 hours. Sieve the particles with a # 25 mesh screen. The oversized granules were crushed by a F i t z p a t r i c grinder equipped with # 1 8 mesh filter and mesh. The sieved and milled granules were mixed with magnesium stearate, and the mixture was compressed into tablets using a rotary tablet press.

Example 1 0. Formulation of a pharmaceutical composition containing a beclofen active coating and an enteric core. Immediate release (IR) in each capsule. Enteric coating (EC) in each capsule. Total weight in each capsule (w / w) Weight (mg)% (w / w) Weight (mg)% (w / w) Weight (mg) Micronized Beklow 13.36 19.00 21.87 21.00 16.79 40.00 Sugar ball granules, NF (mesh size 20-25 ) 83.48 118.73 34.11 32.75 63.58 151.48 2910 Hydroxypropyl Methylcellulose (type 2910), USP (Pharmacoat 606, 6 cps) 2.67 3.80 4.37 4.20 3.36 8.00 Talc, USP (ALTALC 500V USP BC ( * 1814)) 0.49 0.70 9.60 9.22 4.16 9.92 C-type methacrylic acid copolymer (Methacrylic Acid) »NF (Eudragit L100-55)--15.53 14.91 6.26 14.91 A-type methacrylic acid copolymer (Methacrylic Acid), NF (Eudragit L100-55) —-10.61 10.19 4.28 10.19 Triethyl Citrate NF--3.91 3.75 1.57 3.75 Total: 100.0 142.23 100.00 96.02 100.00 238.25 52 200536523

Type 2 910 hydroxypropylmethyl cellulose U S P was added to an appropriate amount of pure water and mixed until the hydroxypropyl fluorenyl cellulose was completely dissolved. Becloprofen was then added to the aforementioned solution until homogeneously dispersed. The suspension was passed through a # 40 mesh screen into a stainless steel container. Sugar pellets are injected into a fluidized bed coater with Wurster inserts and heated until the exhaust temperature reaches 50 ± 5 ° C. The aforesaid active suspension was coated on sugar sphere particles by air-jet method, and then the temperature was 60 ° C. 10 °. Dry at C for 5 minutes. This immediate release (IR) core was sieved through a # 1 6 mesh stainless steel screen. Collect an acceptable immediate release core and mix with USP talc in an inclined cone blender for about one minute. Pure water and acetone were mixed to prepare an casing solution. Triethyl citrate and C-type methacrylic acid copolymer are mixed in the solution until completely dissolved. Mix talc until completely dispersed in the above solution. The IR core was then coated with an enteric coating-soluble solution using a fluid bed coating device in the manner described above to produce an enteric core. The core of the casing was screened by # 1 4 division's indiscriminate steel filter. An acceptable casing core was collected and mixed with USP talc in an inclined cone mixer for about one minute. An appropriate amount of the IR core and an appropriate amount of the casing core were coated in the capsule to form a beclofen ER capsule. Example 11. Becprofen tablets The tablets having the following pharmaceutical composition were prepared according to the procedure described in Example 9. Component 579-7C 579-10A PX01802 PX02002 53 200536523 Beclofen, U Mutual? '20 2〇 ^ 2910 Hydroxypropyl Methylcellulose (type 2910), USP (Pharmacoat 606, 6 cps) 0 60 2280 Hydroxypropyl Methylcellulose (type 2280) »USP (Methocel K100LV) 20 0 2280 Hydroxypropyl Methylcellulose, type 2280, USP (Methocel K100M) 0 0 Microcrystalline Cellulose, NF (Avicel PH101) 59 59 Stearic acid Money (Magnesium Stearate), NF 1 1 ----- > Pure water, USP lozenge weight 100 U〇

60 120 59 々 唧 唧 唧 、 刀 刀 唧 模式 刀 怖 显示 显示 显示 显示 显示 系 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 显示 2 模式 模式 模式 模式 中 中 中 中 中 中 显示 显示 模式 显示 显示 显示 显示 显示 显示 显示 显示 怖 显示 显示 显示 显示 显示 显示 怖 怖 怖 显示 显示 显示 显示 显示 显示 显示 2. 2. [fig (ER) capsules. 20 male becprofen delayed-release capsules were prepared according to the procedure described in Example 7. Component PX01903 PX02103 PX02503 PB01403 PB00903 (A) Micronized becprofen, USP 20.0 20.0 20.0 20 20 Sugar ball granules 125.0 125.0 125.0 125.0 125.0 54 200536523

Hydroxypropyl Methylcellulose (type 2910), USP (Pharmacoat 606) 8.6 8.6 8.6 4.0 4.0 Hydromellose Phthalate »NF (HPMCP; HP- 50) 24.4 25.6 25.6 0.0 0.0 Ammonio Methacrylate copolymer Type A, NF (Eudragit RL100) 0.0 1.5 1.1 0.0 0.0 Ammonio Methacrylate B-type ammonium methacrylate copolymer copolymer Type B), NF (Eudragit RS100) 0.0 2.3 2.6 0.0 0.0 Type A methacrylic acid copolymer (Type A), NF (Eudragit L100) 0.0 0.0 0.0 13.2 13.2 Type C methacrylic acid copolymer (Methacrylic Acid , Type C), NF (Eudragit L100-55) 0.0 0.0 0.0 8.1 0.0 Triethyl Citrate, NF 2.7 2.8 2.8 3.0 3.0 Dibutyl Sebacate, NF 0.0 0.4 0.4 0.0 0.0 Talc, USP 0.0 2.6 2.6 5.7 5.7 Magnesium Stearate, NF 0.0 0.8 0.8 0.0 0.0 Isopropyl Alcohol, USP 0.0 — — — — Acetone NF purified water, USP dissolution profile pattern of the formulations shown in FIG. 4. 55 200536523 Example 1 3. Becprofen delayed-release (ER) capsules. Beclofenol delayed-release (ER) capsules with the following formulations were prepared according to the procedures described in Example 10.

Becprofen ER (ER1A) capsule 30 mg pharmaceutical composition (Lot PB01903) IR / ER (EC1) = 2: 1 component Immediate release per capsule (IR) EC1 per capsule total weight per capsule ( w / w) Weight (mg)% (w / w) Weight (mg)% (w / w) Weight (mg) _ Micronized Becprofen 8.22 20.0 4.11 10.0 12.33 30.0 Sugar pellets, NF (mesh 20- 25) 51.36 125.0 25.68 62.5 77.04 187.5 2910 Hydroxypropyl Methylcellulose (type 2910), USP (Pharmacoat 606) 1.64 4.0 0.82 2.0 2.47 6.0 Talc, USP (ALTALC 500V USP BC (* 1814 )) 0.33 0.8 2.49 6.05 2.81 6.85 Methacrylic Acid (Type C), NF (Eudragit L100-55)--4.59 11.16 4.59 11.16 Triethyl Citrate ♦ NF- --0.76 1.86 0.76 1.86 Total 61.55 149.8 38.45 93.57 100.00 243.37 Beclofen ER (ERIB) capsules 3011 ^ Pharmaceutical composition (1 ^ 301301) IR / ER (EC1) = 1: 2 components per Immediate release (IR) in capsules EC1 in capsules Total weight in capsules (w / w) Weight (mg)% (w / w) Weight (mg)% (w / w) Weight (mg) Micronized bekeprofen 3.82 10.0 7.63 20.0 11.45 30.0 Sugar pellets, NF (sieve 23.85 62.5 47.70 125.0 71.55 187.5 56 200536523

Heads 20-25) Hydroxypropyl Methylcellulose, type 2910, USP (Pharmacoat 606) 0.76 2.0 1.53 4.0 2.29 6.0 Talc, USP (ALTALC 500V USP BC (* 1814)) 0.15 0.4 4.62 12.1 4.77 12.5 Methacrylic Acid (Type C) »NF (Eudragit L100-55)--8.52 22.32 8.52 22.32 Triethyl Citrate» NF-- 1.42 3.72 1.42 3.72 Total 28.58 74.9 71.42 187.14 100.00 262.04 Becprofen ER (ER2A) capsule 30 mg Pharmaceutical composition (Lot PB02003) IR / ER (EC2) = 2: 1 component Immediate release (IR) in each capsule EC2 per capsule Total weight per capsule% (w / w) Weight (mg)% (w / w) Weight (mg)% (w / w) Weight (mg) Micronized becprofen 8.34 20.0 4.17 10.0 12.51 30.0 Sugar ball granules, NF (mesh 20-25) 52.14 125.0 26.07 62.5 78.21 187.5 2910 Hydroxypropyl Methylcellulose (type 2910), USP (Pharmacoat 606) 1.67 4.0 0.83 2.0 2.50 6.0 Talc , USP (ALTALC 500V USP BC (* 1814)) 0.33 0.8 1.38 3.29 1.71 4.09 Methacrylic Acid (Type C), NF (Eudragit L100-55)--1.68 4.03 1.68 4.03 Methacrylic Acid (Type A) »NF ( Eudragit L1 00)-2.76 6.62 2.76 6.62 Triethyl Citrate, NF--0.63 1.5 0.63 1.5 Total 62.48 149.8 37.52 89.94 100.00 239.74 57 200536523 Beclofen ER (ER2B) capsule 3〇11 ^ Pharmaceutical composition (1 ^ (^? 302103) IR / ER (EC2) = 1: 2 component (immediate release per capsule) (IR) EC2 per capsule total weight per capsule (w / w) weight (mg)% (w / w) Weight (mg)% (w / w) Weight (mg) Micronized becprofen 3.92 10 7.85 20.0 11.78 30.0 Sugar sphere particles, NF (mesh 20-25) 24.53 62.5 49.06 125.0 73.59 187.5 2910 Hydroxypropyl Methylcellulose (type 2910), USP (Pharmacoat 606) 0.78 2.0 1.57 4.0 2.35 6.0 Talc, USP (ALTALC 500V USP BC (* 1814)) 0.16 0.4 2.58 6.58 2.74 6.98 Methacrylic Acid (Type C), NF (Eudragit L10 0-55)--3.16 8.06 3.16 8.06 Methacrylic Acid, Type A > NF (Eudragit L1 00)--5.20 13.24 5.20 13.24 Triethyl Citrate ) »NF —-1.18 3.0 1.18 3.0 Total 29.39 74.9 70.60 179.88 100.00 254.78

The dissolution profile of the aforementioned formulation is shown in Figure 5. Example 14. Becloprofen delayed-release (ER) capsules Becloprofen delayed-release (ER) capsules having the following pharmaceutical composition were prepared according to the procedures described in Example 10, except for the casing-soluble material therein. It is tributyl citrate and hydroxypropyl fluorenyl cellulose phthalate, not triethyl citrate and C-type methacrylic acid copolymer. 58 200536523

PX03503-30 formula ingredient immediate release (IR) per capsule (EC) total weight per capsule (w / w) weight (mg)% (w / w) weight (mg)% (w / w) Weight (mg) Micronized Beklow 12.37 20.00 9.17 10.00 11.06 30.0 Sugar sphere particles S, NF (mesh 20-25) 77.33 125.03 57.31 62.50 69.12 187.53 2910 Hydroxypropyl Methylcellulose, type 2910), USP (Pharmacoa t 606) 10.30 16.65 7.63 8.32 9.20 24.97 Hypromellose Phthalate 5 NF (HPMCP, HP-50)--11.77 12.83 4.73 12.83 Ethyl lemon Acetyltributyl Citrate »NF--0.47 0.51 0.19 0.51 Talc, USP--13.65 14.89 5.70 15.46 Total 100.0 161.68 100.0 109.05 100.0 271.30 PX03403-30 Components are released immediately in each capsule (IR ) In each capsule (EC) Total weight in each capsule (w / w) Weight (mg)% (w / w) Weight (mg)% (w / w) Weight (mg) Micronized beloprofen 12.37 6.00 9.17 24.00 9.65 30.0 Sugar ball granules, NF (mesh 20-25) 77.32 37.50 5 7.31 149.98 60.30 187.48 2910 Hydroxypropyl Methylcellulose (type 2910), USP (Pharmacoat606) 10.31 5.00 7.63 19.98 8.03 24.98 59 200536523 Hypromellose Phthalate »NF ( HPMCP, HP-50)--11.77 30.80 9.91 30.80 Acetyltributy 1 Citrate, NF--0.47 1.23 0.40 1.23 Talc, USP--13.65 35.73 11.71 36.41 Total 100.0 48.50 100.0 261.72 100.0 310.9

The dissolution profile of the aforementioned formulation is shown in Figure 5. Example 15. Beclofenol delayed-release (ER) capsules. A bekeprofen extended release (ER) type capsule having the following pharmaceutical composition was prepared according to the procedure described in Example 10. Beclofen capsules are prepared in different dose strengths, such as 10 male, 15 male, 20 male, 25 male, 30 male, 35 male, and 40 male. Becprofen ER (ER2B) capsules 40 mg pharmaceutical composition (Lot RB04042-60A) IR / EC = 19: 21 components immediate release per capsule (IR) total weight per capsule (EC) per capsule% (w / w) Weight (mg)% (w / w) Weight (mg)% (w / w) Weight (mg) Micronized Becprofen 13.36 19.00 21.87 21.00 16.79 40.00 Sugar pellets, NF (mesh 20- 25) 83.48 118.73 34.11 32.75 63.58 151.48 2910 Hydroxypropyl Methylcellulose (type 2910), USP (Pharmacoat 606) 2.67 3.80 4.37 4.20 3.36 8.00 Talc, USP 0.49 0.70 9.60 9.22 4.16 9.92 60 200536523 (ALTALC 500V USP BC (* 1814)) Methacrylic Acid (Type C) »NF (Eudragit L100-55)--15.53 14.91 6.26 14.91 Methacrylic Acid (Methacrylic Acid) , Type A) »NF (Eudragit L1 00)--10.61 10.19 4.28 10.19 Triethyl Citrate NF--3.91 3.75 1.57 3.75 Total 100.0 142.23 100.00 96.02 100.00 238.25

Example 1 6. Determining the plasma concentration distribution pattern of the formula containing beclofen. A bioavailability study was completed with the participation of 20 healthy volunteers, which compared a 36 male silk prepared according to Example 15 Beclofen formula, this formula contains 12 male becloprofen immediate-release ingredients and 24 male becprofen's enteric coating controlled release ingredients, the rest of the excipients are adjusted appropriately. This formulation was compared with an immediate release reference spinner (Watson Laboratories, Inc.) of 20 male silks under fasting conditions. After the patient fasted overnight for 10 hours, the test sample was taken orally with 240 ml of water at room temperature. Except for the water given when taking the medicine, do not drink any liquid within 1 hour before and after taking the medicine. At 2, 6, 8 and 12 hours after taking the drug, the patient drank 240 ml of water at room temperature. In addition, the patient drank 480 ml of liquid during lunch and dinner. Blood samples were taken 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 1, 2, 16 and 24 hours after medication. The results are shown in Figure 6. In addition, based on the data obtained from the dose intensity of 20 male silk, Figure 6 shows the simulated plasma concentration of 30-male silk immediate-release beclofen. 61

200536523 Example 1 7. Determine the steady-state plasma distribution of the formula containing beclofen. Based on the bioavailability data of a single dose, it is possible to calculate a 40-gram becloline prepared according to Example 15 once an hour. Formula and beclofen stabilized plasma levels of immediate release Becklow formula (Watson Laboratories, Inc) taking 20 grams of silk every 8 hours. The results are shown in Figure 7, in which (C) represents the 40-filament silk type of the present invention, and (D) represents the 20-filament immediate release dosage form of the reference. This result shows that, in a stable state, the 40-milligram silk dosage form of the present invention will reach a CM IN within 12 hours after the administration, compared to the CM IN that is released 8 hours after the administration. This invention has now been fully described, and a person of ordinary skill in the art will understand that the method of the invention can be carried out without departing from the scope and scope of the invention and the scope of the invention and the scope of any embodiments. Mould 12 Fenfen concentrated fruit is used in Zhizhi

[Schematic description] Figure 1A is the in vitro dissolution profile of the 20 male silk (mg) baker fen tablet formulation prepared according to Example 8, which is based on the US drug Paddle solubility determination method at 50 revolutions per minute, Measured in 900 ml of simulated gastric juice (pH 1.2) at 37 ° C. FIG. 1B is an in vitro dissolution profile of a 20-g Beclox lozenge formulation prepared according to Example 11 according to the US Pharmacopoeia Paddle Luodian Yufen 62 62365365 degree measurement method at Sn. 50 rpm, 37 Under the condition of ° C, it is obtained in a sufficient amount in 900 ml of simulated intestinal fluid (pH 6.8). Figure 2 shows the external dissolution profile of a bekeprofen tablet formulation of 20 male silk prepared according to Example 11. It is based on the solubility determination of Paddle in the United States Pharmacopoeia, and the soil casing is set at 50 rpm and 37 ° C. Under the conditions, measured in a 900 ml mold (P 1 · 2) for 1 hour 'and then replaced with simulated intestinal fluid (p Η 6 · 8).

Figure 3 is the in vitro dissolution profile of a 20-keke bekeprofen tablet prepared according to Example 2, which is based on the US Pharmacopoeia Basket / combination test method at 75 rpm and 37 ° C. , Measured in 900ml of simulated gastric juice (PH 1.2). Figure 4 shows the in vitro solubility determination method of the lozenge formula in gastric juice (pH 1.2). The dissolution profile of 20 male becprofen prepared according to Example 12 was obtained according to the US Pharmacopoeia Basket. At 75 rpm and 37 ° C, after 2 hours of 900ml simulation, replace it with the measured value of simulated intestinal fluid (pH 6.8).

Fig. 5 is a formula showing the distribution of the male Becqueline gelatin gel prepared according to Example 13 and μ according to the US Pharmacopoeia

Basket / Valley determination method Photographed under the conditions of ΓΡΐη and 37 ° C in 900 ml of chess moon liquid (ρΗΐ · 2) and measured. Hours were subsequently replaced with simulated intestinal fluid (pH 6.8). Figure 6 shows the plasma distribution pattern described in the body. Fig. 7 of the formula of beclofen tablet in Example 16 is a model obtained from the measurement of the method described in the example 63 200536523 Plasma concentration map of beclofen quasi-steady state, where (c) represents the present invention Of the 40 male silk dosage forms, and (D) represents the reference 20 male silk immediate release dosage forms. [Description of main component symbols] None

64

Claims (1)

200536523 Patent application scope: 1. A pharmaceutical dosage form comprising a controlled release type ingredient, wherein the controlled release type ingredient comprises a type B gamma-aminobutyric acid receptor agonist and a pharmaceutically acceptable excipient; and The controlled-release component exhibits an in vitro dissolution distribution pattern in the simulated intestinal fluid medium, which includes less than about 70% of the beta-type γ-aminobutyric acid receptor agonist released after one hour, in 4 hours Later, at least 20% of the beta-type gamma-aminobutyric acid receptor agonist was released, and at least about 30% of the beta-aminobutyric acid receptor agonist was released after 6 hours. 2 · The pharmaceutical dosage form according to item 1 of the scope of the patent application, wherein the controlled release dosage form exhibits an in vitro dissolution distribution pattern in a medium simulating gastric juice / intestinal fluid (alternating time is one hour), which includes one hour later Releases less than about 80% of type B aminobutyric acid receptor agonist, releases at least about 30% of type B gamma-aminobutyric acid receptor agonist after 4 hours, and releases at least about 6 hours 40% of type B gamma-aminobutyric acid receptor agonist. 3. The pharmaceutical dosage form according to item 1 of the scope of the patent application, wherein the controlled-release component exhibits an in vitro dissolution distribution pattern in the simulated intestinal fluid medium, which includes the release of less than about 50% after one hour. Β Type B gamma-aminobutyric acid receptor agonist, which releases at least about 40% of type B gamma-aminobutyric acid receptor agonist after 4 hours, and release at least about 50% of β after 6 hours Γ-aminobutyric acid receptor agonist. 65 200536523 4. The pharmaceutical dosage form according to item 3 of the scope of patent application, wherein the controlled release dosage form exhibits an in vitro dissolution distribution pattern in a simulated gastric / intestinal fluid (alternating time of one hour) medium including one hour later Less than about 70% of type B gamma-aminobutyric acid receptor agonist released, at least about 40% of type B gamma-aminobutyric acid receptor agonist released after 4 hours, and after 6 hours Releases at least about 50% of a Type B gamma-aminobutyric acid receptor agonist. 5. The pharmaceutical dosage form according to item 1 of the scope of the patent application, further comprising an immediate-release component containing a beta-gamma-aminobutyric acid receptor agonist and a pharmaceutically acceptable excipient; wherein the immediate The release-type component exhibits an in vitro dissolution profile in simulated gastric juice including less than about 80% of the beta-type gamma-aminobutyric acid receptor agonist released after one hour; and wherein the immediate-release component and the The proportion of this controlled release ingredient From about 1:10 to 10: 1. 6. The pharmaceutical dosage form according to item 5 of the scope of the patent application, wherein the type B gamma-aminobutyric acid receptor agonist is beclofen. 7. The pharmaceutical dosage form according to item 6 of the scope of patent application, wherein the ratio of the immediate release component to the controlled release ingredient is from about 1: 4 to 4: 66 200536523 8. As described in item 7 of the scope of patent application The pharmaceutical dosage form, wherein the ratio of the immediate-release component to the controlled-release component is from about 1: 2 to 2: 9. A pharmaceutical dosage form comprising an enteric-coated controlled-release component, wherein the enteric-coated controlled-release component comprises a type B gamma-aminobutyric acid receptor agonist and a pharmaceutically acceptable excipient; and wherein the casing Soluble controlled-release components exhibit an in vitro dissolution profile in a simulated gastric / intestinal fluid (two-hour alternation time) medium, which includes less than about 10% of Type B gamma-aminobutyric acid released after 2 hours Receptor agonist, which releases at least about 40% of type B gamma-aminobutyric acid receptor agonist after 3 hours, and releases at least about 70% of type B gamma-aminobutyric acid receptor agonist after 6 hours Agent. 10 · The pharmaceutical dosage form according to item 9 of the scope of the patent application, wherein the enteric-coated controlled-release component exhibits an in vitro dissolution distribution pattern in a medium simulating gastric / intestinal fluid (alternating time is two hours), which includes Less than about 10% of beta-type γ-aminobutyric acid receptor agonist is released after 2 hours, at least about 50% of beta-type γ-aminobutyric acid receptor agonist is released after 3 hours, and After hours, at least about 80% of the beta-gamma-aminobutyric acid receptor agonist was released. 67 200536523 1 1 · According to the pharmaceutical dosage form described in item 10 of the scope of the patent application, the enteric-coated controlled-release component exhibits an in vitro dissolution distribution pattern in a simulated gastric / intestinal fluid (alternating hours) medium, which releases less after hours. At about 10% of the type B gamma-aminobutyric acid receptors, at least about 60% of the type B gamma-aminobutyric acid agent was released after 3 hours, and at least about 90% of the type B gamma-amino-butyric acid agents were released after 6 hours. Receptor agonist. 1 2. The pharmaceutical dosage form as described in item 9 of the scope of patent application, an immediate-release component containing a beta-type γ-aminobutyric acid receptor agonist and a drug-relieving excipient; wherein the immediate-release type The component represents an it dissolution distribution pattern in simulated gastric juice, which includes releasing less than the wheat B-type γ-aminobutyric acid receptor agonist after one hour; and wherein the immediate-release component and the controlled-release component are separated from the 1: 10 to 10: 1. 1 3. The pharmaceutical dosage form described in item 12 of the scope of patent application, the type B gamma-aminobutyric acid receptor agonist is beclofen. 1 4. The ratio of the immediate release ingredient of the pharmaceutical dosage form to the controlled release ingredient as described in item 13 of the scope of the patent application is about 4: 1 °, where the interval is two > Body excitement, butyric acid further includes: the above can be connected; the I ratio of I 80% in vitro is about which 1: 4 to 68 200536523 1 5 · The pharmaceutical dosage form described in item 14 of the scope of patent application, The ratio of the immediate-release component to the controlled-release component is from about 1: 2 to 2: 1 °. 16. A pharmaceutical dosage form comprising a type B gamma-aminobutyric acid receptor agonist and a pharmaceutically acceptable excipient, wherein the pharmaceutical dosage form is exhibited in a medium simulating gastric / intestinal fluid (alternating time is two hours) medium An in vitro dissolution profile that includes less than about 75% of a Type B gamma-aminobutyric acid receptor agonist released after 2 hours, and at least about 80% of a Type B gamma-amino group released after 3 hours Butyric acid receptor agonist. 1 7. The pharmaceutical dosage form as described in item 16 of the scope of the patent application, wherein the pharmaceutical dosage form exhibits an in vitro dissolution distribution pattern in a medium simulating gastric juice / intestinal fluid (two hours alternate time), which includes release after 2 hours Less than about 65% of the type B gamma-aminobutyric acid receptor agonist and at least about 90% of the type B gamma-aminobutyric acid receptor agonist were released after 3 hours. 18. The pharmaceutical dosage form according to item 16 of the scope of the patent application, wherein the beta-gamma-aminobutyric acid receptor agonist is beclofen. 19. A pharmaceutical dosage form comprising a type B gamma-aminobutyric acid receptor agonist and a pharmaceutically acceptable excipient, wherein when the pharmaceutical dosage form is used in an oral form, at least 80% of Beclofen is sucked in the body 69 200536523 oral Beck at the time of receipt The average time for casing of benzoic acid to form casings is greater than about 2.5 hours. 20. The pharmaceutical dosage form as described in item 19 of the scope of patent application, when the pharmaceutical dosage form is taken in a form, under fasting conditions, at least the average time when at least loprofen is absorbed in the body is about 3 to 4.5, 2 1 . The pharmaceutical dosage form as described in the scope of the patent application, item 20, a coating-soluble controlled release ingredient and an immediate release ingredient. 2 2. The pharmaceutical dosage form as described in item 21 of the scope of the patent application, the soluble controlled release component is selected from the group consisting of: cellulose acetate, cellulose acetate trimellitate, and hydroxypropylphosphonium cellulose Esters, polyvinyl acetate phthalates, carboxymethyl ethyl fluorene polymerized methacrylic acid / methacrylic acid methacrylates, and mixtures thereof. Oral in vivo after fasting 23. The pharmaceutical dosage form described in item 21 of the patent application range, when the pharmaceutical dosage form is used orally under the conditions, the dosage form shows an average maximum plasma distribution of beclofen from 2.5 to 5.5 hours mode. 24. The pharmaceutical dosage form as described in item 21 of the scope of application for a patent, after the pharmaceutical dosage form, the dosage form provides a time of about 80% after about 12 hours. It contains the phthalate di-ortho-fibre complex where one is in the range of about one in service value and one is in which the performance of a stable in vivo plasma distribution pattern of 70 200536523 CM IN. 25. The pharmaceutical dosage form according to any one of claims 6, 1, 3, 18, or 19 in the scope of patent application, wherein the amount of beclofen is between about 2 and 150 male silk. 26. The pharmaceutical dosage form according to item 25 of the scope of patent application, wherein the amount of beclofen is about 20 male silk. 27. The pharmaceutical dosage form according to item 25 of the scope of patent application, wherein the amount of beclofen is about 25 male silk. 28. The pharmaceutical dosage form as described in item 25 of the scope of patent application, wherein the amount of beclofen is about 30 male silk. 2 9. The pharmaceutical dosage form as described in item 25 of the scope of patent application, wherein the amount of beclofen is about 35 male silk. 30. The pharmaceutical dosage form as described in item 25 of the scope of patent application, wherein the amount of beclofen is about 40 male silk. 31. The pharmaceutical dosage form according to any one of claims 6, 1, 3, 18, or 19 in the scope of patent application, wherein beclofen is formulated into an immediate-release bead and 71 200536523 A combination of controlled release beads. 3 2 · The pharmaceutical dosage form described in item 31 of the scope of patent application, the dosage form is a lozenge. 33. The pharmaceutical dosage form described in item 31 of the scope of patent application, wherein the dosage form is a capsule. 34. A pharmaceutical dosage form comprising an immediate-release component of fen and a casing-controlling-release component of beclofen, wherein the casing-control-release-containing component comprises a polymer from: cellulose acetate phthalate Formates, cellulose acetate metaesters, hydroxypropyl fluorenyl cellulose phthalates, polyethylene acetate, carboxymethyl ethyl cellulose, copolymerized methyl groups! In the group consisting of fluorenyl acrylate and mixtures thereof; and wherein, when the pharmaceutical dosage form is used orally, the average time when fasting, such as at least 80% of beclofen, is absorbed in the body is about 4.5 hours . 35. The pharmaceutical dosage form as described in item 34 of the scope of the patent application, wherein the polymer is a copolymerized methacrylic acid. 36. A pharmaceutical dosage form comprising an immediate-release component wherein the becloploline is a benzotripinene phthalate 3 dilute acid / • case, which is 3 to which the baker 72 200536523 lofen and a Becloprofen, a controlled-release component, wherein the controlled-release component comprises a matrix dosage form; and wherein, when the pharmaceutical dosage form is used in an oral form, at least 80% of the beclofen The average time at absorption is between about 3 and 4.5 hours. 73