HK1126394B - Solid oral pharmaceutical compositions for once daily dosing containing pregabalin, a matrix forming agent and a swelling agent - Google Patents

Description

Solid pharmaceutical composition comprising pregabalin, a matrix forming agent and a swelling agent and suitable for once daily oral administration

Technical Field

The present invention relates to a solid pharmaceutical composition containing pregabalin (pregabalin) suitable for once daily (QD) oral administration.

Background

Pregabalin or (S) - (+) -3-aminomethyl-5-methyl-hexanoic acid can bind to the α -2- δ (α 2 δ) subunit of calcium channels and are involved in the endogenous inhibitory neurotransmitter γ -aminobutyric acid (GABA) associated with the regulation of neuronal activity in the brain. As described in U.S. patent No. 5,563,175 to r.b. silverman et al, pregabalin has anti-seizure activity and is useful in the treatment of the following conditions: epilepsy, pain, physiological disorders associated with psychomotor stimuli, inflammation, gastrointestinal injury, alcoholism, insomnia, fibromyalgia, and various psychiatric disorders including anxiety, depression, mania, and bipolar disorder. Pregabalin has been approved in the united states for the treatment of diabetic peripheral neuropathy, post-herpetic neuralgia, and as an adjunct treatment in adult partial seizures. Pregabalin may be used as an Immediate Release (IR) formulation in a capsule and administered to a patient 2 or 3 times daily (BID or TID).

Many patients receiving 2 or more daily doses of pregabalin or other drugs will likely benefit from taking the drug once daily. The convenience of QD dosing generally improves patient compliance, especially for elderly patients and patients taking multiple medications. The daily administration of the composition can also be used for reducing the highest blood (C) level_MAX) While reducing or avoiding potential, undesirable dose-related side effects, and also by increasing the minimum concentration (C) in plasma_MIN) Thereby increasing the efficacy of the medicine.

However, administering pregabalin once daily can suffer from a number of problems. For QD dosing, the compositions commonly used for Extended Release (ER) are problematic because pregabalin is not absorbed uniformly by the Gastrointestinal (GI) tract. Clinical studies have shown that pregabalin is absorbed in the small intestine and ascending colon of humans, but rarely outside the hepatic flexure of the colon. This means that the average absorption window (absorption window) of pregabalin is on average about 6 hours or less, and thus the drug released from a conventional ER dosage form (over 6 hours) is wasted because the dosage form has passed the colonic hepatic flexure. Furthermore, pregabalin is a gamma-amino acid that undergoes intramolecular cyclization under standard storage conditions to form the lactam, 4-isobutyl-pyrrolidin-2-one. See, for example, WO99/10186 and WO 99/59573 to A.Aomatsu. Although it is known that inactive components of pharmaceutical compositions may affect lactam formation, it is difficult to predict which type of excipient may lead to undesired lactam formation.

Disclosure of Invention

The present invention provides a stable pharmaceutical composition comprising pregabalin which is suitable for once daily oral administration. When administered in a solid dosage form, such as a tablet, the pharmaceutical composition is retained in the stomach for a longer time than an IR dosage form. The pharmaceutical composition can continuously release pregabalin when being retained in the stomach. Eventually, the pharmaceutical composition exits the stomach into the small intestine, where it sustains release of pregabalin. Extending the release time of pregabalin in the stomach effectively widens the absorption window associated with IR dosing, thereby allowing QD dosing. Furthermore, stability studies have shown that no individual component of the pharmaceutical composition contributes to the undesired formation of lactams.

In one aspect, the present invention provides a pharmaceutical composition suitable for QD administration and comprising an active pharmaceutical ingredient and an excipient. The active pharmaceutical ingredient comprises pregabalin or a pharmaceutically acceptable complex, salt, solvate or hydrate of pregabalin, and the excipient comprises a matrix forming agent and a swelling agent. The texturizing agent comprises polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP), and the swelling agent comprises cross-linked polyvinylpyrrolidone. Pharmaceutical compositions typically comprise from about 5% to about 60% by weight of the active pharmaceutical ingredient; the pharmaceutical composition typically comprises about 5% to about 45% by weight of a matrix forming agent; and the pharmaceutical composition typically comprises from about 5% to about 70% by weight of the swelling agent.

In another aspect of the invention there is provided a solid dosage form, such as a tablet, which is suitable for once daily oral administration. The solid dosage form comprises the pharmaceutical composition. Upon contact with water present in, for example, the gastric fluid of a human, the dosage form swells or expands to about 9 millimeters or more.

In another aspect, the invention provides a method of treating a condition or disorder in a patient responsive to pregabalin. The method comprises orally administering the above pharmaceutical composition to a patient once a day.

In another aspect, the invention provides a method of treating a condition or disorder in a patient responsive to pregabalin, the method comprising orally administering to the patient the pharmaceutical composition once daily. The pharmaceutical composition comprises pregabalin and one or more excipients. The composition is suitable for administration to a patient at any time within 24 hours to achieve a single steady state maximum concentration of pregabalin of 9 micrograms/ml or less and a steady state minimum concentration of pregabalin of about 0.7 micrograms/ml or more.

Detailed Description

Definitions and abbreviations

The following definitions are used herein unless otherwise stated.

"about," "about," and the like, when used in conjunction with a numerical variable, generally mean that the value of the variable and all values of the variable are within experimental error (e.g., within 95% confidence interval for the mean) or within ± 10% of the stated value, or more.

"patient" refers to a mammal, including a human.

"pharmaceutically acceptable" substances are those which are, within the scope of normal medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.

"therapeutic effect" generally refers to reversing, soothing, inhibiting the progression of, or preventing a condition or disorder in a patient, or preventing one or more symptoms of the condition or disorder in a patient.

"treatment" refers to the effect of "therapeutic effect" as defined above.

"agent," "drug," "active pharmaceutical ingredient," and the like refer to a compound (e.g., pregabalin) that can be used to treat a patient in need of treatment.

A "therapeutically effective amount" of an agent refers to an amount of the agent that can be used to treat a patient, which is generally in the range of about 0.001 to about 100 mg/kg/day, often in the range of about 0.1 to about 50 mg/kg/day for an adult. For adults, typical daily doses of drugs range from about 1 mg to about 1000 mg. In the case of pregabalin, the daily dose for an adult may be in the range of about 50 mg to about 1800 mg, often in the range of about 50 mg to about 900 mg.

An "inert" substance refers to a substance that can affect the bioavailability of a drug but that is otherwise not pharmaceutically active.

"excipient" or "adjuvant" refers to any inert substance.

"pharmaceutical composition" refers to a combination of one or more drugs and one or more excipients.

"pharmaceutical product", "pharmaceutical dosage form", "final dosage form" and the like refer to a pharmaceutical composition that is administered to a patient in need of treatment, which may generally be in the form of: tablets, capsules, sachets containing powders or granules, liquid solutions or suspensions, patches and the like.

"solvate" means a molecular complex comprising a drug (e.g., pregabalin) and a stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is intimately associated with the drug, the complex formed has a well-defined stoichiometry, independent of humidity. However, when the solvent has weak binding properties (as in channel solvates and hygroscopic compounds), the solvent content depends on humidity and drying conditions. In this case, the complex is usually non-stoichiometric.

"hydrate" means a solvate comprising a drug and either stoichiometric or non-stoichiometric amounts of water.

When used in conjunction with a pharmaceutical composition or dosage form, "retained in the stomach" means that at least a portion of the dosage form remains in the stomach of the patient after about 3 hours or more of oral administration, which is significantly longer than the average retention time of the corresponding IR dosage form. When retained in the stomach, the dosage form releases the drug continuously.

When used in conjunction with a pharmaceutical composition or dosage form, "release", "released", and the like, means that a portion of the drug leaves the dosage form after exposure to an aqueous environment. Unless otherwise stated, e.g. the United states Pharmacopeia, 28thRevision, Chapter 711, Second Supplement (8.1/2005 to 12.31/2005), the amount of drug released from the dosage form was measured by a dissolution test in water (37 ℃, initial pH 6.8, using device 2). The results of this dissolution test are reported as% release as a function of time, or time to release (t)_N) Wherein N is the% (w/w) of drug released or dissolved. For the purposes of this disclosure, a drug is released when at least 90% of the drug has been released from the dosage form (i.e., at t)₉₀Lower), the drug is completely released.

When compared to Pharmacokinetic (PK) parameters such as the lowest concentration (C) of drug in the patient's plasma_MIN) And maximum concentration (C)_MAX) "steady state" when used in conjunction with "steady state" refers to an approximately constant value of the PK parameter resulting from repeated administration of the dosage form at uniform dosing intervals. For dosage forms containing pregabalin, typically about 24 to 48 hours C after the first administration_MAXAnd C_MINA steady state value is reached.

A test dosage form is "bioequivalent" to a reference dosage form if the 90% confidence interval estimate of the ratio of the mean of the total exposure resulting from treatment with the test dosage form to the mean of the total exposure resulting from treatment with the reference dosage form is in the range of 80% to 125%. Herein, the ratio is expressed as a percentage (100% x test/reference) and the 90% confidence interval is expressed as a percentage of the reference mean. For single dose studies, total exposure is the area under the plasma concentration-time curve from time zero (time of administration) to time infinity; for steady state studies, total exposure is the area under the plasma concentration-time curve over the dosing interval. See U.S. department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, guide for Industry, Bioavailability and bioefficacy studios for Orallyadministered Drug Products-General Considerations (Rev.1, March 2003).

"Low soluble" materials are compounds that are classified as "poorly soluble", "slightly soluble", "minimally soluble", or "substantially insoluble", i.e., compounds having a solubility of from 1 part water to about 30-100 parts water, about 100-1,000 parts water, about 1,000-10,000 parts water, or about 10,000 or more parts water, respectively, when measured at room temperature and at a pH of 5 to 7.

Table 1 lists the abbreviations used throughout the specification.

TABLE 1 list of abbreviations

Description of abbreviations

ACN acetonitrile

API active pharmaceutical ingredient

aq aqueous

BID twice daily

CAP cellulose acetate phthalate

CAT cellulose acetate trimellitate

CEC carboxyethyl cellulose

CMC carboxymethyl cellulose

CMEC carboxymethyl ethyl cellulose

C_MAXMaximum concentration of API in patient plasma

C_MINAPI minimum concentration in patient plasma

dpm decay/min

EC ethyl cellulose

Extended ER release

Et₃N-Triethylamine

GABA gamma-aminobutyric acid

GI gastrointestinal tract

HDPE high density polyethylene

HEC hydroxyethyl cellulose

HPC hydroxypropyl cellulose

HPCAP hydroxypropyl cellulose acetate phthalate

HPCAS hydroxypropyl cellulose acetate succinate

HPLC high pressure liquid chromatography

HPMC hydroxypropyl methylcellulose

HPMCAP hydroxypropyl methylcellulose acetate phthalate

HMPCAS hydroxypropyl methylcellulose acetate succinate

HPMCAT hydroxypropyl cellulose acetate trimellitate

HPMCP hydroxypropyl methylcellulose phthalate

IR immediate Release

kp kilogram force

L, W, H, V length, width, height, volume

MC methyl cellulose

Me methyl group

Mn number average molecular weight

Mv intrinsic viscosity based molecular weight

Mw weight average molecular weight

number of n samples

PE polyethylene

PEG polyethylene glycol

PPG polypropylene glycol

PK pharmacokinetics

PVA polyvinyl alcohol

PVAc polyvinyl acetate

PVP polyvinylpyrrolidone

PVPP polyvinyl polypyrrolidone

QD once daily

Relative humidity of RH

rpm revolutions per minute

RT at room temperature, about 20 ℃ to 25 DEG C

s second

t_RRetention time of the dosage form in the stomach of a patient

t_NThe release (water dissolution) time of the drug of the dosage form, wherein N is the release%; n is not less than

90 corresponds to complete release

t_maxReaches C after application_MAXTime of

TID 3 times daily

USP United States Pharmacopeia (United States Pharmacopeia)

VA vinyl acetate

v/v volume/total volume X100%

w/v weight (g)/total volume (ml). times.100%

w/w weight (mass)/total weight (mass) × 100%

Any reference herein to temperature ranges, pH ranges, weight (mass) ranges, molecular weight ranges, percentage ranges, and the like, whether expressed using the phrases "range" or "respective ranges," includes the endpoints specified, as well as points between the endpoints.

As mentioned above, the dosed pharmaceutical composition comprises an Active Pharmaceutical Ingredient (API) and an excipient. The active pharmaceutical ingredient comprises pregabalin or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof. The API typically comprises from about 5% to about 60% by weight of the pharmaceutical composition, which typically corresponds to a solid dosage form (e.g., tablet) containing from about 50 mg to about 600 mg of pregabalin. In addition to pregabalin, other useful active pharmaceutical ingredients may include those having similar half-life (e.g., about 9 hours or less) and absorption characteristics in the GI tract.

Pregabalin can be made using known methods. In some of these processes, a racemic mixture of 3-aminomethyl-5-methyl-hexanoic acid is synthesized and then resolved into the R-and S-enantiomers. This method is described in the following patents: U.S. patent No. 5,563,175 to silverman et al; U.S. patent 6,046,353 to t.m. grote et al; U.S. patent 5,840,956 to t.m. grote et al; U.S. Pat. No. 5,637,767 to t.m. grote et al; huckabee & d.m. sobieray, U.S. patent 5,629,447, and b.k.huckabee & d.m. sobieray, U.S. patent 5,616,793. In each process, the racemate is reacted with a chiral acid (resolving agent) to form a pair of diastereomeric salts, which can be separated by known techniques such as fractional crystallization and chromatography. In other methods, pregabalin is synthesized directly using a chiral adjuvant, (4R, 5S) -4-methyl-5-phenyl-2-oxazolidinone. See, for example, U.S. patents 6,359,169, 6,028,214, 5,847,151, 5,710,304, 5,684,189, 5,608,090, and 5,599,973 to Silverman et al. In another method, a chiral cyano precursor of (S) -3-aminomethyl-5-methylhexanoic acid is made by asymmetric hydrogenation of a cyano-substituted olefin, followed by reduction to produce pregabalin. See U.S. patent application 2003/0212290A1 to Burk et al.

The pharmaceutical compositions may take any pharmaceutically acceptable form of pregabalin, including the free form (zwitterion) and pharmaceutically acceptable complexes, salts, solvates, hydrates and polymorphs thereof. Salts include, but are not limited to, acid addition salts and base addition salts, including hemisalts. Pharmaceutically acceptable acid addition salts may include: non-toxic salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like; and nontoxic salts derived from organic acids such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkane dicarboxylic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Potentially useful salts include acetate, aspartate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, pyrosulfate, bisulfite, sulfite, borate, camphorsulfonate, caprylate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, salicylate (hibenzate), hydrochloride, chloride, hydrobromide, bromide, hydroiodide, iodide, isethionate, isobutyrate, lactate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthenate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, methyl benzoate, di-or tri-ethylsulfonate, di-or tri-alkylbenzenesulfonate, Palmitate, pamoate (pamoate), phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, terephthalate, propionate, glucarate, sebacate, stearate, suberate, succinate, tartrate, tosylate, trifluoroacetate, and the like.

Pharmaceutically acceptable base salts can include non-toxic salts derived from bases including metal cations, such as alkali metal cations or alkaline earth metal cations, and amines. Examples of potentially useful salts include, but are not limited to: aluminum salt, arginine salt, N' -dibenzylethylenediamine salt, calcium salt, chloroprocaine (chloroprocaine) salt, choline salt, diethanolamine salt, diethylamine salt, dicyclohexylamine salt, ethylenediamine salt, glycine salt, lysine salt, magnesium salt, N-methylglucamine salt, hydramine salt (olamine), potassium salt, procaine salt, sodium salt, tromethamine (tromethamine) salt, zinc salt, and the like. For a discussion of useful acid and base addition salts, see s.m. berge et al, J of pharm. sci., 66: 1-19 (1977); see also Stahl and Wermuth, Handbook of pharmaceutical Salts: properties, Selection, and Use (2002).

A pharmaceutically acceptable salt of pregabalin can be made by: reacting the free (or zwitterionic) form with the desired acid or base; removing an acid-or base-labile protecting group from a suitable precursor of pregabalin; opening a suitable ring system (lactam) precursor using the desired acid or base; or one salt of pregabalin is converted to another by reacting it with a suitable acid or base or by contacting it with a suitable ion exchange column. All of these transformations are generally carried out in a solvent. The salt formed may be precipitated and collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization of the resulting salt varied from being fully ionized to being barely ionized.

Pregabalin may exist in unsolvated and solvated forms (including hydrates) and in other multicomponent complexes where the drug and at least one additional component are present in stoichiometric or non-stoichiometric amounts. Multicomponent complexes (other than salts and solvates) include clathrates (drug-host inclusion complexes) and pharmaceutical co-crystals. The latter is defined as a crystalline complex of neutral molecular components held together by non-covalent interactions. The co-crystals can be made by the following process: a melt crystallization method; by solvent recrystallization or by physical milling of the components together. See, e.g., o.almarson & m.j.zaworotko, chem.comm.1889-1896 (2004). For a general review of multicomponent complexes, see j.k.haleblian, j.pharm.sci.64 (8): 1269-88(1975).

Useful forms of pregabalin include various polymorphs and crystals of pregabalin, the enantiomeric R-enantiomer of pregabalin, and various mixtures of pregabalin and the R-enantiomer, including racemic mixtures of pregabalin and the R-enantiomer.

In addition, the pharmaceutical composition may use a prodrug of pregabalin. Such Prodrugs can be made by replacing the appropriate functional group of pregabalin with a functional group known as the "pro-fragment" as described, for example, in Design of produgs (1985) by h. Thus, examples of prodrugs may include derivatives of pregabalin in which an ester group is substituted for a carboxylic acid group, or an amide group is substituted for an amino group.

Useful forms of pregabalin may also include compounds labeled with a pharmaceutically acceptable isotope in which one or more atoms are replaced by an atom having the same atomic mass or mass number as the atom in which it is the majority of atoms in nature, but an atomic mass or mass number different from the atomic mass or mass number of the atom in which it is the majority of atoms in nature. Examples of isotopes suitable for inclusion in pregabalin include the hydrogen isotope(s) ((R))²H and³H) carbon isotope (c)¹¹C、¹³C and¹⁴C) and isotopes of nitrogen (¹³N and¹⁵n). Isotopically labeled forms of pregabalin can generally be prepared by techniques known to those skilled in the art.

In addition to the API, the pharmaceutical composition includes various excipients (including a matrix forming agent and a swelling agent). For oral solid dosage forms (e.g., tablets), the matrix-forming agent may provide structural integrity and help control or prolong the rate of drug release and other functions. The pharmaceutical composition may comprise from about 5% to about 45%, typically from about 20% to about 35% by weight of matrix forming agent.

Useful matrix forming agents include physical mixtures of polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP). Polyvinylpyrrolidone (PVP), also known as povidone or povidone, is a homopolymer of 1-vinyl-pyrrolidin-2-one, typically having a molecular weight Mw of about 1X 10³To about 1X 10⁷About 2.5X 10³To about 3X 10⁶Or about 1X 10⁴To about 1X 10⁵. Polyvinylpyrrolidone is available from BASF under the trade nameAvailable from ISP under the trade name ofPolyvinyl acetate (PVAc) is a homopolymer of vinyl acetate, typically having a molecular weight (Mw) of about 1X 10⁵To about 1X 10⁶. The matrix forming agent may comprise from about 0 wt% to about 90 wt% PVAc, from about 20 wt% to about 90 wt% PVAc, from about 40 wt% to about 90 wt% PVAc, from about 60 wt% to about 90 wt% PVAc, from about 70 wt% to about 90 wt% PVAc, or from about 80 wt% to about 90 wt% PVAc, based on the total weight of PVAc and PVP. In some cases, the matrix forming agent comprises about 70 wt.% to about 85 wt.% PVAc, based on the total weight of PVAc and PVP. Useful matrix forming agents are available from BSAF under the trade name BSAFAn 80/19(w/w) mixture of nominal PVAc and PVP.

The pharmaceutical composition includes other excipients, including swelling agents. As the name suggests, swelling agents may absorb water from the gastric fluid, thereby causing the size of the solid dosage form to expand, and may also affect the drug release rate by, for example, creating channels or by forming hydrocolloids. The swelling agent is soluble or insoluble in water. The pharmaceutical composition may comprise from about 5% to about 70%, from about 10% to about 70%, or from about 15% to about 70% by weight of the swelling agent. In some cases, the pharmaceutical composition may comprise from about 10% to about 55%, from about 20% to about 55%, or from about 30% to about 55% by weight of the swelling agent.

Useful swelling agents include crosslinked homopolymers of 1-vinyl-pyrrolidin-2-one, also known as crospovidone, and polyvinylpolypyrrolidone (PVPP). Cross-linked polyvinylpyrrolidone is insoluble in water and is available from BASF under the trade nameAndand is available from ISP under the trade nameAnd

in addition to crosslinked polyvinylpyrrolidone, swelling agents may include polyethylene oxide (PEO), also known as polyethylene oxide (polyoxirane) and polyethylene oxide (polyoxyyethylene). Polyethylene oxide is a homopolymer of ethylene oxide, typically having a molecular weight (Mw) of about 1X 10⁵To about 1X 10⁷Or about 1X 10⁶To about 1X 10⁷. Polyethylene oxides are available in various grades according to molecular weight from Union carbide under the trade name Union carbideWhen used in combination with crosslinked polyvinylpyrrolidone, the pharmaceutical composition typically comprises from about 5% to about 35% or from about 10% to about 25% by weight of PEO, and the pharmaceutical composition typically comprises from about 10% to about 35% or from about 20% to about 30% by weight of crosslinked polyvinylpyrrolidone.

In addition to the matrix forming agent and the swelling agent, the pharmaceutical composition may optionally include a gelling agent that modifies (e.g., prolongs) the drug release profile of the dosage form. Gelling agents, also known as hydrocolloids, include synthetic and natural polymers that generally have low water solubility (e.g., are slightly to poorly soluble). When contacted with water, the gel forms a viscous mixture (having a viscosity greater than water) that retards the diffusion of the drug through the dosage form, thereby prolonging the time over which the drug is released from the dosage form. The gelling agent is typically present in an amount of about 0% to about 25%, about 5% to about 25%, or about 5% to about 20% by weight, based on the weight of the pharmaceutical composition. Useful gelling agents include carbomers, polysaccharides, or both.

Carbomers are polymers of acrylic acid, crosslinked with allyl ethers of allyl sucrose or pentaerythritol, and are also referred to in various instances as carboxypolymethylene polymers, polyacrylic acid, and carboxyvinyl polymers. The carbomer has from about 56% to about 68% carboxyl segments on a dry basis and a number average molecular weight of about 1X 10⁵To about 1X 10¹⁰Or about 7X 10⁵To about 4X 10⁹. Carbomer is available from RITA under the trade name RITAAvailable from Noveon under the trade nameAnd

representative polysaccharides include xanthan gum, inulin, guar gum, chitosan, carob gum and carrageenan, which may be used alone or in combination. Xanthan gum, also known as corn gum, has a molecular weight (Mw) of about 2X 10⁶The polysaccharide of (4). The polymer consists of individual β -D-glucose fragment backbones linked by (1 → 4) glycosidic linkages and trisaccharide side chains linked to alternating glucopyranose fragments. Each side ofThe chain is composed of a β -D-glucuronic acid fragment linked to a β -D-mannose fragment and an α -D-mannose fragment through (1 → 4) and (1 → 2) glycosidic bonds, respectively. The α -D-mannose fragment is linked to the backbone via a (1 → 3) glycosidic bond, and the majority of the terminal β -D-mannose fragment is linked to the pyruvate fragment. Xanthan gum is usually prepared as a sodium, potassium or calcium salt and is available in various grades having different particle sizes, available from CP Kelco under the trade name CP KelcoAndavailable from Rhodia under the trade name RhodiaAnd is available under the trade name r.t. vanderbilt Company, Inc

Inulin, also known as oligofructose and polyfructose, is a class of natural polysaccharides consisting of a linear chain of β -D-fructose segments linked by (2 → 1) glycosidic bonds, the molecules being generally capped with glucose molecules. The number of D-fructose fragments ranges from 2 to about 140, usually from about 25 to about 30. Inulin is available from Sensus Operations CV under the trade name

Guar gums, also known as guar galactomannans, guar flour and Jaguar gum (jaguargum), have a molecular weight (Mw) of about 2X 10⁵The hydrophilic colloidal polysaccharide of (1). Guar gum consists of a linear chain of β -D-mannose segments linked by (1 → 4) glycosidic linkages, and has a monosaccharide side chain consisting of an α -D-galactose segment linked to a glucopyranose segment by a (1 → 6) glycosidic linkage. The ratio of β -D-mannose fragments to α -D-galactose fragments is generally in the range of about 1: 1.4 to about 1: 2, number averageThe quantum is usually about 2X 10⁵. Guar gum is derived from natural sources, and synthetic derivatives are also available, including guar acetate, guar phthalate, guar acetate phthalate, guar gum oxide, and sodium carboxymethyl guar. Gum is available in a variety of particle sizes and is available from Aqualon under the trade name AqualonAvailable from Danisco under the trade name DaniscoAnd MEYPRODOR.

Chitosan has a variety of names including chitosan hydrochloride, chitosani hydrochloridum, deacetylated chitin (chitin), deacylated chitin, poly- β - (1, 4) -2-amino-2-deoxy-D-glucose, 2-amino-2-deoxy- (1, 4) - β -D-glucopyranose, β -1, 4-poly-D-glucosamine, poly-D-glucosamine and poly- (1, 4- β -D-glucopyranose). Chitosan is a polysaccharide insoluble in water and is composed of a copolymer of beta-D-glucosamine and N-acetyl-beta-D-glucosamine, wherein the copolymer is prepared by deacetylation and depolymerization of chitin. The degree of deacetylation and depolymerization varies depending on the manufacturer, but the degree of deacetylation is usually about 80% or more, and the number average molecular weight is usually about 1X 10⁴To about 1X 10⁶。

Carob gum is a natural polysaccharide, also known as locust bean gum, locust bean powder, locust bean gum, shishire (Cheshire) gum, carob gum, and st. Like guar gum, carob bean is a galactomannan. The carob bean is composed of a backbone of β -D-mannose fragments linked by (1 → 4) glycosidic linkages, and comprises side chains combined from a single β -D-galactose fragment linked to every 4 th or 5 th D-mannopyranose by a (1 → 6) glycosidic linkage. The carob bean has a molecular weight (Mw) of about 5 × 10⁴To about 3X 10⁶And can be obtained in various particle sizes, and can be obtainedFrom Danisco under the trade nameAnd

carrageenans, also known as irish seaweed extract and irish moss extract, are hydrophilic colloidal polysaccharides consisting essentially of potassium D-galactosyl sulfate, sodium sulfate, calcium sulfate, magnesium sulfate or ammonium sulfate and 3, 6-anhydro-D-galactose copolymers. The pyranose fragments are linked by alternating alpha (1 → 3) and beta (1 → 4) glycosidic linkages. There are at least 3 types of carrageenan, which are known as lambda carrageenan, iota carrageenan and kappa carrageenan, these 3 carrageenans being distinguished by the content of sulfate esters and 3, 6-anhydrous pyranoid galactose fragments. Lambda-carrageenan is a non-gelling polymer containing about 35% by weight sulfate groups and no 3, 6-anhydrogalactose segments; iota carrageenan is a gel polymer containing 32% by weight sulfate groups and about 30% 3, 6-anhydrogalactose fragments; while kappa carrageenan is a relatively strong (i.e., non-elastomeric, brittle, or hard) gel polymer containing about 25% by weight sulfate segments and about 34% 3, 6-anhydrogalactose segments. Carrageenan is available in a variety of grades based on gel type, aqueous solubility and viscosity when mixed with water, available from FMC corporation under the trade name ofAnd

other useful polysaccharides include cellulosic derivatives that are water soluble over at least a portion of the pH range of 1 to 8. Useful polymers therefore include ionizable and non-ionizable cellulosic polymers, including those having ether or ester substituents or both ether and ester substituents and copolymers thereof, including so-called "enteric" and "non-enteric" polymers.

Examples of ionic cellulosic polymers include carboxymethyl cellulose (CMC) and its sodium or calcium salts; carboxyethyl cellulose (CEC); carboxymethyl ethyl cellulose (CMEC); hydroxyethyl methyl cellulose acetate phthalate; hydroxyethyl methyl cellulose acetate succinate; hydroxypropyl methylcellulose phthalate (HPMCP); hydroxypropyl methylcellulose succinate; hydroxypropyl cellulose acetate phthalate (HPCAP); hydroxypropyl cellulose acetate succinate (HPCAS); hydroxypropyl methylcellulose acetate phthalate (HPMCAP); hydroxypropyl methyl cellulose acetate succinate (HPMCAS); hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT); butyrate hydroxypropyl cellulose phthalate; carboxymethyl ethyl cellulose and its sodium salt; cellulose Acetate Phthalate (CAP); methyl cellulose acetate phthalate; cellulose acetate benzoate (CAT); cellulose acetate terephthalate; cellulose acetate isophthalate; cellulose propionate phthalate; cellulose propionate trimellitate; cellulose butyrate benzenetricarboxylate; and mixtures thereof. These ionic cellulose polymers are available from a number of commercial suppliers. For example, CMC sodium is available from Hercules under the trade name of carboxymethyl substitution (e.g., about 0.7 to about 1.2) in various grades based on particle size and anhydrous glucose unitAnd

examples of nonionic cellulose include Methyl Cellulose (MC); ethyl Cellulose (EC); hydroxyethyl cellulose (HEC); hydroxypropyl cellulose (HPC); hydroxypropylmethylcellulose (HPMC); hydroxypropyl methylcellulose acetate; hydroxyethyl methyl cellulose; hydroxyethyl cellulose acetate; hydroxyethyl ethyl cellulose; and mixtures thereof. The nonionic cellulosic materials can be obtained from various suppliersIs of industrial origin. For example, MC is available from Dow Chemical Company under the trade nameWherein each anhydroglucose unit has from about 27.5% to about 31.5% methoxy (by weight); HPC may have a molecular weight of about 8X 10⁴To about 1.2X 10⁶Grades in the (Mw) range (e.g., EF, EXF, LF, JF, GF, MF, HF, and HXF) are available from Hercules under the trade nameHEC can be present at a molecular weight of about 9X 10⁴To about 1.3X 10⁶(Mv) grades (e.g., L, G, M, H, H and HHX) available from Hercules under the trade name HerculesHPMC is available from Hercules under the trade name of MP843, MP814, MP824, MP844 and MP874 in various grades based on aqueous viscosityAnd are available from the Dow Chemical Company under the trade name of E, F, J, K and 310 in various grades (e.g., E, F, J, K and 310) having about 18% to about 29% methoxy groups (by weight) and about 5% to about 27% 2-hydroxypropoxy groups (by weight), respectively, per anhydroglucose unit

The pharmaceutical composition may optionally include one or more lubricants to aid in various processing steps including component mixing and tableting. When present, the pharmaceutical compositions typically comprise from about 0.5% to about 2% (by weight) of a lubricant. Representative lubricants include talc, stearic acid and its metal salts, including calcium stearate, magnesium stearate, and zinc stearate; stearic acid esters, including polyoxyethylene stearate, glyceryl monostearate, and palm stearinGlycerides of acids and the like; glyceryl behenate (e.g. glycerol behenate)Available from Gattefosse Inc.), sodium lauryl sulfate, hydrogenated vegetable oil, mineral oil, poloxamer (a copolymer of ethylene oxide and propylene oxide), polyethylene glycol, sodium chloride, and mixtures thereof.

The pharmaceutical composition may include other excipients, such as diluents or fillers, in an amount of about 0% to about 30% by weight of the composition. Diluents can improve the flow characteristics of the pharmaceutical composition and can enhance the physical properties of the tablet, such as increased compression strength or hardness, reduced friability, etc., during mixing and tableting of the components. Representative diluents include monosaccharides, disaccharides, polyhydric alcohols, and mixtures thereof, such as dextrose, lactose monohydrate, spray-dried lactose monohydrate, anhydrous lactose, sucrose, mannitol, spray-dried mannitol, xylitol, and sorbitol. Other useful diluents may include microcrystalline cellulose, starch, pregelatinized starch, calcium phosphate dihydrate, anhydrous dibasic calcium phosphate, and mixtures thereof.

To prepare a pharmaceutical product, the components of the pharmaceutical composition are typically dry blended using, for example, a V-cone blender. The resulting mixture is then compacted in a press to produce individual (unit) dosage forms (tablets). To improve the homogeneity of the product, the components can be combined and mixed in stages. For example, the API is granulated with one or more components by a fluid bed or extrusion granulation process and then mixed with the remaining components. Similarly, the API may be first dry blended with one or more matrix-forming agents and then blended with other excipients, such as swelling agents, gelling agents, diluents, lubricants, and the like, in one or more blending operations. The size of one or more of the components is controlled, if desired, by sieving or grinding or both prior to mixing. To prepare the final drug product, the compressed dosage form may be subjected to further processing, such as polishing, film coating, and the like. For a discussion of dry and wet and dry granulation, grinding, screening, tableting, film coating and other techniques for preparing pharmaceutical products, see a.r. gennaro (ed.), Remington: the Science and Practice of Pharmacy (20 th edition, 2000); lieberman et al (ed.), Pharmaceutical document Forms: tbablets, Vol.1-3 (2 nd edition, 1990); and D.K.Parikh & C.K.Parikh, Handbook of Pharmaceutical Granulation Technology, Vol.81 (1997).

The pharmaceutical composition is ingested in its entirety and begins to swell or expand when it contacts the gastric fluid (water) in the stomach of a patient. The dosage form may have any shape, including a circular or oval tablet, which is defined by a pair of circular or oval convex or planar surfaces (connected by a continuous, substantially flat side surface); a polygonal (e.g., triangular, quadrilateral, pentagonal, hexagonal, etc.) tablet having rounded corners and edges and defined by a pair of convex or planar polygonal surfaces (e.g., triangular, quadrilateral, pentagonal, hexagonal, etc.) connected by substantially planar side surfaces; and cylindrical tablets having hemispherical or semi-ellipsoidal ends and a circular or elliptical cross-section.

The QD dosage form may be retained in the stomach by size exclusion, by taking meals, by taking medications before sleep, and by some combination of these methods. For retention by size exclusion only, the dosage form expands to a certain size, preventing it from exiting the stomach via the pylorus. Since the average diameter of the pylorus in an adult human is about 13 mm, the size of the dosage form after expansion ranges from about 13 mm to about 20 mm or more, from about 15 mm to about 20 mm or more, or from about 17 mm to about 20 mm or more. As used herein, the "size" of the dosage form corresponds to the longest linear dimension of the cross-section of the dosage form having the smallest area. For example, a circular tablet has a size corresponding to its diameter, while a cylindrical tablet has a size corresponding to the diameter of its circular cross-section or the major axis of its oval cross-section.

To achieve QD dosing, the dosage form is retained in the stomach for several hours (e.g., t)_R≧ 3, 4, 5, or 6 hours) and for a long time (e.g., t)₉₀> 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 hours) to release pregabalin. The residence time of the dosage form in the patient's stomach is generally about 3Hour to about 11 hours (3 ≦ t)_R11 ≦ 6), from about 6 hours to about 14 hours (6 ≦ t)_R14) or from about 8 hours to about 14 hours (8. ltoreq. t)_R14) for about 12 hours to about 16 hours (12. ltoreq. t)₉₀16) for about 12 hours to about 18 hours (12. ltoreq. t)₉₀18) for about 12 hours to about 20 hours (12. ltoreq. t)₉₀20 ≦ 20), from about 14 hours to about 20 hours (14 ≦ t)₉₀20) or from about 16 hours to about 20 hours (16. ltoreq. t)₉₀Less than or equal to 20) releases pregabalin. As described in the PK simulations in the examples below, QD dosage forms that release pregabalin for a period of about 4 to about 6 hours longer than the time that the dosage form resides in the stomach appear to minimize variability from patient to patient.

Since eating may retard gastric emptying and sleep may reduce GI motility, the dosage form may be administered once daily after a meal or before sleep (e.g., during about an hour of sleep). To take advantage of both effects and further prolong drug release, the QD dosage form may be taken after the last meal before bedtime (e.g., after a evening meal). For QD dosage forms taken at or before meal or taken at or during meal and before sleep, little size-exclusion dosage form is required to be retained in the stomach. In these cases, for example, the size of the dosage form after expansion may be about 9 millimeters or more.

Steady state C of QD dosage forms at any time during the day_MAXSteady state C of corresponding API immediate release formulations that are administered nearly equal to or less than 2-or 3 times daily_MAX. Likewise, ideally QD, steady state C of the formulation_MINSteady state C of IR formulations almost equal to or greater than 2-or 3-times daily_MIN. The IR formulation containing 300 mg of pregabalin ingested twice daily has an average steady state C of about 8.9 micrograms/ml_MAXAnd a mean steady state C of about 2.8. mu.g/ml_MINWhereas an IR formulation containing 150 mg pregabalin taken twice daily has an average steady state C of about 4.4 micrograms/ml_MAXAnd a mean steady state C of about 1.4. mu.g/ml_MIN. QD formulations containing pregabalin may desirably achieve an average steady state C of about 9 micrograms/ml or less_MAXAnd about 0Average steady state C of 7. mu.g/ml or more_MIN。

Examples of the invention

The following examples are given for illustration and not for limitation. The following procedures measure drug release (water solubility), swelling, rigidity and stability of the drug as a function of time, unless otherwise stated.

Solubility of drug

The amount of API released by a drug sample immersed in an aqueous dissolution medium at 37 ℃ (0.06N HCl or 0.5M acetate buffer) was determined using USP Apparatus 2 (stir plate) or Apparatus 3 (reciprocating drum) operating at 50rpm or 5dpm, respectively. Samples of the dissolution medium (1 ml) were taken, typically at 1, 2, 4, 6, 9, 12, 16 and 24 hours, and analyzed by HPLC under the following conditions: column: zorbax SB-CN, 150 mm x 4.6 mm, 5 micron particle size; column temperature: 23 ℃; detector wavelength: 210 nanometers; flow rate 1 ml/min; injection volume: 25 microliter; mobile phase composition: 0.05M sulfonic acid/Hexane and 2 mL Et₃N; the pH was adjusted to 3.1 using orthophosphoric acid: ACN (880: 130); the operation time is as follows: for 8 minutes.

Swelling Property of drug

The increase in drug size over time after immersion in 0.06N HCl aqueous dissolution medium was determined using USP Apparatus 2 (stir plate). Periodically, a sample of the drug is removed from the dissolution medium and its diameter is measured using a caliper.

Rigidity of medicine

The drug samples were placed in USP Apparatus 2 (stir plate) containing 0.06N HCl aqueous dissolution medium. Drug samples were periodically taken and their stiffness was measured using a texture analyzer (TA132) under the following set conditions: a 5kg load cell; TA-81/4 "ball probe; 0.5 grams of trigger force; 0.2 mm/sec test speed; 10 points/second acquisition rate; a distance of 10 mm.

Stability of drug

The stability test was performed by placing the drug samples in open HDPE bottles or induction sealed HDPE bottles and storing at 40 ℃ and 75% relative humidity. At different time intervals, e.g. every 2 weeks for initial screening, and every 3 weeks, 6 weeks or 3 months for subsequent testing, drug samples were removed and analyzed for pregabalin content (%, w/w) and lactam content (% wt lactam/initial weight of pregabalin) using HPLC.

Examples 1 to 11

Tables 2 and 3 show the compositions of the laboratory scale batches (25 grams) containing pregabalin and various excipients; tables 4 and 5 show the drug release results as a function of time. For each formulation, all tablet components except magnesium stearate were includedBlending in a mixer for about 15 minutes to make the pharmaceutical product. Magnesium stearate was passed through a #20 standard sieve and was mixed with a spatulaThe contents of the mixer were combined. Then is atThe resulting crude blend was mixed in a mixer for 4 minutes to obtain the final blend. 3000 pounds (examples 1 to 5) or 2000 pounds (examples 6 to 11) of pressure and 0.1 minute off-pressure time were used, respectivelyEach final blend was compacted in a press to give tablets having an average hardness value of about 30kp and nominal tablet weights of 1 gram and 1.125 grams. For some formulations (examples 1 to 5), pregabalin was employed by a high shear granulatorCoated and then blended with other excipients.

Examples 12 to 14

Table 6 shows the compositions of the lab scale batches (100 grams) containing pregabalin and excipients; table 7 shows the drug release results as a function of time. For each composition, pregabalin and pregabalin were first combined in an extruder-granulatorAnd making into medicine. The remaining tablet components, except magnesium stearate, were blended with the formed pregabalin granules in a 1-pint V-blender for about 15 minutes. Magnesium stearate was passed through a #20 standard sieve and combined with the contents of the V-blender using a spatula. The resulting crude blend was then mixed in a V-blender for 4 minutes to obtain the final mixture. Using simulationsPressing machine (i.e. the press machineCompaction simulator) each final blend was compressed using an average pressure of about 21kN and an average residence time of 12 milliseconds. The tablet has an average hardness of about 20kp and a nominal tablet weight of about 1 gram.

Examples 15 to 23

Table 8 shows the compositions of the lab scale batches containing pregabalin and excipients; table 9 shows lactam formation as a function of time. Each formulation was made using a method similar to examples 12 to 14 above.

Examples 24 to 30

Table 10 shows the compositions of the lab scale batches containing pregabalin and excipients; table 11 shows drug release as a function of time; tables 12 and 13 show the change in tablet expansion and tablet rigidity after immersion in aqueous solution; table 14 shows the formation of lactam as a function of time. Pharmaceutical products of partial compositions (examples 25 to 29) were made using a method similar to examples 12 to 14.

The drug product of example 24 was prepared by blending all of the tablet components except magnesium stearate in a 16-quart V-blender for 15 minutes. Magnesium stearate was passed through a #30 standard sieve and combined with the contents of the V-blender using a spatula. The crude blend was then mixed in a V blender for an additional 5 minutes to obtain the final blend. In thatThe final blend was compressed using diamond (quadrilateral) dies (0.6299 "× 0.748", 0.700 "cup depth, 0.0040" flash face) and triangular dies (0.6665 "× 0.6906", 0.0600 "cup depth, 0.0040" flash face). For the diamond-shaped process, 10 tablets with an average tablet hardness of 8.6kp were obtained at a pre-compression setting of about 2.1kN and a lower main compression setting of about 36 kN. For the triangular process, 10 tablets with an average tablet hardness of 9.0kp were obtained at a pre-compression setting of about 2.2kN and a lower main compression setting of about 39.8 kN. The weight loss during the friability test was 0.3% and 0.2% for the diamond-shaped tablets and the triangular tablets, respectively.

Use ofThe tablet hardness of the resulting tablet (example 24) was substantially lower than the tablet produced in the previous example. Thus, the magnesium stearate content in the composition was reduced from 1% to 0.5% to improve the tablet hardness (example 30). A drug product was made in a similar manner to example 24, except that the batch was reduced from 4 kg to 2 kg and the blending time was reduced to 4 minutes after the magnesium stearate was added. In thatThe final blend was compressed using a triangular tool. Precompression at 2.8kNAt the force setting and lower main compression force setting of 41.5kN, the tablets had an average (n ═ 10) hardness of 15.2kp and a weight loss of 0% in the friability test. When the pre-compression force setting and the lower main compression force setting became 3.1kN and 33.2kN, respectively, the tablet had an average (n-10) hardness of 12.1kp and exhibited a weight loss of 0.07% in the friability test.

Example 31

Table 15 shows the simulated steady state lowest (C) in plasma for QD pharmaceutical compositions containing 600 mg pregabalin_MIN) And maximum (C)_MAX) Pregabalin concentration and relative to C_MAXTime of (d). The composition is retained in stomach t_R3, 5,8 or 10 hours, and total dissolution time t₁₀₀6, 8, 10, 12 or 16 hours. For comparison, table 15 shows the steady state PK parameters for an IR pharmaceutical composition containing 300 mg pregabalin taken twice daily.

PK simulations are based on QD dosage forms with the normalized dissolution profiles provided in table 16. Further, the PK simulations shown in table 15 employ the following assumptions: (1) for each simulation, the pharmaceutical composition may be retained in the stomach for a specific time (t)_R) (ii) a (2) The total effective absorption time (time window) was 6 hours (average absorption time window of the small intestine and time of ascending part of colon in stomach) plus t_R(ii) a (3) The absorption rate in the lower part of the small intestine is similar to that in the upper part; and (4) the effectiveness of the pharmaceutical composition when taken with food, taken at bedtime, or taken with food and taken at bedtime has no effect on the absorption rate. It has been demonstrated that food can delay t of IR formulations_maxBut does not affect the extent of absorption of the drug. However, sleep is likely to reduce the rate of drug absorption, and thus simulations may underestimate t_maxThe delay of (2).

As described above, the results in table 15 are based on the average absorption time window associated with 6 hours of the IR formulation, where PK profiles may differ for each patient receiving QD doses. Indeed, PK simulations for the following QD dosage forms indicate that t₁₀₀(or t)₉₀) Ratio t_RVariability between patients can be reduced by about 4 to 6 hours, and the QD dosage form contains 600 mg of pregabalin with a t of 12 hours₁₀₀And t of 5 hours_RWherein t is_RVarying between 3.4 hours and 7.7 hours.

Example 32

A single dose pharmacokinetic study was performed to evaluate the performance of the QD formulation of example 30. QD dosage forms are provided (1) in a fasted state, (2) after a high fat breakfast (morning treatment) and (3) after a high fat dinner (evening treatment) according to guidelines established by the united states food and Drug Administration. See U.S. department of Health and human services, Food and Drug Administration, Center for Drug Evaluation and research, guide for Industry, Food-Effect biology and FedBioavailability students (Decumber 2002). Herein, "high fat" means that 50% of the total calorie content in the diet comes from fat. The pharmacokinetic results of these 3 treatments were compared with those obtained with the same dose (300 mg) of an immediate release formulation (capsule) consisting of pregabalin, lactose monohydrate, corn starch and talc.

According to pregabalin C_MAXAnd t_maxThe value, relative to the IR capsule, for all 3 QD formulation treatments, the highest exposure was lower and occurred slower, which indicates a slower rate of absorption by the QD formulation. Mean t of QD formulations for fasting treatment_maxAbout 4 hours, compared to the average t of the IR capsules_maxMore than 2 times slower than 1.5 hours. T of QD formulation ingested after high fat diet_maxIncreased to about 10 hours (9.7 hours in the morning and 10.7 hours in the evening). The QD formulation for fasting treatment had a total pregabalin exposure that was less than half of the total pregabalin exposure of the IR capsule, based on the average area under the plasma concentration-time curve from time zero to time infinity. However, when the QD formulation was ingested after a high fat meal, the total pregabalin exposure for morning and evening treatments was similar to that from IR capsules. In thatUpon intake of QD formula after a high fat meal, the total exposure obtained was bioequivalent to the IR formulation and acceptable properties were obtained for once daily dosing.

It is noted that, as used in this specification and the appended claims, singular articles such as "a," "an," and "the" may refer to an object or objects unless the context clearly dictates otherwise. Thus, for example, a composition containing "a compound" can include one compound or 2 or more compounds.

It is to be understood that the above description is intended to be illustrative, and not restrictive. Many embodiments will be apparent to those of skill in the art upon reading the above description. The scope of the invention should, therefore, be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references, including patents, patent applications, and publications, are hereby incorporated by reference in their entirety.

TABLE 2 pharmaceutical compositions containing pregabalin (% w/w) -examples 1 to 5

TABLE 3 pharmaceutical compositions containing Pregabalin (% w/w) -examples 6 to 11

TABLE 4 Release of Pregabalin (% w/w) as a function of time (hours) -examples 1 to 5

The measurements were performed using a USP 3 apparatus containing 0.06N aqueous HCl at 37 ℃.

Each release data in examples 1-3 is an average of 2 samples; the release data for examples 4 and 5 are single sample values.

TABLE 5 Release of Pregabalin (% w/w) as a function of time (hours) -examples 6 to 11

The assay was performed at 37 ℃ using a buffer containing 0.05M aqueous acetate (pH 4.5). Each of the release data for examples 8-11 is an average of 2 specimens; the release data for examples 6 and 7 are for a single sample.

TABLE 6 pharmaceutical compositions containing pregabalin (% w/w) -examples 12 to 14

TABLE 7 Release of Pregabalin (% w/w) as a function of time (hours) -examples 12 to 14

The measurements were performed using a USP 3 apparatus containing 0.06N aqueous HCl at 37 ℃.

The release data for each of examples 12-14 is an average of 2 samples.

TABLE 8 pharmaceutical compositions containing Pregabalin (% w/w) -examples 15 to 23

TABLE 9 formation of lactam (%, lactam weight/initial weight of Pregabalin)

With the exception of example 19, which was stored in a closed vial, all samples were stored in an open vial at 40 ℃ at 75% RH.

TABLE 10 pharmaceutical compositions containing Pregabalin (% w/w) -examples 24 to 30

TABLE 11 Release of Pregabalin (% w/w) as a function of time (hours) -examples 24 to 30

The measurements were performed using a USP 2 apparatus containing 0.06N aqueous HCl at 37 ℃.

TABLE 12 tablet size (L, H, W in mm) and volume (V in mm)³Meter) as a function of time (hours) -example 24&30

TABLE 13 rigidity in g.mm as a function of time in hours examples 24&30

TABLE 14 Pregabalin (% w/w) and the corresponding lactam content (% based on the weight of Pregabalin) as a function of time-examples 25 to 30

TABLE 15 simulated steady state PK parameters for IR and QD dosage forms containing Pregabalin

1.C_MINOccurs before the next dose is administered (i.e., 12 and 24 hours after administration of the BID and QD dosage forms, respectively).

2. The time of administration of the last dose.

3. An IR formulation containing 300 mg pregabalin was administered twice daily.

4. QD formulations containing 600 mg pregabalin.

TABLE 16 amount of Pregabalin released from dosage forms as a function of time (normalization)

Time/t₁₀₀% w/w of dissolution

0.0 0

0.0658 21

0.132 32

0.263 47

0.526 68

0.789 85

1.0 100

Claims (11)

1. A pharmaceutical composition comprising 5 to 60% by weight of an active pharmaceutical ingredient comprising pregabalin or a pharmaceutically acceptable salt, or hydrate thereof, 5 to 45% by weight of a matrix forming agent comprising polyvinyl acetate and polyvinylpyrrolidone, and 5 to 70% by weight of a swelling agent comprising cross-linked polyvinylpyrrolidone, wherein the pharmaceutical composition is suitable for once daily oral administration.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition can expand to a size of 9 millimeters or more upon contact with water.

3. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is retained in the stomach of a patient for 3 to 14 hours after oral administration.

4. The pharmaceutical composition of claim 3, wherein the release time of the active pharmaceutical ingredient is 4 to 6 hours longer than the time the pharmaceutical composition is retained in the stomach of a patient after oral administration.

5. The pharmaceutical composition of claim 3, wherein the release time of the active pharmaceutical ingredient is within 12 hours to 20 hours.

6. The pharmaceutical composition of claim 3, wherein the active pharmaceutical ingredient has an in vivo steady state C of 9 micrograms/ml or less_MAXOr an in vivo steady state C of 0.7. mu.g/ml or more_MINOr an in vivo steady state C of 9. mu.g/ml or less_MAXAnd an in vivo steady state C of 0.7. mu.g/ml or more_MIN。

7. The pharmaceutical composition of claim 3, wherein the swelling agent further comprises polyethylene oxide.

8. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is bioequivalent to an immediate release formulation comprising pregabalin, lactose monohydrate, corn starch, and talc.

9. The pharmaceutical composition of claim 3, for use in treating a condition or disorder in a patient responsive to pregabalin.

10. The pharmaceutical composition of claim 9, wherein the condition or disorder is selected from epilepsy, pain, diabetic peripheral neuropathy, physiological disorders associated with psychomotor stimuli, inflammation, gastrointestinal damage, alcoholism, insomnia, anxiety, depression, mania, and bipolar disorder.

11. The pharmaceutical composition of claim 9, wherein the condition or disorder is selected from post-herpetic neuralgia and fibromyalgia.