US20070269511A1 - Solid pharmaceutical compositions containing pregabalin - Google Patents

Solid pharmaceutical compositions containing pregabalin Download PDF

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Publication number
US20070269511A1
US20070269511A1 US11/555,988 US55598806A US2007269511A1 US 20070269511 A1 US20070269511 A1 US 20070269511A1 US 55598806 A US55598806 A US 55598806A US 2007269511 A1 US2007269511 A1 US 2007269511A1
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United States
Prior art keywords
pharmaceutical composition
pregabalin
hours
state
active pharmaceutical
Prior art date
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Abandoned
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US11/555,988
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English (en)
Inventor
Howard Bockbrader
Yun Cho
Steven Diaz Santiago
Majid Mahjour
Thomas Reynolds
Pushpa Shao
Zezhi Shao
Jiansheng Wan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Warner Lambert Co LLC
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Warner Lambert Co LLC
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=37965070&utm_source=***_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20070269511(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to US11/555,988 priority Critical patent/US20070269511A1/en
Application filed by Warner Lambert Co LLC filed Critical Warner Lambert Co LLC
Publication of US20070269511A1 publication Critical patent/US20070269511A1/en
Priority to US13/267,352 priority patent/US20120029081A1/en
Priority to US13/472,704 priority patent/US20120232149A1/en
Priority to US13/706,971 priority patent/US20130102675A1/en
Priority to US13/947,433 priority patent/US20130303618A1/en
Priority to US14/181,785 priority patent/US8945620B2/en
Priority to US14/570,115 priority patent/US9144559B2/en
Priority to US14/831,205 priority patent/US20150352066A1/en
Priority to US15/074,042 priority patent/US20160250147A1/en
Priority to US15/418,907 priority patent/US20170136125A1/en
Priority to US15/686,549 priority patent/US10022447B2/en
Abandoned legal-status Critical Current

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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
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    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
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    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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    • A61K2039/541—Mucosal route
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Definitions

  • This invention relates to solid pharmaceutical compositions containing pregabalin which are suitable for once daily (QD) oral dosing.
  • Pregabalin or (S)-(+)-3-aminomethyl-5-methyl-hexanoic acid, binds to the alpha-2-delta ( ⁇ 2 ⁇ ) subunit of a calcium channel and is related to the endogenous inhibitory neurotransmitter ⁇ -aminobutyric acid (GABA), which is involved in the regulation of brain neuronal activity.
  • GABA endogenous inhibitory neurotransmitter ⁇ -aminobutyric acid
  • Pregabalin exhibits anti-seizure activity, as discussed in U.S. Pat. No. 5,563,175 to R. B.
  • Silverman et al. and is useful for treating, among other conditions, epilepsy, pain, physiological conditions associated with psychomotor stimulants, inflammation, gastrointestinal damage, alcoholism, insomnia, fibromyalgia, and various psychiatric disorders, including anxiety, depression, mania, and bipolar disorder.
  • pregabalin has been approved for the treatment of diabetic peripheral neuropathy, postherpetic neuralgia, and as an adjunctive treatment for partial onset seizures in adults.
  • Pregabalin is available as an immediate release (IR) formulation in capsules and is administered to patients two- or three-times daily (BID or TID).
  • IR immediate release
  • QD dosing generally improves patient compliance, especially for elderly patients and for patients taking multiple medications. Once per day dosing may also lessen or prevent potentially undesirable dose-related effects by reducing peak blood levels (C MAX ) and may also increase drug efficacy by increasing minimum plasma concentrations (C MIN ).
  • pregabalin Once daily dosing of pregabalin, however, presents numerous challenges.
  • Conventional extended release (ER) compositions are problematic for QD dosing because pregabalin is not absorbed uniformly in the gastrointestinal (GI) tract.
  • GI gastrointestinal
  • Clinical studies indicate that pregabalin is absorbed in the small intestine and the ascending colon in humans, but is poorly absorbed beyond the hepatic flexure. This suggests that the mean absorption window for pregabalin is, on average, about six hours or less—any drug release from a conventional ER dosage form beyond six hours would thus be wasted because the dosage form has traveled beyond the hepatic flexure.
  • pregabalin is a ⁇ -amino acid which under normal storage conditions may undergo intramolecular cyclization to form a lactam, 4-isobutyl-pyrrolidin-2-one. See, e.g., WO 99/10186 and WO 99/59573, both to A. Aomatsu. Although it is known that the non-active components of the pharmaceutical composition may affect lactam formation, it is difficult to predict which excipients may lead to undesirable lactam formation.
  • the present invention provides a stable pharmaceutical composition containing pregabalin that is useful for once daily oral dosing.
  • a solid dosage form such as a tablet
  • the pharmaceutical composition When administered as a solid dosage form, such as a tablet, the pharmaceutical composition is retained in the stomach for a longer period of time than an IR dosage form. While it is retained in the stomach, the pharmaceutical composition continuously releases pregabalin. Eventually, the pharmaceutical composition passes out of the stomach and into the small intestine where it may continue to release pregabalin. Extending the period of time during which pregabalin is released in the stomach effectively widens the absorption window associated with IR dosing, thereby permitting QD dosing. Furthermore, stability studies suggest that none of the components of the pharmaceutical composition promote undesirable lactam formation.
  • the active pharmaceutical ingredient includes pregabalin, or a pharmaceutically acceptable complex, salt, solvate or hydrate of pregabalin, and the excipients include a matrix forming agent and a swelling agent.
  • the matrix forming agent includes polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP), and the swelling agent includes cross-linked polyvinylpyrrolidone.
  • the active pharmaceutical ingredient typically comprises from about 5% to about 60% of the pharmaceutical composition by weight; the matrix forming agent typically comprises from about 5% to about 45% of the pharmaceutical composition by weight, and the swelling agent typically comprises from about 5% to about 70% of the pharmaceutical composition by weight.
  • a further aspect of the invention provides a solid dosage form, such as a tablet, which is adapted for once daily oral dosing.
  • the solid dosage form comprises the pharmaceutical composition described above.
  • water which is present, for example, in the gastric fluid of humans, the dosage form swells or expands to a size of about 9 mm or greater.
  • An additional aspect of the invention provides a method of treating a condition or disorder in a subject that is responsive to pregabalin.
  • the method includes orally administering to the subject once per day the pharmaceutical composition described above.
  • Another aspect of the invention provides a method of treating a condition or disorder in a subject that is responsive to pregabalin, the method comprising orally administering to the subject a pharmaceutical composition once daily.
  • the pharmaceutical composition comprises pregabalin and one or more excipients.
  • the composition is adapted to provide the subject in any 24-hour period with a single steady-state maximum pregabalin concentration of 9 ⁇ g/mL or less and a steady-state minimum pregabalin concentration of about 0.7 [g/mL or greater.
  • Subject refers to a mammal, including a human.
  • “Pharmaceutically acceptable” substances refers to those substances which are within the scope of sound medical judgment suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit-to-risk ratio, and effective for their intended use.
  • Treating generally refers to reversing, alleviating, inhibiting the progress of, or preventing a disorder or condition in a subject, or to preventing one or more symptoms of such disorder or condition in the subject.
  • Treatment refers to the act of “treating” as defined immediately above.
  • Drug “Drug,” “drug substance,” “active pharmaceutical ingredient,” and the like, refer to a compound (e.g., pregabalin) that may be used for treating a subject in need of treatment.
  • pregabalin a compound that may be used for treating a subject in need of treatment.
  • “Therapeutically effective amount” of a drug refers to the quantity of the drug that may be used for treating a subject and is generally in the range of about 0.001 to about 100 mg/kg/day for an adult, and is often in the range of about 0.1 to about 50 mg/kg/day for an adult.
  • a typical daily dose of a drug is in the range of about 1 mg to about 1000 mg.
  • the daily dose for an adult human may be in the range of about 50 mg to about 1800 mg and is often in the range of about 50 mg to about 900 mg.
  • “Inert” substances refer to those substances that may influence the bioavailability of the drug, but are otherwise pharmaceutically inactive.
  • Example or “adjuvant” refers to any inert substance.
  • “Pharmaceutical composition” refers to the combination of one or more drug substances and one or more excipients.
  • “Drug product,” “pharmaceutical dosage form,” “dosage form,” “final dosage form” and the like refer to a pharmaceutical composition that is administered to a subject in need of treatment and generally may be in the form of tablets, capsules, sachets containing powder or granules, liquid solutions or suspensions, patches, and the like.
  • Solvate describes a molecular complex comprising the drug substance (e.g., pregabalin) and a stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol).
  • the solvent When the solvent is tightly bound to the drug the resulting complex will have a well-defined stoichiometry that is independent of humidity.
  • the solvent when the solvent is weakly bound, as in channel solvates and hygroscopic compounds, the solvent content will be dependent on humidity and drying conditions. In such cases, the complex will often be non-stoichiometric.
  • “Hydrate” describes a solvate comprising the drug substance and a stoichiometric or non-stoichiometric amount of water.
  • “Retained in the stomach,” when used in connection with a pharmaceutical composition or dosage form, means that at least a portion of the dosage form remains in a subject's stomach following oral administration for about three or more hours, which is substantially longer than the average residence time of a corresponding IR dosage form. While it is retained in the stomach, the dosage form continuously releases the drug.
  • “Release,” “released,” and the like when used in connection with a pharmaceutical composition or dosage form, refers to the portion of the drug substance that leaves the dosage form following contact with an aqueous environment. Unless otherwise indicated, the quantity of drug released from a dosage form is measured by dissolution testing in water (37° C., initial pH of 6.8, using apparatus 2) as described the United States Pharmacopeia, 28th Revision, Chapter 711, Second Supplement, (Aug. 1, 2005 to Dec. 31, 2005). The results of the dissolution testing are reported as % (w/w) released as a function of time or as the release time, t N , where N is the % (w/w) of drug released or dissolved. For the purposes of this disclosure, complete drug release occurs when at least 90% of the drug has been released from the dosage form (i.e., at t 90 ).
  • Step-state when used in connection with pharmacokinetic (PK) parameters such as the minimum (C MIN ) and maximum (C MAX ) concentrations of the drug substance in the blood plasma of the subject, refers to the approximately constant values of the PK parameters that result from repeated administration of a dosage form at uniform dosing intervals.
  • PK pharmacokinetic
  • C MIN minimum
  • C MAX maximum
  • steady-state values of C MAX and C MIN usually occur about 24 to 48 hours following first administration.
  • a test dosage form is “bioequivalent” to a reference dosage form if the 90% confidence interval estimate for the ratio of the mean value of the total exposure from treatment with the test dosage form to the mean value of the total exposure from treatment with the reference dosage form lies within the range of 80% to 125%.
  • the ratio is expressed as a percentage (100% ⁇ testreference) and the 90% confidence interval is expressed as a percentage of the reference mean.
  • the total exposure is the area under the plasma concentration-time curve from time zero (time of dosing) to time infinity; for steady-state studies, the 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, Guidance for Industry, Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations (Rev. 1, March 2003).
  • “Poorly soluble” substances are those that are classified as “sparingly soluble,” “slightly soluble,” “very slightly soluble,” or “practically insoluble,” i.e., compounds having a solubility of one part of water to about 30-100 parts of water, about 100-1000 parts of water, about 1000-10,000 parts of water, or about 10,000 or greater parts of water, respectively, when measured at room temperature and a pH of 5 to 7.
  • N dosage form drug release (aqueous dissolution) time where N is % released; N ⁇ 90 corresponds to complete release t MAX time to reach C MAX following administration TID three times daily USP United States Pharmacopoeia VA vinylacetate v/v volume/total volume ⁇ 100, % w/v weight (g)/total volume (mL) ⁇ 100, % w/w weight (mass)/total weight (mass) ⁇ 100, %
  • any reference in this disclosure to a temperature range, a pH range, a weight (mass) range, a molecular weight range, a percent range, etc., whether expressly using the words “range” or “ranges,” includes the indicated endpoints and points between the end points.
  • the peroral pharmaceutical composition comprises an active pharmaceutical ingredient (API) and excipients.
  • the active pharmaceutical ingredient includes pregabalin or a pharmaceutically acceptable complex, salt, solvate or hydrate thereof.
  • the API generally comprises from about 5% to about 60% of the pharmaceutical composition by weight, which would typically correspond to a solid dosage form (e.g., tablet) that contains from about 50 mg to about 600 mg of pregabalin.
  • other useful active pharmaceutical ingredients may include those having a similar half-life (e.g., about 9 hours or less) and absorption characteristics in the GI tract.
  • Pregabalin may be prepared using known methods. In some of these methods, a racemic mixture of 3-aminomethyl-5-methyl-hexanoic acid is synthesized and subsequently resolved into its R- and S-enantiomers. Such methods are described in U.S. Pat. No. 5,563,175 to R. B. Silverman et al., U.S. Pat. No. 6,046,353 to T. M. Grote et al., U.S. Pat. No. 5,840,956 to T. M. Grote et al., U.S. Pat. No. 5,637,767 to T. M. Grote et al., U.S. Pat. No. 5,629,447 to B. K.
  • pregabalin is prepared via asymmetric hydrogenation of a cyano-substituted olefin to produce a chiral cyano precursor of (S)-3-aminomethyl-5-methyl hexanoic acid, which is subsequently reduced to yield pregabalin. See U.S. Patent Application 2003/0212290 A1 to Burk et al.
  • the pharmaceutical composition may employ any pharmaceutically acceptable form of pregabalin, including its free form (zwitterion), and its pharmaceutically acceptable complexes, salts, solvates, hydrates, and polymorphs.
  • Salts include, without limitation, acid addition salts and base addition salts, including hemisalts.
  • Pharmaceutically acceptable acid addition salts may include nontoxic salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Potentially useful salts include acetate, aspartate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, pyrosulfate, bisulfite, sulfite, borate, camsylate, caprylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride, chloride, hydrobromide, bromide, hydroiodide, iodide, isethionate, isobutyrate, lactate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,
  • Pharmaceutically acceptable base salts may include nontoxic salts derived from bases, including metal cations, such as an alkali or alkaline earth metal cation, as well as amines.
  • examples of potentially useful salts include, without limitation, aluminum, arginine, N,N′-dibenzylethylenediamine, calcium, chloroprocaine, choline, diethanolamine, diethylamine, dicyclohexylamine, ethylenediamine, glycine, lysine, magnesium, N-methylglucamine, olamine, potassium, procaine, sodium, tromethamine, zinc, and the like.
  • 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).
  • the pharmaceutically acceptable salts of pregabalin may be prepared by reacting its free (or zwitterionic) form with a desired acid or base; by removing an acid- or base-labile protecting group from a suitable precursor of pregabalin; by ring-opening a suitable cyclic (lactam) precursor using a desired acid or base; or by converting one salt of pregabalin to another by reaction with an appropriate acid or base or by contact with a suitable ion exchange column. All of these transformations are typically carried out in a solvent.
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the resulting salt may vary from completely ionized to almost non-ionized.
  • Pregabalin may exist in unsolvated and solvated forms (including hydrates) and in the form of other multi-component complexes in which the drug and at least one additional component is present in stoichiometric or non-stoichiometric amounts.
  • Multi-component complexes include clathrates (drug-host inclusion complexes) and pharmaceutical co-crystals. The latter are defined as crystalline complexes of neutral molecular constituents that are bound together through non-covalent interactions.
  • Co-crystals may be prepared by melt crystallization, by recrystallization from solvents, or by physically grinding the components together. See, e.g., O. Almarsson & M. J. Zaworotko, Chem. Comm. 1889-1896 (2004).
  • pregabalin include all of its polymorphs and crystal habits, the corresponding R-enantiomer of pregabalin, and various mixtures of pregabalin and the R-enantiomer, including a racemic mixture of pregabalin and the R-enantiomer.
  • the pharmaceutical composition may employ prodrugs of pregabalin.
  • prodrugs may be prepared by replacing appropriate functional groups of pregabalin with functionalities known as “pro-moieties,” as described, for example, in H. Bundgaar, Design of Prodrugs (1985). Examples of prodrugs would thus include derivatives of pregabalin in which an ester group replaces the carboxylic acid group or an amide group replaces the amino group.
  • Useful forms of pregabalin may also include pharmaceutically acceptable isotopically labeled compounds in which one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number that predominates in nature.
  • isotopes suitable for inclusion in pregabalin include isotopes of hydrogen ( 2 H and 3 H), carbon ( 11 C, 13 C and 14 C), and nitrogen ( 13 N and 15 N).
  • Isotopically labeled forms of pregabalin may generally be prepared by techniques known to those skilled in the art.
  • the pharmaceutical composition includes various excipients, including a matrix forming agent and a swelling agent.
  • a matrix forming agent For peroral solid dosage forms (e.g., tablets), the matrix forming agent imparts structural integrity and helps control or extend the rate of drug release, among other functions.
  • the matrix forming agent may comprise about 5% to about 45% of the pharmaceutical composition by weight and often comprises about 20% to about 35% of the pharmaceutical composition by weight.
  • Useful matrix forming agents include physical mixtures of polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP).
  • Polyvinylpyrrolidone (PVP) which is also known as povidone or povidonum, is a homopolymer of 1-vinyl-pyrrolidin-2-one, typically having a molecular weight (Mw) of about 1 ⁇ 10 3 to about 1 ⁇ 10 7 , about 2.5 ⁇ 10 3 to about 3 ⁇ 10 6 , or about 1 ⁇ 10 4 to about 1 ⁇ 10 5 .
  • Polyvinylpyrrolidone is available from BASF under the trade name KOLLIDON® and from ISP under the trade name PLASDONE®.
  • Polyvinyl acetate is a homopolymer of vinyl acetate, typically having a molecular weight (Mw) of about 1 ⁇ 10 5 to about 1 ⁇ 10 6 .
  • the matrix forming agent may comprise from about 0% to about 90% PVAc by weight, from about 20% to about 90% PVAc by weight, from about 40% to about 90% PVAc by weight, from about 60% to about 90% PVAc by weight, from about 70% to about 90% PVAc by weight, or from about 80% to about 90% PVAc by weight.
  • the matrix forming agent comprises from about 70% to about 85% PVAc by weight, based on the total weight of PVAc and PVP.
  • a useful matrix forming agent is available from BASF under the trade name KOLLIDON® SR, which is nominally an 80/19 (w/w) mixture of mixture of PVAc and PVP, respectively.
  • the pharmaceutical composition includes other excipients, including a swelling agent.
  • the swelling agent absorbs water from the gastric fluid which causes the solid dosage form to expand in size, and may also influence the drug release rate by, for example, creating channels or by forming a hydrocolloid.
  • Swelling agents may be soluble or insoluble in water.
  • the swelling agent may comprise about 5% to about 70% of the pharmaceutical composition by weight, about 10% to about 70% of the pharmaceutical composition by weight, or about 15% to about 70% of the pharmaceutical composition by weight. In many cases, the swelling agent may comprise about 10% to about 55% of the pharmaceutical composition by weight, about 20% to about 55% of the pharmaceutical composition by weight, or about 30% to about 55% of the pharmaceutical composition by weight.
  • Useful swelling agents include cross-linked homopolymers of 1-vinyl-pyrrolidin-2-one, which are known as crospovidone, crospovidonum, cross-linked povidone, and polyvinylpolypyrrolidone (PVPP).
  • Crospovidones which are insoluble in water, are available from BASF under the trade names KOLLIDON® CL and KOLLIDON® CL-10 and from ISP under the trade names POLYPLASDONE® XL and POLYPLASDONE® XL-10.
  • the swelling agent may include polyethylene oxide (PEO), which is also known as polyoxirane and polyoxyethylene.
  • PEO polyethylene oxide
  • Polyethylene oxides are homopolymers of ethylene oxide, typically having a molecular weight (Mw) of about 1 ⁇ 10 5 to about 1 ⁇ 10 7 or about 1 ⁇ 10 6 to about 1 ⁇ 10 7 .
  • Mw molecular weight
  • Polyethylene oxides are supplied in various grades based on molecular weight and are commercially available from Union Carbide under the trade name POLYOX®.
  • the PEO typically comprises from about 5% to about 35% or from about 10% to about 25% of the pharmaceutical composition by weight
  • the crospovidone typically comprises from about 10% to about 35% or from about 20% to about 30% of the pharmaceutical composition by weight.
  • the pharmaceutical composition may optionally include a gelling agent, which modifies (e.g. extends) the drug release characteristics of the dosage form.
  • Gelling agents which are also known as hydrocolloids, include synthetic and naturally occurring polymers that are typically poorly soluble (e.g., slightly soluble to sparingly soluble) in water. When exposed to water, the gelling agent forms a viscous mixture (i.e., viscosity greater than water) that retards diffusion of the drug through the dosage form thereby extending the time for drug release from the dosage form.
  • the gelling agent typically comprises from about 0% to about 25%, from about 5% to about 25%, or from about 5% to about 20% of the pharmaceutical composition based on weight.
  • Useful gelling agents include carbomers, polysaccharides or both.
  • Carbomers are acrylic acid polymers which are cross-linked with allylsucrose or allyl ethers of penaerythritol and are known variously as carboxy polymethylene, polyacrylic acid, and carboxyvinyl polymers. Carbomers have from about 56% to about 68% carboxy moieties on a dry basis and have number-average molecular weights of about 1 ⁇ 10 5 to about 1 ⁇ 10 10 or about 7 ⁇ 10 5 to about 4 ⁇ 10 9 . Carbomers are available from RITA under the trade name ACRITAMER® and from Noveon under the trade names CARBOPOL® and PEMULEN®.
  • polysaccharides include xanthan gum, inulin, guar gum, chitosan, ceratonia, and carregeenan, either alone or in combination.
  • Xanthan gum which is also known as corn sugar gum, is a polysaccharide having a molecular weight (Mw) of about 2 ⁇ 10 6 .
  • the polymer is comprised of a primary chain of ⁇ -D-glucose moieties linked by (1 ⁇ 4) glycosidic bonds, as well as trisaccharide side chains, which are attached to alternating glucopyranose moieties.
  • Each of the side chains is comprised of a ⁇ -D-glucuronic acid moiety which is linked to ⁇ -D-mannose moiety and an ⁇ -D-mannose moiety via (1 ⁇ 4) and (1 ⁇ 2) glycosidic bonds, respectively.
  • the ⁇ -D-mannose moiety is linked to the primary chain via a (1 ⁇ 3) glycosidic bond and a majority of the terminal ⁇ -D-mannose moieties are linked to pyruvate moieties.
  • Xanthan gum is typically prepared as a sodium, potassium, or calcium salt, and is available in various grades having different particle sizes from CP Kelco under the trade names KELTROL® and XANTURAL®, from Rhodia under the trade name RHODIGEL®, and from R. T. Vanderbilt Company, Inc. under the trade name VANZAN®.
  • Inulin which is also known as oligofructose and polyfructose, is a class of naturally occurring polysaccharides comprised of a linear chain of ⁇ -D-fructose moieties linked by (2 ⁇ 1) glycosidic bonds, which is usually terminated with a glucose molecule.
  • the number of D-fructose moieties may range from 2 to about 140, but typically ranges from about 25 to about 30.
  • Inulins are available from Sensus Operations CV under the trade name FRUTAFIT®.
  • Guar gum which is also known as guar galactomannan, guar flour, and jaguar gum, is a hydrocolloidal polysaccharide having a molecular weight (Mw) of about 2 ⁇ 10 5 .
  • Guar gum is comprised of a linear chain of ⁇ -D-mannose moieties linked by (1 ⁇ 4) glycosidic bonds and having monosaccharide side chains comprised of ⁇ -D-galactose moieties linked to the glucopyranose moieties by (1 ⁇ 6) glycosidic bonds.
  • the ratio of ⁇ -D-mannose moieties to ⁇ -D-galactose moieties generally ranges from about 1:1.4 to about 1:2 and the number-average molecular weight is typically about 2 ⁇ 10 5 .
  • Guar gun is obtained from natural sources, but synthetic derivatives are also available, including guar acetate, guar phthalate, guar acetate phthalate, oxidized guar gum, and sodium carboxymethyl guar. Guar gum is available in various particles sizes from Aqualon under the trade name GALACTASOL® and from Danisco under the trade names MEYPRO® Guar and MEYPRODOR.
  • Chitosan is known by a variety of names including chitosan hydrochloride, chitosani hydrochloridum, deacetylated chitin, deactylchitin, poly- ⁇ -(1,4)-2-amino-2-deoxy-D-glucose, 2-amino-2-deoxy-(1,4)- ⁇ -D-glucopyranan, ⁇ -1,4-poly-D-glucosamine, poly-D-glucosamine, and poly-(1,4- ⁇ -D-glucopyranosamine).
  • Chitosan is a class of sparingly water-soluble polysaccharides comprised of copolymers of ⁇ -D-glucosamine and N-acetyl- ⁇ -D-glucosamine, which are prepared by deacetylation and depolymerization of chitin.
  • the extent of deacetylation and depolymerization varies from manufacturer, but deacetylation of about 80% or greater and number-average molecular weights of about 1 ⁇ 10 4 to about 1 ⁇ 10 6 are typical.
  • Ceratonia is a naturally occurring polysaccharide which is also known as carob bean gum, carob flour, ceratonia gum, Cheshire gum, locust bean gum, and St. John's bread. Like guar gum, ceratonia is a galactomannan. It is comprised of a primary chain of ⁇ -D-mannose moieties linked by (1 ⁇ 4) glycosidic bonds and includes side chains comprised of single ⁇ -D-galactose moieties which are linked to every fourth or fifth D-mannopyranose moiety by (1 ⁇ 6) glycosidic bonds.
  • the molecular weight (Mw) of Ceratonia may range from about 5 ⁇ 10 4 to about 3 ⁇ 10 6 and is available in various particle sizes from Danisco under the trade names GRINDSTED®LBG and MEYPRO® LBG.
  • Carregeenan which is also known as Chondrus extract and Irish moss extract, is a hydrocolloid polysaccharide comprised primarily of potassium, sodium, calcium, magnesium, or ammonium sulfate esters of D-galactose and 3,6-anhydro-D-galactose copolymers.
  • the pyranose moieties are linked by alternating ⁇ (1 ⁇ 3) and ⁇ (1 ⁇ 4) glycosidic bonds.
  • Lambda-carrageenan is a non-gelling polymer which contains about 35% sulfate ester groups by weight and no 3,6-anhydrogalactose moieties; l-carrageenan is a gelling polymer which contains about 32% sulfate ester groups by weight and about 30% 3,6-anhydrogalactose moieties; and ⁇ -carrageenan is a comparatively stronger (i.e., inelastic, brittle or firm) gelling polymer which contains about 25% sulfate ester moieties by weight and about 34% 3,6-anhydrogalactose moieties.
  • Carrageenan is available in a number of grades based on gelling type, aqueous solubility, and viscosity when blended with water and can be obtained from FMC Corporation under the trade names GELCARIN®, VISCARIN® and SEASPEN®.
  • useful polysaccharides include cellulosic derivatives which exhibit aqueous solubility over at least a portion of the pH range of 1 to 8, inclusive.
  • Useful polymers thus include ionizable and nonionizable cellulosic polymers, including those having ether or ester or ether and ester substituents and copolymers thereof, including so-called “enteric” and “non-enteric” polymers.
  • Exemplary ionic cellulosic polymers include carboxymethylcellulose (CMC) and its sodium or calcium salts; carboxyethylcellulose (CEC); carboxymethylethylcellulose (CMEC); hydroxyethylmethylcellulose acetate phthalate; hydroxyethylmethylcellulose acetate succinate; hydroxypropylmethylcellulose phthalate (HPMCP); hydroxypropylmethylcellulose succinate; hydroxypropylcellulose acetate phthalate (HPCAP); hydroxypropylcellulose acetate succinate (HPCAS); hydroxypropylmethylcellulose acetate phthalate (HPMCAP); hydroxypropylmethylcellulose acetate succinate (HPMCAS); hydroxypropylmethylcellulose acetate trimellitate (HPMCAT); hydroxypropylcellulose butyrate phthalate; carboxymethylethylcellulose and its sodium salt; cellulose acetate phthalate (CAP); methylcellulose acetate phthalate; cellulose acetate trimellitate (CAT); cellulose acetate
  • the ionic cellulosic polymers are available from numerous commercial suppliers.
  • sodium CMC may be obtained from Hercules under the trade names AQUALON® and BLONASE® in various grades based on particle size and degree (e.g., about 0.7 to about 1.2) of carboxymethyl-substitution of the anhydroglucose units.
  • nonionic cellulosics include methylcellulose (MC); ethyl cellulose (EC); hydroxyethyl cellulose (HEC); hydroxypropylcellulose (HPC); hydroxypropylmethylcellulose (HPMC); hydroxypropylmethylcellulose acetate; hydroxyethylmethylcellulose; hydroxyethylcellulose acetate; hydroxyethylethylcellulose; and mixtures thereof.
  • MC methylcellulose
  • EC ethyl cellulose
  • HEC hydroxyethyl cellulose
  • HPC hydroxypropylcellulose
  • HPMC hydroxypropylmethylcellulose
  • HPMC hydroxypropylmethylcellulose acetate
  • the nonionic cellulosics are available from a variety of commercial sources.
  • MC may be obtained from the Dow Chemical Company under the trade name METHOCEL® A, which has about 27.5% to about 31.5% methoxy groups per anhydroglucose unit based on weight
  • HPC may be obtained from Hercules under the trade name KLUCEL® in various grades (e.g., EF, EXF, LF, JF, GF, MF, HF, and HXF) having molecular weights ranging from about 8 ⁇ 10 4 to about 1.2 ⁇ 10 6 (Mw);
  • HEC may be obtained from Hercules under the trade name NATROSOL® 250 in various grades (e.g., L, G, M, H, H, and HHX) having molecular weights ranging from about 9 ⁇ 10 4 to about 1.3 ⁇ 10 6 (Mv);
  • HPMC may be obtained from Hercules under the trade name BENECEL® in various grades (e.g., MP 843, MP 814, MP 824, MP 844, and MP 874)
  • the pharmaceutical composition may optionally include one or more lubricants, which aid in various processing steps including component blending and tableting.
  • the lubricants typically comprise from about 0.5% to about 2% of the pharmaceutical composition based on weight.
  • 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, glyceryl palmitostearate, and the like; glyceryl behenate (e.g., COMPRITOL®, which is available from Gattefosse Inc.), sodium lauryl sulfate, hydrogenated vegetable oil, mineral oil, poloxamers (copolymers of ethylene oxide and propylene oxide), polyethylene glycol, sodium chloride, and mixtures thereof.
  • COMPRITOL® which is available from Gattefosse Inc.
  • the pharmaceutical composition may include other excipients, such diluents or fillers, which comprise from about 0% to about 30% of the composition by weight.
  • Diluents may improve the flow characteristics of the pharmaceutical composition during component blending and tableting and may enhance the physical properties of tablets, providing, for example, increased compression strength or hardness, decreased friability, and so on.
  • 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, dihydrous calcium phosphate, anhydrous dicalcium phosphate, and mixtures thereof.
  • the components of the pharmaceutical composition are typically dry blended using, e.g., a v-cone blender.
  • the resulting mixture is subsequently compacted in a press to yield individual (unit) dosages (tablets).
  • the components may be combined and blended in stages.
  • the API may be granulated with one or more of the components by, e.g., fluid bed or extrusion granulation, and then blended with the remaining components.
  • the API may be first dry blended with one or more matrix forming agents, while other excipients, such as swelling agents, gelling agents, diluents, lubricants, and the like, may be subsequently admixed in one or more blending operations.
  • one or more of the components may be sized by screening or milling or both.
  • the compressed dosage forms may undergo further processing, such as polishing, coating, and the like.
  • polishing such as polishing, coating, and the like.
  • wet and dry granulation, milling, screening, tableting, coating, and the like as well as a description of alternative techniques for preparing drug products, see A. R. Gennaro (ed.), Remington: The Science and Practice of Pharmacy (20th ed., 2000); H. A. Lieberman et al. (ed.), Pharmaceutical Dosage Forms: Tablets, Vol. 1-3 (2d ed., 1990); and D. K. Parikh & C. K. Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81 (1997).
  • the pharmaceutical composition is ingested whole and begins to swell or expand when it contacts the gastric fluid (water) in the subject's stomach.
  • the dosage form may have any shape, and includes disk- or oval-shaped tablets defined by a pair of circular or elliptical convex or planar surfaces which are connected by a continuous, substantially flat lateral surface; polygonal-shaped (e.g., triangular, quadrangular, pentagonal, hexagonal, etc.) tablets which have rounded corners and edges and are defined by a pair of convex or planar multi-sided surfaces (e.g., triangles, quadrilaterals, pentagons, hexagons, etc.) that are connected by substantially flat lateral surfaces; and cylindrical-shaped tablets having hemispherical or hemispheroidal ends and having circular or elliptical cross-sections.
  • the QD dosage form may be retained in the stomach by size exclusion, by dosing with a meal, by dosing before bedtime, or by some combination of these mechanisms.
  • the dosage form expands to a size that prevents it from exiting the stomach through the pylorus. Since the average diameter of the pylorus in an adult is about 13 mm, the size of the dosage form following expansion would range from about 13 mm to about 20 mm or larger, from about 15 mm to about 20 mm or larger, or from about 17 mm to about 20 mm or larger.
  • the “size” of the dosage form corresponds to the largest linear dimension of a cross-section of the dosage form having the smallest area.
  • the size of a disk-shaped tablet corresponds to its diameter
  • the size of a cylindrical-shaped tablet corresponds to the diameter of its circular cross-section or to the long axis of its elliptical cross-section.
  • the dosage form is retained in the stomach for several hours (e.g., t R ⁇ 3, 4, 5 or 6 hours) and releases pregabalin over an extended period of time (e.g., t 90 >10,11, 12,13, 14,15, 16, 17, 18, 19 or 20 hours).
  • the dosage form is typically retained in the subject's stomach for a period of time that ranges from about 3 hours to about 11 hours (3 ⁇ t R ⁇ 11), from about 6 hours to about 14 hours (6 ⁇ t R ⁇ 14), or from about 8 hours to about 14 hours (8 ⁇ t R ⁇ 14), and it releases pregabalin over a period of time that ranges from about 12 hours to about 16 hours (12 ⁇ t 90 ⁇ 16), from about 12 hours to about 18 hours (12 ⁇ t 90 ⁇ 18), from about 12 hours to about 20 hours (12 ⁇ t 90 ⁇ 20), from about 14 hours to about 20 hours (14 ⁇ t 90 ⁇ 20), or from about 16 hours to about 20 hours (16 ⁇ t 90 ⁇ 20).
  • QD dosage forms that release pregabalin over a period of time that is about 4 hours to about 6 hours longer than the time the dosage form is retained in the stomach appear to minimize variability among patients.
  • the dosage form may be administered once daily after a meal or before bedtime (e.g., within about one hour of sleep).
  • the QD dosage form may be taken after the last meal before bedtime (e.g., after an evening meal).
  • the dosage form may be retained in the stomach with little or no size expansion. In such cases, for example, the size of the dosage form following expansion may be about 9 mm or more.
  • the QD dosage form achieves a steady-state C MAX that is about equal to or less than the steady-state C MAX of a corresponding immediate release formulation of the API that is taken two- or three-times daily.
  • the QD formulation ideally achieves a steady-state C MIN that is about equal to or greater than the steady-state C MIN of the IR formulation that is taken two- or three-times daily.
  • a QD formulation containing pregabalin would ideally achieve an average steady sate C MAX of about 9 ⁇ g/mL or less and an average steady-state C MIN of about 0.7 ⁇ g/mL or greater.
  • the amount of API released from drug product samples immersed in aqueous dissolution media (0.06 N HCl or 0.5 M acetate buffer) at 37° C. is measured using a USP Apparatus 2 (paddles) or Apparatus 3 (reciprocating cylinder), which are operated at 50 rpm or 5 dpm, respectively.
  • Samples of the dissolution media (1 mL) are typically taken at 1, 2, 4, 6, 9, 12, 16, and 24 hours and are analyzed using HPLC under the following conditions: column: Zorbax SB-CN, 150 mm ⁇ 4.6 mm, 5 ⁇ m particle size; column temperature: 23° C.; detector wavelength: 210 nm; flow rate 1 mL/min; injection volume: 25 ⁇ L; mobile phase composition: 0.05 M sulfonic acid/hexane and 2 mL Et 3 N; pH adjusted to 3.1 with orthophosphoric acid:ACN (880:130); run time: 8 min.
  • the increase in the size of the drug product as a function of time following immersion in 0.06 N HCl aq dissolution media is carried out using a USP Apparatus 2 (paddles). Samples of the drug product are periodically withdrawn from the dissolution media and their dimensions measured using calipers.
  • Samples of the drug product are placed in a USP Apparatus 2 (paddles) containing 0.06 N HCl aq dissolution media. Samples of the drug product are periodically withdrawn and their rigidity measured using a texture analyzer (TA 132) with the following settings: 5 kg load cell; TA-81 ⁇ 4′′ ball probe; 0.5 g trigger force; 0.2 mm/s test speed; 10 points/s acquisition rate; 10 mm distance.
  • TA 132 texture analyzer
  • Stability testing is carried out by placing samples of the drug product in open HDPE bottles or induction-sealed HDPE bottles, which are stored at 40° C. and 75% relative humidity. Samples of the drug product are pulled at various time intervals—e.g., at 2 weeks for initial screening and at 3 weeks, 6 weeks, or 3 months for subsequent testing—and analyzed for pregabalin content (%, w/w) and lactam content (%, weight of lactam/initial weight of pregabalin) using HPLC.
  • TABLES 2 and 3 show compositions of laboratory-scale batches (25 g) containing pregabalin and various excipients; TABLES 4 and 5 show results of drug release as a function of time.
  • drug product was prepared by blending all of the tablet components except for magnesium stearate in a TURBULA® mixer for about 15 minutes. Magnesium stearate was passed through a #20 standard sieve and combined with the contents of the TURBULA® mixer using a spatula. The resulting coarse blend was subsequently mixed in the TURBULA® mixer for an additional 4 minutes to obtain a final blend.
  • each of the final blends was compacted in a CARVER® Press using a compression force of 3000 pounds (EXAMPLES 1 to 5) or 2000 pounds (EXAMPLES 6 to 11) and a dwell time of 0.1 min, resulting in tablets with average hardness values of about 30 kp and nominal tablet weights of 1 g and 1.125 g, respectively.
  • pregabalin was coated with COMPRITOL® 888 by high-shear granulation prior to blending with the other excipients.
  • TABLE 6 shows compositions of laboratory-scale batches (100 g) which contain pregabalin and excipients
  • TABLE 7 shows drug release as a function of time.
  • drug product was prepared by first combining pregabalin with COMPRITOL® 888 in an extruder-granulator. With the exception of magnesium stearate, the remaining tablet components were blended with the resulting pregabalin granules in a 1-pint V-blender for about 15 minutes. Magnesium stearate was passed through a #20 standard sieve and was combined with the contents of the V-blender using a spatula. The resulting coarse blend was subsequently mixed in the V-blender for an additional 4 minutes to obtain a final blend.
  • Each of the final blends was compressed using a simulated KORSCH® XL 400 press (i.e., PRESSTER® Compaction Simulator) employing an average compression force of about 21 kN and average dwell time of 12 msec.
  • the tablets displayed an average hardness of about 20 kp and a nominal tablet weight of about 1 g.
  • TABLE 8 shows compositions of laboratory-scale batches which contain pregabalin and excipients; TABLE 9 shows lactam formation as a function of time. Each of the formulations was made using a process similar to that described above in EXAMPLES 12 to 14.
  • TABLE 10 shows compositions of laboratory-scale batches (up to 4 kg) which contain pregabalin and excipients; TABLE 11 shows drug release as a function of time; TABLES 12 and 13 show tablet swelling and changes in tablet rigidity following immersion in an aqueous solution; and TABLE 14 shows lactam formation as a function of time.
  • Drug products for some of the compositions were made using processes similar to those described in EXAMPLES 12 to 14.
  • Drug product for 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 was combined with the contents of the V-blender using a spatula. The resulting coarse blend was subsequently mixed in the V-blender for an additional 5 minutes to obtain a final blend. The final blend was compressed in a MANESTY® Betapress using a diamond-shaped (quadrilateral) punch (0.6299′′ ⁇ 0.748′′, 0.0700′′ cup depth, 0.0040′′ land) and a triangle-shaped punch (0.6665′′ ⁇ 0.6906′′, 0.0600′′ cup depth, 0.0040′′ land).
  • an average tablet hardness of 8.6 kp was obtained for 10 tablets at a pre-compression force setting of about 2.1 kN and a lower main compression setting of about 36 kN.
  • an average tablet hardness of 9.0 kp was obtained for 10 tablets at a pre-compression force setting of about 2.2 kN and a lower main compression setting of about 39.8 kN.
  • the loss in weight upon friability testing was 0.3% for the diamond-shaped tablets and 0.2% for the triangle-shaped tablets, respectively.
  • Tablets prepared using the MANESTY® Betapress (EXAMPLE 24) exhibited substantially lower tablet hardness than those prepared in previous examples. As a result, the magnesium stearate content of the composition was reduced from 1% to 0.5% to improve tablet hardness (EXAMPLE 30).
  • TABLE 15 shows simulated steady-state minimum (C MIN ) and maximum (C MAX ) plasma concentrations of pregabalin, as well as time to C MAX (t MAX ), for QD pharmaceutical compositions that contain 600 mg of pregabalin.
  • TABLE 15 also shows steady-state PK parameters for an IR pharmaceutical composition containing 300 mg of pregabalin which is dosed twice daily.
  • the PK simulations are based on a QD dosage form having a normalized dissolution profile provided in TABLE 16.
  • the PK simulation shown in TABLE 15 assumes that (1) the pharmaceutical composition remains in the stomach the specified time period (t R ) for each simulation; (2) the total effective absorption time (window) is 6 hours—the average absorption window for the small intestine and the ascending portion of the colon of the time in the stomach—plus t R ; (3) the absorption rate in the lower portion of the small intestine is similar to the upper portion; and (4) the effect of taking the pharmaceutical composition with food, at bedtime, or with food and at bedtime, has no effect on the absorption rate.
  • Food has been shown to delay t MAX of IR formulations, but does not appear to affect the extent of drug absorption. Sleep, however, will likely decrease the rate of drug absorption so that the simulations may underestimate the delay in t MAX .
  • results in TABLE 15 are based on an average absorption window associated with an IR formulation of 6 hours—PK profiles of individual patients receiving the QD dosage could differ. Indeed, PK simulations for a QD dosage form containing 600 mg of pregabalin and exhibiting a t 100 of 12 hours and a t R of 5 hours and in which t R varies from 3.4 hours to 7.7 hours suggests that a t 100 (or t 90 ) approximately 4 to 6 hours longer than t R reduces variability among subjects.
  • a single-dose pharmacokinetic study was performed to assess the performance of the QD formulation of EXAMPLE 30.
  • the QD dosage form was given (1) in the fasted state, (2) following a high fat breakfast (morning treatment), and (3) following a high fat supper (evening treatment) in accordance with guidelines established by the U.S. Food and Drug Administration. See, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Guidance for Industry, Food - Effect Bioavailability and Fed Bioequivalence Studies (December 2002).
  • “high-fat” means that approximately 50 percent of the total caloric content of the meal was derived from fat.
  • the pharmacokinetic results of these three treatments were compared to the results obtained for an identical dose (300 mg) of an immediate release formulation (capsule) comprised of pregabalin, lactose monohydrate, maize starch, and talc.
  • t MAX for the QD formulation was about 4 hours for the fasted treatment, more than 2-fold later than the mean t MAX of 1.5 hours for the IR capsule.
  • t MAX for the QD formulation increased to approximately 10 hours (9.7 hours for the morning treatment and 10.7 hours for evening treatment). Based on mean area under the plasma concentration-time curve from time zero to time infinity, total pregabalin exposure for the QD formulation fasted was less than half of that for the IR capsule.
  • Lactam formation (%, weight of lactam/initial weight of pregabalin)

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US11/555,988 US20070269511A1 (en) 2005-11-02 2006-11-02 Solid pharmaceutical compositions containing pregabalin
US13/267,352 US20120029081A1 (en) 2005-11-02 2011-10-06 Solid Pharmaceutical Compositions Containing Pregabalin
US13/472,704 US20120232149A1 (en) 2005-11-02 2012-05-16 Solid pharmaceutical compositions containing pregabalin
US13/706,971 US20130102675A1 (en) 2005-11-02 2012-12-06 Solid Pharmaceutical Compositions Containing Pregabalin
US13/947,433 US20130303618A1 (en) 2005-11-02 2013-07-22 Solid Pharmaceutical Compositions Containing Pregabalin
US14/181,785 US8945620B2 (en) 2005-11-02 2014-02-17 Solid pharmaceutical compositions containing pregabalin
US14/570,115 US9144559B2 (en) 2005-11-02 2014-12-15 Solid pharmaceutical compositions containing pregabalin
US14/831,205 US20150352066A1 (en) 2005-11-02 2015-08-20 Solid Pharmaceutical Compositions Containing Pregabalin
US15/074,042 US20160250147A1 (en) 2005-11-02 2016-03-18 Solid Pharmaceutical Compositions Containing Pregabalin
US15/418,907 US20170136125A1 (en) 2005-11-02 2017-01-30 Solid Pharmaceutical Compositions Containing Pregabalin
US15/686,549 US10022447B2 (en) 2005-11-02 2017-08-25 Solid pharmaceutical compositions containing pregabalin

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US13/472,704 Abandoned US20120232149A1 (en) 2005-11-02 2012-05-16 Solid pharmaceutical compositions containing pregabalin
US13/706,971 Abandoned US20130102675A1 (en) 2005-11-02 2012-12-06 Solid Pharmaceutical Compositions Containing Pregabalin
US13/947,433 Abandoned US20130303618A1 (en) 2005-11-02 2013-07-22 Solid Pharmaceutical Compositions Containing Pregabalin
US14/181,785 Active US8945620B2 (en) 2005-11-02 2014-02-17 Solid pharmaceutical compositions containing pregabalin
US14/570,115 Active US9144559B2 (en) 2005-11-02 2014-12-15 Solid pharmaceutical compositions containing pregabalin
US14/831,205 Abandoned US20150352066A1 (en) 2005-11-02 2015-08-20 Solid Pharmaceutical Compositions Containing Pregabalin
US15/074,042 Abandoned US20160250147A1 (en) 2005-11-02 2016-03-18 Solid Pharmaceutical Compositions Containing Pregabalin
US15/418,907 Abandoned US20170136125A1 (en) 2005-11-02 2017-01-30 Solid Pharmaceutical Compositions Containing Pregabalin
US15/686,549 Active US10022447B2 (en) 2005-11-02 2017-08-25 Solid pharmaceutical compositions containing pregabalin

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US13/472,704 Abandoned US20120232149A1 (en) 2005-11-02 2012-05-16 Solid pharmaceutical compositions containing pregabalin
US13/706,971 Abandoned US20130102675A1 (en) 2005-11-02 2012-12-06 Solid Pharmaceutical Compositions Containing Pregabalin
US13/947,433 Abandoned US20130303618A1 (en) 2005-11-02 2013-07-22 Solid Pharmaceutical Compositions Containing Pregabalin
US14/181,785 Active US8945620B2 (en) 2005-11-02 2014-02-17 Solid pharmaceutical compositions containing pregabalin
US14/570,115 Active US9144559B2 (en) 2005-11-02 2014-12-15 Solid pharmaceutical compositions containing pregabalin
US14/831,205 Abandoned US20150352066A1 (en) 2005-11-02 2015-08-20 Solid Pharmaceutical Compositions Containing Pregabalin
US15/074,042 Abandoned US20160250147A1 (en) 2005-11-02 2016-03-18 Solid Pharmaceutical Compositions Containing Pregabalin
US15/418,907 Abandoned US20170136125A1 (en) 2005-11-02 2017-01-30 Solid Pharmaceutical Compositions Containing Pregabalin
US15/686,549 Active US10022447B2 (en) 2005-11-02 2017-08-25 Solid pharmaceutical compositions containing pregabalin

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WO2012003968A1 (en) 2010-07-06 2012-01-12 Grünenthal GmbH Novel gastro- retentive dosage forms comprising a gaba analog and an opioid
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WO2013114281A1 (en) 2012-01-30 2013-08-08 Ranbaxy Laboratories Limited Pregabalin gr tablets
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WO2015114509A1 (en) 2014-01-28 2015-08-06 Ranbaxy Laboratories Limited Stabilized gastroretentive tablets of pregabalin
US20170273896A1 (en) * 2015-05-26 2017-09-28 Isa Odidi Controlled extended release pregabalin
CN107920987A (zh) * 2015-05-26 2018-04-17 艾萨·欧蒂迪 控制延缓释放普瑞巴林
US10561602B2 (en) * 2015-05-26 2020-02-18 Isa Odidi Controlled extended release pregabalin
US12029820B2 (en) 2015-09-29 2024-07-09 Acorda Therapeutics, Inc. Sustained release compositions of 4-aminopyridine
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JP4334610B2 (ja) 2009-09-30
ZA200803115B (en) 2009-09-30
CA2628200A1 (en) 2007-05-10
SI1945186T1 (sl) 2014-03-31
AU2006310217A1 (en) 2007-05-10
AP2008004465A0 (en) 2008-06-30
US10022447B2 (en) 2018-07-17
US20130303618A1 (en) 2013-11-14
ME00482B (me) 2011-10-10
EP1945186B1 (en) 2014-01-22
US20150352066A1 (en) 2015-12-10
EA012377B1 (ru) 2009-10-30
US20160250147A1 (en) 2016-09-01
TW200803831A (en) 2008-01-16
DK1945186T3 (en) 2014-03-17
IL190827A0 (en) 2008-12-29
CA2628200C (en) 2011-01-25
EA200800931A1 (ru) 2008-10-30
RS20080181A (xx) 2009-07-15
US20170348420A1 (en) 2017-12-07
BRPI0618211A2 (pt) 2011-08-23
EP1945186A2 (en) 2008-07-23
PL1945186T3 (pl) 2014-05-30
IL190827A (en) 2012-08-30
CN101330907A (zh) 2008-12-24
US20140163103A1 (en) 2014-06-12
PT1945186E (pt) 2014-03-06
JP2009514847A (ja) 2009-04-09
KR20080059427A (ko) 2008-06-27
NL2000281C2 (nl) 2007-08-07
US9144559B2 (en) 2015-09-29
NL2000281A1 (nl) 2007-05-03
HK1126394A1 (en) 2009-09-04
US20170136125A1 (en) 2017-05-18
CN101330907B (zh) 2012-08-29
WO2007052125A3 (en) 2007-09-07
WO2007052125A2 (en) 2007-05-10
US20120232149A1 (en) 2012-09-13
ECSP088422A (es) 2008-05-30
US20130102675A1 (en) 2013-04-25
US8945620B2 (en) 2015-02-03
UY29890A1 (es) 2007-05-31
BRPI0618211B8 (pt) 2021-05-25
TWI330080B (en) 2010-09-11
US20120029081A1 (en) 2012-02-02
CR9950A (es) 2008-05-28
BRPI0618211B1 (pt) 2020-11-17
DOP2006000241A (es) 2007-05-31
AR058175A1 (es) 2008-01-23
NO20081816L (no) 2008-05-08
ES2449231T3 (es) 2014-03-18
US20150094371A1 (en) 2015-04-02
KR101012533B1 (ko) 2011-02-07
PE20070693A1 (es) 2007-08-11
AU2006310217B2 (en) 2012-08-16
GT200600474A (es) 2007-06-08
MA30135B1 (fr) 2009-01-02
NZ567414A (en) 2011-09-30

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