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WO2006078811A2 - Preparations pharmaceutiques qui procedes d'utilisation - Google Patents

Preparations pharmaceutiques qui procedes d'utilisation Download PDF

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Publication number
WO2006078811A2
WO2006078811A2 PCT/US2006/001887 US2006001887W WO2006078811A2 WO 2006078811 A2 WO2006078811 A2 WO 2006078811A2 US 2006001887 W US2006001887 W US 2006001887W WO 2006078811 A2 WO2006078811 A2 WO 2006078811A2
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WO
WIPO (PCT)
Prior art keywords
composition
gabapentin
active ingredient
independent
tablets
Prior art date
Application number
PCT/US2006/001887
Other languages
English (en)
Other versions
WO2006078811A3 (fr
Inventor
Rodney A. Brown
Stephen H. Curry
Michael Rubenstein
Michael R. Violante
Original Assignee
Pharmanova Inc.
Quay Pharmaceuticals Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=36692870&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2006078811(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Pharmanova Inc., Quay Pharmaceuticals Ltd. filed Critical Pharmanova Inc.
Priority to EP06718892A priority Critical patent/EP1838291A4/fr
Priority to MX2007008833A priority patent/MX2007008833A/es
Priority to CA002595470A priority patent/CA2595470A1/fr
Priority to AU2006206423A priority patent/AU2006206423A1/en
Priority to JP2007552260A priority patent/JP2008528494A/ja
Priority to BRPI0614021-1A priority patent/BRPI0614021A2/pt
Publication of WO2006078811A2 publication Critical patent/WO2006078811A2/fr
Publication of WO2006078811A3 publication Critical patent/WO2006078811A3/fr
Priority to IL184735A priority patent/IL184735A0/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
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    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
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    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
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    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • the present invention relates to new pharmaceutical formulations and to new medical uses of gabapentin and pregabalin. Background of the Invention
  • Gabapentin (U.S. Patent Nos. 4,024, 175 and 4,087,544) is a known GABA (gamma amino-butyric acid) analogue that has been used clinically to treat epilepsy, neuropathic pain and a number of other conditions. Gabapentin also has potentially useful therapeutic effects in other chronic pain states, e.g., muscular and skeletal pain; in psychiatric disorders, e.g., panic, anxiety, depression, alcoholism and manic behavior; in movement disorders, e.g., multiple sclerosis, action tremors, tardive dyskinesia, etc.; in migraine; in bipolar disease; in muscle spasm and as an analgesic. More recently, U.S. Patent No. 6,310,098 demonstrated that gabapentin can be used to treat hot flashes (hot flushes).
  • hot flashes hot flushes
  • gabapentin is formulated as an immediate release unit dose tablet or capsule formulation containing 100, 300, 400, 600 or 800 mg of the active agent. These unit doses are usually administered three times a day (TID) with a maximum dosage of 3,600 mg, or more usually 2,700 mg. TID administration is inconvenient and patient compliance with TID dosages is often erratic. Depending on the condition to be treated the consequences of missing or mistiming a dose can be serious.
  • U.S. Patent No. 6,723,340 discloses a tablet formulation of gabapentin that is designed to be retained in the stomach and to release the gabapentin in the stomach.
  • This formulation provides sustained delivery of gabapentin, but only to the stomach and the upper small intestine.
  • This formulation provides prolonged time of controlled release in the stomach and upper gastrointestinal (GI) tract, and enhanced opportunity for absorption in the stomach and upper GI tract rather than the lower portions of the GI tract.
  • GI gastrointestinal
  • Such a formulation must be taken continuously to maintain therapeutic blood concentrations. Intermittent administration would require a delay in time to reach therapeutic blood concentrations so this formulation is not appropriate for a medication to be taken only as required. All absorption of gabapentin in this formulation would be expected to occur in the stomach and/or upper small intestine, particularly the duodenum.
  • U.S. Patent No. 6,818,787 discloses certain prodrugs of gabapentin and U.S. Patent No. 6,465,012 discloses certain improved immediate release formulations of gabapentin.
  • the former describes an attempt to provide sustained release of gabapentin by attaching a promoiety to the gamma amino and/or the carboxyl group of gabapentin (and other GABA analogs) to improve bioavailability and transport to the brain.
  • This patent describes new chemical entities that bypass the known active transport mechanism for gabapentin and related compounds delaying absorption to further down the intestinal tract.
  • the '012 patent describes a tablet formulation with improved compressibility characteristics, but does not provide any sustained release of gabapentin.
  • U.S. Patent No. 5,906,832 discloses a variety of continuous administration formulations of a large number of anti-epileptic drugs focusing on osmotic formulations of phenytoin. It also makes passing reference to gabapentin, but does not disclose the specific parts of the gastrointestinal tract where the drug is to be released, and in particular does not disclose rapid release of the gabapentin in the lower small intestine. This formulation does not include any immediate release component and must be taken continuously to maintain therapeutic blood concentrations. Intermittent administration would require a delay in time to reach therapeutic blood concentrations so this formulation is not appropriate for a medication to be taken only as required.
  • the drug, pregabalin has similar properties to gabapentin.
  • Pregabalin is available only in immediate release form with no sustained release formulation currently available. This drug, therefore, is taken TID to maintain therapeutic blood levels.
  • TID administration is inconvenient and patient compliance with TID dosage is often erratic. Depending on the condition to be treated, the consequences of missing or mistiming a dose can be serious.
  • the present invention is directed to a composition
  • a composition comprising an active ingredient coated by a pH independent soluble polymer excipient, an active ingredient coated by a pH independent insoluble polymer excipient, and an active ingredient coated by a pH dependent soluble polymer excipient.
  • the active ingredient may be from gabapentin and pregabalin.
  • the pH independent soluble polymer excipient is hydroxypropylmethyl cellulose.
  • the pH independent insoluble polymer excipient may be Eudragit RL30D, Eudragit RS30D, or a combination thereof.
  • the pH dependent soluble polymer may be Eudragit L30D-55, Eudragit FS30D, or a combination thereof.
  • the present invention is also directed to the composition wherein the pH independent insoluble polymer has a thickness of 25 to 150 microns.
  • the pH dependent soluble polymer has a thickness of 25 to 150 microns.
  • the present invention is also directed to the active ingredient in the form of min-tablets coated by either the pH independent insoluble polymer, the pH independent soluble polymer, or the pH dependent soluble polymer.
  • the present invention is further directed to the composition further comprising a disintegrant, a flavor component, a colorizer, a sweetener, a binder, a lubricant, a plasticizer, or a combination thereof.
  • the present invention is also directed to an oral controlled-release formulation of gabapentin, adapted to a rapid release in part and a sustained release in part of the gabapentin in the stomach and upper small intestine (thereby providing the drug to the stomach and the upper small intestine) and to release in part in the lower or middle to lower small intestine.
  • the formulation is adapted to release the gabapentin or other active ingredients in three phases.
  • gabapentin or other active ingredients is released rapidly in the stomach; in the second phase, gabepentin or other active ingredients is released over a sustained release period mainly in the lower stomach, duodenum and jejunum sections of the small intestine; and in the third phase, the release of gabepentin or other active ingredients is delayed until the jejunum and ileum sections of the small intestine, wherein gabepentin or other active ingredients is released rapidly.
  • the present invention is also directed to the composition, wherein 20 to 60%, or from 25 to 50%, or from 35 to 45% of gabapentin or other active ingredients are released in the first phase, e.g., within a period of up to 2 or within 3 hours after dosing. These quantities of gabapentin or other active ingredients will for the most part be released in the stomach.
  • the present invention is also directed to the composition, wherein 20 to 60%, or from 25 to 50%, or from 35 to 45% of gabapentin or other active ingredients are released in the second phase, e.g., within a period of up to 12 or within 6 hours or within 1 to 5 hours after dosing.
  • the present invention is also directed to the composition, wherein 15 to 50%, or from 30 to 45%, or from 30 to 40% of the gabapentin or other active ingredients are released rapidly after a delay of 3 to 10, or 4 to 8 hours after dosing.
  • These quantities of the active ingredient will be, for the most part, released in the middle to lower small intestine include the jejunum and ileum.
  • One objective of the release of the drug in the third phase is to make drug readily available at a time when the blood levels of the drug released in the earlier phases are likely to be decreasing.
  • Another aspect of the present invention is directed to the composition comprising an active ingredient encapsulated by a pH independent soluble polymer excipient, an active ingredient encapsulated by a pH independent insoluble polymer excipient, and an active ingredient encapsulated by a pH dependent soluble polymer excipient wherein 20-60% of the active ingredient is released by the pH independent soluble polymer excipient within a period up to 3 hours after dosing, wherein 20-60% of the active ingredient is released by the pH independent insoluble polymer excipient within a period up to 12 hours after dosing, and wherein 15-50% of the active ingredient is released by the pH dependent soluble polymer excipient after a delay of 3 to 10 hours after dosing.
  • the present invention is also directed to the composition wherein 25-50% of the active ingredient encapsulated by a pH independent soluble polymer to be released within a period of up to 2 or 3 hours.
  • the present invention is also directed to the composition wherein 35-45% of the active ingredient encapsulated by a pH independent soluble polymer to be released within in a period of up to 2 or 3 hours.
  • Another aspect of the present invention is directed to the composition wherein 25 to 50% of the active ingredient encapsulated by a pH independent insoluble polymer is to be release over a sustained period up to 12 hours or up to 6 hours, or up or between 1 to 5 hours.
  • the present invention is also directed to the composition wherein 25-35% of the active ingredient is released over a sustained period up to 12 hours or up to 6 hours, or between 1 to 5 hours.
  • the present invention is also directed to the composition wherein 30 to 45% of the active ingredient is released from the pH dependent soluble polymer after a delay of 3 to 10, or 4 to 8 hours.
  • the present invention is also directed to the composition wherein 30 to 40% of the active ingredient is released from the pH dependent soluble polymer after a delay of 3 to 12, or 4 to 8 hours.
  • These proportions of the active ingredient released by the pH dependent soluble polymer will be released in the middle to lower sections of the small intestine including the jejunum and the ileum of the small intestine.
  • the sum of release of the active ingredient over the three phases or from the soluble, insoluble pH independent polymers and the pH dependent polymer is near 100%.
  • the present invention is also directed to a composition wherein the AUC drug plasma level of the gabapentin is greater than 100 to 200% of that obtainable for an equivalent dose of conventional immediate release gabapentin, e.g., that sold under the trademark Neurontin®.
  • the present invention may determine AUC as either by the integration of the data points from time zero to time infinity, when those data points are concentrations (levels) of gabapentin in plasma following single doses of gabapentin either as Neurontin® or as a formulation according to this invention (Xenolev-CRTM) in healthy volunteers, and/or in the target population, or by the integration of the equivalent data points during one dosing interval at the pharmacokinetic steady state in which long-term daily dosing balances daily elimination.
  • the present invention determines its formulation kinetics' T max as the same as, or up to 3.0 times greater than the corresponding T max for an equivalent dose of conventional immediate release formulation.
  • the time to C max is from 2 to 6 hours from dosing.
  • the peak plasma concentration of gabapentin (C ma ⁇ ) is lower than for an equivalent dose of conventional immediate release formulation, e.g., as low as 0.5 of that C max .
  • the plasma concentration of the gabapentin is up to 3 times, or 1.5 to 2.5 times that provided by a conventional release formulation at 8 to 24 hours after dosing.
  • a formulation wherein the time from C max to 50% of C max is from 2 to 24 hours, 3 to 12 hours, or 4 to 8 hours.
  • Gabapentin or other active ingredient formulations that are essentially 100% immediate release demonstrate nonlinearity in absorption such that the AUC is not doubled with doubling of the dose.
  • the present invention is also directed to the composition wherein the active ingredient or gabapentin is released at a C max and AUC (absolute bioavailability of active ingredient) that is 25-100%, 30-100%, 35-100%, 40-100%, 45%-100%, 50%-100%, 55-100%, 60-100%, 65%-100%, 70%-100%,, 75%-100%, 80%-100%, 85-100%, 90-100%, 95%-100%, proportional to the dosage strength of gabapentin or an active ingredient.
  • a C max and AUC absolute bioavailability of active ingredient
  • the AUC may correspondingly increase by 0.5x, 0.6x, 0.7x, 0.8x, 0.9x, Ix (times), l.lx, 1.2x, 1.3x, 1.4x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x, or 2.0x.
  • the bioavailability of gabapentin from the invention is from about 1.0 to about 1.5 that of immediate release gabapentin at lower doses, and from about 1.0 to about 3.0 that of immediate release gabapentin at higher doses.
  • gabapentin or other active ingredient is in a single dose of a formulation totaling 900 mg or 800 mg or 700 mg or 600 mg or 500 mg or 400 mg or 375 mg or 350 mg or 325 mg or 300 mg or 275 mg or 250 mg of gabapentin, wherein 180 mg to 540 mg, 160 to 480 mg, 140 to 420 mg, 120 to 360 mg, 100 to 300 mg, 80 to 240 mg, 75 to 225 mg, 70 to 210 mg, 65 to 195 mg, 60 to 180 mg, 55 to 165 mg, and 50 to 150 mg of gabapentin or other active ingredient is released in the first phase from the pH independent soluble polymer.
  • the present invention also is directed to 180 mg to 540 mg, 160 to 480 mg, 140 to 420 mg, 120 to 360 mg, 100 to 300 mg, 80 to 240 mg, 75 to 225 mg, 70 to 210 mg, 65 to 195 mg, 60 to 180 mg, 55 to 165 mg, and 50 to 150 mg of gabapentin or other active ingredient is released over a sustained period during the second phase from the pH independent insoluble polymer.
  • the present invention is also directed to 270 to 405 mg, 240 to 360 mg, 210 to 315 mg, 180 to 270 mg, 150 to 225 mg, 120 to 180 mg, 110 to 170 mg, 105 to 160 mg, 100 to 150 mg, 80 to 125 mg, and 75 to 115 mg of the gabapentin or other active ingredient is released during third phase from the pH dependent soluble polymer.
  • lower mg ranges will be required, and can be simply calculated from the above data for smaller overall dosages of the drug.
  • the present invention is also directed to using the composition in dosing regimens of 500 mg of gabapentin or an active ingredient administered twice daily as a single unit dose or as two unit doses of 250 mg each, or 900 mg of gabapentin or active ingredient administered twice daily as three unit doses of 300 mg each or as two unit doses of 450 mg each or 750 mg of gabapentin or active ingredient administered twice daily as single unit doses or as two unit doses of 375 mg each.
  • compositions produced by a process comprising the steps of separately mixing an active ingredient a pH independent soluble polymer, a pH independent insoluble polymer, and a pH dependent soluble polymer, forming the resulting mixtures into mini-tablets, and filling the mixture of mini-tablets into a capsule suitable for oral administration.
  • the present invention is also directed to a composition produced by the process comprising the steps of mixing an active ingredient with a filler, granulating the mixture, blending the granulated mixture with a lubricant, compressing the blended mixture into mini-tablets, coating the mini-tablets with excipients from a pH independent soluble polymer, a pH independent insoluble polymer, and a pH dependent soluble polymer, drying the coated mini-tables, and formulating the mixture of coated mini-tablets into a single unit dosage form suitable for oral administration.
  • the present invention is also directed to a composition comprising gabapentin or pregabalin or other active ingredient used for the treatment of a neurological disorder or injury selected from the group consisting of epilepsy, in the treatment of seizures secondary to stroke, head/brain trauma or peri- or post-operative neurosurgery, multiple sclerosis, or involuntary action tremors.
  • the present invention is also directed to a composition comprising gabapentin or pregabalin or other active ingredient used for the treatment of chronic pain associated with neuropathic, muscular and skeletal pain, tardive dyskinesia or migraines, reflex sympathetic dystrophy syndrome (RSD) [also known as complex regional pain syndrome (CRPS)] and fibromyalgia or muscle disorders.
  • RSD reflex sympathetic dystrophy syndrome
  • CRPS complex regional pain syndrome
  • the present invention is also directed to a composition comprising psychiatric disorders such as, but not limited, to bipolar disease, panic, anxiety, depression, alcoholism and manic behavior.
  • the formulations or compositions may also be used to treat the conditions described in U.S. Patent No. 6,310,098 (which is incorporated herein by reference) and in particular hormonal variation in menopausal other related syndromes of hot flashes, fever, nausea and emesis.
  • the present invention is also directed to treatment of symptoms of post menopausal woman selected from the group consisting of urge incontinence, vaginal dryness, and dry eye syndrome.
  • Figure 1 shows the cumulative in vitro dissolution profile for a formulation comprising 80% percent of the Batch B mini-tablets, 10% of the Batch C mini-tablets wherein Eudragit RL30D and Eudragit RS30D are at a ratio of 2:8, and 10% Batch D mini-tablets with a 15% Eudragit L30D-55 content.
  • Figure 1 shows three different tests of the gabapentin capsules with milligrams of gabapentin released shown on the y axis.
  • Fig. 2 shows the cumulative in vitro dissolution profile for a formulation comprising 20% percent of the Batch B mini-tablets, 40% of the Batch C mini-tablets wherein Eudragit RL30D and Eudragit RS30D are at a ratio of 2:8, and 40% Batch D mini-tablets with a 15% Eudragit L30D-55 content.
  • Figure 2 shows three different tests of the gabapentin capsules with milligrams of gabapentin released shown on the y axis.
  • the present invention is directed to a composition comprising an active ingredient coated by a pH independent soluble polymer excipient, an active ingredient coated by a pH independent soluble polymer excipient, and an active ingredient coated by a pH dependent soluble polymer excipient.
  • the present invention is directed to a composition or formulation comprising an active ingredient such as gabapentin, and the drug pregablin.
  • compositions or formulation of the present invention include, but are not limited to the table below.
  • composition's active ingredients including gabapentin may be applied for uses by any convenient means, including orally using a formulation according to the invention for the treatment of neurological disorders or injury, treatment of chronic pain, treatment of psychiatric disorders or mental disease, treatment of menstrual related symptoms, and post-menopausal related symptoms.
  • the dosage for these uses will generally be lower than that used for epilepsy and will generally be in the range of 100 to 3,000 mg per day which may be given in divided doses up to 2 or 3 times per day.
  • an immediate release formulation, or a formulation according to the invention is used, the dosages are as given below in relation to the formulation according to the invention.
  • drugs i.e., active ingredients in particular pharmaceutical formulations
  • they necessarily pass through the gastrointestinal tract.
  • Active ingredients in a formulation or composition of the present invention first enter the highly acidic environment of the stomach, where the pH ranges from pH 1-3.
  • the small intestine comprising of the duodenum, jejunum and ileum, is predominantly where nutrient/drug absorption occurs.
  • the small intestine progresses from a highly acidic environment ( ⁇ pH 4-5 in the duodenum) to a less acidic environment ( ⁇ pH 6- 7 in the jejunum and ileum).
  • an excipient is defined as an inert substance used as a diluent or vehicle for a drug.
  • the excipient may be in a form of a solid forming coating, or a liquid coating, or semi-solid capsule that coats an active drug ingredient such as gabapentin.
  • the excipients in the present invention are defined in three different coating forms being a pH independent soluble polymer, a pH independent insoluble polymer, and a pH dependent soluble polymer.
  • the pH dependent soluble polymer is soluble in a particular pH environment. Accordingly, the soluble polymer becomes soluble at a particular pH rather than a soluble at any pH.
  • a pH independent soluble polymer is defined as pharmaceutically grade carrier or vehicle that readily dissolves in the soluble environment including the stomach, and include, for example and without limitation, calcium phosphate dihydrate, calcium sulfate dihydrate, microcrystalline cellulose, cellulose derivatives, dextrose, gelatin, lactose, anhydrous lactose, spray-dried lactose, lactose monohydrate, mannitol, starches, sorbitol and sucrose.
  • Further examples include acacia, hydroxypropylmethylcellulose, hydroxypropylcellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, polyethyleneglycol, cellulose acetate butyrate, hydroxyethyl cellulose, ethyl cellulose, polyvinyl alcohol, polypropylene, dextrans, dextrins, hydroxypropyl-beta- cyclodextrin, chitosan, copolymers of lactic and glycolic acid, lactic acid polymers, methacrylic acid co-polymer containing acidic groups, glycolic acid polymers, polyorthoesters, polyanyhydrides, polyvinyl chloride, polyvinyl acetate, polyvinylalcohol, polyethylene glycol co-polymer, ethylene vinyl acetate, lectins, carbopols, silicon elastomers, polyacrylic polymers, maltodextrins, fructos
  • a pH independent insoluble polymer is also used in the composition to coat the active ingredient.
  • a pH independent insoluble polymer is a pharmaceutically grade carrier or vehicle that coats an active drug ingredient such as gabapentin.
  • pH independent insoluble polymer examples include, but are not limited to, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, aminoacryl methacrylate co-polymer E including methyl cellulose, ethyl cellulose, or a combination thereof and aminoalkylmethane acrylate co-polymers RS and RL, including Eudgragit RL30D, and Eudragit RS30 D.
  • the pH independent insoluble polymer may have a low permeability and swelling such as Eudragit RS30D or a pH independent insoluble polymer having a high permeability and swelling such as Eudragit RL30D.
  • Such variations in the permeability of the insoluble pH independent membrane affect the release kinetics of the active ingredient or gabapentin allowing for a sustained release up to 12 hours after original dosing in the stomach and upper small intestine including the duodenum.
  • a pH dependent soluble polymer is a pharmaceutically grade carrier or vehicle that coats an active ingredient such as gabapentin.
  • the pH dependent soluble polymer include, but are not limited to, natural polymers such as purified shellac and white shellac, synthetic polymers such as cellulose derivative polymers: hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethyl cellulose, cellulose acetate trimellitate, cellulose acetate phthalate, acrylic polymers such as those obtained from acrylic acid and/or methacrylic acid, polymers obtained from acrylic acid and/or methacrylic acid and a carboxylic ester, and polyvinyl alcohol type polymers such as polyvinyl acetate phthalate.
  • pH dependent soluble polymers include those with a carboxyl group obtained from acrylic acid and/or methacrylic acid or those obtained from acrylic acid and/or methacrylic acid and a carboxylic ester.
  • carboxylic ester used herein include acrylic esters and methacrylic esters such as methyl acrylate, ethyl acrylate, n-propyl acrylate, isopropyl acrylate, n-butyl acrylate, isobutyl acrylate, t-butyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, methyl methacrylate, ethyl methacrylate, n-propyl methacrylate, isopropyl methacrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, n-butyl methacrylate, isobutyl methacrylate and t-butyl methacrylate.
  • Examples of methacrylic acid-methyl methacrylate co-polymers include Eudragit LlOO or SlOO.
  • the pH dependent soluble polymer Eudragit L30D-55 and Eudragit FS30D may be used in the composition. Such pH dependent soluble polymers dissolve in a certain pH environment rather than upon the soluble contents.
  • Eudragit L30D-55 can be used for dissolution of the active ingredient above pH 5.5
  • Eudragit FS30D may be used for dissolution of the active ingredient above pH 7.0 to provide a release in the small intestine including the duodenum, jejunum, and ileum.
  • Eudragit L30D-55 would be susceptible to dissolution of the active ingredient such as gabapentin when pH changes to over pH 5.5 at some point in the duodenum of the small intestine while Eudragit FS30D would dissolve above pH 7.0 at some point in the jejunum and ileum.
  • the pH dependent soluble polymer may also be combined with a disintegrant, which will affect the release of the active ingredient of the formulation or composition.
  • the composition of the present invention may further comprise a disintegrant, a flavor component, a colorizer, a sweetener a binder, a filler, a lubricant, a glidant, a plasticizer or a combination thereof.
  • the core mini-tablets of gabapentin or other active agents may be formed using conventional techniques, e.g., they may contain disintegrants; including, but not limited to, croscarmellose sodium or sodium starch glycolate; binders, including, but not limited to, polyvinylpyrrolidone; fillers including, but not limited to microcrystalline cellulose and/or lubricants including, but not limited to, magnesium stearate.
  • examples of glidant include, but are not limited to, talc, and colloidal anhydrous silica.
  • Gabapentin in powder form may be coated directly or may be granulated, using known dry or wet techniques (compacting), followed if desired by screening and tabletting to obtain the desired particle size.
  • the coating may, if desired also contain a plasticizer or adjuvant.
  • Suitable plasticizers for use in the second and third phase coating including but not limited to, polyethylene glycol, dibutyl phthalate, diethyl phthalate, dibutyl sebecate and citric acid esters,phthalates, phosphates, citrates, adipates, tartrates, sebacates, succinates, glycolates, glycerolates, benzoates, myristates, polyethylene glycols, polypropylene glycols, and halogenated phenyl, triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate
  • Suitable adjuvants for inclusion in these coatings include talc, silicon dioxide, titanium dioxide, coloring agents, soya lecithin and magnesium stearate.
  • Suitable barrier coatings for placing each of the various coated mini-tables or other power forms of the active ingredient as described above include, but are not limited to, hydroxypropylmethylcellulose, methycellulose, and shellac.
  • the various coatings used above may contain different coloring agents to enable them to be readily distinguished and also to provide a distinguishing multicolored appearance to the overall formulation, e.g., where the mixture of the various components is put up in a clear capsule.
  • the present invention is also directed to an oral controlled-release formulation of gabapentin, adapted to release part of the gabapentin in the stomach (thereby providing the drug to the stomach and the upper small intestine) and to begin to rapidly release in part in the lower small intestine including in part in the duodenum, and in part in the jejunum and ileum.
  • the formulation is adapted to release the gabapentin or other active ingredients in three phases. In the first phase, gabepentin or other active ingredients is released rapidly in the stomach. The release of gabapentin or other active ingredients is controlled by a pH independent soluble polymer coating.
  • gabepentin or other active ingredients is released over a sustained period mainly in the lower stomach, duodenum and jejunum sections of the small intestine.
  • the release of gabapentin or other active ingredients is controlled by the pH independent insoluble polymer coating and is dependent upon the water permeability of said coating membrane.
  • the release of gabepentin or other active ingredients is delayed until the jejunum and ileum sections of the small intestine, wherein gabepentin or other active ingredients is released rapidly dependent upon the pH dependent polymer coating that dissolves in various pH's ranging from 4 to 10.
  • the immediate (first phase) release component which are designed to release the gabapentin quickly when ingested into the stomach, may be formed by making mini-tablets using a pH-independent soluble polymer as the coating. These may or may not incorporate a disintegrant. These mini-tablets, which may for convenience be the core mini-tablets described immediately above, may be provided with a barrier coat (which can serve to protect the gabapentin from interaction with any subsequent coatings), e.g., in a pan coater or by spraying in a fluid bed system.
  • a barrier coat which can serve to protect the gabapentin from interaction with any subsequent coatings
  • This barrier coat may be provided by use of a suitable polymer, e.g., hydroxpropylmethylcellulose, dissolved or suspended in an organic solvent, or a mixture of organic solvents, or a mixture of organic solvents and water, or in solution, dispersion or aqueous emulsion.
  • a suitable polymer e.g., hydroxpropylmethylcellulose, dissolved or suspended in an organic solvent, or a mixture of organic solvents, or a mixture of organic solvents and water, or in solution, dispersion or aqueous emulsion.
  • the thickness of the mini-tablet coating at the various stages of its production may also be varied to achieve the required release characteristics of the drug through the coating.
  • the coatings may have a thickness of 25 to 150 microns.
  • the second phase component is designed to achieve a timed release of the gabapentin or other active ingredient using a pH independent insoluble polymer as the coating.
  • This may, for convenience, be the immediate release component or some other suitable gabapentin-containing mini-tablet, carrying a coating of pH independent insoluble polymer.
  • This coating may for example be one or a mixture of a water-insoluble polymer having high permeability and swelling that is pH independent, e.g., Eudragit RL30D, and a water-insoluble polymer having low permeability and swelling that is pH independent, e.g., Eudragit RS30D.
  • This coating may, if desired, contain a plasticizer or adjuvant.
  • the third phase component may be formed from mini-tablets, which may contain a disintegrant, which are coated with a pH-dependent soluble polymer or enteric material including, but not limited to, cellulose acetate phthalate, hydroxypropylmethylcellullose phthalate or an anionic methacrylic acid polymer such as Eudragit L30D-55 for dissolution above pH 5.5, or Eudragit FS30D for dissolution above pH 7.0.
  • a pH-dependent soluble polymer or enteric material including, but not limited to, cellulose acetate phthalate, hydroxypropylmethylcellullose phthalate or an anionic methacrylic acid polymer such as Eudragit L30D-55 for dissolution above pH 5.5, or Eudragit FS30D for dissolution above pH 7.0.
  • the pH dependent soluble polymer Eudragit L30D-55 dissolves and releases the active ingredient in environments with pH 5.5 or above, and can be targeted for the duodenum to the jejunum wherein the environmental pH
  • the pH dependent soluble polymer Eudragit FS30D dissolves and releases the active ingredient in environments with pH 7.0 or higher, and can be targeted for the jejunum and ileum, wherein the pH environment changes to over 7.
  • This release of the gabapentin in the lower small intestine is achieved by coating with a membrane with pH-dependent solubility, and more particularly with a membrane which is soluble at a pH greater than 5.5, so that it remains intact in the stomach and the upper part of the small intestine (duodenum) and dissolves when a pH of greater than 5.5 is reached in the lower small intestine (i.e., the jejunum and ileum), thus releasing the drug.
  • the formulation is coated with an Eudragit S membrane (which dissolves at a pH higher than 7), there is little or no release in solutions up to pH 6. But when the pH increases to greater than 7, a rapid dissolution of the drug occurs.
  • the present invention is also directed to a formulation of gabapentin administered such that it is effective for the desired treatment. Effective amounts of the gabapentin will depend upon the patient (patients with renal insufficiency may need lower doses than those with normal kidney function), the condition to be treated, the frequency of administration, and the specific composition according to the invention used to deliver the gabapentin. While individual needs vary, determination of optimal ranges of effective amounts of gabapentin is within the skill of the art.
  • the formulation may be administered in doses of between 100 and 1500 mg to be taken either in the morning for the suppression of symptoms occurring mostly during the daytime, or at night for the suppression of symptoms occurring mostly at night, or both, thus giving a total daily dose of from 100 to 3000 mg of gabapentin.
  • Doses of 250 to 750 mg morning and/or night giving a total daily dose of 250 to 1500 mg, and doses of 350 to 600 mg morning and/or night giving a daily dose of 350 to 1200 mg may also be administered.
  • the formulation may have three components, a first immediate release component, a second sustained release component (over the lower stomach and duodenum) and a third component designed to release its gabapentin content in the lower small intestine such as the jejunum and ileum.
  • the provision of these three components may be achieved in a number of different ways.
  • One such way is by forming a core of the last component bearing (e.g., surrounded by) a layer of the sustained release component, which in turn bears (e.g., is surrounded by) a further layer of the immediate release component.
  • the desired release pattern may be achieved by providing a mixture, in appropriate proportions, of three separate components having the desired release characteristics.
  • the excipients to be used in the three components may be chosen from those known in the art to provide the desired properties to that component.
  • a process for the production of a formulation according to the invention which comprises mixing the active ingredient with one or more suitable excipients, diluents or carriers and forming the resulting mixture into a suitable controlled release formulation.
  • Each unit dose contains from 50 to 95%, or 60% to 80% w/w of the gabapentin.
  • the formulation of the present invention is a multidose formulation in the form of mini tablets for example.
  • Multidose formulations comprise a plurality of small units (tablets) in which the individual units that make up a unit dose spread in a wide area of the gastrointestinal tract thus avoiding or reducing any possible problems of irritation of the mucosa due to a high concentration of the formulation.
  • Multidose forms of the gabapentin may be in the form of crystals, granules, pellets or tablets of very small dimensions (mini-tablets), some or all of which are coated as described below.
  • the size of the small units of the multidose forms may vary from 0.1 to 3.5 mm, but does not exceed 5 mm.
  • the smaller these small units are, the wider the distribution in the gastrointestinal tract.
  • units greater than 5 mm are retained in a full stomach, units smaller than 5 mm pass through the stomach much more rapidly and in a similar way to liquids.
  • the description that follows refers to gabapentin in mini-tablet form, but it is also valid for the other multidose forms, e.g., crystals, pellets and granules.
  • the coated mini-tablets may be dried with hot air, e.g., at about 3O 0 C, for a suitable time, e.g., about 30 minutes.
  • mini-tablets of gabapentin may be formed by a first step involving mixing the drag with a suitable filler, granulating the mixture using a binder solution, drying the granules and, if desired screening them, blending with a lubricant, and where desired a disintegrant, and compressing the mixture, e.g., using a rotary or single punch tableting machine with punches having a diameter of say 3 mm.
  • a second step in which some of these mini-tablets are coated, e.g., by spraying in a coating pan, with a solution/suspension, e.g., an alcoholic or aqueous solution, of a suitable polymer mixture, optionally together with a plasticizer and/or adjuvant and drying to form an inner coating on the tablets.
  • a solution/suspension e.g., an alcoholic or aqueous solution
  • a suitable polymer mixture optionally together with a plasticizer and/or adjuvant and drying to form an inner coating on the tablets.
  • the coating applied in this step provides a barrier to protect the active ingredient from interacting with subsequent coatings.
  • some of these tablets may be subjected to a third step in which a further coating designed to achieve a timed release of the drug is applied.
  • Some of the mini-tablets product of the second step may be provided, in a fourth step, with an enteric coating, e.g., by spraying the mini-tablets with a solution or suspension of enteric coating material.
  • the final composition may then be made up by mixing the products of the second and/or third and fourth steps in such proportions as to give the desired overall release profile, and then formulating the mixture into a single unit dosage form, e.g., by filling into capsules or monodose sachets, or in other pharmaceutical forms suitable for oral administration.
  • the amount of drug released in vivo at each of these times may be predicted by use of the in vitro dissolution rate method described in the US Pharmacopoeia, e.g., a suitable combination of the tests set out in Example 5. Accordingly, we provide formulations having dissolution rates in Example 5 and corresponding to the percentages to be released as set out above.
  • the amount of drug released in vivo can be evaluated in healthy volunteers who are first screened for acute or recurrent illness, for prescription, over the counter (OTC) or illegal drug use, and/or for any other reasons making them unsuitable for participation in pharmacokinetic studies.
  • volunteers are assigned to the treatment to be received and equipped with an in-dwelling venous catheter for blood collection.
  • the doses are given at time zero, and blood samples are collected through the catheter at predetermined intervals over the next 48 hours.
  • the plasma is separated from the blood by centrifugation, and then assayed for gabapentin content using a validated analytical method. Data are displayed, and evaluated using pharmacokinetic software for C max (maximum concentration), T max (time to maximum concentration), AUC (area under the curve) and other pharmacokinetic parameters.
  • the present invention is also directed to a composition wherein the AUC drug plasma level of the gabapentin is greater than 100 to 200% of, that obtainable for an equivalent dose of conventional immediate release gabapentin, e.g., that sold under the trademark Neurontin®.
  • AUC is evaluated either by the integration of the data points from time zero to time infinity, when those data points are concentrations (levels) of gabapentin in plasma following single doses of gabapentin either as Neurontin® or as a formulation according to this invention (Xenolev-CRTM) in healthy volunteers, and/or in the target population, or by the integration of the equivalent data points during one dosing interval at the pharmacokinetic steady state in which long- term daily dosing balances daily elimination.
  • the T max is the same as, or up to 3.0 times greater than, the corresponding T max for an equivalent dose of conventional immediate release formulation.
  • the time to C max is desirably from 2 to 6 hours from dosing.
  • the peak plasma concentration of gabapentin is lower than for an equivalent dose of conventional immediate release formulation, e.g., as low as 0.5 of that C max .
  • the plasma concentration of the gabapentin is 1.5 to 2.0 to 3.0 times that provided by a conventional release formulation at 8 to 24 hours after dosing.
  • a formulation wherein the time from C max to 50% of C ma ⁇ is from 2 to 24 hours, or 3 to 12 hours, or 4 to 8 hours is envisioned.
  • a formulation wherein the time from C max to 50 percent of C max is greater than the corresponding time for an immediate release gabapentin by a factor of 1.1 to 3, or 1.5 to 2.5, is further envisioned.
  • Gabapentin formulations that are essentially 100% immediate release i.e., not according to this invention) demonstrate nonlinearity in absorption such that the AUC is not doubled with doubling of the dose.
  • the present invention active ingredients or gabapentin is released at a C max and AUC (absolute bioavailability of active ingredient) that is 25-100%, 30-100%, 35-100%, 40-100%, 45%-100%, 50%-100%, 55-100%, 60-100%, 65%-100%, 70%- 100%,, 75%-100%, 80%-100%, 85-100%, 90-100%, 95%-100%, proportional to the dosage strength of gabapentin or an active ingredient.
  • C max and AUC absolute bioavailability of active ingredient
  • the AUC may correspondingly increase by 0.5x, 0.6x, 0.7x, 0.8x, 0.9x, Ix (times), l.lx, 1.2x, 1.3x, 1.4x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x, or 2.Ox.
  • the C max may correspondingly increase by 0.5x, 0.6x, 0.7x, 0.8x, 0.9x, Ix (times), l.lx, 1.2x, 1.3x, 1.4x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x, or 2.Ox.
  • the bioavailability of gabapentin from the invention is from about 1.0 to about 1.5 that of immediate release gabapentin at lower doses, and from about 1.0 to about 3.0 that of immediate release gabapentin at higher doses.
  • T max should be unchanged with increase or decrease in dose. Equivalence in other pharmacological and physiological situations is also evaluated using plasma concentrations. For example, it is well known from peer-reviewed medical literature that there is no effect of food on the concentrations of gabapentin in plasma following oral administration.
  • a dose of a formulation according to the invention providing 900 mg of gabapentin (which may be administered as, e.g., 2 unit doses of 450 mg or 3 unit doses of 300 mg each) and given twice daily can give plasma peaks and troughs, after dosing to steady state, of approximately 4.4 and 2.3 micrograms per ml respectively, with the peaks approximately 5 hours after each dosage and the troughs just before each subsequent dose.
  • an immediate release dosage of 900 mg given twice daily will give a peak at 3 to 4 hours after each dosage the peak being approximately 6.3 micrograms per ml, and the troughs being approximately 2 micrograms per ml, the trough again being just before the subsequent dose.
  • peaks and troughs with 600 mg of an immediate release formulation given three times per day have values of approximately 4.7 and 1.95 micrograms per ml respectively.
  • a formulation according to the invention administered as 900 mg doses twice a day (bd) can match closely the peaks and troughs of 600 mg doses administered TID.
  • the values given in this paragraph are for an average adult human.
  • the desired proportion of those components can be determined by administration of each component separately to healthy volunteers and performing the pharmacokinetic analyses as described above. Straightforward mathematical calculations can then be used to define the exact proportion of each component to achieve the desired overall release profile of the active ingredient.
  • Unit doses of the formulation according to the invention can contain 500 mg or less of gabapentin. One or more of these unit doses may be used to make up the dose to be administered at any one time. Unit doses containing more than 500 mg of gabapentin can be difficult for some patients to swallow and may lead to erratic compliance with the desired dosage regimen. The unit doses are in solid form. [0059] Hot-melt extrusion is known as a method for producing polymer-based sustained-release pharmaceutical formulations.
  • Suitable polymers include derivatized cellulose, poly(methacrylate) derivatives, poly(ethylene-co-vinyl acetate), poly(ethylene), poly(vinyl acetate-co-methacrylic acid), epoxy resins and caprolactones.
  • an effective amount of powdered gabapentin is mixed with a polymer, and optionally with a plasticizer such as polyethylene glycol. Other components may be added as required.
  • the ratio of the gabapentin to the excipients is generally from about 0.01 to about 99.99%, or from about 20 to about 80% w/w, depending on the desired release profile.
  • the mixture is then placed in the hopper of an extruder and passed through the heated area of the extruder at a temperature that will melt or soften the mixture to form a matrix throughout which the gabapentin is dispersed.
  • the molten or softened mixture is then extruded through a die, or other such element, at which time, the mixture (now called the extrudate) begins to harden. Since the extradate is still warm or hot upon leaving the die, it may be easily shaped, molded, chopped, ground, spheronized into beads, cut into strands, tabletted or otherwise processed to the desired physical form.
  • a further formulation technique that may be used to provide the desired release profile is that known as hot melt extrusion.
  • the equipment used to produce the hot melt formulation may be any commercially available model equipped to handle dry feed and having a solid conveying zone, one or more heating zones, and an extrusion die.
  • a two-stage single screw extruder such as that manufactured by CW. Brabender Instruments Incorporated (NJ) is one such apparatus. It is particularly advantageous for the extruder to possess multiple separate temperature controllable heating zones.
  • Many conditions may be varied during the extrusion process to arrive at a particularly desired release pattern. Such conditions include, by way of example, composition of the formulation, feed rate, operating temperature, extruder screw RPM, residence time, die configuration, heating zone length and extruder torque and/or pressure. Methods for the optimization of such conditions are known to the skilled artisan.
  • the hot-melt extrusion may require higher processing temperature, pressure and/or torque than when an excipient having a lower molecular weight is employed.
  • a plasticizer and, optionally, an antioxidant, in a formulation comprising very high molecular weight excipients, processing temperature, pressure and/or torque may be reduced.
  • the hot melt formulations may optionally be covered with various coatings as described above.
  • the administration of the gabapentin can be carried out in combination with other suitable therapeutic treatments that are useful for treating the condition(s) to be treated.
  • the treatments may be curative, but more usually will be prophylactic.
  • the patient to be treated may be e.g., a human.
  • the patient can be either female or male.
  • the hot flash may be a primary symptom resulting from menopausal or post menopausal hormonal variation.
  • the hot flash can also be drug-induced by an anti-estrogen compound (e.g., tamoxifen, leuprolide acetate, etc.) or surgically induced by removal of estrogen-producing tissues (e.g., total abdominal hysterectomy, bilateral salpingo-oophorectomy, etc.).
  • an anti-estrogen compound e.g., tamoxifen, leuprolide acetate, etc.
  • surgically induced by removal of estrogen-producing tissues e.g., total abdominal hysterectomy, bilateral salpingo-oophorectomy, etc.
  • the hot flashes typically occur as a side-effect of androgen-dependent therapy for metastatic prostate cancer. They can be either surgically induced (e.g., bilateral orchiectomy) or drug-induced (e.g., treatment with a gonadotrophin-releasing- hormone agonist, leuprolide acetate, etc.).
  • the present invention encompasses either reducing the number of symptomatic events, reducing the severity of symptomatic events, or both.
  • the gabapentin can also act as an anti-pyretic agent, thereby moderating thermoregulation of a patient.
  • the present invention also provides a method of treating fever in a patient by administering a composition according to the invention to a patient experiencing a fever under conditions effective to treat the fever.
  • the present invention encompasses reducing or eliminating the fever, either completely or for a limited duration of time after each dose (e.g., up to about 24 hours).
  • the gabapentin can also act as anti-emetic agent for the treatment of nausea and emesis.
  • Nausea and emesis are often induced by stimulation of either the cliemoreceptor trigger zone or the emesis (or vomiting) centre in the central nervous system (CNS).
  • Such stimulation can be caused by afferent stimulation (e.g., tactile pharyngeal impulses, labyrinthine disturbances, motion, increased intracranial pressure, pain, distension of viscera or psychological factors) or blood born emetic substances (e.g., as seen during pregnancy, cancer chemotherapy, uraemia, radiation therapy, electrolyte and endocrine disturbances, or the presence of chemical emetics).
  • afferent stimulation e.g., tactile pharyngeal impulses, labyrinthine disturbances, motion, increased intracranial pressure, pain, distension of viscera or psychological factors
  • blood born emetic substances e.g., as seen during pregnancy,
  • a further aspect of the present invention relates to a method of treating nausea and emesis by administering a composition according to the invention to a patient experiencing nausea and/or emesis under conditions effective to treat the nausea and/or emesis.
  • the present invention encompasses reducing or eliminating the feeling of nausea as well as reducing or eliminating the frequency of emesis, either completely or for a limited time after each dose (e.g., up to about 24 hours).
  • Administration of the formulation can occur while a patient is experiencing nausea or emesis or in anticipation of the patient experiencing nausea or emesis.
  • U.S. Patent No. 6,310,098 mentions the use of gabapentin in the treatment of hormonal variations, but very much emphasizes the use in post menopausal or menopausal women.
  • gabapentin can be used to treat dysmenorrhea and/or reduce or eliminate the unpleasant effects, e.g., premenstrual tension, mood swings, and pain, for example in the lower abdomen, which are caused by menstruation.
  • the gabapentin may be given before or at the first signs of menstruation or may be used to treat the adverse effects once the menstruation has started. The treatment may be continued for as long as the menstruation lasts.
  • Powdered gabapentin was blended with microcrystalline cellulose (Avicel pHlOl) in a high shear mixer-granulator.
  • the powder mixture containing the desired amount of gabapentin was then granulated using a binder solution of polyvinylpyrrolidone (Kollidon K30 BASF).
  • the binder solution was added to the powder mixture in the granulator in aliquots over a period of time (usually about 5 minutes, but depending on the batch size) until a suitable granulated mass was formed.
  • the wet granules were then discharged from the granulator and dried in a hot-air oven (Gallenkamp Hotbox) to produce dry granules.
  • the dry granules were screened through a sieve (lOOO ⁇ m Erweka), and blended with sodium starch glycolate super disintegrant (Explotab) and then further blended with magnesium stearate (BP Thew Arnott) as a lubricant and analyzed for drug content, before being fed to the hopper of a single punch (concentric cam) or rotary tablet press (F3 Manesty) fitted with 3.0mm deep concave punches to form tablets of ca 2.3mm thickness (Batch A mini-tablets). These tablets have the following composition:
  • Batch B Another batch, Batch B, of mini-tablets was prepared in a similar manner to that described for Batch A, with the exception that Batch B was coated (Huttlin Microlab fluid bed coater) with a barrier coat of Methocel E5
  • Batch B forms the immediate release (first phase) component of the drug delivery system. These tablets have the same composition as the Batch A tablets except that the hydroxypropylmethylcellulose forms 5% of the overall weight of the tablets, and they have an average thickness of 2.5 mm. The resulting cumulative in vitro dissolution profile for these Batch B mini-tablets is shown in Example 5.
  • Batch B mini-tablets from Example 2 were coated with a membrane of Eudragit polymers (Degussa AG) to achieve a timed release of the drug.
  • the mini- tablets were placed in the coating machine, (bottom spray Wurster), and a mixture of Eudragit RL30D (a water-insoluble polymer having high permeability and swelling that is pH independent insoluble polymer, i.e., methacrylate copolymer with trimethyl-ammonioethylmethacrylate functional groups) and Eudragit RS30D (a water-insoluble polymer having low permeability and swelling that is pH independent— methacrylate copolymer with trimethyl-ammonioethylmethacrylate functional groups).
  • Eudragit RL30D a water-insoluble polymer having high permeability and swelling that is pH independent insoluble polymer, i.e., methacrylate copolymer with trimethyl-ammonioethylmethacrylate functional groups
  • talc glidant
  • triethyl citrate plasticiser
  • L30D-55 anionic polymer with methacrylic acid as a functional group
  • FS30D for dissolution above pH 7.0
  • anionic polymer with methacrylic acid as a functional group from Degussa AG anionic polymer with methacrylic acid as a functional group from Degussa AG.
  • a formulation comprising 80 percent Batch B minitabs, 10 percent Batch C
  • Example 7 Dissolution of Various Formuations of Batch B, C, and D
  • a formulation comprising 20 percent Batch B minitabs, 40 percent Batch C (10% RL/RS (2:8) minitabs and 40 percent Batch D (15% L30D-55) minitabs (the percentages being w/w) was added to Size 00 gelatin capsules to a total dose of 375 mg gabapentin.
  • the dissolution conditions used were as per Example 6. The test was repeated three times (see Figure 2) .
  • Example 8 In Vivo Pharmacological Properties of Formulations Containing Batch B. Batch C, and Batch D
  • Example 6 and 7 can be predicted to have the properties shown in the following table when used in humans.
  • the table also shows comparable properties for a 600 mg single dose of reference immediate-release (IR) gabapentin in humans. Delayed dissolution in laboratory experiments can be used to predict delayed dissolution in vivo. These simulated numbers reflect the physical properties demonstrated in dissolution studies shown in Example 5 and Figures 1 and 2.
  • IR immediate-release
  • Control data are actual data from clinical observations; other data are predicted (simulated) values, and are composites for the designated mixtures of IR, SR and DR in each case; simulations are for a 375 mg dose.
  • Example 9 Capsules of Formulations Comprising Batch B, Batch C, and Batch D to Human
  • Capsules of Batch B minitabs from Example 2, Batch C minitabs from Example 3, Batch D minitabs from Example 4, and the capsules of Examples 6 and 7 are administered to healthy human volunteers at a dose of 375 mg gabapentin and blood samples taken at appropriate time intervals. These samples are then analyzed to provide the pharmacokinetic profile for the batch or capsule under examination.
  • Example 10 Analysis of Gabapentin Using Reversed Phase Gradients
  • Analysis of gabapentin dissolution samples is by reversed phase gradient HPLC using varying proportions of pH 7.8 phosphate buffer and methanol as mobile phase.
  • Gabapentin is derivatized with orthophthalaldehyde (OPA) to improve its UV absorption and phenylalanine is employed as an internal standard.
  • OPA orthophthalaldehyde
  • the derivatization reaction takes place in the autosampler. Separation is performed on a Zorbax Eclipse AAA 4.6 x 150 mm, 5 ⁇ m particle size HPLC column (Agilent part no. 994400-902) and detection is by UV absorbance at 338 nm. Quantification of gabapentin in samples is on the basis of peak area measurements, with calibration against standards of known gabapentin concentration.
  • Example 11 Treatment of Hot Flashes using Gabapentin Formulations
  • the following formulation is used. Around 360 mg of gabapentin is coated by a suitable pH independent soluble polymer, for example, hydroxypropylmethylcellulose. Next, 270 mg of gabapentin is coated by different two water insoluble polymers, one having high permeability and the other having low permeability, both, however, having swelling that is pH independent.
  • Eudragit RL30D high permeability
  • Eudragit RS30D low permeability
  • 270 mg of gabapentin is coated with both Eudragit L30D-55 and Eudragit FS30D.
  • the coated gabapentin tablets above are dried and then packaged into a single unit dosage form for oral administration.
  • Ingestion results in (1) an immediate release of the hydroxypropylmethylcellulose-coated gabapentin in the stomach, (2) a sustained released dose of the water insoluble-coated gabapentin in the stomach and upper small intestine, and (3) a delayed release of gabapentin into the upper and lower small intestine due to the dissolution properties of Eudragit L30D-55 (dissolution above pH 5.5) and Eudragit FS30D (dissolution above pH 7.0).
  • Example 12 In Vitro and In Vivo Dissolution Rates of Pregabalin and Formulations Thereof
  • the active ingredient pregabalin can be substituted for gabapentin in Batches B, C, and D as described in Examples 2-4.
  • the in vitro studies of pregabalin can be conducted similarly as in Example 5.
  • In vivo studies can be conducted by using a 900 mg of pregabalin formulation. Around 360 mg of pregabalin is coated by a suitable pH independent soluble polymer, for example, hydroxypropylmethylcellulose. Next, 270 mg of pregabalin is coated by different two water insoluble polymers, one having high permeability and the other having low permeability, both, however, having swelling that is pH independent.
  • Eudragit RL30D high permeability
  • Eudragit RS30D low permeability
  • 270 mg of pregabalin is coated with both Eudragit L30D-55 and Eudragit FS30D.
  • the coated pregabalin tablets above are dried and then packaged into a single unit dosage form for oral administration.

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Abstract

La présente invention concerne de nouvelles préparations pharmaceutiques et de nouvelles utilisations médicales de gabapentine et de pregabaline. Ces préparations peuvent comprendre jusqu'à trois composants comprenant un composant à libération immédiate, un composant à libération soutenue et un composant à libération retardée. La proportion de chaque composant dans cette préparation peut-être réglée de façon à obtenir l'AUC souhaité et l'effet thérapeutique suivant l'administration à une personne par voie orale.
PCT/US2006/001887 2005-01-21 2006-01-20 Preparations pharmaceutiques qui procedes d'utilisation WO2006078811A2 (fr)

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EP06718892A EP1838291A4 (fr) 2005-01-21 2006-01-20 Preparations pharmaceutiques qui procedes d'utilisation
MX2007008833A MX2007008833A (es) 2005-01-21 2006-01-20 Formulaciones farmaceuticas y metodos de uso.
CA002595470A CA2595470A1 (fr) 2005-01-21 2006-01-20 Preparations pharmaceutiques qui procedes d'utilisation
AU2006206423A AU2006206423A1 (en) 2005-01-21 2006-01-20 Pharmaceutical formulations and methods of use
JP2007552260A JP2008528494A (ja) 2005-01-21 2006-01-20 医薬製剤および使用方法
BRPI0614021-1A BRPI0614021A2 (pt) 2005-01-21 2006-01-20 formulações farmacêuticas e métodos de uso
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WO2008077599A1 (fr) 2006-12-22 2008-07-03 Recordati Ireland Limited Thérapie combinée de troubles du tractus urinaire inférieur à l'aide de ligands de l'α2δ et d'ains
WO2009066325A1 (fr) * 2007-11-23 2009-05-28 Lupin Limited Compositions pharmaceutiques de prégabaline à libération contrôlée
RU2432161C1 (ru) * 2007-07-27 2011-10-27 Мерц Фарма Гмбх Унд Ко. Кгаа Новые комбинации нерамексана для лечения нейродегенеративных расстройств
WO2012150246A1 (fr) * 2011-05-05 2012-11-08 Hennig Arzneimittel Gmbh & Co. Kg Forme galénique pour libération ciblée de principes actifs
WO2013032185A1 (fr) * 2011-08-26 2013-03-07 근화제약주식회사 Préparation à libération prolongée contenant de la prégabaline
WO2013100873A1 (fr) * 2011-12-19 2013-07-04 Mahmut Bilgic Formulation pharmaceutique de prégabaline (taille de particules 300-2500 micromètres)
US20170216212A1 (en) * 2007-11-23 2017-08-03 Gruenenthal Gmbh Tapentadol compositions
CN107073048A (zh) * 2014-08-29 2017-08-18 若素制药株式会社 含有乳酸菌的组合物
US9770422B2 (en) 2012-01-06 2017-09-26 Elcelyx Therapeutics, Inc. Compositions and methods for treating metabolic disorders
WO2018015946A1 (fr) * 2016-07-17 2018-01-25 Mapi Pharma Ltd. Formes galéniques à libération prolongée de prégabaline
US9962344B2 (en) 2011-01-07 2018-05-08 Elcelyx Therapeutics, Inc. Chemosensory receptor ligand-based therapies
US9974752B2 (en) 2014-10-31 2018-05-22 Purdue Pharma Methods and compositions particularly for treatment of attention deficit disorder
US10028923B2 (en) 2011-01-07 2018-07-24 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US10154972B2 (en) 2011-01-07 2018-12-18 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US10159658B2 (en) 2011-01-07 2018-12-25 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
EP3302425A4 (fr) * 2015-05-26 2018-12-26 Isa Odidi Prégabaline à libération prolongée contrôlée
US10668031B2 (en) 2011-01-07 2020-06-02 Anji Pharma (Us) Llc Biguanide compositions and methods of treating metabolic disorders
US10722473B2 (en) 2018-11-19 2020-07-28 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
WO2022119430A1 (fr) 2020-12-04 2022-06-09 Laboratorios Silanes S.A. De C.V. Composition pharmaceutique solide recouverte et stable d'un analgésique et d'un antiépileptique contre la douleur
US11759441B2 (en) 2011-01-07 2023-09-19 Anji Pharmaceuticals Inc. Biguanide compositions and methods of treating metabolic disorders
US11974971B2 (en) 2011-01-07 2024-05-07 Anji Pharmaceuticals Inc. Compositions and methods for treating metabolic disorders

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JP7021108B2 (ja) 2016-04-19 2022-02-16 コナリス リサーチ インスティテュート アクチェンゲゼルシャフト ニコチンアミドの経口薬学的組成物
JP6919119B2 (ja) * 2017-01-23 2021-08-18 日新製薬株式会社 ３位が置換されたγ−アミノ酪酸誘導体を含有する圧縮固形医薬組成物。
CN112023032B (zh) * 2020-09-14 2022-03-18 广东鼎信医药科技有限公司 一种含有消化酶的药物组合物及其制备方法
CN116898819B (zh) * 2023-06-09 2024-02-06 则正(上海)生物科技有限公司 一种普瑞巴林缓释剂及其制备方法

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Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008077599A1 (fr) 2006-12-22 2008-07-03 Recordati Ireland Limited Thérapie combinée de troubles du tractus urinaire inférieur à l'aide de ligands de l'α2δ et d'ains
RU2432161C1 (ru) * 2007-07-27 2011-10-27 Мерц Фарма Гмбх Унд Ко. Кгаа Новые комбинации нерамексана для лечения нейродегенеративных расстройств
US9028865B2 (en) 2007-11-23 2015-05-12 Lupin Limited Controlled release pharmaceutical compositions of pregabalin
WO2009066325A1 (fr) * 2007-11-23 2009-05-28 Lupin Limited Compositions pharmaceutiques de prégabaline à libération contrôlée
US20170216212A1 (en) * 2007-11-23 2017-08-03 Gruenenthal Gmbh Tapentadol compositions
US8454993B2 (en) 2007-11-23 2013-06-04 Lupin Limited Controlled release pharmaceutical compositions of pregabalin
US11974971B2 (en) 2011-01-07 2024-05-07 Anji Pharmaceuticals Inc. Compositions and methods for treating metabolic disorders
US9962344B2 (en) 2011-01-07 2018-05-08 Elcelyx Therapeutics, Inc. Chemosensory receptor ligand-based therapies
US10610500B2 (en) 2011-01-07 2020-04-07 Anji Pharma (Us) Llc Chemosensory receptor ligand-based therapies
US10159658B2 (en) 2011-01-07 2018-12-25 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
US10201511B2 (en) 2011-01-07 2019-02-12 Elcelyx Therapeutics, Inc. Compositions and methods for treating metabolic disorders
US10154972B2 (en) 2011-01-07 2018-12-18 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US11759441B2 (en) 2011-01-07 2023-09-19 Anji Pharmaceuticals Inc. Biguanide compositions and methods of treating metabolic disorders
US10668031B2 (en) 2011-01-07 2020-06-02 Anji Pharma (Us) Llc Biguanide compositions and methods of treating metabolic disorders
US11065215B2 (en) 2011-01-07 2021-07-20 Anji Pharma (Us) Llc Biguanide compositions and methods of treating metabolic disorders
US10028923B2 (en) 2011-01-07 2018-07-24 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
WO2012150246A1 (fr) * 2011-05-05 2012-11-08 Hennig Arzneimittel Gmbh & Co. Kg Forme galénique pour libération ciblée de principes actifs
EA025128B1 (ru) * 2011-05-05 2016-11-30 Хенниг Арцнаймиттель Гмбх Унд Ко. Кг Лекарственная форма для целевого высвобождения активных веществ
WO2013032185A1 (fr) * 2011-08-26 2013-03-07 근화제약주식회사 Préparation à libération prolongée contenant de la prégabaline
WO2013100873A1 (fr) * 2011-12-19 2013-07-04 Mahmut Bilgic Formulation pharmaceutique de prégabaline (taille de particules 300-2500 micromètres)
US9770422B2 (en) 2012-01-06 2017-09-26 Elcelyx Therapeutics, Inc. Compositions and methods for treating metabolic disorders
US10603291B2 (en) 2012-01-06 2020-03-31 Anji Pharma (Us) Llc Compositions and methods for treating metabolic disorders
CN107073048A (zh) * 2014-08-29 2017-08-18 若素制药株式会社 含有乳酸菌的组合物
CN107073048B (zh) * 2014-08-29 2021-09-10 若素制药株式会社 含有乳酸菌的组合物
US10111839B2 (en) 2014-10-31 2018-10-30 Purdue Pharma Methods and compositions particularly for treatment of attention deficit disorder
US10449159B2 (en) 2014-10-31 2019-10-22 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10507186B2 (en) 2014-10-31 2019-12-17 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10512613B2 (en) 2014-10-31 2019-12-24 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10512612B2 (en) 2014-10-31 2019-12-24 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US9974752B2 (en) 2014-10-31 2018-05-22 Purdue Pharma Methods and compositions particularly for treatment of attention deficit disorder
US10568841B2 (en) 2014-10-31 2020-02-25 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10500162B2 (en) 2014-10-31 2019-12-10 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US11896722B2 (en) 2014-10-31 2024-02-13 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10292938B2 (en) 2014-10-31 2019-05-21 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10688060B2 (en) 2014-10-31 2020-06-23 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
US10292939B2 (en) 2014-10-31 2019-05-21 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
EP3302425A4 (fr) * 2015-05-26 2018-12-26 Isa Odidi Prégabaline à libération prolongée contrôlée
US10561602B2 (en) 2015-05-26 2020-02-18 Isa Odidi Controlled extended release pregabalin
AU2017300185B2 (en) * 2016-07-17 2023-02-02 Mapi Pharma Ltd. Extended release dosage forms of pregabalin
US20190298675A1 (en) * 2016-07-17 2019-10-03 Mapi Pharma Ltd. Extended release dosage forms of pregabalin
WO2018015946A1 (fr) * 2016-07-17 2018-01-25 Mapi Pharma Ltd. Formes galéniques à libération prolongée de prégabaline
US11026908B2 (en) 2016-07-17 2021-06-08 Mapi Pharma Ltd. Extended release dosage forms of pregabalin
US10722473B2 (en) 2018-11-19 2020-07-28 Purdue Pharma L.P. Methods and compositions particularly for treatment of attention deficit disorder
WO2022119430A1 (fr) 2020-12-04 2022-06-09 Laboratorios Silanes S.A. De C.V. Composition pharmaceutique solide recouverte et stable d'un analgésique et d'un antiépileptique contre la douleur
KR20230117591A (ko) 2020-12-04 2023-08-08 라보라토리오스 실레인즈, 에스.에이. 드 씨.브이. 통증 경감을 위한 오피오이드 진통제 및 항경련제를함유하는 안정한 코팅된, 고형의 약학적 조성물

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