WO2015114655A2 - Modified release tablet of pregabalin - Google Patents

Modified release tablet of pregabalin Download PDF

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Publication number
WO2015114655A2
WO2015114655A2 PCT/IN2015/000032 IN2015000032W WO2015114655A2 WO 2015114655 A2 WO2015114655 A2 WO 2015114655A2 IN 2015000032 W IN2015000032 W IN 2015000032W WO 2015114655 A2 WO2015114655 A2 WO 2015114655A2
Authority
WO
WIPO (PCT)
Prior art keywords
modified release
release tablet
pregabalin
tablet according
pharmaceutically acceptable
Prior art date
Application number
PCT/IN2015/000032
Other languages
English (en)
French (fr)
Other versions
WO2015114655A3 (en
Inventor
Nilesh Patel
Umesh Setty
Ashish Sehgal
Original Assignee
Intas Pharmaceuticals Limited
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.)
Filing date
Publication date
Application filed by Intas Pharmaceuticals Limited filed Critical Intas Pharmaceuticals Limited
Publication of WO2015114655A2 publication Critical patent/WO2015114655A2/en
Publication of WO2015114655A3 publication Critical patent/WO2015114655A3/en

Links

Classifications

    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • 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
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the present invention relates to a modified release tablet comprising pregabalin with pharmaceutically acceptable excipients, wherein the modified release tablet substantially maintains its hydrodynamic balance and physical integrity for the time period during which the drug is released into the stomach. Further it relates to a process for the preparation of the modified release tablet.
  • Pregabalin is an analogue of the physiologically important endogenous neurotransmitter [gamma] -amino butyric acid (GABA), which is involved in the regulation of neural processes.
  • GABA neurotransmitter
  • the lUPAC name of pregabalin [.INN] is (S)-3-(aminomethyl)-5-methyl hexanoic acid.
  • the chemical structure of pregabal in is shown in formula below:
  • Pregabalin is disclosed in U.S. Patent Nos. 6,197,819 and 5,563,175, which describe its use in the treatment of seizure disorders.
  • U.S. Patent No. 6,1 17,906 discloses the use of pregabalin in treating anxiety, while U.S. Patent No. 6,001 ,876 discloses its use in treating pain.
  • pregabalin is available as conventional immediate-release capsules marketed by CP Pharms/Pfizer under the brand name Lyrica ® .
  • Lyrica ® Capsules requires two or three times a day dosing.
  • a once-daily tablet is desirable.
  • pregabalin cannot be absorbed in the entire gastrointestinal tract (GIT).
  • GIT gastrointestinal tract
  • Pregabalin is only absorbed in the upper sections of the gut. It is therefore desirable to have a dosage form which has a longer retention time in the upper GIT and which, during that time, releases the active agent continuously over a longer period of time.
  • the U.S. Publication Application No. 2007/026951 1 discloses a pregabalin formulation containing matrix forming agent and a swelling agent, wherein the matrix forming agent is polyvinyl acetate and polyvinylpyrrolidone, and the swelling agent is cross-linked polyvinylpyrrolidone.
  • the U.S. Publication Application No. 2010/0255067 describes pharmaceutical compositions comprising pregabalin, a hydrophobic release controlling agent, and other pharmaceutically acceptable excipients.
  • the U.S. Publication Application No. 2013/149253 describes oral dosage form for the modified release of pregabalin, comprising pregabalin in a matrix comprising a swelling agent, a matrix former and a buoyancy agent or alternatively a sedimentation agent. Therefore, a modified release tablet that retains in the upper parts of the gastrointestinal tract would be an ideal dosage form for pregabalin.
  • the objective of the present invention is to develop a modified release tablet of pregabalin.
  • the primary object of the invention is to provide a modified release tablet comprising pregabalin with pharmaceutically acceptable excipients, wherein the modified release tablet substantially maintains its hydrodynamic balance and physical integrity for the time period during which the drug is released into the stomach.
  • Another object of the invention is to provide a modified release tablet comprising pregabalin with at least one low-density excipient, at least one swelling agent, at least one gelling agent, and optionally a bubble-generating mixture, wherein the modified release tablet substantially maintains its hydrodynamic balance and physical integrity for the time period during which the drug is released into the stomach.
  • Another object of the invention is to provide a process for the preparation of a modified release tablet of pregabalin.
  • the invention relates to a modified release tablet comprising pregabalin with pharmaceutically acceptable excipients, wherein the modified release tablet substantially maintains its hydrodynamic balance and physical integrity for the time period during which the drag is released into the stomach.
  • the invention in another embodiment, relates to a modified release tablet comprising pregabalin with at least one low-density excipient, at least one swelling agent, at least one gelling agent, and optionally a bubble-generating mixture, wherein the modified release tablet substantially maintains its hydrodynamic balance and physical integrity for the time period during which the drug is released into the stomach.
  • the invention relates to a modified release tablet comprising pregabalin with colloidal silicon dioxide as a low-density excipient, croscarmellose sodium as swelling agent and hydroxy ethyl cellulose (HEC) as gelling agent.
  • colloidal silicon dioxide as a low-density excipient
  • croscarmellose sodium as swelling agent
  • HEC hydroxy ethyl cellulose
  • the invention relates to a modified release tablet comprising pregabalin with ethyl cellulose (EC 20 cps) as a low-density excipient, sodium starch glycolate as swelling agent, polyvinyl pyrrolidone (PVP) as gelling agent, and additionally a bubble-generating mixture.
  • EC 20 cps ethyl cellulose
  • PVP polyvinyl pyrrolidone
  • the invention relates to a process for the preparation of a modified release tablet of pregabalin, preferably direct compression method.
  • the present invention relates to a modified release tablet comprising pregabalin with pharmaceutically acceptable excipients, wherein the modified release tablet substantially maintains its hydrodynamic balance and physical integrity for the time period during which the drug is released into the stomach.
  • the "modified release tablet” remains in the patient's stomach following oral administration, which is substantially longer than the average residence time of a corresponding immediate release dosage form.
  • hydrodynamic balance for the purpose of the invention means that the tablet maintains its balance within the stomach such that it does not sink or passes away through the pylorus, but the tablet remains suspended on the surface of the gastric fluid during which the drug is released into the stomach.
  • the term "physical integrity" for the purpose of the invention refers to the tablet strength that maintains the tablet structure in an intact form and thus it does not rupture into smaller units, during which the drug is released into the stomach.
  • the present invention may employ any pharmaceutically acceptable form of pregabalin, including its free form (zwitter ion), and its pharmaceutically acceptable complexes, acid addition salts, base .
  • addition salts solvates, hydrates, and polymorphs.
  • the present invention relates to a modified release tablet comprising pregabalin with at least one low-density excipient, at least one swelling agent, at least one gelling agent, and optionally a bubble-generating mixture, wherein the modified release tablet substantially maintains its hydrodynamic balance and physical integrity for the time period during which the drug is released into the stomach.
  • the "low-density excipient" of the present invention includes microcrystalline cellulose (MCC) PH 105 grade, colloidal silicon dioxide (commonly known as Aerosil 200), ethyl cellulose (EC 20 cps) or combinations or copolymers thereof.
  • the excipient MCC PH 105 grade here refers to micro crystalline cellulose having mean particle size of 20 microns and bulk density of 0.2 to 0.3 gm/cc.
  • excipient Aerosil ⁇ grade here refers to colloidal silicon dioxide having mean particle size of 12-16 nm and tapped density of 0.05gm/cc.
  • the excipient EC 20 cps grade here refers to ethyl cellulose having mean particle size of 5-60 microns and bulk density of 0.2gm/cc.
  • the "swelling agent" of the present invention includes croscarmellose sodium, sodium starch glycolate (SSG), microcrystalline. cellulose (MCC), starch, cross- linked homopolymers of l-vinyl-pyrrolidin-2-one (Crospovidone) or combinations or copolymers thereof.
  • the swelling agent absorbs water from the gastric fluid and thereby the tablet expands in size larger than the pylorus.
  • the swelling agent is generally used in an amount ranging from about 5% to about 30% by weight of the tablet composition.
  • the "gelling agent" of the present invention includes polyvinyl pyrrolidone (PVP), polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol such as carbomers (carbopols), alginates, preferably sodium alginate, hydroxyalkyl cellulose, especially hydroxyethyl cellulose (HEC), xanthan gum or combinations or copolymers thereof.
  • PVP polyvinyl pyrrolidone
  • carbomers carbomers
  • alginates preferably sodium alginate
  • hydroxyalkyl cellulose especially hydroxyethyl cellulose (HEC), xanthan gum or combinations or copolymers thereof.
  • the gelling agent includes excipient that forms a gel when in contact with gastric fluid and thereby modifies the drug release characteristics of the tablet.
  • the gelling agent is generally used in an amount ranging from about 0.5% to about 40% by weight of the tablet composition.
  • the "bubble-generating mixture" of the present invention includes, non-limiting examples, such as bicarbonate/ascorbic acid, bicarbonate/tartaric acid, bicarbonate/citric acid, carbon ate/tartaric acid, carbonate/citric acid and/or carbonate/ascorbic acid.
  • the modified release tablet of the present invention when comes in contact with gastric fluid it readily forms bubbles that get entrapped within the well-defined tablet structure such that the tablet maintains its hydrodynamic balance and physical integrity for the time period during which pregabalin is released into the stomach.
  • the modified release tablet may also comprise further pharmaceutically acceptable excipients such as diluents, binders, rate-controlling agents, lubricants, wetting agent, glidants and coating excipients.
  • excipients such as diluents, binders, rate-controlling agents, lubricants, wetting agent, glidants and coating excipients.
  • the present invention may employ the rate controlling agents, preferably hydroxy propyl methyl cellulose (HPMC) or other pharmaceutically acceptable excipients.
  • rate controlling agents preferably hydroxy propyl methyl cellulose (HPMC) or other pharmaceutically acceptable excipients.
  • the modified release tablet of pregabalin is designed for once-daily administration and achieves bioequivalence with immediate release dosage form of pregabalin that is taken two- or three-times daily.
  • the invention in another embodiment, relates to a process for the preparation of a modified release tablet of pregabalin. It can be prepared by routine tableting method including direct compression, granulation and pelletization methods. Preferably, the process for the preparation is direct compression method.
  • Example 1 Modified Release Tablet of Pregabalin.
  • the modified release tablet of the present invention is prepared by Direct Compression method in the procedural steps as described below.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
PCT/IN2015/000032 2014-01-21 2015-01-20 Modified release tablet of pregabalin WO2015114655A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN198/MUM/2014 2014-01-21
IN198MU2014 IN2014MU00198A (enrdf_load_stackoverflow) 2014-01-21 2015-01-20

Publications (2)

Publication Number Publication Date
WO2015114655A2 true WO2015114655A2 (en) 2015-08-06
WO2015114655A3 WO2015114655A3 (en) 2016-01-28

Family

ID=53757862

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2015/000032 WO2015114655A2 (en) 2014-01-21 2015-01-20 Modified release tablet of pregabalin

Country Status (2)

Country Link
IN (1) IN2014MU00198A (enrdf_load_stackoverflow)
WO (1) WO2015114655A2 (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106606495A (zh) * 2015-10-27 2017-05-03 四川海思科制药有限公司 一种普瑞巴林缓释片药物组合物及其制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL2000281C2 (nl) * 2005-11-02 2007-08-07 Pfizer Prod Inc Vaste farmaceutische samenstellingen die pregabaline bevatten.
WO2009066325A1 (en) * 2007-11-23 2009-05-28 Lupin Limited Controlled release pharmaceutical compositions of pregabalin
EP2415460A1 (de) * 2010-08-03 2012-02-08 ratiopharm GmbH Orale Darreichungsform von Pregabalin
WO2012035559A2 (en) * 2010-09-17 2012-03-22 Panacea Biotec Ltd Sustained release pharmaceutical compositions comprising pregabalin

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106606495A (zh) * 2015-10-27 2017-05-03 四川海思科制药有限公司 一种普瑞巴林缓释片药物组合物及其制备方法

Also Published As

Publication number Publication date
IN2014MU00198A (enrdf_load_stackoverflow) 2015-08-28
WO2015114655A3 (en) 2016-01-28

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