WO2011053003A2 - Gastric-retentive sustained release formulation containing pregabalin, polyethyleneoxide and pva-peg graft copolymer - Google Patents

Gastric-retentive sustained release formulation containing pregabalin, polyethyleneoxide and pva-peg graft copolymer Download PDF

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WO2011053003A2
WO2011053003A2 PCT/KR2010/007456 KR2010007456W WO2011053003A2 WO 2011053003 A2 WO2011053003 A2 WO 2011053003A2 KR 2010007456 W KR2010007456 W KR 2010007456W WO 2011053003 A2 WO2011053003 A2 WO 2011053003A2
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tablet
pregabalin
polyethyleneoxide
gastric
graft copolymer
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PCT/KR2010/007456
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WO2011053003A3 (en
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Il Hwan Cho
Il Ki Hong
Kyung Min Shin
Da Won Oh
A Ra Ahn
Hyun Jung Noh
Hyun Ah Kang
Hong Chul Jin
Bo Hyun Sung
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Cj Cheiljedang Corporation
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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • 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
    • 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
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a gastric-retentive sustained release formulation containing pregabalin or a pharmaceutically acceptable salts thereof, polyethyleneoxide and polyvinylalcohol-polyethyleneglycol graft copolymer. More specifically, the present invention relates to a gastric-retentive sustained release formulation that can be administered once a day by controlling the release of drug, in which a swelling property of the gastric-retentive sustained release formulation is increased as well as a floatability of the gastric-retentive sustained release formulation is improved by using a gastric-retentive drug delivery system containing pregabalin or a pharmaceutically acceptable salts thereof, as an active component, polyethyleneoxide as a swelling agent, and polyvinylalcohol-polyethyleneglycol graft copolymer as an release-controlling agent.
  • Pregabalin is an analogue of gamma-aminobutyric acid (GABA), and its chemical name is (S)-3-(aminomethyl)-5-methylhexanoic acid.
  • GABA gamma-aminobutyric acid
  • a Chemical formula of pregabalin is C 8 H 17 NO 2 , its molecular weight is 159.23, and its formula is as follows:
  • Pregabalin is a white crystalline powder that has a white or bright yellow color, and easily dissolves in water or a basic and acidic aqueous solution.
  • Pregabalin is an analogue of ⁇ -aminobutyric acid (GABA), and bound to a calcium channel in a central nervous system.
  • GABA ⁇ -aminobutyric acid
  • pregabalin is available on the market as an oral immediate-release capsules(Lyrica capsules as a trade name available from Pfizer) that can be administered tiwce a day from 150 mg to maximum 600 mg as a dosage per a day for treatment of a neuropathic pain, an epilepsy, a fibromylagia, and the like.
  • Pregabalin is currently available only as an immediate-release formulation, not a sustained-release formulation.
  • pregabalin Since pregabalin is generally absorbed well and does not bind to plasma proteins, it is not interaction with other drugs and unaffected by food and drink. Most of drug is mostly absorbed in the upper gastrointestinal tract; time to maximum plasma concentration(T max ) is within 1.5 hours; a half-life is 6 hours; and steady state is reached after about 24-48 hours. When using a drug for the treatment, it is administered twice or third a day, and may be gradually increased from 150 mg in the early stages to maximum 600 mg at intervals of 7 days. When administering single-dose (25-300 mg) and multiple-dose (75-900 mg/day), a maximum plasma concentration(C max ) and an area under the curve (AUC) are linearly increased.
  • a way of administrating of twice or third a day that is a clinical way of taking pregabalin causes patients to be considerably uncomfortable, and specifically, a drug compliance of the patients who should take a drug during a long time or a large quantity of drugs altogether to be greatly decreased. Also, a lack of administration may lead to great danger as to showing completely different aspect to the condition of patients who is administered the drug that is gradually increased judging by a drug reaction and thereafter lacked of administration, according to diseases, specifically in case of pregabalin having a half-life of 6 hours since it is known that the concentration of it reaches to the steady state at 24-48 hours after initial taking of drug.
  • pregabalin is adsorbed in the upper gastrointestinal tract by L-amino acid transporter. Many medicines are most effective when the medicines can be used on or near an absorption region at constant rate, but when using a general oral sustained release technique, the drug release after 6 hours that the drug reached on the lower gastrointestinal track is not effective.
  • US Patent Registration No. 6340475 and Korean Patent Registration No. 10-0545480 disclose the gastric-retentive oral dosage forms of highly soluble drugs.
  • the gastric-retentive dosage forms are designed only using polyethyleneoxide or hydroxypropyl methylcellulose(HPMC)
  • HPMC hydroxypropyl methylcellulose
  • US Patent Publication No. 20070269511 and Korean Patent Publication No. 2008-0059427 disclose the sustained release formulation using a gastric-retentive system of pregabalin. It is a method of producing the formulation that can be swelled at least minimum 9 mm when administrating after a meal or before bed, by using a mixture of polyvinylpyrrolidone and polyvinylacetate that are used for the control of release to stay pregabalin in stomach as a matrix and using a crosslinked polyvinlypyrrolidone as a swelling agent.
  • the hardness of the formulation in a body may be affected by the influence of the crosslinked polyvinylpyrrolidone used for a quick swelling and the formulation may be lacking in a gastric-retentive ability due to the lack of the floating force.
  • Korean Patent Publication No. 2007-0116588 relates to pharmaceutical formulations, in which one formulation contains one or more mini tablets of which release ways are different, containing pregabalin.
  • the pharmaceutical formulations are a mixture type of three mini tablets including an immediate release component, a sustained release component and a delayed release component, in which the proportion of each component in the formulation may be adjusted to achieve the desired AUC and therapeutic effect following oral administration in a human subject.
  • pregabalin of the pharmaceutical formulation produced by the method is scarcely adsorbed under the upper small intestines, so that it is difficult to ensure a clinical significance.
  • the inventors were tried to develop the formulation that can be stayed on the upper gastrointestinal tract for a long time and then be possible to be administered once a day in order to obtain more improved pregabalin profile in the blood considering the pharmacokinetic profiles of drug, minimize a side effect of drug related to the dosage by relatively reducing the maximum concentration in the blood as compared to the existing immediate-release formulation, and improve the drug compliance.
  • a structural stability of the formulation may be enhanced by easily making a film layer inside of the tablet in vivo using the polyvinylalcohol-polyethyleneglycol graft copolymer besides polyethyleneoxide which is form a swelling matrix, as well as a floating may be improved, thereby controlling the release of drug, and finished the present invention.
  • an object of the present invention is to provide a gastric-retentive sustained release formulation that can be administrated once a day, in which the formulation includes pregabalin or a pharmaceutically acceptable salts thereof, as an active component, polyethyleneoxdie as a swelling agent, and polyvinylalcohol-polyethyleneglycol graft copolymer as a release-controlling agent.
  • the present invention provides a gastric-retentive sustained release formulation that can be administrated once a day, in which the formulation includes pregabalin or a pharmaceutically acceptable salts thereof, as an active component, polyethyleneoxdie as a swelling agent, and polyvinylalcohol-polyethyleneglycol graft copolymer as a release-controlling agent.
  • the present invention provides an oral gastric-retentive sustained release medicine containing pregabalin or a pharmaceutically acceptable salts thereof, as an active component, polyethyleneoxdie as a swelling agent, and polyvinylalcohol-polyethyleneglycol graft copolymer as a release-controlling agent.
  • the present invention provides a gastric-retentive sustained release formulation that can be possible to cause pregabalin of which an absorption region is limited to be administrated once a day, in which the release of drug may be controlled and the swelling property and floating of matrix may be improved by using polyethyleneoxide and polyvinylalcohol-polyethyleneglycol graft copolymer.
  • FIG. 1 is a graph showing the result of release test according 2 nd test of comparative release test of the Korean Pharmacopoeia, using the tablets produced in Example 1 and 2, and Comparative Example 1 of the present invention and Lyrica capsules 150 mg (Lyrica Cap. from Pfizer) that is available in the market as a reference formulation; and
  • FIG. 2 is a graph showing the comparative result of the pharmacokinetic pattern when administrating twice a day using the formulation (T: test) produced according to Example 3 of the present invention and Lyrica Capsules TM 75 mg (R: reference) that is available in the market as a reference formulation.
  • a therapeutically effective dose of pregabalin or the pharmaceutically acceptable salts thereof that is used as an active component of the present invention may be used to be contained per unit tablet. Tipically, 50 to 900 mg of pregabalin, and preferably 75 to 600 mg of pregabalin may be produced to be contained, and may be used in a way of administrating once daily as an adequate amount.
  • Polyethyleneoxide used as the swelling agent of the present invention is swelled when contacting with water and then makes a gel layer, thereby playing a role as a matrix that delay the release of pregabalin.
  • the molecular weight of polyethyleneoxide used in the present invention is generally 100,000 to 10,000,000, and preferably 1,000,000 to 7,000,000. 25 to 200 parts by weight, preferably 30 to 300 parts by weight, and most preferably 50 to 200 parts by weight of the polyethyleneoxide may be used based on 100 parts by weight of pregabalin or salt thereof. When the molecular weight is too small, a gelation does not properly occurs, and when the molecular weight is too large, the release of effective components may be restricted due to an excessive gelation.
  • polyethyleneoxide used in the present invention includes Polyox TM (Polyox WSR Coagulant TM available from Dow chemical company), and the like.
  • Polyvinylalcohol-polyethyleneglycol graft copolymer that is used as a release-controlling agent in the present invention is a water-soluble polymer having excellent flexibility and adhesive power, and has a role in helping or controlling the release of drug by rapidly forming a water-soluble film in the matrix inside tablet when contacting with an aqueous solution. At the same time, it has a role in preventing of weakening of sustained-release matrix structure according to the release or dissolution of drug, and when a certain amount of the graft copolymer is contained, the floatability can be improved and the stability can be ensured.
  • 10 to 200 parts by weight, preferably 20 to 150 parts by weight, and most preferably 20 to 100 parts by weight of polyvinylalcohol-polyethyleneglycol graft copolymer used in the present invention may be used based on 100 parts by weight of pregabalin or pharmaceutically acceptable salts thereof.
  • polyvinylalcohol-polyethyleneglycol graft copolymer used in the present invention includes Kollicoat IR TM (available from BASF), and the like.
  • 10 to 200 parts by weight, preferably 20 to 150 parts by weight, and most preferably 20 to 100 parts by weight of polyvinylalcohol-polyethyleneglycol graft copolymer and polyethyleneoxide used in the present invention may be used based on 100 parts by weight of pregabalin or pharmaceutically acceptable salts thereof.
  • the preferable gastric-retentive sustained release formulation of the present invention may include a pharmaceutically acceptable excipient, for example a diluent, a binder or a lubricant, and the like.
  • the diluent may include all kinds of lactose, microcrystalline celluloses, starches, and the like.
  • lactose include a lactose monohydrate, a lactose anhydride, a spray dried lactose monohydrate, and the like
  • microcrystalline celluloses include a microcrystalline cellulose, a silicated microcrystalline cellulose, and the like
  • starches include a corn starch, a pregelatinized starch, and the like.
  • the binder includes polyvinylpyrrolidone vinylacetate (PVP VA-64 TM , BASF), hydroxypropyl cellulose (HPC) and polyacrylate (Carbopol 71G TM , Lubrizol) that shows a binding force at low pH, and the like, for direct compression.
  • PVP VA-64 TM polyvinylpyrrolidone vinylacetate
  • HPC hydroxypropyl cellulose
  • Carbopol 71G TM hydroxypropyl cellulose
  • Lubrizol polyacrylate
  • the lubricant includes magnesium stearate, sodium stearyl fumarate, and glyceryl behenate, and the like.
  • the present invention may include a small amount of film coating that is pharmaceutically acceptable.
  • the film coating may be selected from the various grades of Opadry AMB TM that is a trade name (available from Colorcon). More specifically, there are Opadry II, Opadry fx, Opadry AMB, and the like.
  • the film coating basically uses an aqueous coating process.
  • the techniques for the conventional gastric-retentive sustained release are only designed for increasing the floating force of the tablet or for swelling so that the structure of tables is easily destroyed. Therefore, the purpose for staying at a stomach is difficult to achieve.
  • the drug of the gastric-retentive sustained release formulation according to the present invention is characterized in that it can be swelled more quickly up to the size of the pylorus of stomach, based on an excellent floating force achieved by using polyvinylalcohol-polyethylene graft polymer and a swelling property achieved by using polyethyleneoxide as a swelling agent.
  • the formulation has a property that can safely staying for 2 hours to up to 8 hours at the stomach, so that the release of drug can maintain at the stomach and small intestine for 2 hours to up to 8 hours.
  • the release type can be controlled for 4 hours to 24 hours regardless of pH.
  • pregabalin was mixed with a mixture of 247.5 mg polyethyleneoxide (POLYOX WSR 303) and 100 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR), and then strained through 30-mesh sieve.
  • the mixture was mixed with 2.5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses.
  • the tablet was coated with 15 mg AMB(TM)-based Opadry AMB TM to complete the tablet.
  • Table 1 Each components in the tablet obtained were shown in the following Table 1:
  • 300 mg pregabalin was mixed with a mixture of 300 mg polyethyleneoxide (POLYOX WSR 303) and 130 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve.
  • the mixture was mixed with 15 mg low-substituted hydroxypropyl cellulose (L-HPC), mixed with 5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 750 mg rectangular tablet using Erweka single punch presses.
  • the tablet was coated with 25 mg AMB(TM)-based Opadry AMB TM to complete the tablet.
  • Table 2 Each components in the tablet obtained were shown in the following Table 2:
  • pregabalin was mixed with a mixture of 400 mg polyethyleneoxide (POLYOX WSR 303) and 65 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve.
  • the mixture was mixed with 50 mg low-substituted hydroxypropyl cellulose (L-HPC) and 30 mg Copovidone (Kolidon VA-64® that is a binder, mixed with 5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 700 mg rectangular tablet using Erweka single punch presses.
  • the tablet was coated with 10 mg Opadry II TM to complete the tablet.
  • Table 3 Each components in the tablet obtained were shown in the following Table 3:
  • Comparative Example 1 was prepared for comparing with a method for floating by using sodium bicarbonate as the prior technique.
  • the tablet without polyvinylalcohol-polyethyleneglycol graft copolymer was prepared in order to compare according to the use of polyvinylalcohol-polyethyleneglycol graft copolymer that is a release-controlling agent and used for the present invention.
  • pregabalin was mixed with 445 mg polyethyleneoxide (POLYOX WSR 303), and then strained through 30-mesh sieve.
  • the mixture was mixed with 5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 750 mg rectangular tablet using Erweka single punch presses.
  • the tablet was coated with 22.5 mg AMB(TM)-based Opadry AMB TM to complete the tablet.
  • Table 6 Each components in the tablet obtained were shown in the following Table 6:
  • the tablet was prepared by using hydroxypropyl cellulose (HPMC) that is generally used as a swelling agent in order to compare with polyethyleneoxide that is used as a swelling agent for the present invention.
  • HPMC hydroxypropyl cellulose
  • pregabalin was mixed with a mixture of 295 mg hydroxypropyl cellulose (HPMC) and 150 mg polyvinylalcohol-polyethyleneglycol graft copolymer, and then strained through 30-mesh sieve.
  • HPMC hydroxypropyl cellulose
  • the mixture was mixed with 5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 750 mg rectangular tablet using Erweka single punch presses.
  • the tablet was coated with 22.5 mg AMB(TM)-based Opadry AMB TM to complete the tablet.
  • Table 7 Each components in the tablet obtained were shown in the following Table 7:
  • pregabalin was mixed with a mixture of 632 mg polyethyleneoxide (POLYOX WSR 303) and 10 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR), and then strained through 30-mesh sieve.
  • the mixture was mixed with 8 mg magnesium stearate that was strained through 30-mesh sieve, and then pressed into 800 mg rectangular tablet using Erweka single punch presses.
  • the tablet was coated with 24 mg AMB(TM)-based Opadry AMB TM to complete the tablet.
  • Table 8 Each components in the tablet obtained were shown in the following Table 8:
  • the mixture was mixed with 5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 750 mg rectangular tablet using Erweka single punch presses.
  • the tablet was coated with 15 mg AMB(TM)-based Opadry AMB TM to complete the tablet.
  • Each components in the tablet obtained were shown in the following Table 9:
  • a floatability test and swelling test for Examples 1 to 4 and Comparative Examples 1 to 5 were estimated according to the following test method.
  • a floatability test was performed by using a paddle method in 0.06 N HCl as a release solution. A sample was periodically observed from the release solution of 0.06 N HCl, and then the time and profile for the floatability, and a final shape after 12 hours were observed and shown in the following Table 10.
  • a swelling test was performed by using a paddle method in 0.06 N HCl as a relaease solution. A sample was periodically observed from the release solution of 0.06 N HCl, and then the degree of swelling was measured by using Calipers after 12 hours. The measured results were shown in the following Table 11.
  • a comparative release test of the following Test Example 2 and a beagle dog PK test of the following Test Example 3 were performed using the tablets prepared in Example 2 and 3 that have an excellent swelling property comparing the other Examples based on the above results.
  • a release test according 2 nd test of comparative release test of the Korean Pharmacopoeia was performed by using the formulations produced in Example 2 and 3, the tablet produced in Comparative Example 1, and Lyrica capsules 150 mg (Lyrica Cap® available from Korea Pfizer Pharmaceutical Company) that is available in the market as a reference formulation. The results were shown in FIG. 1.
  • Example 3 As shown in FIG. 1, a tablet shape was destroyed within 2 hours for the tablet produced in Comparative Example 1, and then its release was quickly appeared. However, for the tablet produced in Example 3, while the three-dimensional shape that is a most good tablet was maintained, an ideal release type that is close to zero order release until 12 hours was maintained. Therefore, the beagle dog pharmacokinetic test of Test Example 3 was performed.
  • the formulations were administrated after dinner, and the bloods were collected at fixed times (0, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 10.5, 11, 11.5, 12, 14, 16, 18, 24 hours for the reference formulation and 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 hours for the test formulations), respectively.
  • the test group has 96 % C max and up to 91 % AUC as compared to the reference group that was administrated twice of 75 mg Lyrica Capsule as the reference formulation.
  • T max value of formulation of Example 3 was exhibited up to 7 hours in contrast to T max value of Lyrica Capsule was exhibited about 1 hours. The results were shown in FIG. 2 and Table 12.
  • Example 13 A stressed stability tests for the formulations produced in Example and Comparative Example were measured at 60°C and 80 % relative humidity(RH) for 4 weeks. The stability was identified through analyze of a pregabalin lactam, related compound of pregabalin, which is most produced. The results were shown in Table 13.
  • pregabalin sustained release formulation according to the present invention will be described, but the present invention will not be limited thereto and only more specifically described.
  • pregabalin was mixed with 300 mg polyethyleneoxide (POLYOX WSR 303), 47.5 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) was mixed and then strained through 30-mesh sieve. The mixture was mixed with 2.5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 15 mg Opadry AMB TM to complete the tablet. Each components in the tablet obtained were as follows:
  • pregabalin was mixed with a mixture of 297.5 mg polyethyleneoxide (POLYOX WSR 303 TM ) and 50 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve.
  • the mixture was mixed with 2.5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses.
  • the tablet was coated with 15 mg Opadry AMB TM to complete the tablet.
  • Each components in the tablet obtained were as follows:
  • pregabalin was mixed with a mixture of 247.5 mg polyethyleneoxide (POLYOX WSR 303) and 100 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve.
  • the mixture was mixed with 2.5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses.
  • the tablet was coated with 15 mg AMB TM -based Opadry AMB TM to complete the tablet.
  • Each components in the tablet obtained were as follows:
  • pregabalin was mixed with a mixture of 297.5 mg polyethyleneoxide (POLYOX WSR 303), 25 mg methaacrylic acid type C (Eudragit L-100) and 25 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve.
  • the mixture was mixed with 2.5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses.
  • the tablet was coated with 15 mg AMB TM -based Opadry AMB TM to complete the tablet.
  • Each components in the tablet obtained were as follows:
  • pregabalin was mixed with a mixture of 297.5 mg polyethyleneoxide (POLYOX WSR 303) and 25 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve.
  • POLYOX WSR 303 polyethyleneoxide
  • Kollicoat IR polyvinylalcohol-polyethyleneglycol graft copolymer
  • the mixture obtained was mixed with 2.5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses.
  • the tablet was coated with 15 mg AMB TM -based Opadry AMB TM to complete the tablet.
  • Each components in the tablet obtained were as follows:
  • pregabalin was mixed with a mixture of 247.5 mg polyethyleneoxide (POLYOX WSR 303) and 85 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve.
  • POLYOX WSR 303 polyethyleneoxide
  • Kollicoat IR polyvinylalcohol-polyethyleneglycol graft copolymer
  • L-HPC low-substituted hydroxypropyl cellulose
  • the tablet was coated with 15 mg AMB TM -based Opadry AMB TM to complete the tablet.
  • Each components in the tablet obtained were as follows:
  • 300 mg pregabalin was mixed with a mixture of 300 mg polyethyleneoxide (POLYOX WSR 303) and 150 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve.
  • the mixture was mixed with 15 mg low-substituted hydroxypropyl cellulose (L-HPC)
  • L-HPC low-substituted hydroxypropyl cellulose
  • the tablet was coated with 15 mg AMB TM -based Opadry AMB TM to complete the tablet.
  • Each components in the tablet obtained were as follows:
  • pregabalin was mixed with a mixture of 200 mg polyethyleneoxide (POLYOX WSR 303) and 80 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve.
  • POLYOX WSR 303 polyethyleneoxide
  • Kollicoat IR polyvinylalcohol-polyethyleneglycol graft copolymer
  • L-HPC low-substituted hydroxypropyl cellulose
  • the tablet was coated with 10 mg Opadry AMB TM to complete the tablet.
  • Each components in the tablet obtained were as follows:
  • pregabalin was mixed with a mixture of 330 mg polyethyleneoxide (POLYOX WSR 303) and 70 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve.
  • POLYOX WSR 303 polyethyleneoxide
  • Kollicoat IR polyvinylalcohol-polyethyleneglycol graft copolymer
  • L-HPC low-substituted hydroxypropyl cellulose
  • the tablet was coated with 16 mg Opadry II TM to complete the tablet.
  • Each components in the tablet obtained were as follows:
  • pregabalin was mixed with a mixture of 200 mg polyethyleneoxide (POLYOX WSR 303), 80 mg silicated microcrystalline cellulose (SMCC 90), 95 mg butylated methaacrylic acid (Eudragit E-PO), and 40 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR), and then strained through 30-mesh sieve.
  • the mixture was mixed with 30 mg low-substituted hydroxypropyl cellulose (L-HPC)
  • the mixture obtained was mixed with 7 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 700 mg rectangular tablet using Erweka single punch presses.
  • the tablet was coated with 14 mg Opadry II TM to complete the tablet.
  • Each components in the tablet obtained were as follows:

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Abstract

The present invention relates to a gastric-retentive sustained release formulation containing pregabalin or a pharmaceutically acceptable salts thereof, polyethyleneoxide, and polyvinylalcohol-polyethyleneglycol graft copolymer, in which a swelling property and floatability of matrix is improved by using a polyethyleneoxide and polyvinylalcohol-polyethyleneglycol graft copolymer, thereby controlling the release of the drug.

Description

GASTRIC-RETENTIVE SUSTAINED RELEASE FORMULATION CONTAINING PREGABALIN, POLYETHYLENEOXIDE AND PVA-PEG GRAFT COPOLYMER
The present invention relates to a gastric-retentive sustained release formulation containing pregabalin or a pharmaceutically acceptable salts thereof, polyethyleneoxide and polyvinylalcohol-polyethyleneglycol graft copolymer. More specifically, the present invention relates to a gastric-retentive sustained release formulation that can be administered once a day by controlling the release of drug, in which a swelling property of the gastric-retentive sustained release formulation is increased as well as a floatability of the gastric-retentive sustained release formulation is improved by using a gastric-retentive drug delivery system containing pregabalin or a pharmaceutically acceptable salts thereof, as an active component, polyethyleneoxide as a swelling agent, and polyvinylalcohol-polyethyleneglycol graft copolymer as an release-controlling agent.
Pregabalin is an analogue of gamma-aminobutyric acid (GABA), and its chemical name is (S)-3-(aminomethyl)-5-methylhexanoic acid. A Chemical formula of pregabalin is C8H17NO2, its molecular weight is 159.23, and its formula is as follows:
[ Formula 1 ]
Figure PCTKR2010007456-appb-I000001
Pregabalin is a white crystalline powder that has a white or bright yellow color, and easily dissolves in water or a basic and acidic aqueous solution. Pregabalin is an analogue of γ-aminobutyric acid (GABA), and bound to a calcium channel in a central nervous system. In addition, pregabalin is available on the market as an oral immediate-release capsules(Lyrica capsules as a trade name available from Pfizer) that can be administered tiwce a day from 150 mg to maximum 600 mg as a dosage per a day for treatment of a neuropathic pain, an epilepsy, a fibromylagia, and the like. Pregabalin is currently available only as an immediate-release formulation, not a sustained-release formulation.
Since pregabalin is generally absorbed well and does not bind to plasma proteins, it is not interaction with other drugs and unaffected by food and drink. Most of drug is mostly absorbed in the upper gastrointestinal tract; time to maximum plasma concentration(Tmax) is within 1.5 hours; a half-life is 6 hours; and steady state is reached after about 24-48 hours. When using a drug for the treatment, it is administered twice or third a day, and may be gradually increased from 150 mg in the early stages to maximum 600 mg at intervals of 7 days. When administering single-dose (25-300 mg) and multiple-dose (75-900 mg/day), a maximum plasma concentration(Cmax) and an area under the curve (AUC) are linearly increased.
A way of administrating of twice or third a day that is a clinical way of taking pregabalin causes patients to be considerably uncomfortable, and specifically, a drug compliance of the patients who should take a drug during a long time or a large quantity of drugs altogether to be greatly decreased. Also, a lack of administration may lead to great danger as to showing completely different aspect to the condition of patients who is administered the drug that is gradually increased judging by a drug reaction and thereafter lacked of administration, according to diseases, specifically in case of pregabalin having a half-life of 6 hours since it is known that the concentration of it reaches to the steady state at 24-48 hours after initial taking of drug.
Most of pregabalin is adsorbed in the upper gastrointestinal tract by L-amino acid transporter. Many medicines are most effective when the medicines can be used on or near an absorption region at constant rate, but when using a general oral sustained release technique, the drug release after 6 hours that the drug reached on the lower gastrointestinal track is not effective.
US Patent Registration No. 6340475 and Korean Patent Registration No. 10-0545480 disclose the gastric-retentive oral dosage forms of highly soluble drugs. However, when the gastric-retentive dosage forms are designed only using polyethyleneoxide or hydroxypropyl methylcellulose(HPMC), it would be difficult to achieve the gastric-retentive dosage form due to a high possibility of drug breakdown according to the dissolution of drug and lack of floating force, as a result it is hard to control the release of drug in a body.
US Patent Publication No. 20070269511 and Korean Patent Publication No. 2008-0059427 disclose the sustained release formulation using a gastric-retentive system of pregabalin. It is a method of producing the formulation that can be swelled at least minimum 9 mm when administrating after a meal or before bed, by using a mixture of polyvinylpyrrolidone and polyvinylacetate that are used for the control of release to stay pregabalin in stomach as a matrix and using a crosslinked polyvinlypyrrolidone as a swelling agent. However, the hardness of the formulation in a body may be affected by the influence of the crosslinked polyvinylpyrrolidone used for a quick swelling and the formulation may be lacking in a gastric-retentive ability due to the lack of the floating force.
In addition, Korean Patent Publication No. 2007-0116588 relates to pharmaceutical formulations, in which one formulation contains one or more mini tablets of which release ways are different, containing pregabalin. the pharmaceutical formulations are a mixture type of three mini tablets including an immediate release component, a sustained release component and a delayed release component, in which the proportion of each component in the formulation may be adjusted to achieve the desired AUC and therapeutic effect following oral administration in a human subject. However, pregabalin of the pharmaceutical formulation produced by the method is scarcely adsorbed under the upper small intestines, so that it is difficult to ensure a clinical significance.
In order to overcome the problems as mentioned above, the inventors were tried to develop the formulation that can be stayed on the upper gastrointestinal tract for a long time and then be possible to be administered once a day in order to obtain more improved pregabalin profile in the blood considering the pharmacokinetic profiles of drug, minimize a side effect of drug related to the dosage by relatively reducing the maximum concentration in the blood as compared to the existing immediate-release formulation, and improve the drug compliance. The inventors found that a structural stability of the formulation may be enhanced by easily making a film layer inside of the tablet in vivo using the polyvinylalcohol-polyethyleneglycol graft copolymer besides polyethyleneoxide which is form a swelling matrix, as well as a floating may be improved, thereby controlling the release of drug, and finished the present invention.
Therefore, an object of the present invention is to provide a gastric-retentive sustained release formulation that can be administrated once a day, in which the formulation includes pregabalin or a pharmaceutically acceptable salts thereof, as an active component, polyethyleneoxdie as a swelling agent, and polyvinylalcohol-polyethyleneglycol graft copolymer as a release-controlling agent.
In order to achieve the object as mentioned above, the present invention provides a gastric-retentive sustained release formulation that can be administrated once a day, in which the formulation includes pregabalin or a pharmaceutically acceptable salts thereof, as an active component, polyethyleneoxdie as a swelling agent, and polyvinylalcohol-polyethyleneglycol graft copolymer as a release-controlling agent.
The present invention provides an oral gastric-retentive sustained release medicine containing pregabalin or a pharmaceutically acceptable salts thereof, as an active component, polyethyleneoxdie as a swelling agent, and polyvinylalcohol-polyethyleneglycol graft copolymer as a release-controlling agent. Specifically, the present invention provides a gastric-retentive sustained release formulation that can be possible to cause pregabalin of which an absorption region is limited to be administrated once a day, in which the release of drug may be controlled and the swelling property and floating of matrix may be improved by using polyethyleneoxide and polyvinylalcohol-polyethyleneglycol graft copolymer.
The above and other objects, features and advantages of the present invention will become apparent from the following description of preferred embodiments given in conjunction with the accompanying drawings, in which:
FIG. 1 is a graph showing the result of release test according 2nd test of comparative release test of the Korean Pharmacopoeia, using the tablets produced in Example 1 and 2, and Comparative Example 1 of the present invention and Lyrica capsules 150 mg (Lyrica Cap. from Pfizer) that is available in the market as a reference formulation; and
FIG. 2 is a graph showing the comparative result of the pharmacokinetic pattern when administrating twice a day using the formulation (T: test) produced according to Example 3 of the present invention and Lyrica CapsulesTM 75 mg (R: reference) that is available in the market as a reference formulation.
Hereinafter, the embodiments of the present invention will be described in detail.
A therapeutically effective dose of pregabalin or the pharmaceutically acceptable salts thereof that is used as an active component of the present invention may be used to be contained per unit tablet. Tipically, 50 to 900 mg of pregabalin, and preferably 75 to 600 mg of pregabalin may be produced to be contained, and may be used in a way of administrating once daily as an adequate amount.
Polyethyleneoxide used as the swelling agent of the present invention is swelled when contacting with water and then makes a gel layer, thereby playing a role as a matrix that delay the release of pregabalin. The molecular weight of polyethyleneoxide used in the present invention is generally 100,000 to 10,000,000, and preferably 1,000,000 to 7,000,000. 25 to 200 parts by weight, preferably 30 to 300 parts by weight, and most preferably 50 to 200 parts by weight of the polyethyleneoxide may be used based on 100 parts by weight of pregabalin or salt thereof. When the molecular weight is too small, a gelation does not properly occurs, and when the molecular weight is too large, the release of effective components may be restricted due to an excessive gelation.
An example of the polyethyleneoxide used in the present invention includes PolyoxTM(Polyox WSR CoagulantTM available from Dow chemical company), and the like.
Polyvinylalcohol-polyethyleneglycol graft copolymer that is used as a release-controlling agent in the present invention is a water-soluble polymer having excellent flexibility and adhesive power, and has a role in helping or controlling the release of drug by rapidly forming a water-soluble film in the matrix inside tablet when contacting with an aqueous solution. At the same time, it has a role in preventing of weakening of sustained-release matrix structure according to the release or dissolution of drug, and when a certain amount of the graft copolymer is contained, the floatability can be improved and the stability can be ensured. 10 to 200 parts by weight, preferably 20 to 150 parts by weight, and most preferably 20 to 100 parts by weight of polyvinylalcohol-polyethyleneglycol graft copolymer used in the present invention may be used based on 100 parts by weight of pregabalin or pharmaceutically acceptable salts thereof.
An example of the polyvinylalcohol-polyethyleneglycol graft copolymer used in the present invention includes Kollicoat IRTM (available from BASF), and the like.
10 to 200 parts by weight, preferably 20 to 150 parts by weight, and most preferably 20 to 100 parts by weight of polyvinylalcohol-polyethyleneglycol graft copolymer and polyethyleneoxide used in the present invention may be used based on 100 parts by weight of pregabalin or pharmaceutically acceptable salts thereof.
In addition to the pregabalin or pharmaceutically acceptable salts thereof as an active component and the above mentioned excipients, the preferable gastric-retentive sustained release formulation of the present invention may include a pharmaceutically acceptable excipient, for example a diluent, a binder or a lubricant, and the like.
The diluent may include all kinds of lactose, microcrystalline celluloses, starches, and the like. Specifically, all kinds of lactose include a lactose monohydrate, a lactose anhydride, a spray dried lactose monohydrate, and the like, the microcrystalline celluloses include a microcrystalline cellulose, a silicated microcrystalline cellulose, and the like, and the starches include a corn starch, a pregelatinized starch, and the like.
The binder includes polyvinylpyrrolidone vinylacetate (PVP VA-64TM, BASF), hydroxypropyl cellulose (HPC) and polyacrylate (Carbopol 71GTM, Lubrizol) that shows a binding force at low pH, and the like, for direct compression.
The lubricant includes magnesium stearate, sodium stearyl fumarate, and glyceryl behenate, and the like.
In addition, the present invention may include a small amount of film coating that is pharmaceutically acceptable. The film coating may be selected from the various grades of Opadry AMBTM that is a trade name (available from Colorcon). More specifically, there are Opadry II, Opadry fx, Opadry AMB, and the like. The film coating basically uses an aqueous coating process.
The techniques for the conventional gastric-retentive sustained release are only designed for increasing the floating force of the tablet or for swelling so that the structure of tables is easily destroyed. Therefore, the purpose for staying at a stomach is difficult to achieve. However, the drug of the gastric-retentive sustained release formulation according to the present invention is characterized in that it can be swelled more quickly up to the size of the pylorus of stomach, based on an excellent floating force achieved by using polyvinylalcohol-polyethylene graft polymer and a swelling property achieved by using polyethyleneoxide as a swelling agent. Therefore, the formulation has a property that can safely staying for 2 hours to up to 8 hours at the stomach, so that the release of drug can maintain at the stomach and small intestine for 2 hours to up to 8 hours. The release type can be controlled for 4 hours to 24 hours regardless of pH.
Hereinafter, the present invention will be described with reference to Examples. However, it is only for illustrating the present invention, and the present invention will not be limited by Examples.
Example 1.
In order to prepare a tablet, 150 mg pregabalin was mixed with a mixture of 247.5 mg polyethyleneoxide (POLYOX WSR 303) and 100 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR), and then strained through 30-mesh sieve. The mixture was mixed with 2.5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 15 mg AMB(TM)-based Opadry AMBTM to complete the tablet. Each components in the tablet obtained were shown in the following Table 1:
[Table 1]
Figure PCTKR2010007456-appb-I000002
Example 2.
In order to prepare a tablet, 300 mg pregabalin was mixed with a mixture of 300 mg polyethyleneoxide (POLYOX WSR 303) and 130 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve. The mixture was mixed with 15 mg low-substituted hydroxypropyl cellulose (L-HPC), mixed with 5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 750 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 25 mg AMB(TM)-based Opadry AMBTM to complete the tablet. Each components in the tablet obtained were shown in the following Table 2:
[Table 2]
Figure PCTKR2010007456-appb-I000003
Example 3.
In order to prepare a tablet, 150 mg pregabalin was mixed with a mixture of 400 mg polyethyleneoxide (POLYOX WSR 303) and 65 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve. The mixture was mixed with 50 mg low-substituted hydroxypropyl cellulose (L-HPC) and 30 mg Copovidone (Kolidon VA-64® that is a binder, mixed with 5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 700 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 10 mg Opadry IITM to complete the tablet. Each components in the tablet obtained were shown in the following Table 3:
[Table 3]
Figure PCTKR2010007456-appb-I000004
Example 4.
In order to prepare a tablet, 300 mg pregabalin was mixed with a mixture of 400 mg polyethyleneoxide (POLYOX WSR 303) and 80 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve. After the mixture was mixed with 60 mg low-substituted hydroxypropyl cellulose (L-HPC) and 50 mg Copovidone (Kolidon VA-64® that is a binder, the mixture obtained was mixed with 10 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 900 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 15 mg Opadry IITM to complete the tablet. Each components in the tablet obtained were shown in the following Table 4:
[Table 4]
Figure PCTKR2010007456-appb-I000005
Comparative Example 1.
Comparative Example 1 was prepared for comparing with a method for floating by using sodium bicarbonate as the prior technique.
In order to prepare a tablet, 150 mg pregabalin was mixed with a mixture of 247.5 mg polyethyleneoxide (POLYOX WSR 303) and 25 mg polyethyleneoxide-polyphenyleneoxide-polyethyleneoxide copolymer (Poloxamer F407TM), mixed with 30 mg silicated microcrystalline cellulose, and then strained through 30-mesh sieve. After the mixture was mixed with 30 mg sodium bicarbonate (NaHCO3) and 15 mg citric acid, the mixture obtained was mixed with 2.5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 15 mg AMB(TM)-based Opadry AMBTM to complete the tablet. Each components in the tablet obtained were shown in the following Table 5:
[Table 5]
Figure PCTKR2010007456-appb-I000006
Comparative Example 2.
The tablet without polyvinylalcohol-polyethyleneglycol graft copolymer was prepared in order to compare according to the use of polyvinylalcohol-polyethyleneglycol graft copolymer that is a release-controlling agent and used for the present invention.
In order to prepare a tablet, 300 mg pregabalin was mixed with 445 mg polyethyleneoxide (POLYOX WSR 303), and then strained through 30-mesh sieve. The mixture was mixed with 5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 750 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 22.5 mg AMB(TM)-based Opadry AMBTM to complete the tablet. Each components in the tablet obtained were shown in the following Table 6:
[Table 6]
Figure PCTKR2010007456-appb-I000007
Comparative Example 3.
The tablet was prepared by using hydroxypropyl cellulose (HPMC) that is generally used as a swelling agent in order to compare with polyethyleneoxide that is used as a swelling agent for the present invention.
In order to prepare a tablet, 300 mg pregabalin was mixed with a mixture of 295 mg hydroxypropyl cellulose (HPMC) and 150 mg polyvinylalcohol-polyethyleneglycol graft copolymer, and then strained through 30-mesh sieve. The mixture was mixed with 5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 750 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 22.5 mg AMB(TM)-based Opadry AMBTM to complete the tablet. Each components in the tablet obtained were shown in the following Table 7:
[Table 7]
Figure PCTKR2010007456-appb-I000008
Comparative Example 4.
In order to prepare a tablet, 150 mg pregabalin was mixed with a mixture of 632 mg polyethyleneoxide (POLYOX WSR 303) and 10 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR), and then strained through 30-mesh sieve. The mixture was mixed with 8 mg magnesium stearate that was strained through 30-mesh sieve, and then pressed into 800 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 24 mg AMB(TM)-based Opadry AMBTM to complete the tablet. Each components in the tablet obtained were shown in the following Table 8:
[Table 8]
Figure PCTKR2010007456-appb-I000009
Comparative Example 5.
In order to prepare a tablet for comparison of polyethyleneoxide (POLYOX WSR 1105 with a molecular weight 900, 000) that has lower molecular weight than that of polyethyleneoxide (POLYOX WSR 303 with a molecular weight 7,000,000) used in the present invention, 300 mg pregabalin was mixed with a mixture of 300 mg polyethyleneoxide (POLYOX WSR 303 with a molecular weight 900,000) and 145 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR), and then strained through 30-mesh sieve. The mixture was mixed with 5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 750 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 15 mg AMB(TM)-based Opadry AMBTM to complete the tablet. Each components in the tablet obtained were shown in the following Table 9:
[Table 9]
Figure PCTKR2010007456-appb-I000010
Test Example 1.
A floatability test and swelling test for Examples 1 to 4 and Comparative Examples 1 to 5 were estimated according to the following test method.
Floatability Test
A floatability test was performed by using a paddle method in 0.06 N HCl as a release solution. A sample was periodically observed from the release solution of 0.06 N HCl, and then the time and profile for the floatability, and a final shape after 12 hours were observed and shown in the following Table 10.
Swelling test
A swelling test was performed by using a paddle method in 0.06 N HCl as a relaease solution. A sample was periodically observed from the release solution of 0.06 N HCl, and then the degree of swelling was measured by using Calipers after 12 hours. The measured results were shown in the following Table 11.
A comparative release test of the following Test Example 2 and a beagle dog PK test of the following Test Example 3 were performed using the tablets prepared in Example 2 and 3 that have an excellent swelling property comparing the other Examples based on the above results.
[Table 10]
Floatability Test (Examples 1 to 4 and Comparative Examples 1 to 5)
Figure PCTKR2010007456-appb-I000011
[Table 11]
Swelling Test (Examples 1 to 4 and Comparative Examples 1 and 4)
Figure PCTKR2010007456-appb-I000012
Test Example 2.
A release test according 2nd test of comparative release test of the Korean Pharmacopoeia was performed by using the formulations produced in Example 2 and 3, the tablet produced in Comparative Example 1, and Lyrica capsules 150 mg (Lyrica Cap® available from Korea Pfizer Pharmaceutical Company) that is available in the market as a reference formulation. The results were shown in FIG. 1.
As shown in FIG. 1, a tablet shape was destroyed within 2 hours for the tablet produced in Comparative Example 1, and then its release was quickly appeared. However, for the tablet produced in Example 3, while the three-dimensional shape that is a most good tablet was maintained, an ideal release type that is close to zero order release until 12 hours was maintained. Therefore, the beagle dog pharmacokinetic test of Test Example 3 was performed.
Test Example 3.
Two groups were prepared for each group having 12 beagle dogs. The test for identifying the pharmaceutical behavior was performed when administrating twice a day of 75 mg Lyrica Capsule that is most low content among the products available from the market as a reference formulation and when administrating once a day of formulation of Example 3.
The formulations were administrated after dinner, and the bloods were collected at fixed times (0, 0.5, 1, 1.5, 2, 4, 6, 8, 10, 10.5, 11, 11.5, 12, 14, 16, 18, 24 hours for the reference formulation and 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 24 hours for the test formulations), respectively. As a result, it was confirmed that the test group has 96 % Cmax and up to 91 % AUC as compared to the reference group that was administrated twice of 75 mg Lyrica Capsule as the reference formulation. In addition, Tmax value of formulation of Example 3 was exhibited up to 7 hours in contrast to Tmax value of Lyrica Capsule was exhibited about 1 hours. The results were shown in FIG. 2 and Table 12.
[Table 12]
Pharmacokinetic parameter comparison between the administration of Example 3 and Lyrica Capsule®75 mg Bid as the reference formulation.
Figure PCTKR2010007456-appb-I000013
Test Example 4.
A stressed stability tests for the formulations produced in Example and Comparative Example were measured at 60℃ and 80 % relative humidity(RH) for 4 weeks. The stability was identified through analyze of a pregabalin lactam, related compound of pregabalin, which is most produced. The results were shown in Table 13.
[Table 13]
The Result Table of Stressed Stability Test
Figure PCTKR2010007456-appb-I000014
The pregabalin sustained release formulation according to the present invention will be described, but the present invention will not be limited thereto and only more specifically described.
Preparation Example 1.
In order to prepare a tablet, after 150 mg pregabalin was mixed with 300 mg polyethyleneoxide (POLYOX WSR Coagulant), 47.5 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) was mixed and then strained through 30-mesh sieve (standard mesh is 30 sieve and size of sieve is 590 μm). The mixture was mixed with 2.5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 15 mg AMBTM-based Opadry AMBTM to complete the tablet. Each components in the tablet obtained were as follows:
Figure PCTKR2010007456-appb-I000015
Preparation Example 2.
Like Preparation Example 1, after 150 mg pregabalin was mixed with 300 mg polyethyleneoxide (POLYOX WSR 303), 47.5 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) was mixed and then strained through 30-mesh sieve. The mixture was mixed with 2.5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 15 mg Opadry AMBTM to complete the tablet. Each components in the tablet obtained were as follows:
Figure PCTKR2010007456-appb-I000016
Preparation Example 3.
In order to prepare a tablet, 150 mg pregabalin was mixed with a mixture of 297.5 mg polyethyleneoxide (POLYOX WSR 303TM) and 50 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve. The mixture was mixed with 2.5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 15 mg Opadry AMBTM to complete the tablet. Each components in the tablet obtained were as follows:
Figure PCTKR2010007456-appb-I000017
Preparation Example 4.
In order to prepare a tablet, 150 mg pregabalin was mixed with a mixture of 247.5 mg polyethyleneoxide (POLYOX WSR 303) and 100 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve. The mixture was mixed with 2.5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 15 mg AMBTM-based Opadry AMBTM to complete the tablet. Each components in the tablet obtained were as follows:
Figure PCTKR2010007456-appb-I000018
Preparation Example 5.
In order to prepare a tablet, 150 mg pregabalin was mixed with a mixture of 297.5 mg polyethyleneoxide (POLYOX WSR 303), 25 mg methaacrylic acid type C (Eudragit L-100) and 25 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve. The mixture was mixed with 2.5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 15 mg AMBTM-based Opadry AMBTM to complete the tablet. Each components in the tablet obtained were as follows:
Figure PCTKR2010007456-appb-I000019
Preparation Example 6.
In order to prepare a tablet, 150 mg pregabalin was mixed with a mixture of 297.5 mg polyethyleneoxide (POLYOX WSR 303) and 25 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve. After the mixture was mixed with 25 mg glyceryl behenate (Compritol 188) that was strained through 30-mesh sieve, the mixture obtained was mixed with 2.5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 15 mg AMBTM-based Opadry AMBTM to complete the tablet. Each components in the tablet obtained were as follows:
Figure PCTKR2010007456-appb-I000020
Preparation Example 7.
In order to prepare a tablet, after 150 mg pregabalin was mixed with a mixture of 152.5 mg polyethyleneoxide (POLYOX WSR 303), 95 mg hydroxylpropyl methylcellulose (HPMC) K100LV, and 75 mg silicated microcrystalline cellulose, the mixture obtained was mixed with 25 mg polyvinylalcohol-polyethyleneglycol graft copolymer and then strained through 30-mesh sieve. The mixture was mixed with 2.5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 15 mg AMBTM-based Opadry AMBTM to complete the tablet. Each components in the tablet obtained were as follows:
Figure PCTKR2010007456-appb-I000021
Preparation Example 8.
In order to prepare a tablet, 150 mg pregabalin was mixed with a mixture of 247.5 mg polyethyleneoxide (POLYOX WSR 303) and 85 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve. After the mixture was mixed with 15 mg low-substituted hydroxypropyl cellulose (L-HPC), the mixture obtained was mixed with 2.5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 15 mg AMBTM-based Opadry AMBTM to complete the tablet. Each components in the tablet obtained were as follows:
Figure PCTKR2010007456-appb-I000022
Preparation Example 9.
In order to prepare a tablet, 300 mg pregabalin was mixed with a mixture of 300 mg polyethyleneoxide (POLYOX WSR 303) and 150 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve. After the mixture was mixed with 15 mg low-substituted hydroxypropyl cellulose (L-HPC), the mixture obtained was mixed with 5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 750 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 15 mg AMBTM-based Opadry AMBTM to complete the tablet. Each components in the tablet obtained were as follows:
Figure PCTKR2010007456-appb-I000023
Preparation Example 10.
In order to prepare a tablet, 150 mg pregabalin was mixed with a mixture of 200 mg polyethyleneoxide (POLYOX WSR 303) and 80 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve. After the mixture was mixed with 65 mg low-substituted hydroxypropyl cellulose (L-HPC), the mixture obtained was mixed with 5 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 500 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 10 mg Opadry AMBTM to complete the tablet. Each components in the tablet obtained were as follows:
Figure PCTKR2010007456-appb-I000024
Preparation Example 11.
In order to prepare a tablet, 300 mg pregabalin was mixed with a mixture of 330 mg polyethyleneoxide (POLYOX WSR 303) and 70 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR) and then strained through 30-mesh sieve. After the mixture was mixed with 90 mg low-substituted hydroxypropyl cellulose (L-HPC), the mixture obtained was mixed with 10 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 800 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 16 mg Opadry IITM to complete the tablet. Each components in the tablet obtained were as follows:
Figure PCTKR2010007456-appb-I000025
Preparation Example 12.
In order to prepare a tablet, 150 mg pregabalin was mixed with a mixture of 200 mg polyethyleneoxide (POLYOX WSR 303), 80 mg silicated microcrystalline cellulose (SMCC 90), 95 mg butylated methaacrylic acid (Eudragit E-PO), and 40 mg polyvinylalcohol-polyethyleneglycol graft copolymer (Kollicoat IR), and then strained through 30-mesh sieve. After the mixture was mixed with 30 mg low-substituted hydroxypropyl cellulose (L-HPC), the mixture obtained was mixed with 7 mg magnesium stearate that was strained through 30-mesh sieve, and then compressed into 700 mg rectangular tablet using Erweka single punch presses. The tablet was coated with 14 mg Opadry IITM to complete the tablet. Each components in the tablet obtained were as follows:
Figure PCTKR2010007456-appb-I000026

Claims (7)

  1. A gastric-retentive sustained release formulation that can be administrated once a day, comprising 25 to 500 parts by weight of polyethyleneoxide as a swelling agent, and 10 to 200 parts by weight of polyvinylalcohol-polyethyleneglycol graft copolymer as an release-controlling agent, based on 100 parts by weight of pregabalin or a pharmaceutically acceptable salts thereof as an active component.
  2. The gastric-retentive sustained release formulation according to claim 1, wherein the content of polyethyleneoxide is 50 to 300 parts by weight based on 100 parts by weight of pregabalin or a pharmaceutically acceptable salts thereof.
  3. The gastric-retentive sustained release formulation according to claim 1, wherein the content of polyvinylalcohol-polyethyleneglycol graft copolymer is 20 to 100 parts by weight based on 100 parts by weight of pregabalin or a pharmaceutically acceptable salts thereof.
  4. The gastric-retentive sustained release formulation according to claim 1, wherein the release region of pregabalin as an active component is maintained at a stomach and small intestinal for up to 2 hours to 8 hours, and the release of pregabalin is controlled for 4 hours to 24 hours.
  5. The gastric-retentive sustained release formulation according to claim 1, wherein the capacity of pregabalin that is contained in the formulation for administrating once a day is 50 to 900 mg.
  6. The gastric-retentive sustained release formulation according to claim 1, wherein the molecular weight of the polyethyleneoxide is at least 100,000 to 10,000,000.
  7. The gastric-retentive sustained release formulation according to claim 1, wherein the used amount of polyvinylalcohol-polyethyleneglycol graft copolymer and polyethyleneoxide is 20 to 300 parts by weight based on 100 parts by weight of pregabalin or a pharmaceutically acceptable salts thereof.
PCT/KR2010/007456 2009-10-28 2010-10-28 Gastric-retentive sustained release formulation containing pregabalin, polyethyleneoxide and pva-peg graft copolymer WO2011053003A2 (en)

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WO2013015578A1 (en) * 2011-07-26 2013-01-31 Yuhan Corporation Sustained release tablet comprising pregabalin through two-phase release-controlling system
WO2015114509A1 (en) * 2014-01-28 2015-08-06 Ranbaxy Laboratories Limited Stabilized gastroretentive tablets of pregabalin
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US11026908B2 (en) 2016-07-17 2021-06-08 Mapi Pharma Ltd. Extended release dosage forms of pregabalin
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WO2011151708A1 (en) 2010-06-01 2011-12-08 Rubicon Research Private Limited Gastroretentive dosage forms of gaba analogs
WO2013015578A1 (en) * 2011-07-26 2013-01-31 Yuhan Corporation Sustained release tablet comprising pregabalin through two-phase release-controlling system
WO2015114509A1 (en) * 2014-01-28 2015-08-06 Ranbaxy Laboratories Limited Stabilized gastroretentive tablets of pregabalin
US11026908B2 (en) 2016-07-17 2021-06-08 Mapi Pharma Ltd. Extended release dosage forms of pregabalin
WO2019238068A1 (en) * 2018-06-13 2019-12-19 北京泰德制药股份有限公司 Sustained-release pregabalin composition and preparation method therefor
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CN111053749B (en) * 2018-10-16 2022-07-15 北京泰德制药股份有限公司 Pregabalin sustained-release composition and preparation method thereof
US11974974B2 (en) 2019-07-03 2024-05-07 Alvogen, Inc. Controlled-release tablets, method of making, and method of use thereof
GB2624861A (en) * 2022-11-28 2024-06-05 Orbit Pharma Ltd Sustained release pharmaceutical compositions comprising pregabalin or pharmaceutically acceptable salts thereof

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