WO2002069936A2 - Composition pharmaceutique amelioree d'ibuprofene et procede de production de telles compositions - Google Patents

Composition pharmaceutique amelioree d'ibuprofene et procede de production de telles compositions Download PDF

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Publication number
WO2002069936A2
WO2002069936A2 PCT/IB2002/000534 IB0200534W WO02069936A2 WO 2002069936 A2 WO2002069936 A2 WO 2002069936A2 IB 0200534 W IB0200534 W IB 0200534W WO 02069936 A2 WO02069936 A2 WO 02069936A2
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WO
WIPO (PCT)
Prior art keywords
acid
composition
ibuprofen
active ingredient
soft gelatin
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2002/000534
Other languages
English (en)
Other versions
WO2002069936A3 (fr
Inventor
Prashant Manohar Mandaogade
Ujwal Damu Kolhe
Abhijit Mukund Deshmukh
Mailatur Sivaraman Mohan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Reddys Laboratories Ltd
Original Assignee
Dr Reddys Laboratories 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.)
Filing date
Publication date
Application filed by Dr Reddys Laboratories Ltd filed Critical Dr Reddys Laboratories Ltd
Priority to AU2002244865A priority Critical patent/AU2002244865A1/en
Publication of WO2002069936A2 publication Critical patent/WO2002069936A2/fr
Publication of WO2002069936A3 publication Critical patent/WO2002069936A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the present invention relates to the improved pharmaceutical compositions of ibuprofen for enhanced solubilization as soft gelatin capsules.
  • the present invention also proposes the improved soft gelatin capsule gel mass composition to obtain a product with improved solubilization characteristics.
  • One of the further aspects of the present invention is to avoid the use of polyethylene glycol or hydroxide ion species containing solvents as solubilizers for the preparation of soft gelatin capsules containing ibuprofen.
  • (R)(-)-ibuprofen is converted in liver to (S)(+)-ibuprofen after absorption from GI tract. The inversion is about 0.69 for (R)(-)-isomer to (S)(+)-isomer of ibuprofen.
  • Total (S)(+) isomer availability from racemate is about 84.5%. Looking at the bioavailability of ibuprofen as (S)(+)- isomer, the racemate results in bioavailability of 70.7% compared to bioavailability of 92.0% for (S)(+)-ibuprofen.
  • Patent No. ES-OS 0299668 describes the production of hard gelatin capsules by filling with melts. Melt embedded materials pose a problem of crystal modification and altered bioavailability. Also this type of dosage form is not suitable for rapid releasing form but generally is intended to give sustained release form.
  • Patent No. WO 8802625 describes the production of soft gelatin capsule, which is filled with dissolved raw ibuprofen.
  • ibuprofen is dissolved in polyethylene glycol and further solubility is enhanced by neutralizing the ibuprofen with KOH.
  • This type of administration is not suitable for (S)(+)-ibuprofen, since either undesirable high decrease in content generally occur as a result of esterif ⁇ cation reactions of (S)(+)-Ibuprofen with alcohol in this type of solution of active compound or else racemization of (S)(+)-ibuprofen occur as a result of addition of KOH.
  • Mortan et al. U.S. Pat. No. 5,376,688 discloses the preparation of pharmaceutically accepted solution of acidic, basic and amphoteric pharmaceutical agent suitable for encapsulation in gelatin capsule for subsequent oral administration and include pharmaceutical agent, an ion species and solvent system.
  • the present investigation uses alkali metal bicarbonate to carry out partial ionization of ibuprofen and subsequent conversion into alkali metal salt.
  • Potassium hydroxide and other hydroxide ion species containing agents are avoided in the present invention, instead alkali metal bicarbonate is used for the partial or complete conversion of ibuprofen into its alkali metal salts.
  • potassium bicarbonate facilitates the conversion of ibuprofen to potassium ibuprofen with the help of the evolved carbon dioxide in the above reaction, which is referred as gas powered technique of solubilization in this specification and in the appended claims.
  • Yu et al. U.S. Pat. No. 5,360,615 teaches the use of polyvinyl pyrollidone, polyethylene glycol and propylene glycol to enhance the solubility of acidic pharmaceutical agent.
  • the invention of Yu et al. neither teaches nor describes the use of Labrasol to enhance the solubility of acidic pharmaceutical agent.
  • the present invention avoids the use of polyethylene glycol as solvent for solubilizing ibuprofen or (S)(+)-ibuprofen before filling into softgels as polyethylene glycol is not suitable fill material/solvent for (S)(+)-ibuprofen. It is reported in the prior literature that the use of polyethylene glycol in the formulation of (S)(+)-ibuprofen causes undesirable high decrease in content due to esterification or the racemization of (S)(+)-ibuprofen.
  • gas powered technique utilizing alkali metal bicarbonate is used to carry out the partial ionization of ibuprofen.
  • polyethylene glycol as suggested by U.S. Pat. No. 5,071,643 is not suitable for the formulation of (S)(+)-ibuprofen.
  • non aqueous medium is preferred choice as fill medicaments during soft gelatin capsule manufacturing, as they do not imbibe water from wet gelatin ribbons.
  • the fill material should be easily dispersible in aqueous media.
  • Labrasol possess both these characteristics due to its amphiphilic nature. It aids the solubilization of poorly water-soluble drugs and subsequent dispersion in gastric fluid by forming a microemulsion, which produces large surface area for the faster and uniform absorption of active ingredient. Absorption of drug solubilized in Labrasol is generally not affected by the presence or absence of food in stomach.
  • the Present invention overcomes the problem of retardation of active ingredient from the capsule composition.
  • the invention also presents the solvents for improved solubilization of (S)(+)- ibuprofen while avoiding the use of polyethylene glycol as solvent.
  • active ingredient refers to ibuprofen or (S)(+)-ibuprofen as free base or as alkali metal salt or mixtures thereof.
  • active ingredient is (S)(+)-ibuprofen, it is not necessary to convert it to its alkali metal salt, however when the active ingredient is ibuprofen it should be converted into its alkali metal salt either partially or completely in order to obtain better solubilization as per this invention.
  • gas powered solubilization technique means the process of conversion of ibuprofen or (S)(+)-ibuprofen into its cationic salt by adding the alkali metal bicarbonate as dry powder or as aqueous solution, in Labrasol, Transcutol, or mixtures thereof, containing the active ingredient.
  • the active ingredient and alkali metal salt can also be added to Labrasol, Transcutol or mixtures thereof.
  • the said mixture may optionally contain amino acids depending on the intended final product as per this invention.
  • Transcutol means Transcutol P, which is chemically Diethylene Glycol Monoethyl Ether, procured from Gattefosse, France.
  • Labrasol is chemically Caprylocaproyl Macrogol-8 Glycerides, procured from Gattefosse, France.
  • metal ion carbonate used in this specification and in the appended claims means carbonates selected from any of the metals from sodium, lithium or potassium, more preferably potassium.
  • Soft gelatin capsule has its conventional meaning (soft elastic gelatin capsule or softgel).
  • improved solubilization used in this specification and in the appended claims means the increased solubility of active ingredient, which increases the bioavailability of the active ingredient from soft gelatin capsule.
  • the solvent means any of the ingredients, without active ingredient, selected from Labrasol, vegetable oils, glycin or mixtures thereof.
  • hydrooxide ion containing solvent means the solvents/vehicles/capsule fill materials, used to fill soft gelatin capsule, which have high free hydroxyl value like methanol, ethanol, polyethylene glycol etc.
  • solvents, vehicles or capsule fill material are used interchangeably in this specification.
  • Anidrisorb is anidrisorb 85/70 which is aqueous solution of D-sorbitol and sorbitans, supplied by Roquette, France.
  • Sorbitol special solution is aqueous sorbitol and sorbitol and sorbitol anhydrides, supplied by SPI Pharma., France.
  • the Labrasol or Transcutol of the present invention may be replaced with any of the solvents selected from the group consisting of coconut oil; corn oil; olive oil; palm oil; peanut oil; safflower oil; sesame oil; soybean oil; hydrogenated castor oil; hydrogenated coconut oil; partially hydrogenated soybean oil; glyceryl tricaprate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryl tricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate; saturated polyglycolized glycerides (Gelucire 44/14, Gelucire 14 50/13 and
  • the carboxylic acids are selected from the groups consisting of benzoic acid, fumaric acid, maleic acid, citric acid, ascorbic acid, edetic acid, lactic acid, sorbic acid, tartaric acid, adipic acid, succinic acid, gluconic acid, or a salt thereof.
  • the pH of the composition before filling into softgel is in the range of 2.5 to 7.5.
  • the temperature should be in the range of 25-65°C to carry out the conversion of ibuprofen or (S)(+)- ibuprofen into its alkali metal salt form.
  • composition to be incorporated in soft gelatin capsule
  • Example 2 Soft gelatin capsule gel mass composition As described in example 1. Composition to be incorporated in soft gelatin capsule
  • composition to be incorporated in soft gelatin capsule

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  • 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)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un principe actif, l'ibuprofène ou (S)(+)-ibuprofène en tant que base libre ou en tant que sels de métal alcalin, ou que de mélanges desdits composants, sous forme d'une capsule en gélatine molle, lesdites capsules en gélatine molle présentant une composition de masse de gel de capsule en gélatine molle permettant de favoriser la solubilisation du principe actif. L'invention concerne également le procédé de production d'une telle capsule en gélatine molle ou d'une telle composition de masse de gel de gélatine molle. Un autre aspect de l'invention permet d'éviter l'utilisation de polyéthylène glycol ou d'espèces d'ions hydroxydes contenant des solvants en tant que solubilisateurs, pour la préparation de capsules en gélatine molle contenant ledit principe actif.
PCT/IB2002/000534 2001-03-02 2002-02-22 Composition pharmaceutique amelioree d'ibuprofene et procede de production de telles compositions Ceased WO2002069936A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002244865A AU2002244865A1 (en) 2001-03-02 2002-02-22 Pharmaceutical composition of ibuprofen

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN187/MAS/2001 2001-03-02
IN187MA2001 2001-03-02
IN204/MAS/2001 2001-03-07
IN204MA2001 2001-03-07

Publications (2)

Publication Number Publication Date
WO2002069936A2 true WO2002069936A2 (fr) 2002-09-12
WO2002069936A3 WO2002069936A3 (fr) 2003-02-20

Family

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PCT/IB2002/000534 Ceased WO2002069936A2 (fr) 2001-03-02 2002-02-22 Composition pharmaceutique amelioree d'ibuprofene et procede de production de telles compositions

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Country Link
AU (1) AU2002244865A1 (fr)
WO (1) WO2002069936A2 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2404336A (en) * 2003-07-30 2005-02-02 Cipla Ltd Stabilisation of therapeutic agents using a carbonate salt of an amino acid, preferably in the presence of a saccharide, & pharmaceutical compositions thereof
WO2005063219A3 (fr) * 2003-12-23 2005-08-11 Ranbaxy Lab Ltd Capsules en gelatine molle contenant de l'ibuprofene
WO2008052033A3 (fr) * 2006-10-25 2008-06-12 Mcneil Ppc Inc Composition d'ibuprofène
WO2008005742A3 (fr) * 2006-06-30 2008-07-10 Mcneil Ppc Inc Capsules dures emplies d'un liquide contenant de l'ibuprofène
WO2009069139A1 (fr) * 2007-11-28 2009-06-04 Alkem Laboratories Ltd. Forme posologique fournissant un remplissage liquide contenant de l'ibuprofène
CN102204882A (zh) * 2011-03-22 2011-10-05 韩彬 布洛芬的药物组合物
US10966926B2 (en) 2010-04-14 2021-04-06 Vitux Group As Oral pharmaceutical dispersion compositions

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3178470A1 (fr) * 2011-04-11 2017-06-14 Vitux Group AS Compositions pharmaceutiques sous forme de dispersion pour administration orale

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1197038B (it) * 1986-08-01 1988-11-25 Zambon Spa Composizione farmaceutica ad attivita' analgesica
US5376688A (en) * 1992-12-18 1994-12-27 R. P. Scherer Corporation Enhanced solubility pharmaceutical solutions
GB9405304D0 (en) * 1994-03-16 1994-04-27 Scherer Ltd R P Delivery systems for hydrophobic drugs
US5858401A (en) * 1996-01-22 1999-01-12 Sidmak Laboratories, Inc. Pharmaceutical composition for cyclosporines
JP4713698B2 (ja) * 1997-03-05 2011-06-29 スージェン， インク． 疎水性薬剤の処方
GB2331458B (en) * 1997-11-21 2002-07-31 Gursharan Singh Moonga Solubilising systems for difficult pharmaceutical actives for preparing concentrated stable solutions for encapsulation into soft gelatine

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2404336A (en) * 2003-07-30 2005-02-02 Cipla Ltd Stabilisation of therapeutic agents using a carbonate salt of an amino acid, preferably in the presence of a saccharide, & pharmaceutical compositions thereof
WO2005063219A3 (fr) * 2003-12-23 2005-08-11 Ranbaxy Lab Ltd Capsules en gelatine molle contenant de l'ibuprofene
WO2008005742A3 (fr) * 2006-06-30 2008-07-10 Mcneil Ppc Inc Capsules dures emplies d'un liquide contenant de l'ibuprofène
WO2008052033A3 (fr) * 2006-10-25 2008-06-12 Mcneil Ppc Inc Composition d'ibuprofène
WO2009069139A1 (fr) * 2007-11-28 2009-06-04 Alkem Laboratories Ltd. Forme posologique fournissant un remplissage liquide contenant de l'ibuprofène
US10966926B2 (en) 2010-04-14 2021-04-06 Vitux Group As Oral pharmaceutical dispersion compositions
CN102204882A (zh) * 2011-03-22 2011-10-05 韩彬 布洛芬的药物组合物
CN102204882B (zh) * 2011-03-22 2013-07-24 韩彬 布洛芬的药物组合物

Also Published As

Publication number Publication date
WO2002069936A3 (fr) 2003-02-20
AU2002244865A1 (en) 2002-09-19

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