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WO2009153798A1 - Dextrine réticulée utilisée comme agent désintégrant/excipient dans un comprimé - Google Patents

Dextrine réticulée utilisée comme agent désintégrant/excipient dans un comprimé Download PDF

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Publication number
WO2009153798A1
WO2009153798A1 PCT/IN2008/000376 IN2008000376W WO2009153798A1 WO 2009153798 A1 WO2009153798 A1 WO 2009153798A1 IN 2008000376 W IN2008000376 W IN 2008000376W WO 2009153798 A1 WO2009153798 A1 WO 2009153798A1
Authority
WO
WIPO (PCT)
Prior art keywords
cross
dextrin
tablet
cld
linked
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/IN2008/000376
Other languages
English (en)
Inventor
Satyanarayana Kota
Rambhau Devraj
Bhujanga Rao Adibhatla Kali Satya
Nannapaneni Venkaiah Chowdary
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.)
Natco Pharma Ltd
Original Assignee
Natco Pharma 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 Natco Pharma Ltd filed Critical Natco Pharma Ltd
Priority to PCT/IN2008/000376 priority Critical patent/WO2009153798A1/fr
Publication of WO2009153798A1 publication Critical patent/WO2009153798A1/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
    • A61K9/20—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 inventions deals with use of cross-linked dextrin as disintegrant in a pharmaceutical tablet formulation.
  • Tablet dosage form is most widely used, popular, convenient solid dosage form.
  • a tablet contains drugs and excipients.
  • Excipients are non-active ingredients, which are mixed with pharmacologically active compounds (drug/active pharmaceutical ingredient).
  • Excipients used in tablet formulation are binders, disintegrants, diluents, lubricants, glidants, surfactants, dyes and flavouring agents.
  • Disintegrants are the important component of the tablet excipients. Disintegrants are usually added to cause the compressed tablet to break apart when placed in aqueous medium. Typical disintegrants are maize, potato starch, gelatinized starches, alginic acid crosscarmellose, crdsspovidone, sodium starch glycolate etc. Disintegrants swell on contact with water, which cause the tablet to break.
  • the classical disintegrants such as starches of maize, corn, tapioca, wheat, potato, and alginic acid etc. are used in 5-20% w/w of tablet. Tablets made using these disintegrants typically exhibit disintegration time about 10-30 min at hardness of 6-8 kg.
  • Superdisintegrants are new class of disintegrants, which are used in 1-10% w/w of the tablet weight. Superdinsintegrants exhibit disintegration time of 1- 5 minutes. In some cases even less than 1 min. At present there are 3-4 superdinsintegrants, which are used industrially. These are crosscormellose sodium (Sodium salt of cross-linked, partly O- carboxymethylated cellulose, Ac-Di-SoI), Sodium starch glycolate (O-carboxymethy starch, primojel or Explotab), Crosspovidone (Polyplasdorie XL) etc. (http://pharmtech.findpharmaxom/ ⁇ harmtech/Excipients/A-Com ⁇ arative-Study-of- Current-Superdisintegrants/ArticleStandard/Article/detail/378399)
  • Dextrin is a starch derivative, is chemically a mixture of polymerized glucosans with molecular formula of (CgHiOOs) n XH 2 O. It is low molecular weight carbohydrate obtained by partial hydrolysis of starch of by heat, alkali, and enzymes. Starch source may be from maize, corn, potato etc. Dextrin is available in two grades based upon the solubility. White dextrin is partially soluble in water, whereas yellow dextrin is completely soluble in water. Dextrin is commercially available in abundant quantities quite economically.
  • Dextrin is partially hydrolyzed starch. It is partially or completely soluble in water depending on the degree of hydrolysis. White dextrin is partially soluble in water, whereas yellow dextrin is completely soluble in water. Treating the hydroxy groups of polysaccharide dextrin with bifunctional cross-linking agentyield cross-linked dextrin. Cross-linking induces hydrophobization to hydrophilic dextrin, which in turn induces swelling property to dextrin in water.
  • the objective of the present invention is to describe tablet-disintegrating property of cross-linked dextrins.
  • the main objective of present invention is to cross-link dextrin with 2-50 g cross-linking agent per 100 g dextrin to produce 2-50% cross-linked dextrin.
  • the important objective of present invention is to use cross-linked dextrin as disintegrant in the formulation of tablets prepared by wet granulation in ratio of 0.1-20 g per 100 gram tablet granules, which show the disintegration time of less than 1 minute to 20 minutes.
  • Yet another objective of present invention is to use cross-linked dextrins as disintegrant in the formulation of tablets prepared by direct compression method in ratio of 0.1-20 g per 100 gram tablet granules which show the disintegration time of less than 1 minute to
  • the two carbohydrate chains present in the dextrin can be linked by a bifunctional linking agent by a covalent bond. In this linkage reaction, the hydroxy groups of the chains are involved.
  • a typically cross-linked dextrin can be depicted as follow.
  • the degree of cross linking is from 2 to 50, preferably from 20 to 50, and it is prepared by cross-linking dextrin with a cross-linking agent in a relative amount of 2 to 50 g of cross-linking agent per 100 g of dextrin is employed.
  • Cross-linked dextrin having degree of cross-linking less than 15% is found to be soluble in water and between 15-20% is partially soluble in water.
  • Cross-linked dextrins with degree of cross-linking greater than 20% are found to be insoluble in water.
  • the cross-linking agent used to cross-link dextrin can be epichlorohydrin, bis- epoxypropylether, ethylene glycol-bis-epoxy propyl ether, sodium trimetaphosphate (STMP), adipic-acetic anhydride, phosphorus oxy chloride, formaldehyde or a diepoxide, such as vinylcyclohexene dioxide or butadiene dioxide, vinylcyclohexene dioxide or butadiene dioxide.
  • STMP sodium trimetaphosphate
  • adipic-acetic anhydride phosphorus oxy chloride
  • formaldehyde or a diepoxide such as vinylcyclohexene dioxide or butadiene dioxide, vinylcyclohexene dioxide or butadiene dioxide.
  • use is made of epichlorohydrin.
  • Disintegrating property of a disintegrant is related to swelling capacity of the material in water.
  • Dextrin cross-linked with 20, 25, 30, 35, 40, 45, 50% epichlorohydrin are evaluated for swelling property in water for different time intervals.
  • 1 gram of dextrin cross-linked with various percentages of cross- linking agent is taken in 50 ml graduated, stoppered measuring cylinder and water is added till 40 ml mark and shaken gentle for 30 seconds and further water is added till 50 ml mark and allowed stand for 240 minutes.
  • the swelling capacity is noted at 15, 30, 60, and 240 minutes.
  • the highest swelling capacity of 12 ml is observed with 20% cross- linked, which is selected for further evaluation of disintegrating property.
  • tablets are initially prepared using 20% cross- linked dextrin (CLD-20) by wet granulation method. These tablets are prepared using paracetamol as active pharmaceutical ingredient, dicalcium phosphate as diluent, starch paste as binder and magnesium stearate as lubricant and CLD-20 is used as disintegrant at 2.5, 5, 7.5, 10% concentrations.
  • CLD-20 cross- linked dextrin
  • tablets are also prepared with marketed disintegrants such as corn starch and croscarmellose.
  • a typical tablet formulation is shown in Table 2a. The formulated tablets are compressed at two different compressional strength to give tablets with hardness of 6-8 kg and 8-10 kg. These tablets are evaluated for disintegration time by USP method.
  • Tablets prepared using CLD-20 in concentration range 2.5-10% showed disintegration time of 0.4-0.6 minutes at 6-8 kg hardness and 0.5-3.3 minutes at hardness of 8-10 kgs respectively.
  • a comparison of disintegrating time with other disintegrants indicates that the cross-linked dextrin (CLD-20) is superior to cornstarch by about 14 times, and about 5 times to superdisintegrant crosscarmellose at 2.5% disintegrant concentration respectively.
  • the fast disintegration time exhibited at low concentration of CLD-20 is comparable superdinsintegrants.
  • cross-linked dextrins could be categorized as superdinsintegrant.
  • Data of disintegration time of tablets formulated using CLD-20 with 2.5-10% concentration at compressional strength of 6-8 and 8- 10 are shown in Table 2b.
  • tablets are prepared by direct compression method also.
  • the tablet formulation is composed of 2.5-10% of CLD-20 as a disintegrant, Avicel PH 102 as a binder, magnesium stearate as a lubricant and dry dicalcium phosphate as a diluent and folic acid as the drug substance.
  • the tablet formulation is shown in Table 3a. Tablet granules are compressed at two different compressional strength to give tablets with hardness of 6-8 and 8-10 Kg. Table 3b shows the disintegration time of the various tablets.
  • the compound was fed orally to mice at 100, 500, 1000, 2000mg/kg mice and observed for behavior for 4h and mortality for 72h.
  • Paracetamol drug
  • dicalcium phosphate dicalcium phosphate
  • CLD-20 starch paste
  • binder starch paste
  • the granules were dried and milled then mixed with magnesium strearate (lubricant) and compressed into tablets at two different compressional forces to give tablets with harness of 6-8 kg and 8-10 kg.
  • the tablets were evaluated for disintegration time according to USP protocol.
  • the composition of 250 mg tablet is shown in Table 2a and disintegration data are shown in Table 2b.
  • disintegrants corn starch, crosscarmellose.
  • Table 2a Tablet Formulation by Wet Granulation Method
  • Table 3a Tablet formulation by Direct Compression method
  • mice weighing 25-30gm were divided into two groups of six animals each.
  • CLD-20 was suspended in normal saline and fed orally to mice at a dose of 100, 500, 1000, 2000mg/kg body weight.
  • the negative control animals were fed with normal saline. The animals were observed for behavioral changes during the first 4 hours and mortality if any for 72 hours.

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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)

Abstract

Les agents désintégrants constituent les principaux composants d'un comprimé. La réticulation d'une dextrine et d'une épichlorohydrine entraîne l'hydrophobisation de la dextrine hydrophile, permettant dès lors d'obtenir un bon pouvoir gonflant dans l'eau. Selon l'invention, on réticule la dextrine avec de l'épichlorohydrine, selon divers rapports de poids entre la dextrine et l'épichlorohydrine. La réticulation s'effectue selon un rapport de 5 à 50% d'épichlorohydrine. On obtient une capacité maximale de gonflement avec une réticulation de 20%. On évalue l'action de désintégration de la dextrine réticulée en préparant des comprimés de paracétamol selon un procédé de granulation par voie humide et des comprimés d'acide folique selon un procédé de compression directe. Les comprimés préparés par granulation par voie humide avec 20% de dextrine réticulée se sont désintégrés en moins d'une minute et le comprimé préparé par compression directe s'est désintégré en moins de quatre minutes.
PCT/IN2008/000376 2008-06-16 2008-06-16 Dextrine réticulée utilisée comme agent désintégrant/excipient dans un comprimé Ceased WO2009153798A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2008/000376 WO2009153798A1 (fr) 2008-06-16 2008-06-16 Dextrine réticulée utilisée comme agent désintégrant/excipient dans un comprimé

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2008/000376 WO2009153798A1 (fr) 2008-06-16 2008-06-16 Dextrine réticulée utilisée comme agent désintégrant/excipient dans un comprimé

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WO2009153798A1 true WO2009153798A1 (fr) 2009-12-23

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016004974A1 (fr) * 2014-07-07 2016-01-14 Roquette Italia S.P.A. Polymère à base d'une maltodextrine pour l'encapsulation de composés organiques
WO2016100861A1 (fr) 2014-12-19 2016-06-23 Baxter International, Inc. Composition hémostatique fluidifiable
WO2021254662A1 (fr) * 2020-06-16 2021-12-23 Roquette Freres Matrice à base de dérivé d'amidon réticulé
WO2022177432A1 (fr) 2021-02-18 2022-08-25 Lumiforte Holding B.V. Peinture d'ombrage biodégradable

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4010259A (en) * 1975-07-17 1977-03-01 Johansson J A Olof Disinfectants containing iodine complexed to a hydrophilic organic carrier
GB2084871A (en) * 1980-09-10 1982-04-21 Johansson Johan Alfred Olof An element containing a therapeutic or palliative agent
US4462982A (en) * 1981-10-05 1984-07-31 Tanabe Seiyaku Co., Ltd. Microcapsules and method of preparing same
US6013284A (en) * 1993-03-02 2000-01-11 Biovector Therapeutics S.A. Synthetic particulate vectors and preparation process
WO2008117300A2 (fr) * 2007-03-23 2008-10-02 Natco Pharma Limited Procédé perfectionné pour la préparation d'iode cadexomère

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4010259A (en) * 1975-07-17 1977-03-01 Johansson J A Olof Disinfectants containing iodine complexed to a hydrophilic organic carrier
GB2084871A (en) * 1980-09-10 1982-04-21 Johansson Johan Alfred Olof An element containing a therapeutic or palliative agent
US4462982A (en) * 1981-10-05 1984-07-31 Tanabe Seiyaku Co., Ltd. Microcapsules and method of preparing same
US6013284A (en) * 1993-03-02 2000-01-11 Biovector Therapeutics S.A. Synthetic particulate vectors and preparation process
WO2008117300A2 (fr) * 2007-03-23 2008-10-02 Natco Pharma Limited Procédé perfectionné pour la préparation d'iode cadexomère

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016004974A1 (fr) * 2014-07-07 2016-01-14 Roquette Italia S.P.A. Polymère à base d'une maltodextrine pour l'encapsulation de composés organiques
CN106573992A (zh) * 2014-07-07 2017-04-19 罗盖特意大利公司 用于包封有机化合物的基于麦芽糖糊精的聚合物
JP2017523277A (ja) * 2014-07-07 2017-08-17 ロケット イタリア エス．ピー．エイ． 有機化合物をカプセル封入するための、マルトデキストリンをベースとするポリマー
CN106573992B (zh) * 2014-07-07 2021-03-09 罗盖特意大利公司 用于包封有机化合物的基于麦芽糖糊精的聚合物
WO2016100861A1 (fr) 2014-12-19 2016-06-23 Baxter International, Inc. Composition hémostatique fluidifiable
WO2021254662A1 (fr) * 2020-06-16 2021-12-23 Roquette Freres Matrice à base de dérivé d'amidon réticulé
CN115697303A (zh) * 2020-06-16 2023-02-03 罗盖特公司 基于交联淀粉衍生物的基质
WO2022177432A1 (fr) 2021-02-18 2022-08-25 Lumiforte Holding B.V. Peinture d'ombrage biodégradable

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