WO2004073713A1 - Preparation de gel a base de pirfenidone - Google Patents

Preparation de gel a base de pirfenidone Download PDF

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Publication number
WO2004073713A1
WO2004073713A1 PCT/JP2004/001968 JP2004001968W WO2004073713A1 WO 2004073713 A1 WO2004073713 A1 WO 2004073713A1 JP 2004001968 W JP2004001968 W JP 2004001968W WO 2004073713 A1 WO2004073713 A1 WO 2004073713A1
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WO
WIPO (PCT)
Prior art keywords
gel
gel preparation
concentration
solvent component
active ingredient
Prior art date
Application number
PCT/JP2004/001968
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English (en)
Japanese (ja)
Inventor
Kaori Ikeda
Yuichi Takasu
Kazumasa Morimoto
Original Assignee
Shionogi & Co., 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 Shionogi & Co., Ltd. filed Critical Shionogi & Co., Ltd.
Publication of WO2004073713A1 publication Critical patent/WO2004073713A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the present invention relates to gels for treating fibrotic diseases of the skin.
  • 5-Methyl-11-phenyl-1- (1H) -pyridone is a drug known as Pirfenidone, which has an antifibrotic action (Japanese Patent Laid-Open No. 2-215719).
  • the formulation of pirfenidone includes capsules, tablets, tablets, ointments and the like.
  • “Hydrophilic ointment containing 5 to 10% of pirfenidone” is mentioned, but no specific composition is described.
  • Anti-fiber means pulmonary fibrosis, arteriosclerosis, skin fibrosis 'I', and the repair or normalization of pathological fibrotic tissue in keloids.
  • JP-T-Hei 2002-526447 (W000 / 16775) describes gels, ointments and creams as external preparations for treating fibrotic diseases of the skin.
  • the gel described in JP-T-Hei 2002-526447 uses carboxybutyl polymer (CVP> as a gel-forming agent. This gel is contained in the ionic component of the preparation and the biological component at the administration site.
  • W094 / 26249 (Tokuhyo Hei 8-510251) describes capsules, tablets, creams, ointments and the like as preparations containing N-substituted 2- (1H) pyridone as an active ingredient.
  • JP-A-3-151339 discloses a nonionic water-soluble cellulose ether (such as partially hydrophobized hydroxypropylmethylcellulose (HM-HPMC)) treated with a modifying agent having an alkyl group having 6 to 26 carbon atoms. Gels containing are described. It is described as a stable gel that has less interaction with drugs and does not require a neutralizing base compared to carboxybutyl polymer (CVP). Not listed.
  • CVP carboxybutyl polymer
  • tetracycline hydrochloride, kanamycin and gentamicin sulfate are described as active ingredients
  • modified cellulose ether, ethanol, isopropanol, glycerin, polyethylene glycol 400, and propylene glycol are described as solvent components.
  • HM-H PMCs are less susceptible to changes in pH and less susceptible to salt formation with drugs than CVP.
  • water / "ethanol, water isopropanol, benzyl alcohol, and dimethyl sulfoxide are described as solvents with high solubility of HM-HPMC. Gel pill phenodon is not described.
  • the concentration of the active ingredient is 0 .; 15 to 15 W / W%, the concentration of partially hydrophobic hydroxypropylmethylcellulose is 0.5 to 5 W / W%, and the concentration of the solvent component is 5 to
  • the gel according to the above (1) which is 70 W / W%.
  • the shape retention and spreadability of the preparation are not affected by ions or pH, and A preparation excellent in transferability to the skin is obtained.
  • CVP carboxybutyl polymer
  • the range of the solvent content can be set broadly by appropriately selecting the type and amount of the nonionic gelling agent, the concentration range of pinialidone can be broadly adjusted.
  • the solvent composition can be selected in consideration of skin irritation and skin absorption as well as possible.
  • a gel in which the drug is dissolved in a solvent that is miscible with water at an arbitrary ratio without causing phase separation is formed stably, so that a preparation with excellent drug uniformity can be obtained.
  • Figure 1 is a graph showing the viscosity changes with respect to P H gels.
  • Figure 2 Graph showing the inhibition of granulation formation by the gel in the rat; BEST MODE FOR CARRYING OUT THE INVENTION
  • a gel means a preparation in which a drug solution comprising a solvent that is miscible with water at an arbitrary ratio is imparted with shape retention and spreadability by a gelling agent.
  • the gel of the present invention containing pirfenidone as an active ingredient treats fibrotic diseases of the skin, for example, keloids, hypertrophic scars, fibrotic lesion tissues, contact warts, contact dermatitis and postoperative burns Useful to do.
  • fibrotic diseases of the skin for example, keloids, hypertrophic scars, fibrotic lesion tissues, contact warts, contact dermatitis and postoperative burns Useful to do.
  • the ⁇ partially hydrophobized hydroxypropylmethyl cellulose '' contained in the gel of the present invention is an external gel base also referred to as modified HPMC, in which a hydroxy group in the molecule is substituted with an alkyl group having 6 to 26 carbon atoms.
  • modified HPMC external gel base also referred to as modified HPMC, in which a hydroxy group in the molecule is substituted with an alkyl group having 6 to 26 carbon atoms.
  • Non-ionic water-soluble cellulose ethers include hydroxypropyl methyl cellulose.
  • Hydroxypropyl methylcellulose is a cellulose hydride A compound in which a loxy group is substituted by a methyl group or a hydroxypropyl group, and is derived to a methoxy group or a hydroxypropoxyl group, respectively.
  • the substitution rate of the methyl group is 10% to 35%
  • the substitution rate of the hydroxypropoxyl group is 2% to 15%. More preferably, a compound having a methyl group substitution rate of 18% to 25% and a hydroxypropoxyl group substitution rate of 3% to 13%, and a methyl group substitution rate of 26% to 32%.
  • a compound having a hydroxypropoxyl group substitution rate of 5% to 9%, or a methyl group substitution rate of 26% to 32% and a hydroxypropoxyl group substitution rate of 6 ° / 0 to: L 3% compound For example, hydroxypropylmethylcellulose 2208, 2906, or 2910, the 13th Revised Japanese Pharmacopoeia.
  • the partially hydrophobized hydroxypropyl methylcellulose (modified HPMC) used in the present invention can be obtained. Is obtained.
  • a modified HPMC By changing the introduction ratio of the alkyl group having 6 to 26 carbon atoms to the substituted hydroxymethylcellulose, a modified HPMC can be obtained in which the range of the solvent amount can be variously changed. For example, by reducing the introduction rate in the modified HPMC such as 0.1 to 0.7%, the amount of solvent required in the gel can be reduced. On the other hand, by increasing the introduction rate as high as 2.6 to 2%, the solvent content can be set high, and a formulation in which pirfenidone is dissolved at a high concentration can be obtained. In addition, by setting the introduction rate to 0.9 to 2.2%, a drug product with characteristics intermediate between the two can be obtained.
  • Modified HPMC is readily prepared by the method described in Japanese Patent No. 2610052. Alternatively, it is commercially available from Daido Kasei under the trade name Sangelose.
  • the concentration of the partially hydrophobized hydroxypropylmethyl cellulose is preferably 0.5 to 5 W / W%, more preferably 1 to 2 W / W% based on the whole gel.
  • the solvent component that can be contained in the gel preparation of the present invention is also used for reducing the skin irritation and improving skin transferability used for dissolving pirfenidone.
  • the preferred solvent component in the present invention is propylene glycol, isopropanol, polyethylene glycol, N-methyl-1-pyrrolidone, benzyl alcohol or a mixture thereof.
  • Coal 400 polyethylene glycol with a weight average molecular weight of 380 to 420 is preferred.
  • Typical formulations and typical ratios (W / W% based on the whole formulation) of the present invention are as follows.
  • Deionized water 10 to 94.4 W / W In the process of dispersing the denatured HPMC in heated deionized water and then cooling, add the pyrphenidone dissolved in the solvent component and stir. Easy to do Is prepared.
  • the gel of the present invention can further contain an antioxidant, a preservative, and the like.
  • Example 1 The present invention is described in more detail by the following examples. However, the present invention is not limited to this.
  • Example 1
  • a gel was prepared in the same manner as in Example 1 with the composition shown in the following table (W / W ° / o), and filled in a 5 g tube.
  • Table 3
  • Example 2-3 Example 2-3, Example 2-4, Example 2-5, Example 2-6, Example 2-7, Example 2-8, Example 2-9, Example 2-10, Example The gels prepared in 2-11 and Example 2-12 were stored at 40 ° C for 3 months, and the content of pirfenidone was measured by HPLC (absolute calibration method).
  • Example 2 -6 103.10%
  • Example 2-8 106.90%
  • Example 2-1, Example 2-2, Example 2-3, Example 2-8, Example 2-11, and Example 2-12 were administered to the rat abdomen at 300 mg each, The amount of intradermal transfer after time was measured.
  • the administration was performed by attaching a glass cell to the abdomen of the rat, from which the hair had been removed using a razor, and placing the preparation in the cell to keep the administration area constant.
  • occlusion administration in which the top of the glass cell was covered with a rubbed lid, and open administration in which the lid was removed were performed.
  • Example 2-1 50.8 ⁇ 13.9 16.0 ⁇ 2.3
  • Table 5 shows that gels using denatured HPMC (Sangelose 90L) as a gelling agent have good intradermal distribution and can easily transfer pirueyudon into the skin. Is shown. It is also possible to increase the amount of intradermal distribution by changing the solvent composition as shown in Table 5, and it is possible to increase the amount of picliidone as in Examples 2-11 and 2-12. Sufficient intradermal distribution can be maintained.
  • a gel was prepared with the composition (W / W%) shown in the table below and filled in a 5 g tube.
  • a gel was prepared with the composition (W / W%) in the table below c
  • a gel was prepared with the composition (WM) shown in the table below.
  • Example 5-1 Gels of Example 5-1, Example 5-2, Example 5-3, Example 5-4, Control example 1-1, Control example 1-2, Control example 1-3, Control example 1-4 was measured with an E-type viscometer.
  • the gel was tested for its ability to inhibit granulation formation according to the method described in Jpn Pharmacology Journal 99, 241-246 (1992).
  • Example 3-1, Example 2-3 and Control A were applied once a day for 14 days.
  • all cases were euthanized with over anesthesia, the granulation tissue around the mini-pump was excised including the pump, the granulation was incised, the pump was removed, and the weight of the granulation tissue after 145 was measured.
  • the significant difference test with control A was performed by Dunnett's test. In addition, 5 animals were used for each group.
  • Control A had 25% w / w of propylene dalicol, polyethylene glycolone 4
  • a preparation having excellent drug stability and skin transfer properties can be obtained by selecting a solvent component suitable for pirfenidone. Also, by selecting the type of denatured HPMC, gels with various amounts of solvent are formed, the range of concentration of picliidone is widened, and the amount of solvent is reduced to obtain a formulation with less skin irritation.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une préparation de gel contenant du HPMC dénaturé ainsi que du 5-méthyl-1-phényl-2-(1h)-pyridone ou un sel ou ester pharmaceutiquement acceptable de ladite préparation. On obtient ainsi une préparation de gel pour le traitement de maladies des fibres de la peau, laquelle préparation présente d'excellentes propriétés de rétention de forme, d'étalement et de migration cutanée d'un médicament.
PCT/JP2004/001968 2003-02-21 2004-02-20 Preparation de gel a base de pirfenidone WO2004073713A1 (fr)

Applications Claiming Priority (2)

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JP2003045110 2003-02-21
JP2003-45110 2003-02-21

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008146796A1 (fr) * 2007-05-25 2008-12-04 Lead Chemical Co., Ltd. Timbre transdermique médicamenteux comprenant du 5-méthyle-1-phéynyle-2-(1h)-pyridone
WO2009022899A1 (fr) * 2007-08-14 2009-02-19 Cell Therapy Technology, S.A. De C.V. Gel à base de pirfénidone
WO2010058844A1 (fr) * 2008-11-21 2010-05-27 リードケミカル株式会社 Matériau adhésif contenant de la 5-méthyl-1-phényl-2-(1h)-pyridone
WO2010065755A1 (fr) 2008-12-04 2010-06-10 Concert Pharmaceuticals, Inc. Pyridinones deutérées
US9408836B2 (en) 2011-07-19 2016-08-09 Cell Therapy and Technology S.A. DE C.V. Pharmaceutical composition containing pirfenidone in sustained-release tablet form
US9949959B2 (en) 2012-03-28 2018-04-24 Cell Therapy and Technology S.A. DE C.V. Semi-solid topical composition containing pirfenidone and modified diallyl disulfide oxide (M-DDO) for eliminating or preventing acne
US10792258B2 (en) 2012-08-23 2020-10-06 Excalibur Pharmaceuticals, Inc. Antiseptic, antiseborrheic and exfoliating composition to remove or prevent acne
US11576905B2 (en) 2017-08-15 2023-02-14 Excalibur Pharmaceuticals, Inc. Topical semisolid composition containing an antimicrobial agent and pirfenidone for the treatment of chronic skin damage

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02215719A (ja) * 1989-02-15 1990-08-28 Yamauchi Akitomo 線維化病変組織の修復並びに線維化病変の阻止剤
JPH03151330A (ja) * 1989-11-07 1991-06-27 Shin Etsu Chem Co Ltd 外用ゲル基剤
JPH08510251A (ja) * 1993-05-07 1996-10-29 ビー マーゴリン、ソロモン 線維症の病変の修復と予防のための組成物および方法
JP2002526447A (ja) * 1998-09-18 2002-08-20 メファ・アクチェンゲゼルシャフト アルキルフェニルピリドンの局所製剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02215719A (ja) * 1989-02-15 1990-08-28 Yamauchi Akitomo 線維化病変組織の修復並びに線維化病変の阻止剤
JPH03151330A (ja) * 1989-11-07 1991-06-27 Shin Etsu Chem Co Ltd 外用ゲル基剤
JPH08510251A (ja) * 1993-05-07 1996-10-29 ビー マーゴリン、ソロモン 線維症の病変の修復と予防のための組成物および方法
JP2002526447A (ja) * 1998-09-18 2002-08-20 メファ・アクチェンゲゼルシャフト アルキルフェニルピリドンの局所製剤

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SAITO I. ET AL: "Synthesis of Hydrophobically-modified Hydroxypropyl Methylcellulose and Its Fundamental Characteristics for a Thickning Agent", PHARMACEUTICAL SCIENCE AND TECHNOLOGY, vol. 52, no. 4, 1992, pages 272 - 279, XP002981503 *
SAITOH I. ET AL: "Preparation and Evaluation of Gel Ointment Using Hydrophobically-modified Hydroxypropyl Methylcellulose", JOURNAL OF PHARMACEUTICAL SCIENCE AND TECHNOLOGY, vol. 52, no. 4, 1992, pages 280 - 287, XP002981504 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008290984A (ja) * 2007-05-25 2008-12-04 Lead Chemical Co Ltd ５−メチル−１−フェニル−２−（１ｈ）−ピリドン含有貼付剤
US8287900B2 (en) 2007-05-25 2012-10-16 Lead Chemical Co., Ltd. Medicated patch comprising 5-methyl-1-phenyl-2-(1H)-pyridone
WO2008146796A1 (fr) * 2007-05-25 2008-12-04 Lead Chemical Co., Ltd. Timbre transdermique médicamenteux comprenant du 5-méthyle-1-phéynyle-2-(1h)-pyridone
US10376500B2 (en) 2007-08-14 2019-08-13 Cell Therapy and Technology S.A. DE C.V. Gel containing pirfenidone
WO2009022899A1 (fr) * 2007-08-14 2009-02-19 Cell Therapy Technology, S.A. De C.V. Gel à base de pirfénidone
US8492412B2 (en) 2007-08-14 2013-07-23 Cell Therapy And Technology, S.A. De C.V. Gel containing pirfenidone
US11779574B2 (en) 2007-08-14 2023-10-10 Excalibur Pharmaceuticals, Inc. Gel containing pirfenidone
US11083719B2 (en) 2007-08-14 2021-08-10 Excalibur Pharmaceuticals, Inc. Gel containing Pirfenidone
WO2010058844A1 (fr) * 2008-11-21 2010-05-27 リードケミカル株式会社 Matériau adhésif contenant de la 5-méthyl-1-phényl-2-(1h)-pyridone
US8568770B2 (en) 2008-11-21 2013-10-29 Lead Chemical Co., Ltd. Adhesive material containing 5-methyl-1-phenyl-2-(1H)-pyridone
WO2010065755A1 (fr) 2008-12-04 2010-06-10 Concert Pharmaceuticals, Inc. Pyridinones deutérées
US9962374B2 (en) 2011-07-19 2018-05-08 Cell Therapy and Technology S.A. DE C.V. Process for the preparation of a pharmaceutical composition containing pirfenidone in sustained-release tablet form and its application in the regression of human chronic renal failure, breast capsular contracture and hepatic fibrosis
US10383862B2 (en) 2011-07-19 2019-08-20 Cell Therapy and Technology S.A. DE C.V. Methods of using a pharmaceutical composition containing pirfenidone in sustained-release tablet form
US11040030B2 (en) 2011-07-19 2021-06-22 Excalibur Pharmaceuticals, Inc. Methods of using a pharmaceutical composition containing pirfenidone in sustained-release tablet form
US11052074B2 (en) 2011-07-19 2021-07-06 Excalibur Pharmaceuticals, Inc. Process for the preparation of a pharmaceutical composition containing pirfenidone in sustained-release tablet form and its application in the regression of human chronic renal failure, breast capsular contracture and hepatic fibrosis
US9408836B2 (en) 2011-07-19 2016-08-09 Cell Therapy and Technology S.A. DE C.V. Pharmaceutical composition containing pirfenidone in sustained-release tablet form
US11013727B2 (en) 2012-03-28 2021-05-25 Excalibur Pharmaceuticals, Inc. Semi-solid topical composition containing pirfenidone and modified diallyl disulfide oxide (M-DDO) for eliminating or preventing acne
US9949959B2 (en) 2012-03-28 2018-04-24 Cell Therapy and Technology S.A. DE C.V. Semi-solid topical composition containing pirfenidone and modified diallyl disulfide oxide (M-DDO) for eliminating or preventing acne
US11766426B2 (en) 2012-03-28 2023-09-26 Excalibur Pharmaceuticals, Inc. Semi-solid topical composition containing pirfenidone and modified diallyl disulfide oxide (M-DDO) for eliminating or preventing acne
US10792258B2 (en) 2012-08-23 2020-10-06 Excalibur Pharmaceuticals, Inc. Antiseptic, antiseborrheic and exfoliating composition to remove or prevent acne
US11576905B2 (en) 2017-08-15 2023-02-14 Excalibur Pharmaceuticals, Inc. Topical semisolid composition containing an antimicrobial agent and pirfenidone for the treatment of chronic skin damage

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