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WO1993009781A1 - Comprime de trapidile a liberation prolongee - Google Patents

Comprime de trapidile a liberation prolongee Download PDF

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Publication number
WO1993009781A1
WO1993009781A1 PCT/JP1992/001472 JP9201472W WO9309781A1 WO 1993009781 A1 WO1993009781 A1 WO 1993009781A1 JP 9201472 W JP9201472 W JP 9201472W WO 9309781 A1 WO9309781 A1 WO 9309781A1
Authority
WO
WIPO (PCT)
Prior art keywords
trapidil
acid
tablet
release
sustained
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/JP1992/001472
Other languages
English (en)
Japanese (ja)
Inventor
Minoru Okada
Makoto Suzuki
Yutaka Kawamura
Shuichi Kasai
Akira Iwasa
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.)
SSP Co Ltd
Original Assignee
SSP 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 SSP Co Ltd filed Critical SSP Co Ltd
Publication of WO1993009781A1 publication Critical patent/WO1993009781A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to sustained-release trapidil tablets, and more particularly, to sustained-release trapidil tablets in which the release of trapidil from the tablets is less affected by PH and is constant, and the effect is maintained for a long time.
  • Trapidil is widely used in clinical practice as a circulatory function improver for angina, sequelae of cerebral infarction, sequelae of cerebral hemorrhage, and the like. However, this is because the half-life of elimination from the blood is as short as about 1.5 hours (Hisa Nakagawa et al .; Pharmaceutical Journal 1 (H (6), 635-6339 (19984))). They had to be taken three times a day, which was complicated or difficult to take, and caused non-compliance, which was not desirable in terms of disease management, and their pharmacological effects were often not sufficiently exerted.
  • an object of the present invention is to provide a sustained-release formulation of Travidil in which the release rate is not affected by PH and a constant effect can be maintained for a long time.
  • the present inventors have conducted intensive studies and as a result, if a tablet is prepared by blending an organic acid and a box with trapidil, the release rate can be changed by changing the type and amount of the box. In addition to this, it was found that the release rate can be freely changed by changing the type and amount of the organic acid, so that a sustained-release trapidil tablet for the above purpose can be obtained. Completed the invention.
  • the present invention provides a sustained-release travidil characterized by comprising: (1) Travidil, (b) 100 to 50 parts by weight of an organic acid per 100 parts by weight of trapidil, and (c) a wax. .
  • FIG. 1 is a diagram showing the results of a dissolution test of the tablets of Examples 1-1
  • FIG. Fig. 3 shows the results of the dissolution test of the tablet of Comparative Example 11-1
  • Fig. 4 shows the results of the dissolution fiber of the difficult example 31-1
  • Figure 5 shows the results of the dissolution test of the tablet of Example 4-1
  • Figure 6 shows the results of the dissolution test of the tablet of Difficult Example 5-1
  • FIG. 8 is a view showing the urinary excretion of Travisi variant when the tablet of Example 1-1 and the city were administered to healthy adult males.
  • FIG. 8 shows ⁇ ffi Examples 7-1, 8-1, and 9
  • FIG. 11 is a view showing elution results of elution of 1, 1, 1, 1, 3-1, 4-1, and 5-1.
  • the trapidil used in the present invention is represented by the structural formula of 7-ethylpyramino-5-methyl [1,2,4] toazolo [1,5-a] pyrimidine, and is widely used as a circulation improving agent. Is what it is.
  • the citric acid, citric acid, citric acid, fumaric acid, ®H, adipic acid, ascorbic acid, apples, etc. may be used as the sulphonic acid in the present invention, and may be used alone or in combination of two or more. it can.
  • the amount of these organic acids varies depending on the type, but it must be 100 to 50 parts by weight per 100 parts by weight of Travisi. Dependency ⁇
  • the waxes mean oils, waxes, hydrocarbons, idiots 1 and aryle colliles, esteriles, and metal salts of fatty acids.
  • oil release include vegetable fats such as cocoa butter, palm fat, mokuro and coconut oil, animal fats such as beef tallow, quince, horse fat, sheep fat, hardened rapeseed oil, hardened castor oil, and hardened coconut oil.
  • Oil, hardened ⁇ Hardened oil derived from plants such as oil, hardened fish oil, hardened whale oil, hardened oil derived from animal fats and oils of Hiraido beef H, etc. are included.
  • waxes include the power j renau no ⁇ ⁇ ⁇ , candelilla wax, Paveyry wax, ⁇ pocury wax, ethno.
  • Plant waxes such as zole wax, beeswax, beeswax, insect wax, whale wax, shellac wax, wool wax and other animal waxes.
  • No. is a specific example of carbon.
  • umami acids include hydrapric acid, pendecanoic acid, raperic acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, mariregalic acid, stearic acid, nonadecanoic acid, araquinic acid, heneicosanoic acid, and behenic acid.
  • Trichosanoic acid (I Examples include gnoceric acid, pentacosanoic acid, serotinic acid, heptacosanoic acid, nonacosanoic acid, melisic acid, gentriacontanic acid, and dotriacontanic acid.
  • higher alcohols include lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, arakyl alcohol, behenyl alcohol, Carnavir alcohol, serilyrecoryanyl alcohol, myrisyl alcohol and the like.
  • esters include fatty acid esters such as myristyl benzoyl remitate, behenyl bebenate, ceryl lignoserate, lacseryl citrate, and lacceryl lataterate, monoglyceride laurate, Monoglyceride ristate, monoglyceride stearate, monoglyceride behedinate, monoglyceride oleate, monodiglyceride oleate, triglyceride laurate, triglyceride myristate, triglyceride stearate, triglyceride stearate, Glycerin fatty acid esters such as acetyl stearic acid glyceride and hydroxystearic acid triglyceride are exemplified.
  • fatty acid esters such as myristyl benzoyl remitate, behenyl bebenate, ceryl lignoserate, lacseryl citrate, and lacceryl la
  • metal salts of higher fatty acids include calcium stearate, magnesium stearate, aluminum stearate, zinc stearate, zinc palmitate, zinc myristate, magnesium myristate, and the like. These waxes may be used alone or in combination of two or more kinds. The amount of the wax is preferably 25 to 400 parts by weight based on 100 parts by weight of trapidil.
  • the production method of the present invention is not particularly limited, it is produced by preparing a tableting powder comprising a mixture of trapidil, an organic acid, and resins, adding a lubricant and the like as necessary, and compression molding.
  • the tableting powder may be prepared, for example, by (1) a method of adding wet excipients and binders to trapidil, organic acids, and / or other additives as necessary, followed by wet granulation or dry granulation, and (2) trapidil. (3) trapidil and an organic dish, excipients and binders, etc. Pack melted into powder added with It can be manufactured by a method of gradually adding and mixing, and can be pulverized and classified if necessary. Alternatively, a powder obtained by adding a mk binder, a lubricant, and the like to trapidil, an organic acid, and a box, if necessary, may be directly tabletted.
  • the sustained-release Travidil® of the present invention thus obtained may be used as it is, or may be a tablet or a multilayer tablet in which components having different releases are arranged in separate layers. It is good.
  • the view of the present invention will be specifically described with reference to difficult examples, but the present invention is not limited thereto.
  • Tableting powder A (200 g) was mixed with magnesium stearate (2 g), and the mixture was tableted so as to obtain a 505 mg / tablet.
  • the sustained-release trapidil tablet of the present invention Obtained.
  • Example 11 The sustained-release trapidil tablet of the present invention obtained in Example 1: The elution of Example 11 was carried out by the rotary paddle method (Japanese Pharmacopoeia, 1st and 2nd revision, dissolution test method) at 5 O rpm and PH. I.2 (Japanese Pharmacopoeia 1st and 2nd revision, Soil test method 1st liquid), PH 4.0
  • Tableting powder B (255 g) was mixed with magnesium stearate (3 g), and the mixture was tableted to give a tablet weight of (258 mg) to obtain a comparative tablet: Comparative Example 11-1.
  • Comparative tablet obtained in Comparative Example 1 Comparative Example 11 Elution of 11 was measured under the same conditions as in Test Example 1. The results are shown in FIG. Comparative tablet sustained-released with hydroxypropylmethylcellulose: Comparative Example 11-1 releases trapidil over a long period of time, but it can be seen that dissolution is rapid in the PH 1.2 test solution.
  • Tableting powders C to H were mixed with magnesium stearate according to the following formulation, tableted, and sustained-release trapidil tablets of the present invention shown in Table 2: Example 2-1-2-3 and comparative tablets: Comparative Example 2-1 to 2_3 were obtained.
  • Example 2 [ ⁇ The sustained release trapidil tablet of the present invention obtained in Example 2: ⁇ Example 2 1-1 and 2-3 and Comparative tablet: Comparative Example 2-1 to 2-3 (Japan Pharmacopeia one first 2 amendments, eluting ⁇ ) by, 5 O rp ra. in, P H 1. 2 (Japanese Pharmacopoeia one first 2 amended, disintegration method first liquid) and PH 6. 8 (Japanese Pharmacopoeia 1st and 2nd revision, disintegration m2 solution) was measured as a solution. Table 3 shows the difference between the elution rates of PH 1.2 and PH 6.8.
  • Tableting powder J 200 g was mixed with magnesium stearate 2 g, and the mixture was tableted to give a tablet 505 nig, and the sustained-release trapidil tablet of the present invention: HI6 Example 4-11 was used. Obtained.
  • Tableting powder K 200 g was mixed with magnesium stearate 2 g, and the mixture was tableted to give a tablet weight of 500 mg, and a sustained-release trapidil tablet of the present invention:
  • the sustained-release trapidil tablets of the present invention obtained in Examples 3, 4 and 5: The dissolution of Examples 3-1, 4-1 and 5-1 was measured under the same conditions as in Test Example 1. The results are shown in Figs. 4, 5 and 6, respectively. It can be seen that the sustained release Travidil tablet of the present invention releases trapidil for a long time. Furthermore, it can be seen that there is almost no difference in the elution profile of the ⁇ -field between the various pH test solutions.
  • Hardened castor oil, beeswax, solid paraffin, carnauba ⁇ , stearic acid, and glycerin fatty acid ester were heated and melted according to the formulation in Table 4, and Travidil and fumaric acid were added.After cooling, pulverized, powder for tableting L ⁇ . I got Table 4
  • Tableting powder P200 g was mixed with magnesium stearate 2 g, and the mixture was tableted so as to obtain 505 mg per tablet.
  • the sustained-release trapidil tablet of the present invention Example 7-1 Obtained.
  • Tableting powder Q 200 g was mixed with magnesium stearate 2 g, and the mixture was tableted so as to obtain 500 mg per tablet to obtain a sustained-release trapidil tablet of the present invention: m8-1. Was.
  • Tableting powder R20Og was mixed with magnesium stearate (2 g), and the mixture was tableted to give a tablet weight of 505 mg, and the sustained-release trapidile agent of the present invention: Difficult Example 9-1 Obtained.
  • the sustained-release trapidil tablets of the present invention obtained in Jonggong 7, 8, 9: Example 7-1, 8-1, and 9-11 dissolution by the rotary paddle method (Japanese Pharmacopoeia-Revised 12th, Dissolution PH of 6 and 8 (Japanese Pharmacopoeia 1st and 2nd revision, disintegration test method liquid 2) was measured as a difficult liquid at 5 O rpm by the test method.
  • the results are shown in FIG. 8 together with the results of PH 6.8 in Examples 1-1, 3-1 and ffi-411 and H-5-1. It can be seen that the slow-acting trapidil of the present invention releases trapidil for a long time. Furthermore, it can be seen that by changing the organic acid fraction, elution profiles of various types of release can be obtained.
  • the sustained-release trapidil tablet of the present invention since the release level is influenced by PH and is constant and the effect lasts for a long time, it is possible to obtain a sufficient effect of trapidil once or twice a day. it can. Therefore, it is useful as a circulatory function improving agent in the treatment of scissors heart disease, sequelae of armpit infarction, sequelae of cerebral hemorrhage and the like.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Molecular Biology (AREA)
  • Psychiatry (AREA)
  • Urology & Nephrology (AREA)
  • Biophysics (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Comprimé de trapidile à libération prolongée, comprenant 100 parties en poids de trapidile, 10 à 50 parties en poids d'un acide organique, et une cire. Ce comprimé présente un taux de libération constant qui est à peine affecté par la valeur pH et une efficacité de longue durée, de sorte qu'un seul comprimé administré une ou deux fois par jour apporte à l'organisme assez de trapidile pour que l'effet pharmacologique soit suffisant. Un tel comprimé peut donc être administré en tant qu'agent améliorant les fonctions circulatoires pour traiter l'angine de poitrine, les séquelles d'infarctus cérébral et d'hémorragie cérébrale, etc.
PCT/JP1992/001472 1991-11-14 1992-11-11 Comprime de trapidile a liberation prolongee Ceased WO1993009781A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP3/299096 1991-11-14
JP29909691A JP3195391B2 (ja) 1991-11-14 1991-11-14 徐放性トラピジル錠

Publications (1)

Publication Number Publication Date
WO1993009781A1 true WO1993009781A1 (fr) 1993-05-27

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Application Number Title Priority Date Filing Date
PCT/JP1992/001472 Ceased WO1993009781A1 (fr) 1991-11-14 1992-11-11 Comprime de trapidile a liberation prolongee

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JP (1) JP3195391B2 (fr)
WO (1) WO1993009781A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009008487A1 (fr) * 2007-07-12 2009-01-15 Takeda Pharmaceutical Company Limited Préparation enrobée
WO2017176652A2 (fr) 2016-04-04 2017-10-12 Sinopia Biosciences, Inc. Traitement de syndrome extrapyramidal à l'aide de trapidil

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2745500B1 (fr) * 1996-03-04 1998-04-03 Synthelabo Formulations pharmaceutiques a liberation prolongee contenant de la mizolastine
JP2002087960A (ja) * 2000-07-14 2002-03-27 Toyama Chem Co Ltd 徐放性錠剤

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6327439A (ja) * 1986-07-18 1988-02-05 Eisai Co Ltd 持続性薬効製剤
JPS6463521A (en) * 1987-07-31 1989-03-09 Chiesi Farma Spa Trapidyl-containing drug composition, manufacture and related therapeutical use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6327439A (ja) * 1986-07-18 1988-02-05 Eisai Co Ltd 持続性薬効製剤
JPS6463521A (en) * 1987-07-31 1989-03-09 Chiesi Farma Spa Trapidyl-containing drug composition, manufacture and related therapeutical use

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009008487A1 (fr) * 2007-07-12 2009-01-15 Takeda Pharmaceutical Company Limited Préparation enrobée
JPWO2009008487A1 (ja) * 2007-07-12 2010-09-09 武田薬品工業株式会社 被覆製剤
US9427434B2 (en) 2007-07-12 2016-08-30 Takeda Pharmaceutical Company Limited Coated preparation
WO2017176652A2 (fr) 2016-04-04 2017-10-12 Sinopia Biosciences, Inc. Traitement de syndrome extrapyramidal à l'aide de trapidil
US10350212B2 (en) 2016-04-04 2019-07-16 Sinopia Biosciences, Inc. Treating extrapyramidal syndrome using trapidil
US11628170B2 (en) 2016-04-04 2023-04-18 Sinopia Biosciences, Inc. Treating extrapyramtdal syndrome using trapidil
US12268691B2 (en) 2016-04-04 2025-04-08 Sinopia Biosciences, Inc. Treating extrapyramidal syndrome using trapidil

Also Published As

Publication number Publication date
JPH05139975A (ja) 1993-06-08
JP3195391B2 (ja) 2001-08-06

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