CN1033562A - 经皮肤吸收的药物配方 - Google Patents

经皮肤吸收的药物配方 Download PDF

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CN1033562A
CN1033562A CN88108555A CN88108555A CN1033562A CN 1033562 A CN1033562 A CN 1033562A CN 88108555 A CN88108555 A CN 88108555A CN 88108555 A CN88108555 A CN 88108555A CN 1033562 A CN1033562 A CN 1033562A
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ointment
pharmaceutical formulation
skin
ibudilast
skin absorption
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上条信二
今井淳
小平广道
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Kyorin Pharmaceutical Co Ltd
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Kyorin Pharmaceutical Co Ltd
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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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

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

Abstract

本发明提供用于支气管气喘和脑血管病症的含 3-异丁酰-2-异丙基吡唑并(1，5-a)吡啶作为有效 成分的经皮肤吸收的药物配方。该配方提供极好的 持续释放和长效作用特征，并能显著减轻如恶心和呕 吐等副作用。

Description

本发明涉及经皮肤吸收的含3-异丁酰-2-异丙基吡唑并[1，5-a]吡啶（按其国际非专利名称，下文称为ibudilast）的药物配方，它是用于支气管气喘和脑血管病症的一个改进药物。
业已知道，Ibudilast是Irikura等研制成功的化合物（Japanese    Patent    Publication    Sho    52-29318，相应的美国专利3，850，941，英国专利1，378，375等）并通过临床试验已提供用于预防和治疗支气管气喘，并且还报道了它作为脑血管病症的改进药物的进一步用途。当ibudilast按剂量为人类口服给药时，它不能达到控制持续释放，由于从消化道迅速吸收而导致血清中浓度急剧升高，结果产生如恶心和呕吐等副作用。因而，在有关口服药物的范围内，提议该化合物采用持续释放的胶囊、片剂等（Japanese    laid-Open    Patent    Application    Sho    60-193913，相应的EP-A-O    156243）。由于发现了防止血清中浓度急剧升高的基质，已成功地将该化合物制备成用于直肠给药的剂型（Japanese    laid-Open    Patent    Application    Sho    60-193913）。
由于支气管气喘和脑血管病症通常多在儿童和老年病人中发病，因此，迫切需要改进ibudilast的剂量形式，使其更易给药。
本发明人就有关确保容易给药和极好的持续释放或长效作用特点的剂量形式进行了广泛的研究。研究的结果，我们发现ibudilast具有极好的经皮肤吸收特性，终于创制了含有ibudilast作为有效成分并能减轻如呕吐等副作用的经皮肤吸收的药物制剂。
该经皮肤吸收的药物配方可以油膏、乳剂、硬膏剂等的给药形式应用。
油基质、水溶性基质、悬浮基质、水包油型的乳剂基质和油包水型的乳剂基质均能用作油膏或乳剂的基质。ibudilast油膏可以使用这些基质中的任一种来制备，但是，作为具有极好吸收和长效作用特性的基质来说，油包水型的乳剂基质为特别优选。
为制备油膏，将1-10%（重量）的ibudilast与油膏基质掺合，如需要可以进行加热得到均质的混合物，经固化后得到所述药物。
硬膏剂可以膏药、泥敷剂、皮肤膏药、橡皮膏胶布等给药形式使用。为制备ibudilast硬膏剂，最好将油膏基质与ibudilast掺和，或采用将ibudilast与其它成分如基质、内衬料、背衬料等一起在布料上形成。在硬膏剂中ibudilast的浓度范围为0.5-10mg/cm2，优选为1-5mg/cm2。
为了能控制从硬膏剂上释放药物，可以采用这样一种方法，其中的药物释放层是在贮药层和胶粘质之间形成，同时将膏剂各成分加以修改。
因而，按本发明得到的ibudilast的经皮肤吸收的药物配方有极好的吸收特性，可以在如支气管痉挛或其它类似疾病的任何情况下使用，并且能方便地应用，还能明显地减轻恶心、呕吐等副作用。另外，该硬膏剂剂型能随意控制剂量，并且该药物具有能避免衣服被油膏基质或药物污染等许多优点。
下列实施例是有关实施本发明的说明，但并不作为对本发明范围的限制。
实施例1
47.5g液体石蜡和47.5g白凡士林混合后，将混合物加热至约60℃使其溶解。将5gibudilast加入溶液并溶解，然后将溶液于搅拌下冷却至室温，制成油状油膏。
实施例2
47.5g    macrogol-4000和47，5g    macrogol-400一起均匀混合，然后将5gibudilast加至该混合物内，混合后制成macrogol油膏。
实施例3
23.75g白凡士林、19g十八烷醇、3.8g聚氧乙烯氢化蓖麻油60、0.9g单硬脂酸甘油酯和5gibudilast一起混合，将混合物在75℃进行搅拌。另外将0.095g对羟基苯甲酸甲酯和0.095g对羟基苯甲酸丙酯溶于11.4g丙二醇，将360g纯化水加至该溶液中，然后将该混合物加热至75℃。再将此溶液加入前面的溶液中，搅拌形成胶乳，将胶乳冷却并且搅拌，最后固化制成亲水性油膏。
实施例4
将380g白凡士林、95g十六烷醇、47.5g芥子蜂蜡、47.5g倍半油酸脱水山梨醇酯、47.5g    macrogol和50g    ibudilast一起加热熔化并保持在75℃。向该溶液中加入预先制备的溶液（该溶液是通过将0.95g对羟苯甲酸甲酯和0.95g对羟苯甲酸丁酯加至约374ml纯化水中产生的），混合物在80℃加热。产生的混合物混合到成为胶乳状，然后冷却并混合直至固化形成吸收性的油膏。
实施例5
25g十八烷醇、5g硬脂酸、5g聚甘醇-6000和5g    1，2，6-己三醇一起在80℃-85℃加热溶解，然后向其中加入5.3gibudilast并搅拌混合。向溶液里加入60g另外准备的丙二醇。在90℃加热并搅拌，然后将得到的混合物搅拌冷却直至固化，得到一种FAPG油膏。
实施例6
向20g纯水中加入1g    Carboball-934，让其溶胀，然后向其中加入由12g丙二醇、30g乙醇、2g己二酸二异丙酯和5.3gibudilast混合而制成的溶液。再向该混合物中加入由1.1g二异丙醇胺溶于10ml纯化水另外制备的溶液，进一步再向溶液中加入23.9g纯化水并搅拌均匀至形成凝胶状油膏。
实施例7
5gibudilast溶于100ml硅氧烷粘合剂溶液，产生的液体施加于一张非硬质聚氯乙烯薄片上，于60℃干燥30分钟制成硬膏剂。
试验1
将按上述实施例制备的经皮肤吸收的药物配制剂进行测定，以确定其经皮肤的吸收比值。
该试验程序如下：用剪毛器在体重为3kg的患白化病的家兔背部剃除毛之后，将按上述实施例所述方法制备的各种油膏以1.5g的量施用于所说的剃除毛的皮肤表面。施用油膏5小时后，将油膏回收并测定ibudilast的残留量，计算它们的吸收比值。该结果示于表1。
表1    Ibudilast油膏的吸收比值
实施例    油膏类型    吸收比值（%）
1    油状油膏    17.3
2    Macrogol油膏    3.5
3    吸收性油膏    42.6
4    FAPG油膏    13.1
在上列任何油膏中都确认到经皮肤吸收了ibudilast。尤其，吸收性油膏具有高的经皮肤吸收比值。
试验2
测定使用按上述实施例制备的经皮肤吸收的油膏后的血清浓度。
该试验如下进行：准备一只体重约3kg的患白化病家兔，用剪毛器在其背部剃除毛并施予1.6g量（每只兔）的按实施例4的油膏，经过预定时间后制备血样，从血样中分离血清并经高效液相色谱法测定ibudilast在血清中浓度。结果示于表2。
表2    Ibudilast在家兔血清中的浓度（毫微克/毫升）
药物    1小时    2小时    3小时    4小时    6小时
吸收性油膏    62    119    68    92    77
在施用油膏一小时后，开始显示高数值的ibudilast血清浓度并且此高数值能保持一段较长的时间，该结果说明作为经皮肤吸收的药物配方是有效的。
如上所述，按本发明的经皮肤吸收的药物配方能减轻当口服给药时产生的如恶心、呕吐等副作用，并能有效地长时间保持在血中高浓度。

Claims (4)

1、一种含有3-异丁酰-2-异丙基吡唑并[1，5-a]吡啶作为活性成分的经皮肤吸收的药物配方。
2、按权利要求1的经皮肤吸收的药物配制剂，其中该经皮肤吸收的药物配制剂是油膏形式。
3、按权利要求1的经皮肤吸收的药物配制剂，其中该经皮肤吸收的药物配制剂是硬膏剂形式。
4、按权利要求2或3的经皮肤吸收的药物配方，其中所述3-异丁酰-2-异丙基吡唑并[1，5-a]吡啶的药量范围为1-10%（重量）。
CN88108555A 1987-12-10 1988-12-09 经皮肤吸收的药物配方 Pending CN1033562A (zh)

Applications Claiming Priority (2)

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JP312593/87 1987-12-10
JP62312593A JPH01153633A (ja) 1987-12-10 1987-12-10 経皮吸収製剤

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US (1) US5602165A (zh)
EP (1) EP0319902B1 (zh)
JP (1) JPH01153633A (zh)
KR (1) KR950005868B1 (zh)
CN (1) CN1033562A (zh)
AU (1) AU618976B2 (zh)
CA (1) CA1318598C (zh)
DE (1) DE3888800T2 (zh)
ES (1) ES2063020T3 (zh)
HU (1) HU200689B (zh)

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Publication number Priority date Publication date Assignee Title
JPH0225418A (ja) * 1988-07-14 1990-01-26 Kyorin Pharmaceut Co Ltd イブジラスト脂肪乳剤およびその製造方法
JPH08133974A (ja) * 1994-11-04 1996-05-28 Sekisui Chem Co Ltd 経皮吸収貼付剤
GB0524959D0 (en) * 2005-12-07 2006-01-18 Pharmakodex Ltd Topical compositions for treatment of respiratory disorders

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5229318B2 (zh) * 1972-03-30 1977-08-01
JPS5645507A (en) * 1979-09-21 1981-04-25 Toshiba Electric Equip Lighting device
JPS59167516A (ja) * 1983-03-14 1984-09-21 Kyorin Pharmaceut Co Ltd 抗アレルギ−剤
JPS59167590A (ja) * 1983-03-14 1984-09-21 Kyorin Pharmaceut Co Ltd ピラゾロ〔１，５−ａ〕ピリジン誘導体、その製法及びそれを含有する治療剤
JPH0621066B2 (ja) 1984-03-14 1994-03-23 杏林製薬株式会社 ３―イソブチリル―２―イソプロピルピラゾロ〔１，５―ａ〕ピリジンの徐放性医薬品組成物
US4568343A (en) * 1984-10-09 1986-02-04 Alza Corporation Skin permeation enhancer compositions
JPS6263520A (ja) * 1985-09-14 1987-03-20 Kyorin Pharmaceut Co Ltd 抗リウマチ剤
JPH01153634A (ja) * 1987-12-10 1989-06-15 Kyorin Pharmaceut Co Ltd 吸入剤
DK0431519T3 (da) * 1989-12-04 1994-07-04 Searle & Co System til transdermal indgivelse af albuterol

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KR890009396A (ko) 1989-08-01
EP0319902B1 (en) 1994-03-30
CA1318598C (en) 1993-06-01
US5602165A (en) 1997-02-11
DE3888800T2 (de) 1994-08-11
AU2649288A (en) 1989-06-15
DE3888800D1 (de) 1994-05-05
AU618976B2 (en) 1992-01-16
KR950005868B1 (ko) 1995-06-02
EP0319902A2 (en) 1989-06-14
HUT49054A (en) 1989-08-28
EP0319902A3 (en) 1990-01-31
ES2063020T3 (es) 1995-01-01
HU200689B (en) 1990-08-28
JPH01153633A (ja) 1989-06-15

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