WO1998003162A1 - Medicinal compositions - Google Patents

Medicinal compositions Download PDF

Info

Publication number
WO1998003162A1
WO1998003162A1 PCT/JP1997/002448 JP9702448W WO9803162A1 WO 1998003162 A1 WO1998003162 A1 WO 1998003162A1 JP 9702448 W JP9702448 W JP 9702448W WO 9803162 A1 WO9803162 A1 WO 9803162A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
cyclodextrin
composition according
weight
pharmaceutically acceptable
Prior art date
Application number
PCT/JP1997/002448
Other languages
French (fr)
Japanese (ja)
Inventor
Atsushi Sakai
Rumiko Kuma
Tsuneo Fujii
Tadashi Mishina
Kenji Chiba
Original Assignee
Yoshitomi Pharmaceutical Industries, 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 Yoshitomi Pharmaceutical Industries, Ltd. filed Critical Yoshitomi Pharmaceutical Industries, Ltd.
Priority to AU34608/97A priority Critical patent/AU3460897A/en
Publication of WO1998003162A1 publication Critical patent/WO1998003162A1/en
Priority to US09/231,484 priority patent/US6476004B1/en

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to a pharmaceutical composition containing 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. More specifically, 2-amino-2 2- [2- ( 4-year-old octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof with a cyclodextrin compound, and a pharmaceutical composition which can be formulated as a liquid preparation. .
  • the present inventors have proposed a method for preparing 2-amino-2- [2-1 (41 years old) which can be used as a liquid preparation such as an injection or an ophthalmic solution with little side effects such as hemolysis and little local irritation.
  • [Cutylphenyl] ethyl] Propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof was obtained through a variety of studies to obtain a pharmaceutical composition.
  • the present invention has been completed.
  • the present invention is characterized in that cyclodextrins are blended with 2-amino-2- [2- (4-year-old octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof. It is intended to provide a pharmaceutical composition which is easy to formulate, has reduced side effects such as hemolysis, and is suitable for a liquid preparation having little local irritation.
  • the present invention has also found that, by further adding a saccharide selected from a monosaccharide, a disaccharide and a sugar alcohol to the composition, a liquid composition having further improved irritation can be obtained.
  • the pharmaceutical composition of the present invention comprises 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof, a cyclodextrin, if desired, as an active ingredient. And a saccharide, and a conventional pharmaceutically acceptable carrier or diluent, preferably a carrier or diluent suitable for liquids.
  • 2-amino-2- [2- (4 One year old octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof can be produced by the method described in International Publication W094 / 08943.
  • a preferred compound is 2-amino-2- [21- (4-year-old tylphenyl) ethyl] propane-1,3-diol hydrochloride.
  • 2-amino-2- [2- (4-year-old octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof is added in an amount of 0.01% based on the total weight of the composition. -20% by weight, especially 0.1-10% by weight is preferred.
  • the cyclodextrin used in the present invention is a natural cyclodextrin, a branched cyclodextrin, an alkylene cyclodextrin or a hydroxyalkylcyclodextrin, and specifically, -cyclodextrin.
  • the saccharide used in the present invention is selected from monosaccharides, disaccharides and sugar alcohols, and specifically, glucose, fructose, D-maltose, lactose, sucrose (sucrose), D-mannitol, D-xylitol , D-sorbitol, and these can be used alone or in combination of two or more.
  • the amount of these saccharides is from 1 to 3 parts by weight per part by weight of 2-amino-2-12- (4-year-old octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof. 100 parts by weight, especially 5 to 80 parts by weight, is preferred.
  • the pharmaceutical form of the pharmaceutical composition of the present invention is a liquid, specifically, an injection, an eye drop, a nasal drop, an ear drop, a drop, a liquid for oral administration, a liquid for inhalation, and a mouth lotion.
  • the pharmaceutical composition of the present invention can be commercially available as a finished liquid preparation, or can be commercially available as a kit of a powder or a lyophilized product containing an active ingredient or the like and a lyophilized solution.
  • the active ingredient 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1.3-diol or its pharmaceutically acceptable acid addition salt (particularly hydrochloride) is dissolved in purified water. After aseptic filtration, the obtained solution is filled in a vial, and then freeze-dried under vacuum to obtain a freeze-dried product.
  • an aqueous solution in which the cyclodextrins used in the present invention and, if necessary, saccharides are dissolved in distilled water is prepared.
  • the freeze-dried product may be dissolved in the dissolution solution before use.
  • These lysates are 2-amino-21- (2- (4-year-old octylphenyl) ethyl) propane-1, 3-diol
  • the pharmaceutically acceptable acid addition salt is used in a 5-fold to 2000-fold amount (weight part) with respect to the pharmaceutically acceptable acid addition salt.
  • distilled water is preferably distilled water for injection.
  • the freeze-dried product is usually filled in a vial, replaced with nitrogen, sealed with a rubber stopper, and sealed with aluminum, so that it can be stored at room temperature for a long period of time.
  • the cyclodextrins and the saccharides to be added as required are not added to the dissolution solution as described above, but instead of the active ingredient 2-amino-2- [2- (4-octylphenyl) ethyl] propane
  • the lyophilized product may be contained together with 1,3-diol or a pharmaceutically acceptable acid addition salt thereof.
  • the amount of cyclodextrin is preferably 1 to 50 parts by weight, particularly preferably 10 to 30 parts by weight, based on 1 part by weight of the active ingredient.
  • the saccharides to be added as required are preferably 1 to 100 parts by weight, particularly preferably 5 to 80 parts by weight, per 1 part by weight of the active ingredient.
  • a solvent for example, a solvent, a tonicity agent, a pH adjuster, a buffer, an antioxidant, a thickener, a surfactant, a preservative, a humectant,
  • a flavoring agent, a coloring agent, and the like can also be appropriately compounded.
  • these additives can be added when formulating the composition of the present invention, and are dissolved when used in the above kit preparation. Can also be added to the dissolving solution.
  • the pharmaceutical composition of the present invention can be used as a liquid preparation, particularly as a method for suppressing rejection after organ or bone marrow transplantation, maintaining immunotherapy, eye diseases such as Behcet's disease or uveitis, psoriasis, atopic dermatitis, and contact. It can be used for the treatment of dermatitis including dermatitis and allergic dermatitis. More specifically, the pharmaceutical preparation of the present invention is useful for the prevention or treatment of various indications (immunosuppression in organ or bone marrow transplantation, various autoimmune diseases, various allergic diseases, etc.) conventionally performed with oral preparations. Can be used.
  • composition of the present invention can be used as a liquid preparation for organ or tissue transplantation.
  • ⁇ Torted paper For example, resistance to heart, kidney, liver, lung, bone marrow, cornea, fallen, small intestine, limb, muscle, nerve, fat marrow, duodenum, skin *, transplantation of islet cells, xenograft) Or rejection, graft-versus-host (GvH) disease due to bone marrow or small bowel transplantation, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, nephrotic syndrome lupus, Hashimoto goiter, multiple sclerosis , Myasthenia gravis, type I diabetes, type II diabetes mellitus, uveitis, nephrotic syndrome, steroid-dependent and steroid-resistant nephrosis, palmar plantar pustulosis, allergic encephalomyelitis, glomerulonephritis Etc., and for the treatment and prevention of infectious diseases caused by pathogenic microorganisms
  • the onset of inflammatory, proliferative and hyperproliferative skin diseases, and immune-mediated diseases in the skin such as psoriasis, psoriatic arthritis, topical eczema (atopic dermatitis), contact dermatitis, and (Eczema dermatitis, seborrheic skin) * flame, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, vascular edema, vasculitis, erythema, increased skin eosinophils It can also be used to treat acne, acne, alopecia areata, eosinophilic fasciitis and atherosclerosis.
  • the compositions of the invention more particularly prevent alopecia, form hair buds and / or develop and grow hair, so that female or male pattern baldness or senile alopecia It can be used to do hair restoration, such as treatment for hair.
  • compositions of the invention may be used for respiratory diseases such as sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia and reversible obstructive airway diseases such as bronchial asthma, pediatric asthma, allergic asthma, intrinsic asthma, extrinsic asthma It is also applicable to the treatment of asthma, including dusty asthma, especially chronic or refractory asthma (eg, late onset asthma and airway hyperreactivity), bronchitis and the like.
  • the composition of the present invention can also be used for treating liver damage associated with ischemia.
  • eye diseases such as conjunctivitis, keratoconjunctivitis, keratitis, spring catarrhals and Behcet's disease It is also effective for severe uveitis, herpes keratitis, keratoconus, corneal epithelial degeneration, corneal vitiligo, pemphigus, Mohren's ulcer, scleritis, Graves' eye disease and severe intraocular inflammation.
  • eye diseases such as conjunctivitis, keratoconjunctivitis, keratitis, spring catarrhals and Behcet's disease It is also effective for severe uveitis, herpes keratitis, keratoconus, corneal epithelial degeneration, corneal vitiligo, pemphigus, Mohren's ulcer, scleritis, Graves' eye disease and severe intraocular inflammation.
  • composition of the present invention also includes mucosal or vascular inflammation [eg, leukotriene B4-mediated disease, stomach ulcer, vascular injury due to ischemic disease and thrombotic disease, ischemic bowel disease, inflammatory bowel disease (eg, Crohn's disease and ulcerative colitis), necrotizing colitis], and can also be used to prevent or treat intestinal damage associated with burns.
  • mucosal or vascular inflammation eg, leukotriene B4-mediated disease, stomach ulcer, vascular injury due to ischemic disease and thrombotic disease, ischemic bowel disease, inflammatory bowel disease (eg, Crohn's disease and ulcerative colitis), necrotizing colitis
  • the composition of the present invention is selected from gastric diseases such as interstitial nephritis, Good Bastian syndrome, hemolytic uremic syndrome and diabetic nephropathy; polymyositis, Guillain-Barre syndrome, Meniere's disease and radiculopathy Endocrine disorders such as hyperthyroidism and Graves' disease; pure erythrocytosis, aplastic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, granules Blood diseases such as cytopenia and lack of erythropoiesis: bone diseases such as osteoporosis; respiratory diseases such as sarcoidosis, pulmonary fibrosis and idiopathic interstitial pneumonia: skin myositis, vulgaris Dermatosis such as vitiligo, fish vulgaris, psoriasis, photoallergic susceptibility and percutaneous T-cell lymphoma; cardiovascular diseases such as arteriosclerosis, a
  • compositions of the present invention may be used to treat intestinal inflammation Z allergies, such as Coe iac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, and ulcerative colitis; and food-related allergic diseases It is suitable for the prevention or treatment of symptoms that are not directly related to the gastrointestinal tract, such as migraine, soreness and eczema.
  • the composition of the present invention since the composition of the present invention has an activity of promoting hypertrophy and hyperplasia of hepatic cells, the composition of the present invention includes immunogenic diseases (eg, including autoimmune hepatitis, primary biliary cirrhosis, and sclerosing cholangitis).
  • Immungenic diseases eg, including autoimmune hepatitis, primary biliary cirrhosis, and sclerosing cholangitis.
  • Chronic autoimmune liver disease eg, partial liver resection, acute liver death (eg, toxin, viral hepatitis, soil death due to shock or oxygen deprivation), viral hepatitis B, non-A / non-B hepatitis
  • acute liver death eg, toxin, viral hepatitis, soil death due to shock or oxygen deprivation
  • viral hepatitis B non-A / non-B hepatitis
  • composition of the present invention can also be used as a composition for an antibacterial agent, and thus can be used for treating diseases caused by pathogenic microorganisms and the like.
  • the composition of the present invention may be used for the treatment of malignant rheumatoid arthritis, amyloidosis, fulminant hepatitis, Shy 'Dore-Iger syndrome, pustular psoriasis, Behcet's disease, systemic lupus erythematosus, endocrine ophthalmopathy, progressive systemic sclerosis, mixed sexual connective tissue disease, aortic inflammation group, Wegener's granuloma, active chronic hepatitis, Evans syndrome, hay fever, idiopathic hypoparathyroidism, Addison's disease (autoimmune adrenalitis), autoimmune orchitis , Autoimmune ovitis, cold hemagglutininosis, paroxysmal cold hemoglobinuria, pernicious anemia, adult
  • composition of the present invention can be optionally used in combination with other immunosuppressants, steroid agents (blednisolone, methylprednisolone, dexamethasone, hydrocortisone, etc.) or non-steroid anti-inflammatory agents.
  • steroid agents blednisolone, methylprednisolone, dexamethasone, hydrocortisone, etc.
  • non-steroid anti-inflammatory agents are particularly preferred as other immunosuppressants.
  • immunosuppressants are azathioprine, brequinar sodium, deoxyspargarine, mizoribine, mycophenolic acid 2 One selected from monomorpholinethyl ester, cyclosporine, rapamycin, tacrolimus hydrate, leflunomide and OKT-3.
  • composition of the present invention may vary depending on the indication, its symptoms, the gender and age of the patient, the place of application, and the like.
  • the present compound is preferably used in an amount of 0.001 to 20% by weight, preferably 0.0000.
  • 1 to 10% by weight once or several times a day for example, 2 to 5 times
  • a clinically favorable effect can be obtained.
  • the present compound means 2-amino-2- [2- (4-year-old butylyl) ethyl] propane-11,3-diol hydrochloride.
  • D-mannitol 5.0% The above composition is dissolved in distilled water for injection to give a total injection of 10 ml. C If necessary, ordinary additives such as a preservative may be blended.
  • the above composition is dissolved in distilled water for injection (can be mixed with usual additives such as preservatives, if necessary). After aseptic filtration, a total of 1 Om1 is filled in a vial and freeze-dried according to a conventional method. And use it as an injection.
  • the above composition is dissolved in distilled water for injection (where necessary, conventional additives such as preservatives may be added). After aseptic filtration, a total of 1 Om1 is filled into a vial, and frozen according to a conventional method. Dry and use as injection.
  • Example 6 The above composition is dissolved in distilled water for injection to give a total of 1 Oml of injection. C If necessary, ordinary additives such as a preservative may be blended. Example 6
  • This compound 0.1% ⁇ -cyclodextrin (trade name: Celdex A-100) 1.0% D-mannitol 5.0 ⁇
  • the above composition is dissolved in sterile purified water, and the total amount of eye drops is 10m ⁇ . And If necessary, ordinary additives such as a preservative may be added.
  • D-mannitol 5.0% The above composition is dissolved in sterile purified water to give a total amount of 1% ophthalmic solution. If necessary, ordinary additives such as a preservative may be added.
  • Example 1 The formulation of Example 1 was repeatedly administered intravenously to a 5-week-old LEW rat for 5 days, and the swelling ratio of the tail ⁇ (tail diameter of the drug-administered group-diameter of the control tail) ⁇ tail of the control Confirm the presence or absence of local irritation using the diameter x 100 ⁇ as an index As a result, the result was 0% in Example 1, indicating that the preparation of Example 1 did not show local irritation.
  • Pharmaceutical compositions suitable for solutions containing diol or a pharmaceutically acceptable acid addition salt thereof are provided.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Nanotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biophysics (AREA)
  • Immunology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Medicinal compositions which can be processed into solutions and are useful in inhibiting rejection reactions against the transplantation of organs or bone marrow, in the maintenance immunotherapy therefor or in treating autoimmune diseases, characterized by containing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or pharmaceutically acceptable acid-addition salts thereof and cyclodextrins optionally together with saccharides, if required.

Description

明 細 書  Specification
医薬組成物  Pharmaceutical composition
技術分野 Technical field
本発明は、 有効成分として 2—アミノー 2— 〔2— （4—ォクチルフエ ニル） ェチル〕 プロパン一 1 , 3—ジオールまたはその医薬上許容しうる 酸付加塩を含有する医薬組成物に関する。 さらに詳しくは、 臓器 （腎臓、 肝臓、 心臓、 小腸等） または骨髄移植時の拒絶反応の抑制もしくはその維 持免疫療法または自己免疫疾患の処置に適した、 2—ァミノ— 2— 〔2— ( 4一才クチルフエ二ル） ェチル〕 プロパン一 1， 3—ジオールまたはそ の医薬上許容しうる酸付加塩にシクロデキス卜リン類を配合したことを特 徴とする液剤として処方しうる医薬組成物に関する。  The present invention relates to a pharmaceutical composition containing 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. More specifically, 2-amino-2 2- [2- ( 4-year-old octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof with a cyclodextrin compound, and a pharmaceutical composition which can be formulated as a liquid preparation. .
背景技術 Background art
2—アミノー 2— 〔2— （4—ォクチルフヱニル） ェチル〕 プロパン一 1， 3—ジオールまたはその医薬上許容しうる酸付加塩は、 たとえば、 国 際公開 W0 9 4 / 0 8 9 4 3号公報により臓器または骨髄移植における拒 絶反応の抑制剤として、 また乾癬、 ベーチュッ ト病等の様々な自己免疫疾 患およびリゥマチ疾患の治療薬として有用であることが知られている。 上記化合物は、 経口投与用製剤として開発されているが、 臓器または骨 髄移植時の拒絶反応の抑制剤として使用する場合、 できるだけ速やかに効 果を発揮させるためには移植直後に投与することが望ましいが、 患者の状 態から経口投与は困難であるため、 注射によらなければならない。 また、 上記化合物をべ一チ ッ ト病等の眼疾患に使用する場合、 点眼液として適 用する必要がある。  2-Amino-2- [2- (4-octylphenyl) ethyl] Propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof is disclosed, for example, in International Publication WO09 / 08943. It is known to be useful as an inhibitor of rejection in organ or bone marrow transplantation, and as a therapeutic agent for various autoimmune diseases such as psoriasis and Behcet's disease and rheumatic diseases. The above compounds have been developed as preparations for oral administration, but when used as an inhibitor of rejection during organ or bone marrow transplantation, they should be administered immediately after transplantation in order to exert their effects as quickly as possible. Although desirable, oral administration is difficult due to the condition of the patient, and must be done by injection. When the above compounds are used for eye diseases such as Behcet's disease, they need to be applied as eye drops.
上記国際公開 WO 9 4 / 0 9 9 4 3号公報には、 該化合物を注射剤とし て調製することが記載されており、 そのための溶解剤としてポリエチレン グリコールおよびエタノールを用いることが開示されている。 しかしなが ら、 ポリエチレングリコールは局所刺激性や溶血性などの好ましくない作 用を有するため、 その使用には問題がある。 またエタノールも局所刺激性 のため、 注射剤の処方には適さない。 The above-mentioned International Publication WO94 / 09943 describes that the compound is prepared as an injection, and polyethylene glycol is used as a dissolving agent therefor. The use of glycols and ethanol is disclosed. However, its use is problematic because polyethylene glycol has undesirable effects such as local irritation and hemolysis. Ethanol is also not suitable for injection formulation because of local irritation.
発明の開示 Disclosure of the invention
上記の状況に鑑み、 本発明者らは、 溶血性等の副作用や局所刺激性の少 ない、 注射剤や点眼剤などの液剤とすることができる 2—アミノー 2— 〔2 一 （4一才クチルフヱニル） ェチル〕 プロパン一 1， 3—ジオールまたは その医薬上許容しうる酸付加塩を含有する医薬組成物を得るべく、 種々研 究を重ねた結果、 シクロデキストリン類を配合することにより、 その目的 が達成されることを知り、 本発明を完成した。  In view of the above-mentioned situation, the present inventors have proposed a method for preparing 2-amino-2- [2-1 (41 years old) which can be used as a liquid preparation such as an injection or an ophthalmic solution with little side effects such as hemolysis and little local irritation. [Cutylphenyl] ethyl] Propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof was obtained through a variety of studies to obtain a pharmaceutical composition. The present invention has been completed.
すなわち、 本発明は、 2—アミノー 2— 〔2— （4一才クチルフヱニル） ェチル〕 プロパン一 1， 3—ジオールまたはその医薬上許容しうる酸付加 塩にシクロデキストリン類を配合することを特徴とする、 かつ製剤化が容 易で、 かつ溶血性等の副作用が軽減され、 しかも局所刺激性の少ない液剤 に適した、 医薬組成物を提供するものである。 本発明はまた、 該組成物に、 さらに、 単糖類、 二糖類または糖アルコールから選ばれる糖類を配合する ことによって、 刺激性が一層改良された液剤組成物が得られることも見出 した。  That is, the present invention is characterized in that cyclodextrins are blended with 2-amino-2- [2- (4-year-old octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof. It is intended to provide a pharmaceutical composition which is easy to formulate, has reduced side effects such as hemolysis, and is suitable for a liquid preparation having little local irritation. The present invention has also found that, by further adding a saccharide selected from a monosaccharide, a disaccharide and a sugar alcohol to the composition, a liquid composition having further improved irritation can be obtained.
本発明の医薬組成物は、 活性成分として 2—アミノー 2— 〔2— （4一 ォクチルフヱニル） ェチル〕 プロパン一 1 , 3—ジオールまたはその医薬 上許容しうる酸付加塩、 シクロデキストリン類、 所望により、 さらに糖類、 および通常の医薬上許容しうる担体または希釈剤、 好ましくは液剤に適し た担体または希釈剤とからなる。  The pharmaceutical composition of the present invention comprises 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof, a cyclodextrin, if desired, as an active ingredient. And a saccharide, and a conventional pharmaceutically acceptable carrier or diluent, preferably a carrier or diluent suitable for liquids.
本発明の医薬組成物における活性成分である 2—アミノー 2— 〔2— （4 一才クチルフヱニル） ェチル〕 プロパン— 1, 3—ジオールまたはその医 薬上許容しうる酸付加塩は、 国際公開 W094/08943号公報に記載 された方法によって製造される。 好ましい化合物は、 2—ァミノ一 2— 〔2 一 （4一才クチルフヱニル） ェチル〕 プロパン一 1, 3—ジオール塩酸塩 である。 The active ingredient in the pharmaceutical composition of the present invention, 2-amino-2- [2- (4 One year old octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof can be produced by the method described in International Publication W094 / 08943. A preferred compound is 2-amino-2- [21- (4-year-old tylphenyl) ethyl] propane-1,3-diol hydrochloride.
2—ァミノ一 2— 〔2— （4一才クチルフヱニル） ェチル〕 プロパン一 1, 3—ジオールまたはその医薬上許容しうる酸付加塩の配合量は、 組成 物の全重量に対して 0. 01〜20重量％、 特に 0. 1〜10重量％が好 ましい。  2-amino-2- [2- (4-year-old octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof is added in an amount of 0.01% based on the total weight of the composition. -20% by weight, especially 0.1-10% by weight is preferred.
本発明で使用するシクロデキストリン類とは、 天然シクロデキストリン、 分枝シクロデキストリン、 アルキルンクロデキストリンまたはヒ ドロキシ アルキルシクロデキス トリンであり、 具体的には ーシクロデキス トリ ン The cyclodextrin used in the present invention is a natural cyclodextrin, a branched cyclodextrin, an alkylene cyclodextrin or a hydroxyalkylcyclodextrin, and specifically, -cyclodextrin.
[例えば、 商品名 ：セルデックス A— 100 (日本食品化工 （株） 製） ] 、 ^—シクロデキストリ ン [例えば、 商品名 ：セルデックス B— 100 (日 本食品化工 （株） 製） ] 、 アーシクロデキストリン [例えば、 商品名： セ ルデックス G— 100 (日本食品化工 （株） 製） ] 、 ドデカキスー 2, 6 一 0—メチル一α—シクロデキストリン、 テトラデカキスー 2, 6-0- メチルー 3—シクロデキストリン、 へキサデ力キスー 2， 6— 0—メチル 一アーシクロデキストリン、 テトラデカキスー 2, 6— 0—ェチルー ー シクロデキストリン、 2—ヒ ドロキンプロピル基によって部分的にエーテ ル化されたな一シクロデキストリン、 2—ヒ ドロキシプロピル基によって 部分的にエーテル化された —シクロデキストリ ン （HP— — CyD)[For example, trade name: Celldex A-100 (manufactured by Nippon Shokuhin Kako Co., Ltd.)], ^ -cyclodextrin [for example, trade name: Celldex B-100 (manufactured by Nippon Shokuhin Kako Co., Ltd.)] , Arcyclodextrin [for example, trade name: Celdex G-100 (manufactured by Nippon Shokuhin Kako Co., Ltd.)], dodecakisoo 2,610-methyl-1α-cyclodextrin, tetradecakisuu 2,6-0-methyl-3- Cyclodextrin, hexadex-kis- 2,6-0-methyl monocyclodextrin, tetradecakis- 2,6-0-ethyl-cyclodextrin, monocyclo which is partially etherified by 2-hydroxyquinpropyl Dextrin, partially etherified by 2-hydroxypropyl group —cyclodextrin (HP——CyD)
[例えば、 商品名：セルデックス HP— /?一 CD (日本食品化工 （株） 製） ] 、 またはグルコースやマルトースが《— 1. 6ダルコシド結合した分岐 ーシクロデキストリンもしくは分岐 ;5—シクロデキストリンなどがあげ られる。 これらシクロデキストリ ンの配合量は、 上記活性成分 1重量部に 対して 1〜5 0重量部、 特に 1 0〜3 0重量部が好ましい。 [For example, product name: Celdex HP-/? Ichi CD (manufactured by Nippon Shokuhin Kako Co., Ltd.)] or glucose or maltose <<-1.6 darcoside-linked branched-cyclodextrin or branched; 5-cyclodextrin, etc. Raised Can be The amount of these cyclodextrins is preferably 1 to 50 parts by weight, and more preferably 10 to 30 parts by weight, based on 1 part by weight of the active ingredient.
本発明で使用する糖類としては、 単糖類、 二糖類または糖アルコールか ら選ばれ、 具体的にはブドウ糖、 果糖、 D—マルトース、 乳糖、 白糖 （ショ 糖） 、 D—マンニトール、 D—キシリ トール、 D—ソルビトールが挙げら れ、 これらは 1種または 2種以上で配合することができる。 これらの糖類 の配合量は、 2—アミノー 2— 12 - ( 4一才クチルフエ二ル） ェチル〕 プロパン一 1 , 3 —ジオールまたはその医薬上許容しうる酸付加塩 1重量 部に対して 1〜1 0 0重量部、 特に 5〜8 0重量部が好ましい。  The saccharide used in the present invention is selected from monosaccharides, disaccharides and sugar alcohols, and specifically, glucose, fructose, D-maltose, lactose, sucrose (sucrose), D-mannitol, D-xylitol , D-sorbitol, and these can be used alone or in combination of two or more. The amount of these saccharides is from 1 to 3 parts by weight per part by weight of 2-amino-2-12- (4-year-old octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof. 100 parts by weight, especially 5 to 80 parts by weight, is preferred.
本発明の医薬組成物の製剤形態は、 液剤であって、 具体的には注射剤、 点眼剤、 点鼻剤、 点耳剤、 点滴用剤、 経口投与用液剤、 吸入剤用液剤、 口 ーシヨン用液剤等であり、 好ましくは、 注射剤 （静脈用、 皮下用、 筋肉内 用等） 、 点眼剤、 点滴用剤である。 これらの製剤形態は、 適応症、 その症 状、 患者の性別，年齢、 適用場所等によって好適に選択され、 当業者に公 知の方法で製剤化される。  The pharmaceutical form of the pharmaceutical composition of the present invention is a liquid, specifically, an injection, an eye drop, a nasal drop, an ear drop, a drop, a liquid for oral administration, a liquid for inhalation, and a mouth lotion. Liquids and the like, and preferably, injections (intravenous, subcutaneous, intramuscular, etc.), eye drops, and infusions. These formulation forms are suitably selected according to the indication, the symptoms thereof, the sex, age, place of application, etc. of the patient, and are formulated by methods known to those skilled in the art.
本発明の医薬組成物は、 液剤製剤完成品として市販に供することもでき るし、 活性成分等含有粉末または凍結乾燥品と溶解液とのキッ トとして市 販に供することもできる。 たとえば、 活性成分の 2—ァミノ— 2— 〔2— ( 4—ォクチルフエニル）ェチル〕 プロパン一 1 . 3—ジオールまたはその 医薬上許容しうる酸付加塩 （特に塩酸塩） を精製水に溶解して得た溶液を 無菌濾過後、 バイアル瓶に充填し、 次いで真空凍結乾燥して凍結乾燥品と する。 一方、 溶解液として本発明にて用いるシクロデキストリン類および 必要に応じて糖類を蒸留水に溶解した水溶液を調製する。 前記凍結乾燥品 は当該溶解液にて用時溶解するとよい。 これら溶解液は、 2—アミノー 2 一 〔2— （4一才クチルフエ二ル） ェチル〕 プロパン一 1 , 3—ジオール  The pharmaceutical composition of the present invention can be commercially available as a finished liquid preparation, or can be commercially available as a kit of a powder or a lyophilized product containing an active ingredient or the like and a lyophilized solution. For example, the active ingredient 2-amino-2- [2- (4-octylphenyl) ethyl] propane-1.3-diol or its pharmaceutically acceptable acid addition salt (particularly hydrochloride) is dissolved in purified water. After aseptic filtration, the obtained solution is filled in a vial, and then freeze-dried under vacuum to obtain a freeze-dried product. On the other hand, an aqueous solution in which the cyclodextrins used in the present invention and, if necessary, saccharides are dissolved in distilled water is prepared. The freeze-dried product may be dissolved in the dissolution solution before use. These lysates are 2-amino-21- (2- (4-year-old octylphenyl) ethyl) propane-1, 3-diol
訂正された用紙 （規則 91 ) またはその医薬上許容しうる酸付加塩に対し、 5倍量から 2 0 0 0倍量 （重 量部） 用いる。 ここで蒸留水とは、 注射剤の場合、 注射用蒸留水が好まし い。 前記凍結乾燥品は、 通常バイアル瓶に充填され、 窒素置換後、 ゴム栓 にて封栓し、 アルミシールを施すことによって、 室温でそのまま長期間保 存が可能となる。 なお、 シクロデキストリン類および必要に応じてさらに 添加される糖類は、 上記のように溶解液に配合する代りに、 活性成分の 2 —アミノー 2— 〔2— ( 4—ォクチルフエ二ル） ェチル〕 プロパン一 1 , 3—ジオールまたはその医薬上許容しうる酸付加塩と一緒に凍結乾燥品に 含有させておくこともできる。 シクロデキストリンの配合量は、 上記活性 成分 1重量部に対して 1 ~ 5 0重量部、 特に 1 0〜3 0重量部が好ましい。 また、 必要に応じてさらに添加される糖類は上記活性成分 1重量部に対し て 1〜1 0 0重量部、 特に 5〜8 0重量部が好ましい。 Corrected form (Rule 91) Alternatively, the pharmaceutically acceptable acid addition salt is used in a 5-fold to 2000-fold amount (weight part) with respect to the pharmaceutically acceptable acid addition salt. Here, in the case of an injection, distilled water is preferably distilled water for injection. The freeze-dried product is usually filled in a vial, replaced with nitrogen, sealed with a rubber stopper, and sealed with aluminum, so that it can be stored at room temperature for a long period of time. The cyclodextrins and the saccharides to be added as required are not added to the dissolution solution as described above, but instead of the active ingredient 2-amino-2- [2- (4-octylphenyl) ethyl] propane The lyophilized product may be contained together with 1,3-diol or a pharmaceutically acceptable acid addition salt thereof. The amount of cyclodextrin is preferably 1 to 50 parts by weight, particularly preferably 10 to 30 parts by weight, based on 1 part by weight of the active ingredient. The saccharides to be added as required are preferably 1 to 100 parts by weight, particularly preferably 5 to 80 parts by weight, per 1 part by weight of the active ingredient.
本発明の医薬組成物中には、 上記成分の他に、 例えば溶剤、 等張化剤、 p H調整剤、 緩衝剤、 抗酸化剤、 増粘剤、 界面活性剤、 保存剤、 保湿剤、 芳香剤および着色剤等も適宜配合することもでき、 これら添加物は、 本発 明の組成物を製剤化する際に、 配合することもでき、 上記キッ ト製剤にお いて用時溶解するための溶解液に添加しておくこともできる。  In the pharmaceutical composition of the present invention, in addition to the above components, for example, a solvent, a tonicity agent, a pH adjuster, a buffer, an antioxidant, a thickener, a surfactant, a preservative, a humectant, A flavoring agent, a coloring agent, and the like can also be appropriately compounded.These additives can be added when formulating the composition of the present invention, and are dissolved when used in the above kit preparation. Can also be added to the dissolving solution.
本発明の医薬組成物は、 液剤として、 特に、 臓器または骨髄移植後の拒 絶反応の抑制やその維持免疫療法、 ベーチュッ ト病またはぶどう膜炎等の 眼疾患、 乾癬、 アトピー性皮膚炎、 接触皮膚炎およびアレルギー性皮廣炎 を含む皮膚炎の治療等に使用し得る。 さらに詳細には、 本発明の医薬製剤 は、 従来経口製剤で行われていた各種適応症 （臓器または骨髄移植におけ る免疫抑制、 各種自己免疫疾患、 各種アレルギー疾患等） の予防または治 療に用いることができる。  The pharmaceutical composition of the present invention can be used as a liquid preparation, particularly as a method for suppressing rejection after organ or bone marrow transplantation, maintaining immunotherapy, eye diseases such as Behcet's disease or uveitis, psoriasis, atopic dermatitis, and contact. It can be used for the treatment of dermatitis including dermatitis and allergic dermatitis. More specifically, the pharmaceutical preparation of the present invention is useful for the prevention or treatment of various indications (immunosuppression in organ or bone marrow transplantation, various autoimmune diseases, various allergic diseases, etc.) conventionally performed with oral preparations. Can be used.
すなわち、 本発明の組成物は、 液剤として器官または組織の移植 （たと  That is, the composition of the present invention can be used as a liquid preparation for organ or tissue transplantation.
Ϊ丁正された用紙 （規則 91 ) えば、 心臓、 腎臓、 肝臓、 肺、 骨髄、 角膜、 降臓、 小腸、 四肢、 筋肉、 神 経、 脂肪髄、 十二指腸、 皮 *、 脬島細胞等の移植、 異種移植を含む） に対 する抵抗または拒絶反応、 骨髄または小腸移植による移植片対宿主 （G v H) 病、 自己免疫性疾患、 たとえば、 慢性関節リウマチ、 全身性紅斑性狼 瘡、 ネフローゼ症候群狼瘡、 橋本甲状腺腫、 多発性硬化症、 重症筋無力症、 I型糖尿病、 I I型成人発症型糖尿病、 ブドウ膜炎、 ネフローゼ症候群、 ステロイ ド依存性およびステロイ ド抵抗性ネフローゼ、 手掌足底膿疱症、 アレルギー性脳脊髄炎、 糸球体腎炎等、 ならびに病原体微生物による感染 症の治療および予防に使用できる。 また、 炎症性、 増殖性および超増殖性 皮膚疾患、 ならびに免疫媒介疾患の皮膚における発症、 たとえば乾癬、 乾 癬様関節炎、 了トピー性湿疹 （ァトピー性皮膚炎）、接触性皮膚炎、 さら には湿疹皮庸炎、 脂漏性皮) *炎、 偏平苔癬、 天疱瘡、 水泡性類天疱瘡、 表 皮水泡症、 じんま疹、 脈管浮腫、 脈管炎、 紅斑、 皮膚好酸球増加症、 ざ瘡、 円形脱毛症、 好酸球性筋膜炎および粥状硬化症の治療にも使用できる。 本 発明組成物は、 より特定的には脱毛を予防し、 毛芽を形成し、 および/ま たは毛髮を発生させ、 かつ成長させることによって、 女性型もしくは男性 型脱毛症または老年性脱毛症の治療のような毛髮の回復を行うのに使用で さる。 ΪTorted paper (Rule 91) For example, resistance to heart, kidney, liver, lung, bone marrow, cornea, fallen, small intestine, limb, muscle, nerve, fat marrow, duodenum, skin *, transplantation of islet cells, xenograft) Or rejection, graft-versus-host (GvH) disease due to bone marrow or small bowel transplantation, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, nephrotic syndrome lupus, Hashimoto goiter, multiple sclerosis , Myasthenia gravis, type I diabetes, type II diabetes mellitus, uveitis, nephrotic syndrome, steroid-dependent and steroid-resistant nephrosis, palmar plantar pustulosis, allergic encephalomyelitis, glomerulonephritis Etc., and for the treatment and prevention of infectious diseases caused by pathogenic microorganisms. Also, the onset of inflammatory, proliferative and hyperproliferative skin diseases, and immune-mediated diseases in the skin, such as psoriasis, psoriatic arthritis, topical eczema (atopic dermatitis), contact dermatitis, and (Eczema dermatitis, seborrheic skin) * flame, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, vascular edema, vasculitis, erythema, increased skin eosinophils It can also be used to treat acne, acne, alopecia areata, eosinophilic fasciitis and atherosclerosis. The compositions of the invention more particularly prevent alopecia, form hair buds and / or develop and grow hair, so that female or male pattern baldness or senile alopecia It can be used to do hair restoration, such as treatment for hair.
本発明の組成物は呼吸器疾患、 たとえばサルコィ ドーシス、 肺繊維症、 特発性間質性肺炎ならびに可逆的閉塞性気道疾患、 たとえば気管支喘息、 小児喘息、 アレルギー性喘息、 内因性喘息、 外因性喘息および塵埃性喘息、 特に慢性もしくは難治性喘息 （たとえば遅発性喘息および気道過敏） 、 気 管支炎等を含む喘息のような症状の治療にも適用可能である。 本発明組成 物は虚血に関連した肝障害の治療にも使用できる。 さらに、 特定の眼疾患、 たとえば結膜炎、 角結膜炎、 角膜炎、 春季カタル、 ベーチ ッ ト病に関連 したブドウ膜炎、 ヘルぺス性角膜炎、 円錐角膜、 角膜上皮変性症、 角膜白 斑、 眼天疱瘡、 モーレン潰瘍、 強膜炎、 グレイブス眼病、 重症眼内炎症等 にも有効である。 Compositions of the invention may be used for respiratory diseases such as sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia and reversible obstructive airway diseases such as bronchial asthma, pediatric asthma, allergic asthma, intrinsic asthma, extrinsic asthma It is also applicable to the treatment of asthma, including dusty asthma, especially chronic or refractory asthma (eg, late onset asthma and airway hyperreactivity), bronchitis and the like. The composition of the present invention can also be used for treating liver damage associated with ischemia. In addition, it is associated with certain eye diseases such as conjunctivitis, keratoconjunctivitis, keratitis, spring catarrhals and Behcet's disease It is also effective for severe uveitis, herpes keratitis, keratoconus, corneal epithelial degeneration, corneal vitiligo, pemphigus, Mohren's ulcer, scleritis, Graves' eye disease and severe intraocular inflammation.
本発明組成物は、 また、 粘膜もしくは血管の炎症 [たとえば、 ロイコト リエン B 4媒介疾患、 胃潰瘍、 虚血性疾患および血栓病に起因する血管損 傷、 虚血性腸疾患、 炎症性腸疾患 （たとえば、 クローン病および潰瘍性大 腸炎） 、 壊死性大腸炎] 、 熱性熱傷に関連した腸損傷の予防または治療に も使用できる。 本発明組成物は間質性腎炎、 グッ ドバスチヤ一症候群、 溶 血性尿毒性症候群および糖尿病性ネフ口パシーのような胃疾患；多発性筋 炎、 ギランバレー症候群、 メニエール病および神経根症から選択される神 経病；甲状腺機能亢進症およびバセドウ氏病のような内分泌疾患；純粋赤 血球無形成症、 無形成貧血、 再生不良性貧血、 特発性血小板減少性紫斑病、 自己免疫溶血性貧血、 顆粒球減少症および赤血球生成欠如のような血液の 病気：骨粗鬆症のような骨の病気；サルコィ ド一シス、 肺繊維症および特 発性間質性肺炎のような呼吸器疾患：皮虜筋炎、 尋常性白斑、 尋常性魚鳞 癬、 光アレルギー性敏感症および皮廣 T細胞リンパ腫のような皮膚病；動 脈硬化、 大動脈炎、 結節性多発動脈炎および心筋症のような循環器疾患； 強皮症、 ぺグネル肉芽腫およびシエーダレン症候群のような膠原病；脂肪 症；好酸性筋膜炎；歯周疾患；ネフローゼ症候群；溶血性尿毒性症候群； ならびに筋ジストロフィーの治療または予防でも使用できる。  The composition of the present invention also includes mucosal or vascular inflammation [eg, leukotriene B4-mediated disease, stomach ulcer, vascular injury due to ischemic disease and thrombotic disease, ischemic bowel disease, inflammatory bowel disease (eg, Crohn's disease and ulcerative colitis), necrotizing colitis], and can also be used to prevent or treat intestinal damage associated with burns. The composition of the present invention is selected from gastric diseases such as interstitial nephritis, Good Bastian syndrome, hemolytic uremic syndrome and diabetic nephropathy; polymyositis, Guillain-Barre syndrome, Meniere's disease and radiculopathy Endocrine disorders such as hyperthyroidism and Graves' disease; pure erythrocytosis, aplastic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, granules Blood diseases such as cytopenia and lack of erythropoiesis: bone diseases such as osteoporosis; respiratory diseases such as sarcoidosis, pulmonary fibrosis and idiopathic interstitial pneumonia: skin myositis, vulgaris Dermatosis such as vitiligo, fish vulgaris, psoriasis, photoallergic susceptibility and percutaneous T-cell lymphoma; cardiovascular diseases such as arteriosclerosis, aortitis, polyarteritis nodosa and cardiomyopathy; It can also be used in the treatment or prevention of dermatosis, collagen diseases such as Pegner's granulomas and Siedalen syndrome; steatosis; eosinophilic fasciitis; periodontal disease; nephrotic syndrome; hemolytic uremic syndrome; and muscular dystrophy.
本発明組成物は腸の炎症 Zアレルギー、 たとえば C o e 1 i a c病、 直 腸炎、 好酸球性胃腸炎、 肥満細胞症、 クローン病および潰瘍性大腸炎；な らびに食品に関連したアレルギー性疾患であって、 胃腸管には直接関係の ない症状を示すもの、 たとえば偏頭痛、 募炎および湿疹の予防または治療 にも適している。 本発明の医薬組成物における活性成分である 2—アミノー 2— 〔2— （4 一才クチルフヱニル） ェチル〕 プロパン一 1， 3—ジオールまたはその医 薬上許容しうる酸付加塩は、 肝臓再生活性およびノまたは肝細胞の肥大お よび過形成を促進する活性を有することから、 本発明組成物は免疫原性疾 患 （たとえば、 自己免疫性肝炎、 原発性胆汁性肝硬変および硬化性胆管炎 を含む慢性自己免疫性肝疾患） 、 部分的肝臓切除、 急性肝臓壌死 （たとえ ば、 毒素、 ウィルス性肝炎、 ショックまたは酸素欠乏による壤死） 、 B型 ウィルス性肝炎、 非 A型/非 B型肝炎および肝硬変のような肝疾患の治療 および予防に使用できる。 The compositions of the present invention may be used to treat intestinal inflammation Z allergies, such as Coe iac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, and ulcerative colitis; and food-related allergic diseases It is suitable for the prevention or treatment of symptoms that are not directly related to the gastrointestinal tract, such as migraine, soreness and eczema. The active ingredient 2-amino-2- [2- (4-year-old tylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof, which is an active ingredient in the pharmaceutical composition of the present invention, has a liver regeneration activity. In addition, since the composition of the present invention has an activity of promoting hypertrophy and hyperplasia of hepatic cells, the composition of the present invention includes immunogenic diseases (eg, including autoimmune hepatitis, primary biliary cirrhosis, and sclerosing cholangitis). Chronic autoimmune liver disease), partial liver resection, acute liver death (eg, toxin, viral hepatitis, soil death due to shock or oxygen deprivation), viral hepatitis B, non-A / non-B hepatitis And for the treatment and prevention of liver diseases such as cirrhosis.
本発明組成物はまた、 抗菌剤用組成物としても使用でき、 したがって病 原体微生物等による病気の治療に使用することができる。 さらに、 本発明 組成物は悪性関節リウマチ、 アミロイ ドーシス、 劇症肝炎、 シャイ ' ドレ 一ガー症候群、 膿疱性乾癬、 ベーチュッ ト病、 全身性エリテマトーデス、 内分泌性眼障害、 進行性全身性硬化症、 混合性結合組織病、 大動脈炎症候 群、 W e g e n e r肉芽腫、 活動性慢性肝炎、 E v a n s症候群、 花粉症、 特発性副甲状腺機能低下症、 アジソン病 （自己免疫性副腎炎）、 自己免疫 性睾丸炎、 自己免疫性卵巣炎、 寒冷血球凝集素症、 発作性寒冷血色素尿症、 悪性貧血、 成人性 T細胞白血病、 自己免疫性萎縮性胃炎、 ルポィ ド肝炎、 尿細管間質性腎炎、 膜性腎炎、 筋萎縮性側索硬化症、 リウマチ熱、 心筋梗 塞後症候群、 交感性眼炎の予防または治療に使用することができる。  The composition of the present invention can also be used as a composition for an antibacterial agent, and thus can be used for treating diseases caused by pathogenic microorganisms and the like. Furthermore, the composition of the present invention may be used for the treatment of malignant rheumatoid arthritis, amyloidosis, fulminant hepatitis, Shy 'Dore-Iger syndrome, pustular psoriasis, Behcet's disease, systemic lupus erythematosus, endocrine ophthalmopathy, progressive systemic sclerosis, mixed Sexual connective tissue disease, aortic inflammation group, Wegener's granuloma, active chronic hepatitis, Evans syndrome, hay fever, idiopathic hypoparathyroidism, Addison's disease (autoimmune adrenalitis), autoimmune orchitis , Autoimmune ovitis, cold hemagglutininosis, paroxysmal cold hemoglobinuria, pernicious anemia, adult T-cell leukemia, autoimmune atrophic gastritis, lupus hepatitis, tubular interstitial nephritis, membrane nephritis It can be used to prevent or treat amyotrophic lateral sclerosis, rheumatic fever, post myocardial infarction syndrome, and sympathetic ophthalmitis.
本発明の組成物は、 場合によっては他の免疫抑制剤、 ステロイ ド剤 （ブ レドニゾロン、 メチルプレドニゾロン、 デキサメサゾン、 ヒドロコルチゾ ン等） または非ステロイ ド性抗炎症薬等と一緒に使用することができる。 他の免疫抑制剤として特に好ましいものは、 ァザチォプリン、 ブレキナー ルナトリウム、 デォキシスパーガリン、 ミゾリビン、 ミコフエノール酸 2 一モルホリノェチルエステル、 シクロスポリ ン、 ラパマイシン、 タクロリ ムス水和物、 レフルノマイ ドおよび O K T— 3から選択される。 The composition of the present invention can be optionally used in combination with other immunosuppressants, steroid agents (blednisolone, methylprednisolone, dexamethasone, hydrocortisone, etc.) or non-steroid anti-inflammatory agents. Particularly preferred as other immunosuppressants are azathioprine, brequinar sodium, deoxyspargarine, mizoribine, mycophenolic acid 2 One selected from monomorpholinethyl ester, cyclosporine, rapamycin, tacrolimus hydrate, leflunomide and OKT-3.
本発明の組成物は、 適応症、 その症状、 患者の性別 ·年齢、 適用場所等 により異なり得るが、 本化合物を 0. 0 0 0 0 1〜2 0重量％、 好ましく は 0. 0 0 0 1〜1 0重量％含むものを、 1日に 1回または数回 （例えば、 2回〜 5回） に分けて適用することにより、 臨床上好ましい効果を示し得 る  The composition of the present invention may vary depending on the indication, its symptoms, the gender and age of the patient, the place of application, and the like. However, the present compound is preferably used in an amount of 0.001 to 20% by weight, preferably 0.0000. By applying 1 to 10% by weight once or several times a day (for example, 2 to 5 times), a clinically favorable effect can be obtained.
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
以下実施例および実験例を挙げて本発明をさらに詳しく説明する。  Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples.
以下の実施例において、 特に記載のない限り、 割合はすべて重量に基づ く。 なお、 実施例中、 本化合物とは 2—アミノー 2— 〔2— （4一才クチ ルフ ニル） ェチル〕 プロパン一 1， 3—ジオール塩酸塩を意味する。  In the following examples, all percentages are by weight unless otherwise indicated. In the examples, the present compound means 2-amino-2- [2- (4-year-old butylyl) ethyl] propane-11,3-diol hydrochloride.
実施例 1  Example 1
下記組成の本化合物含有注射製剤を製造する。  An injection preparation containing the present compound having the following composition is produced.
本化合物 0. 1 % なーシクロデキストリン（商品名：セルデックス A-100) 1 . 0 %  0.1% of this compound 0.1% Cyclodextrin (trade name: Celdex A-100) 1.0%
D—マンニトール 5. 0 % 上記組成物を注射用蒸留水にて溶解させ、 全量 1 0 m 1の注射剤とする c 必要に応じ、 保存剤等通常の添加剤を配合し得る。 D-mannitol 5.0% The above composition is dissolved in distilled water for injection to give a total injection of 10 ml. C If necessary, ordinary additives such as a preservative may be blended.
実施例 2  Example 2
下記組成の本化合物含有注射製剤を製造する。  An injection preparation containing the present compound having the following composition is produced.
本化合物 0. 1 %  This compound 0.1%
2—ヒ ドロキシプロピルによって部分的にエーテル化された —シクロ デキストリン（商品名：セルデックス HP- - CD) 1 . 0 %  2-Partially etherified with hydroxypropyl-Cyclodextrin (trade name: Celdex HP--CD) 1.0%
D—マンニトール 5. 0 % 上記組成物を注射用蒸留水にて溶解させ、 全量 1 Om 1の注射剤とする ( 必要に応じ、 保存剤等通常の添加剤を配合し得る。 D—mannitol 5.0% The above composition is dissolved in distilled water for injection to give a total amount of 1 Om 1 of an injection (if necessary, ordinary additives such as a preservative may be added.
実施例 3  Example 3
下記組成の本化合物含有注射剤を製造する。  An injection containing the present compound having the following composition is produced.
本化合物 0. 1%  This compound 0.1%
ーシクロデキストリン（商品名：セルデックス A-100) 1. 0%  -Cyclodextrin (Product name: Celdex A-100) 1.0%
上記組成物を注射用蒸留水 （必要に応じ、 保存剤等通常の添加剤を配合 し得る） にて溶解させ、 無菌濾過後、 全量 1 Om 1をバイアル瓶に充填し、 常法に従い凍結乾燥し、 注射剤とする。  The above composition is dissolved in distilled water for injection (can be mixed with usual additives such as preservatives, if necessary). After aseptic filtration, a total of 1 Om1 is filled in a vial and freeze-dried according to a conventional method. And use it as an injection.
実施例 4  Example 4
下記組成の本化合物含有注射製剤を製造する。  An injection preparation containing the present compound having the following composition is produced.
本化合物 0. 1%  This compound 0.1%
2—ヒドロキシプロピルによって部分的にエーテル化された； S—シクロ デキストリン（商品名：セルデックス -CD) 1. 0%  Partially etherified with 2-hydroxypropyl; S-cyclodextrin (trade name: Celdex-CD) 1.0%
上記組成物を注射用蒸留水 （必要に応じ、 保存剤等通常の添加剤を配合 し得る。 ） にて溶解させ、 無菌濾過後、 全量 1 Om 1をバイアル瓶に充填 し、 常法に従い凍結乾燥し、 注射剤とする。  The above composition is dissolved in distilled water for injection (where necessary, conventional additives such as preservatives may be added). After aseptic filtration, a total of 1 Om1 is filled into a vial, and frozen according to a conventional method. Dry and use as injection.
実施例 5  Example 5
下記組成の本化合物含有注射製剤を製造する。  An injection preparation containing the present compound having the following composition is produced.
本化合物 0. 1%  This compound 0.1%
2—ヒドロキシプロピルに って部分的にエーテル化された^ーシクロ デキストリン（商品名：セルデックス HP -CD) 2. 0%  ^ -Cyclodextrin partially etherified with 2-hydroxypropyl (trade name: Celdex HP-CD) 2.0%
塩化ナトリウム 0. 9%  0.9% sodium chloride
上記組成物を注射用蒸留水にて溶解させ、 全量 1 Omlの注射剤とする c 必要に応じ、 保存剤等通常の添加剤を配合し得る。 実施例 6 The above composition is dissolved in distilled water for injection to give a total of 1 Oml of injection. C If necessary, ordinary additives such as a preservative may be blended. Example 6
下記組成の本化合物含有点眼剤を製造する。  An eye drop containing the present compound having the following composition is produced.
本化合物 0. 1% α—シクロデキス卜リ ン（商品名：セルデックス A-100) 1. 0% D—マンニトール 5. 0Η 上記組成物を滅菌精製水にて溶解させ、 全量 10m〗の点眼剤とする。 必要に応じ、 保存剤等通常の添加剤を配合し得る。  This compound 0.1% α-cyclodextrin (trade name: Celdex A-100) 1.0% D-mannitol 5.0Η The above composition is dissolved in sterile purified water, and the total amount of eye drops is 10m〗. And If necessary, ordinary additives such as a preservative may be added.
実施例 7  Example 7
下記組成の本化合物含有点眼剤を製造する。  An eye drop containing the present compound having the following composition is produced.
本化合物 0. 1% This compound 0.1%
2—ヒ ドロキシプロピルによって部分的にエーテル化された^—シクロ デキストリン（商品名：セルデックス HP-S- CD) 1. % ^ -Cyclodextrin partially etherified with 2-hydroxypropyl (trade name: Celdex HP-S-CD) 1.%
D—マンニトール 5. 0% 上記組成物を滅菌精製水にて溶解させ、 全量 1 Ο ΙΏ 1の点眼剤とする。 必要に応じ、 保存剤等通常の添加剤を配合し得る。  D-mannitol 5.0% The above composition is dissolved in sterile purified water to give a total amount of 1% ophthalmic solution. If necessary, ordinary additives such as a preservative may be added.
実験例  Experimental example
実施例 1および 2の製剤に対して、 薬安第 2号 （注射剤の局所障害性に 関する試験法 （案） 、 昭和 54年 1月 12日厚生省薬務局安全課） に従い 試料溶液を調製し、 イングロッ ト （Inglot) らの方法 （Biochem. Pharmac ol. , 第 17卷 269頁 1968年） により 540nmでの吸光度を測定した 結果、 実施例 1および 2の製剤は、 有意に溶血性が低減されていることが 判る。  Prepare sample solutions for the preparations of Examples 1 and 2 in accordance with Yakuyasu No. 2 (Test method for local toxicity of injection (draft), Safety Division, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare on January 12, 1979) The absorbance at 540 nm was measured by the method of Inglot et al. (Biochem. Pharmacol., Vol. 17, p. 269, 1968). As a result, the preparations of Examples 1 and 2 showed significantly reduced hemolysis. You can see that it has been done.
実施例 1の製剤について、 5週齢の LEWラッ 卜に 5曰間反復静脈内投 与し、 尾の腫脹率 { (薬物投与群の尾の直径一コントロールの尾の直径） ÷コントロールの尾の直径 X 100} を指標とし局所刺激性の有無を確認 した結果、 実施例 1では 0 %となり、 実施例 1の製剤は、 局所刺激性を示 さないことが判る。 The formulation of Example 1 was repeatedly administered intravenously to a 5-week-old LEW rat for 5 days, and the swelling ratio of the tail {(tail diameter of the drug-administered group-diameter of the control tail) ÷ tail of the control Confirm the presence or absence of local irritation using the diameter x 100} as an index As a result, the result was 0% in Example 1, indicating that the preparation of Example 1 did not show local irritation.
産業上の利用可能性 Industrial applicability
2—ァミノ一 2— 〔2— （4一才クチルフヱニル） ェチル〕 プロパン一 1 , 3—ジオールまたはその医薬上許容しうる酸付加塩にシクロデキスト リ ン類、 さらに必要に応じて糖類を配合することにより、 製剤化が容易で、 かつ溶血性等の副作用が軽減され、 しかも局所刺激性の少ない 2—ァミノ 一 2— 〔2— （4一才クチルフエ二ル） ェチル〕 プロパン一 1 , 3—ジォ ールまたはその医薬上許容しうる酸付加塩を含有する液剤に適した医薬組 成物が提供される。  2-Amino-2- [2- (4-year-old tylphenyl) ethyl] Propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof with cyclodextrins and, if necessary, saccharides This makes it easy to formulate, reduces side effects such as hemolysis, and has little local irritation. 2-Amino-2- (2- (4-year-old octylphenethyl) ethyl) propane-1, 3- Pharmaceutical compositions suitable for solutions containing diol or a pharmaceutically acceptable acid addition salt thereof are provided.

Claims

請 求 の 範 囲 The scope of the claims
1 . 活性成分として 2—アミノー 2— 〔2— （4一才クチルフエニル） ェチル〕 プロパン一 1 , 3—ジオールまたはその医薬上許容しうる酸付加 塩、 シクロデキス卜リン類および通常の医薬上許容される担体または希釈 剤からなる医薬組成物。  1. 2-Amino-2- [2- (4-one-octylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof, a cyclodextrin or a pharmaceutically acceptable pharmaceutically acceptable salt as an active ingredient A pharmaceutical composition comprising a carrier or diluent.
2. シクロデキストリ ン類が天然シクロデキストリ ン、 分岐シクロデキ ス トリ ン、 アルキルシクロデキストリンまたはヒ ドロキンアルキルンクロ デキストリンである請求項 1に記載の医薬組成物。  2. The pharmaceutical composition according to claim 1, wherein the cyclodextrin is a natural cyclodextrin, a branched cyclodextrin, an alkyl cyclodextrin, or a hydroquinine alkylene cyclodextrin.
3. 活性成分の 2—アミ ノー 2— 〔2— （4一才クチルフヱニル） ェチ ル〕 プロパン一 1， 3—ジオールまたはその医薬上許容しうる酸付加塩が 組成物全重量当り 0. 0 1〜2 0重量％含有され、 該活性成分に対してシ クロデキストリン類を該活性成分 1重量部当り、 1〜5 0重量部含有する 請求項 1に記載の医薬組成物。  3. 2-Amino 2- [2- (4-year-old tylphenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof as an active ingredient is added at a ratio of 0.0 to the total weight of the composition. The pharmaceutical composition according to claim 1, which is contained in an amount of 1 to 20% by weight, and contains cyclodextrins in an amount of 1 to 50 parts by weight per 1 part by weight of the active ingredient.
4 . 糖類を含有してなる請求項 1に記載の医薬組成物。  4. The pharmaceutical composition according to claim 1, comprising a saccharide.
5. 糖類が単糖類、 二糖類または糖アルコールから選ばれる請求項 4に 記載の医薬組成物。  5. The pharmaceutical composition according to claim 4, wherein the saccharide is selected from a monosaccharide, a disaccharide, and a sugar alcohol.
6. 糖類が D—マンニトール、 ブドウ糖、 D—キシリ トール、 D—マル トース、 D—ソルビトール、 乳糖、 果糖または白糖から選ばれる 1種また は 2種以上である請求項 4または 5に記載の医薬組成物。  6. The pharmaceutical according to claim 4, wherein the saccharide is one or more selected from D-mannitol, glucose, D-xylitol, D-maltose, D-sorbitol, lactose, fructose or sucrose. Composition.
7. 糖類が活性成分 1重量部当り、 1〜1 0 0重量部含有される請求項 4に記載の医薬組成物。  7. The pharmaceutical composition according to claim 4, wherein the saccharide is contained in an amount of 1 to 100 parts by weight per 1 part by weight of the active ingredient.
8. キッ ト形態である請求項 1に記載の医薬組成物。  8. The pharmaceutical composition according to claim 1, which is in a kit form.
9. 凍結乾燥品の 2—アミノー 2— 〔2— （4一才クチルフエ二ル） ェ チル〕 プロパン一 1 , 3—ジオールまたはその医薬上許容しうる酸付加塩 と、 シクロデキストリン類を含有する水溶液からなる溶解液からなる請求 項 8に記載の医薬組成物。 9. Freeze-dried 2-amino-2- [2- (4-year-old tyl phenyl) ethyl] propane-1,3-diol or a pharmaceutically acceptable acid addition salt thereof and cyclodextrins Claim consisting of a solution consisting of an aqueous solution Item 10. The pharmaceutical composition according to Item 8,
1 0. 2—アミノー 2— 〔2— （4—ォクチルフヱニル） ェチル〕 プロ パン一 1 . 3—ジオールまたはその医薬上許容しうる酸付加塩とシクロデ キストリン類を含有する凍結乾燥品と蒸留水からなる溶解液からなる請求 項 8に記載の医薬組成物。  1 0.2-Amino-2- [2- (4-octylphenyl) ethyl] Propane 1.3-diol or a lyophilized product containing a pharmaceutically acceptable acid addition salt and cyclodextrin and distilled water 9. The pharmaceutical composition according to claim 8, comprising a dissolving solution.
1 1. シクロデキストリ ン類が活性成分 1重量部当り 1〜5 0重量部含 有される請求項 9または 1 0に記載の医薬組成物。  11. The pharmaceutical composition according to claim 9 or 10, wherein the cyclodextrin is contained in an amount of 1 to 50 parts by weight per 1 part by weight of the active ingredient.
1 2. 糖類が凍結乾燥品か溶解液のいずれかにさらに配合されている請 求項 9または 1 0に記載の医薬組成物。  12. The pharmaceutical composition according to claim 9, wherein the saccharide is further incorporated into either a freeze-dried product or a solution.
1 3. 糖類が活性成分 1重量部当り 1〜1 0 0重量部含有される請求項 1 1に記載の医薬組成物。  13. The pharmaceutical composition according to claim 11, wherein the saccharide is contained in an amount of 1 to 100 parts by weight per 1 part by weight of the active ingredient.
PCT/JP1997/002448 1996-07-18 1997-07-15 Medicinal compositions WO1998003162A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU34608/97A AU3460897A (en) 1996-07-18 1997-07-15 Medicinal compositions
US09/231,484 US6476004B1 (en) 1996-07-18 1999-01-14 Pharmaceutical composition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP18938096A JP2002241272A (en) 1996-07-18 1996-07-18 Medicinal composition
JP8/189380 1996-07-18

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09/231,484 Continuation-In-Part US6476004B1 (en) 1996-07-18 1999-01-14 Pharmaceutical composition

Publications (1)

Publication Number Publication Date
WO1998003162A1 true WO1998003162A1 (en) 1998-01-29

Family

ID=16240353

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1997/002448 WO1998003162A1 (en) 1996-07-18 1997-07-15 Medicinal compositions

Country Status (3)

Country Link
JP (1) JP2002241272A (en)
AU (1) AU3460897A (en)
WO (1) WO1998003162A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998037875A1 (en) * 1997-02-27 1998-09-03 Yoshitomi Pharmaceutical Industries, Ltd. Drug composition
WO1999036065A1 (en) * 1998-01-19 1999-07-22 Yoshitomi Pharmaceutical Industries, Ltd. Medicinal compositions
WO2001001978A1 (en) * 1999-06-30 2001-01-11 Mitsubishi Pharma Corporation Medicinal compositions for preventing or treating viral myocarditis
US6423739B1 (en) 2000-02-23 2002-07-23 Daiichi Pharmaceutical Co., Ltd. Method for aiding cerebral recovery following neurodegeneration
US6437165B1 (en) 2000-08-31 2002-08-20 Merck & Co., Inc. Phosphate derivatives as immunoregulatory agents
EP1312359A2 (en) * 1996-11-19 2003-05-21 Novartis AG Use for 1,3-propanediol compounds
US8324283B2 (en) 2003-04-08 2012-12-04 Novartis Ag Solid pharmaceutical compositions comprising a SIP receptor agonist and a sugar alcohol

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002324026B2 (en) * 1996-07-18 2005-07-14 Novartis Ag Pharmaceutical compositions
JP4838497B2 (en) * 2004-04-09 2011-12-14 キッセイ薬品工業株式会社 Pharmaceutical composition for prevention or treatment of rejection after liver transplantation

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58148816A (en) * 1982-02-27 1983-09-05 Nippon Zenyaku Kogyo Kk Low irritant thiamulin injection
JPH05213757A (en) * 1990-08-13 1993-08-24 Senju Pharmaceut Co Ltd Aqueous solution
JPH0616547A (en) * 1992-07-01 1994-01-25 Wakamoto Pharmaceut Co Ltd Antiphlogistic ophthalmic solution
WO1994008943A1 (en) * 1992-10-21 1994-04-28 Yoshitomi Pharmaceutical Industries, Ltd. 2-amino-1,3-propanediol compound and immunosuppressant
JPH07228532A (en) * 1993-04-22 1995-08-29 Senju Pharmaceut Co Ltd Water-soluble solution, method for improving solubility of its active ingredient and stabilization thereof
JPH07316065A (en) * 1994-05-25 1995-12-05 Fujisawa Pharmaceut Co Ltd Pharmaceutical preparation of fr 901469 substance
WO1996006068A1 (en) * 1994-08-22 1996-02-29 Yoshitomi Pharmaceutical Industries, Ltd. Benzene compound and medicinal use thereof
JPH08175985A (en) * 1994-12-26 1996-07-09 Lion Corp Ophthalmic solution
WO1997024112A1 (en) * 1995-12-28 1997-07-10 Yoshitomi Pharmaceutical Industries, Ltd. External preparation

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58148816A (en) * 1982-02-27 1983-09-05 Nippon Zenyaku Kogyo Kk Low irritant thiamulin injection
JPH05213757A (en) * 1990-08-13 1993-08-24 Senju Pharmaceut Co Ltd Aqueous solution
JPH0616547A (en) * 1992-07-01 1994-01-25 Wakamoto Pharmaceut Co Ltd Antiphlogistic ophthalmic solution
WO1994008943A1 (en) * 1992-10-21 1994-04-28 Yoshitomi Pharmaceutical Industries, Ltd. 2-amino-1,3-propanediol compound and immunosuppressant
JPH07228532A (en) * 1993-04-22 1995-08-29 Senju Pharmaceut Co Ltd Water-soluble solution, method for improving solubility of its active ingredient and stabilization thereof
JPH07316065A (en) * 1994-05-25 1995-12-05 Fujisawa Pharmaceut Co Ltd Pharmaceutical preparation of fr 901469 substance
WO1996006068A1 (en) * 1994-08-22 1996-02-29 Yoshitomi Pharmaceutical Industries, Ltd. Benzene compound and medicinal use thereof
JPH08175985A (en) * 1994-12-26 1996-07-09 Lion Corp Ophthalmic solution
WO1997024112A1 (en) * 1995-12-28 1997-07-10 Yoshitomi Pharmaceutical Industries, Ltd. External preparation

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1312359A2 (en) * 1996-11-19 2003-05-21 Novartis AG Use for 1,3-propanediol compounds
EP1312359A3 (en) * 1996-11-19 2004-01-02 Novartis AG Use for 1,3-propanediol compounds
WO1998037875A1 (en) * 1997-02-27 1998-09-03 Yoshitomi Pharmaceutical Industries, Ltd. Drug composition
WO1999036065A1 (en) * 1998-01-19 1999-07-22 Yoshitomi Pharmaceutical Industries, Ltd. Medicinal compositions
WO2001001978A1 (en) * 1999-06-30 2001-01-11 Mitsubishi Pharma Corporation Medicinal compositions for preventing or treating viral myocarditis
AU770495B2 (en) * 1999-06-30 2004-02-26 Akira Matsumori Medicinal compositions for preventing or treating viral myocarditis
US7902261B2 (en) 1999-06-30 2011-03-08 Mitsubishi Tanabe Pharma Corporation Medicinal compositions for preventing or treating viral myocarditis
US6423739B1 (en) 2000-02-23 2002-07-23 Daiichi Pharmaceutical Co., Ltd. Method for aiding cerebral recovery following neurodegeneration
US6437165B1 (en) 2000-08-31 2002-08-20 Merck & Co., Inc. Phosphate derivatives as immunoregulatory agents
US8324283B2 (en) 2003-04-08 2012-12-04 Novartis Ag Solid pharmaceutical compositions comprising a SIP receptor agonist and a sugar alcohol

Also Published As

Publication number Publication date
AU3460897A (en) 1998-02-10
JP2002241272A (en) 2002-08-28

Similar Documents

Publication Publication Date Title
US6476004B1 (en) Pharmaceutical composition
JP4434486B2 (en) Pharmaceutical composition
JP4153563B2 (en) Pharmaceutical composition
ES2230571T3 (en) `PHARMACEUTICAL COMPOSITION INTENDED FOR TOPICAL ADMINISTRATION INCLUDING 2-AMINO-2- (2- (4-OCTILFENIL) ETIL) PROPAN-1,3-DIOL FOR THE TREATMENT OF DISEASES CAUSED BY IMMUNE ALTERATION.
CA2341568A1 (en) Stabilized pharmaceutical composition in lyophilized form
WO1998003162A1 (en) Medicinal compositions
CN101653412B (en) Stable rocuronium bromide composition for injection
BR122020021551B1 (en) ANTIMICROBIAL PHARMACEUTICAL COMPOSITION AND ITS USE
US20130004426A1 (en) Adenosine derivative formulations for medical imaging
AU2005266449B2 (en) Compound formulations of 2-amino-1,3-propanediol compounds
JP2005523329A5 (en)
WO2022078483A1 (en) Quaternary ammonium steroid compound, preparation method therefor, preparation and use
AU2002324026B2 (en) Pharmaceutical compositions
WO2008056657A1 (en) Lyophilized preparation comprising phenanthridine derivative

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH HU IL IS JP KE KG KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 09194441

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 09231484

Country of ref document: US

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA