WO1994025032A1 - Injection stabilisee et procede de stabilisation d'injection - Google Patents

Injection stabilisee et procede de stabilisation d'injection Download PDF

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Publication number
WO1994025032A1
WO1994025032A1 PCT/JP1994/000691 JP9400691W WO9425032A1 WO 1994025032 A1 WO1994025032 A1 WO 1994025032A1 JP 9400691 W JP9400691 W JP 9400691W WO 9425032 A1 WO9425032 A1 WO 9425032A1
Authority
WO
WIPO (PCT)
Prior art keywords
injection
acid
sulfite
sodium
benzoxazine
Prior art date
Application number
PCT/JP1994/000691
Other languages
English (en)
Japanese (ja)
Inventor
Toshiyuki Shibata
Shigemi Kino
Toshio Hamasaki
Takeshi Kakita
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 KR1019950704441A priority Critical patent/KR100188318B1/ko
Publication of WO1994025032A1 publication Critical patent/WO1994025032A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention has a potent and selective serotonin-13 receptor antagonism, and is useful as a therapeutic agent for improving nausea, vomiting and anorexia associated with administration of antineoplastic agents such as cisplatin and the like.
  • 6-chloro-1,3,4-dihydro-4-methyl-3-oxo-1-N-3 monoquinuclidinyl-2H-1,4-benzoxazine-18-carboxamido hydrochloride stabilized injection and injection containing the compound To a stabilizer for the agent.
  • Japanese Unexamined Patent Publication (Kokai) No. 2-2818182 discloses a treatment for improving nausea, vomiting and anorexia associated with administration of an antineoplastic agent such as cisplatin, which has a potent and selective serotonin-3 receptor antagonism.
  • antineoplastic agent such as cisplatin
  • ⁇ 6-Chloro-3,4-dihydro-4-methyl-3-oxo-1N—3-quinuclidinyl-1 2H—1,4,1-benzoxazine-8-carboxamido hydrochloride
  • the compound is also referred to as “the present compound”, and it is disclosed that the compound is used as an oral preparation such as a tablet and a parenteral preparation such as an injection as a pharmaceutical dosage form.
  • the present compound has poor stability, particularly in the state of an aqueous solution or suspension, easily undergoes photolysis, and undergoes a significant color change. It is considered that these liquid preparations are usually covered with a light-shielding container to avoid photolysis. According to this method, it is possible to suppress photodegradation during the distribution process or storage of the drug, but when it is used in a clinical setting, it is often exposed to light, and It is not hard to imagine that rapid color change may occur frequently in some cases.
  • the present invention provides a stable (earth) 16-chloro-1,3-dihydro-4-methyl-3-oxo-1N-3-quinquinidinyl-2H-1, 4- Benzoxazine-8-Carboxamido hydrochloride-containing injection and stabilization method.
  • the present invention is characterized by incorporating a stabilizer against light.
  • the present invention relates to a method for stabilizing an injection, which comprises mixing a stabilizer against light with an injection containing N-3-quinuclidinyl-2H-1,4-benzoxazine-18-carboxamido hydrochloride.
  • the reaction derivative of 8-carboxylic acid (such as acid chloride) with 3-aminoquinuclidine is reacted in a solvent inert to the reaction, preferably in the presence of a deoxidizing agent, and then hydrochlorinated.
  • a solvent inert preferably in the presence of a deoxidizing agent, and then hydrochlorinated.
  • the light stabilizer used in the present invention include sulfurous acid, sulfite, ascorbate, L-cysteine or an acid addition salt thereof, thioglycolic acid or a metal salt thereof, ethylenediamine, salicylic acid or a metal salt thereof. Or one or more selected from phenol or its derivatives.
  • sulfites are preferred, and such include also sulfites and bisulfites, such as sodium sulfite, potassium sulfite, sodium bisulfite, potassium bisulfite, sodium pyrosulfite, and potassium pyrosulfite.
  • sodium pyrosulfite sodium bisulfite including this product can also be used
  • the amount of these stabilizers may vary depending on the type of the stabilizers, but is usually about 0.001 to about 5 parts by weight, preferably about 0.001 parts by weight, per 1 part by weight of the present compound which is an active ingredient. 0 1 to about 2 parts by weight.
  • the stabilized injectable preparation of the present invention may further contain an injectable additive.
  • an osmotic pressure adjusting agent for example, an osmotic pressure adjusting agent, a pH adjusting agent, a preservative, and a soothing agent are used as additives.
  • the osmotic pressure adjusting agent include an electrolyte such as sodium chloride, an amino acid such as glycine, a saccharide such as glucose, and a polyol such as Z or mannitol. It is usually used in an amount of about 5% by weight, based on the total amount of the injection, and in the case of using sodium chloride, about 0.9% by weight in volume.
  • the pH adjuster preferably adjusts the final pH to about 3 to about 5, and acids such as hydrochloric acid, citric acid, acetic acid and lactic acid are used. If necessary, an alkali such as sodium hydroxide may be used.
  • the injection preparation of the present invention is obtained by dissolving the above-mentioned additives such as the present compound, a stabilizer against light, an osmotic pressure adjusting agent and a pH adjusting agent in distilled water for injection, filtering and filling a container for injection. Manufactured by sealing. The filtration is preferably performed in a nitrogen atmosphere, and the filling container is preferably washed with nitrogen in advance. Further, when the solution is filled in the container for injection, it is desired that the air in the container is replaced with nitrogen. After melting, it is preferable to heat and sterilize.
  • the injectable preparation thus obtained is stable to exposure to light, and exhibits an excellent stabilizing effect, in particular, the suppression of color change.
  • the final dosage form is contained in, for example, a light-shielding container, the effect of stabilizing light is further improved.
  • the stabilized injection of the present invention thus obtained exhibits excellent serotonin-3 receptor antagonism, and causes nausea, vomiting, and appetite caused by administration of an antineoplastic agent such as cisbratin to humans and the like. It can be used for amelioration and treatment of depression, and for the treatment of digestive disorders such as chronic gastritis and irritable bowel syndrome.
  • the stabilized injection of the present invention When used for amelioration or treatment of the above-mentioned diseases, it can be safely administered to patients by a route such as intravenous administration, subcutaneous administration, or intramuscular administration.
  • the dosage is usually from about 0.1 to about 5 Omg, preferably from about 1 to about 3 Omg, as an active ingredient (free base) per adult per day.
  • Example 1 1-Chloro-3,4-dihydro-4-methyl-3-oxo-3N-3-quinuclidinyl-2H-1,4 Benzoxazine-18-carboxamido hydrochloride 10 g, sodium pyrosulfite 0.5 g and 18 g of sodium chloride previously sterilized by heating at 250 ° C for 30 minutes or more are dissolved in an appropriate amount of distilled water for injection, and adjusted to a total volume of 2000 ml. The resulting solution was filtered under a nitrogen atmosphere through a membrane filter (pore size 0.45 fim), filled into 2 ml 1 ampules in 2 ml increments, replaced with air and purged with nitrogen, and sealed. Sterilize for 30 minutes at 115 ° C.
  • a membrane filter pore size 0.45 fim
  • Ascorbic acid, sodium salicylate or A 2 ml injection was obtained in the same manner as in Example 1 except that nol was used.
  • the injection used in the experiment was the ampoule for injection of Examples 1 to 4, and the following formulation was used as a comparative injection.
  • Example 1 400 nm 503 nm The injection obtained in Example 1 0.00 0.00
  • the present invention provides a stabilized injection of a compound having a serotonin-3 antagonistic activity and useful as a medicament, and a method of stabilizing an injection. Is done.

Landscapes

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

Abstract

Injection stabilisée contenant un photostabilisant et comprenant comme ingrédient actif du monohydrochlorure de (±)-6-chloro-3,4-dihydro-4-méthyle-3-oxo-N-quinuclidinyle-2H-1,4-benzoxazine-8-carboxamide. On peut inhiber la coloration à l'aide d'au moins un photostabilisant choisi dans le groupe constitué de l'acide sulfurique et de ses sels, de sels d'acide ascorbique, de L-cystéine et de ses sels d'addition d'acide, d'acide thioglycolique et de ses sels métalliques, d'éthylènediamine, d'acide salicylique et de ses sels, ainsi que de phénol et de ses dérivés.
PCT/JP1994/000691 1993-04-28 1994-04-25 Injection stabilisee et procede de stabilisation d'injection WO1994025032A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1019950704441A KR100188318B1 (ko) 1993-04-28 1994-04-25 안정화된 주사제 및 주사제의 안정화법

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP5/124978 1993-04-28
JP12497893 1993-04-28

Publications (1)

Publication Number Publication Date
WO1994025032A1 true WO1994025032A1 (fr) 1994-11-10

Family

ID=14898921

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1994/000691 WO1994025032A1 (fr) 1993-04-28 1994-04-25 Injection stabilisee et procede de stabilisation d'injection

Country Status (3)

Country Link
KR (1) KR100188318B1 (fr)
CN (1) CN1047076C (fr)
WO (1) WO1994025032A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997005860A1 (fr) * 1995-08-04 1997-02-20 Hokuriku Seiyaku Co., Ltd. Solution aqueuse photostable contenant des derives de l'alcool benzylique
JP2008297277A (ja) * 2007-06-01 2008-12-11 Taiyo Yakuhin Kogyo Kk 注射剤の安定化法
WO2010038771A1 (fr) * 2008-09-30 2010-04-08 中外製薬株式会社 Composition pharmaceutique stabilisée à la lumière
CN116158429A (zh) * 2021-11-25 2023-05-26 沈阳中化农药化工研发有限公司 一种含有联苯类化合物稳定的液体制剂

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103432078B (zh) * 2013-08-28 2015-06-17 芦红代 盐酸头孢甲肟的药物组合物
US11185509B2 (en) * 2016-07-29 2021-11-30 Toray Industries, Inc. Solid preparation having improved light stability
CN106943310B (zh) * 2017-01-25 2020-07-17 西安科艺诗生物技术有限公司 一种提高色素蛋白光稳定性的复合物及应用

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4819929B1 (fr) * 1970-05-12 1973-06-18
JPS4911041B1 (fr) * 1969-05-20 1974-03-14
JPS51136818A (en) * 1975-05-20 1976-11-26 Yamanouchi Pharmaceut Co Ltd Method for preparing stable prostaglandine pharma ceuticals
JPS5270014A (en) * 1975-12-05 1977-06-10 Senju Pharma Co Stabilization of pyrido*3*22a*phenoxadine compounds
JPS58203910A (ja) * 1982-05-20 1983-11-28 Nikken Kagaku Kk ドパミン含有点滴静注用剤
JPS60169430A (ja) * 1984-02-14 1985-09-02 Teijin Ltd プロスタグランジン類製剤用組成物
JPS63310815A (ja) * 1987-06-10 1988-12-19 Nippon Kayaku Co Ltd 安定な総合ビタミン凍結乾燥製剤
JPH0228182A (ja) * 1987-10-22 1990-01-30 Yoshitomi Pharmaceut Ind Ltd ベンズオキサジン化合物
JPH02124823A (ja) * 1988-11-02 1990-05-14 Eisai Co Ltd セファロスポリン含有注射用組成物
JPH0356418A (ja) * 1989-06-06 1991-03-12 Pharmachemie Bv 冷蔵庫温度で安定なホリニン酸塩水溶液並びにその製造方法

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4911041B1 (fr) * 1969-05-20 1974-03-14
JPS4819929B1 (fr) * 1970-05-12 1973-06-18
JPS51136818A (en) * 1975-05-20 1976-11-26 Yamanouchi Pharmaceut Co Ltd Method for preparing stable prostaglandine pharma ceuticals
JPS5270014A (en) * 1975-12-05 1977-06-10 Senju Pharma Co Stabilization of pyrido*3*22a*phenoxadine compounds
JPS58203910A (ja) * 1982-05-20 1983-11-28 Nikken Kagaku Kk ドパミン含有点滴静注用剤
JPS60169430A (ja) * 1984-02-14 1985-09-02 Teijin Ltd プロスタグランジン類製剤用組成物
JPS63310815A (ja) * 1987-06-10 1988-12-19 Nippon Kayaku Co Ltd 安定な総合ビタミン凍結乾燥製剤
JPH0228182A (ja) * 1987-10-22 1990-01-30 Yoshitomi Pharmaceut Ind Ltd ベンズオキサジン化合物
JPH02124823A (ja) * 1988-11-02 1990-05-14 Eisai Co Ltd セファロスポリン含有注射用組成物
JPH0356418A (ja) * 1989-06-06 1991-03-12 Pharmachemie Bv 冷蔵庫温度で安定なホリニン酸塩水溶液並びにその製造方法

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997005860A1 (fr) * 1995-08-04 1997-02-20 Hokuriku Seiyaku Co., Ltd. Solution aqueuse photostable contenant des derives de l'alcool benzylique
US5952387A (en) * 1995-08-04 1999-09-14 Hokuriku Seiyaku Co., Ltd. Photostable aqueous solution containing benzyl alcohol derivatives
US6162833A (en) * 1995-08-04 2000-12-19 Hokuriku Seiyaku Co., Ltd. Photostable aqueous solution comprising benzyl alcohol derivatives
JP2008297277A (ja) * 2007-06-01 2008-12-11 Taiyo Yakuhin Kogyo Kk 注射剤の安定化法
WO2010038771A1 (fr) * 2008-09-30 2010-04-08 中外製薬株式会社 Composition pharmaceutique stabilisée à la lumière
US9072791B2 (en) 2008-09-30 2015-07-07 Denki Kagaku Kogyo Kabushiki Kaisha Photostabilized pharmaceutical compositions
CN116158429A (zh) * 2021-11-25 2023-05-26 沈阳中化农药化工研发有限公司 一种含有联苯类化合物稳定的液体制剂

Also Published As

Publication number Publication date
KR960701638A (ko) 1996-03-28
CN1121691A (zh) 1996-05-01
CN1047076C (zh) 1999-12-08
KR100188318B1 (ko) 1999-06-01

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