WO2017038732A1 - Formulation pharmaceutique contenant de l'eau de montélukast - Google Patents

Formulation pharmaceutique contenant de l'eau de montélukast Download PDF

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Publication number
WO2017038732A1
WO2017038732A1 PCT/JP2016/075118 JP2016075118W WO2017038732A1 WO 2017038732 A1 WO2017038732 A1 WO 2017038732A1 JP 2016075118 W JP2016075118 W JP 2016075118W WO 2017038732 A1 WO2017038732 A1 WO 2017038732A1
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WO
WIPO (PCT)
Prior art keywords
montelukast
water
preparation
pharmaceutical preparation
preparation according
Prior art date
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PCT/JP2016/075118
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English (en)
Japanese (ja)
Inventor
慶裕 菱川
由佳理 垣野
中村　淳子
Original Assignee
大蔵製薬株式会社
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Priority to JP2017537873A priority Critical patent/JPWO2017038732A1/ja
Publication of WO2017038732A1 publication Critical patent/WO2017038732A1/fr

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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
    • A61K9/06—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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K47/22—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • the present invention belongs to the technical field of hydrous pharmaceutical preparations such as jelly.
  • the present invention relates to a water-containing pharmaceutical preparation containing montelukast or a pharmaceutically acceptable salt thereof (hereinafter also referred to simply as “montelukast”) as an active ingredient.
  • the present invention relates to a water-containing pharmaceutical preparation that is stable and suitable for use by children and the elderly, including montelukast effective for the treatment of bronchial asthma and the like.
  • Patent Document 1 discloses a stable non-hygroscopic amorphous montelukast.
  • Patent Document 2 discloses a coated solid preparation of montelukast stabilized for a long period of time by coating with a coating agent containing PVA and swellable clay.
  • Patent Document 3 discloses a pharmaceutical composition of montelukast stabilized by various additives. The montelukast formulation described in Patent Document 3 shows high stability for 3 months under conditions of 40 ° C. and 75% humidity.
  • stabilization is achieved by using a montelukast orally disintegrating film having a loss on drying of 1 to 8% by weight. The above all relate to solid preparations that are relatively easy to stabilize montelukast.
  • Patent Document 5 realizes an oily and stable liquid oral pharmaceutical composition of montelukast by including montelukast, mineral oil, desiccant, and additives. This is a method of protecting and stabilizing montelukast by suspending it in mineral oil. However, since it contains mineral oil, it is not desirable in terms of ease of drinking.
  • a water-containing preparation such as a jelly or syrup that can be easily taken is preferred for children or the elderly.
  • montelukast since montelukast has an unstable physical property of easily decomposing into water, it is not easy to realize a preparation such as a jelly agent having a high water content.
  • conventional montelukast fine granules can be taken and mixed with water-containing foods such as baby food (ice cream, rice, carrot, applesauce), and adjusted milk at the time of taking. Yes.
  • baby food ice cream, rice, carrot, applesauce
  • the main object of the present invention is to provide a stable and novel water-containing pharmaceutical preparation containing montelukast which is effective for bronchial asthma and the like, which is suitable for taking by children and the elderly.
  • the “hydrated pharmaceutical preparation” refers to a pharmaceutical preparation in which an active ingredient is dissolved, dispersed or suspended in water, or a pharmaceutical preparation comprising a step of dissolving, dispersing or suspending an active ingredient in water in the production thereof.
  • oily raw materials such as oil, fats and oils, and fats are not included, but may be included within a range not impairing the effects of the present invention.
  • Specific dosage forms include, for example, jelly, syrup, liquid, injection, dry syrup containing water during the production process, orally disintegrating tablet, and the like.
  • the present inventors have found that the above problem can be solved by at least adjusting the pH in the preparation to a certain range, and have completed the present invention.
  • Examples of the present invention include the following.
  • a water-containing pharmaceutical preparation comprising montelukast or a pharmaceutically acceptable salt thereof as an active ingredient and having a pH in the range of 4 to 10.
  • the water-containing pharmaceutical preparation according to [5], wherein the oxygen scavenger is iron or an oxide thereof, titanium or an oxide thereof, or an organic oxygen-absorbing resin.
  • the present invention it is possible to keep montelukast stable for a long period of time, there is no need to adjust the mixing to foods etc. at the time of taking, and the convenience of patients such as being able to be taken easily even by children and elderly people.
  • High montelukast water-containing pharmaceutical preparations can be provided.
  • -X- indicates the result when the storage temperature is 40 ° C
  • - ⁇ -indicates the result when the storage temperature is The results at 60 ° C. are shown respectively. It represents the change over time in the total content of related substances at each storage temperature.
  • the vertical axis represents the total content (%) of related substances in the preparation, and the horizontal axis represents the storage period (days).
  • -X- indicates the result when the storage temperature is 40 ° C
  • - ⁇ -indicates the result when the storage temperature is The results at 60 ° C. are shown respectively. It represents the time course of the total content of related substances by exposure to each sample. The vertical axis represents the total content (%) of related substances in the preparation, and the horizontal axis represents the exposure time (minutes).
  • ⁇ ⁇ ⁇ indicates the result of the preparation of the present invention
  • ⁇ ⁇ ⁇ indicates the result of Singlea
  • ⁇ indicates the result of the wet Singrea.
  • the pharmaceutically acceptable salt of montelukast is not particularly limited as long as it can form a salt with montelukast and is pharmaceutically acceptable.
  • examples thereof include alkali metal salts such as potassium, alkaline earth metal salts such as calcium and magnesium, inorganic salts such as aluminum salts, and organic amines such as dicyclohexylamine, amantadine and cyclopropylamine. Of these, sodium salts are preferred.
  • montelukast Montelukast is in a state of being dissolved, dispersed or suspended in the preparation of the present invention or when water is included in the production process.
  • montelukast is dissolved in the preparation of the present invention.
  • the main medium of the preparation of the present invention is water, and examples of such water include normal water, purified water, and water for injection, and are not particularly limited as long as they are pharmaceutically acceptable. It is preferable to use deoxygenated water.
  • a solubilizer can be added, and it is preferable to add it.
  • the solubilizer include a surfactant and an alcohol solvent.
  • HLB value hydrophilic / lipophilic balance value
  • those having 16 or more are suitable, and those having 16 or more are preferable.
  • sodium lauryl sulfate, glycerin fatty acid ester (caprylic acid) , Myristic acid, lauric acid, etc.), polysorbate 80, and poloxamer sodium lauryl sulfate, glycerin fatty acid ester (myristic acid), poloxamer (polyoxyethylene (105) polyoxypropyl (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol) are preferred, and lauryl sulfate. Sodium is more preferred.
  • alcohol solvent examples include ethanol, propylene glycol, glycerin, and macrogol. Of these, ethanol and propylene glycol are preferred. One or more of these can be used in combination as appropriate.
  • a solubilizer is usually selected in consideration of taste factors.
  • the content of montelukast in the preparation of the present invention is not particularly limited as long as it is an effective dose of montelukast or less, but it is suitably within the range of 0.04 to 100 mg / g, and 0.1 to 10 mg. / G is preferable, and the range of 1 to 2 mg / g is more preferable. If it is less than 0.04 mg / g, the dosage of the preparation of the present invention may be increased, and if it is more than 100 mg / g, there may be a problem in the solubility, dispersibility or suspension of montelukast.
  • the total weight of the preparation of the present invention varies depending on the form of the preparation of the present invention, but in the case of a jelly agent, for example, a range of about 0.1 to 100 g is appropriate, and a range of about 0.5 to 30 g. The inside is preferable.
  • the preparation of the present invention is adjusted within the range of pH 4-10. As a result, the stability of montelukast can be improved, and the formation of montelukast crystals and decomposition products (mainly sulfoxides, which are related substances of montelukast) can be suppressed.
  • the pH is preferably in the range of 7.8 to 9.5, more preferably in the range of pH 9.0 to 9.5.
  • a pH adjuster can be used and is not particularly limited as long as it is pharmaceutically acceptable.
  • examples of the pH adjuster include phosphoric acid or a salt thereof, citric acid or a salt thereof, carbonic acid or a salt thereof, maleic acid, glycine, hydrochloric acid, sodium hydroxide and the like. Of these, carbonic acid or a salt thereof is preferred. One or more of these can be used in combination as appropriate.
  • buffer solutions such as a phosphate buffer, a citrate buffer, a citrate phosphate buffer, and a carbonate buffer, can also be used.
  • the dissolved oxygen concentration in the preparation is suitably 5 mg / L or less.
  • the stability of montelukast in the preparation of the present invention can be improved, and the production of decomposition products (mainly sulfoxides that are analogs of montelukast) can be suppressed.
  • the smaller the dissolved oxygen concentration in the preparation, the better. Therefore, the dissolved oxygen concentration in the preparation is preferably 4 mg / L or less, more preferably 2 mg / L or less.
  • an oxygen scavenger can be used.
  • the oxygen scavenger those generally used can be used, and specific examples include iron or an oxide thereof, titanium or an oxide thereof, and an organic oxygen-absorbing resin. Among these, iron or its oxide, titanium or its oxide is preferable. One or more of these can be used in combination as appropriate.
  • an oxygen scavenger is affixed inside the packaging material (for example, AGELESS (registered trademark), manufactured by Mitsubishi Gas Chemical Company), or an oxygen scavenger is kneaded into the packaging material (for example, Oxyguard (registered trademark)). ), Manufactured by Toyo Seikan Co., Ltd.), the oxygen in the preparation may be actively reduced by forcibly removing oxygen.
  • an antioxidant can be added to the preparation of the present invention in order to keep the oxygen concentration in the preparation low.
  • Antioxidants include, for example, ascorbic acid or its salt, nitrite, sulfite, erythorbic acid or its salt, dibutylhydroxytoluene, thioglycolic acid or its salt, hydroquinone, edetic acid or its salt, methionine, tocopherol, butyl Mention may be made of hydroxyanisole. Among these, sodium ascorbate is preferable. One or more of these can be used in combination as appropriate.
  • a gelling agent is usually used in order to obtain a jelly-like form (jelly agent).
  • a gelling agent is not particularly limited as long as it can be pharmaceutically acceptable and can gel a liquid (water) into a viscous semi-solid, for example, high molecular polysaccharides, gelatin, Mention may be made of sodium polyacrylate.
  • polymeric polysaccharides are preferred.
  • Specific examples of the polymer polysaccharide include pectin, agar, carrageenan, gellan gum, xanthan gum, locust bean gum, guar gum, tara gum, alginic acid or a salt thereof, and mannanoic acid. One or more of these can be used in combination as appropriate.
  • the content of the gelling agent (eg, polymeric polysaccharide) in the preparation of the present invention varies depending on the gelling agent used, the pH of the preparation of the present invention, etc., but is usually in the range of 0.01 to 10%. It is preferably in the range of 0.03% to 5%, and more preferably in the range of 0.05% to 3%. If it is less than 0.01%, gelation may be insufficient, and if it is more than 10%, it may become too hard to cause trouble in swallowing.
  • Additives other than those described above can be added as long as the effects of the present invention are not impaired.
  • additives include sweeteners, flavoring agents, fragrances, thickeners, preservatives, and excipients. These can be added at a concentration of 80% or less in the preparation of the present invention.
  • the shape of the packaging material (container) for enclosing the preparation of the present invention is not particularly limited, and for example, an ampoule shape, a vial shape, a cup shape, an envelope shape, a stick shape, a blister pack, and the like are appropriately selected. Moreover, what can interrupt
  • montelukast since montelukast is unstable to light, it is appropriate to enclose it in a light-shielding packaging material (container) such as a light-shielding bottle or aluminum.
  • the material is preferably a material that does not transmit oxygen and light, such as glass having a light shielding property, plastic having a light shielding property and oxygen shielding ability, aluminum, or aluminum laminate.
  • the preparation of the present invention is particularly a jelly agent, for example, it is preferable to enclose it with an aluminum wrapping material laminated with a film having an oxygen scavenger.
  • the preparation of the present invention is a conventional method for producing jelly preparations, syrup preparations, liquid preparations, injections, dry syrup preparations containing water during the manufacturing process, orally disintegrating tablets, etc. Can be manufactured according to.
  • the filling process after the end of the sterilization process may be a manufacturing process in which measures for preventing decomposition of montelukast due to heat load are taken as much as possible, such as keeping the temperature of the preparation liquid to a temperature close to the gelation temperature. More preferred.
  • the pharmaceutical preparation of the present invention can be used in a pharmaceutically appropriate amount for the indication disease observed in montelukast.
  • indications include bronchial asthma and allergic rhinitis.
  • the dosage of the preparation of the present invention varies depending on the type of disease to be applied, the age of the patient, the patient's condition, etc., but the amount of montelukast is, for example, within the range of 1-50 mg / day, and 3-20 mg / day. Is preferably within the range of 4 to 10 mg / day. It is preferable to divide this dose once or several times a day (preferably once a day) and administer it orally before going to bed.
  • the age of the indication patient is not particularly limited, but the preparation of the present invention is particularly excellent for taking children and the elderly who are generally poor in swallowing a solid preparation.
  • HPLC high performance liquid chromatography
  • Example 1 The preparation of the present invention (jelly agent) having the formulation shown in Table 6 below was prepared by a conventional method. This jelly agent was clear.
  • Example 4 Influence of oxygen
  • the preparation of the present invention (jelly agent) of Example 1 was kneaded with an aluminum packaging material containing oxygen scavenger (titanium oxide was incorporated into the oxygen absorbing layer).
  • Stuff Montelukast 4mg / 1 formulation 2g
  • test items related substances and pH were measured.
  • the generation of individual related substances was suppressed to 1% or less, the generation of total related substances was suppressed to 3% or less, and the change in pH was also suppressed and stable.
  • the dissolved oxygen concentration in the preparation was 5 mg / L or less.
  • the preparation of the present invention is excellent in stability and easy to take, it is particularly useful for patients such as children and the elderly who are generally poor in swallowing solid preparations.

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

Abstract

Le principal problème de l'invention est d'obtenir une formulation pharmaceutique contenant de l'eau de montélukast qui peut être facilement absorbée même par des patients jeunes ou âgés. Une formulation pharmaceutique contenant de l'eau (par exemple, une gelée), contenant, en tant qu'ingrédient actif, du montélukast ou un de ses sels pharmaceutiquement acceptables, dans laquelle le pH est compris entre 4 et 10 peut être donnée en exemple de l'invention. La concentration en oxygène dissous dans la formulation selon l'invention est de préférence inférieure ou égale à 5 mg/L. La formulation pharmaceutique contenant de l'eau selon l'invention est spécialement utile pour les patients jeunes ou âgés qui sont généralement moins capables d'avaler les formulations solides.
PCT/JP2016/075118 2015-08-31 2016-08-29 Formulation pharmaceutique contenant de l'eau de montélukast WO2017038732A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2017537873A JPWO2017038732A1 (ja) 2015-08-31 2016-08-29 モンテルカストの含水医薬製剤

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JP2015170216 2015-08-31
JP2015-170216 2015-08-31

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WO2017038732A1 true WO2017038732A1 (fr) 2017-03-09

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002104997A (ja) * 2000-09-26 2002-04-10 Kyorin Pharmaceut Co Ltd 食品又は医薬品易服用化剤
CN1883481A (zh) * 2005-06-22 2006-12-27 晟德大药厂股份有限公司 白三烯素拮抗剂口服液组成
EP2716279A1 (fr) * 2012-10-04 2014-04-09 Lamda UK Ltd. Solutions orales contenant des antagonistes des leucotriènes
WO2014080784A1 (fr) * 2012-11-20 2014-05-30 大蔵製薬株式会社 Préparation pharmaceutique aqueuse d'olanzapine présentant une stabilité à long terme
CN104840427A (zh) * 2014-02-13 2015-08-19 长春海悦药业有限公司 一种含有孟鲁司特钠的药物组合物
US20150306031A1 (en) * 2014-04-25 2015-10-29 R.P. Scherer Technologies, Llc Stable montelukast solution

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002104997A (ja) * 2000-09-26 2002-04-10 Kyorin Pharmaceut Co Ltd 食品又は医薬品易服用化剤
CN1883481A (zh) * 2005-06-22 2006-12-27 晟德大药厂股份有限公司 白三烯素拮抗剂口服液组成
EP2716279A1 (fr) * 2012-10-04 2014-04-09 Lamda UK Ltd. Solutions orales contenant des antagonistes des leucotriènes
WO2014080784A1 (fr) * 2012-11-20 2014-05-30 大蔵製薬株式会社 Préparation pharmaceutique aqueuse d'olanzapine présentant une stabilité à long terme
CN104840427A (zh) * 2014-02-13 2015-08-19 长春海悦药业有限公司 一种含有孟鲁司特钠的药物组合物
US20150306031A1 (en) * 2014-04-25 2015-10-29 R.P. Scherer Technologies, Llc Stable montelukast solution

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NERELLA, A. ET AL.: "Formulation and evaluation of in-situ mucoadhesive nasal gel of montelukast sodium", DER PHARMACIA SINICA, vol. 5, no. 2, 2014, pages 1 - 8, XP055366386, ISSN: 0976-8688 *
SHAKALISAVA, Y. ET AL.: "Determination of montelukast sodium by capillary electrophoresis", J. SEP. SCI., vol. 31, no. 6-7, April 2008 (2008-04-01), pages 1137 - 1143, XP055366388, ISSN: 1615-9314 *

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