WO2002076442A1 - Preparation liquide aqueuse stable - Google Patents

Preparation liquide aqueuse stable Download PDF

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Publication number
WO2002076442A1
WO2002076442A1 PCT/JP2002/002877 JP0202877W WO02076442A1 WO 2002076442 A1 WO2002076442 A1 WO 2002076442A1 JP 0202877 W JP0202877 W JP 0202877W WO 02076442 A1 WO02076442 A1 WO 02076442A1
Authority
WO
WIPO (PCT)
Prior art keywords
vitamin
castor oil
aqueous liquid
polyoxyethylene
liquid preparation
Prior art date
Application number
PCT/JP2002/002877
Other languages
English (en)
Japanese (ja)
Inventor
Yutaka Morishita
Norihisa Hatano
Kenji Morishima
Original Assignee
Santen Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Santen Pharmaceutical Co., Ltd. filed Critical Santen Pharmaceutical Co., Ltd.
Publication of WO2002076442A1 publication Critical patent/WO2002076442A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals

Definitions

  • the present invention relates to a stable aqueous solution characterized by blending a bimin A and a polyoxyethylene castor oil, and particularly to an aqueous solution which can be suitably used for ophthalmic pharmaceutical preparations such as eye drops.
  • Vitamin A is a component that is essential for maintaining vital functions.
  • deficiency of bimin A in the eyes causes various eye diseases such as night blindness and keratoconjunctivitis. Therefore, attempts have been made to supplement vitamin A with eye drops.
  • vitamin A has extremely low solubility in water, and even if it can be dissolved in water, it tends to become cloudy and precipitate over time. Vitamin A is an unstable substance, and if it is used as an aqueous preparation, it will be degraded in a short period of time, and it will be extremely difficult to stably store an aqueous preparation containing biminmin A over a long period.
  • JP-A-3-38519 contains a nonionic surfactant such as polyoxyethylene hydrogenated castor oil and liquid paraffin. It has been proposed to stabilize the ophthalmic solution containing vitamin A by the following method.
  • Japanese Patent Application Laid-Open No. 6-24783 discloses the use of polyoxyethylene hydrogenated castor oil, vitamin E and ethylenediaminetetraacetic acid. Thus, it has been proposed to solubilize vitamin A and stabilize eye drops over time.
  • the present inventors have conducted intensive studies to solubilize vitamins A to obtain an aqueous preparation which is stable for a long period of time, and found that by blending polyoxyethylene castor oil, a known polyoxyethylene cured product was obtained. It has been found that a stabilizing effect superior to the case where castor oil is blended is exhibited. In addition, they found that the stability of the aqueous solution was enhanced by adding vitamin Es and ethylenediaminetetraacetic acid to the aqueous solution. That is, the aqueous liquid preparation of the present invention contains at least vitamins A and polyoxyethylene castor oil as its compounding components.
  • the vitamin A includes, in addition to vitamin A itself, a mixture containing vitamin A such as vitamin A oil, a derivative having vitamin A activity such as retenal, retinoic acid, and a fatty acid ester of vitamin A. It is. Specifically, there are 1.7 million international units (I.U.) / G of retinol palmitate manufactured by Roche Co., Ltd. of Japan.
  • the amount of the vitamin A in the aqueous solution is not particularly limited, but is 0.001 to 2.0% by weight, and more preferably 0.003 to 1.0% by weight.
  • the amount of vitamin A may be appropriately selected in consideration of the use of the aqueous liquid formulation and the like.For example, when used as eye drops, the amount of vitamin A is 0.05 to 0.5. It is desirable to make it 5% by weight.
  • Polyoxyethylene castor oil is obtained by addition polymerization of castor oil with ethylene oxide.
  • ethylene oxide ethylene oxide
  • Specific examples include Cremophor manufactured by B-85, Nikkor CO—20T manufactured by Nikko Chemicals Co., Ltd. X, CO-6 OTX, etc.
  • polyoxyethylene hydrogenated castor oil is obtained by addition polymerization of hydrogenated castor oil with hydrogen added to the double bond of castor oil and acetic acid, and the difference in average number of moles of ethylene oxide (P)
  • its chemical properties are completely different from polyoxetylene castor oil.
  • the amount of the polyoxyethylene castor oil in the aqueous liquid formulation is not particularly limited, but is 0.001 to 5.0% by weight, and more preferably 0.01 to 3.0% by weight. Since polyoxyethylene castor oil is blended to solubilize and stabilize vitamins A, it is desirable that the blending amount be as small as possible as long as the transparency and stability of the aqueous solution containing vitamins A is maintained.
  • the aqueous liquid preparation of the present invention may contain vitamin Es, ethylenediaminetetraacetic acid or a salt thereof. By mixing vitamin Es, the aqueous solution is more stabilized, and when ethylenediaminetetraacetic acid or a salt thereof is added, the aqueous solution is further stabilized.
  • vitamins E are used not only for the purpose of stabilizing the aqueous preparation but also as an effective drug by itself. That is, it is said that vitamins E have an antioxidant effect and are closely related to disorders of blood circulation, improvement of blood flow retention in capillaries, and suppression of oxidation of the lens of the eye.
  • vitamins E include tocopherol, tocopherol acetate, and tocopherol succinate.
  • the amount of vitamin E is 0.001 to 1.0% by weight, more preferably 0.01 to 0.5% by weight. If the amount of vitamin E is less than 0.001% by weight, the stabilizing effect of vitamin E is reduced.
  • tetrasodium salt and disodium salt can be preferably used.
  • Ethylenediaminetetraacetic acid or its salt Is from 0.0001 to 0.5% by weight, more preferably from 0.005 to 0.3% by weight. If the amount of ethylenediaminetetraacetic acid or a salt thereof is less than 0.001% by weight, the stabilizing effect of ethylenediaminetetraacetic acid or a salt thereof is reduced.
  • the aqueous liquid preparation of the present invention has high safety for the human body and is particularly preferably used as eye drops. Further, since the aqueous liquid preparation of the present invention has little adsorption to contact lenses and plastic containers, it can be used as eye drops for contact lens wearers. It can also be used as an aqueous solution for food.
  • tonicity agents such as 1-menthol
  • buffers such as sodium, potassium salt sodium, sorbitol, mannitol and the like.
  • preservatives such as 1-menthol
  • thickeners drugs other than vitamins A and E
  • tonicity agent to which a fragrance such as 1-menthol can be appropriately added include glycerin, propylene glycol, polyethylene glycol, sodium salt sodium, potassium salt sodium, sorbitol, mannitol and the like.
  • citric acid for example, citric acid, boric acid, sodium hydrogen phosphate, glacial acetic acid, tromethol, epsilon-amino diprotic acid and the like can be mentioned.
  • the pH regulator include citric acid, phosphoric acid, acetic acid, 7K sodium oxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.
  • preservatives include sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, paraoxybenzoate, sodium benzoate, dibutylhydroxytoluene, chlorobutanol, and chlorhexidine dalconate. it can.
  • thickener examples include cellulosic polymers such as hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, and hydroxyethylcellulose, and polyvinyl alcohol and polyvinylpyrrolidone. Can be.
  • Min A acids and E group such as various vitamins (vitamin B 2, vitamin B 6, vitamin 8 1 2, Panthenol, etc.), decongestant, tetrahydrozoline, naphazoline, etc.), anti-inflammatory agents (dipotassium dalycyrrhizinate, epsilon-amino cabronate, allantoin, etc.), antihistamines (chlorpheniramine maleate, diphenhydramine hydrochloride, etc.), anti-allergy Drugs (such as sodium cromoglycate), antibacterial agents (such as sulfamethoxazole), amino acids (such as potassium L-aspartate, aminoethylsulfonic acid, and sodium chondroitin sulfate), drugs such as sodium hyaluronate and neostigmine methyl sulfate Can be added.
  • vitamins vitamin B 2, vitamin B 6, vitamin 8 1 2, Panthenol, etc.
  • decongestant tetrahydrozo
  • a nonionic surfactant such as polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 400, etc. is further added to the aqueous liquid preparation of the present invention. can do.
  • the pH of the aqueous »J of the present invention is preferably in the range of 4 to 8, more preferably 5 to 8. If the pH of the aqueous solution is outside the above range, the stability of vitamin A over time will decrease.
  • the pH is preferably set to 6.5 to 7.5, and the osmotic pressure ratio is preferably set to around 1.0.
  • the storage container for the aqueous »j of the present invention is not particularly limited, and examples thereof include containers made of materials such as polypropylene, polyethylene terephthalate, and glass.
  • the aqueous liquid preparation of Comparative Example 1 containing oil (hereinafter referred to as “HCO-60”) was prepared by a conventional method.
  • boric acid was added to each solution as a buffer, and pH was adjusted to 7.0 by adding sodium hydroxide as needed.
  • Each aqueous solution was kept at 60, and the residual ratio of retinopalmitate (vitamin A) after one week was measured using a high performance liquid chromatograph. Table 1 shows the results.
  • Test Examples 1 to 5 in which polyoxyethylene castor oil was blended used polyoxyethylene hydrogenated castor oil. Compared with Comparative Example 1, the residual ratio of vitamin A is improved.
  • Aqueous liquid preparations having the components shown in Test Examples 6 to 8 and Comparative Example 2 in Table 2 were prepared by a conventional method. Further, boric acid was added as a buffer to each solution, and the pH was adjusted to 7.0 by adding sodium hydroxide as needed. Each aqueous solution was kept at 60 ° C, and after 2 weeks, the residual ratio of retinol palmitate was measured using a high-performance liquid chromatograph. Table 2 shows the results.
  • Aqueous liquid preparations having the components shown in Test Examples 9 to 13 and Comparative Example 3 in Table 3 were prepared by a conventional method. Further, boric acid was added as a buffer to each solution, and pH was adjusted to 7.0 by adding sodium hydroxide as needed. Keep each aqueous solution at 60 ° C, After one week, the residual ratio of retinol palmitate was measured using a high performance liquid chromatograph. Table 3 shows the results.
  • Formulation examples when the aqueous preparation of the present invention is used as eye drops are shown below.
  • U. Polyoxyethylene (p 35) Castor oil 0.2 g Acetic acid d-a-tocopherol 0.05% Sodium edetate 0.055 g Pyridoxine hydrochloride 0.1 g aminoethyl sulfonic acid 1.0 g sodium chloride 0.43 g boric acid 0.5 g sodium chloride benzalkonium (10% aqueous solution) 0.05 g dibutylhydroxytoluene 0.005 g dilute hydrochloric acid
  • Retinol luminate 32,500 1.
  • O g Pyridoxine hydrochloride 0. 1 g Aminoethyl sulfonic acid 1.0 g Sodium hyaluronate 0.05 g g Sodium chloride 0.3 g Boric acid 0.5 g Benzalkonidium chloride (10% aqueous solution) 0.05 g
  • the aqueous solution containing vitamin A and polyoxyethylene castor oil of the present invention has a transparent appearance and can be stably stored for a long period of time, so that night blindness and keratoconjunctiva caused by vitamin A deficiency are caused. It is useful as a prophylactic or therapeutic agent for symptoms such as sickness.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Nutrition Science (AREA)
  • Ophthalmology & Optometry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une préparation aqueuse qui contient de la vitamine A solubilisée, ayant un aspect transparent, et étant stable pour une longue durée. La préparation liquide aqueuse, qui possède une stabilité de longue durée, peut être obtenue par incorporation d'une vitamine A et de l'huile de ricin au polyoxyéthylène. La stabilité de la préparation liquide à base d'eau est davantage améliorée par l'incorporation d'une vitamine E et de l'éthylènediamine tétraacétate (ou un de ses sels) en plus de à la vitamine A et de l'huile de ricin au polyoxyéthylène.
PCT/JP2002/002877 2001-03-27 2002-03-26 Preparation liquide aqueuse stable WO2002076442A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2001-89908 2001-03-27
JP2001089908 2001-03-27

Publications (1)

Publication Number Publication Date
WO2002076442A1 true WO2002076442A1 (fr) 2002-10-03

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PCT/JP2002/002877 WO2002076442A1 (fr) 2001-03-27 2002-03-26 Preparation liquide aqueuse stable

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4075333A (en) * 1975-02-14 1978-02-21 Hoffmann-La Roche, Inc. Stable injectable vitamin compositions
JPS60149531A (ja) * 1984-01-18 1985-08-07 Lion Corp 持続性局所用剤組成物
JPS62138146A (ja) * 1985-12-10 1987-06-20 Tiger Yakuhin Kogyo Kk 家畜用固形ビタミンの製法
JPH0338519A (ja) * 1989-07-04 1991-02-19 Taisho Pharmaceut Co Ltd ビタミンａ類含有点眼剤
JPH06247853A (ja) * 1993-02-23 1994-09-06 Lion Corp 安定なビタミンａ類及びビタミンｅ類可溶化点眼剤

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4075333A (en) * 1975-02-14 1978-02-21 Hoffmann-La Roche, Inc. Stable injectable vitamin compositions
JPS60149531A (ja) * 1984-01-18 1985-08-07 Lion Corp 持続性局所用剤組成物
JPS62138146A (ja) * 1985-12-10 1987-06-20 Tiger Yakuhin Kogyo Kk 家畜用固形ビタミンの製法
JPH0338519A (ja) * 1989-07-04 1991-02-19 Taisho Pharmaceut Co Ltd ビタミンａ類含有点眼剤
JPH06247853A (ja) * 1993-02-23 1994-09-06 Lion Corp 安定なビタミンａ類及びビタミンｅ類可溶化点眼剤

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