CN114099428A - Temperature-insensitive idebenone oral liquid and preparation method thereof - Google Patents

Temperature-insensitive idebenone oral liquid and preparation method thereof Download PDF

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Publication number
CN114099428A
CN114099428A CN202111410287.1A CN202111410287A CN114099428A CN 114099428 A CN114099428 A CN 114099428A CN 202111410287 A CN202111410287 A CN 202111410287A CN 114099428 A CN114099428 A CN 114099428A
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idebenone
oral liquid
essence
mixture
purified water
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CN114099428B (en
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王丽丽
王志国
崔婧
林锐彬
崔雪惠
曾令康
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Shenzhen Neptunus Pharmaceutical Research Institute Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention discloses an idebenone oral liquid insensitive to temperature and a preparation method thereof. And the preparation method comprises the following steps: firstly, mixing a flavoring agent and a proper amount of purified water according to a certain proportion and then uniformly stirring; adding a pH regulator; ③ adding idebenone, solubilizer, preservative and ethanol, stirring until the mixture is dissolved by visual observation, adding purified water to fix the volume, filtering and filling to obtain the final product. Compared with the traditional tablet, the idebenone oral liquid prepared by the invention is insensitive to temperature, stable in quality, accurate in metering, convenient to take and good in taste.

Description

Temperature-insensitive idebenone oral liquid and preparation method thereof
Technical Field
The invention relates to an idebenone preparation, in particular to an idebenone oral liquid insensitive to temperature and a preparation method thereof.
Background
Idebenone is an intelligent promoting drug developed and marketed in 1986 by Nippon Wutian chemical industry Co. Has effects in activating mitochondrial function, improving brain function metabolism and brain dysfunction, increasing utilization rate of glucose in brain, and promoting ATP generation; can improve metabolism of neurotransmitter 5-hydroxytryptamine in brain, and has strong effects of resisting oxidation and scavenging free radicals. Is clinically used for treating Parkinson's disease, Alzheimer's disease, multi-infarct dementia, cerebral ischemia and cerebral failure, juvenile and adult vision damage caused by Leber Hereditary Optic Neuropathy (LHON), and the like.
Idebenone is orange yellow or orange crystalline powder, and the melting point is 52-55 ℃. At present, the dosage form sold in China only comprises tablets, and the product of the dosage form is extremely sensitive to temperature in the processes of production, transportation and storage, and is easy to generate the phenomenon of similar oil production caused by the melting and even the melting of raw material medicines separated from the surface of the tablets due to temperature. This phenomenon is common to idebenone solid preparations. As global warming continues to rise in temperature, this phenomenon frequently occurs. After the tablets produce oil, the appearance, content, dissolution and stability of the preparation can be seriously influenced, so that the curative effect is influenced, and even potential safety hazards exist. After the tablet sold in the market is taken, the tablet can be absorbed only by the processes of disintegration, dispersion and dissolution in the gastrointestinal tract, and the absorption is slow, so that the drug effect can not be quickly exerted.
In addition, most of patients with brain function metabolism and brain function disorder who are clinically administered with idebenone have swallowing problems, and some patients are old people or children, and oral tablet patients have poor drug administration compliance, cannot be treated according to the doctor's regulations, even refuse to take the drug, slightly reduce the treatment effect, and seriously aggravate the illness state and even endanger the life.
Disclosure of Invention
Aiming at the problems of the existing preparation, the invention aims to provide an idebenone oral solution insensitive to temperature and a preparation method thereof, which solve the problems of extremely sensitive temperature and easy occurrence of raw material medicine melting caused by temperature, and have the characteristics of stable quality, accurate measurement, convenient taking and good taste.
The invention is realized by the following technical scheme:
an idebenone oral liquid insensitive to temperature comprises idebenone, solubilizer, pH regulator, antiseptic, correctant and purified water. The components in parts by weight are 3-30 parts of idebenone, 1-30 parts of solubilizer, a proper amount of pH regulator, 1-5 parts of preservative, a proper amount of flavoring agent, 500 parts of ethanol and purified water which is supplemented to a constant volume of 1000 parts.
The ethanol contains C2H6O is between 1-100% (ml/ml), preferably 75-100% (ml/ml). The oral solution has a pH of 3.5-4.5.
The solubilizer is selected from polyoxyethylene hydrogenated castor oil RH40, poloxamer 188, polysorbate 80, polyoxyethylene castor oil, or their mixture;
the pH regulator is selected from sodium dihydrogen phosphate, phosphoric acid, citric acid, sodium citrate, hydrochloric acid, sodium hydroxide, or their mixture;
the preservative is selected from benzoic acid and its salt, sorbic acid and its salt, hydroxyphenylacetates or hydroxybenzoate, or their mixture;
the correctant is selected from steviosin, sucralose, aspartame, liquid sorbitol, xylitol, maltitol solution, sucrose, Mel, Hami melon essence, fructus Citri Tangerinae essence, strawberry essence, fructus Citri Limoniae essence, fructus Musae essence, and Rubi fructus essence, or their mixture;
the preparation method of the temperature-insensitive stable idebenone oral liquid comprises the following steps:
firstly, mixing a flavoring agent and a proper amount of purified water according to a certain proportion and then uniformly stirring;
adding a pH regulator;
③ adding idebenone, solubilizer, preservative and ethanol, stirring until the mixture is dissolved by visual observation, adding purified water to fix the volume, filtering and filling to obtain the final product.
Compared with the prior art, the invention has the beneficial effects that:
(1) the production process of the invention has no heating process, and the temperature control is not needed in the production process, thereby avoiding the influence of the temperature in the granulating, drying and coating processes in the production of tablets on the product quality, reducing the source of quality risk in the production process from the source, having simple preparation process, saving the production cost and being suitable for industrial mass production;
(2) the idebenone oral liquid is an oral liquid, and idebenone is dissolved in the liquid in a molecular form, so that the quality problem caused by oil production caused by temperature reasons in the transportation and storage processes of oral tablets is avoided, and the quality of products is further ensured;
(3) the product is an oral solution, overcomes the problem of difficult administration for patients with swallowing problem, and has the advantages of no disintegration and dispersion process, rapid absorption, and rapid therapeutic effect.
Detailed Description
The present invention will be described in further detail with reference to the following examples, but the specific embodiments of the present invention are not limited thereto.
Example 1 preparation of idebenone oral liquid
(1) Components
Idebenone 3g
Polysorbate 80 5g
Potassium sorbate 1g
Hydrochloric acid 0.02g
Xylitol, its preparation method and use 100g
Stevia rebaudianum extract 2g
Raspberry essence 4ml
75% ethanol 320ml
Purified water Adding water to 1000ml
(2) Preparation method
Mixing xylitol, steviosin, raspberry essence and a proper amount of purified water according to a certain proportion, and uniformly stirring; adding hydrochloric acid to regulate pH; ③ adding idebenone, polysorbate 80, potassium sorbate and 75 percent ethanol, stirring until the mixture is dissolved by visual observation, adding purified water to a constant volume, filtering and filling to obtain the final product.
Example 2 preparation of idebenone oral liquid
(1) Components
Idebenone 15g
Poloxamer 188 17g
Hydroxypropyl methyl ester 2.7g
Hydroxypropyl ethyl ester 0.3g
Citric acid 0.12g
Citric acid sodium salt 1.3g
Aspartame 5g
Lemon essence 3ml
Anhydrous ethanol 410ml
Purified water Adding water to 1000ml
(2) Preparation method
Mixing aspartame, lemon essence and a proper amount of purified water according to a certain proportion and then uniformly stirring; adding citric acid and sodium citrate to regulate pH value; ③ adding idebenone, poloxamer 188, hydroxypropyl methyl ester, hydroxypropyl ethyl ester and absolute ethyl alcohol, stirring until the mixture is dissolved by visual observation, adding purified water to fix the volume, filtering and filling to obtain the final product.
Example 3 preparation of idebenone oral liquid
(1) Components
Figure BDA0003373486100000041
Figure BDA0003373486100000051
(2) Preparation method
Mixing maltitol solution, aspartame, Hami melon essence and a proper amount of purified water according to a certain proportion and then uniformly stirring; adding sodium dihydrogen phosphate and phosphoric acid to regulate pH value; ③ adding idebenone, polyoxyethylene castor oil, sorbic acid and absolute ethyl alcohol, stirring until the mixture is dissolved by visual observation, adding purified water to fix the volume, filtering and filling to obtain the final product.
Example 4 preparation of idebenone oral liquid
(1) Components
Idebenone 30g
Polyoxyethylene hydrogenated castor oil RH40 30g
Sodium benzoate 1g
Sodium dihydrogen phosphate 15g
Phosphoric acid 0.6g
Liquid sorbitol 300g
Sucralose 10g
Orange essence 5ml
95% ethanol 500ml
Purified water Adding water to 1000ml
(2) Preparation method
Mixing liquid sorbitol, sucralose, orange essence and a proper amount of purified water according to a certain proportion, and then uniformly stirring; adding sodium dihydrogen phosphate and phosphoric acid solution to regulate pH value; ③ adding idebenone, polyoxyethylene hydrogenated castor oil RH40, sodium benzoate and 95 percent ethanol, stirring until the mixture is dissolved by visual observation, adding purified water to fix the volume, filtering and filling to obtain the final product.
Example 5 experiment of high temperature Effect factors of idebenone oral liquid
The samples (idebenone oral solution) and control samples (idebenone film-coated tablets and idebenone sugar-coated tablets) prepared in example 4 were left at high temperature (60 ℃. + -. 2 ℃) for 10 days, and properties and related substances of the samples were examined as indices. The specific results are shown in the following table:
Figure BDA0003373486100000061
Figure BDA0003373486100000071
the results show that:
the sample (idebenone oral solution) prepared in example 4 and the control sample (idebenone film-coated tablet, idebenone sugar-coated tablet) were left at high temperature (60 ℃. + -. 2 ℃) for 10 days, and the properties and related substances of the idebenone oral solution were not significantly changed. The control samples (idebenone film-coated tablets and idebenone sugar-coated tablets) have obvious changes in properties, the phenomenon of oil production caused by the fusion and exudation of the raw material medicines on the surface occurs, and related substances are obviously increased along with the oil production.
Therefore, the present invention can obtain a stable idebenone product which is not sensitive to temperature. The sensitivity to temperature is greatly reduced, the stability is obviously improved, the practical problem can be solved, and the method is suitable for popularization.
The above examples are only for illustrating the technical solutions of the present invention, and are not limited thereto. Those of ordinary skill in the art will understand that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.

Claims (7)

1. The temperature-insensitive idebenone oral liquid is characterized by comprising idebenone, a solubilizer, a pH regulator, a preservative, a flavoring agent, ethanol and purified water, wherein the ethanol contains C2H6O is between 1-100% (ml/ml) and the pH of the oral solution is 3.5-4.5.
2. The idebenone oral liquid according to claim 1, characterized by comprising, in parts by weight:
Figure FDA0003373486090000011
the ethanol contains C2H6O is between 75-100% (ml/ml).
3. The idebenone oral liquid according to claim 1 or 2, characterized in that: the solubilizer is selected from one or a mixture of polyoxyethylene hydrogenated castor oil RH40, poloxamer 188, polysorbate 80 and polyoxyethylene castor oil.
4. The idebenone oral liquid according to claim 1 or 2, characterized in that: the pH regulator is selected from one or a mixture of sodium dihydrogen phosphate, phosphoric acid, citric acid, sodium citrate, hydrochloric acid and sodium hydroxide.
5. The idebenone oral liquid according to claim 1 or 2, characterized in that: the preservative is selected from one or a mixture of benzoic acid and salts thereof, sorbic acid and salts thereof, hydroxyphenylacetates and hydroxybenzoate.
6. The idebenone oral liquid according to claim 1 or 2, characterized in that: the flavoring agent is selected from one or mixture of steviosin, sucralose, aspartame, liquid sorbitol, xylitol, maltitol solution, sucrose, honey, Hami melon essence, orange essence, strawberry essence, lemon essence, banana essence, and raspberry essence.
7. The method for preparing idebenone oral liquid according to claim 1, comprising the steps of:
firstly, mixing a flavoring agent and a proper amount of purified water according to a certain proportion and then uniformly stirring;
adding a pH regulator;
③ adding idebenone, solubilizer, preservative and ethanol, stirring until the mixture is dissolved by visual observation, adding purified water to fix the volume, filtering and filling to obtain the final product.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1053520A (en) * 1996-06-03 1998-02-24 Takeda Chem Ind Ltd Antifatigue agent
CN113143855A (en) * 2021-04-29 2021-07-23 北京阳光诺和药物研究股份有限公司 Bromhexine hydrochloride oral liquid and preparation method thereof
WO2021186061A1 (en) * 2020-03-19 2021-09-23 Bemido Sa Idebenone for the treatment of acute respiratory distress syndrome (ards) in patients diagnosed with a coronavirus infection

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1053520A (en) * 1996-06-03 1998-02-24 Takeda Chem Ind Ltd Antifatigue agent
WO2021186061A1 (en) * 2020-03-19 2021-09-23 Bemido Sa Idebenone for the treatment of acute respiratory distress syndrome (ards) in patients diagnosed with a coronavirus infection
CN113143855A (en) * 2021-04-29 2021-07-23 北京阳光诺和药物研究股份有限公司 Bromhexine hydrochloride oral liquid and preparation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOËL SCHLATTER,ET AL.: "Stability study of oral paediatric idebenone suspensions", 《PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY》 *

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