CN114099428B - Idebenone oral liquid insensitive to temperature and preparation method thereof - Google Patents

Idebenone oral liquid insensitive to temperature and preparation method thereof Download PDF

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Publication number
CN114099428B
CN114099428B CN202111410287.1A CN202111410287A CN114099428B CN 114099428 B CN114099428 B CN 114099428B CN 202111410287 A CN202111410287 A CN 202111410287A CN 114099428 B CN114099428 B CN 114099428B
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Prior art keywords
idebenone
essence
parts
oral liquid
purified water
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CN114099428A (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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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 idebenone oral liquid insensitive to temperature and a preparation method thereof. The preparation method comprises the following steps: (1) mixing the flavoring agent and a proper amount of purified water according to a certain proportion and uniformly stirring; (2) adding a pH regulator; (3) adding idebenone, solubilizer, antiseptic, and ethanol, stirring to dissolve, adding purified water to desired volume, filtering, and packaging. 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

Idebenone oral liquid insensitive to temperature 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 a smart accelerator developed and marketed by the chemical industry Co., ltd., japan in 1986. Has activating effect on 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 antioxidant and free radical scavenging effects. Clinically, the traditional Chinese medicine composition is used for treating teenagers, adult vision injury and the like caused by parkinsonism, alzheimer's disease, multi-infarct dementia, cerebral ischemia and cerebral failure and Leber Hereditary Optic Neuropathy (LHON).
Idebenone is orange or orange crystalline powder with a melting point of 52-55 ℃. At present, the domestic commercial dosage form is only tablets, and the dosage form product is extremely sensitive to temperature in the production, transportation and storage processes, and is easy to cause the phenomena of melting of raw materials caused by temperature reasons and even similar oil precipitation from the surfaces of the tablets. This phenomenon is common to idebenone solid formulations. As the global warming continues to rise, this phenomenon frequently occurs. After the tablet is oiled, the appearance, content, dissolution and stability of the preparation can be seriously affected, so that the curative effect is affected, and even potential safety hazards exist. After the tablet is taken, the tablet can be absorbed only by the processes of disintegration, dispersion and dissolution in the gastrointestinal tract, and the tablet can not rapidly exert the drug effect due to slow absorption.
In addition, most patients with brain function metabolism and brain dysfunction who are clinically dosed idebenone have swallowing problems, some patients are old people or children, the oral tablet patients have poor medication compliance, the patients cannot be treated according to doctor's prescription, even the patients cannot take the medicine, the treatment effect is reduced if the patients are light, and the patients are aggravated if the patients are serious, even the lives of the patients are endangered.
Disclosure of Invention
Aiming at the problems of the existing preparation, the invention aims to provide idebenone oral solution insensitive to temperature and a preparation method thereof, solves the problems of extremely sensitive temperature and easy melting of raw materials caused by temperature reasons, and has the characteristics of stable quality, accurate measurement, convenient administration 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, proper amount of pH regulator, 1-5 parts of preservative, proper amount of corrective, 100-500 parts of ethanol and adding purified water to fix volume to 1000 parts.
The ethanol contains C 2 H 6 O is between 1 and 100% (ml/ml), preferably 75 to 100% (ml/ml). The pH of the oral solution is between 3.5 and 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 salts thereof, sorbic acid and salts thereof, hydroxyphenylacetates or hydroxybenzoates or a mixture of the two;
the above correctant is selected from steviosin, sucralose, aspartame, liquid sorbitol, xylitol, maltitol solution, sucrose, mel, hami melon essence, orange essence, strawberry essence, lemon essence, banana essence, rubi fructus essence, or mixture thereof;
the preparation method of the stable idebenone oral liquid insensitive to temperature comprises the following steps:
(1) mixing the flavoring agent and a proper amount of purified water according to a certain proportion and uniformly stirring;
(2) adding a pH regulator;
(3) adding idebenone, solubilizer, antiseptic, and ethanol, stirring to dissolve, adding purified water to desired volume, filtering, and packaging.
Compared with the prior art, the invention has the beneficial effects that:
(1) The production process has no heating process, does not need to control the temperature of the production process, avoids the influence of the temperature in granulating and drying and coating in tablet production on the quality of the product, reduces the quality risk source in the production process from the source, has simple preparation process, saves the production cost and is suitable for industrial mass production;
(2) The idebenone is an oral solution, idebenone is dissolved in the solution in a molecular form, so that the problem of quality caused by oil discharge 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 of patients with swallowing problem, and has no disintegration and dispersion processes, rapid absorption and rapid curative effect.
Detailed Description
The following examples will describe the present invention in further detail, but the embodiments of the present invention are not limited thereto.
Example 1 preparation of idebenone oral liquid
(1) Component (A)
Idebenone (AIDEBYNON) 3g
Polysorbate 80 5g
Potassium sorbate 1g
Hydrochloric acid 0.02g
Xylitol 100g
Steviosin (stevia rebaudiana) 2g
Raspberry essence 4ml
75% ethanol 320ml
Purified water Adding water to 1000ml
(2) Preparation method
(1) Xylitol, steviosin, raspberry essence and a proper amount of purified water are mixed according to a certain proportion and then stirred uniformly; (2) adding hydrochloric acid to adjust the pH; (3) adding idebenone, polysorbate 80, potassium sorbate, and 75% ethanol, stirring to dissolve, adding purified water to desired volume, filtering, and packaging.
Example 2 preparation of idebenone oral liquid
(1) Component (A)
Idebenone (AIDEBYNON) 15g
Poloxamer 188 17g
Hydroxypropyl methyl ester 2.7g
Hydroxypropyl ethyl ester 0.3g
Citric acid 0.12g
Sodium citrate 1.3g
Aspartame 5g
Lemon essence 3ml
Absolute ethyl alcohol 410ml
Purified water Adding water to 1000ml
(2) Preparation method
(1) Mixing aspartame, lemon essence and a proper amount of purified water according to a certain proportion and uniformly stirring; (2) adding citric acid and sodium citrate to adjust pH; (3) adding idebenone, poloxamer 188, hydroxypropyl methyl, hydroxypropyl ethyl, and absolute ethanol, stirring to dissolve, adding purified water to desired volume, filtering, and packaging.
Example 3 preparation of idebenone oral liquid
(1) Component (A)
(2) Preparation method
(1) Mixing maltitol solution, aspartame, hami melon essence and a proper amount of purified water according to a certain proportion, and uniformly stirring; (2) adding sodium dihydrogen phosphate and phosphoric acid to regulate pH; (3) adding idebenone, polyoxyethylene castor oil, sorbic acid and absolute ethanol, stirring until visual dissolution, adding purified water to fix volume, filtering, and packaging.
Example 4 preparation of idebenone oral liquid
(1) Component (A)
Idebenone (AIDEBYNON) 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
(1) Mixing liquid sorbitol, sucralose, orange essence and a proper amount of purified water according to a certain proportion, and uniformly stirring; (2) adding sodium dihydrogen phosphate and phosphoric acid solution to regulate pH; (3) adding idebenone, polyoxyethylene hydrogenated castor oil RH40, sodium benzoate, and 95% ethanol, stirring to dissolve visually, adding purified water to desired volume, filtering, and packaging.
Example 5 idebenone oral liquid high temperature influence factor experiment
The samples (idebenone oral solution) prepared in example 4 and the control samples (idebenone film-coated tablet and idebenone sugar-coated tablet) were allowed to stand at a high temperature (60 ℃.+ -. 2 ℃) for 10 days, and examined using the properties of the samples and the related substances as indicators. The specific results are shown in the following table:
the results show that:
the samples (idebenone oral solution) prepared in example 4 and the control samples (idebenone film coated tablet and idebenone sugar coated tablet) were left for 10 days at high temperature (60 ℃ + -2 ℃), and the properties of idebenone oral solution and related substances were not significantly changed. The characters of the control sample (idebenone film coated tablet and idebenone sugar coated tablet) are obviously changed, and the phenomenon of oil production on the surface of the melted and exuded crude drug also appears, so that related substances are obviously increased.
Thus, the present invention can obtain a stable idebenone product insensitive to temperature. The temperature sensitivity is greatly reduced, the stability is obviously improved, the actual problem can be solved, and the method is suitable for popularization.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting. Those of ordinary skill in the art will appreciate that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims (2)

1. The idebenone oral liquid insensitive to temperature is characterized by comprising the following components in parts by weight:
idebenone (AIDEBYNON) 30 parts of Solubilizer 30 parts of PH regulator Proper amount of Preservative agent 1-5 parts Flavoring agent Proper amount of Ethanol 100-500 parts Purified water Adding water to 1000 parts
Wherein the solubilizer is polyoxyethylene hydrogenated castor oil RH40, the pH regulator is selected from one or a mixture of sodium dihydrogen phosphate and phosphoric acid, the preservative is selected from one or a mixture of benzoic acid and salts thereof, and the flavoring agent is selected from one or a mixture of steviosin, sucralose, aspartame, liquid sorbitol, xylitol, maltitol solution, sucrose, honey, cantaloupe essence, orange essence, strawberry essence, lemon essence, banana essence and raspberry essence; ethanol containing C 2 H 6 O is between 75-100% (ml/ml); the pH of the idebenone oral liquid is 3.5-4.5.
2. The preparation method of idebenone oral liquid according to claim 1, comprising the following steps:
(1) mixing the flavoring agent and a proper amount of purified water according to a certain proportion and uniformly stirring;
(2) adding a pH regulator;
(3) adding idebenone, solubilizer, antiseptic, and ethanol, stirring to dissolve, adding purified water to desired volume, filtering, and packaging.
CN202111410287.1A 2021-11-25 2021-11-25 Idebenone oral liquid insensitive to temperature and preparation method thereof Active CN114099428B (en)

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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
Stability study of oral paediatric idebenone suspensions;Joël Schlatter,et al.;《Pharmaceutical Development and Technology》;20160901;第22卷(第2期);第296-299页 *

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