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WO2018169306A1 - Formulation liquide aqueuse contenant de l'alfoscérate de choline - Google Patents

Formulation liquide aqueuse contenant de l'alfoscérate de choline Download PDF

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Publication number
WO2018169306A1
WO2018169306A1 PCT/KR2018/002987 KR2018002987W WO2018169306A1 WO 2018169306 A1 WO2018169306 A1 WO 2018169306A1 KR 2018002987 W KR2018002987 W KR 2018002987W WO 2018169306 A1 WO2018169306 A1 WO 2018169306A1
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WO
WIPO (PCT)
Prior art keywords
liquid formulation
choline alfoscerate
aqueous liquid
acid
aqueous
Prior art date
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Ceased
Application number
PCT/KR2018/002987
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English (en)
Korean (ko)
Inventor
박경희
윤재희
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Daewoong Pharmaceutical Co Ltd
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Daewoong Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by Daewoong Pharmaceutical Co Ltd filed Critical Daewoong Pharmaceutical Co Ltd
Publication of WO2018169306A1 publication Critical patent/WO2018169306A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/08—Solutions
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/664—Amides of phosphorus 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
    • A61K47/08—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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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

Definitions

  • the present invention relates to an aqueous liquid formulation containing choline alfoscerate.
  • L-alpha-glycerylphosphorylcholine (alpha-GPC), called choline alfoscerate, is a natural choline compound found in the brain. Choline alfoscerate is a precursor of acetylcholine, one of the neurotransmitters in the brain, and is metabolized in the body to act as acetylcholine.
  • Choline alfoscerate is naturally present in all cells of the body, but its amount decreases as aging progresses. Therefore, administration of choline alfoscerate is known to have a therapeutic effect on diseases in which neurotransmitter degradation is a symptom.
  • choline alfoscerate is sold as a cerebrovascular disease and cerebral metabolism improving agent, and main effects and effects are as follows.
  • choline alfoscerate is characterized by exhibiting deliquescent (deliquescence) that is easily dissolved by absorbing moisture in the environment. Therefore, choline alfoscerates have been commercially available in the form of soft capsules obtained by filling choline alfoscerates dissolved in oil-based solvents (eg, concentrated glycerin) in soft gelatin capsules.
  • oil-based solvents eg, concentrated glycerin
  • Korean Patent Publication No. 10-2009-0088564 discloses a choline alfoscerate-containing pharmaceutical preparation, which comprises choline alfoscerate adsorbed on colloidal silicon dioxide.
  • Korean Patent Registration No. 10-1172699 discloses a pharmaceutical preparation comprising an adsorbate obtained by adsorbing choline alfoscerate at a weight ratio of 1 to 2 with respect to magnesium aluminate silicate.
  • Patent Document 3 is a particle coating of choline alfoscerate with water-soluble polymers such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, methacrylic acid copolymer, polyethylene oxide
  • water-soluble polymers such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, methacrylic acid copolymer, polyethylene oxide
  • Patent Document 1 Korean Patent Publication No. 10-2009-0088564
  • Patent Document 2 Korean Patent Registration No. 10-1172699
  • Patent Document 3 Korean Patent Registration No. 10-1257919
  • Liquid formulations are advantageous formulations for patients who have difficulty swallowing drugs compared to capsules or tablets.
  • Patients in need of administration of choline alfoscerate are primarily elderly.
  • Dementia patients, especially those who forget how to swallow food are just biting the food in their mouths or spitting out or swallowing while they are swallowing. This is called dysphagia.
  • Dysphagia can occur gradually as the dementia worsens, sometimes as a side effect of medication (neuro-stabilizers, antipsychotics).
  • it is not easy to take bulky medicines such as tablets and capsules oral liquid preparations can increase the convenience of taking medications for these dysphagia patients, thereby increasing the compliance.
  • choline alfoscerate Since choline alfoscerate is deliquescent, it is conventionally used as a method for blocking water, using a method such as packing in an aluminum bag to avoid contact with air after filling choline alfoscerate in a soft capsule, or the aforementioned patent document. Only the method of adsorbing choline alfoscerate to excipients, such as 1 and 2, was used, but no attempt was made to formulate choline alfoscerate as a liquid formulation.
  • the present inventors have tried to develop a formulation that can simultaneously improve the stability and dosage convenience of choline alfoscerate formulations, and the commercially available choline alfoscerate oral aqueous liquid formulation of the following composition simultaneously realizes excellent formulation stability and dosage convenience.
  • the present invention has been completed by confirming that a preparation that exhibits bioequivalence with a soft capsule can be obtained.
  • the present invention provides an aqueous liquid formulation of choline alfoscerate which is excellent in the stability of choline alfoscerate and excellent storage stability of the formulation while improving the patient's convenience of medication.
  • the present inventors studied the composition of a stable liquid formulation under long-term storage or harsh storage conditions in the liquid state.
  • an aqueous liquid preparation comprising choline alfoscerate or a pharmaceutically acceptable salt thereof, an aqueous solvent, a pH adjusting agent, a preservative, and a viscosity adjusting agent, wherein an aqueous liquid preparation having a pH of 3.5 to 7.5 of the aqueous liquid preparation is such. It was confirmed that the stability conditions were satisfied.
  • the pH of the choline alfoscerate aqueous liquid formulation may preferably be 4 to 7.
  • the pH of the aqueous liquid formulation can be adjusted by adding an appropriate amount of pH adjusting agent to choline alfoscerate dissolved in an aqueous solvent.
  • PH regulators include, but are not limited to, organic or inorganic acids or salts thereof selected from citric acid, fumaric acid, lactic acid, tartaric acid, succinic acid, maleic acid, acetic acid, tartaric acid, oxalic acid and phosphoric acid; Or at least one component selected from the group consisting of sodium hydroxide, potassium hydroxide, aqueous ammonia and ammonium carbonate.
  • the aqueous solvent may be included in an amount of 80 to 99 parts by weight based on 100 parts by weight of the total liquid formulation.
  • the aqueous solvent may be, for example, water or a mixture of water and ethanol.
  • choline alfoscerate or a pharmaceutically acceptable salt thereof may be included in an amount of 1 to 10 parts by weight based on 100 parts by weight of the total liquid preparation.
  • a preservative means a substance that inhibits the growth of microorganisms in the liquid formulation of the present invention, including, for example, but not limited to paraoxybenzoic acid, benzoic acid, sorbic acid and salts thereof, all used in the art Conventional preservatives may be used.
  • the preservative may be included in an amount of 0.002 to 0.5 parts by weight based on 100 parts by weight of the total liquid formulation.
  • paraben-based preservatives such as methyl paraben, propyl paraben or mixtures thereof may be used as the preservative.
  • Liquid formulations according to the invention may further comprise one or more pharmaceutically acceptable additives selected from the group consisting of sweetening, flavoring, and coloring agents.
  • a sweetener means an additive which is added for the purpose of improving medication compliance by imparting sweetness to the liquid formulation.
  • Sweeteners included in the liquid formulation of the present invention are, for example, sugar, fructooligosaccharide, xylitol, maltodextrin, steviaside, aspartame, oligosaccharide, sorbitol, fructose, honey, malt, syrup , Cooked sugar, L-glutamic acid, L-glutamate, sodium saccharin, sodium saccharin, citric acid, tartaric acid, sodium tartarate, lactic acid, adipic acid, fumaric acid, sodium fumarate, potato extract (pyrozine), licorice extract (glycyrrhetenic acid), tagangka Extracts (monellin), tauumatin (thaumatin), saccharin, aspartame, acesulfame, dulcin, cyclamate sodium, glucitol, and the like.
  • the sweetener of the present invention may be added in an amount of 0.001 to 5 parts by weight based on a total of 100 parts by weight of the liquid formulation of the present invention.
  • Flavoring agent refers to a substance that improves compliance by taking a flavour when the liquid preparation is taken, for example apple flavor, cherry flavor, orange flavor, strawberry flavor, banana flavor, grape flavor, mango flavor, peach flavor Various fruit flavors and comprehensive fruit flavors such as; Vanilla flavor; Mint flavor; One or more substances selected from the group consisting of red ginseng aroma and honey aroma can be used.
  • the flavoring agent may be added in an amount of 0.001 to 5 parts by weight based on 100 parts by weight of the total liquid formulation.
  • the liquid formulation may also contain an appropriate amount of a pharmaceutically acceptable colorant.
  • the liquid formulation according to the present invention may have a viscosity that is suitable for patients to take and that pouch packaging is possible.
  • the liquid formulation according to the present invention may include a viscosity modifier.
  • the viscosity modifier is, for example, carbomer, polyethylene oxide having a molecular weight of 5,000 to 5,000,000, hydroxypropyl methylcellulose, hydroxypropyl cellulose, xanthan gum, guar gum, tragacanth gum, lucostong gum, carrageenan , Polyvinylpyrrolidone, polyvinyl alcohol, vinylpyrrolidone-vinylacetate copolymer, microcrystalline cellulose-carboxymethylcellulose sodium mixture, micronized crospovidone, carboxymethylcellulose and its derivatives, alginic acid and its derivatives, silicone emulsions, One or more components selected from the group consisting of glycerol and mixtures thereof.
  • the viscosity modifier may be xanthan gum, glycerin or mixtures thereof.
  • the content of the viscosity modifier may vary depending on the type, and the viscosity of the liquid formulation according to the present invention may be preferably 10 cps to 100 cps, for example, 10 cps to 80 cps, 20 cps to 60 cps.
  • the viscosity can be measured, for example, with the following measuring instruments and conditions: Brookfield viscometer. DV-II + Pro. Spindle 18. 25 °C, 75rpm
  • the liquid preparation according to the present invention is excellent in stability of choline alfoscerate and properties of liquid preparation even under long-term storage conditions or harsh conditions.
  • the amount of analogue produced in the liquid formulation is 0.1 to 5.0 weight based on the weight of choline alfoscerate or a pharmaceutically acceptable salt thereof. May be%.
  • the choline alfoscerate aqueous liquid formulation of the present invention having excellent formulation stability has a choline alfoscerate soft capsule or choline having the same active ingredient dose as choline alfoscerate in the liquid formulation.
  • bioequivalent levels of blood concentration-time curve area (AUC) and peak blood concentration (C max ) are shown.
  • the invention also provides the use of an aqueous choline alfoscerate liquid formulation for treating or preventing the following diseases in a subject:
  • the 'subject' refers to a warm-blooded animal such as a mammal suffering from a specific disease, disorder or disease, for example, human, orangutan, chimpanzee, mouse, rat, dog, cow, chicken, pig, goat , Amounts, and the like, but is not limited to these examples.
  • a specific disease, disorder or disease for example, human, orangutan, chimpanzee, mouse, rat, dog, cow, chicken, pig, goat , Amounts, and the like, but is not limited to these examples.
  • 'treatment' includes but is not limited to alleviating the symptoms, removing the cause of the symptoms temporarily or permanently, or preventing or slowing the appearance of the symptoms and the progression of the disease, disorder or condition.
  • An effective amount of the active ingredient of the liquid formulation of the present invention means an amount required to achieve treatment of a disease.
  • the pharmaceutical composition of the present invention may be administered 1 to 3 times a day, and may be taken in the range of 200 to 1200 mg, preferably 400 mg to 1000 mg, based on choline alfoscerate, but is not limited thereto. It doesn't happen.
  • the aqueous liquid formulation may comprise 400 mg choline alfoscerate.
  • an aqueous liquid formulation containing 400 mg of choline alfoscerate in a single dose may be packaged into an aluminum pouch and commercialized.
  • the aqueous liquid preparation containing choline alfoscerate according to the present invention has little generation of decomposition products of choline alfoscerate under long-term storage conditions and severe storage conditions, and the properties of the preparations are stable.
  • dementia patients it may be difficult to identify and comply with the storage (storage) conditions of medicines, and the choline alfoscerate aqueous liquid preparation according to the present invention, which has excellent stability even in severe storage conditions, is particularly effective in patients with dementia. It is possible to provide choline alfoscerate formulations that are excellent, easy to carry and store, and convenient to take.
  • Test Example 1 Storage stability according to pH of choline alfoscerate aqueous solution
  • the choline alpose was stored for 2 weeks while the liquid preparation according to Preparation Examples 1 to 8 was stored in a chamber set at an accelerated storage condition of a temperature of 40 ° C. and a relative humidity of 75%. The content of serrate and the pH stability were compared together. Before the sample was put into the temperature set chamber, the pH value of each preparation was finally measured and then put into the chamber, and the choline alfoscerate liquid solution taken out at each time point was sufficiently stirred for 10 minutes, and then the pH of each solution was measured through a pH meter. The content test was analyzed according to the choline alfoscerate content test method. The pH measured value and the choline alfoscerate content of the main component of the choline alfoscerate aqueous solution were shown in [Table 2].
  • the aqueous choline alfoscerate pharmaceutical composition of the present invention can be confirmed that the pH stability and choline alfoscerate content of the liquid for 2 weeks under accelerated storage conditions in the pH 2 ⁇ 8 range. there was.
  • the content test standard is 95.0 ⁇ 105.0%, and the content test value is included in the standard.
  • Test Example 2 to confirm the storage stability in more severe storage conditions, the temperature of the liquid and the choline alfoscerate content was compared for 4 weeks in a chamber set at a temperature of 60 and 80 degrees.
  • a storage stability test was conducted by adding a sample in the pH 9 range. Before putting the sample into the temperature set chamber, the pH value of each preparation was finally measured and then put into the chamber. The choline alfoscerate aqueous solution taken out at each time point was visually observed in a transparent beaker, recorded, and then tested for content. Proceeded. At this time, the content test was conducted in the same manner as in Test Example 1, the choline alfoscerate content is shown in [Table 3] and [Table 4].
  • the choline alfoscerate content was changed depending on the pH of the liquid even when stored at a temperature of 80 degrees for 28 days.
  • the storage condition at 80 ° C it was confirmed that the appearance changed from white opaque liquid to brown color after 28 days of storage, but the choline alfoscerate content was stable at the final pH of 4 ⁇ 8.
  • the results were similar to those at the 60 ° C storage condition.
  • pH 2 ⁇ 3 and pH 9 it was confirmed that the stability of choline alfoscerate was more rapidly lowered to a content value lower than the storage condition of 60 degrees.
  • the pH of the aqueous liquid preparation mainly containing choline alfoscerate is 3 to 8, especially 4 to 7, it is possible to provide a pharmaceutical composition that is stable in choline alfoscerate and high in pH stability even when exposed to severe environment for a long time.
  • Example 4 In order to evaluate the bioequivalence between the preparation of Example 4 and the reference drug (Geun glutinine), a healthy subject was subjected to a PK test.
  • a dose corresponding to 1200 mg of choline alfoscerate was administered to the reference drug and the test drug (Preparation Example 4), respectively, and the test was completed according to the 2 * 2 cross test method.
  • Bioavailability parameters such as blood concentration-time curve area (AUC) and peak blood concentration (Cmax) obtained from drug concentration data in each plasma were statistically considered to evaluate the bioequivalence between the two preparations.
  • the concentration of choline in plasma was analyzed using LC / MS / MS method.
  • the drug equivalence criteria are calculated by log-converting the blood concentration-time curve area (AUC) and the highest blood concentration (C max ) of the reference and test drugs according to the bioequivalence test of the Pharmacologic Equivalence Standard. In the 90% confidence interval of the converted mean difference, if both items meet the log 0.8 ⁇ log 1.25, the drug equivalence test is considered equivalent. However, in accordance with the BioExemption Regulation, 1) the difference between the log-converted average value of the comparative evaluation items of the control and test drugs is within log 0.9 to log 1.11, and 2) all If all conditions are equal under the conditions, equality is determined.
  • the AUCt T / R ratio of the reference drug and the test drug (Preparation Example 4) was 1.034 and the Tmax T / R ratio was 0.904, which was close to 1, and the bioavailability was confirmed by the average AUtC and Tmax of the reference drug and the test drug.

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  • Pharmacology & Pharmacy (AREA)
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Abstract

La présente invention concerne une formulation liquide aqueuse contenant de l'alfoscérate de choline. Dans des conditions de conservation à long terme et des conditions de conservation rigoureuses, la formulation liquide aqueuse contenant de l'alfoscérate de choline, selon la présente invention, produit très peu de produits décomposés d'alfoscérate de choline et les propriétés de la formulation sont stables. De plus, la formulation a une excellente commodité d'administration, de façon à permettre d'améliorer l'observance d'administration de patients âgés atteints de dysphagie nécessitant une administration d'alfoscérate de choline.
PCT/KR2018/002987 2017-03-17 2018-03-14 Formulation liquide aqueuse contenant de l'alfoscérate de choline Ceased WO2018169306A1 (fr)

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KR1020170033749A KR101744538B1 (ko) 2017-03-17 2017-03-17 콜린 알포세레이트를 함유하는 수성 액상 제제
KR10-2017-0033749 2017-03-17

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KR101744538B1 (ko) * 2017-03-17 2017-06-09 주식회사 대웅제약 콜린 알포세레이트를 함유하는 수성 액상 제제
KR102210417B1 (ko) 2018-04-24 2021-02-02 한국유나이티드제약 주식회사 콜린알포세레이트를 함유하는 액상 시럽제제
WO2019208898A1 (fr) * 2018-04-24 2019-10-31 한국유나이티드제약 주식회사 Préparation de sirop liquide contenant de l'alfoscérate de choline
KR102148374B1 (ko) * 2018-11-21 2020-08-27 삼익제약주식회사 콜린알포세레이트를 포함하는 이층 코팅 정제 및 이의 제조 방법

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CN102138892A (zh) * 2010-02-03 2011-08-03 广州汉光医药进出口有限公司 甘磷酸胆碱注射制剂及其配制方法和检测方法
KR20140020838A (ko) * 2010-11-30 2014-02-19 리체르파르마 에스. 알. 엘. 점막의 완전성을 보존하거나 회복시키기 위한 국소용 조성물
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KR20130121796A (ko) * 2013-10-18 2013-11-06 한국프라임제약주식회사 콜린알포세레이트를 함유하는 약학 제제, 및 그의 제조방법
KR20160054216A (ko) * 2014-11-06 2016-05-16 환인제약 주식회사 콜린알포세레이트를 함유하는 정제 및 그 제조방법
KR101744538B1 (ko) * 2017-03-17 2017-06-09 주식회사 대웅제약 콜린 알포세레이트를 함유하는 수성 액상 제제

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