WO2016161576A1 - Pastilles contenant du chlorhydrate de cystéine et leur procédé de préparation - Google Patents

Pastilles contenant du chlorhydrate de cystéine et leur procédé de préparation Download PDF

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Publication number
WO2016161576A1
WO2016161576A1 PCT/CN2015/076062 CN2015076062W WO2016161576A1 WO 2016161576 A1 WO2016161576 A1 WO 2016161576A1 CN 2015076062 W CN2015076062 W CN 2015076062W WO 2016161576 A1 WO2016161576 A1 WO 2016161576A1
Authority
WO
WIPO (PCT)
Prior art keywords
cysteine hydrochloride
pellet
preparation
mother
pellets
Prior art date
Application number
PCT/CN2015/076062
Other languages
English (en)
Chinese (zh)
Inventor
李健
盛晓霞
Original Assignee
杭州领业医药科技有限公司
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 杭州领业医药科技有限公司 filed Critical 杭州领业医药科技有限公司
Priority to CN201580061217.6A priority Critical patent/CN106999434B/zh
Priority to PCT/CN2015/076062 priority patent/WO2016161576A1/fr
Publication of WO2016161576A1 publication Critical patent/WO2016161576A1/fr

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Classifications

    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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

Definitions

  • the invention relates to a pellet with cysteine hydrochloride as a main component, and belongs to the technical field of medicine and food.
  • Cysteine hydrochloride (English name: Cysteine Hydrochloride), chemical name is 2-amino-3-mercaptopropionate, its molecular formula is C 3 H 8 NO 2 SCl, molecular weight is 157.62, the chemical formula is as follows :
  • Cysteine hydrochloride is a sulfur-containing amino acid which has an antioxidant action and is mainly used as an antioxidant for injections in pharmaceuticals. Since this product is an amphoteric amino acid, it can form a salt with an acidic drug or a salt with a basic drug, and can be used as a co-solvent and a prodrug carrier. In addition to being used as an antioxidant in the food industry, it is also used as a spice, bread fermentation accelerator, and the like. For some drugs whose solubility decreases with increasing pH, cysteine hydrochloride can be combined with these drugs to form a preparation to promote its dissolution and release, so as to maximize its efficacy. For certain low pH chemically stable drugs, the stability of the quality is guaranteed. At present, cysteine hydrochloride is made into a drug-loaded pill, and as a base pill, it has not been reported in the literature at home and abroad, and no such product has been introduced.
  • An object of the present invention is to provide a pellet having cysteine hydrochloride as a main component.
  • the pellets are not only easy to form, but also fully utilize the original properties of cysteine hydrochloride; for drugs with a decrease in solubility with increasing pH, the dissolution can be improved. At the same time, it can also alleviate the stimulation of contact with the cysteine hydrochloride dust and ensure the use of cysteine hydrochloride pellets.
  • the invention relates to a pellet containing cysteine hydrochloride as a main component, which comprises cysteine hydrochloride and other pharmaceutically acceptable binders, anti-adherents and optionally dilution Agent.
  • the cysteine hydrochloride which is a main component of the pellet of the present invention is cysteine hydrochloride anhydrate, cysteine hydrochloride hydrate or a pharmaceutically acceptable solvate.
  • the binder of the present invention is one of povidone, polyacrylic resin, cellulose, or a mixture of any two thereof.
  • the anti-adhesive agent of the present invention is one of talc, magnesium stearate, and finely divided silica gel or a mixture of any two or more thereof.
  • the diluent according to the present invention is one of microcrystalline cellulose, starch, mannitol, sorbitol or a mixture of any two or more thereof.
  • a preparation method of pellets containing cysteine hydrochloride as a main component comprising the following steps:
  • a part of the slurry prepared in the step (1) is mixed with a suitable amount of cysteine hydrochloride, a diluent or a mixture of cysteine hydrochloride and a diluent by a wet granulator.
  • the wet material is obtained by wet granulation, and the soft material is obtained by passing the soft material through a 16-80 mesh screen to obtain a mother nucleus;
  • the mother core is put into a centrifugal granulation coating machine, the rotation speed is adjusted to rotate the mother core, and the remaining suspension is sprayed on the mother core, and after drying, the cysteine hydrochloride pellets are obtained.
  • the cysteine hydrochloride pellets prepared by the above preparation method can obtain pellets of different particle diameters by preparing the mother nucleus of different particle diameters or adjusting the amount of the suspension.
  • the pellet diameter is preferably 0.2 to 1.2 mm.
  • Cysteine hydrochloride has antioxidant properties, and cysteine hydrochloride pellets can be used as a drug carrier to protect the drug from oxidation.
  • Cysteine hydrochloride is strong in hydrochloric acid.
  • the cysteine hydrochloride pellets of the present invention can improve the solubility of these drugs and thereby improve their dissolution. degree.
  • the cysteine hydrochloride pellet of the present invention uses ethanol as a suspension solvent, is easy to volatilize, can prepare low-moisture pellets, and can be prepared into a pellet preparation for some moisture-sensitive drugs.
  • the cysteine hydrochloride pellet of the present invention can alleviate the stimulation of the contact person by the cysteine hydrochloride dust and ensure the use effect of the cysteine hydrochloride pellet.
  • cysteine hydrochloride pellets of the present invention can ensure the stability of their quality.
  • High performance liquid phase analysis (HPLC) data was taken from Agilent 1260.
  • a C 18 column was used, 2.7 ⁇ m ⁇ 150 mm ⁇ 4.6 mm, column temperature 40 ° C, wavelength 225 nm, flow rate 1.0 mL / min, injection volume 10 ⁇ L.
  • Buffer 1.5g disodium hydrogen phosphate dissolved in 900mL water, adjusted to pH value of 3.1 ⁇ 0.1 with phosphoric acid, and then made up to 1000mL;
  • the gradient is as follows:
  • the various reagents or starting materials used in the examples are commercially available unless otherwise specified.
  • the particle size of the microcrystalline cellulose pellets, the starch pellets, and the sucrose pellets is 600 to 800 ⁇ m.
  • Dabigatran etexilate mesylate is a pH-dependent drug whose solubility decreases with increasing pH, so the cysteine hydrochloride pellets prepared in the present invention (Example 1) are commercially available. Microcrystalline cellulose pellets, starch pellets and sucrose pellets are used as the pellet core, and the outer layer is sprayed with the galactosyl methanesulfonate active material layer (the preparation method of the active material layer is referred to the patent document CN100528157C), and the ratio is obtained after drying. The dissolution rate of dabigatran etexilate mesylate pellets prepared in the four different pellet cores was compared with the addition of the group ester mesylate pellets. The results are shown in Table 1.
  • the experimental method is as follows: the cysteine hydrochloride pellets prepared in the first embodiment of the invention, the commercially available microcrystalline cellulose pellets, the commercially available starch pellets and the commercially available sucrose pellets are prepared as pellet cores, respectively. 6 parts of each of the genomic group of pellets (containing 150 mg of dabigatran etexilate), and under the dissolution apparatus, check by 100 rpm, basket method, medium water 900 ml dissolution method, press 0, 5, 10, 15, 30 min. Samples were taken for sampling, each time 10 ml, 0.45 ⁇ m polyethersulfone membrane was filtered through 4.0 ml, and the filtrate was taken for analysis under high performance liquid chromatography. The results are shown in Table 1.
  • the dabigatran etexilate mesylate pellets prepared by using the cysteine hydrochloride pellets of the present invention as pellet cores have faster dissolution rates than the other three pellet cores of dabigatran etexilate.
  • the mesylate salt pellets can reach 95% or more within 15 minutes, indicating that the main drug is completely dissolved, and the dabigatran etexilate mesylate pellets prepared by the other three pellet cores cannot be completely dissolved.
  • the dabigatran etexilate mesylate pellet prepared by using the cysteine hydrochloride of the present invention as a pellet core can reach the therapeutic concentration in a short time, and the onset is rapid, while the other three
  • the dabigatran etexilate mesylate pellet prepared by the pellet core cannot achieve this effect.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une pastille dont le composant principal est le chlorhydrate de cystéine, qui contient le chlorhydrate de cystéine et un autre liant pharmaceutiquement acceptable, un agent anticollant et un diluant facultatif. Pour un médicament dans lequel la solubilité diminue à mesure que le pH augmente, la pastille de chlorhydrate de cystéine préparée présente une vitesse de dissolution améliorée et d'autres avantages.
PCT/CN2015/076062 2015-04-08 2015-04-08 Pastilles contenant du chlorhydrate de cystéine et leur procédé de préparation WO2016161576A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201580061217.6A CN106999434B (zh) 2015-04-08 2015-04-08 一种含半胱氨酸盐酸盐的微丸及其制备方法
PCT/CN2015/076062 WO2016161576A1 (fr) 2015-04-08 2015-04-08 Pastilles contenant du chlorhydrate de cystéine et leur procédé de préparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2015/076062 WO2016161576A1 (fr) 2015-04-08 2015-04-08 Pastilles contenant du chlorhydrate de cystéine et leur procédé de préparation

Publications (1)

Publication Number Publication Date
WO2016161576A1 true WO2016161576A1 (fr) 2016-10-13

Family

ID=57071653

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/076062 WO2016161576A1 (fr) 2015-04-08 2015-04-08 Pastilles contenant du chlorhydrate de cystéine et leur procédé de préparation

Country Status (2)

Country Link
CN (1) CN106999434B (fr)
WO (1) WO2016161576A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003155232A (ja) * 2001-09-07 2003-05-27 Takeda Chem Ind Ltd 不快な臭いが低減されたｌ−システイン配合固形製剤およびその製造方法
JP2004269384A (ja) * 2003-03-06 2004-09-30 Kyowa Hakko Kogyo Co Ltd 吸水性アミノ酸被覆顆粒
JP2006188473A (ja) * 2005-01-07 2006-07-20 Asahi Kasei Chemicals Corp コーティング顆粒の製造方法
CN101897674A (zh) * 2009-05-25 2010-12-01 范敏华 L-半胱氨酸片及其制备方法
CN102675174A (zh) * 2011-03-16 2012-09-19 江苏磊鑫医药科技有限公司 一种l-半胱氨酸盐酸盐的生产工艺

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3866715B2 (ja) * 2002-03-07 2007-01-10 ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト ３−［（２−｛［４−（ヘキシルオキシカルボニルアミノ−イミノ−メチル）−フェニルアミノ］−メチル｝−１−メチル−１ｈ−ベンゾイミダゾール−５−カルボニル）−ピリジン−２−イル−アミノ］−プロピオン酸エチルエステル及びその塩の経口適用の投与形態
WO2014060561A1 (fr) * 2012-10-19 2014-04-24 Sanovel Ilac Sanayi Ve Ticaret A.S. Formulations pharmaceutiques orales contenant du dabigatran
CN104095830A (zh) * 2014-05-22 2014-10-15 万特制药(海南)有限公司 一种甲磺酸盐达比加群酯胶囊的制备方法
CN104434882A (zh) * 2014-11-05 2015-03-25 烟台东诚药业集团股份有限公司 含达比加群酯或其盐和水合物的微丸药物组合物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003155232A (ja) * 2001-09-07 2003-05-27 Takeda Chem Ind Ltd 不快な臭いが低減されたｌ−システイン配合固形製剤およびその製造方法
JP2004269384A (ja) * 2003-03-06 2004-09-30 Kyowa Hakko Kogyo Co Ltd 吸水性アミノ酸被覆顆粒
JP2006188473A (ja) * 2005-01-07 2006-07-20 Asahi Kasei Chemicals Corp コーティング顆粒の製造方法
CN101897674A (zh) * 2009-05-25 2010-12-01 范敏华 L-半胱氨酸片及其制备方法
CN102675174A (zh) * 2011-03-16 2012-09-19 江苏磊鑫医药科技有限公司 一种l-半胱氨酸盐酸盐的生产工艺

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHE, WENSHI ET AL.: "Progress on Pellets Preparation Technology", HEILONGJIANG MEDICINE JOURNAL, vol. 25, no. 5, 31 December 2012 (2012-12-31), pages 693 - 695 *

Also Published As

Publication number Publication date
CN106999434A (zh) 2017-08-01
CN106999434B (zh) 2020-05-22

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