CN109045008B - Stable carbocisteine pharmaceutical composition - Google Patents

Stable carbocisteine pharmaceutical composition Download PDF

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Publication number
CN109045008B
CN109045008B CN201811061847.5A CN201811061847A CN109045008B CN 109045008 B CN109045008 B CN 109045008B CN 201811061847 A CN201811061847 A CN 201811061847A CN 109045008 B CN109045008 B CN 109045008B
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carbocisteine
pharmaceutical composition
stabilizer
hydroxypropyl cellulose
sodium
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CN109045008A (en
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高悦译
刘恩桂
陈新颖
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Guangzhou Lixin Pharmaceutical Co Ltd
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Guangzhou Lixin Pharmaceutical Co Ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38Cellulose; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/08Solutions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/10Expectorants

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Inorganic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention belongs to pharmaceutical technology fields, more particularly to stable carbocisteine pharmaceutical composition and its preparation, comprising carbocisteine 3~10%, sodium hydroxide 3~10% and stabilizer 0.05~0.2%, the stabilizer is by hydroxypropyl cellulose and maltonic acid sodium by 1:(0.1~1) weight ratio form.Carbocisteine pharmaceutical composition provided by the invention has excellent long-time stability, the pharmaceutical composition still stable clarification after 20 DEG C of shady places are stored 36 months, active constituent content decline only between 0.3~0.4%, achieves significant progress compared with prior art.

Description

Stable carbocisteine pharmaceutical composition
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to stable carbocisteine pharmaceutical composition.
Background technique
Carbocisteine is containing there are two the multielement compound of carboxyl and an amino, and clinic is diluted frequently as sputum Medicine, makes that organ, glandular secretion increases in bronchus after oral, sputum becomes alkene, so that sputum be made to be easy to expectoration, take orally it is rapid-action, The visible obvious curative effects of rear 4h are taken, solid pharmaceutical preparation, such as tablet are normally manufactured as.
Compared to solid pharmaceutical preparation, the limited improvement mouthfeel of liquid preparation energy, enhancing absorbs, and improves bioavilability.But by In carbocisteine, solubility is lower (only 0.16% or so) in water, although improving into the carbocisteine dissolubility after salt , but since its aqueous solution is in acidity, it finds in practical applications, the solution can become from clear state after long-term preservation The state of flocculent deposit.
Maltonic acid sodium, alias are sodium gluconate, CAS 527-07-1, molecular formula C20H25NaO10, for white Crystalline particle or powder, are highly soluble in water, are slightly soluble in alcohol, do not dissolve in ether, are used for food additives, complexant for electroplating, print The equal toner of dyer's industry, steel surface processing agent etc., but it is not directed to its effect in terms of stablizing carbocisteine.
Hydroxypropyl cellulose usually as pharmaceutic adjuvant, disintegrating agent and be using tablet, particle can be shortened extensively The disintegration time of the solid formulations such as agent, capsule, but it is not directed to its effect in terms of stablizing carbocisteine.
Summary of the invention
The present invention is intended to provide a kind of stable carbocisteine pharmaceutical composition, by the way that stabilizer is added so that carbocisteine Pharmaceutical composition is placed more stable for a long time.
In order to achieve the above object, the invention adopts the following technical scheme: stable carbocisteine pharmaceutical composition, includes Carbocisteine 3~10%, sodium hydroxide 3~10% and stabilizer 0.05~0.2%, the stabilizer by hydroxypropyl cellulose and Maltonic acid sodium press 1:(0.1~1) weight ratio composition.
Preferably, the stabilizer is made of hydroxypropyl cellulose and maltonic acid sodium by the weight ratio of 1:0.3.
Preferably, the average substitution molal quantity of the hydroxypropyl cellulose is 0.05~0.2;It is highly preferred that the hydroxypropyl The average substitution molal quantity of base cellulose is 0.06.
It should be noted that the hydroxypropyl cellulose of low degree of substitution by alkali cellulose and propylene oxide at high temperature under high pressure Reaction is neutralized after reaction, is recrystallized, washing, crushing is made.
Averagely replacing molal quantity is the preparation of 0.26 hydroxypropyl cellulose:
It takes in 100 parts of the paper pulp sodium hydrate aqueous solutions for being impregnated in 40%, after so that paper pulp is absorbed sodium hydrate aqueous solution, applies Plus-pressure removes remaining sodium hydrate aqueous solution, and the weight ratio by alkaline hydrated oxide relative to cellulose is adjusted to 0.55, Weight ratio by moisture relative to cellulose is adjusted to 0.90, and alkali cellulose obtained is chopped up, be encased in it is internal have stir It mixes in the pressurized reactor of machine, is passed through nitrogen, be added 24 parts of propylene oxide, react 3h at 50 DEG C, in acetic acid and remaining After sodium hydroxide, with 50 DEG C of water washing, 80 DEG C of aeration-dryings obtain colorless solid and molal quantity are averagely replaced to be 0.26 hydroxyl Propyl cellulose.
Averagely replacing molal quantity is the preparation of 0.06 hydroxypropyl cellulose:
Difference with above-mentioned preparation method is: reaction temperature is 85 DEG C, reaction time 0.5h, obtains average substitution and rubs The hydroxypropyl cellulose that your number is 0.06.
Averagely replacing molal quantity is the preparation of 0.45 hydroxypropyl cellulose:
Difference with above-mentioned preparation method is: the additional amount of propylene oxide is 45 parts, obtains average substitution molal quantity and is 0.45 hydroxypropyl cellulose.
It preferably, further include corrigent.
Preferably, the corrigent is selected from one or more of Aspartame, lactose, fructose.
It preferably, further include antioxidant.
Preferably, the antioxidant in tocopherol, sodium sulfite, sodium pyrosulfite and sodium sulfite at least one Kind.
The present invention also provides the preparation methods of above-mentioned carbocisteine pharmaceutical composition, comprising the following steps:
A) take sodium hydroxide and carbocisteine that carbocisteine solution is made;
B) be added stabilizer into above-mentioned solution, stirring, filtering, sterilize to get.
Carbocisteine and sodium hydroxide are weakly acidic (pH=6.2~6.8) at the solution after salt, in the weak acid environment Under, carbocisteine solution can not be stored steadily in the long term, on the one hand maltonic acid sodium, which is added, can make the pH of carbocisteine solution Stablize between 7.1~7.3, on the other hand the hydroxypropyl cellulose combination of itself and low degree of substitution is achieved synergy by discovery Effect.Test proves that carbocisteine pharmaceutical composition produced by the present invention is still clarified after shady place is placed 36 months, pH Nothing is decreased obviously, and carbocisteine content is still maintained at 99.0% or more in solution.And it is added without low substitution degree hydroxy-propyl fiber Element or the long-time stability for being added without carbocisteine pharmaceutical composition made from maltonic acid sodium have bright compared with Example 1 Aobvious decline, is embodied in, aerosolised particles occurs in the two after storing under the same conditions 24 months, cigarette occur after 36 months Hazy precip, the content of carbocisteine also have 6~7% fall.In addition, thrilling be, when changing stabilizer When the average substitution molal quantity of middle hydroxypropyl cellulose, although the character of finished product without significant change, the content of carbocisteine with 1 ratio of embodiment decreased significantly.
The invention has the following advantages that
The present invention provides a kind of carbocisteine pharmaceutical compositions with excellent long-time stability, and said preparation is at 20 DEG C Still stable clarification after shady place is stored 36 months, active constituent content decline only between 0.3~0.4%, with the prior art Compared to achieving significant progress.
Specific embodiment
The specific embodiment of form by the following examples makees further specifically above content of the invention It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.
Embodiment 1, carbocisteine pharmaceutical composition
Preparation method: taking sodium hydroxide to be dissolved in partial purification water, sodium hydroxide solution be prepared, and takes the carboxylic of recipe quantity First department is smooth, is dissolved in partial purification water, and above-mentioned sodium hydroxide solution is slowly added dropwise, and stirring adds until carbocisteine is completely dissolved Recipe quantity: hydroxypropyl cellulose, maltonic acid sodium and lactose is added, sufficiently in the tocopherol for entering recipe quantity after being sufficiently stirred Stirring be allowed to be completely dissolved, measure pH value of solution, add water constant volume, filter, sterilizing to get.
Embodiment 2, carbocisteine pharmaceutical composition
Preparation method reference implementation example 1.
Embodiment 3, carbocisteine pharmaceutical composition
Preparation method reference implementation example 1.
Comparative example 1, carbocisteine pharmaceutical composition
Comparative example 1 the difference from embodiment 1 is that, the average substitution molal quantity of hydroxypropyl cellulose is 0.26, remaining ginseng Number and operation are as described in Example 1.
Comparative example 2, carbocisteine pharmaceutical composition
Comparative example 2 the difference from embodiment 1 is that, the average substitution molal quantity of hydroxypropyl cellulose is 0.45, remaining ginseng Number and operation are as described in Example 1.
Comparative example 3, carbocisteine pharmaceutical composition
Comparative example 3 the difference from embodiment 1 is that, stabilizer is hydroxypropyl cellulose, remaining parameter and operation as implement Shown in example 1.
Comparative example 4, carbocisteine pharmaceutical composition
Comparative example 4 the difference from embodiment 1 is that, stabilizer be maltonic acid sodium, remaining parameter and operation as implement Shown in example 1.
Comparative example 5, carbocisteine pharmaceutical composition
Comparative example 5 the difference from embodiment 1 is that, be added without stabilizer, remaining parameter and operation are as described in Example 1.
Test example one, long-term stable experiment
The sample that Example 1 and comparative example 1~5 are prepared, in (20 DEG C) of shady place store 0,3,6,12,18, 24,36 months, its pH value, character variation are observed, while using the content of carbocisteine in HPLC method measurement solution, test knot Fruit is as shown in the following table 1~7.
1 embodiment of table, 1 sample stability test result
2 comparative example of table, 1 sample stability test result
3 comparative example of table, 2 sample stability test result
4 comparative example of table, 3 sample stability test result
5 comparative example of table, 4 sample stability test result
6 comparative example of table, 5 sample stability test result
By upper table 1~3, it is found that stabilizer of the present invention can play, to significantly improve carbocisteine pharmaceutical composition steady in a long-term The effect of property, after storing 36 months at 20 DEG C, solution is still clarified, and pH is without being decreased obviously, and carbocisteine content in solution It is still maintained at 99.0% or more, especially example 1 group, carbocisteine content remains at 99.2% after storage 36 months, 0.3% is only had dropped with when starting.And 6 data of contrast table, it is added without stabilizer, same carbocisteine pharmaceutical composition is in phase It is stored under conditions of and unstable state occurs within 18 months, flocculent deposit occur within 36 months, pH is dropped to from original 6.6 5.3, and 11.0% is had dropped when the relatively beginning of carbocisteine content.
It can be found by the data of observation table 4,5,7, be deposited between hydroxypropyl cellulose and maltonic acid sodium in stabilizer In collective effect, because, comparative example 3 (being added without hydroxypropyl cellulose) and comparative example 4 (being added without maltonic acid sodium) The long-time stability of carbocisteine pharmaceutical composition obtained decreased significantly compared with Example 1, be embodied in, the same terms There are aerosolised particles after 24 months in lower storage, occurred smoke-like precipitating after 36 months, and the content of carbocisteine also has 6~ 7% fall.In addition, thrilling be, when the average substitution molal quantity for changing hydroxypropyl cellulose in stabilizer When, although the property of finished product, without significant change, content and 1 ratio of embodiment of carbocisteine decreased significantly.
The above-described embodiments merely illustrate the principles and effects of the present invention, and is not intended to limit the present invention.It is any ripe The personage for knowing this technology all without departing from the spirit and scope of the present invention, carries out modifications and changes to above-described embodiment.Cause This, institute is complete without departing from the spirit and technical ideas disclosed in the present invention by those of ordinary skill in the art such as At all equivalent modifications or change, should be covered by the claims of the present invention.

Claims (8)

1. stable carbocisteine pharmaceutical composition, which is characterized in that include carbocisteine 3~10%, sodium hydroxide 3~10% With stabilizer 0.05~0.2%, the stabilizer presses 1:(0.1~1 by hydroxypropyl cellulose and maltonic acid sodium) weight Than composition;The average substitution molal quantity of the hydroxypropyl cellulose is 0.05~0.2.
2. pharmaceutical composition as described in claim 1, which is characterized in that the stabilizer is by hydroxypropyl cellulose and D- grape Sodium saccharate is formed by the weight ratio of 1:0.3.
3. pharmaceutical composition as described in claim 1, which is characterized in that the average substitution molal quantity of the hydroxypropyl cellulose It is 0.06.
4. pharmaceutical composition as described in claim 1, which is characterized in that further include corrigent.
5. pharmaceutical composition as claimed in claim 4, which is characterized in that the corrigent is selected from Aspartame, lactose and fruit One or more of sugar.
6. pharmaceutical composition as described in claim 1, which is characterized in that further include antioxidant.
7. pharmaceutical composition as claimed in claim 6, which is characterized in that the antioxidant is selected from tocopherol, pyrosulfurous acid At least one of sodium and sodium sulfite.
8. the preparation method of pharmaceutical composition as described in claim 1, which comprises the following steps:
A) take sodium hydroxide and carbocisteine that carbocisteine solution is made;
B) be added stabilizer into above-mentioned solution, stirring, filtering, sterilize to get.
CN201811061847.5A 2018-09-12 2018-09-12 Stable carbocisteine pharmaceutical composition Active CN109045008B (en)

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Publication number Priority date Publication date Assignee Title
CN112438947B (en) * 2019-09-04 2022-08-26 武汉武药科技有限公司 Carbocisteine oral solution and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104511025A (en) * 2013-09-27 2015-04-15 北京诚济制药有限公司 Carbocisteine oral liquid and preparation method thereof
CN107714643A (en) * 2017-11-28 2018-02-23 华益药业科技(安徽)有限公司 A kind of carbocisteine oral administration solution and preparation method thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104511025A (en) * 2013-09-27 2015-04-15 北京诚济制药有限公司 Carbocisteine oral liquid and preparation method thereof
CN107714643A (en) * 2017-11-28 2018-02-23 华益药业科技(安徽)有限公司 A kind of carbocisteine oral administration solution and preparation method thereof

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