CN109045008B - Stable carbocisteine pharmaceutical composition - Google Patents
Stable carbocisteine pharmaceutical composition Download PDFInfo
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- 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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- China
- Prior art keywords
- carbocisteine
- pharmaceutical composition
- stabilizer
- hydroxypropyl cellulose
- sodium
- Prior art date
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- GBFLZEXEOZUWRN-VKHMYHEASA-N S-carboxymethyl-L-cysteine Chemical compound OC(=O)[C@@H](N)CSCC(O)=O GBFLZEXEOZUWRN-VKHMYHEASA-N 0.000 title claims abstract description 49
- 229960004399 carbocisteine Drugs 0.000 title claims abstract description 49
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 36
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 24
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 24
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 24
- 239000003381 stabilizer Substances 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 12
- 239000011734 sodium Substances 0.000 claims abstract description 12
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 12
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims abstract description 11
- 229950006191 gluconic acid Drugs 0.000 claims abstract description 11
- 238000006467 substitution reaction Methods 0.000 claims description 13
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 5
- 239000003963 antioxidant agent Substances 0.000 claims description 4
- 230000003078 antioxidant effect Effects 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 0.000 claims description 3
- 229960001295 tocopherol Drugs 0.000 claims description 3
- 229930003799 tocopherol Natural products 0.000 claims description 3
- 235000010384 tocopherol Nutrition 0.000 claims description 3
- 239000011732 tocopherol Substances 0.000 claims description 3
- 108010011485 Aspartame Proteins 0.000 claims description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical group OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 2
- 239000000605 aspartame Substances 0.000 claims description 2
- 229960003438 aspartame Drugs 0.000 claims description 2
- 235000010357 aspartame Nutrition 0.000 claims description 2
- 235000013399 edible fruits Nutrition 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 235000009754 Vitis X bourquina Nutrition 0.000 claims 1
- 235000012333 Vitis X labruscana Nutrition 0.000 claims 1
- 240000006365 Vitis vinifera Species 0.000 claims 1
- 235000014787 Vitis vinifera Nutrition 0.000 claims 1
- IDAGXRIGDWCIET-SDFKWCIISA-L disodium;(2s,3s,4s,5r)-2,3,4,5-tetrahydroxyhexanedioate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O IDAGXRIGDWCIET-SDFKWCIISA-L 0.000 claims 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-N disulfurous acid Chemical compound OS(=O)S(O)(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-N 0.000 claims 1
- 125000002640 tocopherol group Chemical group 0.000 claims 1
- 230000007423 decrease Effects 0.000 abstract description 3
- 238000005352 clarification Methods 0.000 abstract description 2
- 239000000470 constituent Substances 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 18
- 239000000243 solution Substances 0.000 description 13
- 235000011121 sodium hydroxide Nutrition 0.000 description 10
- 230000000694 effects Effects 0.000 description 7
- 229920002678 cellulose Polymers 0.000 description 6
- 239000001913 cellulose Substances 0.000 description 6
- 238000013112 stability test Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 5
- 206010036790 Productive cough Diseases 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- -1 hydroxypropyl Chemical group 0.000 description 3
- 210000003802 sputum Anatomy 0.000 description 3
- 208000024794 sputum Diseases 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 241000208340 Araliaceae Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 2
- 235000003140 Panax quinquefolius Nutrition 0.000 description 2
- 229920001131 Pulp (paper) Polymers 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 235000008434 ginseng Nutrition 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical group CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000009713 electroplating Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000000176 sodium gluconate Substances 0.000 description 1
- 235000012207 sodium gluconate Nutrition 0.000 description 1
- 229940005574 sodium gluconate Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
Classifications
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic 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
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
Landscapes
- 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
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.
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| CN201811061847.5A CN109045008B (en) | 2018-09-12 | 2018-09-12 | Stable carbocisteine pharmaceutical composition |
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| CN201811061847.5A CN109045008B (en) | 2018-09-12 | 2018-09-12 | Stable carbocisteine pharmaceutical composition |
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Citations (2)
| 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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| 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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