CN101019826A - Composition and great volume injection containing bromhexine salt and the injection preparing process - Google Patents
Composition and great volume injection containing bromhexine salt and the injection preparing process Download PDFInfo
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- CN101019826A CN101019826A CN 200710090358 CN200710090358A CN101019826A CN 101019826 A CN101019826 A CN 101019826A CN 200710090358 CN200710090358 CN 200710090358 CN 200710090358 A CN200710090358 A CN 200710090358A CN 101019826 A CN101019826 A CN 101019826A
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- China
- Prior art keywords
- bromhexine
- salt
- injection
- compositions
- stabilizing agent
- Prior art date
- Legal status (The legal status 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 status listed.)
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Links
- OJGDCBLYJGHCIH-UHFFFAOYSA-N bromhexine Chemical class C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N OJGDCBLYJGHCIH-UHFFFAOYSA-N 0.000 title claims abstract description 92
- 239000007924 injection Substances 0.000 title claims abstract description 44
- 238000002347 injection Methods 0.000 title claims abstract description 44
- 239000000203 mixture Substances 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 74
- 239000003381 stabilizer Substances 0.000 claims abstract description 29
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 21
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical group C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 21
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 21
- 229920001983 poloxamer Polymers 0.000 claims abstract description 21
- 229960000502 poloxamer Drugs 0.000 claims abstract description 21
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims abstract description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims abstract description 3
- UCDKONUHZNTQPY-UHFFFAOYSA-N bromhexine hydrochloride Chemical compound Cl.C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N UCDKONUHZNTQPY-UHFFFAOYSA-N 0.000 claims description 32
- 238000003756 stirring Methods 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 229960003870 bromhexine Drugs 0.000 claims description 29
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 27
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 21
- 239000008215 water for injection Substances 0.000 claims description 20
- 239000008103 glucose Substances 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 230000001476 alcoholic effect Effects 0.000 claims description 14
- 239000011780 sodium chloride Substances 0.000 claims description 13
- -1 hydroxypropyl Chemical group 0.000 claims description 12
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 8
- 238000001802 infusion Methods 0.000 claims description 8
- 239000012982 microporous membrane Substances 0.000 claims description 8
- 230000008961 swelling Effects 0.000 claims description 8
- 238000005303 weighing Methods 0.000 claims description 8
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 5
- 235000003704 aspartic acid Nutrition 0.000 claims description 5
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 5
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 5
- 239000004310 lactic acid Substances 0.000 claims description 5
- 235000014655 lactic acid Nutrition 0.000 claims description 5
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 230000004907 flux Effects 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000006184 cosolvent Substances 0.000 abstract description 4
- 239000002131 composite material Substances 0.000 abstract description 2
- RFRMMZAKBNXNHE-UHFFFAOYSA-N 6-[4,6-dihydroxy-5-(2-hydroxyethoxy)-2-(hydroxymethyl)oxan-3-yl]oxy-2-(hydroxymethyl)-5-(2-hydroxypropoxy)oxane-3,4-diol Chemical compound CC(O)COC1C(O)C(O)C(CO)OC1OC1C(O)C(OCCO)C(O)OC1CO RFRMMZAKBNXNHE-UHFFFAOYSA-N 0.000 abstract 1
- 239000013078 crystal Substances 0.000 abstract 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 abstract 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 abstract 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 abstract 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 31
- 239000000523 sample Substances 0.000 description 14
- 238000007689 inspection Methods 0.000 description 12
- 206010020565 Hyperaemia Diseases 0.000 description 10
- 206010030113 Oedema Diseases 0.000 description 10
- 208000005392 Spasm Diseases 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 210000003743 erythrocyte Anatomy 0.000 description 7
- 230000001954 sterilising effect Effects 0.000 description 6
- 238000004659 sterilization and disinfection Methods 0.000 description 6
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 4
- 206010036790 Productive cough Diseases 0.000 description 4
- 230000003419 expectorant effect Effects 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- 239000003172 expectorant agent Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 230000007794 irritation Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 208000024794 sputum Diseases 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229920002683 Glycosaminoglycan Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010062717 Increased upper airway secretion Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 240000007711 Peperomia pellucida Species 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940093181 glucose injection Drugs 0.000 description 2
- 239000002932 luster Substances 0.000 description 2
- 208000026435 phlegm Diseases 0.000 description 2
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 2
- 210000003802 sputum Anatomy 0.000 description 2
- 240000006409 Acacia auriculiformis Species 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 206010048865 Hypoacusis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 238000001467 acupuncture Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229960002335 bromhexine hydrochloride Drugs 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229940106164 cephalexin Drugs 0.000 description 1
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000015111 chews Nutrition 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- YRSGDLIATOURQO-UHFFFAOYSA-N ethyl 4-acetyl-5-oxohexanoate Chemical compound CCOC(=O)CCC(C(C)=O)C(C)=O YRSGDLIATOURQO-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 210000002175 goblet cell Anatomy 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses one kind of composition containing bromhexine salt, great volume injection and the injection preparing process. The composite includes bromhexine salt as the active component in 0.03-0.8 wt%, ethanol as co-solvent in 1.5-36 wt%, and stabilizer in 1.0-40 wt%, and has pH 3.0-7.0. The stabilizer is poloxamer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and/or hydroxyethyl cellulose. The composition of the present invention has high stability, and may be preserved for long period without bromhexine salt crystal separated out.
Description
Technical field
The present invention relates to a kind of compositions and bulk capacity injection and injection preparation method that contains bromhexine salt.
Background technology
Bromhexine is the synthetic analog that duck chews colored alkali, has the sticking expectorant effect of stronger dissolving, can make apoplexy due to phlegm acid mucopolysaccharide fiber decompose fracture, and suppress the synthetic of acidoglycoprotein in mucous gland and the goblet cell, making one of acid mucopolysaccharide composition in the sputum---sialic acid content reduces, and reduces sputum viscosity.In addition, bromhexine can also stimulate gastric mucosa reflexive ground to cause that the respiratory tract glandular secretion increases, and makes the sputum dilution, more than acts on the cough that all helps expectorant and goes out.Be first-selected expectorant commonly used both at home and abroad.
Experiment shows: bromhexine can improve the living element of antibiotics such as tetracycline, erythromycin, amoxicillin and cefalexin and penetrate bronchial ability, usually be used for the treatment of respiratory tract infectious disease as adjuvant with antimicrobial drug, comparative study shows that share bromhexine can obtain better effect.
This product still has nauseating property phlegm-dispelling functions.Be mainly used in chronic bronchitis, asthma, bronchiectasis, the sticking expectorant of adularescents such as pneumosilicosis is difficult for the patient of expectoration again; Also can give birth to element and share the treatment respiratory tract infectious disease with antibiotics; Be particularly useful for surgical operation and critical patient.
Bromhexine commonly used at present is a Bisolvon, because Bisolvon is water insoluble, influenced by pH value, cosolvent and compound method etc., and Bisolvon is easily separated out.According to present technical merit, in order to obtain stable bromhexine salt preparation, usually it is formulated as little pin or powder pin, need during use intravenous drip is carried out in its dilution or dissolving then; The bulk capacity injection of bromhexine has been prepared by some producer, but poor stability is easily separated out crystallization, and content descends, and should not apply on a large scale.The inventor's publication number is to disclose in the pro-application of CN1411806 with ethanol as cosolvent, prepares stable Bisolvon glucose injection.In after this several years, the inventor uses the specific stabilizing agent of other can prepare the compositions that contains bromhexine salt that stability is better, zest is littler through deep discovering.
Summary of the invention
The objective of the invention is to overcome above-mentioned defective, promptly overcome the pollution and inconvenience of using powder pin, little pin to be brought, a kind of stable composition that contains bromhexine salt is provided; A further object of the present invention just provides the littler bulk capacity injection that contains the bromhexine salt composite of stimulation and the preparation method of the stable bulk capacity injection that contains the bromhexine salt compositions of preparation is provided.
For achieving the above object, the present invention adopts following technical scheme:
A kind of compositions that contains bromhexine salt of the present invention, described compositions comprises active component bromhexine salt and flux ethanol and stabilizing agent, reaches glucose or sodium chloride, wherein stabilizing agent is one or more combinations in poloxamer, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, the hydroxyethyl-cellulose, and the weight ratio of bromhexine salt and ethanol and stabilizing agent is 1: 30: 40～1: 60: 100.
Preferably, the weight ratio of described bromhexine salt and ethanol and stabilizing agent is 1: 20: 25～1: 50: 60.
In the salt that described bromhexine salt can form for bromhexine hydrochloride, lactic acid bromhexine, acetic acid bromhexine, Aspartic Acid bromhexine, citric acid bromhexine or bromhexine and other acid one or more.
Preferably, described bromhexine salt is one or more in Bisolvon, lactic acid bromhexine, acetic acid bromhexine or the Aspartic Acid bromhexine.
Preferred, described bromhexine salt is a Bisolvon.
The present invention discloses a kind of by the described bulk capacity injection that contains the compositions preparation of bromhexine salt, in the described injection, the weight content of bromhexine salt is 0.03%～0.8%, alcoholic acid weight content is 1.5%～36%, the weight content of stabilizing agent is 1.0%～40%, and the pH value of injection is 3.0～7.0.
Preferably, in the described injection, the weight content of bromhexine salt is 0.06%～0.4%; Alcoholic acid weight content is 3.0%～20%; The weight content 4.0%～20% of stabilizing agent; The pH value of injection is 3.0～5.0.
The invention also discloses a kind of method for preparing described bulk capacity injection, described method comprises the following steps:
Take by weighing stabilizing agent and be dissolved in the water for injection, fully swelling; Measure ethanol, add the injection water, heating adds bromhexine salt, stirring and dissolving; Stir and slowly add the bromhexine salt alcoholic solution in the stabiliser solution down, add glucose or sodium chloride again, fully stirring and dissolving adds water to full dose, stirs, the weight content of measuring bromhexine salt is 0.03%～0.8%, alcoholic acid weight content is 1.5%～36%, and the weight content of stabilizing agent is 1.0%～40%, and the injection pH value is 3.0～7.0, through the following aperture of 0.45 μ m filtering with microporous membrane, fill is in infusion bottle or transfusion bag.
The present composition as active component, adds suitable stabilizing agent with bromhexine salt, is formulated in the certain pH value scope preparation of can long preservation and can not cause the bromhexine salt crystallization to be separated out.
The present invention has enriched prior art, and multiple character, the diverse stabilizing agent of structure are provided, to prepare better bromhexine salt compositions of stability.
Ethanol in the present composition is cosolvent.
According to those skilled in the art's general general knowledge, in compositions of the present invention, also can add pH buffer agent, antibacterial and active carbon etc., its addition is the usual amounts of corresponding dosage form.
Compositions of the present invention can be mixed with bulk capacity injection, injectable powder or small-volume injection, especially is mixed with bulk capacity injection.Its stability of bulk capacity injection according to compositions preparation of the present invention obviously improves, and zest significantly reduces.When the various dosage form of preparation, bromhexine salt example hydrochloric acid bromhexine, lactic acid bromhexine, acetic acid bromhexine, Aspartic Acid bromhexine, citric acid bromhexine etc. can be united glucose preparation or the sodium chloride preparation that forms bromhexine with glucose or sodium chloride, wherein preference Bisolvon glucose preparation.
The specific embodiment
Embodiment 1
Component content (weight %)
Bisolvon 0.075%
Ethanol 3.25%
Poloxamer 1.86%
Hydroxypropyl cellulose 1.86%
Glucose 92.955%
Embodiment 2
Component content (weight %)
Bisolvon 0.32%
Ethanol 13.68%
Poloxamer 7.82%
Hydroxypropyl cellulose 7.82%
Sodium chloride 70.36%
Embodiment 3
Hydroxypropyl cellulose among the embodiment 1 is replaced with hydroxypropyl emthylcellulose.
Embodiment 4
Hydroxypropyl cellulose among the embodiment 2 is replaced with hydroxyethylmethyl-cellulose.
Embodiment 5
Poloxamer among the embodiment 1 is replaced with hydroxypropyl emthylcellulose.
Embodiment 6
Poloxamer among the embodiment 2 is replaced with hydroxyethylmethyl-cellulose.
Embodiment 7 preparations contain the bulk capacity injection of Bisolvon glucose
Bisolvon 0.04g
Ethanol 1.75g
Poloxamer 1.0g
Hydroxypropyl cellulose 1.0g
Glucose 50g
Water for injection adds to 1000ml
Compound method
Take by weighing poloxamer 1.0g, hydroxypropyl cellulose 1.0g and be dissolved in an amount of water for injection, fully swelling; Measure the ethanol of 1.75g, add an amount of water for injection, be heated to proper temperature, add the bromhexine salt of 0.04g, stirring and dissolving; Stirring down slowly adds the bromhexine salt alcoholic solution in the aforementioned swollen stabiliser solution, reenter glucose 50g, fully stirring and dissolving adds water to full dose, after stirring, measure the content and the pH value thereof of bromhexine salt, up to specification after, through the following aperture of 0.45 μ m filtering with microporous membrane, fill is in infusion bottle or transfusion bag, through the routine sterilization, lamp inspection makes salt bromhexine salt bulk capacity injection after the quality inspection.
Embodiment 8 preparations contain the bulk capacity injection of Bisolvon glucose
Bisolvon 0.08g
Ethanol 7.5g
Poloxamer 4.0g
Hydroxypropyl cellulose 4.0g
Glucose 50g
Water for injection adds 1000ml
Compound method
Take by weighing poloxamer 4.0g, hydroxypropyl cellulose 4.0g and be dissolved in an amount of water for injection, fully swelling; Measure the ethanol of 7.5g, add an amount of water for injection, be heated to proper temperature, add the bromhexine salt of 0.08g, stirring and dissolving; Stirring down slowly adds the bromhexine salt alcoholic solution in the aforementioned swollen stabiliser solution, reenter glucose 50g, fully stirring and dissolving adds water to full dose, after stirring, measure the content and the pH value thereof of bromhexine salt, up to specification after, through the following aperture of 0.45 μ m filtering with microporous membrane, fill is in infusion bottle or transfusion bag, through the routine sterilization, lamp inspection makes salt bromhexine salt bulk capacity injection after the quality inspection.
Embodiment 9 preparations contain the bulk capacity injection of Bisolvon glucose
Bisolvon 0.06g
Ethanol 3.5g
Poloxamer 2.0g
Hydroxypropyl cellulose 2.0g
Glucose 50g
Water for injection adds to 1000ml
Compound method
Take by weighing poloxamer 2.0g, hydroxypropyl cellulose 2.0g and be dissolved in an amount of water for injection, fully swelling; Measure the ethanol of 3.5g, add an amount of water for injection, be heated to proper temperature, add the bromhexine salt of 0.06g, stirring and dissolving; Stirring down slowly adds the bromhexine salt alcoholic solution in the aforementioned swollen stabiliser solution, reenter glucose 50g, fully stirring and dissolving adds water to full dose, after stirring, measure the content and the pH value thereof of bromhexine salt, up to specification after, through the following aperture of 0.45 μ m filtering with microporous membrane, fill is in infusion bottle or transfusion bag, through the routine sterilization, lamp inspection makes salt bromhexine salt bulk capacity injection after the quality inspection.
Embodiment 10
Bisolvon 0.04g
Ethanol 1.75g
Poloxamer 1.0g
Hydroxypropyl cellulose 1.0g
Sodium chloride 9.0g
Water for injection adds to 1000ml
Compound method
Take by weighing poloxamer 1.0g, hydroxypropyl cellulose 1.0g and be dissolved in an amount of water for injection, fully swelling; Measure the ethanol of 1.75g, add an amount of water for injection, be heated to proper temperature, add the bromhexine salt of 0.04g, stirring and dissolving; Stirring down slowly adds the bromhexine salt alcoholic solution in the aforementioned swollen stabiliser solution, reenter sodium chloride 9g, fully stirring and dissolving adds water to full dose, after stirring, measure the content and the pH value thereof of bromhexine salt, up to specification after, through the following aperture of 0.45 μ m filtering with microporous membrane, fill is in infusion bottle or transfusion bag, through the routine sterilization, lamp inspection makes salt bromhexine salt bulk capacity injection after the quality inspection.
Embodiment 11
Bisolvon 0.06g
Ethanol 3.5 g
Poloxamer 2.0g
Hydroxypropyl cellulose 2.0g
Sodium chloride 9.0g
Water for injection adds to 1000ml
Compound method
Take by weighing poloxamer 2.0g, hydroxypropyl cellulose 2.0g and be dissolved in an amount of water for injection, fully swelling; Measure the ethanol of 3.5g, add an amount of water for injection, be heated to proper temperature, add the bromhexine salt of 0.06g, stirring and dissolving; Stirring down slowly adds the bromhexine salt alcoholic solution in the aforementioned swollen stabiliser solution, reenter sodium chloride 9g, fully stirring and dissolving adds water to full dose, after stirring, measure the content and the pH value thereof of bromhexine salt, up to specification after, through the following aperture of 0.45 μ m filtering with microporous membrane, fill is in infusion bottle or transfusion bag, through the routine sterilization, lamp inspection makes salt bromhexine salt bulk capacity injection after the quality inspection.
Embodiment 12
Bisolvon 0.08g
Ethanol 7.5g
Poloxamer 4.0g
Hydroxypropyl cellulose 4.0g
Sodium chloride 9.0g
Water for injection adds to 1000ml
Compound method
Take by weighing poloxamer 4.0g, hydroxypropyl cellulose 4.0g and be dissolved in an amount of water for injection, fully swelling; Measure the ethanol of 7.5g, add an amount of water for injection, be heated to proper temperature, add the bromhexine salt of 0.08g, stirring and dissolving; Stirring down slowly adds the bromhexine salt alcoholic solution in the aforementioned swollen stabiliser solution, reenter sodium chloride 9g, fully stirring and dissolving adds water to full dose, after stirring, measure the content and the pH value thereof of bromhexine salt, up to specification after, through the following aperture of 0.45 μ m filtering with microporous membrane, fill is in infusion bottle or transfusion bag, through the routine sterilization, lamp inspection makes salt bromhexine salt bulk capacity injection after the quality inspection.
Embodiment 13
Hydroxypropyl cellulose among the embodiment 2 is replaced with hydroxypropyl emthylcellulose.
Embodiment 14
Hydroxypropyl cellulose among the embodiment 1 is replaced with hydroxyethylmethyl-cellulose.
Embodiment 15
Poloxamer among the embodiment 2 is replaced with hydroxypropyl emthylcellulose.
Embodiment 16
Poloxamer among the embodiment 1 is replaced with hydroxyethylmethyl-cellulose.
Bisolvon compositions local irritation test report of the present invention is as follows:
Sample source: embodiment 7-12 sample
Control sample: the little pin of Bisolvon
One, test objective:
When investigating the intravenous drip of Bisolvon composition injection, whether can cause blood vessel irritation.
Two, animal:
Experimental rabbit, male and female half and half, body weight 2.0-2.5kg,
Three, test method
Get 42 of healthy experimental rabbits, fix 1 hour after, at its left auricular vein with a certain amount of test sample of 4# scalp acupuncture intravenous drip (by the conversion of clinical application amount, 1ml/ branch), for three days on end, every day 1 time; Auris dextra gives equivalent 5% glucose injection or sodium chloride injection with same procedure.The close observation vein has or not expansion, spasm and part to have or not phenomenons such as hyperemia, edema.Observing venous simultaneously, hard of hearing corresponding site does not have or insufficiency of blood pipe place difference subcutaneous injection test sample and normal saline solution in the left and right sides, and diameter about 0.5cm in skin mound observes the skin mound and has or not hyperemia, edema and extinction time.After last administration finishes, cut one section away from the about 2cm in needle point the place ahead place blood vessel rapidly, fix with 10% formalin be, conventional embedding, stained, microscopically is observed and is had or not pathological change.
Four, result
| The sample title | The result |
| Embodiment 7 samples | Do not have obviously hyperemia, edema, spasm, do not have expansion and erythrocyte and spill |
| Embodiment 8 samples | Do not have obviously hyperemia, edema, spasm, do not have expansion and erythrocyte and spill |
| Embodiment 9 samples | Do not have obviously hyperemia, edema, spasm, do not have expansion and erythrocyte and spill |
| Embodiment 10 samples | Do not have obviously hyperemia, edema, spasm, do not have expansion and erythrocyte and spill |
| Embodiment 11 samples | Do not have obviously hyperemia, edema, spasm, do not have expansion and erythrocyte and spill |
| Embodiment 12 samples | Do not have obviously hyperemia, edema, spasm, do not have expansion and erythrocyte and spill |
| Small-volume injection | Slight hyperemia, edema, spasm do not have expansion and erythrocyte and spill |
Five, conclusion
Above results suggest, embodiment 7-12 sample does not have obvious irritation to rabbit ear edge vein blood vessel and rabbit ear subcutaneous tissue, the slight hyperemia of small-volume injection, edema, spasm.So can think that the local excitation of Bisolvon compositions is less than non-compositions.
The investigation of Bisolvon composition stable
According to the requirement of two appendix XIXC of Chinese Pharmacopoeia version in 2005 medicine stability test guideline, study on the stability is through 40 ℃ of six months (being equivalent to room temperature 2 years) of acceleration and 12 months study on the stability of long-term stable experiment, and the result is as follows:
40 ℃ are quickened six months results:
| Sample number | Time (moon) | Content (%) | PH value | Clarity | Color and luster | |
| Bisolvon | Glucose | |||||
| Embodiment 7 samples | 0 | 99.5 | 100.1 | 4.1 | Up to specification | Up to specification |
| 6 | 99.6 | 100.0 | 4.1 | Up to specification | Up to specification | |
| Embodiment 8 samples | 0 | 100.9 | 99.8 | 4.2 | Up to specification | Up to specification |
| 6 | 100.8 | 99.7 | 4.2 | Up to specification | Up to specification | |
| Embodiment 9 samples | 0 | 98.6 | 100.5 | 3.8 | Up to specification | Up to specification |
| 6 | 98.5 | 100.3 | 3.9 | Up to specification | Up to specification | |
| Embodiment 10 samples | 0 | 101.2 | 100.5 | 4.0 | Up to specification | Up to specification |
| 6 | 101.0 | 100.6 | 4.0 | Up to specification | Up to specification | |
| Embodiment 11 samples | 0 | 99.3 | 99.5 | 4.5 | Up to specification | Up to specification |
| 6 | 99.2 | 99.4 | 4.5 | Up to specification | Up to specification | |
| Embodiment 12 samples | 0 | 97.9 | 98.3 | 5.0 | Up to specification | Up to specification |
| 6 | 98.0 | 98.2 | 5.0 | Up to specification | Up to specification | |
| Non-composition sample | 0 | 100.7 | 100.3 | 4.6 | Up to specification | Up to specification |
| 6 | 99.3 | 99.8 | 5.0 | Up to specification | Up to specification | |
Accelerated test result show the Bisolvon composition sample through six months changes of contents of 40 ℃ of high temperature within 0.3%, but not six months changes of contents of 40 ℃ of high temperature of composition sample reach 1.4%, pH value also rises 0.4, and visible Bisolvon compositions high-temperature stability is better than non-compositions.
12 months results of 5 long term tests:
| Sample number | Time (moon) | Content (%) | PH value | Clarity | Color and luster | |
| Bisolvon | Glucose | |||||
| Embodiment 7 samples | 0 | 99.5 | 100.1 | 4.1 | Up to specification | Up to specification |
| 12 | 99.5 | 100.0 | 4.1 | Up to specification | Up to specification | |
| Embodiment 8 samples | 0 | 100.9 | 99.8 | 4.2 | Up to specification | Up to specification |
| 12 | 100.5 | 99.7 | 4.1 | Up to specification | Up to specification | |
| Embodiment 9 samples | 0 | 98.6 | 100.5 | 3.8 | Up to specification | Up to specification |
| 12 | 98.7 | 100.3 | 3.9 | Up to specification | Up to specification | |
| Embodiment 10 samples | 0 | 101.2 | 100.5 | 4.0 | Up to specification | Up to specification |
| 6 | 101.1 | 100.5 | 4.0 | Up to specification | Up to specification | |
| Embodiment 11 samples | 0 | 99.3 | 99.5 | 4.5 | Up to specification | Up to specification |
| 6 | 99.1 | 99.2 | 4.6 | Up to specification | Up to specification | |
| Embodiment 12 samples | 0 | 97.9 | 98.3 | 5.0 | Up to specification | Up to specification |
| 6 | 98.1 | 98.4 | 5.0 | Up to specification | Up to specification | |
| Non-composition sample | 0 | 100.7 | 100.3 | 4.6 | Up to specification | Up to specification |
| 6 | 99.8 | 100.0 | 4.9 | Up to specification | Up to specification |
Long-term test results shows that the Bisolvon composition sample places 12 months changes of contents within 0.2% through 25 ℃, but not 12 months changes of contents of 25 ℃ of placements of composition sample reach 1.0%, pH value also rises 0.3, illustrates that Bisolvon compositions long-time stability are better than non-compositions.
5 conclusions: the long-term stable experiment explanation bromhexine composition stable of six months by a definite date accelerated test and 12 months is better than non-compositions.
The present invention is not limited to above-mentioned preferred forms, and other any identical with the present invention or akin products that anyone draws under enlightenment of the present invention all drop within protection scope of the present invention.
Claims (8)
1, a kind of compositions that contains bromhexine salt, it is characterized in that: described compositions comprises active component bromhexine salt and flux ethanol and stabilizing agent, and glucose or sodium chloride, wherein stabilizing agent is one or more combinations in poloxamer, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, the hydroxyethyl-cellulose, and the weight ratio of bromhexine salt and ethanol and stabilizing agent is 1: 30: 40～1: 60: 100.
2, the compositions that contains bromhexine salt as claimed in claim 1 is characterized in that: the weight ratio of described bromhexine salt and ethanol and stabilizing agent is 1: 20: 25～1: 50: 60.
3, the compositions that contains bromhexine salt as claimed in claim 1 or 2 is characterized in that: described bromhexine salt is one or more in Bisolvon, lactic acid bromhexine, acetic acid bromhexine, Aspartic Acid bromhexine, citric acid bromhexine or bromhexine and other the sour salt that forms.
4, the compositions that contains bromhexine salt as claimed in claim 1 or 2 is characterized in that: described bromhexine salt is one or more in Bisolvon, lactic acid bromhexine, acetic acid bromhexine or the Aspartic Acid bromhexine.
5, the compositions that contains bromhexine salt as claimed in claim 1 is characterized in that: described bromhexine salt is a Bisolvon.
6, a kind of arbitrary described bulk capacity injection that contains the compositions preparation of bromhexine salt by claim 1-4, it is characterized in that: in the described injection, the weight content of bromhexine salt is 0.03%～0.8%, alcoholic acid weight content is 1.5%～36%, the weight content of stabilizing agent is 1.0%～40%, and the pH value of injection is 3.0～7.0.
7, bulk capacity injection as claimed in claim 6 is characterized in that: in the described injection, the weight content of bromhexine salt is 0.06%～0.4%; Alcoholic acid weight content is 3.0%～20%; The weight content 4.0%～20% of stabilizing agent; The pH value of injection is 3.0～7.0.PH value be 3.0～5.0
8, a kind of method for preparing bulk capacity injection as claimed in claim 5, it is characterized in that: described method comprises the following steps:
Take by weighing stabilizing agent and be dissolved in the water for injection, fully swelling; Measure ethanol, add the injection water, heating adds bromhexine salt, stirring and dissolving; Stir and slowly add the bromhexine salt alcoholic solution in the stabiliser solution down, add glucose or sodium chloride again, fully stirring and dissolving adds water to full dose, stirs, the weight content of measuring bromhexine salt is 0.03%～0.8%, alcoholic acid weight content is 1.5%～36%, and the weight content of stabilizing agent is 1.0%～40%, and the injection pH value is 3.0～7.0, through the following aperture of 0.45 μ m filtering with microporous membrane, fill is in infusion bottle or transfusion bag.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102293741A (en) * | 2011-08-24 | 2011-12-28 | 石家庄东方药业有限公司 | Bromhexine hydrochlorie injection, its preparation method and application |
| WO2012007352A1 (en) * | 2010-07-12 | 2012-01-19 | Boehringer Ingelheim International Gmbh | Aqueous composition comprising bromhexine |
| CN101502494B (en) * | 2009-04-01 | 2012-10-17 | 王保明 | Bromhexine hydrochloride freeze-dried injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP1121940A1 (en) * | 2000-01-31 | 2001-08-08 | New Pharma Research Sweden AB | Pharmaceutical compositions comprising an antibiotic and bromhexine, and process for their preparation |
| CN1184963C (en) * | 2002-09-10 | 2005-01-19 | 张嵩 | Bromhexine hydrochloride injection and its preparation method |
| CN1259041C (en) * | 2004-02-05 | 2006-06-14 | 马小歧 | Bromhexine Hydrochloride aseptic freeze-drying formulation for injection and its preparation method |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101502494B (en) * | 2009-04-01 | 2012-10-17 | 王保明 | Bromhexine hydrochloride freeze-dried injection and preparation method thereof |
| WO2012007352A1 (en) * | 2010-07-12 | 2012-01-19 | Boehringer Ingelheim International Gmbh | Aqueous composition comprising bromhexine |
| CN103052384A (en) * | 2010-07-12 | 2013-04-17 | 贝林格尔.英格海姆国际有限公司 | Aqueous composition comprising bromhexine |
| JP2013531017A (en) * | 2010-07-12 | 2013-08-01 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Aqueous composition comprising bromhexine |
| EA025640B1 (en) * | 2010-07-12 | 2017-01-30 | Бёрингер Ингельхайм Интернациональ Гмбх | Aqueous composition comprising bromhexine |
| CN103052384B (en) * | 2010-07-12 | 2017-04-05 | 贝林格尔.英格海姆国际有限公司 | Aquo-composition comprising bromhexine |
| CN102293741A (en) * | 2011-08-24 | 2011-12-28 | 石家庄东方药业有限公司 | Bromhexine hydrochlorie injection, its preparation method and application |
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Assignee: Jiangxi Kelun Pharmaceutical Co., Ltd. Assignor: Zhang Song Contract fulfillment period: 2009.6.9 to 2027.4.6 Contract record no.: 2009360000036 Denomination of invention: Composition and great volume injection containing bromhexine salt and the injection preparing process Granted publication date: 20080813 License type: Exclusive license Record date: 20090713 |
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