CN103463565A - Zedoary oil injection and preparation method thereof - Google Patents
Zedoary oil injection and preparation method thereof Download PDFInfo
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- CN103463565A CN103463565A CN2013103941411A CN201310394141A CN103463565A CN 103463565 A CN103463565 A CN 103463565A CN 2013103941411 A CN2013103941411 A CN 2013103941411A CN 201310394141 A CN201310394141 A CN 201310394141A CN 103463565 A CN103463565 A CN 103463565A
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- 238000002347 injection Methods 0.000 title claims abstract description 76
- 239000007924 injection Substances 0.000 title claims abstract description 76
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 235000003405 Curcuma zedoaria Nutrition 0.000 title abstract description 8
- 240000009138 Curcuma zedoaria Species 0.000 title abstract description 8
- 239000001812 curcuma zedoaria berg. rosc. Substances 0.000 title abstract description 8
- 235000019509 white turmeric Nutrition 0.000 title abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000002904 solvent Substances 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- BKVAAWMQOQLENB-UHFFFAOYSA-N 15-hydroxy stearic acid Chemical compound CCCC(O)CCCCCCCCCCCCCC(O)=O BKVAAWMQOQLENB-UHFFFAOYSA-N 0.000 claims abstract description 11
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229950007687 macrogol ester Drugs 0.000 claims abstract description 11
- 239000006184 cosolvent Substances 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims description 46
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 16
- 239000008215 water for injection Substances 0.000 claims description 12
- 239000003643 water by type Substances 0.000 claims description 10
- 230000001954 sterilising effect Effects 0.000 claims description 5
- 238000012545 processing Methods 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000011082 depyrogenation Methods 0.000 claims description 3
- 239000000470 constituent Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 4
- 229940114072 12-hydroxystearic acid Drugs 0.000 abstract 1
- 239000004698 Polyethylene Substances 0.000 abstract 1
- -1 polyethylene Polymers 0.000 abstract 1
- 229920000573 polyethylene Polymers 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 56
- 206010070834 Sensitisation Diseases 0.000 description 15
- 230000008313 sensitization Effects 0.000 description 15
- 241000700199 Cavia porcellus Species 0.000 description 13
- 208000003455 anaphylaxis Diseases 0.000 description 13
- 238000012360 testing method Methods 0.000 description 12
- 206010002198 Anaphylactic reaction Diseases 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 101000656751 Haloarcula marismortui (strain ATCC 43049 / DSM 3752 / JCM 8966 / VKM B-1809) 30S ribosomal protein S24e Proteins 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 10
- 230000036783 anaphylactic response Effects 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000013642 negative control Substances 0.000 description 9
- 239000013558 reference substance Substances 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- 229940093181 glucose injection Drugs 0.000 description 6
- 206010020751 Hypersensitivity Diseases 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 102000002322 Egg Proteins Human genes 0.000 description 4
- 108010000912 Egg Proteins Proteins 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000012797 qualification Methods 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- ZOOODBUHSVUZEM-UHFFFAOYSA-N ethoxymethanedithioic acid Chemical compound CCOC(S)=S ZOOODBUHSVUZEM-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000009423 ventilation Methods 0.000 description 2
- 239000012991 xanthate Substances 0.000 description 2
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- 206010002216 Anaphylactoid reaction Diseases 0.000 description 1
- QRMPRVXWPCLVNI-UHFFFAOYSA-N Curcumenol Natural products C1C(=C)C2CCC(C)C22CC(C(C)C)C1(O)O2 QRMPRVXWPCLVNI-UHFFFAOYSA-N 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- SHWNNYZBHZIQQV-UHFFFAOYSA-J EDTA monocalcium diisodium salt Chemical compound [Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-J 0.000 description 1
- 241000892865 Heros Species 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000002528 anti-freeze Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- ISFMXVMWEWLJGJ-NZBPQXDJSA-N curcumenol Chemical compound CC1=C[C@](O2)(O)C(=C(C)C)C[C@@]22[C@@H](C)CC[C@H]21 ISFMXVMWEWLJGJ-NZBPQXDJSA-N 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention discloses zedoary oil injection and a preparation method thereof. The zedoary oil injection mainly comprises the following components: (1) zedoary oil serving as an active component, (2) 15-hydroxystearic acid macrogol ester (also known as polyethylene glycol-12- hydroxystearic acid ester, and called HS-15 for short) serving as a solubilizing agent, (3) alcohol serving as a cosolvent, and (4) injection for water serving as a solvent. Compared with commercially available injection, the zedoary oil injection has the advantages that the product prepared by adopting a bran-new prescription and technology is in line with the pharmacopoeia criterion for the zedoary oil injection and the safety of clinical medication of the product is also greatly improved.
Description
Technical field
The present invention relates to the pharmaceutical preparation technology field, particularly a kind of Oleum Curcumae injection and preparation method thereof.
Background technology
Oleum Curcumae is to derive from the volatile oil extracted in the rhizomes such as zingiberaceous plant Rhizoma Curcumae, RADIX CURCUMAE, modern medicine study confirms, Oleum Curcumae has antiviral, antibiotic, antitumor, antithrombotic, protects the liver, and treatment psoriasis, cervical erosion, peptic ulcer, enhancing immunity etc. are pharmacologically active extensively.Oleum Curcumae injection often is applied to clinical as antiviral agents, 1988 in July, 2004, case report 221 examples of relevant Oleum Curcumae injection in the case report data base of national drug adverse reaction monitoring center.In case report, patient age mainly concentrates on child below 10 years old, accounts for 62.4%; The medication reason be take respiratory tract infection as main; The main adverse reaction performance has anaphylactoid reaction 64 examples time (accounting for 21%), erythra 45 examples time (accounting for 15%).In addition, dyspnea 17 examples time (accounting for 6%), anaphylactic shock 12 examples time (accounting for 4%), dead 1 example, the Zedoary oil injecting untoward reaction mainly concentrates in anaphylaxis as can be seen here.
The Patent Application Publication of application number 201310194657.1 a kind of Oleum Curcumae injection and preparation method thereof, though studies confirm that, adopt 15-hydroxy stearic acid macrogol ester (to have another name called HS15, be called for short HS15) do the Oleum Curcumae injection safety that solubilizing agent makes and be better than commercially available Oleum Curcumae injection, but its clarity is desirable not enough.
Summary of the invention
The object of the invention is to provide a kind of brand-new prescription and preparation technology's Oleum Curcumae injection, and this Oleum Curcumae injection is steady quality but also have good clinical drug safety not only.
To achieve these goals, the technical solution used in the present invention is:
A kind of Oleum Curcumae injection, it is characterized in that, comprise: (1) is as the Oleum Curcumae of active component, (2) the 15-hydroxy stearic acid macrogol ester as solubilizing agent (has another name called HS15, be called for short HS15), (3) as the medicinal alcohol of cosolvent, or the combination of medicinal alcohol and propylene glycol, (4) are as the water for injection of solvent.In pharmaceutical composition of the present invention, described Oleum Curcumae is 10.0g/L, and HS15 is 50.0g/L～80.0 g/L, and medicinal alcohol is 30.0ml/L～100.0ml/L, and propylene glycol is 100g/L.Described drug solution pH value is 4.0～5.0.
In pharmaceutical composition of the present invention, described injection further comprises other conventional adjuvants, comprises acidity regulator, depyrogenation agent, the hydrochloric acid solution that wherein the acidometer regulator is 1.0mol/L～2.0mol/L, and the depyrogenation agent is active carbon.
The preparation method of described Oleum Curcumae injection comprises following processing step:
1) get the Oleum Curcumae of formula ratio, add the 15-hydroxy stearic acid macrogol ester of formula ratio, stir;
2) slowly add the medicinal alcohol of formula ratio, stir;
3) get 30 ℃～40 ℃ appropriate waters for injection, slowly add, stir while adding, stir after being settled to formula ratio;
4) with hydrochloric acid solution adjust pH to 4.0～5.0, be filtered to the qualified rear embedding of clarity, obtain.
Perhaps, the preparation method of described Oleum Curcumae injection is undertaken by following processing step:
1) get the Oleum Curcumae of formula ratio, add the 15-hydroxy stearic acid macrogol ester of formula ratio, stir;
2) slowly add the medicinal alcohol of formula ratio, stir;
3) slowly add the propylene glycol of formula ratio, stir;
4) get 30 ℃～40 ℃ appropriate waters for injection, slowly add, stir while adding, stir after being settled to formula ratio;
5) with hydrochloric acid solution adjust pH to 4.0～5.0, be filtered to the qualified rear embedding of clarity, 121 ℃ are rotated sterilizing 12 minutes, obtain.
Experimental results show that, the Oleum Curcumae injection that adopts formula of the present invention to make, through with number of patent application 201310194657.1 in the product of embodiment 2 contrasted, the safety of Oleum Curcumae injection of the present invention is equal to the Zedoary oil injecting liquid product of same employing HS15 as solubilizing agent, and both safeties are all higher than commercially available Oleum Curcumae injection; Simultaneously, experiment is proof also, and Oleum Curcumae injection of the present invention obviously is better than above-mentioned reference product on clarity.
The specific embodiment
embodiment 1oleum Curcumae, 80.0g/L HS15,30.0ml/L ethanol and water for injection by 10.0g/L are formulated.(specification: 10ml: 0.1g) (add active carbon)
Get the 10.0g Oleum Curcumae, add 80gHS15, stir; Slowly add 30.0ml ethanol, stir; Get 30 ℃～40 ℃ appropriate waters for injection, slowly add, stir while adding, stir after being settled to 1000.0ml; Add the 0.2g active carbon, after uniform stirring after standing 30min; Adjust pH value to 4.53 with 1.0mol/L hydrochloric acid, be filtered to the qualified rear embedding of clarity, obtain.
embodiment 2oleum Curcumae, 80.0g/L HS15,30.0ml/L ethanol and water for injection by 10.0g/L are formulated.(specification: 10ml: 0.1g) (do not add active carbon)
Get the 10.0g Oleum Curcumae, add 80gHS15, stir; Slowly add 30.0ml ethanol, stir; Get 30 ℃～40 ℃ appropriate waters for injection, slowly add, stir while adding, after being settled to 1000.0ml; Adjust pH value to 4.58 with 1.0mol/L hydrochloric acid, be filtered to the qualified rear embedding of clarity, obtain.
embodiment 3oleum Curcumae, 50.0g/L HS15,100.0ml/L ethanol and water for injection by 10.0g/L are formulated.(specification: 10ml: 0.1g) (add active carbon)
Get the 10.0g Oleum Curcumae, add 50gHS15, stir; Slowly add 100.0ml ethanol, stir; Get 30 ℃～40 ℃ appropriate waters for injection, slowly add, stir while adding, stir after being settled to 1000.0ml, add the 0.2g active carbon, after uniform stirring after standing 30min; With 1.0mol/L hydrochloric acid adjust pH to 4.41, be filtered to the qualified rear embedding of clarity, obtain.
embodiment 4oleum Curcumae, 50.0g/L HS15,100.0ml/L ethanol and water for injection by 10.0g/L are formulated.(specification: 10ml: 0.1g) (do not add active carbon)
Get the 10.0g Oleum Curcumae, add 50gHS15, stir; Slowly add 100.0ml ethanol, stir; Get 30 ℃～40 ℃ appropriate waters for injection, slowly add, stir while adding, after being settled to 1000.0ml; With 1.0mol/L hydrochloric acid adjust pH to 4.49, be filtered to the qualified rear embedding of clarity, obtain.
embodiment 5oleum Curcumae, 50.0g/L HS15,60.0ml/L ethanol, 100g/L propylene glycol and water for injection by 10.0g/L are formulated.(specification: 10ml: 0.1g) (add active carbon)
Get the 10.0g Oleum Curcumae, add 50gHS15, stir; Slowly add 60.0ml ethanol, add the 100g propylene glycol after stirring, stir; Get 30 ℃～40 ℃ appropriate waters for injection, slowly add, stir while adding, stir after being settled to 1000.0ml, add the 0.2g active carbon, after uniform stirring after standing 30min; Adjust pH value to 4.56 with 1.0mol/L hydrochloric acid, be filtered to the qualified rear embedding of clarity, 121 ℃ are rotated sterilizing 12 minutes, obtain.
embodiment 6oleum Curcumae, 50.0g/L HS15,60.0ml/L ethanol, 100g/L propylene glycol and water for injection by 10.0g/L are formulated.(specification: 10ml: 0.1g) (do not add active carbon)
Get the 10.0g Oleum Curcumae, add 50gHS15, stir; Slowly add 60.0ml ethanol, add the 100g propylene glycol after stirring, stir; Get 30 ℃～40 ℃ appropriate waters for injection, slowly add, stir while adding, after being settled to 1000.0ml; Adjust pH value to 4.51 with 1.0mol/L hydrochloric acid, be filtered to the qualified rear embedding of clarity, 121 ℃ are rotated sterilizing 12 minutes, obtain.
reference examples 1adopt patent documentation 201310194657.1 embodiment 2 routine 1(specification: 10ml: 0.1g) in contrast
Get water for injection 100ml, add calcium disodium edetate 0.15g, be stirred to dissolve, add active carbon 0.1g, boil 15 minutes, filter, obtain solution 1; Get Oleum Curcumae 10g (take curcumenol content as 100% feed intake), add 50g HS15, stir evenly; Get water for injection 100ml, the mixed liquor of Oleum Curcumae and HS15 is slowly added, stir evenly, obtain solution 2; Solution 1 and solution 2 is mixed, inject water to 1000ml, the citric acid solution with 10% is regulated pH to 4.0～5.0, filtration, fill, rolls lid, rotates sterilizings 8 minutes through 121 ℃, obtains Oleum Curcumae injection.
reference examples 2adopt commercially available Oleum Curcumae injection example 2 in contrast.
The name of an article: Oleum Curcumae injection
Lot number: 120512
Specification: 10ml:0.1g
Production unit: the glad triumphant company limited of the Jiangsu Long March
embodiment 1---and embodiment 6 compares with reference examples 1 clarity
Detection method foundation: " Chinese pharmacopoeia version appendix IX H visible foreign matters inspection technique in 2010
Instrument and equipment: YB-3 type clarity detecting apparatus
Detection method: get every batch of product, clean container outer wall, rotation and inverting container make the visible foreign matters suspension (noting not making medicinal liquid to produce bubble) existed in medicinal liquid gently, respectively under the black and white background, hand-held test sample cervical region overturns medicinal liquid gently, with visual inspection, surveys (illumination: 1000～1500lx).
Criterion: remove smoke-like microparticle column, metal fillings, chips of glass, length or maximum particle diameter and surpass the obvious external foreign bodies such as the fiber of 2mm and block.Only calculate fine visible foreign matters (such as small particles, brief summary crystalline substance etc.), calculate qualification rate.
Annotate: qualification rate=(total quantity-obvious external foreign body-fine visible foreign matters) ÷ total quantity * 100%
Conclusion: Oleum Curcumae injection prepared apparently higher than patent 201310194657.1 inventive methods by Oleum Curcumae injection clarity qualification rate prepared by the inventive method.
embodiment 1 and reference examples 1, reference examples 2 safety contrasts
whole body is hypersensitive test initiatively
Safety judgment basis: the Cavia porcellus generation hypersensitive difference of active and degree are carried out to its safety of comparison according to different prescription products.
Animal experiment unit: Chengdu qi xanthate thing non-clinical study company limited
1, experiment material:
1.1 supply the reagent product:
The name of an article: Oleum Curcumae injection
Lot number: embodiment 1
Specification: 10ml:0.1g
Production unit: Chengdu Lisite Pharmaceutical Co., Ltd.
1.2 reference substance:
1.2.1 negative control product
The name of an article: 5% glucose injection
Specification: 250ml:12.5g
Lot number: D120902F1
Production unit: Hunan Cologne Pharmaceutical Co., Ltd
1.2.2 model reference substance
The name of an article: egg protein powder:
Specification: 100g
Lot number: F20100819
Production unit: Chemical Reagent Co., Ltd., Sinopharm Group
1.2.3 reference substance 1(reference examples 1)
The name of an article: Oleum Curcumae injection
Lot number: reference examples 1
Specification: 10ml:0.1g
Production unit: Chengdu Lisite Pharmaceutical Co., Ltd.
Preparation foundation: patent documentation 201310194657.1 embodiment 2 preparation methoies
1.2.4 reference substance 2(reference examples 2)
The name of an article: Oleum Curcumae injection
Lot number: 120512
Specification: 10ml:0.1g
Production unit: the glad triumphant company limited of the Jiangsu Long March
Embodiment 1 and reference examples 1, reference examples 2 usage and dosages: adult or child every day 1 time more than 12 years old, each 0.2～0.4g, the each 0.1g of infant more than 6 months
Storage: lucifuge, airtight, antifreeze preservation.
1.3 animal
30 of Cavia porcelluss, body weight 262.2～356.2g, 15 female 15 heros, meet one-level animal standard, and the animal production licence number is provided by Sichuan Province plant of laboratory animal special commission: the SCXK(river) No. 2013-14.Adopt the Cavia porcellus full-valence pellet feed, provided by Sichuan Province plant of laboratory animal special commission.Freely drink urban life drinking-water.Feeding environment is conventional system, 16～26 ℃ of temperature, relative humidity 40～70%, gravity-flow ventilation, ventilation, natural lighting.
1.4 instrument
BS600L type electronic balance: range 600g, precision 0.1g, Shanghai Yousheng Balance Co., Ltd. produces.
FA1004 type electronic balance: range 100g, precision 0.0001g, the flat instrument and meter company limited of upper current chart is produced.
TDL-80-2B type desk centrifuge: Anting Scientific Instrument Factory, Shanghai produces.
2, experimental system and selection reason
Observe and test animal occupancy permit number: the SYXK(river) 2010-096 during test in Chengdu qi xanthate thing non-clinical study company limited Animal House Cavia porcellus observation ward.
Select reason: according to " chemicals zest, anaphylaxis and hemolytic investigative technique guideline " hypersensitive test choice for use Cavia porcellus, be the one-level experimental animal, therefore raise and observe in open systems.
3, test grouping
3.1 test grouping: get 30 of Cavia porcelluss, by the body weight hierarchical grouping, be divided into 5 groups, 6/group, male and female half and half: specific as follows:
Negative control group (5% glucose injection);
Model control group (egg protein powder);
1 group of embodiment (Oleum Curcumae injection embodiment 1);
1 group of reference examples (Oleum Curcumae injection reference examples 1);
2 groups of reference examples (Oleum Curcumae injection reference examples 2);
3.2 test dose design:
3.2.1 dosage design considerations: in hypersensitive test, for fully exposing the immunogenicity of medicinal liquid, should select that concentration is maximum, (clinical dosage is 10mg/kg to the maximum clinical administration mode of dosage as a reference, after conversion, Cavia porcellus dosage is about: 45mg/kg, be that low dose group is 13.5mg//0.5ml, surpass 10mg/ml under this concentration), therefore select stock solution to compare.Specific as follows:
Priming dose:
Negative control group: 0.5ml/ only
Model control group: 1.0mg/0.5ml/ only
1 group of embodiment: 5.0mg/0.5ml/ only (approximately intends adult's dosage for 1.6 times)
1 group of reference examples: 5.0mg/0.5ml/ only (approximately intends adult's dosage for 1.6 times)
2 groups of reference examples: 5.0mg/0.5ml/ only (approximately intends adult's dosage for 1.6 times)
Booster dose:
Negative control group: 1.0ml/ only
Model control group: 2.0mg/1.0ml/ only
1 group of embodiment: 10mg/1.0ml/ only (approximately intends adult's dosage for 3.2 times)
1 group of reference examples: 10mg/1.0ml/ only (approximately intends adult's dosage for 3.2 times)
2 groups of reference examples: 10mg/1.0ml/ only (approximately intends adult's dosage for 3.2 times)
3.2.2 administration capacity: sensitization is 0.5ml/, excites as 1.0ml/.
3.2.3 administering mode: sensitization adopts lumbar injection, excites as intravenous injection.
4, test method
30 Cavia porcelluss require to be divided at random 5 groups according to top grouping, give stage by stage corresponding dosage group drug dose.
Administration cycle and route of administration: the next day lumbar injection 1 sensitization, totally 3 times, after last sensitization, instep intravenous injection in the 14th day excites.
Before sensitization, negative reference substance is prepared: get 5% glucose injection standby.
Before sensitization, the model reference substance is prepared: take appropriate egg protein powder, be dissolved in 5% glucose injection and be made into the solution for standby that concentration is 2mg/ml.
Before sensitization, embodiment 1 injection is prepared: get embodiment 1 Oleum Curcumae injection standby, without preparation.
Before sensitization, reference examples 1 injection is prepared: get reference examples 1 Oleum Curcumae injection standby, without preparation.
Before sensitization, reference examples 2 injection are prepared: get reference examples 2 Oleum Curcumae injections standby, without preparation.
The sensitization method: each group is carried out sensitization by each solution of group lumbar injection, the next day 1 time, totally 3 times.Dosage regimen is in Table 1.
Excite front negative reference substance to prepare: to get 5% glucose injection standby.
Excite front model reference substance to prepare: to take appropriate egg protein powder, be dissolved in 5% glucose injection and be made into the solution for standby that concentration is 2mg/ml.
Excite front embodiment 1 injection to prepare: to get embodiment 1 Oleum Curcumae injection standby, without preparation.
Excite front reference examples 1 injection to prepare: to get reference examples 1 Oleum Curcumae injection standby, without preparation.
Excite front reference examples 2 injection to prepare: to get reference examples 2 Oleum Curcumae injections standby, without preparation.
Exciting method: after last sensitization, the 14th day each group excited by each solution of group instep intravenous injection.Dosage regimen is in Table 2.
Last sensitization and excite the body weight of measuring every group every animal the same day for the first time.
After each sensitization and excite at once to 30 minute after intravenous injection, according to the form below 3 is observed reaction symptom and the death time of every animal in detail.The longest observation 3 hours.By table 4 evaluation criterion, estimated.
5, result of the test and analysis
5.1 overview: during sensitization, the Cavia porcellus ordinary circumstance is observed normally, without abnormal conditions, occurs.
5.2 anaphylaxis: test result analysis is in Table 5.
Annotate: each group compares * * * P1<0.001, * * P1<0.01, * P1<0.05 with negative control group
Each tested group is compared △ △ △ P2<0.001, △ △ P2<0.01, △ P2<0.05 with model control group
1 group of comparison 000 P3<0.001, zero zero P3<0.01, zero P3<0.05 of 2 groups of reference examples and embodiment
1 group of comparison P4<0.001 of 1 group of reference examples and embodiment, P4<0.01, P4<0.05
Table 5 result shows: in Oleum Curcumae injection whole body active sensitivity test, 1.. each organizes the Cavia porcellus body weight all increases to some extent, body weight zero difference between each group.2.. the negative control group Cavia porcellus excites rear anaphylaxis feminine gender, and the model group Cavia porcellus excites the extremely strong positive of rear anaphylaxis, and model control group and negative control group have utmost point significant difference (P<0.001), shows the modeling success.3.. 1 group of embodiment, 1 group of reference examples and negative control group anaphylaxis are all negative, zero difference, show that 1 group of 1 group of embodiment, reference examples are without anaphylaxis, show the Oleum Curcumae injection safety that adopts HS15 to prepare as solubilizing agent higher with the negative control zero difference; 4.. 1 group of embodiment has notable difference (P<0.01) with 2 groups of anaphylaxiss of reference examples, on the Oleum Curcumae injection degree of allergic reaction that shows to adopt HS15 to prepare as solubilizing agent lower than commercially available Oleum Curcumae injection.5.. 1 group of embodiment and 1 group of anaphylaxis of reference examples do not have difference (P>0.05), show that patented product of the present invention and patent documentation 201310194657.1 embodiment 2 Product Safety are equal to.
6, conclusion
According to the Oleum Curcumae injection systemic anaphylaxis, experimental study shows, embodiment 1 is reducing on Cavia porcellus anaphylaxis degree far below reference examples 2, but similar to reference examples 1; Show that this patent Product Safety is equal to the patented product (patent documentation 201310194657.1 embodiments 2) of same employing HS15 as solubilizing agent, and both safeties are all higher than commercially available Oleum Curcumae injection.Oleum Curcumae injection prepared by the inventive method will have wide market prospect.
Claims (8)
1. an Oleum Curcumae injection, be comprised of active component Oleum Curcumae, solubilizing agent, cosolvent and water for injection, and pH value is 4.0～5.0.
2. Oleum Curcumae injection as claimed in claim 1, it is characterized in that, comprising: (1), as the Oleum Curcumae of active component, (2) are as the 15-hydroxy stearic acid macrogol ester of solubilizing agent, (3) as the medicinal alcohol of cosolvent, (4) are as the water for injection of solvent.
3. Oleum Curcumae injection as claimed in claim 2, is characterized in that Oleum Curcumae is 10.0g/L, and 15-hydroxy stearic acid macrogol ester is 50.0g/L～80.0 g/L, and medicinal alcohol is 30.0ml/L～100.0ml/L.
4. Oleum Curcumae injection as claimed in claim 1, it is characterized in that, comprise: (1) is as the Oleum Curcumae of active component, (2) as the 15-hydroxy stearic acid macrogol ester of solubilizing agent, (3) as the combination of medicinal alcohol and the propylene glycol of cosolvent, (4) are as the water for injection of solvent.
5. Oleum Curcumae injection as claimed in claim 4, is characterized in that Oleum Curcumae is 10.0g/L, and 15-hydroxy stearic acid macrogol ester is 50.0g/L～80.0 g/L, and medicinal alcohol is 30.0ml/L～100.0ml/L, and propylene glycol is 100g/L.
6. the preparation method of Oleum Curcumae injection as claimed in claim 2 or claim 3 is characterized in that processing step is as follows:
1) get the Oleum Curcumae of formula ratio, add the 15-hydroxy stearic acid macrogol ester of formula ratio, stir;
2) slowly add the medicinal alcohol of formula ratio, stir;
3) get 30 ℃～40 ℃ appropriate waters for injection, slowly add, stir while adding, stir after being settled to formula ratio;
4) with hydrochloric acid solution adjust pH to 4.0～5.0, be filtered to the qualified rear embedding of clarity, obtain.
7. as the preparation method of claim 4 or 5 described Oleum Curcumae injections, it is characterized in that processing step is as follows:
1) get the Oleum Curcumae of formula ratio, add the 15-hydroxy stearic acid macrogol ester of formula ratio, stir;
2) slowly add the medicinal alcohol of formula ratio, stir;
3) slowly add the propylene glycol of formula ratio, stir;
4) get 30 ℃～40 ℃ appropriate waters for injection, slowly add, stir while adding, stir after being settled to formula ratio;
5) with hydrochloric acid solution adjust pH to 4.0～5.0, be filtered to the qualified rear embedding of clarity, 121 ℃ are rotated sterilizing 12 minutes, obtain.
8. Oleum Curcumae injection as described as claim 1-5, is characterized in that, the constituent of described injection also comprises acidity regulator or depyrogenation agent.
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| CN201310394141.1A CN103463565B (en) | 2013-05-23 | 2013-09-03 | Zedoary oil injection and preparation method thereof |
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| CN2013101946571 | 2013-05-23 | ||
| CN201310194657.1 | 2013-05-23 | ||
| CN201310394141.1A CN103463565B (en) | 2013-05-23 | 2013-09-03 | Zedoary oil injection and preparation method thereof |
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| CN201310394141.1A Expired - Fee Related CN103463565B (en) | 2013-05-23 | 2013-09-03 | Zedoary oil injection and preparation method thereof |
| CN201310469134.3A Expired - Fee Related CN103610638B (en) | 2013-05-23 | 2013-10-10 | Large capacity zedoary turmeric oil injection liquid and preparation method thereof |
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Cited By (2)
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| CN105477531A (en) * | 2014-09-18 | 2016-04-13 | 张蕊 | Large-volume zedoary turmeric oil injection and preparation method thereof |
| CN108096291A (en) * | 2017-12-27 | 2018-06-01 | 信阳农林学院 | Parenteral solution and its application prepared by a kind of taxodiaceae plant volatile oil |
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| CN103239684A (en) * | 2013-05-23 | 2013-08-14 | 张蕊 | Zedoary oil injection and preparation method thereof |
| CN103463564B (en) * | 2013-08-30 | 2016-06-01 | 广州市暨鹏生物科技有限公司 | A kind of external application zedoary oil temperature-sensitivgel gel and its preparation method |
| CN103446048A (en) * | 2013-09-12 | 2013-12-18 | 南京正宽医药科技有限公司 | Famotidine injection and preparation method thereof |
| CN105213952B (en) * | 2014-06-18 | 2019-11-08 | 张蕊 | A kind of Oleum Curcumae injection and preparation method thereof |
| CN114903963B (en) * | 2022-05-31 | 2024-04-26 | 北京格林意锐医药科技有限责任公司 | Zedoary turmeric oil injection and preparation method thereof |
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- 2013-09-03 CN CN201310394141.1A patent/CN103463565B/en not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
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| CN103610638B (en) | 2015-07-15 |
| CN103239684A (en) | 2013-08-14 |
| CN103463565B (en) | 2015-05-20 |
| CN103610638A (en) | 2014-03-05 |
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