CN104288143A - Glycopyrrolate and neosigmine methylsuIfate combined injection and preparation method thereof - Google Patents
Glycopyrrolate and neosigmine methylsuIfate combined injection and preparation method thereof Download PDFInfo
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- CN104288143A CN104288143A CN201410337335.2A CN201410337335A CN104288143A CN 104288143 A CN104288143 A CN 104288143A CN 201410337335 A CN201410337335 A CN 201410337335A CN 104288143 A CN104288143 A CN 104288143A
- Authority
- CN
- China
- Prior art keywords
- injection
- sulfuric acid
- glycopyrronium bromide
- methyl
- neostigmine
- Prior art date
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- Pending
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- 238000002347 injection Methods 0.000 title claims abstract description 69
- 239000007924 injection Substances 0.000 title claims abstract description 69
- VPNYRYCIDCJBOM-UHFFFAOYSA-M Glycopyrronium bromide Chemical compound [Br-].C1[N+](C)(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 VPNYRYCIDCJBOM-UHFFFAOYSA-M 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229940015042 glycopyrrolate Drugs 0.000 title abstract description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 15
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 claims abstract description 9
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 9
- 229940087562 sodium acetate trihydrate Drugs 0.000 claims abstract description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 8
- 230000001954 sterilising effect Effects 0.000 claims abstract description 7
- 239000000654 additive Substances 0.000 claims abstract description 5
- 239000000872 buffer Substances 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 5
- 239000003381 stabilizer Substances 0.000 claims abstract description 5
- 239000001509 sodium citrate Substances 0.000 claims abstract description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims abstract description 3
- 229960002362 neostigmine Drugs 0.000 claims description 44
- 229960002462 glycopyrronium bromide Drugs 0.000 claims description 40
- 150000001875 compounds Chemical class 0.000 claims description 27
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 27
- 239000000047 product Substances 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- JZMJDSHXVKJFKW-UHFFFAOYSA-N methyl sulfate Chemical compound COS(O)(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
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- ALWKGYPQUAPLQC-UHFFFAOYSA-N neostigmine Chemical compound CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 ALWKGYPQUAPLQC-UHFFFAOYSA-N 0.000 claims 7
- 239000003814 drug Substances 0.000 abstract description 18
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- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 6
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- GARJMFRQLMUUDD-UHFFFAOYSA-N 1,1-dimethylpyrrolidin-1-ium Chemical compound C[N+]1(C)CCCC1 GARJMFRQLMUUDD-UHFFFAOYSA-N 0.000 description 1
- -1 2-Cyclopentyl-2-hydroxy-2-phenylacetyl Chemical group 0.000 description 1
- BKILWHYRLBCASZ-UHFFFAOYSA-M 2-[bis(2-hydroxyethyl)amino]ethanol;2-hydroxypropanoate;phenylmercury(1+) Chemical compound CC(O)C([O-])=O.[Hg+]C1=CC=CC=C1.OCCN(CCO)CCO BKILWHYRLBCASZ-UHFFFAOYSA-M 0.000 description 1
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- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
-
- 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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Emergency Medicine (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a stable glycopyrrolate and neosigmine methylsuIfate combined injection and a preparation method thereof. An injection additive is composed of a buffer of citric acid and sodium citrate, a stabilizer sodium acetate trihydrate and an isoosmotic adjusting agent sodium chloride. The pH value of the injection is 3.5-4.0, related substances are basically not increased under the condition of hot-pressure sterilization, the problems do not appear during storage that pH value decreases, visible foreign-matter inspection is unqualified and related substance inspection is unqualified, and the product is guaranteed to accord with prescription on drug standards and is convenient for clinical medication and popularization.
Description
Technical field
The present invention relates to a kind of stable compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection and preparation method thereof, belong to technical field of medicine.
Background technology
The essential information of glycopyrronium bromide is as follows:
English name: Glycopyrrolate
Chinese chemical name: (3RS)-3-[(2SR)-(2-cyclopenta-2-hydroxyl-2-phenylacetyl) oxygen]-1,1-dimethyl pyrrolidine bromate
English language Chemical name: (3RS)-3-[(2SR) (2-Cyclopentyl-2-hydroxy-2-phenylacetyl) oxy]-
1,1-dimethylpyrrolidinium?bromide
Chemical structural formula:
Molecular formula: C
19h
28brNO
3
Relative molecular mass: 398.33
Glycopyrronium bromide white or off-white color crystalline powder, odorless, bitter in the mouth; Fusing point is 193 DEG C ~ 198 DEG C; Be 0.34 at the partition coefficient of n-octyl alcohol/water; Easily molten in water, methanol or ethanol, almost insoluble in chloroform, dichloromethane or ether.
Glycopyrronium bromide injection is colourless or almost anhydrous clear liquid.
Glycopyrronium bromide is a kind of similar atropinic quaternary amines anticholinergic agents, has stronger suppression gastric secretion effect and slight gastrointestinal tract spasmolysis.This medicine can regulate gastrointestinal peristalsis, reduces the excessive secretion of gastric secretion and free acid concentration and suppression trachea and bronchus.In addition, this medicine also has the anti-salivation effect stronger than atropine, and effect is held time longer.In addition, the quaternary ammonium group due to this medicine limits it and passes through the such lipocyte film of such as blood-cerebrospinal fluid barrier, so the untoward reaction relevant to central nervous system occurs few.This medicine is stronger than the atropine effect of equivalent 5 ~ 6 times; Its anti-current saliva effect is good compared with atropine, and sedation comparatively scopolamine is light; Its cardioacceleration, blurred vision, comparatively atropine is light in the untoward reaction such as heating; Retardance platycoria is comparatively remarkable when atropine systemic administration, but this medicine only can cause very little change; This medicine and neostigmine share corrects competitive drug overdose of flaccid muscles, and compared with share neostigmine with atropine, tachycardia occurs less, and only saliva effect is better.
Glycopyrronium bromide injection, mainly as premedication, for preoperative Antimuscarinic effect, reduces saliva, trachea-bronchial epithelial cell and pharyngeal secretion, reduces gastric secretion and free acidity, cardiac vagal inhibitory reflex when block anesthesia induction and intubate.
The essential information of methyl-sulfuric acid neostigmine is as follows:
English name: Neosigmine MethylsuIfate
Chinese chemical name: N, N, N-trimethyl-3-[(dimethylamino) formyloxy] puratized agricultural spray Methylsulfate
English language Chemical name: 3-(N, N-Dimethylcarbamoyloxy)-N, N, N ,-trimethylanilinium methyl sulfate
Chemical structural formula:
Molecular formula: C13H22N2O6S
Relative molecular mass: 334.4
Methyl-sulfuric acid neostigmine is white crystalline powder; Odorless, bitter in the mouth; Have draw moist; Very easily dissolve in water, easily molten in ethanol; Fusing point is 143 ~ 149 DEG C.
Methyl-sulfuric acid neostigmine injection is colourless or almost anhydrous clear liquid.
Methyl-sulfuric acid neostigmine is the ejection preparation of neostigmine.Effect is same with neostigmine bromide.Be usually used in serious and urgent myasthenia gravis, postoperative abdomen flatulence, urine retention.Can be used for excessive poisoning, the paroxysmal supraventricular tachycardia of competitive muscle relaxant.Also for the dyskinesia of craniocerebral injury, tuberculous meningitis, the diseases such as sick convalescent paralysis, optic atrophy and neuritis such as poliomyelitis and encephalitis.Various paralysis, muscle and the neurosiss etc. of relaxing of other internal medicine, gynecological and department of eye.
Compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection is in European Union's approval listing, and because glycopyrronium bromide structure has ester group and quaternary ammonium group, its aqueous solution has degraded and sterilizing unstability; Equally, also having ester group and quaternary ammonium group in methyl-sulfuric acid neostigmine structure, there is degraded and sterilizing unstability in its aqueous solution equally.
The technique of compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection and preparation method, both at home and abroad without any bibliographical information, the prescription of this product and technique, directly determine quality and the stability of this product.
The present inventor is in the favorite outer discovery of research and development compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection process, be in 3.5 ~ 4.0 scopes at pH, with citric acid, trisodium citrate (or citrate buffer) is as buffer agent, using sodium chloride as isoosmotic adjusting agent, using sodium acetate trihydrate as stabilizing agent, by the Study on influencing factors of pH value range many times, sodium acetate trihydrate quantifier elimination, the stability of finally obtained compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection is than according to European Union's listing compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection, (sample of trade name: Robinul-Neostigmine is better.And by pharmacological testing, we prove that the obtained injection of this formula is without hemolytic, blood vessel irritation and anaphylaxis.
This technique not only increases the stability of this product, and also simple possible, is easy to suitability for industrialized production.
Summary of the invention
The object of this invention is to provide a kind of stable compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection, containing glycopyrronium bromide, methyl-sulfuric acid neostigmine and additives, wherein, the buffer that additives are made up of (a) citric acid and sodium citrate, b () stabilizing agent sodium acetate trihydrate, (c) isoosmotic adjusting agent sodium chloride forms.
A kind of stable its pH value of compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection provided by the invention is 3.5 ~ 4.0, and in this pH value range, compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection is the most stable.
A kind of stable compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection provided by the invention, the consumption of its sodium acetate trihydrate is 0.2mg/ml, this consumption, and compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection is the most stable.
A kind of stable its osmotic pressure ratio of compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection provided by the invention is 0.9 ~ 1.1.
Present invention also offers the preparation method of stable compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection, this preparation method is:
A) take the glycopyrronium bromide of formula ratio, methyl-sulfuric acid neostigmine and pharmaceutical carrier, add appropriate water for injection and dissolve;
B) add the injection needle-use activated carbon of 0.6%, 50 DEG C ~ 60 DEG C insulated and stirred 30min, filtering decarbonization, obtains filtrate;
C) be cooled to room temperature, if desired, by the hydrochloric acid of appropriate 0.1N or the sodium hydroxide adjust ph 3.5 ~ 4.0 of 0.1N, add to the full amount of water for injection, measure intermediates content and pH value; After qualified
D) through 0.22 μm of filtering with microporous membrane, fill is in ampere bottle, and 121 DEG C of pressure sterilizing 15min, obtain compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection finished product.
Beneficial effect of the present invention:
The present invention, by creative work, discloses a kind of stable compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection and preparation method thereof.Study discovery by experiment, this product pH value is the most stable 3.5 ~ 4.0, and this product uses buffer as the pH value of stable this product first, and in sterilizing and stability test are investigated, pH value is substantially constant; This product uses sodium acetate trihydrate as the stabilizing agent of this product first, most suitable when its consumption is 0.2mg/ml.
Product of the present invention solves and is carrying out occurring in high temperature sterilize and storage process that pH value declines, solution colour turns yellow, visible foreign matters checks defective, the underproof problem of Related substances separation.
Compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection reasonable recipe of the present invention, technique is simple, good stability.Through influence factor's test, 40 DEG C of accelerated tests 6 months, sample appearance character, pH, active constituent content and related substance etc. had no significant change.
By following experiment, effective achievement of the present invention can be described.
Detailed description of the invention
The following examples can conduct further description the present invention, but these embodiments should as limitation of the scope of the invention.
embodiment 1sample preparation
Prescription:
Glycopyrronium bromide 0.5g
Methyl-sulfuric acid neostigmine 2.5g
Sodium acetate trihydrate 0.2g
Citric acid 1.0g
Citric acid trisodium 1.3g
Sodium chloride 9.0g
0.1N Sodium hydroxide q. s
Injection adds to water 1000ml
| 1000 |
Preparation technology:
A) take the glycopyrronium bromide of formula ratio, methyl-sulfuric acid neostigmine and pharmaceutical carrier, add 80% water for injection and dissolve;
B) add the injection needle-use activated carbon of 0.6%, 50 DEG C ~ 60 DEG C insulated and stirred 30min, filtering decarbonization, obtains filtrate;
C) be cooled to room temperature, if desired, by the sodium hydroxide adjust ph 3.5 ~ 4.0 of 0.1N, add to the full amount of water for injection, measure intermediates content and pH value; After qualified
D) through 0.22 μm of filtering with microporous membrane, fill is in ampere bottle, and 121 DEG C of pressure sterilizing 15min, obtain compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection finished product.
embodiment 2stability test is studied
One, influence factor's experiment investigation
Embodiment 1 sample (specification is 1ml:0.5mg glycopyrronium bromide/2.5mg methyl-sulfuric acid neostigmine), lot number is 140206, batch is 1000, take ampoule as packaging, and influence factor's test of preparation is carried out by this batch sample, according to medicine stability test guideline (Chinese Pharmacopoeia version in 2010 two annex XIX C), by stability high spot reviews project, sample is detected, investigate low temperature, high temperature and strong illumination to the impact of this product.
1, hot test
In thermostatic drying chamber this product being placed in 60 DEG C 10 days, maintain drying baker temperature 60 C ± 2 DEG C, sample respectively at the 5th day and the 10th day, measure by stability high spot reviews project.Result of the test following table.
Compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection high temperature (60 DEG C) experiment investigation result
| Time | Appearance character | pH | Clarity | Particulate matter | Impurity A | Content (%) | Total assorted (%) |
| 0 day | Achromatism and clarity liquid | 3.85 | Clarification | Conform with the regulations | 0.11% | 99.85 | 0.15 |
| 5 days | Achromatism and clarity liquid | 3.86 | Clarification | Conform with the regulations | 0.12% | 99.45 | 0.18 |
| 10 days | Achromatism and clarity liquid | 3.85 | Clarification | Conform with the regulations | 0.13% | 99.90 | 0.18 |
Result of the test: this product is placed 10 days through high temperature 60 DEG C, and sample appearance character and pH have no obvious change, and content, related substance have no significant change.As can be seen here, this product is deposited stable under the high temperature conditions.
2, strong illumination test
This product to be placed in illumination meter 10 days, to maintain illumination 4500lx, sample respectively at the 5th day and the 10th day, measure by stability high spot reviews project.Result of the test sees the following form.
Compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection strong illumination experiment investigation result
| Time | Appearance character | pH | Clarity | Particulate matter | Impurity A | Content (%) | Total assorted (%) |
| 0 day | Achromatism and clarity liquid | 3.85 | Clarification | Conform with the regulations | 0.11% | 99.85 | 0.15 |
| 5 days | Achromatism and clarity liquid | 3.86 | Clarification | Conform with the regulations | 0.11% | 99.88 | 0.15 |
| 10 days | Achromatism and clarity liquid | 3.86 | Clarification | Conform with the regulations | 0.12% | 99.69 | 0.16 |
Result of the test: this product is through strong illumination after 10 days, and its outward appearance, pH value, clarity, content, related substance etc. have no significant change, and this product is insensitive to light as can be seen here, itself is stable.
3, low-temperature test
In refrigerator this product being placed in 4 DEG C 10 days, respectively at the 5th day and sampling in the 10th day, measure by stability high spot reviews project.Result of the test sees the following form.
Compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection low-temperature test investigates result
| Time | Appearance character | pH | Clarity | Particulate matter | Impurity A | Content (%) | Total assorted (%) |
| 0 day | Achromatism and clarity liquid | 3.85 | Clarification | Conform with the regulations | 0.11% | 99.85 | 0.15 |
| 5 days | Achromatism and clarity liquid | 3.85 | Clarification | Conform with the regulations | 0.11% | 99.93 | 0.15 |
| 10 days | Achromatism and clarity liquid | 3.86 | Clarification | Conform with the regulations | 0.11% | 99.90 | 0.15 |
Result of the test: this product is placed 10 days through low temperature 4 DEG C, and sample appearance character, pH value and content have no obvious change, and nodeless mesh is separated out.As can be seen here, this product is deposited stable under cryogenic.
Two, accelerated test is investigated
Embodiment 1 sample (specification is 1ml:0.5mg glycopyrronium bromide/2.5mg methyl-sulfuric acid neostigmine), lot number is 140206,140207,140208, batch is respectively 1000, commercially available product Robinul-Neostigmine injection, lot number is A97355, by new drug requirements of customs declaration, by sample under listing terms of packing, be placed in the climatic chamber of temperature 40 DEG C of relative humiditys 75%, respectively at 1,2,3, sampling in June, result of the test sees the following form.
Compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection accelerated test investigates result
Conclusion: inventive samples injection 40 DEG C ± 2 DEG C, relative humidity be 75% ± 5% condition under place 6 months, every Testing index without significant change, commercially available product poor stability.
embodiment 3local security's experimental study
The auricular vein irritation test of 1 rabbit
1.1 dosage and grouping
If test medicine group and negative control group, the left ear of rabbit instils 0.9% sodium chloride injection, and auris dextra instils injection of the present invention, carries out consubstantiality own control.By reagent injection of the present invention, dosage 7.5mg/37.5mg/kg, is equivalent to 15 times of quantity.Negative control group gives isopyknic 0.9% sodium chloride injection, and administration volume is 10mL/kg.
1.2 medication
White big ear rabbit 3, animal is fixed in rabbit hutch, slowly to instil 0.9% sodium chloride injection respectively at left ear auricular vein, auris dextra auricular vein is instillation injection injection of the present invention slowly, dropped amount is 10mL/kg, drip velocity 1mL/min (20/min), every day 2 times, continuous 5 days.
1.3 index observing
Carry out perusal and record to rabbit injection site before and after administration every day and after last administration 72h, whether blood vessel and the surrounding tissue of observing injection site have the irritant reaction such as redness, mound speckle.After observation period terminates, put to death rabbit, clip auricle, 10% neutral formalin is fixed, specimens paraffin embedding slices, and HE dyes, and carries out histopathological examination.
1.4 result
All rabbit continuous 5d auricular vein instils after injection of the present invention, perusal injection site and away from injection place blood vessel and tissue, be showed no hemorrhage, the abnormal change such as congestion, edema, without significant difference compared with the control sides ear blood vessel of instillation 0.9% sodium chloride injection and surrounding tissue.
Microscopic observation, 0.9% sodium chloride injection matched group and injection medicine group auricular vein blood vessel of the present invention are without vessel wall damage, without thrombosis, without local organization degeneration necrosis, congestion and edema and cell infiltration around blood vessel, around minority blood vessel, only there is stove or be dispersed in cell infiltration.
1.5 conclusion
Injection intravenous drip of the present invention has no stimulation to rabbit local vascular.
The systemic anaphylaxis test of 2 Cavia porcelluss
2.1 dosage and grouping
If by reagent group, positive controls and negative control group.Often organize 6 Cavia porcelluss.Give injection stock solution of the present invention by reagent group, positive controls gives the freshly-slaughtered poultry Ovum Gallus domesticus album of 5%, and negative control group gives 0.9% sodium chloride injection, and during sensitization, administration volume is only 0.5mL/.When exciting, administration volume is only 2mL/.
2.2 sensitization with excite
Cavia porcellus 20, adaptability raises 3 days.Get Cavia porcellus 18, be divided into 3 groups at random by body weight, often organize 6.Remain 2 Cavia porcelluss routine to raise, in order to after booster injection, if when finding that there is anaphylaxis, from intravenous injection booster dose by reagent, observe the similar symptoms of allergic with or without causing by reagent effect, reference when judging for result.
Test medicine group lumbar injection injection of the present invention, positive controls gives the freshly-slaughtered poultry Ovum Gallus domesticus album of 5%, and negative control group gives 0.9% sodium chloride injection, and sensitization administration volume is 0.5mL/ only, the next day 1 time, totally 3 times.During sensitization, every day observes the state of each Cavia porcellus, first and last sensitization and excite the body weight weighing Cavia porcellus the same day, observation body weight change.After last sensitization the 14th day and the 21st day, get 3 Cavia porcellus intravenous injection relative medicines for each group and excite, excite administration volume to be only 2mL/.
2.3 observation index
Excite in rear 30min, symptom shown according to the form below is observed in detail and is recorded the reaction of every Cavia porcellus, the appearance of symptom and extinction time, the longest observation 3 hours.
Symptoms of allergic
| 0 is normal | 7 rapid breathing | 14 instability of gait |
| 1 is unpeaceful | 8 urinate | 15 jump |
| 2 vertical | 9 defecation | 16 pant |
| 3 shake | 10 shed tears | 17 spasm |
| 4 scratch nose | 11 dyspnea | 18 horizontal turns |
| 5 sneezes | 12 wheezing sounds | 19 Cheyne-Stokes respiration |
| 6 coughs | 13 purpuras | 20 is dead |
2.4 evaluation criterion
According to the form below carries out the evaluation of whole body sensitization to injection of the present invention.
Whole body sensitization evaluation criterion
| Symptom | Judge | Evaluate |
| 0 | - | Anaphylaxis is negative |
| 1-4 symptom | + | The weak positive of anaphylaxis |
| 5-10 symptom | + + | Anaphylaxis is positive |
| 11-19 symptom | + + + | Anaphylaxis strong positive |
| 20 | + + + + | The extremely strong positive of anaphylaxis |
2.5 result
During sensitization, the state such as diet, activity of each Cavia porcellus is all normal, and body weight increases all to some extent.Respectively organize Cavia porcellus body weight on the same day to compare, there was no significant difference.
Cavia porcellus body weight change (±
s, g)
When after last administration, 14d and 21d excites, each Cavia porcellus of 5% freshly-slaughtered poultry Ovum Gallus domesticus album positive controls occur all to some extent restless, tremble, scratch nose, sneeze, cough, tic, instability of gait, jump, pant, spasm, Cheyne-Stokes respiration, shock is to the symptoms of allergic such as dead, and majority is dead in about 2min, irritated incidence rate 100%, in strong extremely strong positive anaphylaxis.There is allergic symptom in none example of Cavia porcellus of 0.9% sodium chloride injection group and injection group of the present invention, anaphylaxis is feminine gender.Show that injection in Guinea-pigs of the present invention is without whole body sensitivity response.
Injection Cavia porcellus systemic anaphylaxis result of the test (n=3) of the present invention
2.6 conclusion
Injection in Guinea-pigs of the present invention is without whole body sensitivity response.
The outer hemolytic test of 3 injecting fluids of the present invention
The preparation of 3.1 red cell suspensions
Rabbit Heart gets blood 10mL, puts into sterile beaker, stirs blood 5min gently with sterile glass rod, removing Fibrinogen, make into defibrinated blood, then add 0.9% sodium chloride injection of 100mL, mixing, centrifugal (1500rpm, 10min), get the erythrocyte of precipitation, this washing for several times for another example, until supernatant redfree, the red cell suspension that gained erythrocyte is made into 2% with 0.9% sodium chloride injection is for subsequent use.
3.2 liquid feeding method
Get 7 test tubes, be numbered, 1 ~ No. 5 pipe is test sample pipe, No. 6 pipes are negative control pipe, No. 7 pipes are positive control pipe, by adding 2% red cell suspension, 0.9% sodium chloride injection, distilled water and 15% injection of the present invention shown in table 6 successively, and mixing, cultivate in (37 ± 0.5) DEG C calorstat immediately, examine respectively at 15min, 30min, 45min, 60min, 2h, 3h after putting incubator.
Hemolysis in vitro test application of sample table (mL)
| Test tube number | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 2% rabbit erythrocyte suspension | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
| 0.9% sodium chloride injection | 2.0 | 2.1 | 2.2 | 2.3 | 2.4 | 2.5 | － |
| Distilled water | － | － | － | － | － | － | 2.5 |
| 15% injection of the present invention | 0.5 | 0.4 | 0.3 | 0.2 | 0.1 | － | － |
3.3 observation index
By the standard of " Chemical induced irritation, anaphylaxis and hemolytic investigative technique guideline " to whether having haemolysis and red cell agglutination to judge, to judge the impact of test medicine on hemolysis in vitro.
Hemolysis in vitro test criterion
| Judge | Finding phenomenon |
| Haemolysis (+) | Solution is clear and bright redness, acellular or have a small amount of cell residue at the bottom of pipe |
| Without haemolysis (-) | Erythrocyte all sinks, supernatant achromatism and clarity |
| Red cell agglutination (*) | There is rufous flocky precipitate in solution, do not disperse after jolting |
3.4 result
Result shows, distilled water control tube (positive control) is still red clear solution, causes erythrocyte fragmentation because inside and outside osmotic pressure does not wait, and haemolysis occurs, and red clear solution does not change.All there is layering in various degree in 0.9% sodium chloride injection control tube (negative control) and each liquid injection pipe of the present invention (test medicine) solution within the observed time, the supernatant is achromatism and clarity, occur without haemolysis, occur erythrocyte bottom test tube, and occur without red cell agglutination.Show that injection of the present invention is in the test of routine in vitro test tube method, to rabbit blood without haemolysis.
The outer hemolytic result of the test of injecting fluid of the present invention
Note: "+" is haemolysis, "-" is without haemolysis, and " * " is red cell agglutination
3.5 conclusion
Injection of the present invention to rabbit extracorporeal blood without haemolysis.
Claims (5)
1. a stable compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection, containing glycopyrronium bromide, methyl-sulfuric acid neostigmine and additives, it is characterized in that: the buffer that additives are made up of (a) citric acid and sodium citrate, b () stabilizing agent sodium acetate trihydrate, (c) isoosmotic adjusting agent sodium chloride forms.
2. require a kind of stable compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection described in 1 according to profit, it is characterized in that, the pH value of this injection is 3.5 ~ 4.0.
3. require a kind of stable compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection described in 1 according to profit, it is characterized in that, the consumption of sodium acetate trihydrate is 0.2mg/ml.
4. injection according to claims 1 to 2, is characterized in that, the osmotic pressure ratio of this injection is 0.9 ~ 1.1.
5. the preparation method of stable compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection, is characterized in that comprising following process:
A) take the glycopyrronium bromide of formula ratio, methyl-sulfuric acid neostigmine and pharmaceutical carrier, add appropriate water for injection and dissolve;
B) add the injection needle-use activated carbon of 0.6%, 50 DEG C ~ 60 DEG C insulated and stirred 30min, filtering decarbonization, obtains filtrate;
C) be cooled to room temperature, if desired, by the hydrochloric acid of appropriate 0.1N or the sodium hydroxide adjust ph 3.5 ~ 4.0 of 0.1N, add to the full amount of water for injection, measure intermediates content and pH value; After qualified
D) through 0.22 μm of filtering with microporous membrane, fill is in ampere bottle, and 121 DEG C of pressure sterilizing 15min, obtain compound recipe glycopyrronium bromide methyl-sulfuric acid neostigmine injection finished product.
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| US10456354B1 (en) | 2018-05-09 | 2019-10-29 | Slayback Pharma Llc | Ready-to-use injectable pharmaceutical compositions comprising neostigmine and glycopyrrolate |
| CN111437254A (en) * | 2020-05-28 | 2020-07-24 | 成都欣捷高新技术开发股份有限公司 | Glycopyrronium bromide injection and preparation method thereof |
| CN113230206A (en) * | 2021-03-19 | 2021-08-10 | 成都欣捷高新技术开发股份有限公司 | Neostigmine methosulfate composition and preparation method thereof |
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| US10456354B1 (en) | 2018-05-09 | 2019-10-29 | Slayback Pharma Llc | Ready-to-use injectable pharmaceutical compositions comprising neostigmine and glycopyrrolate |
| US11110054B2 (en) | 2018-05-09 | 2021-09-07 | Slayback Pharma Llc | Ready-to-use injectable pharmaceutical compositions comprising neostigmine and glycopyrrolate |
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| US12151020B2 (en) | 2018-05-09 | 2024-11-26 | Slayback Pharma Llc | Ready-to-use injectable pharmaceutical compositions comprising neostigmine and glycopyrrolate |
| CN111437254A (en) * | 2020-05-28 | 2020-07-24 | 成都欣捷高新技术开发股份有限公司 | Glycopyrronium bromide injection and preparation method thereof |
| CN113230206A (en) * | 2021-03-19 | 2021-08-10 | 成都欣捷高新技术开发股份有限公司 | Neostigmine methosulfate composition and preparation method thereof |
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Application publication date: 20150121 |