CN105769755A - Methyhaaltrexone bromide injection and preparation method thereof - Google Patents
Methyhaaltrexone bromide injection and preparation method thereof Download PDFInfo
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- CN105769755A CN105769755A CN201410808984.6A CN201410808984A CN105769755A CN 105769755 A CN105769755 A CN 105769755A CN 201410808984 A CN201410808984 A CN 201410808984A CN 105769755 A CN105769755 A CN 105769755A
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Abstract
The invention provides a methyhaaltrexone bromide injection, which comprises a methyhaaltrexone bromide bulk drug and a proper amount of auxiliary materials. The invention also provides a preparation method of the methyhaaltrexone bromide injection. The injection is highly stable, and is basically stable under situations such as illumination, high temperature, and the like.
Description
Technical field
The present invention relates to a kind of methyhaaltrexone bromide injection and preparation method thereof, belong to chemicals medicine technical field.
Background technology
Methylnaltrexone bromide (methylnaltrexone bromide, MNTX), English name: Methylnaltrexonebromid, is a kind of selectivity mu opioid receptor antagonists.As a kind of quaternary ammonium salt, limit the methylnaltrexone bromide ability by blood brain barrier, make methylnaltrexone bromide as the opiate receptor antagonist of a kind of peripheral action, act in stomach intestinal tissue, therefore, methylnaltrexone bromide decreases the constipation effect of opioid drug, does not affect the opioid drug analgesic activity to central nervous system simultaneously.
Methylnaltrexone bromide has following characteristics: 1) acts on the μ receptor of periphery, does not activate the opiate receptor of central nervous system, it is possible to what rise is competitive antagonism；2) safety, series of experiments does not all find that it has serious toxic and side effects, and common adverse reactions is stomachache, diarrhoea, flatulence and dizziness；3) effect is fast, and several minutes gets final product onset；4) cathartic and softening agent good effect are led in treatment constipation than stool；5) action pathway is unique, can directly the opiate receptor on gastrointestinal tract in conjunction with onset, it is possible to be combined with opiate receptor through blood distribution whole body.Therefore, methylnaltrexone bromide not only can treat the gastrointestinal side-effect of opioid drug, it is possible to treatment parenteral untoward reaction；6) not by blood brain barrier, the Central Analgesic Effect of opiate is not weakened.
Methylnaltrexone bromide structural formula is as follows:
Yuan Yan manufacturing enterprise: WyethPharmaceuticalsInc..Methyhaaltrexone bromide injection is listed as the approval of opium peripheral acceptor antagonist by FDA and EMEA, does not have listing at present at home.
Summary of the invention
It is an object of the invention to provide a kind of methyhaaltrexone bromide injection, including methylnaltrexone bromide crude drug and appropriate amount of auxiliary materials.The preparation method that the present invention also provides for described methyhaaltrexone bromide injection.
Technical scheme is as follows:
A kind of methyhaaltrexone bromide injection, is made up of methylnaltrexone bromide crude drug and adjuvant, and wherein adjuvant includes disodiumedetate and antioxidant glycine.
Preferably, the methyhaaltrexone bromide injection of the present invention is made up of methylnaltrexone bromide crude drug and adjuvant, and adjuvant includes sodium chloride, disodiumedetate, glycine and water for injection.
Preferred, the methyhaaltrexone bromide injection of the present invention is mainly made up of following crude drug and adjuvant: methylnaltrexone bromide 12 weight portion, sodium chloride 3～5 weight portion, disodiumedetate 0.1～0.3 weight portion, glycine 0.1～0.2 weight portion, water for injection adds to 600 parts by volume, and the unit ratio of weight and volume is g: mL.
Further, the methyhaaltrexone bromide injection of the present invention is mainly made up of following crude drug and adjuvant: methylnaltrexone bromide 12 weight portion, sodium chloride 3.5～4.5 weight portion, disodiumedetate 0.2～0.25 weight portion, glycine 0.1～0.15 weight portion, water for injection adds to 600 parts by volume, and the unit ratio of weight and volume is g: mL.
Further, the methyhaaltrexone bromide injection of the present invention is mainly made up of following crude drug and adjuvant: methylnaltrexone bromide 12 weight portion, sodium chloride 3.9 weight portion, disodiumedetate 0.22 weight portion, glycine 0.12 weight portion, water for injection adds to 600 parts by volume, and the unit ratio of weight and volume is g: mL.
Preferably, methyhaaltrexone bromide injection of the present invention, every 1000 injection are made up of following crude drug and adjuvant: methylnaltrexone bromide 12g, sodium chloride 3.9g, disodiumedetate 0.22g, glycine 0.12g, water for injection adds to 600mL.
The preparation method of methyhaaltrexone bromide injection of the present invention, comprises the following steps:
(1) sodium chloride, disodiumedetate, glycine are joined in water for injection, stirring and dissolving；
(2) methylnaltrexone bromide, stirring and dissolving are added；
(3) coarse filtration: adding the needle-use activated carbon of 0.05% (W/V), 50～70 DEG C of stirring and adsorbing, membrane filtration removes activated carbon；
(4) fine straining: the filtrate after coarse filtration is regulated pH value to 3.0～5.0, use filter membrane fine straining；
(5) by fine straining filtrate fill, sealing, sterilizing.
Above-mentioned steps (3) coarse filtration is with 0.45 μm of membrane filtration；Step (4) fine straining is with 0.22 μm of membrane filtration.
Preferably, above-mentioned steps (4) hydrochloric acid of 1mol/L or the sodium hydroxide solution of 1mol/L regulates pH value to 4.0.
The invention have the advantage that
1, the present invention adopts metal chelating agent disodiumedetate and the combination of antioxidant glycine, achieves the effect that beyond thought injection is stable.Injection of the present invention is highly stable, even if when illumination high temperature, injection of the present invention is also basicly stable；Under condition of different pH, also basicly stable.
2, injection cost of the present invention is low, and adopted adjuvant is domestic common medicinal supplementary material.
3, injection processing technology of the present invention is simple, and product quality is high.
Detailed description of the invention
Illustrate from the present invention faced by prescription screening and pH value selecting party below, and technical scheme is described in detail by embodiment, but this is not limitation of the present invention, those skilled in the art's basic thought according to the present invention, various modifications may be made or improves, but without departing from the basic thought of the present invention, all within the scope of the present invention.
One, prescription screening:
1, antioxidant selects and consumption screening:
Force Degrading experiment from the oxidation of methylnaltrexone bromide crude drug it can be seen that methylnaltrexone bromide solution easily occurs oxidation to degrade Strong oxdiative environment, therefore should add a certain amount of antioxidant in preparation prescription.
It is also few as the adjuvant of antioxidant that consideration can be used in injection; and generally individually have certain pharmacologically active or toxic and side effects, therefore select glycine as antioxidant, and its consumption is screened; for evaluating the different glycine protective capability to preparation, with optimization the best glycine consumption.
Method: add main ingredient by Formulation table, by preparation general technology guidelines, be suitably added H2O2Originate as oxygen atom, under 80 DEG C of high temperature, be accelerated test, sampled respectively at 0,2,4 hour, draft relevant substance method by methylnaltrexone bromide crude drug and measure impurity situation of change, for screening suitable glycine consumption, under result is shown in.
Glycine consumption screening table
Methylnaltrexone bromide antioxidant consumption screening test result
Conclusion: when adding glycine in prescription, the oxidation resistance of preparation can be improved；Under Oxidative demage environment, nitrogen charging technique and to be not added with glycine technology antioxidant capacity all more weak.Therefore select the glycine of 12mg as this prescription antioxidant, namely every injection is measured as 0.12mg containing sweet acid.
2, metal chelating agent selects and consumption screening:
Due to methyhaaltrexone bromide injection in process of production, easily contact with metal implements, and introduce metal ion.For verifying the metal ion stability influence to methyhaaltrexone bromide injection, carry out complexing of metal ion agent and consumption screens.
Method: add main ingredient by Formulation table, by preparation general technology guidelines, and be suitably added FeCl in prescription3Solution is originated as metal ion, and is accelerated test under 60 DEG C of high temperature, samples respectively at 0,4,8 hour, drafts relevant substance method by methylnaltrexone bromide crude drug and measures impurity situation of change, is used for screening complexing of metal ion agent and consumption.
Result is as follows:
Metal chelating agent consumption screening test result
Conclusion: as seen from the experiment, metal ion can cause the unstability of methylnaltrexone bromide；Add complexing of metal ion agent, the stability of preparation can be increased；The consumption of chelating agent becomes positive correlation with preparation stability；The effect of EDTA-2Na is better than sodium citrate, selects EDTA-2Na as this preparation chelating agent, and consumption is every 0.22mg.
Two, pH value selects
The sodium chloride of recipe quantity, EDETATE SODIUM, glycine are added in injection water, stirring and dissolving.The methylnaltrexone bromide of recipe quantity is joined in adjuvant solution, stirring and dissolving.Injection is divided into three parts, adjusts pH3.0,4.0,5.0 respectively with 1mol/L hydrochloric acid.
Take above-mentioned solution respectively at 0,2,4,6,8,24h measure by drafting the relevant substance detecting method of methylnaltrexone bromide, investigate methylnaltrexone bromide stability in different pH value.Result is as follows:
Under condition of different pH, methyhaaltrexone bromide injection impurity situation investigates result
Conclusion: by the data recorded above, it is known that methyhaaltrexone bromide injection is under the condition of pH3.0,4.0,5.0, and main peak area, impurity, outward appearance have no significant change.Therefore the pH value of control this product is between 3.0～5.0.
Embodiment 1:
Preparation process:
(1) sodium chloride, disodiumedetate, glycine join in the water for injection of 600mL, are stirred to dissolve.
(2) add methylnaltrexone bromide, be stirred to dissolve.
(3) coarse filtration: adding the needle-use activated carbon of 0.05% (W/V), stirring and adsorbing 30 minutes at 70 DEG C, 0.45 μm of membrane filtration is except activated carbon.
(4) fine straining: regulate pH value to 4.0 with the sodium hydroxide solution of the hydrochloric acid of 1mol/L or 1mol/L, with 0.22 μm of filter membrane fine straining.
(5) fill, sealing, sterilizing.
Stability contrast experiment:
Sample is carried out influence factor's test, surveys the total impurities of the 10th day.
Sample:
1, the embodiment of the present invention 1
2, according to 27 pages of the 1st form the 2nd row prescriptions of Chinese patent 200780009723.6 description subscript, and the method in 200780009723.6, make comparative example.
By the sample of sample methylnaltrexone bromide injection, being respectively placed in illumination, 40 DEG C and 60 DEG C of influence factor's proof boxs and investigate 10 days, measure its total impurities situation of change, and contrasted with 0 day, concrete data are shown in form:
From above-mentioned experimental result it will be seen that embodiment of the present invention stability is better than comparative example.
Claims (10)
1. a methyhaaltrexone bromide injection, is made up of methylnaltrexone bromide crude drug and adjuvant, and wherein adjuvant includes metal chelating agent disodiumedetate and antioxidant glycine.
2. methyhaaltrexone bromide injection according to claim 1, it is characterised in that adjuvant includes sodium chloride, disodiumedetate, glycine and water for injection.
3. methyhaaltrexone bromide injection according to claim 2, it is characterized in that, mainly comprising of this injection is as follows: methylnaltrexone bromide 12 weight portion, sodium chloride 3～5 weight portion, disodiumedetate 0.1～0.3 weight portion, glycine 0.1～0.2 weight portion, water for injection adds to 600 parts by volume, and wherein weight is g: mL with the unit ratio of volume.
4. methyhaaltrexone bromide injection according to claim 3, it is characterized in that, mainly comprising of this injection is as follows: methylnaltrexone bromide 12 weight portion, sodium chloride 3.5～4.5 weight portion, disodiumedetate 0.2～0.25 weight portion, glycine 0.1～0.15 weight portion, water for injection adds to 600 parts by volume, and the unit ratio of weight and volume is g: mL.
5. methyhaaltrexone bromide injection according to claim 4, it is characterized in that, mainly comprising of this injection is as follows: methylnaltrexone bromide 12 weight portion, sodium chloride 3.9 weight portion, disodiumedetate 0.22 weight portion, glycine 0.12 weight portion, water for injection adds to 600 parts by volume, and the unit ratio of weight and volume is g: mL.
6. the methyhaaltrexone bromide injection according to any one in Claims 1 to 5, it is characterised in that the pH value of this injection is between 3.0～5.0.
7. methyhaaltrexone bromide injection according to claim 6, it is characterised in that the pH value of this injection is 4.0.
8. the preparation method of methyhaaltrexone bromide injection described in any one in claim 1～7, comprises the following steps:
1) sodium chloride, disodiumedetate and glycine are joined in water for injection, stirring and dissolving；
2) methylnaltrexone bromide, stirring and dissolving are added；
3) coarse filtration: in step 2) gained solution adds the needle-use activated carbon of 0.05% (W/V), 50～70 DEG C of stirring and adsorbing, with membrane filtration except activated carbon；
4) fine straining: coarse filtration gained filtrate is regulated pH value to 3.0～5.0, use filter membrane fine straining；
5) by fine straining filtrate fill, sealing, sterilizing.
9. preparation method according to claim 8, it is characterised in that described step 4) sodium hydroxide solution of the hydrochloric acid of middle 1mol/L or 1mol/L regulates pH value to 4.0.
10. preparation method according to claim 8, it is characterised in that step 3) coarse filtration is with 0.45 μm of membrane filtration；Step 4) fine straining is with 0.22 μm of membrane filtration.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110960486A (en) * | 2018-09-29 | 2020-04-07 | 北京凯因科技股份有限公司 | Methylnaltrexone bromide injection composition |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1767831A (en) * | 2003-04-08 | 2006-05-03 | 普罗热尼奇制药公司 | Pharmaceutical formulations containing methylnaltrexone |
| CN101405031A (en) * | 2006-08-04 | 2009-04-08 | 惠氏公司 | Formulations for parenteral delivery of compounds and uses thereof |
| CN101732243A (en) * | 2008-11-26 | 2010-06-16 | 重庆医药工业研究院有限责任公司 | Stable methyl naltrexone injection and preparation method thereof |
| CN102525911A (en) * | 2012-03-20 | 2012-07-04 | 南京臣功制药股份有限公司 | Methyhaaltrexone bromide injection and preparation method thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1767831A (en) * | 2003-04-08 | 2006-05-03 | 普罗热尼奇制药公司 | Pharmaceutical formulations containing methylnaltrexone |
| CN101405031A (en) * | 2006-08-04 | 2009-04-08 | 惠氏公司 | Formulations for parenteral delivery of compounds and uses thereof |
| CN101732243A (en) * | 2008-11-26 | 2010-06-16 | 重庆医药工业研究院有限责任公司 | Stable methyl naltrexone injection and preparation method thereof |
| CN102525911A (en) * | 2012-03-20 | 2012-07-04 | 南京臣功制药股份有限公司 | Methyhaaltrexone bromide injection and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110960486A (en) * | 2018-09-29 | 2020-04-07 | 北京凯因科技股份有限公司 | Methylnaltrexone bromide injection composition |
| CN110960486B (en) * | 2018-09-29 | 2022-05-13 | 北京凯因科技股份有限公司 | Methylnaltrexone bromide injection composition |
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