CN101732243B - Stable methyl naltrexone injection and preparation method thereof - Google Patents
Stable methyl naltrexone injection and preparation method thereof Download PDFInfo
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- CN101732243B CN101732243B CN 200810233125 CN200810233125A CN101732243B CN 101732243 B CN101732243 B CN 101732243B CN 200810233125 CN200810233125 CN 200810233125 CN 200810233125 A CN200810233125 A CN 200810233125A CN 101732243 B CN101732243 B CN 101732243B
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Abstract
The invention relates to a stable methyl naltrexone injection or a pharmaceutical salt injection thereof and a preparation method thereof. The injection comprises methyl naltrexone or pharmaceutical salt thereof and additive, wherein the additive is citric acid buffer salt and antioxidant, and the antioxidant is one or more chosen from thiourea, cysteine, L-cysteine, valine, L-valine and nicotinamide. The prescription of the methyl naltrexone injection of the invention uses no EDTA or derivative thereof in the prescription of a foreign market methyl naltrexone injection but has higher stability than the foreign market methyl naltrexone injection. The preparation method of the stable methyl naltrexone injection of the invention has simple process and is applied to mass production.
Description
Technical field:
The present invention relates to a kind of stable medicaments injection and preparation method thereof; Be specifically related to a kind of methyl naltrexone or its officinal salt; And with citric acid buffer salt and one or more antioxidant of being selected from thiourea, cysteine, L-cysteine, valine, L-valine, nicotiamide as additives, especially methylnaltrexone bromide becomes the injection of effective ingredient.
Background technology:
The chemical structural formula of methylnaltrexone bromide (methylnaltrexone bromide) is:
Chemical name is 17-ring third methyl-4,5-epoxy-3,14-dihydroxy-17-methyl-6-oxygen-and, bromide (5a)
Methylnaltrexone bromide is white or off-white color crystalline powder, and is water-soluble, no hygroscopicity, and fusing point is 251 ℃, and pH is approximately 4.6, and octanol/water partition coefficient (logP) is-1.12.
The methylnaltrexone bromide injection is colourless or almost colourless clear and bright solution.
Methylnaltrexone bromide is by Wyeth Pharmaceuticals company and Progenics Pharmaceuticals; Inc. the peripheral opioid receptor antagonist developed jointly of company; (specification: trade name 12mg/0.6ml) is RELISTOR to its injection of FDA approval, is mainly used in the constipation that treatment is caused by the opium treatment clinically.
WO02098422 discloses a kind of with the method for methyl naltrexone treatment because of the inductive immunosuppressant disease of opium (like HIV); In the description of this patent, mention the injection of methyl naltrexone; Its active substance consumption is 0.05-0.5mg/kg; Buffer is acetate buffer (1-2%W/V), citrate buffer solution (1-3% W/V), and antiseptic is selected from Acetochlorone, nipalgin is first-class.
World patent WO2008019115 discloses the injection of methyl naltrexone or its officinal salt, comprises calcium salt and chelating agen as stabilizing agent, and the also available chelating agen that contains calcium salt is as stabilizing agent.This patent also discloses the method for preparing of methyl naltrexone injection: preparation earlier contains the solution of methyl naltrexone or its officinal salt, isoosmotic adjusting agent and calcium salt chelating agen; This solution and divide of sterilizing is filled in one or more sealed containers.
The Chinese patent CN1767831 of Progenics Pharm Inc. application discloses the pharmaceutical preparation of the solution that comprises methyl naltrexone or its salt, and principal character is behind autoclaving or room temperature held 6 months, and the degraded concentration of methyl naltrexone is no more than 2%.Its dependent claims limits said preparation respectively and contains chelating agen (EDTA etc.), and buffer (Acidum Citricum etc.), pH value are 2-6, antioxidant, isotonic agent, cryoprotector (polyhydric alcohol) or opium material, and methyl naltrexone concentration is 0.1-100mg/ml.Wherein, antioxidant is selected from ascorbic acid derivates, fourth hydroxyl fennel ether, butylated hydroxytoluene, alkyl gallates, sodium pyrosulfite, sodium sulfite, sodium dithionite, sodium thioglycollate, rongalite, tocopherol and derivant, thioglycerol and sodium sulfite.
The inventor is unexpected the discovery in development methylnaltrexone bromide injection process; In pH3～4 scopes; With citric acid, trisodium citrate (or citrate buffer) as buffer agent, with sodium chloride as isoosmotic adjusting agent; With one or more materials that are selected from thiourea, cysteine, L-cysteine, valine, L-valine, nicotiamide as antioxidant; Under the situation that does not have chelating agen to exist, the stability of the methylnaltrexone bromide injection that makes is better than the sample that the prescription by listing RELISTOR prepares.And we do not have hemolytic, blood vessel irritation and anaphylaxis through the injection that this prescription of pharmacological testing proof makes.Owing to contain phenolic hydroxyl group in the methylnaltrexone bromide chemical structural formula; Oxidized easily, so we also carry out nitrogen filled protection except in prescription, adding the antioxidant in preparation technology; Itself and oxygen are further isolated; This technology has not only improved the stability of these article, and also simple possible is easy to suitability for industrialized production.
Summary of the invention:
Of the present inventionly supplied a kind of stable methyl naltrexone injection, contained methyl naltrexone or its officinal salt and additives, it is characterized in that: additives comprise (a) citrate buffer and (b) one or more antioxidant.Wherein, the officinal salt of said methyl naltrexone is an inorganic salt, and example hydrochloric acid salt, hydrobromate, sulfate and other acylate are preferably hydrobromate, i.e. methylnaltrexone bromide.
Methyl naltrexone injection of the present invention, wherein the concentration of methyl naltrexone is 1.0～50.0mg/ml, is preferably 10～30mg/ml, more preferably 20mg/ml.
Methyl naltrexone injection of the present invention, its pH scope is 3.0～4.0.
Methyl naltrexone injection of the present invention, the concentration range of its citrate buffer is: 0.5mg/ml～10mg/ml.
Methyl naltrexone injection of the present invention, its described antioxidant is selected from one or more in the following reagent: thiourea, cysteine, L-cysteine, valine, L-valine, nicotiamide, its concentration range is: 0.01～5mg/ml.
In one embodiment; Methyl naltrexone injection of the present invention; Contain methyl naltrexone or its officinal salt; Its concentration is 1.0～50.0mg/ml, and concentration is the antioxidant that citrate buffer and one or more of 0.5mg/ml～10mg/ml are selected from one group of thiourea, cysteine, L-cysteine, valine, L-valine and nicotiamide.The wherein preferred 10-30mg/ml of the concentration of methyl naltrexone, more preferably 20mg/ml.Also further comprise isotonic agent sodium chloride in this embodiment.The PH of the injection of this embodiment is 3.0-4.0.
In another embodiment; Methyl naltrexone injection of the present invention contains methyl naltrexone or its officinal salt, and its concentration is 1.0～50.0mg/ml; Concentration is the citrate buffer of 0.5mg/ml～10mg/ml; With one or more antioxidant that is selected from one group of thiourea, cysteine, L-cysteine, valine, L-valine and nicotiamide, its concentration range is: 0.01～5mg/ml, the PH of this injection are 3.0～4.0.Wherein, the preferred 10-30mg/ml of the concentration of methyl naltrexone, more preferably 20mg/ml.PH usable acid or alkali are regulated, example hydrochloric acid, hydrobromic acid, citric acid or its buffer, sodium hydroxide solution etc.Also further comprise isotonic agent sodium chloride in this embodiment.
In another specific embodiments; Methyl naltrexone injection of the present invention contains methyl naltrexone or its officinal salt, and its concentration is 1.0～50.0mg/ml, preferred 10-30mg/ml; Citrate buffer; Its concentration is 0.5mg/ml～10mg/ml, and one or more are selected from the antioxidant of one group of thiourea, cysteine, L-cysteine, valine, L-valine and nicotiamide, and its concentration is 0.01～5mg/ml; With a kind of isotonic agent of sodium chloride, the PH of this injection is 3.0～4.0.Wherein, the preferred 10-30mg/ml of the concentration of methyl naltrexone, more preferably 20mg/ml.PH usable acid or alkali are regulated, example hydrochloric acid, hydrobromic acid, citric acid or its buffer, sodium hydroxide solution etc., preferred hydrochloric acid or sodium hydroxide solution.
In a specific embodiments again, methyl naltrexone injection of the present invention is by methyl naltrexone or its officinal salt; Its concentration is 1.0～50.0mg/ml, preferred 10-30mg/ml; Citrate buffer, its concentration are 0.5mg/ml～10mg/ml, and one or more are selected from the antioxidant of one group of thiourea, cysteine, L-cysteine, valine, L-valine and nicotiamide; Its concentration is 0.01～5mg/ml, and a kind of isotonic agent of sodium chloride and water for injection are formed.Wherein, the PH of this injection is 3.0～4.0, and PH usable acid or alkali are regulated, example hydrochloric acid, hydrobromic acid, citric acid or its buffer, sodium hydroxide solution etc., preferred hydrochloric acid or sodium hydroxide solution; The concentration of methyl naltrexone is 20mg/ml more preferably.
In above-mentioned all specific embodiments, the officinal salt of said methyl naltrexone is an inorganic salt, and example hydrochloric acid salt, hydrobromate, sulfate, and other acylate are preferably hydrobromate, i.e. methylnaltrexone bromide; Sodium chloride is as isoosmotic adjusting agent, and its concentration is that scope is 1mg/ml～20mg/ml, preferred 5mg/ml～10mg/ml.
In above-mentioned all specific embodiments, wherein, the preferred 1mg/ml～5mg/ml of the concentration of citrate buffer (in citric acid and trisodium citrate weight sum).Citrate buffer can make through citric acid and sodium hydroxide reaction; Also can make through sodium citrate and hydrochloric acid reaction; Can also get through the citric acid and the sodium citrate mixing of constant weight proportioning; Wherein, The weight ratio scope of citric acid and sodium citrate is 1:10 to 10:1, and preferred 1:1.5 to 1.5:1 is by densitometer; The concentration range of the two all can be 0.5mg/ml～5mg/ml, preferred 1mg/ml～1.5mg/ml.The conventional method for preparing preparation of the available buffer of the preparation of citrate buffer.
The present invention also provides a kind of method for preparing of stable methylnaltrexone bromide injection; This method for preparing is that injection additives such as methyl naltrexone and sodium chloride, antioxidant and citric acid buffer salt are dissolved in an amount of water for injection; Be mixed with solution; Depyrogenation, available in case of necessity hydrochloric acid or sodium hydrate regulator solution pH value to 3.0～4.0, fine straining, fill, fill nitrogen, seal, sterilize finished product.The gained injection is that 0.6ml contains bromination methyl naltrexone 12mg.
Concrete method for preparing is: take by weighing respectively recipe quantity methylnaltrexone bromide, sodium chloride, be selected from antioxidant, citric acid and the trisodium citrate of one group of thiourea, cysteine, L-cysteine, valine, L-valine and nicotiamide, with an amount of water for injection dissolving, add an amount of needle-use activated carbon; Stir depyrogenation, filtering decarbonization obtains filtrating just; Measure pH value, water for injection is added to amount of preparation in pH to 3.0～4.0 of available in case of necessity hydrochloric acid or sodium hydroxide solution regulator solution; Gained solution is used the mixed cellulose ester microporous membrane fine straining, and nitrogen is filled in fill; Seal, sterilization gets product.
In one embodiment, the kind of the present invention method for preparing methyl naltrexone injection comprises following process:
A) take by weighing methylnaltrexone bromide, citric acid buffer salt, one or more antioxidant, with an amount of water for injection dissolving;
B) in last step solution, add proper amount of active carbon, stir depyrogenation, filtering decarbonization obtains filtrating;
C) measure pH value of filtrate, regulate pH to 3.0～4.0 with hydrochloric acid or sodium hydroxide in case of necessity, add the injection water to configuration amount;
D) will go up step gained solution fine straining, must filtrate, irritate in ampoule bottle or glass tube vial, and charge into aseptic nitrogen and protect, seal; Then,
E) use flowing steam sterilization, obtain methylnaltrexone bromide injection finished product.
In said method; Described methyl naltrexone injection comprises methyl naltrexone or its officinal salt and additives, it is characterized in that: additives comprise (a) citrate buffer; (b) one or more antioxidant; Wherein, its officinal salt of methyl naltrexone is hydrobromate, i.e. methylnaltrexone bromide.
In said method, also can add isoosmotic adjusting agent sodium chloride in step a), antioxidant is selected from one or more of thiourea, cysteine, L-cysteine, valine, L-valine and nicotiamide.
Specific embodiment
Below further illustrate the present invention through embodiment, but be not limited to scope of embodiments.
Embodiment 1
Methylnaltrexone bromide injection prescription (prescription) is seen table 1.
The tabulation of table 1 methylnaltrexone bromide injection formula
| Prescription | 1 | 2 | 3 | 4 | 5 | 6 (commercially available prescriptions) |
| Methylnaltrexone bromide | 0.72g | 0.48g | 0.48g | 0.48g | 0.24g | 0.48g |
| NaCl | 0.168g | 0.12g | 0.12g | 0.12g | 0.12g | 0.156g |
| Citric acid | 0.036g | 0.03g | 0.03g | 0.03g | 0.03g | - |
| Trisodium citrate | 0.026g | 0.024g | 0.024g | 0.024g | 0.024g | - |
| Thiourea | 0.020g | 0.012g | - | - | - | |
| The L-cysteine | - | - | 0.12g | - | - | - |
| L-a word used in person's names propylhomoserin | - | - | - | 0.072g | - | - |
| Nicotiamide | - | - | - | - | 0.024g | - |
| Glycine | - | - | - | - | - | 0.0072g |
| EDTA-2Na | - | - | - | - | - | 0.0096g |
| Water for injection | 24ml | 24ml | 24ml | 24ml | 24ml | 24ml |
| PH value | 3.20 | 3.59 | 3.48 | 3.57 | 3.45 | 3.36 |
Preparation technology:
1, the supplementary material that takes by weighing recipe quantity adds the water for injection of recipe quantity, stirring and dissolving in beaker.
2, the needle-use activated carbon of adding 0.05% stirs 30min;
3, filter, measure pH value, regulate pH value with HCl or NaOH in case of necessity;
4, with the mixed cellulose ester microporous membrane fine straining of 0.22u;
5, be sub-packed in the 3ml lyophilizing bottle every bottle of 0.6ml;
6, fill nitrogen, tamponade;
7, use flowing steam sterilization, obtain the methylnaltrexone bromide injection.
Embodiment 2
Stability test: sample is carried out influence factor's test, survey the 10th day related substance.
The sample of the methylnaltrexone bromide injection that above-mentioned 6 prescriptions are made places respectively in illumination, 40 ℃ and 60 ℃ of influence factor's proof boxs and investigates 10 days, measures its related substance situation of change, and with compared in 0 day, concrete data are seen table 2.
10 days influence factor's result of the tests of table 2
Conclusion: the sample that adopts prepared injection liquid samples of the present invention and external commercially available prod to write out a prescription carries out stability test under the same conditions; The result shows that the stability of methylnaltrexone bromide injection of the present invention is better than the stability of sample by external commercially available prescription, and does not add chelating agen in the prescription of the present invention.
Claims (8)
1. stable methyl naltrexone injection; Contain methyl naltrexone or its officinal salt and additives; It is characterized in that: additives are by (a) citrate buffer; (b) be selected from one or more antioxidant in thiourea, cysteine, L-cysteine, valine, L-valine and the nicotiamide, (c) isoosmotic adjusting agent sodium chloride is formed.
2. methyl naltrexone injection according to claim 1, said officinal salt are the inorganic salt that is selected from hydrochlorate, hydrobromate and sulfate.
3. methyl naltrexone injection according to claim 2, said officinal salt are methylnaltrexone bromide.
4. according to the arbitrary described methyl naltrexone injection of claim 1-3, wherein the concentration of methyl naltrexone is 1.0～50.0mg/ml.
5. methyl naltrexone injection according to claim 1, wherein, the concentration of methyl naltrexone is 20mg/ml.
6. according to the arbitrary described methyl naltrexone injection of claim 1-3, it is characterized in that the pH scope is 3.0～4.0.
7. according to the arbitrary described methyl naltrexone injection of claim 1-3, the concentration range of its described citrate buffer is 0.5mg/ml～10mg/ml.
8. method for preparing methyl naltrexone injection according to claim 1 is characterized in that this method comprises following process:
A) take by weighing methylnaltrexone bromide, citric acid buffer salt, one or more are selected from antioxidant, the isoosmotic adjusting agent of thiourea, cysteine, L-cysteine, valine, L-valine and nicotiamide, with an amount of water for injection dissolving;
B) add proper amount of active carbon, stir depyrogenation, filtering decarbonization obtains filtrating;
C) pH value of mensuration solution is regulated pH to 3.0～4.0 with hydrochloric acid or sodium hydroxide, adds the injection water to amount of preparation;
D) with gained solution fine straining, must filtrate, irritate in ampoule bottle or glass tube vial, charge into aseptic nitrogen and protect, seal;
E) use flowing steam sterilization, obtain methylnaltrexone bromide injection finished product.
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| CN102166185B (en) * | 2011-03-30 | 2016-01-20 | 重庆健能医药开发有限公司 | Isotonic naloxone injection and preparation method thereof |
| CN103385889B (en) * | 2013-07-22 | 2014-12-03 | 珠海经济特区生物化学制药厂 | Carbohydrate and electrolyte mixed injection and preparation method thereof |
| CN104116707B (en) * | 2014-08-03 | 2016-11-23 | 张星一 | A kind of pharmaceutical composition containing methylnaltrexone bromide |
| CN105769755A (en) * | 2014-12-23 | 2016-07-20 | 北大方正集团有限公司 | Methyhaaltrexone bromide injection and preparation method thereof |
| 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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| CN101208344A (en) * | 2005-05-25 | 2008-06-25 | 普罗热尼奇制药公司 | (R)-N-methylnaltrexone, processes for its synthesis and its pharmaceutical use |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101208344A (en) * | 2005-05-25 | 2008-06-25 | 普罗热尼奇制药公司 | (R)-N-methylnaltrexone, processes for its synthesis and its pharmaceutical use |
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