CN104127380A - Pharmaceutical composition of naloxone hydrochloride injection and preparation method of pharmaceutical composition - Google Patents
Pharmaceutical composition of naloxone hydrochloride injection and preparation method of pharmaceutical composition Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, relates to a pharmaceutical composition of a naloxone hydrochloride injection and a preparation method of pharmaceutical composition, and particularly relates to a pharmaceutical composition of a naloxone hydrochloride injection. The pharmaceutical composition comprises naloxone hydrochloride, and particularly comprises naloxone hydrochloride, saccharides, organic acid and injection water. The naloxone hydrochloride in the pharmaceutical composition is added to the composition in a form of 17-allyl-4,5alpha-epoxy-3,14-dihydroxy-pyran-6-methadone hydrochloride dehydrate; the saccharides are selected from one or more of the following components: mannitol, sorbitol, lactose, maltose, glycine, mycose, glucose and the like. The pharmaceutical composition disclosed by the invention can be used after opioid compound anaesthesia to resist respiratory depression caused by the medicine and prompt patients to revive, is used for respiratory depression caused by excessive opioids and complete or partial reversion of the opioids, is used for saving acute alcohol poisoning, and is used for diagnosing excessive acute opioids.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of pharmaceutical composition of naloxone hydrochloride, particularly relate to the injection pharmaceutical composition of this naloxone hydrochloride, also relate to the preparation method of this pharmaceutical composition.
Background technology
Naloxone hydrochloride, its English name Naloxone Hydrochloride, is the hydrochloride dihydrate of naloxone alkali, chemistry is by name: 17-pi-allyl-4,5 α-epoxy radicals-3,14-dihydroxy morphinan-6-ones hydrochloride dihydrate, its chemical structural formula is:
Naloxone hydrochloride is white crystals or crystalline powder, easily molten in water, in methanol, dissolves, almost insoluble in chloroform or ether.
Naloxone is pure opiate receptor antagonistic, and itself is without intrinsic activity.But the each opioid receptor of energy competitive antagonism, has very strong affinity to μ receptor.Naloxone comes into force rapidly, and antagonism is strong.Naloxone reverses all effects of opiate agonist simultaneously, comprises analgesia.It also has and the incoherent analepsia effect of antagonism opiate receptor in addition.Can reverse rapidly the respiration inhibition that opioid analgesics causes, can cause fever, make cardiovascular function hyperfunction.This product still has Antishock function.Do not produce dependency, withdrawal symptom and the respiration inhibition of morphine sample.
Naloxone hydrochloride indication is clinically: the acute poisoning of narcosis analgesic and ethanol acute poisoning, and first-selected for known or doubt the respiration inhibition and the stupor etc. that cause for opioid drug is excessive, the person's that also can be used for opioid addiction Differential Diagnosis.
Naloxone hydrochloride is the widest opiate receptor antagonistic of current clinical practice.Be mainly used in:
1. rescue narcosis analgesic acute poisoning, the respiration inhibition of this class medicine of antagonism, and make emergence;
2. the residual action of antagonism narcosis analgesic.Neonate is subject to narcosis analgesic in its parent affect and cause respiration inhibition, available this product antagonism;
3. rescue acute alcoholism: quiet note naloxone 0.4～0.6mg, can make patient clear-headed;
4. pair doubt as narcosis analgesic addict, quiet note 0.2～0.4mg can excite withdrawal symptom, has diagnostic value;
5. the short effect of waking up, may activate physiological awakening system by cholinergic effect and make patient clear-headed, wakens and shock and some coma patient for general anesthesia.
Common dose: naloxone 5 μ g/kg, intramuscular injection 10 μ g/kg again after 15min.Or first give loading: 1.5～3.5 μ g/kg, maintain with 3 μ g/kgh.Can intramuscular injection or quiet note when withdrawal treatment: each 0.4～0.8mg.With in methadone withdrawal process, can try out low dose of methadone (5～10mg every day), per half an hour is to Allylnoroxymorphone 1.2mg, for time a few hours (3～6 hours), then use Allylnoroxymorphone instead, use weekly and can reach withdrawal object 3 times.
Version Chinese Pharmacopoeia in 2010 recorded naloxone hydrochloride crude drug with and injection with small volume, and wherein pay special attention to monitor the content of the impurity II in crude drug and preparation.
Chinese Patent Application No. 03107128.7 discloses a kind of naloxone freeze-dried powder and preparation technology thereof, wherein comprise naloxone, pH adjusting agent and other pharmaceutical carriers, the disclosed preparation technology of this invention: the naloxone that takes recipe quantity is dissolved in water for injection, make naloxone solution, add appropriate pharmaceutical carrier, regulate pH value, sterile filling, lyophilization, takes out after vacuum gland, and jewelling lid labeling gets product.It is believed that according to the obtained naloxone freeze-dried powder of this invention preparation technology stability better, effect duration is long, and outward appearance is loose porous, is easy to dissolve.
Chinese Patent Application No. 200410022077.5 discloses a kind of Hydrochloric Acid Naloxone Powder Needle Preparation And Its Preparation Method, get naloxone hydrochloride, be placed in sterile chamber, add appropriate sterile water for injection, add glycine, stirring makes molten, hydro-oxidation sodium active carbon, stirs, and adds sterile water for injection to full dose, aseptic filtration final vacuum lyophilization and get final product, compared with prior art: it is believed that this invention uses for drug addiction treatment; Select aseptic subpackaged injectable powder, lyophilized injectable powder, adopt glycine to do excipient, products obtained therefrom quality is loose, after adding water, dissolves and returns to the original characteristic of medicinal liquid rapidly; Water content is low, not oxidizable, is conducive to product and stores for a long time; Dosage is accurate, good appearance; Good stability, safe, evident in efficacy.
Chinese Patent Application No. 200410083899.4 discloses a kind of naloxone hydrchloride freeze-dried powder preparation for injection, said preparation is made up of the naloxone hydrochloride of medicine effective quantity and appropriate pharmaceutical carrier, wherein the percentage by weight of naloxone hydrochloride in preparation can be 0.08%～70.59%, and its content range in preparation is generally 0.1～12mg; Pharmaceutical carrier can be one or more in mannitol, glucose, sodium chloride, beta-schardinger dextrin-, dextran, fructose, sorbitol etc., preferably manna alcohol and glucose, and its percentage by weight in preparation can be 29.41%～99.92%.
Chinese Patent Application No. 200410053584.5 discloses a kind of injectable powder and preparation technology thereof taking naloxone hydrochloride as principal agent.Naloxone hydrochloride injectable powder described in this invention is that 0.05-5mg/ml naloxone hydrochloride and water for injection dissolubility pharmaceutic adjuvant form by concentration, prepares by freeze drying process.Water soluble adjuvant is mainly lyophilizing caffolding agent, also can add effective adjuvant on other pharmaceuticss.The present invention overcomes the deficiency of existing preparation, and injectable powder product stability is good, transport, store convenient, add water for injection after gained injection check through quality standard, indices all meets the requirements.
Chinese Patent Application No. 200410006569.5 discloses a kind of stable Allylnoroxymorphone lyophilized injectable powder and preparation technology thereof, relate to the novel formulation of Allylnoroxymorphone medicine, this invention Allylnoroxymorphone lyophilized injectable powder is made up of naloxone hydrochloride, proppant and pH adjusting agent, it is believed that and overcome the deficiencies in the prior art, there is steady quality, be convenient to the feature of storage and transport.
Chinese Patent Application No. 200810132053.3 discloses a kind of naloxone hydrochloride nano granule powder injection formulation, the raw material that contains following portions by weight: 0.4～4 part of naloxone hydrochloride, 0.15～2 part of dextran, 0.5～8 part of sodium sulfite, 0.2～4 part, sodium sulfate, 0.6～10 part of alpha-cyanoacrylate alkane ester, 10～1200 parts of frozen-dried supporting agents.
But above-mentioned lyophilized formulations adds adjuvant too much, likely cause unknown side effect, affect patient safety.In view of this, the inventor provides a kind of prescription more simple naloxone hydrochloride freeze-dry preparation, only adds a kind of adjuvant of mannitol, has overcome because adjuvant adds the side effect too much bringing, and patient uses safer.Prescription simply means the higher requirement of freeze-dry process proposition simultaneously, the present invention improves with regard to freeze-drying time, mode etc. on traditional freeze-dry process, make the preparation outward appearance that is made into full, for white loose block or powder, solubility is good, there is better stability, also reduce the production cost of product simultaneously because of the minimizing of supplementary product consumption.
Chinese Patent Application No. 201110201548.9 discloses naloxone hydrochloride freeze-dried powder and preparation method thereof.In this prescription, adopt disodium edetate as chelating agent, but CDE electronic publication is pointed out in " about using the relevant situation investigation of disodium edetate in intravenous administration formulation and analyzing ", is caused hypocalcemia thereby use disodium edetate may cause blood calcium to decline in intravenous injection.
Chinese Patent Application No. 200910008479.2 discloses compositions and the preparation method of naloxone hydrochloride and polyvinylpyrrolidone, and this freeze-dried powder is made up of naloxone hydrochloride and polyvinylpyrrolidone.But in injection, add polyvinylpyrrolidone, easily form subcutaneous granuloma in injection site, and may in organ, accumulate.
Naloxone hydrochloride aqueous injection is also a kind of clinical application option of this area.
CN 103877016 A (application number 201410143687.4) disclose a kind of new naloxone hydrochloride injection pharmaceutical composition and preparation method thereof, prescription is simple, in prescription, add after a certain amount of malic acid, the stability of naloxone hydrochloride aqueous solution obviously increases, and malic acid is nontoxic non-stimulated, safety is better, preparation technology's easy operating of the present invention simultaneously, and the product quality preparing is controlled.
CN 102166185 A (201110078923.5) disclose a kind of grade and have oozed Naloxone injection, contain naloxone or its water solublity officinal salt, glucose, citric acid, sodium citrate in described injection.Allegedly this injection good stability, known impurity level wherein changes little.
But this area still expects there is the new method of preparing naloxone hydrochloride injection, expect that product that this method obtains has in such as following at least one of good preparation quality: steady quality, chemical stability is good, safety is good etc.
Summary of the invention
The object of the present invention is to provide a kind of new method of preparing naloxone hydrochloride injection, expect that product that this method obtains has in such as following at least one of good preparation quality: steady quality, chemical stability is good, safety is good etc.The inventor have been surprisingly found that, uses the hydrochloride for injection Naloxone injection that method of the present invention obtains at least to possess an above-mentioned advantage.The present invention is based on this discovery and be accomplished.
For this reason, first aspect present invention provides a kind of pharmaceutical composition of naloxone hydrochloride injection, and this pharmaceutical composition comprises naloxone hydrochloride.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, comprising naloxone hydrochloride, saccharide, organic acid and water for injection.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein naloxone hydrochloride is with 17-pi-allyl-4,5 α-epoxy radicals-3, and the form of 14-dihydroxy morphinan-6-ones hydrochloride dihydrate is added in described compositions.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, in the time of the active component metering in compositions, be with 17-pi-allyl-4,5 α-epoxy radicals-3,14-dihydroxy morphinan-6-ones hydrochloride form meter.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein said saccharide is to be selected from following one or more: mannitol, sorbitol, lactose, maltose, glycine, trehalose, glucose etc.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein, in the naloxone hydrochloride of 1 weight portion, the amount of saccharide is 20～200 weight portions, for example 20～150 weight portions, for example 20～100 weight portions, for example 20～75 weight portions.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein said organic acid is to be selected from following one or more: fumaric acid, citric acid, tartaric acid.In one embodiment, described organic acid is citric acid.In the present invention, described citric acid can use its anhydride, also can use for example its monohydrate of its hydrate, no matter with which kind of form of volume add, its consumption all can be converted to the amount calculating of its anhydride.In the present invention's instantiation hereinafter, if not otherwise indicated, citric acid used is all to add with monohydrate, and calculates its formula with the amount of its anhydride and feed intake.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein, in the naloxone hydrochloride of 1 weight portion, organic acid consumption is 0.1～1 weight portion, for example, be 0.15～0.75 weight portion, for example, be 0.2～0.5 weight portion.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein 17-pi-allyl-4,5 α-epoxy radicals-3, the concentration of 14-dihydroxy morphinan-6-ones hydrochlorate is 0.2～5mg/ml, for example 0.25～2mg/ml, for example 0.4mg/ml, for example 1mg/ml.Concentration can be determined the consumption of water for injection in injecta composition thus, that is, use this concentration to limit the consumption that can specify in addition water for injection.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, its pH value is in 3.0～6.5 scopes.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein also optionally contain acid-base modifier, it is for example selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.In one embodiment, the consumption of described acid-base modifier is to make the pH value of described medicinal composition solution in 3.0～6.5 scopes.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein also optionally contain trace as 2,2 ' of impurity-bis-naloxones.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, wherein impurity 2,2 '-bis-naloxone content is less than 4%, for example, be less than 3%, for example, be less than 2.5%, for example, be less than 2.0%, for example, be less than 1.0%, for example, be less than 0.75%.According to the present invention, in the time characterizing the content of various impurity, can use official method to measure, also can use other method to measure, due to 2,2 '-bis-naloxones are a kind of commercially available impurity, no matter therefore how analytical method changes, can determine the wherein content of this impurity by external standard method.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, it places 24 months appellations such as () it also can be described as in the present invention, and room temperature is disposed, room temperature is disposed 24 months, 20 DEG C disposal, 20 DEG C of disposal 24 months under 15～20 DEG C of conditions, compare when initial, impurity II is 2, the room temperature of 2 '-bis-naloxones increases percent and is less than 100%, particularly room temperature increase percent is less than 75%, and particularly room temperature increase percent is less than 50%.
In the present invention, term " room temperature increase percent ", the room temperature that is impurity II content increases percent (%), refer under the normal temperature condition of 15～20 DEG C and place 24 months, the difference that in sample, 24 months content of this impurity deducts 0 month content gained of this impurity is multiplied by 100% again divided by 0 month content of this impurity, calculates with following formula:
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, it places 6 months (it also can be described as in the present invention and high-temperature treatment, high-temperature treatment June, 40 DEG C of disposal, 40 DEG C disposes the appellations such as June) under 40 DEG C of conditions, compare when initial, impurity II content high temperature increases percent and is less than 100%, particularly high temperature increase percent is less than 80%, and particularly high temperature increase percent is less than 60%.
In the present invention, term " high temperature increase percent ", the high temperature that is impurity II content increases percent (%), refer under the hot conditions of 40 DEG C and place 6 months, the difference that in sample, this impurity content in June deducts 0 month content gained of this impurity is multiplied by 100% again divided by 0 month content of this impurity, calculates with following formula:
In the time calculating above-mentioned " room temperature increase percent " and " high temperature increase percent ", wherein this impurity is at the content of each testing time point, refers to the content that uses method described in the version Chinese Pharmacopoeias in 2010 that the present invention mentions to measure this impurity at described testing time point obtaining.
Have been surprisingly found that, compositions of the present invention is presenting beat all feature of the present invention aspect room temperature increase percent and/or high temperature increase percent, and the injectable powder compositions that art methods obtains or commercially available injectable powder compositions are difficult to obtain the above results completely.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, it is by comprising prepared by following step substantially:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and inject water to its recipe quantity, stir, measure pH and optional mensuration active component content, be adjusted to pH3.0～6.5 with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, every bottle of wherein said naloxone hydrochloride injection comprises 17-pi-allyl-4,5 α-epoxy radicals-3, the amount of 14-dihydroxy morphinan-6-ones hydrochlorate is 0.1～10mg, for example 0.2～5mg, for example 0.4mg, 0.8mg, 1mg, 1.2mg, 1.5mg, 2mg, 3mg, 5mg.
Further, second aspect present invention provides the method for the pharmaceutical composition described in a kind of arbitrary embodiment of for example first aspect present invention of pharmaceutical composition of preparing naloxone hydrochloride injection, and it comprises the following steps:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and inject water to its recipe quantity, stir, measure pH and optional mensuration active component content, be adjusted to pH3.0～6.5 with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
According to the method for the arbitrary embodiment of second aspect present invention, described pharmaceutical composition comprises naloxone hydrochloride, saccharide and organic acid.
According to the method for the arbitrary embodiment of second aspect present invention, in described pharmaceutical composition, naloxone hydrochloride is with 17-pi-allyl-4,5 α-epoxy radicals-3, and the form of 14-dihydroxy morphinan-6-ones hydrochloride dihydrate is added in described compositions.
According to the method for the arbitrary embodiment of second aspect present invention, saccharide described in described pharmaceutical composition is to be selected from following one or more: mannitol, sorbitol, lactose, maltose, glycine, trehalose, glucose etc.
According to the method for the arbitrary embodiment of second aspect present invention, in described pharmaceutical composition, in the naloxone hydrochloride of 1 weight portion, the amount of saccharide is 20～200 weight portions, for example 20～150 weight portions, for example 20～100 weight portions, for example 20～75 weight portions.
According to the method for the arbitrary embodiment of second aspect present invention, organic acid described in described pharmaceutical composition is to be selected from following one or more: fumaric acid, citric acid, tartaric acid.In one embodiment, described organic acid is citric acid.In the present invention, described citric acid can use its anhydride, also can use for example its monohydrate of its hydrate, no matter with which kind of form of volume add, its consumption all can be converted to the amount calculating of its anhydride.In the present invention's instantiation hereinafter, if not otherwise indicated, citric acid used is all to add with monohydrate, and calculates its formula with the amount of its anhydride and feed intake.
According to the method for the arbitrary embodiment of second aspect present invention, in described pharmaceutical composition, in the naloxone hydrochloride of 1 weight portion, organic acid consumption is 0.1～1 weight portion, for example, be 0.15～0.75 weight portion, for example, be 0.2～0.5 weight portion.
According to the method for the arbitrary embodiment of second aspect present invention, 17-pi-allyl-4 in described pharmaceutical composition, 5 α-epoxy radicals-3, the concentration of 14-dihydroxy morphinan-6-ones hydrochlorate is 0.2～5mg/ml, for example 0.25～2mg/ml, for example 0.4mg/ml, for example 1mg/ml.
According to the method for the arbitrary embodiment of second aspect present invention, described pharmaceutical composition pH value is in 3.0～6.5 scopes.
According to the method for the arbitrary embodiment of second aspect present invention, in described pharmaceutical composition, also optionally contain acid-base modifier, it is for example selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.In one embodiment, the consumption of described acid-base modifier is, makes described pharmaceutical composition dissolve with water for injection and be diluted to 17-pi-allyl-4,5 α-epoxy radicals-3, when the concentration of 14-dihydroxy morphinan-6-ones hydrochlorate is 1mg/ml, the pH value of solution is in 3.0～6.5 scopes.
According to the method for the arbitrary embodiment of second aspect present invention, impurity 2 in described pharmaceutical composition, 2 '-bis-naloxone content is less than 4%, for example, be less than 3%, for example, be less than 2.5%, for example, be less than 2.0%, for example, be less than 1.0%, for example, be less than 0.75%.
According to the method for the arbitrary embodiment of second aspect present invention, described pharmaceutical composition is placed 24 months appellations such as () it also can be described as in the present invention, and room temperature is disposed, room temperature is disposed 24 months, 20 DEG C disposal, 20 DEG C of disposal 24 months under 15～20 DEG C of conditions, compare when initial, impurity II is 2, the room temperature of 2 '-bis-naloxones increases percent and is less than 100%, particularly room temperature increase percent is less than 75%, and particularly room temperature increase percent is less than 50%.
According to the method for the arbitrary embodiment of second aspect present invention, described pharmaceutical composition is placed 6 months (it also can be described as in the present invention and high-temperature treatment, high-temperature treatment June, 40 DEG C of disposal, 40 DEG C disposes the appellations such as June) under 40 DEG C of conditions, compare when initial, impurity II content high temperature increases percent and is less than 100%, particularly high temperature increase percent is less than 80%, and particularly high temperature increase percent is less than 60%.
According to the method for the arbitrary embodiment of second aspect present invention, every bottle of naloxone hydrochloride injection described in described pharmaceutical composition comprises 17-pi-allyl-4,5 α-epoxy radicals-3, the amount of 14-dihydroxy morphinan-6-ones hydrochlorate is 0.1～10mg, for example 0.2～5mg, for example 0.4mg, 0.8mg, 1mg, 1.2mg, 1.5mg, 2mg, 3mg, 5mg.
Arbitrary embodiment of either side according to the present invention, is also added with sodium chloride in wherein said pharmaceutical composition.In one embodiment, 17-pi-allyl-4 in described pharmaceutical composition, 5 α-epoxy radicals-3, the weight ratio of 14-dihydroxy morphinan-6-ones hydrochlorate and sodium chloride is 1:0.05～0.5, for example 1:0.75～0.4, for example 1:0.1～0.3.
In the step of the above-mentioned preparation method of the present invention, although the step of the concrete steps of its description in some details or described in the preparation example of language description up and down literary composition detailed description of the invention part distinguished to some extent, but, detailed open the above method step of completely can summarizing of those skilled in the art's full text according to the present invention.
Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characterictic goes for this technical characterictic in other embodiment, as long as they there will not be contradiction.The invention will be further described below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
In the present invention, if not otherwise indicated, measuring impurity II in various materials when the content of 2,2 '-bis-naloxones, is all to carry out according to method described in the related substance inspection method in 717 pages of naloxone hydrochloride crude drug that record of version Chinese Pharmacopoeia in 2010.In the present invention, if not otherwise indicated, in the time measuring the content of naloxone hydrochloride in the material of various compositionss, be all to carry out according to method described in the content assaying method in 718 pages of naloxone injections that record of version Chinese Pharmacopoeia in 2010.
Have been found that injection of the present invention has good pharmaceutical properties and for example has good chemical stability.
Naloxone hydrochloride is opioid recdptor antagonistic, is mainly used in clinically opioid drug combined anesthesia postoperative, and the respiration inhibition of such drug-induced of antagonism, impels emergence; Excessive for opioid drug, reverse wholly or in part the respiration inhibition that opioid drug causes; Rescue acute alcoholism; For the excessive diagnosis of acute opioid drug.
Detailed description of the invention
Can conduct further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and is not deviating under the prerequisite of the spirit and scope of the present invention, can carry out various variations and modification to the present invention.The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the operational approach that the object of the invention uses, the present invention still does to describe in detail as far as possible at this.Following examples further illustrate the present invention, instead of restriction the present invention.
The below object of preparation process in order to give an example, and comparability based on respectively giving an example and making some specific description, those skilled in the art can therefrom summarize according to existing knowledge the method that the present invention prepares lyophilized injectable powder that obtains completely.Dosing is prepared in various compositionss below, and if not otherwise indicated, total dosing amount of every batch is 10000ml.But list formula and when preparation process, for injection, illustrate and fill a prescription and method for making with the composition of other material of every 1mg part naloxone hydrochloride and corresponding weight portion.In the time of subpackage, every bottle is 1mg containing active ingredient hydrochloric acid naloxone.In the time of dosing, in the time using acid-base modifier (being pH adjusting agent), be 1M hydrochloric acid solution or 1M sodium hydroxide solution, using on the basis of described auxiliary agent, the amount of this acid-base modifier is to make in the pH value prescribed limit of medicinal liquid.
In following test, if not otherwise indicated, the crude drug naloxone hydrochloride of use is with 17-pi-allyl-4,5 α-epoxy radicals-3, and the form of 14-dihydroxy morphinan-6-ones hydrochloride dihydrate is added.
In following test, if not otherwise indicated, the crude drug naloxone hydrochloride of use is same batch, and after measured, wherein naloxone hydrochloride content is 99.61%, and impurity II content is 0.12%.
embodiment 1: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 30mg,
Citric acid 0.3mg,
Water for injection, adds to 1ml in right amount,
Injection target pH value=4.0;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 2: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 20mg,
Citric acid 0.5mg,
Water for injection, adds to 0.5ml in right amount,
Injection target pH value=3.0;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 3: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 30mg,
Citric acid 0.2mg,
Water for injection, adds to 4ml in right amount,
Injection target pH value=6.5;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 4: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 20mg,
Citric acid 0.15mg,
Water for injection, adds to 1ml in right amount,
Injection target pH value=5.0;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 5: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 100mg,
Citric acid 0.75mg,
Water for injection, adds to 2ml in right amount,
Injection target pH value=4.5;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
The each compositions sample of above embodiment 1-5 gained is placed 24 months to carry out room temperature disposal under 15～20 DEG C of conditions, and measuring impurity II room temperature in each sample increases percent, and the impurity II room temperature of five samples increases percent all in 23～46% scopes as a result.The each compositions sample of above embodiment 1-5 gained is placed 6 months to carry out high-temperature treatment under 40 DEG C of conditions, and measuring impurity II high temperature in each sample increases percent, and the impurity II high temperature of five samples increases percent all in 29～52% scopes as a result.
supplement example 1:with reference to formula and the method for above embodiment 1-5, different is only the maltose not using wherein, obtains 5 compositions samples; 5 compositions samples of gained are placed 24 months to carry out room temperature disposal under 15～20 DEG C of conditions, and measuring impurity II room temperature in each sample increases percent, and the impurity II room temperature of five samples increases percent all in 163～244% scopes as a result; 5 compositions samples of gained are placed 6 months to carry out high-temperature treatment under 40 DEG C of conditions, and measuring impurity II high temperature in each sample increases percent, and the impurity II high temperature of five samples increases percent all in 194～277% scopes as a result.With reference to formula and the method for above embodiment 1-5, different is only the citric acid (but being still adjusted to regulation pH value with 1M hydrochloric acid solution or 1M sodium hydroxide solution) not using wherein, obtains 5 compositions samples; 5 compositions samples of gained are placed 24 months to carry out room temperature disposal under 15～20 DEG C of conditions, and measuring impurity II room temperature in each sample increases percent, and the impurity II room temperature of five samples increases percent all in 163～233% scopes as a result; 5 compositions samples of gained are placed 6 months to carry out high-temperature treatment under 40 DEG C of conditions, and measuring impurity II high temperature in each sample increases percent, and the impurity II high temperature of five samples increases percent all in 187～278% scopes as a result.With reference to formula and the method for above embodiment 1-5, different is only the mannitol that maltose is wherein replaced with to equivalent, obtains 5 compositions samples; 5 compositions samples of gained are placed 24 months to carry out room temperature disposal under 15～20 DEG C of conditions, and measuring impurity II room temperature in each sample increases percent, and the impurity II room temperature of five samples increases percent all in 178～284% scopes as a result; 5 compositions samples of gained are placed 6 months to carry out high-temperature treatment under 40 DEG C of conditions, and measuring impurity II high temperature in each sample increases percent, and the impurity II high temperature of five samples increases percent all in 191～286% scopes as a result.With reference to formula and the method for above embodiment 1-5, different is only the lactose that maltose is wherein replaced with to equivalent, obtains 5 compositions samples; 5 compositions samples of gained are placed 24 months to carry out room temperature disposal under 15～20 DEG C of conditions, and measuring impurity II room temperature in each sample increases percent, and the impurity II room temperature of five samples increases percent all in 163～255% scopes as a result; 5 compositions samples of gained are placed 6 months to carry out high-temperature treatment under 40 DEG C of conditions, and measuring impurity II high temperature in each sample increases percent, and the impurity II high temperature of five samples increases percent all in 193～277% scopes as a result.With reference to formula and the method for above embodiment 1-5, different is only the trehalose that maltose is wherein replaced with to equivalent, obtains 5 compositions samples; 5 compositions samples of gained are placed 24 months to carry out room temperature disposal under 15～20 DEG C of conditions, and measuring impurity II room temperature in each sample increases percent, and the impurity II room temperature of five samples increases percent all in 193～256% scopes as a result; 5 compositions samples of gained are placed 6 months to carry out high-temperature treatment under 40 DEG C of conditions, and measuring impurity II high temperature in each sample increases percent, and the impurity II high temperature of five samples increases percent all in 189～293% scopes as a result.With reference to formula and the method for above embodiment 1-5, different is only the fumaric acid that citric acid is wherein replaced with to equivalent, obtains 5 compositions samples; 5 compositions samples of gained are placed 24 months to carry out room temperature disposal under 15～20 DEG C of conditions, and measuring impurity II room temperature in each sample increases percent, and the impurity II room temperature of five samples increases percent all in 151～233% scopes as a result; 5 compositions samples of gained are placed 6 months to carry out high-temperature treatment under 40 DEG C of conditions, and measuring impurity II high temperature in each sample increases percent, and the impurity II high temperature of five samples increases percent all in 176～269% scopes as a result.Prepare injection with reference to the formula of CN 103877578 A (201410147880.5) embodiment 19 and according to the embodiment of the present invention 1 method for making, the formula of CN 102727449 A (201110087470.2) embodiment 1 is also prepared injection according to the embodiment of the present invention 1 method for making, prepare injection with reference to the formula of the solution four (pH value 3.5) of CN 102274196 B (201110201548.9) embodiment 1 and according to the embodiment of the present invention 1 method for making, prepare three compositionss, these three compositionss are placed 24 months to carry out room temperature disposal under 15～20 DEG C of conditions, in measuring wherein, impurity II room temperature increases percent, the impurity II room temperature of these three samples of result increases percent all within the scope of 166-245%, these three compositions samples are placed 6 months to carry out high-temperature treatment under 40 DEG C of conditions, and measuring impurity II high temperature in this sample increases percent, and the impurity II high temperature of these three samples of result increases percent all in 203～277% scopes.With reference to formula and the method for above embodiment 1-5, different is only the tartaric acid that citric acid is wherein replaced with to equivalent, obtains 5 compositions samples; 5 compositions samples of gained are placed 24 months to carry out room temperature disposal under 15～20 DEG C of conditions, and measuring impurity II room temperature in each sample increases percent, and the impurity II room temperature of five samples increases percent all in 164～253% scopes as a result; 5 compositions samples of gained are placed 6 months to carry out high-temperature treatment under 40 DEG C of conditions, and measuring impurity II high temperature in each sample increases percent, and the impurity II high temperature of five samples increases percent all in 188～296% scopes as a result.Above result shows, only has when at maltose and citric acid, the two is used in combination, and inhibition of impurities II is along with product storage time extends and increases effectively.In addition, commercially available product naloxone hydrochloride injection (the accurate word H20059406 of traditional Chinese medicines) is placed 24 months to carry out room temperature disposal under 15～20 DEG C of conditions, and it is 216% that impurity II room temperature wherein increases percent; Under 40 DEG C of conditions, place 6 months to carry out high-temperature treatment, it is 263% that impurity II high temperature wherein increases percent.
reference examples 1:
Prescription: naloxone hydrochloride 0.4mg, glucose 45mg, citric acid 3mg, sodium citrate 1mg, water for injection adds to 1ml;
Method for making: recipe quantity glucose, citric acid, sodium citrate are added to appropriate water for injection and dissolve, add appropriate needle-use activated carbon, heated and stirred, filtering decarbonization adds the naloxone hydrochloride accurately taking in the fine straining liquid of cool to room temperature, stirs evenly dissolving, add water to amount of preparation 1ml, surveying pH is 4.5, and with 0.22 μ m mixed cellulose ester microporous membrane filtration sterilization, concentration is 0.4mg/1ml, every ampoule subpackage 1ml, sealing by fusing, 115 DEG C of pressure sterilizings 30 minutes, get product.
reference examples 2:
Prescription: naloxone hydrochloride 1mg, glucose 55mg, citric acid 1mg, sodium citrate 3mg, water for injection adds to 1ml;
Method for making: recipe quantity glucose, citric acid, sodium citrate are added to appropriate water for injection and dissolve, add appropriate needle-use activated carbon, heated and stirred, filtering decarbonization adds the naloxone hydrochloride accurately taking in the fine straining liquid of cool to room temperature, stirs evenly dissolving, add water to amount of preparation 1ml, surveying pH is 5.5, and with 0.22 μ m mixed cellulose ester microporous membrane filtration sterilization, concentration is 1mg/1ml, every ampoule subpackage 1ml, sealing by fusing, 115 DEG C of pressure sterilizings 30 minutes, get product.
The each compositions sample of above reference examples 1-2 gained is placed 24 months to carry out room temperature disposal under 15～20 DEG C of conditions, and measuring impurity II room temperature in each sample increases percent, and the impurity II room temperature of five samples increases percent all in 67～76% scopes as a result.The each compositions sample of above reference examples 1-2 gained is placed 6 months to carry out high-temperature treatment under 40 DEG C of conditions, and measuring impurity II high temperature in each sample increases percent, and the impurity II high temperature of five samples increases percent all in 63～74% scopes as a result.
reference examples 3, reference examples 4:with reference to formula and the method for above reference examples 1, reference examples 2, different is only wherein not add active component, obtains two injection respectively.
Tetra-injection of reference examples 1-4 are sent out to document according to king, and (king sends out, Deng, HPLC method checks the limitation of 5 hydroxymethyl furfural in Dextran 40 sodium chloride injection, northwest pharmaceutical journal the 26th the 6th phase of volume of December in 2011,410-411 page) method measure these four samples 5 hydroxymethyl furfural (it can be described as impurity III in the present invention) content in sample after experience is placed 6 months under 40 DEG C of conditions, and increase the account form of percent with reference to impurity II high temperature, calculating the high temperature of impurity III after this high-temperature treatment increases percent; Result reference examples 1,2 liang of sample impurity III high temperature of reference examples increase percent all in 162～194% scopes; And 4 liang of sample impurity III high temperature of reference examples 3, reference examples increase percents all in 35～48% scopes.Visible, naloxone can impel the generation of glucose exemplary impurity.In addition, the each sample of embodiment of the present invention 1-20, after placing disposal in 6 months under these 40 DEG C of conditions, has not all detected 5 hydroxymethyl furfural.
reference examples 5(CN 103877016 A, 201410143687.4):
Prescription: naloxone hydrochloride 1mg, malic acid 0.2mg, water for injection are to 1ml;
Method for making: add 90% water for injection in dosing cylinder, add malic acid and naloxone hydrochloride, be stirred to dissolving; Getting appropriate 0.1mol/L salt acid for adjusting pH value is 3.6, adds to the full amount of water for injection, and stirs evenly, for subsequent use; Filter, embedding is to 1ml ampoule bottle; Adopt 100 DEG C of flowing steam sterilizations 30 minutes, packaging, obtains injection.
Reference examples 5 resulting composition samples are placed 24 months to carry out room temperature disposal under 15～20 DEG C of conditions, and it is 63% that impurity II room temperature increases percent; Under 40 DEG C of conditions, place 6 months to carry out high-temperature treatment, it is 66% that impurity II high temperature increases percent.But this batch of injection liquid samples placed after 6 months under 40 DEG C of conditions, investigate from appearance character, 18% the sample (investigating sample size >500 props up) of having an appointment has white massive deposit, be what thing although it be unclear that this deposit, this is completely unacceptable for drug safety.In addition, the each sample of embodiment of the present invention 1-20, after placing disposal in 6 months under these 40 DEG C of conditions, is investigated from appearance character, has been showed no sample (every Lot sample is investigated sample size >500 and propped up) and has had white massive deposit.
test example 1: safety testing
Investigate the present invention's hemolytic and local irritation of embodiment 1-5 and reference examples 2 each samples above with reference to the method for CN 103877578 A it [0132]-[0142] section.The each naloxone hydrochloride compositions of result: embodiment of the present invention 1-5 sample to family's rabbit erythrocyte without haemolysis and cause cohesion, but reference examples 2 presents obvious haemolysis; Embodiment of the present invention 1-5 and the each naloxone hydrochloride compositions of reference examples 2 sample are to blood vessel nonirritant.
embodiment 6: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 50mg,
Citric acid 0.5mg,
Water for injection, adds to 1ml in right amount,
Injection target pH value=4.3;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 7: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 40mg,
Citric acid 0.5mg,
Water for injection, adds to 1ml in right amount,
Injection target pH value=5.5;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 8: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 50mg,
Citric acid 0.3mg,
Water for injection, adds to 1ml in right amount,
Injection target pH value=4.0;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 9: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 80mg,
Citric acid 0.6mg,
Water for injection, adds to 1.5ml in right amount,
Injection target pH value=5.0;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 10: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 40mg,
Citric acid 0.2mg,
Water for injection, adds to 0.5ml in right amount,
Injection target pH value=3.5;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 11: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 45mg,
Citric acid 0.35mg,
Water for injection, adds to 1ml in right amount,
Injection target pH value=5.0;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 12: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 40mg,
Citric acid 0.5mg,
Water for injection, adds to 1ml in right amount,
Injection target pH value=6.0;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 13: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 70mg,
Citric acid 0.2mg,
Water for injection, adds to 2ml in right amount,
Injection target pH value=4.0;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 14: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 80mg,
Citric acid 0.7mg,
Water for injection, adds to 4ml in right amount,
Injection target pH value=4.5;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 15: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 25mg,
Citric acid 0.2mg,
Water for injection, adds to 3ml in right amount,
Injection target pH value=5.0;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 16: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 50mg,
Mannitol 20mg,
Citric acid 0.25mg,
Water for injection, adds to 2ml in right amount,
Injection target pH value=4.0;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 17: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 40mg,
Lactose 20mg,
Citric acid 0.4mg,
Water for injection, adds to 2ml in right amount,
Injection target pH value=5.0;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 60%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 18: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 40mg,
Tartaric acid 0.10mg,
Citric acid 0.35mg,
Water for injection, adds to 1ml in right amount,
Injection target pH value=4.5;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 70%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 19: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 80mg,
Disodium edetate 0.2mg,
Citric acid 0.4mg,
Water for injection, adds to 1ml in right amount,
Injection target pH value=5.5;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 80%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
embodiment 20: prepare naloxone hydrochloride pharmaceutical composition
Formula:
Naloxone hydrochloride 1mg,
Maltose 40mg,
Citric acid 0.5mg,
Water for injection, adds to 1ml in right amount,
Injection target pH value=5.0;
Method for making:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (approximately 90%) water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and add to the full amount of water for injection, stir, measure pH and optional mensuration active component content, be adjusted to regulation pH value with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
supplement example 2:
In the various examples of the present invention, all use conventional charcoal absorbing process.This supplements example and considers impact and the solution of this charcoal absorbing process on technology controlling and process.
Be determined at the concentration (C1) of active component in the solution before active carbon adds, and be determined at the concentration (C2) of active component in the solution after filtering decarbonization, the loss (%) of calculating active component in this charcoal absorbing process with following formula: loss (%)=[(C1-C2) ÷ C1] × 100%
Result: in preparation process, in charcoal absorbing process, the loss of active component is all in 4～8% scopes at above embodiment 1-5, supplementary example 1, reference examples 1-4, reference examples 5, the each sample of embodiment 6-20.Although this adsorption losses can feed intake so that the actual drug content in finished product conforms to sign content by use excess raw material medicine in actual production.But because this crude drug cost of naloxone is high, strong to the activity of body, the real value of as far as possible having reduced the loss.
In this supplementary example, with reference to formula and the method for embodiment 1-5, different is only adds appropriate sodium chloride with active component together with also, for the active component of every 1 weight portion, in five supplementary examples, the amount of sodium chloride is respectively 0.2 weight portion, 0.1 weight portion, 0.3 weight portion, 0.25 weight portion, 0.15 weight portion; Be determined at the loss of active component in charcoal absorbing process with said method, five are supplemented in experiment in charcoal absorbing process the loss of active component all in 0.4～0.8% scope as a result.In this supplementary example, with reference to formula and the method for embodiment 6-20, different is only adds appropriate sodium chloride with active component together with also, and the weight ratio of active component and sodium chloride is 1:0.2; Be determined at the loss of active component in charcoal absorbing process with said method, 15 are supplemented in experiment in charcoal absorbing process the loss of active component all in 0.3～0.9% scope as a result, are unexpectedly presented at while adding appropriate sodium chloride in the present invention's formula, to help avoid charcoal and adsorb the drug loss causing.
20 samples of reference example 1-20 method gained in 15 samples of above embodiment 6-20 gained and supplementary example 2, under 15～20 DEG C of conditions, place 24 months to carry out room temperature disposal, measuring impurity II room temperature in each sample increases percent, and the impurity II room temperature of five samples increases percent all in 18～48% scopes as a result.20 samples of reference example 1-20 method gained in 15 samples of above embodiment 6-20 gained and supplementary example 2, under 40 DEG C of conditions, place 6 months to carry out high-temperature treatment, measuring impurity II high temperature in each sample increases percent, and the impurity II high temperature of five samples increases percent all in 25～54% scopes as a result.
In 20 samples of above embodiment 1-20 gained and supplementary example 2,20 samples of reference example 1-20 method gained are being placed after 6 months under 40 DEG C of conditions, and target pH value when medicinal liquid pH value and its preparation is basic identical, are no more than ± 0.2 pH value unit.
20 samples of reference example 1-20 method gained in 20 samples of above embodiment 1-20 gained and supplementary example 2, impurity 2 wherein after measured, 2 '-bis-naloxone content is all less than 0.75% (original state), it is little that the naloxone hydrochloride aqueous injection specifying more than pharmacopeia is less than 4% limit, and after long-term time storage, can not be increased to 4% limit yet.
20 samples of reference example 1-20 method gained in 20 samples of above embodiment 1-20 gained and supplementary example 2, can also every bottle the different volumes such as subpackage 0.5ml, 2ml, 3ml, 5ml, the compositions that contains different pharmaceutical amount in obtaining every bottle.
Claims (10)
1. a pharmaceutical composition for naloxone hydrochloride injection, this pharmaceutical composition comprises naloxone hydrochloride.
2. according to the pharmaceutical composition of claim 1, comprising naloxone hydrochloride, saccharide, organic acid and water for injection.
3. according to the pharmaceutical composition of claim 1, wherein naloxone hydrochloride is with 17-pi-allyl-4,5 α-epoxy radicals-3, and the form of 14-dihydroxy morphinan-6-ones hydrochloride dihydrate is added in described compositions; And/or
In the time of the active component metering in compositions, be with 17-pi-allyl-4,5 α-epoxy radicals-3,14-dihydroxy morphinan-6-ones hydrochloride form meter.
4. according to the pharmaceutical composition of claim 1, wherein
Described saccharide is to be selected from following one or more: mannitol, sorbitol, lactose, maltose, glycine, trehalose, glucose etc.; And/or
In the naloxone hydrochloride of 1 weight portion, the amount of saccharide is 20～200 weight portions, for example 20～150 weight portions, for example 20～100 weight portions, for example 20～75 weight portions.
5. according to the pharmaceutical composition of claim 1, wherein
Described organic acid is to be selected from following one or more: fumaric acid, citric acid, tartaric acid; And/or
In the naloxone hydrochloride of 1 weight portion, organic acid consumption is 0.1～1 weight portion, for example, be 0.15～0.75 weight portion, for example, be 0.2～0.5 weight portion.
6. according to the pharmaceutical composition of claim 1, wherein
17-pi-allyl-4,5 α-epoxy radicals-3, the concentration of 14-dihydroxy morphinan-6-ones hydrochlorate is 0.2～5mg/ml, for example 0.25～2mg/ml, for example 0.4mg/ml, for example 1mg/ml;
Its pH value is in 3.0～6.5 scopes;
Wherein also optionally contain acid-base modifier, it is for example selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination;
The consumption of described acid-base modifier is to make the pH value of described medicinal composition solution in 3.0～6.5 scopes; And/or
In described pharmaceutical composition, be also added with sodium chloride; For example, 17-pi-allyl-4 in described pharmaceutical composition, 5 α-epoxy radicals-3, the weight ratio of 14-dihydroxy morphinan-6-ones hydrochlorate and sodium chloride is 1:0.05～0.5, for example 1:0.75～0.4, for example 1:0.1～0.3.
7. according to the pharmaceutical composition of claim 1, wherein
Also optionally contain trace as 2,2 ' of impurity-bis-naloxones
Wherein impurity 2,2 '-bis-naloxone content is less than 4%, for example, be less than 3%, for example, be less than 2.5%, for example, be less than 2.0%, for example, be less than 1.0%, for example, be less than 0.75%
It places 24 months under 15～20 DEG C of conditions, compares when initial, and the impurity II i.e. room temperature of 2,2 '-bis-naloxones increases percent and is less than 100%, and particularly room temperature increases percent and is less than 75%, and particularly room temperature increases percent and is less than 50%;
It places 6 months under 40 DEG C of conditions, compares when initial, and impurity II content high temperature increases percent and is less than 100%, and particularly high temperature increases percent and is less than 80%, and particularly high temperature increases percent and is less than 60%.
8. according to the pharmaceutical composition of claim 1, it is by comprising prepared by following step substantially:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and inject water to its recipe quantity, stir, measure pH and optional mensuration active component content, be adjusted to pH3.0～6.5 with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
9. according to the pharmaceutical composition of claim 1, every bottle of wherein said naloxone hydrochloride injection comprises 17-pi-allyl-4,5 α-epoxy radicals-3, the amount of 14-dihydroxy morphinan-6-ones hydrochlorate is 0.1～10mg, for example 0.2～5mg, for example 0.4mg, 0.8mg, 1mg, 1.2mg, 1.5mg, 2mg, 3mg, 5mg.
10. the method for the pharmaceutical composition described in preparation claim 1-9 any one, it comprises the following steps:
(a) take naloxone hydrochloride, saccharide and the organic acid of recipe quantity, add water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and inject water to its recipe quantity, stir, measure pH and optional mensuration active component content, be adjusted to pH3.0～6.5 with acid-base modifier if desired;
(c) gained solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain injection pharmaceutical composition.
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|---|---|---|---|---|
| CN1626083A (en) * | 2004-08-09 | 2005-06-15 | 复旦大学 | Powder and injection preparation of hydrochloric naloxone and preparation method |
| CN102166185A (en) * | 2011-03-30 | 2011-08-31 | 重庆健能医药开发有限公司 | Isotonic naloxone injection and preparation method thereof |
| CN102727427A (en) * | 2011-04-08 | 2012-10-17 | 重庆药友制药有限责任公司 | Isotonic naloxone injection and preparation method thereof |
| CN103877016A (en) * | 2014-04-11 | 2014-06-25 | 成都苑东药业有限公司 | Pharmaceutical composition of naloxone hydrochloride injection and preparation method thereof |
| CN103877578A (en) * | 2014-04-11 | 2014-06-25 | 成都苑东药业有限公司 | Pharmaceutical naloxone hydrochloride composition for injection and preparation method of pharmaceutical naloxone hydrochloride composition |
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| CN1626083A (en) * | 2004-08-09 | 2005-06-15 | 复旦大学 | Powder and injection preparation of hydrochloric naloxone and preparation method |
| CN102166185A (en) * | 2011-03-30 | 2011-08-31 | 重庆健能医药开发有限公司 | Isotonic naloxone injection and preparation method thereof |
| CN102727427A (en) * | 2011-04-08 | 2012-10-17 | 重庆药友制药有限责任公司 | Isotonic naloxone injection and preparation method thereof |
| CN103877016A (en) * | 2014-04-11 | 2014-06-25 | 成都苑东药业有限公司 | Pharmaceutical composition of naloxone hydrochloride injection and preparation method thereof |
| CN103877578A (en) * | 2014-04-11 | 2014-06-25 | 成都苑东药业有限公司 | Pharmaceutical naloxone hydrochloride composition for injection and preparation method of pharmaceutical naloxone hydrochloride composition |
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Address after: 611531 Tiantaishan Pharmaceutical Co., Ltd., 88 Tianxing Avenue, Qionglai City, Chengdu City, Sichuan Province Patentee after: Chengdu Tiantaishan Pharmaceutical Co.,Ltd. Address before: 611531 Tiantaishan Pharmaceutical Co., Ltd., 88 Tianxing Avenue, Qionglai City, Chengdu City, Sichuan Province Patentee before: CHENGDU TIANTAISHAN PHARMACEUTICAL Co.,Ltd. |