CN104146971A

CN104146971A - Injection-use naloxone hydrochloride powder injection medicine composition and preparation method thereof

Info

Publication number: CN104146971A
Application number: CN201410424309.3A
Authority: CN
Inventors: 吴国庆; 左伟; 伍隆霞; 苟治君; 肖流婷; 赵东明
Original assignee: CHENGDU TIANTAISHAN PHARMACEUTICAL Co Ltd
Current assignee: CHENGDU TIANTAISHAN PHARMACEUTICAL CO LTD
Priority date: 2014-08-23
Filing date: 2014-08-23
Publication date: 2014-11-19
Anticipated expiration: 2034-08-23
Also published as: CN104146971B

Abstract

The invention belongs to the technical field of medicines, relates to an injection-use naloxone hydrochloride powder injection medicine composition and a preparation method thereof and particularly relates to the injection-use naloxone hydrochloride powder injection medicine composition which includes naloxone hydrochloride and especially includes the naloxone hydrochloride, a freeze-drying excipient and medicinal additives. The naloxone hydrochloride is added to the composition in the form of 17-allyl-4,5[alpha]-epoxy-3,14-dihydroxylmorphinan-6-one hydrochloride dihydrate. The freeze-drying excipient is selected from one or more of mannitol, sorbitol, lactose, maltose, glycine, trehalose, glucose and the like. The medicine composition can be used of post-operation of compound anesthesia with opioid medicines and has an antagonism effect of respiratory depression caused by the opioid medicines for promoting analepsia of a patient. The medicine composition is used in overdose of the opioid medicines, is used for reversing the respiratory depression caused by the opioid medicines completely or partially, is used for rescuing acute alcoholism and is used for diagnosis of acute opioid medicines overdose.

Description

Hydrochloride for injection naloxone injectable powder pharmaceutical composition and method for making

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 pharmaceutical composition of the lyophilization injectable powder 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 hydrochloric acid naloxone 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.

But this area still expects there is the new method of preparing hydrochloride for injection naloxone injectable powder, expect that product that this method obtains has in for example following at least one of good preparation quality: outward appearance is good, steady quality, solubility, compatibility stability is good and production cost is lower and chemical stability is good.

Summary of the invention

The object of the present invention is to provide a kind of new method of preparing hydrochloride for injection naloxone injectable powder, expect that product that this method obtains has in for example following at least one of good preparation quality: outward appearance is good, steady quality, solubility, compatibility stability is good and production cost is lower and chemical stability is good.The inventor have been surprisingly found that, uses the hydrochloride for injection naloxone injectable powder 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 hydrochloride for injection naloxone injectable powder, and this pharmaceutical composition comprises naloxone hydrochloride.

According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, comprising naloxone hydrochloride, freeze-dried excipient and medicinal auxiliary agent.

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 freeze-dried excipient 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 freeze-dried excipient 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 medicinal auxiliary agent is to be selected from following one or more: fumaric acid, citric acid, tartaric acid.In one embodiment, described medicinal auxiliary agent 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, the consumption of medicinal auxiliary agent 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 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 3.0～4.0 scopes.Generally speaking, because above-mentioned medicinal auxiliary agent of the present invention and consumption thereof can make the acid-base value of compositions reach above-mentioned scope, thereby generally, the present invention does not need especially additionally to use acid-base modifier.

As everyone knows, the lyophilization injectable powder (conventionally referred to as lyophilized injectable powder or freeze-dried powder) obtaining through freezing-vacuum drying, it is first by each dissolution with solvents for material (being typically with water dissolution), be mixed with a solution, then make this solution carry out freezing, carry out again evacuation, distillation, dry and Powdered thing or the block of the one substantially anhydrous (typically water content, lower than 5%, is particularly usually less than 3%) that obtains.Therefore, the acid-base value of this solid lyophilized products is controlled by the pH value of process for preparation regulator solution conventionally; Or can adjust so that the solid lyophilized products obtaining is controlled the pH value of this dissolve/dilute liquid under the dissolve/dilute degree of regulation and control (this is called the acid-base value of controlling solid lyophilized products) by prescription; A rear mode is more generally used conventionally, for example in pharmacopeia, contained many lyophilized injectable powders are all controlled the acid-base value of goods in this way, and the acid-base value of this mode control product recipe quantity of concrete regulation acid-base modifier not conventionally, and only specify the acid-base value of finished product.Be equally applicable to be of the present inventionly, according to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, the amount of wherein said optional acid-base modifier is, make 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 amount of the pH value of solution in 3.3～4.0 scopes.

According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, the moisture of described lyophilization injectable powder is lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 4%.

According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, the solution of described lyophilization injectable powder before lyophilization is except comprising naloxone hydrochloride, freeze-dried excipient and medicinal auxiliary agent, also comprise water for injection, the solid content of described solution is 1.5～10% (w/v), for example 1.5～7.5% (w/v), for example 1.5～5% (w/v), for example 2～4% (w/v).

According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, described lyophilization injectable powder with water for injection redissolve to substantially with lyophilization before solution phase with volume, solid content in gained solution is 1.5～10% (w/v), for example 1.5～7.5% (w/v), for example 1.5～5% (w/v), for example 2～4% (w/v).

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, freeze-dried excipient and the medicinal auxiliary agent 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 pH3.3～3.7 with acid-base modifier if desired;

(c) by medicinal liquid aseptic filtration, fill is in cillin bottle;

(d) moisture is removed in lyophilization, and tamponade to obtain final product.

According to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, the wherein filtered filtrate of step (c) gained, wherein solid content is to be 3～20% (w/v), preferably 3～15% (w/v), more more preferably 3～10%.Thus, the consumption of water for injection in can determining step (a).

According to the pharmaceutical composition of the arbitrary embodiment of first aspect present invention, every bottle of wherein said hydrochloride for injection naloxone injectable powder 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 hydrochloride for injection naloxone injectable powder, and it comprises the following steps:

(c) by medicinal liquid aseptic filtration, fill is in cillin bottle;

According to the method described in the arbitrary embodiment of second aspect present invention, the wherein filtered filtrate of step (c) gained, wherein solid content is to be 3～20% (w/v), preferably 3～15% (w/v), more more preferably 3～10%.Thus, the consumption of water for injection in can determining step (a).

According to the method for the arbitrary embodiment of second aspect present invention, described pharmaceutical composition comprises naloxone hydrochloride, freeze-dried excipient and medicinal auxiliary agent.

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, freeze-dried excipient 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 freeze-dried excipient 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, medicinal auxiliary agent described in described pharmaceutical composition is to be selected from following one or more: fumaric acid, citric acid, tartaric acid.In one embodiment, described medicinal auxiliary agent 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, the consumption of medicinal auxiliary agent 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, 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 3.0～4.0 scopes.Generally speaking, because above-mentioned medicinal auxiliary agent of the present invention and consumption thereof can make the acid-base value of compositions reach above-mentioned scope, thereby generally, the present invention does not need especially additionally to use acid-base modifier.

According to the method for the arbitrary embodiment of second aspect present invention, the moisture of described lyophilization injectable powder is lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 4%.

According to the method for the arbitrary embodiment of second aspect present invention, in described pharmaceutical composition, also optionally contain trace as 2,2 ' of impurity-bis-naloxones.

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 hydrochloride for injection naloxone injectable powder 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.

The preparation process of lyophilization injectable powder is to well known to a person skilled in the art pharmaceutical technology, for example two kinds of schematic freeze-drying curves shown in following freeze-drying curve A and freeze-drying curve B:

In the instantiation of below preparing in lyophilization injectable powder, if not otherwise specified, freeze-drying curve used is freeze-drying curve A.

Moisture in lyophilization injectable powder is generally below 8%, preferably lower than 5%, more preferably less than 4%.Moisture Control can be controlled by suitable adjustment lyophilization program.Moisture in this lyophilization injectable powder can be measured according to many known methods, for example dry weight-loss method.

In the time of preparation lyophilized injectable powder of the present invention, in the medicinal liquid of preparing, solid content is 1.5～20% (w/v), for example 2～15% (w/v), for example 2～12% (w/v).Because normally carrying out lyophilization in tubulose cillin bottle, lyophilized injectable powder obtains, those skilled in the art understand this product and are obtaining finished product even before for doctor, conventionally all present a round pie, although lecture is than the volume of original aqueous solution few (slightly dwindling) in the volume theory of this cake, but this dwindling can not narrow down to former aqueous solution volume 50% conventionally conventionally, conventionally can be between the 80-120% of former aqueous solution volume, be more typically between the 90-100% of former aqueous solution volume, and can be observed former aqueous solution liquid level vestige in finished product cillin bottle, (main body cake remains in the liquid level vestige on bottle wall dwindling because of lyophilizing, even if the dried frozen aquatic products in cillin bottle is former thereby be Powdered because a variety of causes for example collides etc., conventionally still can retain original liquid level vestige), vestige also can estimate the aqueous solution volume of this freeze-dried composition before lyophilization accordingly.Therefore, although the present invention is to provide a kind of substantially anhydrous lyophilization injectable powder, but still can roughly estimate it in the time preparing according to this injectable powder, the at least medicine liquid volume before lyophilization starts, according to the weight of the dry end-product in this volume and cillin bottle estimating, also can calculate in the time of preparation lyophilized injectable powder of the present invention the content of the solid content in the medicinal liquid of preparing.Therefore, according to the lyophilized injectable powder of first aspect present invention, the solid content of its medicinal liquid in the time of preparation is 1.5～10% (w/v), for example 1.5～7.5% (w/v), for example 1.5～5% (w/v), for example 2～4% (w/v).

Term " solid content " refers to solid matter (for example reactive compound of the present invention and whole excipient used, weight/gram) for example join, in solvent (water for injection), after dissolving, obtain a solution, the weight of described solid matter for example, divided by the percent (weight/volume percent, g/100ml) of whole liquor capacity.For example in the present invention, add appropriate aqueous solution for injection with other solid content of 1mg reactive compound and the about 24mg of total, be mixed with the solution that final volume is 1ml, its solid content is 2.5%.

In the present invention, symbol %, the linguistic context using according to it, can have those skilled in the art and hold intelligible implication.For example, in the time mentioning solid content, this symbol represents the percent (w/v, for example g/100ml) of weight/volume; For example in the time of " water content " mentioned in lyophilization injectable powder, for example water content is below 8% again, and now this symbol % represents the percent (w/w, g/100g) of w/w.Generally speaking,, in the time that solid is dispersed in liquid, % represents weight/volume percent; Solid be dispersed in solid or liquid dispersion in solid for example, when (water content of powder pin), % represents w/w percent.In other cases, unless otherwise noted, symbol % represents w/w percent.

In the time of preparation medicinal liquid of the present invention, as well known to those skilled in the art, can example according to appointment the microporous filter membrane of 0.45um carry out coarse filtration filtration, by liquid medicine filling to before in cillin bottle, can example according to appointment the microporous filter membrane of 0.22um carry out fine straining filtration with degerming, can filter repeatedly if desired.

According to injectable powder of the present invention, it redissolves with water for injection, and the time of typically redissolving is in 30 seconds, preferably in 20 seconds, more preferably in 15 seconds.

According to lyophilized injectable powder of the present invention, its water is made in every 1ml and is measured containing the solution of reactive compound 1mg and according to the method under two annex VI H items of Chinese Pharmacopoeia version in 2010, and the pH value of this solution is 3.3～3.7.

Lyophilized injectable powder provided by the invention can be preserved at least 24 months in cool dark place, can meet the Storage Requirement of general lyophilization injectable powder.

Have been found that lyophilization injectable powder 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 1000ml.But list formula and when preparation process, for injectable powder, 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.No matter be liquid drugs injection or powder pin, 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), for 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 the pH value of the medicinal liquid before lyophilization in 3.3～3.7 scopes.

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%.

In following test, if not otherwise indicated, while using activated carbon adsorption, consumption is the upper conventional amount of producing, and 0.1%.

embodiment 1: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 30mg,

Citric acid 0.3mg;

Method for making:

(b) mend and inject water to 1ml, stir, measure pH and optional mensuration active component content, be adjusted to pH3.3～3.7 with acid-base modifier if desired;

(c) by medicinal liquid aseptic filtration, fill in cillin bottle, every bottle of subpackage 1ml;

embodiment 2: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 20mg,

Citric acid 0.5mg;

Method for making:

(d) moisture is removed in lyophilization (using freeze-drying curve B to carry out), and tamponade, to obtain final product.

embodiment 3: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 75mg,

Citric acid 0.2mg;

Method for making:

embodiment 4: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 100mg,

Citric acid 0.75mg;

Method for making:

embodiment 5: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 20mg,

Citric acid 0.15mg;

Method for making:

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 21～43% 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 26～51% 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 154～232% 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 188～265% 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 166～227% 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 181～269% 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 174～246% 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 195～274% 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 168～241% 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 191～283% 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 185～263% 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 184～272% 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 158～236% 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 186～262% scopes as a result.With reference to the formula of the formula of CN 103877578 A embodiment 19 and method for making, CN 102727449 A embodiment 1 and method for making, with reference to formula and the method for making of the solution four (pH value 3.5) of CN 102274196 B embodiment 1, 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, and the impurity II room temperature of these three samples of result increases percent all within the scope of 154-232%; 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 187～262% 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 145～247% 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 181～274% 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 hydrochloride for injection naloxone injectable powder is placed 24 months to carry out room temperature disposal at (the accurate word H20080550 of traditional Chinese medicines) under 15～20 DEG C of conditions, and it is 183% 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 214% that impurity II high temperature wherein increases percent.

reference examples 1:

Prescription: naloxone hydrochloride 0.4mg, glucose 45mg, citric acid 3mg, sodium citrate 1mg;

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, stir evenly dissolving, add water to amount of preparation 1ml, surveying pH is 4.5, with 0.22 μ m mixed cellulose ester microporous membrane filtration sterilization, concentration is 0.4mg/1ml, every ampoule subpackage 1ml.Carry out lyophilization according to embodiment 1 step (d) method and remove moisture, tamponade, obtains injectable powder.

reference examples 2:

Prescription: naloxone hydrochloride 1mg, glucose 55mg, citric acid 1mg, sodium citrate 3mg;

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, stir evenly dissolving, add water to amount of preparation 1ml, surveying pH is 5.5, with 0.22 μ m mixed cellulose ester microporous membrane filtration sterilization, concentration is 1mg/1ml, every ampoule subpackage 1ml.Carry out lyophilization according to embodiment 1 step (d) method and remove moisture, tamponade, obtains injectable powder.

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 64～73% 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 61～74% 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 injectable powder respectively.

Tetra-injectable powder 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 147～171% scopes; And 4 liang of sample impurity III high temperature of reference examples 3, reference examples increase percents all in 31～43% 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.

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;

Method for making:

embodiment 7: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 40mg,

Citric acid 0.5mg;

Method for making:

embodiment 8: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 50mg,

Citric acid 0.3mg;

Method for making:

embodiment 9: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 80mg,

Citric acid 0.6mg;

Method for making:

embodiment 10: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 40mg,

Citric acid 0.2mg;

Method for making:

embodiment 11: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 45mg,

Citric acid 0.35mg;

Method for making:

(b) mend and inject water to 1ml, stir, measure pH and optional mensuration active component content, be adjusted to pH3.3～3.5 with acid-base modifier if desired;

embodiment 12: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 40mg,

Citric acid 0.5mg;

Method for making:

embodiment 13: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 70mg,

Citric acid 0.2mg;

Method for making:

embodiment 14: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 80mg,

Citric acid 0.7mg;

Method for making:

embodiment 15: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 25mg,

Citric acid 0.2mg;

Method for making:

(b) mend and inject water to 1ml, stir, measure pH and optional mensuration active component content, be adjusted to pH3.6～3.7 with acid-base modifier if desired;

embodiment 16: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 50mg,

Mannitol 20mg,

Citric acid 0.25mg;

Method for making:

(b) mend and inject water to 1ml, stir, measure pH and optional mensuration active component content, be adjusted to pH3.5～3.7 with acid-base modifier if desired;

embodiment 17: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 40mg,

Lactose 20mg,

Citric acid 0.4mg;

Method for making:

embodiment 18: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 40mg,

Tartaric acid 0.10mg,

Citric acid 0.35mg;

Method for making:

(b) mend and inject water to 1ml, stir, measure pH and optional mensuration active component content, be adjusted to pH3.1～3.3 with acid-base modifier if desired;

embodiment 19: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 80mg,

Disodium edetate 0.2mg,

Citric acid 0.4mg;

Method for making:

embodiment 20: prepare naloxone hydrochloride pharmaceutical composition

Formula:

Naloxone hydrochloride 1mg,

Maltose 40mg,

Citric acid 0.5mg;

Method for making:

(b) mend and inject water to 1ml, stir, measure pH and optional mensuration active component content, be adjusted to pH3.3～3.4 with acid-base modifier if desired;

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, 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 19～45% 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 24～56% scopes as a result.

20 samples of reference example 1-20 method gained in 20 samples of above embodiment 1-20 gained and supplementary example 2, dissolve and be diluted to 17-pi-allyl-4 with water for injection, 5 α-epoxy radicals-3, when the concentration of 14-dihydroxy morphinan-6-ones hydrochlorate is 1mg/ml, the pH value of solution is all in 3.0～4.0 scopes.

20 samples of reference example 1-20 method gained in 20 samples of above embodiment 1-20 gained and supplementary example 2, its moisture is all lower than 5%.

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

1. the pharmaceutical composition of hydrochloride for injection naloxone injectable powder, this pharmaceutical composition comprises naloxone hydrochloride.

2. according to the pharmaceutical composition of claim 1, comprising naloxone hydrochloride, freeze-dried excipient and medicinal auxiliary agent.

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.

4. according to the pharmaceutical composition of claim 1, wherein said freeze-dried excipient is to be selected from following one or more: mannitol, sorbitol, lactose, maltose, glycine, trehalose, glucose etc.; Further,

Wherein, in the naloxone hydrochloride of 1 weight portion, the amount of freeze-dried excipient 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 said medicinal auxiliary agent is to be selected from following one or more: fumaric acid, citric acid, tartaric acid; Further,

Wherein, in the naloxone hydrochloride of 1 weight portion, the consumption of medicinal auxiliary agent 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

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 3.0～4.0 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, the moisture of described lyophilization injectable powder is lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 4%; Or,

The solution of described lyophilization injectable powder before lyophilization is except comprising naloxone hydrochloride, freeze-dried excipient and medicinal auxiliary agent, also comprise water for injection, the solid content of described solution is 1.5～10% (w/v), for example 1.5～7.5% (w/v), for example 1.5～5% (w/v), for example 2～4% (w/v); Or,

Described lyophilization injectable powder with water for injection redissolve to substantially with lyophilization before solution phase with volume, solid content in gained solution is 1.5～10% (w/v), for example 1.5～7.5% (w/v), for example 1.5～5% (w/v), for example 2～4% (w/v).

8. according to the pharmaceutical composition of claim 1, wherein also optionally contain trace as 2,2 ' of impurity-bis-naloxones; Or,

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%; Or,

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%; Or,

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%.

9. according to the pharmaceutical composition of claim 1, it is by comprising prepared by following step substantially:

(c) by medicinal liquid aseptic filtration, fill is in cillin bottle;

(d) moisture is removed in lyophilization, and tamponade to obtain final product;

Or, further,

Every bottle of wherein said hydrochloride for injection naloxone injectable powder 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;

Or, further,

Described compositions has as described in description embodiment 1-20 any one fills a prescription.

10. the method for the pharmaceutical composition of preparation claim 1-9 any one, it comprises the following steps:

(c) by medicinal liquid aseptic filtration, fill is in cillin bottle;