CN104127380B - 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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- CN104127380B CN104127380B CN201410422026.5A CN201410422026A CN104127380B CN 104127380 B CN104127380 B CN 104127380B CN 201410422026 A CN201410422026 A CN 201410422026A CN 104127380 B CN104127380 B CN 104127380B
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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 pharmaceutical technology field is and in particular to a kind of pharmaceutical composition of Naloxone Hydrochloride, more particularly to
The injection pharmaceutical composition of this Naloxone Hydrochloride, further relates 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 entitled: 17- pi-allyl -4,5 α-epoxy radicals -3,14- dihydroxy morphinan-6-ones hydrochloride dihydrate, its chemistry knot
Structure formula is:
Naloxone Hydrochloride is white crystals or crystalline powder, readily soluble in water, dissolves in methyl alcohol, in chloroform or
Almost insoluble in ether.
Naloxone is opiate receptor antagonistic purely, no intrinsic activity itself.But can each OPIOIDS of competitive antagonism be subject to
Body, has very strong affinity to μ receptor.Naloxone comes into force rapidly, and antagonism is strong.Naloxone reverses opiate agonist institute simultaneously
There is effect, including analgesia.In addition it also has the incoherent analepsia effect with antagonism opiate receptor.Opium can be reversed rapidly to ease pain
The respiration inhibition that guiding drug rises, can cause fever, make cardiovascular function hyperfunction.This product still has Antishock function.Do not produce
The dependency of coffee sample, withdrawal symptom and respiration inhibition.
Naloxone Hydrochloride indication clinically is: the acute poisoning of narcosis analgesic and ethanol acute poisoning, first
It is selected to respiration inhibition that is known or excessively causing suspected of opioid drug and stupor etc. it can also be used to opioid addiction person
Differential Diagnosiss.
Naloxone Hydrochloride is current clinical practice opiate receptor antagonistic the widest.It is mainly used in:
1. save narcosis analgesic acute poisoning, the respiration inhibition of this kind of medicine of antagonism, and make emergence；
2. the residual action of antagonism narcosis analgesic.Neonate is affected by narcosis analgesic in its parent and causes to breathe
Suppression, available this product antagonism；
3. save acute alcoholism: intravenous naloxone 0.4～0.6mg, patient awoke can be made；
4., pair suspected of narcosis analgesic addict, intravenous 0.2～0.4mg can excite withdrawal symptom, have diagnostic value；
5. promoting wakening, may be activated physiology sexual arousal system and so that patient is regained consciousness by cholinergic effect, for general anesthesia
Waken and shock and some coma patients.
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, is maintained with 3 μ g/kg h.Can intramuscular injection or intravenous during withdrawal treatment: 0.4～0.8mg every time.Giving up process with methadone
In, low dose of methadone (daily 5～10mg) can be tried out, per half an hour, when being (3～6 is little a few hours to Allylnoroxymorphone 1.2mg
When), then use Allylnoroxymorphone instead, can reach withdrawal purpose using 3 times weekly.
Version Chinese Pharmacopoeia has recorded naloxone hydrochloride crude drug and its injection with small volume within 2010, and wherein special
Note monitoring 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 its preparation technology, wherein
Comprise naloxone, ph regulator and other pharmaceutical carriers, the preparation technology disclosed in this invention: weigh the naloxone of recipe quantity
It is dissolved in water for injection, makes naloxone solution, add appropriate pharmaceutical carrier, adjust ph value, sterile filling, lyophilization,
Take out after vacuum gland, jewelling lid labeling gets product.It is believed that according to naloxone freeze-dried powder obtained by this present invention
More preferably, effect duration is long for preparation stability, outward appearance loose porous it is easy to dissolving.
Chinese Patent Application No. 200410022077.5 discloses a kind of naloxone hydrochloride powder pin preparation and preparation method thereof,
Take Naloxone Hydrochloride, be placed in sterile chamber, plus appropriate sterile water for injection, plus glycine, stir and make molten, hydro-oxidation sodium work
Property charcoal, stirring, plus sterile water for injection is to full dose, vacuum lyophilization after aseptic filtration obtains final product, compared with prior art: it is believed that
This invention is used for drug addiction treatment and uses；From aseptic subpackaged injectable powder, lyophilized injectable powder, excipient is done using glycine, gained produces
Quality ground is loose, and rapid dissolving after adding water returns to the original characteristic of medicinal liquid；Water content is low, not oxidizable, is conducive to product long
Phase stores；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, should
Preparation is made up of the Naloxone Hydrochloride of medicine effective quantity and appropriate pharmaceutical carrier, wherein Naloxone Hydrochloride weight in the formulation
Percentage ratio can be 0.08%～70.59%, and its content range in the formulation is usually 0.1～12mg；Pharmaceutical carrier is permissible
It is one or more of Mannitol, glucose, sodium chloride, beta-schardinger dextrin-, dextran, Fructose, Sorbitol etc., preferably manna
Alcohol and glucose, its percentage by weight in the formulation can be 29.41%～99.92%.
Chinese Patent Application No. 200410053584.5 disclose a kind of injectable powder with Naloxone Hydrochloride as principal agent and its
Preparation technology.Naloxone Hydrochloride injectable powder described in this invention is 0.05-5mg/ml Naloxone Hydrochloride and water for injection by concentration
Dissolubility pharmaceutic adjuvant forms, and is prepared by freeze drying process.Water soluble adjuvant is mainly lyophilizing caffolding agent, also can add other
Effective adjuvant on pharmaceuticss.The present invention overcomes the shortcomings of existing preparation, and injectable powder product stability is good, and transport, storage are convenient,
After adding water for injection, gained injection is checked through quality standard, and indices all meet the requirements.
Chinese Patent Application No. 200410006569.5 discloses a kind of stable Allylnoroxymorphone lyophilized injectable powder and its preparation
Technique, is related to the novel formulation of Allylnoroxymorphone medicine, and this invention Allylnoroxymorphone lyophilized injectable powder is adjusted by Naloxone Hydrochloride, proppant and ph
Agent forms it is believed that overcoming the deficiencies in the prior art, has steady quality, is easy to the feature stored and transport.
Chinese Patent Application No. 200810132053.3 discloses a kind of naloxone hydrochloride nano granule powder injection formulation, under containing
State the raw material of parts by weight: 0.4～4 part of Naloxone Hydrochloride, 0.15～2 part of dextran, 0.5～8 part of sodium sulfite, sulphuric acid
0.2～4 part of sodium, 0.6～10 part of alpha-cyanoacrylate alkyl ester, 10～1200 parts of frozen-dried supporting agent.
But, above-mentioned lyophilized formulations add adjuvant excessive it is possible to cause unknown side effect, affect patient safety.There is mirror
In this, current inventor provides a kind of simpler Naloxone Hydrochloride lyophilized formulations of prescription, only add a kind of adjuvant of Mannitol,
Overcome and add side effect that is excessive and bringing because of adjuvant, patient uses safer.Prescription simply means to lyophilizing work simultaneously
Skill proposes higher requirement, and the present invention has carried out improving with regard to freeze-drying time, mode etc. so that being made in traditional lyophilized technique
Formulation aesthetics are full, are white loose block or powder, and solubility is good, has more preferable stability, simultaneously also because adjuvant is used
Amount minimizing and reduce the production cost of product.
Chinese Patent Application No. 201110201548.9 discloses naloxone hydrochloride freeze-dried powder and preparation method thereof.Should
In prescription adopt disodium edetate as chelating agent, but cde electronic publication " with regard in intravenous administration formulation using disodium edetate
Relevant Survey and Inquiry and analysis " in point out, in intravenous injection using disodium edetate may lead to blood calcium decline thus causing
Hypocalcemia.
Chinese Patent Application No. 200910008479.2 discloses the compositionss of Naloxone Hydrochloride and Polyvinylpyrrolidone
And preparation method, this freeze-dried powder is made up of Naloxone Hydrochloride and Polyvinylpyrrolidone.But add polyethylene pyrrole in injection
Pyrrolidone, easily forms subcutaneous granuloma in injection site, and may accumulate in organ.
Naloxone Hydrochloride aqueous injection is also a kind of clinical application option of this area.
Cn 103877016 a (application number 201410143687.4) discloses a kind of new naloxone hydrochloride injection medicine
Compositions and preparation method thereof, prescription is simple, after adding a certain amount of malic acid in prescription, Naloxone Hydrochloride aqueous solution steady
Qualitative obvious increase, and malic acid is nontoxic non-stimulated, more preferably, preparation technology of the present invention is easily operated simultaneously, is prepared into for safety
The product quality arriving is controlled.
Cn 102166185 a (201110078923.5) discloses a kind of isotonic Naloxone injection, in described injection
Containing naloxone or its water solublity officinal salt, glucose, citric acid, sodium citrate.It is said that this injection good stability, wherein
Known impurity level change little.
But this area still expects there is the new method preparing naloxone hydrochloride injection, expect what this method obtained
Product have excellent preparation quality for example following at least one: steady quality, chemical stability are excellent, safety is good
Deng.
Content of the invention
It is an object of the invention to provide a kind of new method preparing naloxone hydrochloride injection, expect that this method obtains
To product have excellent preparation quality for example following at least one: steady quality, chemical stability are excellent, safety
OK etc..Present inventors have surprisingly discovered that, make the hydrochloride for injection Naloxone injection being obtained by the present invention at least
Possesses said one advantage.The present invention is based on this and finds and be accomplished.
For this reason, first aspect present invention provides a kind of pharmaceutical composition of naloxone hydrochloride injection, this drug regimen
Thing includes Naloxone Hydrochloride.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, including Naloxone Hydrochloride, saccharide, has
Machine acid and water for injection.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein Naloxone Hydrochloride are with 17- allyl
The form of base -4,5 α-epoxy radicals -3,14- dihydroxy morphinan-6-ones hydrochloride dihydrate is added in described compositionss
's.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, to the active component metering in compositionss
When, it is with 17- pi-allyl -4,5 α-epoxy radicals -3,14- dihydroxy morphinan-6-ones hydrochloride form meter.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein said saccharide is selected from following one
Plant or multiple: Mannitol, Sorbitol, Lactose, maltose, glycine, trehalose, glucose etc..
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein with the Naloxone Hydrochloride of 1 weight portion
Meter, the amount of saccharide is 20～200 weight portions, such as 20～150 weight portions, such as 20～100 weight portions, such as 20～75 weight
Part.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein said organic acid is 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
In, described citric acid can use its anhydride, also can use its hydrate such as its monohydrate, though with volume which kind of
Form is added, and the amount that its consumption all can be converted to its anhydride calculates.In the present invention in detail below example, such as not another
External declaration, citric acid used is all to be added with monohydrate, and calculates its formula with the amount of its anhydride and feed intake.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein with the Naloxone Hydrochloride of 1 weight portion
Meter, the consumption of organic acid is 0.1～1 weight portion, e.g. 0.15～0.75 weight portion, e.g. 0.2～0.5 weight portion.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein 17- pi-allyl -4,5 α-epoxy radicals -
The concentration of 3,14- dihydroxy morphinan-6-ones hydrochlorates is 0.2～5mg/ml, such as 0.25～2mg/ml, such as 0.4mg/
Ml, such as 1mg/ml.Can determine that the consumption of water for injection in injecta composition by this concentration, i.e. limiting using this concentration can
So that the consumption of water for injection need not be dictated otherwise.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, its ph value is in the range of 3.0～6.5.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein also optionally contains acid-alkali accommodation
Agent, it is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, salt
Acid, phosphoric acid, nitric acid, sulphuric acid or a combination thereof.In one embodiment, the consumption of described acid-base modifier is so that described medicine
The ph value of compositions solution is in the range of 3.0～6.5.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, the wherein also optionally conduct containing trace
The 2,2 ' of impurity-bis- naloxones.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein impurity 2,2 '-bis- naloxone contents
Less than 4%, e.g., less than 3%, e.g., less than 2.5%, e.g., less than 2.0%, e.g., less than 1.0%, e.g., less than 0.75%.
According to the present invention, when characterizing the content of various impurity, it is possible to use official method measures, also can be measured using other methods,
Because 2,2 '-bis- naloxones are a kind of commercially available impurity, no matter therefore how analysis method changes, external standard method can be used
To determine the content of wherein this impurity.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it places 24 under the conditions of 15～20 DEG C
Month (it is also referred to as in the present invention, and room temperature is disposed, room temperature disposes 24 months, 20 DEG C dispose, 20 DEG C dispose the appellations such as 24 months), with
Compare when initial, impurity ii is that the room temperature of 2,2 '-bis- naloxones increases percent less than 100%, and particularly room temperature increases by hundred
Fraction is less than 75%, and particularly room temperature increases percent less than 50%.
In the present invention, term " room temperature increase percent ", that is, room temperature increase percent (%) of impurity ii content, refers to
Place 24 months under 15～20 DEG C of normal temperature condition, in sample, 24 months contents of this impurity deduct 0 month content gained of this impurity
Difference is multiplied by 100% again divided by 0 month content of this impurity, that is, be calculated as follows:
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it places 6 months (its under the conditions of 40 DEG C
It is also referred to as high-temperature treatment, high-temperature treatment June, the appellation such as 40 DEG C of disposal, 40 DEG C of disposal June in the present invention), with initial phase
Relatively, impurity ii content high temperature increases percent less than 100%, and particularly high temperature increases percent less than 80%, particularly high
Temperature increases percent and is less than 60%.
In the present invention, term " high temperature increase percent ", that is, high temperature increase percent (%) of impurity ii content, refers to
Place 6 months under 40 DEG C of hot conditionss, the difference that in sample, this impurity June content deducts this 0 month content gained of impurity is removed
It is multiplied by 100% again with 0 month content of this impurity, that is, be calculated as follows:
When computationally stating " room temperature increase percent " and " high temperature increase percent ", wherein this impurity is in each testing time
The content of point, refer to the version Chinese Pharmacopoeia methods describeds in 2010 being referred to using the present invention measure obtain in the described testing time
The content of this impurity of point.
It has been unexpectedly discovered that the compositionss of the present invention increase percent in room temperature and/or high temperature increases percent
Aspect assumes beat all feature of the present invention, and the injectable powder compositionss that art methods obtain or commercially available powder
Injection compositionss are but difficult to obtain the above results completely.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is substantially pressed and includes the steps
Preparation:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add water for injection, make dissolving, add activity
Charcoal, stirring, filtering decarbonization；
B () is mended and is injected water to its recipe quantity, stir, and measures solution ph and optional mensure active component contains
Amount, is adjusted to ph3.0～6.5 with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein said naloxone hydrochloride injection
Every bottle includes 17- pi-allyl -4, and the amount of 5 α-epoxy radicals -3,14- dihydroxy morphinan-6-ones hydrochlorate is 0.1～10mg,
Such as 0.2～5mg, such as 0.4mg, 0.8mg, 1mg, 1.2mg, 1.5mg, 2mg, 3mg, 5mg.
Further, second aspect present invention provides a kind of pharmaceutical composition preparing naloxone hydrochloride injection for example
The method of the pharmaceutical composition described in first aspect present invention any embodiment, it comprises the following steps:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add water for injection, make dissolving, add activity
Charcoal, stirring, filtering decarbonization；
B () is mended and is injected water to its recipe quantity, stir, and measures solution ph and optional mensure active component contains
Amount, is adjusted to ph3.0～6.5 with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
The method of any embodiment according to a second aspect of the present invention, described pharmaceutical composition include Naloxone Hydrochloride,
Saccharide and organic acid.
The method of any embodiment according to a second aspect of the present invention, in described pharmaceutical composition Naloxone Hydrochloride be with
The form of 17- pi-allyl -4,5 α-epoxy radicals -3,14- dihydroxy morphinan-6-ones hydrochloride dihydrate is added to described group
In compound.
The method of any embodiment according to a second aspect of the present invention, saccharide described in described pharmaceutical composition is to be selected from down
One or more of row: Mannitol, Sorbitol, Lactose, maltose, glycine, trehalose, glucose etc..
The method of any embodiment according to a second aspect of the present invention, with the hydrochloric acid of 1 weight portion in described pharmaceutical composition
Naloxone meter, the amount of saccharide is 20～200 weight portions, such as 20～150 weight portions, such as 20～100 weight portions, such as 20～
75 weight portions.
The method of any embodiment according to a second aspect of the 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 its hydrate such as its monohydrate, no matter with body
Amass which kind of form is added, the amount that its consumption all can be converted to its anhydride calculates.In the present invention in detail below example,
If not otherwise indicated, citric acid used is all to be added with monohydrate, and calculates its formula with the amount of its anhydride and feed intake.
The method of any embodiment according to a second aspect of the present invention, with the hydrochloric acid of 1 weight portion in described pharmaceutical composition
Naloxone meter, the consumption of organic acid is 0.1～1 weight portion, e.g. 0.15～0.75 weight portion, e.g. 0.2～0.5 weight
Part.
The method of any embodiment according to a second aspect of the 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, such as 0.25～2mg/ml, for example
0.4mg/ml, such as 1mg/ml.
The method of any embodiment according to a second aspect of the present invention, described pharmaceutical composition ph value is in 3.0～6.5 scopes
Interior.
The method of any embodiment according to a second aspect of the present invention, also optionally contains soda acid in described pharmaceutical composition
Regulator, it is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, phosphoric acid hydrogen two
Potassium, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or a combination thereof.In one embodiment, the consumption of described acid-base modifier be so that
Described pharmaceutical composition is being dissolved with water for injection and is being diluted to 17- pi-allyl -4,5 α-epoxy radicals -3,14- dihydroxy morphine
Mutter -6- keto hydrochloride concentration be 1mg/ml when, the ph value of solution is in the range of 3.0～6.5.
The method of any embodiment according to a second aspect of the present invention, impurity 2 in described pharmaceutical composition, 2 '-Shuan Na Lip rivers
Ketone content is less than 4%, e.g., less than 3%, e.g., less than 2.5%, e.g., less than 2.0%, e.g., less than 1.0%, e.g., less than
0.75%.
The method of any embodiment according to a second aspect of the present invention, described pharmaceutical composition is transferred in 15～20 DEG C of conditions
Put 24 months (it is also referred to as in the present invention, and room temperature is disposed, room temperature disposes 24 months, 20 DEG C dispose, 20 DEG C dispose and 24 months etc. claim
Meaning), with initial when compared with, impurity ii be 2,2 '-bis- naloxones room temperature increase percent be less than 100%, particularly room temperature
Increase percent and be less than 75%, particularly room temperature increases percent less than 50%.
The method of any embodiment according to a second aspect of the present invention, described pharmaceutical composition places 6 under the conditions of 40 DEG C
Individual month (it is also referred to as high-temperature treatment, high-temperature treatment June, the appellation such as 40 DEG C of disposal, 40 DEG C of disposal June in the present invention), with
Compare when initial, impurity ii content high temperature increases percent and is less than 100%, and particularly high temperature increases percent less than 80%,
Particularly high temperature increases percent less than 60%.
The method of any embodiment according to a second aspect of the present invention, the Naloxone Hydrochloride described in described pharmaceutical composition
Every bottle of injection include 17- pi-allyl -4,5 α-epoxy radicals -3,14- dihydroxy morphinan-6-ones hydrochlorate amount be 0.1～
10mg, such as 0.2～5mg, such as 0.4mg, 0.8mg, 1mg, 1.2mg, 1.5mg, 2mg, 3mg, 5mg.
According to any embodiment of either side of the present invention, in wherein said pharmaceutical composition, it has been also added with sodium chloride.
In one embodiment, 17- pi-allyl -4 in described pharmaceutical composition, 5 α-epoxy radicals -3,14- dihydroxy morphinan-6-ones
The weight of hydrochlorate and sodium chloride is than for 1:0.05～0.5, such as 1:0.75～0.4, such as 1:0.1～0.3.
Although the concrete steps of its description are in some details or language in the step of the above-mentioned preparation method of the present invention
Step described in preparation example with following detailed description part in description is otherwise varied, however, people in the art
Member can summarize approach described above step completely according to the detailed disclosure of full text of the present invention.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not
Contradiction occurs.Additionally, in any embodiment of either side of the present invention, arbitrary technical characteristic goes for other real
Apply this technical characteristic in scheme, as long as they are not in contradiction.The invention will be further described below.
All documents recited in the present invention, their full content is incorporated herein by, and if these are civilian
When implication expressed by offering is inconsistent with the present invention, it is defined by the statement of the present invention.Additionally, the present invention use various terms and
Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and
Phrase is described in more detail and explains, the term referring to and phrase if any inconsistent with common art-recognized meanings, with institute of the present invention table
The implication stated is defined.
In the present invention, if not otherwise indicated, measure the content that the impurity ii in various materials is 2,2 '-bis- naloxones
When, it is all according to institute in the Related substances separation method in version Chinese Pharmacopoeia in 2010 page 717 naloxone hydrochloride crude drug recording
The method of stating is carried out.In the present invention, if not otherwise indicated, measure various compositionss material in Naloxone Hydrochloride content
When, it is all according to side described in the content assaying method in version Chinese Pharmacopoeia in 2010 page 718 naloxone injections recording
Method is carried out.
It has been found that injection of the present invention has good pharmaceutical properties for example has excellent chemical stability.
Naloxone hydrochloride is opioid recdptor antagonistic, and it is postoperative to be clinically mainly used in opioid drug combined anesthesia, short of money
Resist the respiration inhibition of such drug-induced, promote emergence；Excessive for opioid drug, reverse opiatess wholly or in part
Drug-induced respiration inhibition；Rescue acute alcoholism；For the excessive diagnosis of acute opioid drug.
Specific embodiment
The present invention can be conducted further description by the following examples, however, the scope of the present invention does not limit
In following embodiments.One of skill in the art is it is understood that on the premise of without departing substantially from the spirit and scope of the present invention, permissible
Various change and modification are carried out to the present invention.The present invention to test used in material and test method carry out generality
And/or specifically describe.Although for realize many materials that the object of the invention used and operational approach be it is known in the art that
But the present invention still here describes in detail as far as possible.Following examples further illustrate the present invention, rather than limit this
Bright.
Hereafter preparation process is for the purpose illustrated, and the comparability based on each citing and make some specific description,
Those skilled in the art can therefrom summarize, according to existing knowledge, the method obtaining that the present invention prepares lyophilized injectable powder completely.Under
Face is joined liquid and is prepared in various compositionss, and if not otherwise indicated, the liquid measure of always joining of every batch is 10000ml.But list formula and system
During standby process, for injection, formula is illustrated with the composition of every 1mg part Naloxone Hydrochloride and other materials of corresponding weight portion
And preparation method.In subpackage, every bottle of naloxone containing active ingredient hydrochloric acid is 1mg.When joining liquid, when using acid-base modifier
When (i.e. ph regulator), it is 1m hydrochloric acid solution or 1m sodium hydroxide solution, on the basis of employing described auxiliary agent, this soda acid
The amount of regulator is in the ph value prescribed limit make medicinal liquid.
In tests below, if not otherwise indicated, the crude drug Naloxone Hydrochloride of use is with 17- pi-allyl -4,5 α-ring
The form of epoxide -3,14- dihydroxy morphinan-6-ones hydrochloride dihydrate is added.
In tests below, if not otherwise indicated, the crude drug Naloxone Hydrochloride of use is with a batch of, and through surveying
Fixed, wherein Naloxone Hydrochloride content is 99.61%, and impurity ii content is 0.12%.
Embodiment 1: preparation 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=4.0；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 2: preparation 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=3.0；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 3: preparation 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=6.5；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 4: preparation 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=5.0；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 5: preparation 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=4.5；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Above example 1-5 gained each compositionss sample, places 24 months to carry out at room temperature under the conditions of 15～20 DEG C
Put, measuring impurity ii room temperature in each sample increases percent, and the impurity ii room temperature of five samples increases percent all 23 as a result
In the range of～46%.Above example 1-5 gained each compositionss sample, places 6 months to carry out at high temperature under the conditions of 40 DEG C
Put, measuring impurity ii high temperature in each sample increases percent, and the impurity ii high temperature of five samples increases percent all 29 as a result
In the range of～52%.
Supplementary example 1:Formula with reference to above example 1-5 and method, different is only not use maltose therein, obtains
To 5 compositionss samples；5 compositionss samples of gained place 24 months to carry out room temperature disposal under the conditions of 15～20 DEG C, survey
In fixed each sample, impurity ii room temperature increases percent, as a result the impurity ii room temperature of five samples increase percent all 163～
In the range of 244%；5 compositionss samples of gained place 6 months to carry out high-temperature treatment under the conditions of 40 DEG C, measure in each sample
Impurity ii high temperature increases percent, and the impurity ii high temperature of five samples increases percent all in the range of 194～277% as a result.
With reference to the formula of above example 1-5 and method, different be only do not use citric acid therein (but still use 1m hydrochloric acid molten
Liquid or 1m sodium hydroxide solution are adjusted to regulation ph value), obtain 5 compositionss samples；5 compositionss samples of gained are 15～20
24 months are placed to carry out room temperature disposal, measuring impurity ii room temperature in each sample increases percent, five examinations as a result under the conditions of DEG C
The impurity ii room temperature of sample increases percent all in the range of 163～233%；5 compositionss samples of gained are transferred in 40 DEG C of conditions
Put 6 months to carry out high-temperature treatment, measuring impurity ii high temperature in each sample increases percent, and the impurity ii of five samples is high as a result
Temperature increases percent all in the range of 187～278%.Formula with reference to above example 1-5 and method, different is only by it
In maltose replace with the Mannitol of equivalent, obtain 5 compositionss samples；5 compositionss samples of gained are in 15～20 DEG C of bars
24 months are placed to carry out room temperature disposal, measuring impurity ii room temperature in each sample increases percent, as a result five samples under part
Impurity ii room temperature increases percent all in the range of 178～284%；5 compositionss samples of gained place 6 under the conditions of 40 DEG C
The moon, measuring impurity ii high temperature in each sample increased percent, and the impurity ii high temperature of five samples increases as a result to carry out high-temperature treatment
Plus percent is all in the range of 191～286%.Formula with reference to above example 1-5 and method, different is only will be therein
Maltose replaces with the Lactose of equivalent, obtains 5 compositionss samples；5 compositionss samples of gained are transferred in 15～20 DEG C of conditions
Put 24 months to carry out room temperature disposal, measuring impurity ii room temperature in each sample increases percent, the impurity ii of five samples as a result
Room temperature increases percent all in the range of 163～255%；5 compositionss samples of gained place 6 months to enter under the conditions of 40 DEG C
Row high-temperature treatment, measuring impurity ii high temperature in each sample increases percent, and the impurity ii high temperature of five samples increases percentage as a result
Number is all in the range of 193～277%.Formula with reference to above example 1-5 and method, different is only by maltose therein
Replace with the trehalose of equivalent, obtain 5 compositionss samples；5 compositionss samples of gained place 24 under the conditions of 15～20 DEG C
To carry out room temperature disposal, measuring impurity ii room temperature in each sample increases percent, the impurity ii room temperature of five samples as a result within individual month
Increase percent all in the range of 193～256%；5 compositionss samples of gained place 6 months to carry out height under the conditions of 40 DEG C
Temperature is disposed, and measuring impurity ii high temperature in each sample increases percent, and the impurity ii high temperature increase percent of five samples is equal as a result
In the range of 189～293%.Formula with reference to above example 1-5 and method, different is only to replace citric acid therein
For the fumaric acid of equivalent, obtain 5 compositionss samples；5 compositionss samples of gained are placed 24 months under the conditions of 15～20 DEG C
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 as a result
Percent is all in the range of 151～233%；5 compositionss samples of gained place 6 months to carry out at high temperature under the conditions of 40 DEG C
Put, measuring impurity ii high temperature in each sample increases percent, and the impurity ii high temperature of five samples increases percent all 176 as a result
In the range of～269%.Formula with reference to cn 103877578 a (201410147880.5) embodiment 19 is simultaneously implemented according to the present invention
Example 1 preparation method is prepared injection, the formula of cn 102727449 a (201110087470.2) embodiment 1 and is shone the embodiment of the present invention
1 preparation method prepares injection, the solution four (ph value 3.5) with reference to cn 102274196 b (201110201548.9) embodiment 1
Formula simultaneously prepares injection according to the embodiment of the present invention 1 preparation method, prepares three compositionss, this three compositionss are at 15～20 DEG C
Under the conditions of place 24 months to carry out room temperature disposal, measuring wherein middle impurity ii room temperature increases percent, this three samples of result
Impurity ii room temperature increase percent all in the range of 166-245%；This three compositionss samples place 6 under the conditions of 40 DEG C
The moon, measuring impurity ii high temperature in this sample increased percent, the impurity ii high temperature of this three samples of result to carry out high-temperature treatment
Increase percent all in the range of 203～277%.Formula with reference to above example 1-5 and method, different is only by wherein
Citric acid replace with the tartaric acid of equivalent, obtain 5 compositionss samples；5 compositionss samples of gained are in 15～20 DEG C of conditions
To carry out room temperature disposal, measuring impurity ii room temperature in each sample increases percent, and five samples is miscellaneous as a result within 24 months for lower placement
Matter ii room temperature increases percent all in the range of 164～253%；5 compositionss samples of gained are placed 6 months under the conditions of 40 DEG C
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 as a result
Percent is all in the range of 188～296%.Result above shows, only when maltose is applied in combination with both citric acid,
Impurity ii can be effectively suppressed to extend with product storage time and increase.In addition, commercially available product naloxone hydrochloride injection (traditional Chinese medicines
Quasi- word h20059406) place 24 months under the conditions of 15～20 DEG C to carry out room temperature disposal, impurity ii room temperature therein increases by hundred
Fraction is 216%；Place 6 months to carry out high-temperature treatment under the conditions of 40 DEG C, impurity ii high temperature therein increases percent and is
263%.
Reference examples 1:
Prescription: Naloxone Hydrochloride 0.4mg, glucose 45mg, citric acid 3mg, sodium citrate 1mg, water for injection adds to
1ml；
Preparation method: recipe quantity glucose, citric acid, sodium citrate are added appropriate water for injection dissolving, adds appropriate pin to live
Property charcoal, heated and stirred, filtering decarbonization, the fine straining liquid being cooled to room temperature adds the Naloxone Hydrochloride accurately weighing, stirs evenly molten
Solution, adds water to amount of preparation 1ml, and surveying ph is 4.5, and with 0.22 μm of 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；
Preparation method: recipe quantity glucose, citric acid, sodium citrate are added appropriate water for injection dissolving, adds appropriate pin to live
Property charcoal, heated and stirred, filtering decarbonization, the fine straining liquid being cooled to room temperature adds the Naloxone Hydrochloride accurately weighing, stirs evenly molten
Solution, adds water to amount of preparation 1ml, and surveying ph is 5.5, and with 0.22 μm of 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 compositionss sample of above reference examples 1-2 gained, places 24 months to carry out at room temperature under the conditions of 15～20 DEG C
Put, measuring impurity ii room temperature in each sample increases percent, and the impurity ii room temperature of five samples increases percent all 67 as a result
In the range of～76%.The each compositionss sample of above reference examples 1-2 gained, places 6 months to carry out at high temperature under the conditions of 40 DEG C
Put, measuring impurity ii high temperature in each sample increases percent, and the impurity ii high temperature of five samples increases percent all 63 as a result
In the range of～74%.
Reference examples 3, reference examples 4:Respectively refer to above reference examples 1, the formula of reference examples 2 and method, different is only it
In be not added with active component, obtain two injection.
Tetra- injection of reference examples 1-4 are sent out document according to king, and (king sends out, etc. hplc method inspection Dextran 40 sodium chloride note
Penetrate the limitation of 5 hydroxymethyl furfural in liquid, northwest pharmaceutical journal the 6th phase of volume 26 in December, 2011, the 410-411 page) method
(it in the present invention may be used the 5 hydroxymethyl furfural measuring after this four samples are placed 6 months under the conditions of 40 DEG C of experience in sample
Referred to as impurity iii) content, and the calculation with reference to impurity ii high temperature increase percent, calculate impurity iii through this high-temperature treatment
High temperature afterwards increases percent；Result reference examples 1,2 liang of sample impurity iii high temperature of reference examples increase percents all 162～
In the range of 194%；And reference examples 3,4 liang of sample impurity iii high temperature of reference examples increase percent all in the range of 35～48%.Can
See, naloxone can promote the generation of glucose exemplary impurity.In addition, each sample of embodiment of the present invention 1-20 is through under the conditions of this 40 DEG C
Place and postpone at 6 months, be all not detected by 5 hydroxymethyl furfural.
Reference examples 5(cn 103877016 a, 201410143687.4):
Prescription: Naloxone Hydrochloride 1mg, malic acid 0.2mg, water for injection to 1ml；
Preparation method: add 90% water for injection in joining fluid cylinder, add malic acid and Naloxone Hydrochloride, stir to dissolving；Take
It is 3.6 that appropriate 0.1mol/l hydrochloric acid adjusts ph value, adds to the full amount of water for injection, stirs evenly, standby；Filter, embedding is to 1ml ampoule bottle
In；Using 100 DEG C of flowing steam sterilizations 30 minutes, packaging, obtain injection.
Reference examples 5 resulting composition sample places 24 months to carry out room temperature disposal, impurity ii under the conditions of 15～20 DEG C
It is 63% that room temperature increases percent；Place 6 months to carry out high-temperature treatment under the conditions of 40 DEG C, impurity ii high temperature increases percent
For 66%.But this batch of injection liquid samples, after placing 6 months under the conditions of 40 DEG C, are investigated from appearance character, are had about 18%
Sample (investigation sample size > 500) has white chunks deposit although what thing this deposit unclear is, but this
It is entirely unacceptable for drug safety.In addition, each sample of embodiment of the present invention 1-20 is through placing 6 under the conditions of this 40 DEG C
Postpone at individual month, investigate from appearance character, be showed no sample (every Lot sample investigation sample size > 500) and have white blocks
Shape deposit.
Test example 1: safety testing
With reference to cn 103877578 a its [0132]-[0142] section method investigate example 1 above -5 of the present invention and
The hemolytic of each sample of reference examples 2 and local irritation.Result: embodiment of the present invention 1-5 each Naloxone Hydrochloride compositionss sample
To family's rabbit erythrocyte no haemolysis and cause cohesion, but reference examples 2 assume obvious haemolysiss；Embodiment of the present invention 1-5
Each Naloxone Hydrochloride compositionss sample is to blood vessel nonirritant with reference examples 2.
Embodiment 6: preparation 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=4.3；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 7: preparation 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=5.5；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 8: preparation 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=4.0；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 9: preparation 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=5.0；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 10: preparation 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=3.5；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 11: preparation 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=5.0；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 12: preparation 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=6.0；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 13: preparation 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=4.0；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 14: preparation 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=4.5；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 15: preparation 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=5.0；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 16: preparation 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=4.0；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 17: preparation 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=5.0；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 60%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 18: preparation 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=4.5；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 70%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 19: preparation 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=5.5；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 80%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Embodiment 20: preparation 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=5.0；
Preparation method:
A () weighs Naloxone Hydrochloride, saccharide and the organic acid of recipe quantity, add appropriate (about 90%) water for injection, make molten
Solution, adds activated carbon, stirring, filtering decarbonization；
B () is mended and is added to the full amount of water for injection, stir, and measures solution ph and optional mensure active component content,
Adjusted to regulation ph value with acid-base modifier if necessary；
(c) resulting solution essence consider after embedding in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtain final product injection medicine group
Compound.
Supplementary example 2:
All using to conventional charcoal absorbing process in the various example of the present invention.This supplement example considers this charcoal absorbing process pair
The impact of technology controlling and process and solution.
Measure the concentration (c1) of active component in the solution before activated carbon adds, and measure molten after filtering decarbonization
The concentration (c2) of active component in liquid, is calculated as follows the loss (%) of active component in this charcoal absorbing process: loss (%)
=[(c1-c2) ÷ c1] × 100%
Result: in above example 1-5, supplement example 1, reference examples 1-4, reference examples 5, each sample of embodiment 6-20 in preparation
During, in charcoal absorbing process, the loss of active component is all in the range of 4～8%.Although this adsorption losses are in actual production
In can feed intake by using excess raw material medicine so that actual drug content in finished product is consistent with indicating content.But due to
Naloxone this crude drug high cost, strong to the activity of body, reduce loss has real value as far as possible.
In this supplement example, with reference to the formula of embodiment 1-5 and method, different be only with active component also together with add
Appropriate sodium chloride, 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；Measure in charcoal absorbing process with said method
The loss of active component, five are supplemented the loss of active component in charcoal absorbing process in experiment all in 0.4～0.8% scope as a result
Interior.In this supplement example, with reference to the formula of embodiment 6-20 and method, different be only with active component also together with add appropriate
Sodium chloride, active component is 1:0.2 with the weight ratio of sodium chloride；Measure activity in charcoal absorbing process with said method to become
The loss dividing, 15 are supplemented the loss of active component in charcoal absorbing process in experiment all in the range of 0.3～0.9% as a result, go out
People is shown in and helps avoid the drug loss that charcoal absorption causes when adding appropriate sodium chloride in inventive formulation with expecting.
20 examinations of reference implementation example 1-20 method gained in 15 samples of above example 6-20 gained and supplementary example 2
Sample, places 24 months to carry out room temperature disposal, measuring impurity ii room temperature in each sample increases percent under the conditions of 15～20 DEG C,
The impurity ii room temperature of five samples increases percent all in the range of 18～48% as a result.15 examinations of above example 6-20 gained
Reference implementation 20 samples of example 1-20 method gained in sample and supplementary example 2, place 6 months to carry out height under the conditions of 40 DEG C
Temperature is disposed, and measuring impurity ii high temperature in each sample increases percent, and the impurity ii high temperature increase percent of five samples is equal as a result
In the range of 25～54%.
20 examinations of reference implementation example 1-20 method gained in 20 samples of above example 1-20 gained and supplementary example 2
Sample, after placing 6 months under the conditions of 40 DEG C, target ph when medicinal liquid ph value is prepared with it is essentially identical, less than ± 0.2
Individual ph value unit.
20 examinations of reference implementation example 1-20 method gained in 20 samples of above example 1-20 gained and supplementary example 2
Sample, wherein impurity 2,2 '-bis- naloxone contents are respectively less than 0.75% (original state) after measured, receive more than the hydrochloric acid of States Pharmacopoeia specifications
The limit that Lip river ketone aqueous injection is less than 4% is little, and after preserving when long-term, is also not increased to 4% limit.
20 examinations of reference implementation example 1-20 method gained in 20 samples of above example 1-20 gained and supplementary example 2
Sample, the acceptable different volumes such as every bottle of subpackage 0.5ml, 2ml, 3ml, 5ml, the combination containing different pharmaceutical amount in obtaining every bottle
Thing.
Claims (9)
1. a kind of pharmaceutical composition of naloxone hydrochloride injection, including Naloxone Hydrochloride 1 weight portion, maltose 20 ~ 100
Weight portion, citric acid 0.15 ~ 0.75 weight portion and sodium chloride 0.1 ~ 0.3 weight portion；This pharmaceutical composition is to walk by inclusion is following
Rapid method preparation:
A () weighs Naloxone Hydrochloride, maltose, citric acid and the sodium chloride of recipe quantity, add water for injection, make dissolving, then plus
Enter activated carbon, stirring, filtering decarbonization；
B () is mended and is injected water to its recipe quantity, stir, and measures solution ph and optional mensure active component content,
Adjusted to ph3.0～6.5 with acid-base modifier if necessary；
C after () resulting solution fine straining, embedding is in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtains final product injection pharmaceutical composition,
Wherein, 17- pi-allyl -4 in this pharmaceutical composition, 5 α-epoxy radicals -3,14- dihydroxy morphinan-6-ones hydrochlorate dense
Spend for 0.2 ~ 5mg/ml.
2. pharmaceutical composition according to claim 1, wherein Naloxone Hydrochloride are with 17- pi-allyl -4,5 α-epoxy radicals -3,14-
The form of dihydroxy morphinan-6-ones hydrochloride dihydrate is added in described compositionss.
3. pharmaceutical composition according to claim 1, in terms of the Naloxone Hydrochloride of 1 weight portion, the amount of maltose is 20 ~ 75 weight
Part.
4. pharmaceutical composition according to claim 1, in terms of the Naloxone Hydrochloride of 1 weight portion, the consumption of citric acid is 0.2 ~ 0.5
Weight portion.
5. pharmaceutical composition according to claim 1, wherein also contains acid-base modifier, its be selected from sodium hydroxide, potassium hydroxide,
Sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or a combination thereof.
6. pharmaceutical composition according to claim 5, the consumption of described acid-base modifier is so that described pharmaceutical composition solution
Ph value in the range of 3.0 ~ 6.5.
7. pharmaceutical composition according to claim 1, every bottle wherein said of naloxone hydrochloride injection includes 17- allyl
The amount of base -4,5 α-epoxy radicals -3,14- dihydroxy morphinan-6-ones hydrochlorate is 0.2 ~ 5mg.
8. pharmaceutical composition according to claim 1, every bottle wherein said of naloxone hydrochloride injection includes 17- allyl
The amount of base -4,5 α-epoxy radicals -3,14- dihydroxy morphinan-6-ones hydrochlorate be 0.4mg, 0.8mg, 1mg, 1.2mg, 1.5mg,
2mg, 3mg or 5mg.
9. the method for the pharmaceutical composition described in preparation any one of claim 1-8, it comprises the following steps:
A () weighs Naloxone Hydrochloride, maltose, citric acid and the sodium chloride of recipe quantity, add water for injection, make dissolving, then plus
Enter activated carbon, stirring, filtering decarbonization；
B () is mended and is injected water to its recipe quantity, stir, and measures solution ph and optional mensure active component content,
Adjusted to ph3.0～6.5 with acid-base modifier if necessary；
C after () resulting solution fine straining, embedding is in ampoule bottle, 115 DEG C of pressure sterilizings 30 minutes, obtains final product injection pharmaceutical composition,
Wherein, 17- pi-allyl -4 in this pharmaceutical composition, 5 α-epoxy radicals -3,14- dihydroxy morphinan-6-ones hydrochlorate dense
Spend for 0.2 ~ 5mg/ml.
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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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2014
- 2014-08-23 CN CN201410422026.5A patent/CN104127380B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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. |
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