CN1271996C - Medicinal powder injection for respiratory system and preparing method - Google Patents

Medicinal powder injection for respiratory system and preparing method Download PDF

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CN1271996C
CN1271996C CN 200410060814 CN200410060814A CN1271996C CN 1271996 C CN1271996 C CN 1271996C CN 200410060814 CN200410060814 CN 200410060814 CN 200410060814 A CN200410060814 A CN 200410060814A CN 1271996 C CN1271996 C CN 1271996C
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asarone
injection
injectable powder
respiratory system
treatment
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CN1615827A (en
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刘万忠
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Abstract

The present invention discloses medicinal powder injection used for the respiratory system and a preparing method, wherein the medicinal powder injection contains (by weight) asarone and Hydroxypropyl-Beta-cyclodextrin or auxiliary materials. The preparing method comprises the following steps: taking Hydroxypropyl-Beta-cyclodextrin and adding proper quantity of water for injection to dissolve the Hydroxypropyl-Beta-cyclodextrin; then adding asarone, stirring or grinding or dissolving the asarone by ultrasonic, and causing the asarone to become clathrate solution preparation; or freeze drying, or drying under reduced pressure or drying the prepared clathrate solution with spray to prepare asarone powder injection. Compared with other asarone injection, the present invention has the characteristics of simple preparing process, good water solubility of products, stable quality and more secure use.

Description

The medicine injectable powder and the preparation method that are used for respiratory system
Technical field
The present invention relates to a kind of medicine for respiratory system injectable powder that is used for, also relate to the preparation method of this medicine injectable powder simultaneously.
Background technology
Asarone (Asarone) has another name called alpha-ararin or α-asaricin, and its chemical structural formula is as follows:
Figure C20041006081400031
Asarone is a kind of medicine for respiratory system, has expansion of cerebral vascular, reduces cerebral vascular resistance, and the cerebral blood flow increasing amount is improved the effect of cerebral circulation and to the effect of antiplatelet aggregation.Clinical going to school can be used for the treatment of bronchitis, bronchial asthma and pneumonia etc.Because it is fat-soluble higher, fusing point is lower, and bioavailability is lower when preparation oral formulations (as tablet, capsule etc.), and individual variation is bigger, clinically drug administration by injection approach of using more.
Because asarone insoluble in water, also be insoluble to materials such as acidity or alkalescence, therefore present Asarone injection liquid (2ml: 8mg) often need to add organic solvent such as ethanol, Polyethylene Glycol or solubilisings such as surfactant such as tween 80 in the preparation on the market, in order to solve stability problem, also need add antioxidant, complexing of metal ion agent in the prescription, regulate pH value, ultrafiltration and logical noble gas etc., with solve injection quality instability easy to change, easily produce sedimentary problem.Thus Zhi Bei Asarone injection not only side effect big, tangible hemolytic reaction is arranged, and all unstable to light and heat.Therefore, under the prerequisite that guarantees the asarone drug effect, how to improve its solubility property, increase its stability, avoid in the preparation prescription because of using a large amount of cosolvents and stabilizing agent to cause that toxic and side effects just seems particularly important.Existing Herba Asari and injection are all unstable to light and heat, and side effect is obvious.
HP-(the beta-cyclodextrin derivative that HP-β-CD) is the Recent study success, can be used for injecting.It is by beta-schardinger dextrin-(β-CD) and 1, the hydrophilic derivatives that the condensation of 2-expoxy propane forms, its water solublity significantly improves than beta-schardinger dextrin-that (water solublity of beta-schardinger dextrin-is less than 2%, and HP-is soluble in water, at room temperature dissolubility can be up to 50%), but be the beta-cyclodextrin derivative of first injection for intravenous of drugs approved by FDA.Zoopery shows: this product has advantages such as the little and haemolysis of nephrotoxicity is little.By various dose, different way of administration, with mice, rat, rabbit, dog, horse, monkey etc. is laboratory animal, maximum dose level intraperitoneal and intravenously administrable 10g/kg, oral 15g/kg, observe behavior, the dietary habit of animal after the administration, and the organ of animal is carried out histological examination all have no adverse effect.50% solution is to skin, eyes, the equal nonirritant of muscle.Be the lower pharmaceutical pack mixture of a kind of toxicity, can be used as the inclusion agents and the solubilizing agent of drug administration by injection agent.
Summary of the invention
The objective of the invention is to be to provide a kind of medicine injectable powder that is used for respiratory system, this medicine injectable powder has dissolubility preferably in aqueous solution, and it is all more stable to light and heat, decomposition reaction does not take place in long-time placement, avoided simultaneously in the preparation because of with an organic solvent or surfactant cause malicious subsidiary effect.
Another object of the present invention is to prepare the method for treatment medicine for respiratory system injectable powder.
In order to achieve the above object, the present invention adopts following technical measures:
Test shows: HP-β-CD can form clathrate with asarone and increase its dissolubility in water.
In embodiments of the invention, the weight proportion of various compositions following (by weight):
Asarone 8
Beta-cyclodextrin derivative 8-400
Stabilizing agent 0-10
Lyophilizing excipient (skeleton) 0-100
The invention provides the medicine for respiratory system injectable powder, in beta-cyclodextrin derivative, comprise pharmaceutically useful asarone and pharmaceutic adjuvant.Beta-cyclodextrin derivative is a HP-.
The invention provides the medicine for respiratory system injectable powder, be made up of asarone, beta-cyclodextrin derivative and pharmaceutic adjuvant, the pharmaceutic adjuvant weight ratio is 0-10.
The invention provides the medicine for respiratory system injectable powder, be made up of asarone, beta-cyclodextrin derivative and lyophilizing excipient, lyophilizing excipient weight ratio is 0-100.
The step of preparation respiratory system injectable powder is: get HP-, after adding the water for injection dissolving, add asarone, stirring or grinding or ultrasonicly make asarone dissolving and form clathrate (or add other pharmaceutic adjuvant such as stabilizing agent or freeze behind excipient (skeleton) and activated carbon decolorizing), filtration sterilization, be sub-packed in the sterilization cillin bottle,, get the aseptic freeze-dried injectable powder of asarone (block) through lyophilization; Also the aseptic inclusion complex in solution of the asarone of gained can be carried out spray drying or drying under reduced pressure or lyophilization and get sterilized powder, under aseptic condition, carry out packing at last and get asarone sterile powder injection (Powdered thing).
Thinking when being necessary, stabilizing agent, metal chelating agent, the pH regulator agent that in the injectable powder proportioning, can add 0-10 part, stabilizing agent is an antioxidant, antioxidant is sodium sulfite, sodium pyrosulfite, vitamin C or cysteine etc., metal chelating agent is EDTA sodium salt or calcium salt etc., and the pH regulator agent is acidity or alkaline matters such as hydrochloric acid or sodium hydroxide.
Thinking that when being necessary, the lyophilizing excipient that can add 0-100 part in the injectable powder proportioning is as skeleton, the lyophilizing excipient is: mannitol, sorbitol, lactose, dextran or sodium chloride etc.
Asarone sterile powder injection by this method preparation has advantages such as production technology is simple, with low cost, steady quality, and simultaneously prepared product is all more stable to light and heat, and toxic and side effects is very low.This injectable powder not only can intravenous injection, but also can intramuscular injection, and zest is starkly lower than other asarone injection.
The specific embodiment
Embodiment 1: get 80 parts of HP-, after the water for injection of adding 1000ml makes dissolving, added activated carbon decolorizing 30 minutes, filter carbon removal, add 8 parts of asarone crude drug, constantly stir and make dissolving fully, add 0.1mol/L hydrochloric acid or sodium hydroxide solution in case of necessity and regulate pH to 5-7, add the injection water to 2000ml, the fine straining degerming is to clear and bright, be sub-packed in the cillin bottle by every bottle of 2ml, carry out lyophilization then according to a conventional method, promptly get the aseptic freeze-dried injectable powder of asarone (every bottle contains asarone 8mg).Every bottle joins among 0.9% sodium chloride injection or 5%~10% glucose injection 50-100ml intravenous drip during use.Ask for an interview reference examples one: be the asarone crude drug.Ask for an interview reference examples two: be commercial Asarone injection liquid.
Embodiment 2: get 8 parts of HP-, 100 parts in mannitol, after the water for injection of adding 1000ml makes dissolving, added activated carbon decolorizing 30 minutes, filter carbon removal, add 8 parts of asarone crude drug, constantly stir and make dissolving fully, add 0.1mol/L hydrochloric acid or sodium hydroxide solution in case of necessity and regulate pH to 5-7, add the injection water to 2000ml, the fine straining degerming is sub-packed in the cillin bottle by every bottle of 2ml to clear and bright, carry out lyophilization then according to a conventional method, promptly get the aseptic freeze-dried injectable powder of asarone (every bottle contains asarone 8mg).Every bottle joins among 0.9% sodium chloride injection or 5%~10% glucose injection 50-100ml intravenous drip during use.
Embodiment 3: get 40 parts of HP-, 500 parts of glucoses, after the water for injection of adding 1500ml makes dissolving, added activated carbon decolorizing 30 minutes, filter carbon removal, add 8 parts of asarone crude drug, constantly stir and make dissolving fully, add 0.1mol/L hydrochloric acid or sodium hydroxide solution in case of necessity and regulate pH to 5-7, add the injection water to 5000ml, the fine straining degerming is carried out spray drying to clear and bright with gained solution, be sub-packed in the cillin bottle by the asarone of every bottle of 8mg according to a conventional method then, promptly get the asarone sterile powder injection.During use every bottle add 10ml water for injection dissolving after, intravenous injection.
Embodiment 4: get 400 parts of HP-, 80 parts in sodium chloride, 1 part of sodium sulfite, after the water for injection of adding 4000ml makes dissolving, added activated carbon decolorizing 30 minutes, filter carbon removal, add 8 parts of asarone crude drug, constantly stir and make dissolving fully, add 0.1mol/L hydrochloric acid or sodium hydroxide solution in case of necessity and regulate pH to 5-7, add the injection water to 5000ml, the fine straining degerming is to clear and bright, be sub-packed in the cillin bottle by every bottle of 5ml, carry out lyophilization then according to a conventional method, promptly get the aseptic freeze-dried injectable powder of asarone (every bottle contains asarone 8mg).During use every bottle add 10ml water for injection dissolving after, intravenous injection.
Embodiment 5: get 8 parts of HP-, after the water for injection of adding 1000ml makes dissolving, added activated carbon decolorizing 30 minutes, filter carbon removal, add 8 parts of asarone crude drug, constantly stir and make dissolving fully, add 0.1mol/L hydrochloric acid or sodium hydroxide solution in case of necessity and regulate pH to 5-7, add the injection water to 2000ml, the fine straining degerming is to clear and bright, be sub-packed in the cillin bottle by every bottle of 2ml, carry out lyophilization then according to a conventional method, promptly get the aseptic freeze-dried injectable powder of asarone (every bottle contains asarone 8mg).Every bottle joins among 0.9% sodium chloride injection or 5%~10% glucose injection 50-100ml intravenous drip during use.
Embodiment 6: get 40 parts of HP-, after the water for injection of adding 1500ml makes dissolving, add activated carbon decolorizing 30 minutes, filter carbon removal, add 8 parts of asarone crude drug, constantly stir and make dissolving fully, add 0.1mol/L hydrochloric acid or sodium hydroxide solution in case of necessity and regulate pH to 5-7, add the injection water to 5000ml, the fine straining degerming is to clear and bright, gained solution is carried out spray drying, be sub-packed in the cillin bottle by the asarone of every bottle of 8mg according to a conventional method then, promptly get the asarone sterile powder injection.During use every bottle add 10ml water for injection dissolving after, intravenous injection.
Embodiment 7: get 400 parts of HP-, 80 parts in sodium chloride, 1 part of sodium sulfite, after the water for injection of adding 4000ml makes dissolving, added activated carbon decolorizing 30 minutes, filter carbon removal, add 8 parts of asarone crude drug, constantly stir and make dissolving fully, add 0.1mol/L hydrochloric acid or sodium hydroxide solution in case of necessity and regulate pH to 5-7, add the injection water to 5000ml, the fine straining degerming is to clear and bright, be sub-packed in the cillin bottle by every bottle of 5ml, carry out lyophilization then according to a conventional method, promptly get the aseptic freeze-dried injectable powder of asarone (every bottle contains asarone 8mg).During use every bottle add 10ml water for injection dissolving after, intravenous injection.
Embodiment 8: get 80 parts of HP-, 20 parts in sodium chloride, 1 part of sodium pyrosulfite, after the water for injection of adding 1000ml makes dissolving, added activated carbon decolorizing 30 minutes, filter carbon removal, add 8 parts of asarone crude drug, constantly stir and make dissolving fully, add 0.1mol/L hydrochloric acid or sodium hydroxide solution in case of necessity and regulate pH to 5-7, add the injection water to 2000ml, the fine straining degerming is to clear and bright, be sub-packed in the cillin bottle by every bottle of 2ml, carry out lyophilization then according to a conventional method, promptly get the aseptic freeze-dried injectable powder of asarone (every bottle contains asarone 8mg).Every bottle joins among 0.9% sodium chloride injection or 5%~10% glucose injection 50-100ml intravenous drip during use.
The performance test of asarone injectable powder
1, light stability test
Get the sample of asarone injectable powder sample by embodiment one preparation, asarone crude drug (reference examples one), commercial Asarone injection liquid sample (reference examples two), after removing outer package, after putting under the sunlight irradiation certain hour simultaneously, with the HPLC method its content is measured that [chromatographic condition: chromatographic column is Spherisorb-C 18, mobile phase is methanol-water (70: 30), the detection wavelength is 254nm)], the results are shown in Table shown in one.As shown in Table 1: the asarone injectable powder for preparing by this prescription to the stability of light and heat apparently higher than other 2 kinds of samples.
Table one, the asarone injectable powder of pressing embodiment one preparation and reference examples compare * to the stability of light and heat
Test specimen Exposure experiments to light sample (%) Hot test sample (%)
Embodiment one Before the test 100.0 100.0
After the test 99.8 99.1
Reference examples one (crude drug) Before the test 100.0 100.0
After the test 98.2 99.5
Reference examples two (commercial injection) Before the test 100.0 100.0
After the test 96.5 95.4
* annotate: result of calculation is for indicating percentage composition, and initial value is all in 100%.
2, heat stabilization test
Get asarone injectable powder sample, asarone crude drug (reference examples one), commercial Asarone injection liquid sample (reference examples three) by embodiment one preparation, after removing outer package, heating 2 days under 100 ℃ temperature conditions simultaneously measures to its content of test front and back with the HPLC method that [chromatographic condition: chromatographic column is Spherisorb-C 18, mobile phase is methanol-water (70: 30), the detection wavelength is 254nm)], the results are shown in Table shown in one.As shown in Table 1: the asarone injectable powder for preparing by this prescription to the stability of heat apparently higher than control sample.
3, acute toxicity test
Get asarone injectable powder sample, asarone crude drug (reference examples one), commercial Asarone injection liquid sample (reference examples two) by embodiment one preparation, according to acute toxicity test method (chief editor such as Xu Shuyun: " pharmacological experimental methodology ", the People's Health Publisher, in January, 1994), the half of measuring its mice causes death and counts, and the results are shown in Table shown in two.As shown in Table 2: the asarone injectable powder that the toxicity of commercial Asarone injection liquid is higher than the asarone crude drug and is prepared by this law.
Table two, the asarone injectable powder of pressing embodiment one preparation and reference examples compare the acute toxicity of mice
Test specimen The oral LD of mice 50 (mg/kg) Mouse peritoneal injection LD 50 (mg/kg)
Embodiment one 670.8±50.2 380.5±30.2
Reference examples one (crude drug) 675.8±47.6 377.2±36.8
Reference examples two (commercial injection) 642.4±46.6 355.5±27.9
4, hemolytic test
Get by each 1 in the sample of embodiment one and reference examples two (commercial injection), after adding 0.9% sodium chloride injection respectively and being diluted to 5ml, carry out hemolytic test simultaneously.
Experimental technique: get 1 of rabbit, get blood 20ml from its auricular vein, blood is stirred with glass rod in edge joint blood limit, defibrinates to remove.Get and remove defibrinated blood 10ml, add normal saline 10ml, stir, the centrifugal supernatant of removing adds normal saline washing 3-4 time again, makes the supernatant after centrifugal abandoning supernatant no longer occur till the redness.At last be mixed with 2% suspension with normal saline, promptly get red blood cell suspension according to gained blood cell volume.
Get 7 in test tube, after according to the form below three (1), four (1) was arranged and successively added various solution, mix homogeneously was put in 37 ℃ the calorstat then, and observation sample was 0.5,1,2 and 3 hour haemolysis situation.
Result of the test: see Table after the result of the test shown in three (2), four (2), the sample solution developmental tube of embodiment one preparation is the same with physiology saline control pipe, does not all produce haemolysis.And the part haemolysis appears in the Asarone injection liquid liquid sample solution of reference examples two when high concentration.
The various solution additions of sample solution hemolytic test of table three (1) embodiment one and order
The test tube numbering 1 2 3 4 5 6 7
The sample solution of embodiment one (ml) 0 0.1 0.2 0.3 0.4 0.5 Injection water
0.9% normal saline (ml) 2.5 2.4 2.3 2.2 2.1 2.0 2.5
2% red blood cell suspension (ml) 2.5 2.5 2.5 2.5 2.5 2.5 2.5
The sample solution hemolytic test result of table three (2) embodiment one
The test tube numbering 1 2 3 4 5 6 7
37℃,0.5hr - - - - - - +
37℃,1.0hr - - - - - - ++
37℃,3.0hr - - - - - - +++
Annotate :-represent that haemolysis does not take place yet in not coagulation; + expression coagulation; ++ expression part haemolysis; +++expression complete hemolysis.
The various solution additions of sample solution hemolytic test of table four (1) reference examples two and order
The test tube numbering 1 2 3 4 5 6 7
The sample solution of reference examples two (ml) 0 0.1 0.2 0.3 0.4 0.5 Injection water
0.9% normal saline (ml) 2.5 2.4 2.3 2.2 2.1 2.0 2.5
2% red blood cell suspension (ml) 2.5 2.5 2.5 2.5 2.5 2.5 2.5
The sample solution hemolytic test result of table four (2) reference examples two
The test tube numbering 1 2 3 4 5 6 7
37℃,0.5hr - - - - - - +
37℃,1.0hr - - - - - + ++
37℃,3.0hr - - - - - ++ +++
Annotate :-represent that haemolysis does not take place yet in not coagulation; + expression coagulation; ++ expression part haemolysis; +++expression complete hemolysis.

Claims (8)

1. disease medicament injectable powder that is used for the treatment of respiratory system, it comprises asarone and HP-, and weight ratio is 8: 8-400.
2. disease medicament injectable powder that is used for the treatment of respiratory system, it comprises asarone, HP-and pharmaceutic adjuvant, and weight ratio is 8: 8-400: 0-10.
3. a kind of disease medicament injectable powder that is used for the treatment of respiratory system according to claim 2 is characterized in that pharmaceutic adjuvant is stabilizing agent or pH regulator agent.
4. a kind of disease medicament injectable powder that is used for the treatment of respiratory system according to claim 3 is characterized in that stabilizing agent is an antioxidant, and antioxidant is sodium sulfate, vitamin C or cysteine.
5. a kind of disease medicament injectable powder that is used for the treatment of respiratory system according to claim 3 is characterized in that the pH regulator agent is hydrochloric acid or sodium hydroxide.
6. disease medicament injectable powder that is used for the treatment of respiratory system, it comprises asarone, HP-and lyophilizing excipient, and weight ratio is 8: 8-400: 0-100.
7. a kind of disease medicament injectable powder that is used for the treatment of respiratory system according to claim 6 is characterized in that the lyophilizing excipient is mannitol, sorbitol, lactose, dextran or sodium chloride.
8, a kind of described a kind of preparation method that is used for the treatment of the disease medicament injectable powder of respiratory system of claim 1 that realizes, comprise the following steps: to get HP-, after adding the water for injection dissolving, add asarone, stirring or grinding or ultrasonic asarone dissolving and the formation inclusion complex in solution of making, aseptic filtration then divides to be filled to pin with in the bottle, through lyophilization, get the aseptic freeze-dried injectable powder of asarone.
CN 200410060814 2004-09-09 2004-09-09 Medicinal powder injection for respiratory system and preparing method Expired - Fee Related CN1271996C (en)

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Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1313086C (en) * 2005-05-30 2007-05-02 许群 Aarin preparation for injection and preparing process thereof
CN101011354B (en) * 2005-06-07 2011-06-22 中国医学科学院药物研究所 Asarone submicron emulsion and its preparation method
CN105055345B (en) * 2015-09-02 2018-01-30 海南葫芦娃药业集团股份有限公司 Retilian Simplex composition for injection, Retilian Simplex freeze-dried powder and preparation method thereof
CN110840866A (en) * 2018-08-20 2020-02-28 成都新睿泰康科技有限公司 Asarin pharmaceutical composition and application thereof in preventing and treating neurodegenerative diseases

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