CN103845286A - Medicinal composition and preparation thereof - Google Patents
Medicinal composition and preparation thereof Download PDFInfo
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- CN103845286A CN103845286A CN201410101858.7A CN201410101858A CN103845286A CN 103845286 A CN103845286 A CN 103845286A CN 201410101858 A CN201410101858 A CN 201410101858A CN 103845286 A CN103845286 A CN 103845286A
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Abstract
The invention belongs to the technical field of medicines, and discloses a medicinal composition and a preparation thereof. The medicinal composition is prepared into a water injection which consists of ibuprofen, arginine, a pH regulating agent and water for injection, wherein the pH regulating agent comprises arginine. As proved by experimental study, the number of increased impurities in an ibuprofen injection which meets the requirement is small, and a new impurity M is not produced. The preparation prepared by using the medicinal composition is more excellent in quality.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of pharmaceutical composition that contains active component ibuprofen and preparation thereof.
Background technology
When ibuprofen injection is the first approval of U.S. FDA, treat the injection of pain and heating, clinical research confirmation is safe and effective to the inpatient of postoperative moderate and severe pain and heating, and can reduce use amount and the frequency of utilization of opium kind analgesics.
NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) is that the whole world is used one of maximum medicament categories, and the whole world has 3,000 ten thousand people using about every day, one of the most salable medicine of each pharmacy group of the Ye Shi world.NSAIDs applies existing more than 100 year history the mankind, because NSAIDs has good antiinflammatory, antipyretic effect, is widely used in the pain that treatment of arthritis (particularly RA, OA) and various inflammation cause.At present, the ibuprofen product of application is mainly oral formulations clinically, although ibuprofen is higher with respect to other NSAID (non-steroidal anti-inflammatory drug) safety, but due to its gastrointestinal side effect that partly still exists general NSAID (non-steroidal anti-inflammatory drug) to have, and its biological half-life is shorter, maintain treatment concentration and need frequent medication, thereby further increase the gastrointestinal reaction of this medicine, as abdominal distention, dyspepsia, feel sick, vomiting, diarrhoea, digestive tract ulcer etc., even cause gastrointestinal hemorrhage, also increased the detrimental effect of kidney simultaneously, therefore people are devoted to the aspects such as this medicine novel formulation and new agent technology always and study.
The development of ibuprofen injection provides a new use dosage form for clinical again.A lot of traditional pharmaceutical preparation is occurring to change, and a lot of old medicine novel forms have been developed in the development of medicine new technique and new material and utilization, make the application of medicine more meet clinical treatment needs.By inference, approximately 10% will occur with new formulation in the medicine of global marketing in 10 years from now on.Ibuprofen injection becomes the novel formulation of first treatment pain and heating, and its clinical practice safety, effective, has a extensive future.
Summary of the invention
For these reasons, applicant gos deep into systematic research for ibuprofen injection, we find that kind and the weight ratio of the pH adjusting agent of ibuprofen injection product quality and ibuprofen injection has close relationship, experimental study shows, meeting in the ibuprofen injection of above-mentioned requirements impurity, to increase number few, can not produce new impurity M, the quality of the pharmaceutical preparations prepared by pharmaceutical composition of the present invention is more outstanding.
The present invention realizes by following proposal.
A kind of pharmaceutical composition, pharmaceutical composition is prepared into aqueous injection, and aqueous injection consists of: ibuprofen, arginine, pH adjusting agent and water for injection, wherein pH adjusting agent comprises arginine.
Above-mentioned pH adjusting agent is preferably arginine and ethanolamine.
Aforementioned pharmaceutical compositions preferred feedstock: ibuprofen 100 weight portions, arginine 83 weight portions, water for injection.
Wherein pH adjusting agent is preferably: the weight ratio of arginine and ethanolamine is 1:0.2.
The pH value that wherein pH adjusting agent regulates is 7.4-7.8.
Wherein the preparation method of aqueous injection includes but not limited to following:
Getting temperature is 50~60 ℃, and 60% consumption water for injection, joins in airtight Agitation Tank, passes into nitrogen 15 minutes; Take arginine and add in water for injection 30 ℃ of insulated and stirred 30 minutes; Take ibuprofen and add in water for injection 30 ℃ of insulated and stirred 30 minutes; With pH adjusting agent adjusting pH value to 7.4~7.8, stir 30 minutes; Adding w/v is 0.1% needle-use activated carbon, stirs 30min at 50~60 ℃, filters de-charcoal, injects water to 100%; Through 0.22 μ m filtering with microporous membrane; Use neutral ampoule bottle being filled with embedding under nitrogen protection condition; Under 121.0 ℃ of conditions, sterilizing 15min, to obtain final product.
The invention provides the more outstanding ibuprofen injection of a kind of quality.
The invention provides a kind of ibuprofen injection preparation method.
Ibuprofen raw material of the present invention is provided by Cumberland company of the U.S., meets the requirement of American Pharmacopeia.
Ethanolamine of the present invention refers to monoethanolamine or monoethanolamine.
The present invention is by test of many times, take impurity M and newly-increased impurity number as index, determines by screening test, and in ibuprofen injection, pH adjusting agent kind and weight ratio meet certain requirement, just can prepare the more outstanding product of quality.
One, determination method
Ibuprofen impurity A: 2-(4-Isobutyrylphenyl Propionic Acid) 2-(4-isobutyryl phenyl) propanoic acid
Ibuprofen impurity B: 4-Isobutylbenzoic Acid(4-isobutyl-benzene formic acid)
Ibuprofen impurity C:2-[4-(2-methylpropyl) phenyl] propanamide
Ibuprofen impurity E: 1-[4-(2-methylpropyl) phenyl] ethanone
Ibuprofen impurity J:(2RS)-2-[4-(2-methylpropanoyl) phenyl] propanoic acid
Impurity M:2-hydroxy-2-[4-(2-methylpropyl) phenyl] propanoic acid
Ibuprofen impurity N:(2RS)-2-(4-ethylphenyl) propanoic acid
Impurity standard substance of the present invention, ibuprofen standard substance are all purchased from National Institute for Food and Drugs Control.
1, ibuprofen method for detecting impurities
Get this product, dilute and make the solution that every 1ml approximately contains 2mg by mobile phase, as need testing solution; Precision measures 1ml, puts in 100ml measuring bottle, is diluted to scale by mobile phase, shakes up, then gets 1ml, puts in 10ml measuring bottle, is diluted to scale by mobile phase, shakes up, in contrast solution.Be 214nm except detecting wavelength, according to the chromatographic condition under assay item.Get contrast solution 20 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height of main constituent chromatographic peak be about 10%~25% of full scale.Precision measures need testing solution and the each 20 μ l of contrast solution again, and injection liquid chromatography, records 2 times to main constituent peak retention time of chromatogram respectively.Number of theoretical plate calculates and should be not less than 5000 by ibuprofen peak, and the separating degree that ibuprofen peak is adjacent impurity peaks should meet the requirements.
2, in arginine, other aminoacid detect
Get arginine appropriate, add 0.1mol/L dissolve with hydrochloric acid solution and dilute and make the solution that approximately contains 10mg in every 1ml, as need testing solution; Precision measures 1ml, puts in 250ml measuring bottle, is diluted to scale with 0.1mol/L hydrochloric acid solution, shakes up, in contrast solution; Separately get arginine reference substance and lysine hydrochloride reference substance each appropriate, put in same measuring bottle, make the solution that approximately contains respectively arginine 10mg and lysine hydrochloride 0.4mg in every 1ml with 0.1mol/L dissolve with hydrochloric acid solution dilution, as system suitability solution; According to thin layer chromatography (two appendix V of Chinese Pharmacopoeia version in 2010
B) test, draw the each 5 μ l of above-mentioned three kinds of solution, put respectively on same silica gel g thin-layer plate, with normal propyl alcohol-
Liquor ammoniae fortis (6:3) is developing solvent, launches after about 20cm, dries, and is dried approximately 10 minutes at 90 ℃, lets cool, and spray, with the normal propyl alcohol solution of 1% 1,2,3-indantrione monohydrate, is heated to speckle at 90 ℃ and occurs, inspects immediately.Contrast solution should show a speckle clearly, and system suitability solution should show two speckles that separate completely.Need testing solution, as aobvious impurity speckle, must not exceed 1, the principal spot comparison of its color and contrast solution, darker (being less than 0.4%).
3, determination of ibuprofen detects
Ibuprofen reference substance
Source: Nat'l Pharmaceutical & Biological Products Control Institute
Structure:
[assay] measured according to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010).
Chromatographic condition and system suitability chromatographic column: GraceSmart RP185u150mm × 4.6mm; Measure water 600ml, phosphoric acid 0.5ml, acetonitrile 340ml mixes, and being diluted with water to 1000ml is mobile phase; Detection wavelength is 263nm; Flow velocity 2.0ml/ minute.Number of theoretical plate calculates and should be not less than 5000 by ibuprofen peak.
Algoscopy
Precision measures this product 0.5ml, puts in 100ml measuring bottle, is diluted to scale by mobile phase, shakes up.Precision measures 20 μ l, and injection liquid chromatography, records chromatogram; Separately get ibuprofen reference substance appropriate, accurately weighed, add the mobile mutual-assistance and dissolve and quantitatively dilute and make the solution that approximately contains 0.5mg in every 1ml, be measured in the same method., to obtain final product with calculated by peak area by external standard method.
Two, pH screening test research
Test 1 group: ibuprofen 400g, arginine 332g weight portion, water for injection, pH adjusting agent is arginine.
Test 2 groups: ibuprofen 400g, arginine 332g weight portion, water for injection, pH adjusting agent is arginine and ethanolamine, its weight ratio 1:1.
Test 3 groups: ibuprofen 400g, arginine 332g weight portion, water for injection, pH adjusting agent is arginine and ethanolamine, its weight ratio 1:0.5.
Test 4 groups: ibuprofen 400g, arginine 332g weight portion, water for injection, pH adjusting agent is arginine and ethanolamine, its weight ratio 1:0.2.。
Test 5 groups: ibuprofen 400g, arginine 332g weight portion, water for injection, 1M hydrochloric acid solution.
Test 6 groups: ibuprofen 400g, arginine 332g weight portion, water for injection, 1M phosphoric acid solution.
Test 7 groups: ibuprofen 400g, arginine 332g weight portion, water for injection, 1M citric acid soln.
Preparation method: getting temperature is 55 ℃, and 60% consumption water for injection, joins in airtight Agitation Tank, passes into nitrogen 15 minutes; Take arginine and add in water for injection 30 ℃ of insulated and stirred 30 minutes; Take ibuprofen and add in water for injection 30 ℃ of insulated and stirred 30 minutes; With pH adjusting agent adjusting pH value to 7.6, stir 30 minutes; Adding w/v is 0.1% needle-use activated carbon, stirs 30min at 55 ℃, filters de-charcoal, injects water to 100%; Through 0.22 μ m filtering with microporous membrane; Use neutral ampoule bottle being filled with embedding under nitrogen protection condition; Under 121.0 ℃ of conditions, sterilizing 15min, obtains 1000 bottles of aqueous injection (every bottle of 4ml).
Get above-mentioned preparation, impurity is checked, testing result is as follows:
The different preparation related substance of table 1 testing result
Test brief summary: above-mentioned test shows, adopt hydrochloric acid, phosphoric acid, citric acid as pH adjusting agent, in preparation, impurity M, impurity A, impurity E all significantly increase (it is more than 5 times increasing multiple), total impurities content significantly increases (increase multiple and exceed 5 times), other unknown impuritie numbers exceed 6, therefore, we determine that employing arginine is as pH adjusting agent.
Three, arginine and the test of ethanolamine weight ratio
Test method: get 1 group of " two, the research of pH screening test " test-
Test the preparation of 4 groups, test as follows:
(1) exposure experiments to light: get different tests scheme preparation, be placed in the proof box of medicine strong illumination, place 10 days under illumination 4500Lx ± 500Lx condition, sampling in the 10th day, detect, result is compared with 0 month data.
(2) hot test: get different tests scheme preparation, be placed in small beaker, diaphragm seal sealing.Be placed on electric drying oven with forced convection, under 60 ℃ ± 1 ℃ condition, place 10 days, detect in sampling in the 10th day, result is compared with 0 month data.
(3) high wet test: get different tests scheme preparation, be placed in small beaker, be placed in respectively and fill NaCl saturated solution and KNO
3the close drying device of saturated solution, damp condition is respectively RH75%.It is placed in respectively to electric drying oven with forced convection, under 25 ℃ ± 1 ℃ condition, places 10 days, detect in sampling in the 10th day, result is compared with 0 month data.
Result of the test: by table 2, table 3, table 4.
Different preparation related substance testing results under table 2 illumination condition
Different preparation related substance testing results under table 3 hot conditions
Different preparation related substance testing results under table 4 super-humid conditions
Test brief summary: show through stability test, test 1 group, test 2 groups, test 3 groups of preparation impurity M content be greater than 0.1%, newly-increased impurity number is more than 6, and test 4 groups, be that ibuprofen injection pH adjusting agent is arginine and ethanolamine, the two,, for the preparation group that weight ratio is 1:0.2, does not produce impurity M, newly-increased impurity is less than 5, and this product quality is outstanding.
Preparation Example
Embodiment 1
Ibuprofen 100g, arginine 83g, water for injection, pH adjusting agent is arginine and ethanolamine, weight ratio is 1:0.2.
Getting temperature is 50 ℃,
60% consumption water for injection, joins in airtight Agitation Tank, passes into nitrogen 15 minutes; Take arginine and add in water for injection 30 ℃ of insulated and stirred 30 minutes; Take ibuprofen and add in water for injection 30 ℃ of insulated and stirred 30 minutes; With pH adjusting agent adjusting pH value to 7.4, stir 30 minutes; Adding w/v is 0.1% needle-use activated carbon, stirs 30min at 50 ℃, filters de-charcoal, injects water to 100%; Through 0.22 μ m filtering with microporous membrane; Use neutral ampoule bottle being filled with embedding under nitrogen protection condition; Under 121.0 ℃ of conditions, sterilizing 15min, obtains 1000 bottles of aqueous injection (every bottle of 4ml).
Embodiment 2
Ibuprofen 100g, arginine 83g, water for injection, pH adjusting agent is arginine and ethanolamine, weight ratio is 1:0.2.
Getting temperature is 60 ℃,
60% consumption water for injection, joins in airtight Agitation Tank, passes into nitrogen 15 minutes; Take arginine and add in water for injection 30 ℃ of insulated and stirred 30 minutes; Take ibuprofen and add in water for injection 30 ℃ of insulated and stirred 30 minutes; With pH adjusting agent adjusting pH value to 7.8, stir 30 minutes; Adding w/v is 0.1% needle-use activated carbon, stirs 30min at 60 ℃, filters de-charcoal, injects water to 100%; Through 0.22 μ m filtering with microporous membrane; Use neutral ampoule bottle being filled with embedding under nitrogen protection condition; Under 121.0 ℃ of conditions, sterilizing 15min, obtains 1000 bottles of aqueous injection (every bottle of 4ml).
Embodiment 3
Ibuprofen 100g, arginine 83g, water for injection, pH adjusting agent is arginine and ethanolamine, weight ratio is 1:0.2.
Getting temperature is 55 ℃,
60% consumption water for injection, joins in airtight Agitation Tank, passes into nitrogen 15 minutes; Take arginine and add in water for injection 30 ℃ of insulated and stirred 30 minutes; Take ibuprofen and add in water for injection 30 ℃ of insulated and stirred 30 minutes; With pH adjusting agent adjusting pH value to 7.4, stir 30 minutes; Adding w/v is 0.1% needle-use activated carbon, stirs 30min at 55 ℃, filters de-charcoal, injects water to 100%; Through 0.22 μ m filtering with microporous membrane; Use neutral ampoule bottle being filled with embedding under nitrogen protection condition; Under 121.0 ℃ of conditions, sterilizing 15min, obtains 1000 bottles of aqueous injection (every bottle of 4ml).
Embodiment 4
Ibuprofen 100g, arginine 83g, water for injection, pH adjusting agent is arginine and ethanolamine, weight ratio is 1:0.2.
Getting temperature is 56 ℃,
60% consumption water for injection, joins in airtight Agitation Tank, passes into nitrogen 15 minutes; Take arginine and add in water for injection 30 ℃ of insulated and stirred 30 minutes; Take ibuprofen and add in water for injection 30 ℃ of insulated and stirred 30 minutes; With pH adjusting agent adjusting pH value to 7.5, stir 30 minutes; Adding w/v is 0.1% needle-use activated carbon, stirs 30min at 56 ℃, filters de-charcoal, injects water to 100%; Through 0.22 μ m filtering with microporous membrane; Use neutral ampoule bottle being filled with embedding under nitrogen protection condition; Under 121.0 ℃ of conditions, sterilizing 15min, obtains 1000 bottles of aqueous injection (every bottle of 4ml).
Embodiment 5
Ibuprofen 100g, arginine 83g, water for injection, pH adjusting agent is arginine and ethanolamine, weight ratio is 1:0.2.
Getting temperature is 58 ℃,
60% consumption water for injection, joins in airtight Agitation Tank, passes into nitrogen 15 minutes; Take arginine and add in water for injection 30 ℃ of insulated and stirred 30 minutes; Take ibuprofen and add in water for injection 30 ℃ of insulated and stirred 30 minutes; With pH adjusting agent adjusting pH value to 7.7, stir 30 minutes; Adding w/v is 0.1% needle-use activated carbon, stirs 30min at 58 ℃, filters de-charcoal, injects water to 100%; Through 0.22 μ m filtering with microporous membrane; Use neutral ampoule bottle being filled with embedding under nitrogen protection condition; Under 121.0 ℃ of conditions, sterilizing 15min, obtains 1000 bottles of aqueous injection (every bottle of 4ml).
Embodiment 6
Ibuprofen 1000g, arginine 830g, water for injection, pH adjusting agent is arginine and ethanolamine, weight ratio is 1:0.2.
Getting temperature is 55 ℃,
60% consumption water for injection, joins in airtight Agitation Tank, passes into nitrogen 15 minutes; Take arginine and add in water for injection 30 ℃ of insulated and stirred 30 minutes; Take ibuprofen and add in water for injection 30 ℃ of insulated and stirred 30 minutes; With pH adjusting agent adjusting pH value to 7.6, stir 30 minutes; Adding w/v is 0.1% needle-use activated carbon, stirs 30min at 55 ℃, filters de-charcoal, injects water to 100%; Through 0.22 μ m filtering with microporous membrane; Use neutral ampoule bottle being filled with embedding under nitrogen protection condition; Under 121.0 ℃ of conditions, sterilizing 15min, obtains 10000 bottles of aqueous injection (every bottle of 4ml).
Described embodiment includes but not limited to above-mentioned.
Claims (6)
1. a pharmaceutical composition, pharmaceutical composition is prepared into aqueous injection, and aqueous injection consists of: ibuprofen, arginine, pH adjusting agent and water for injection, is characterized in that pH adjusting agent comprises arginine.
2. a kind of pharmaceutical composition according to claim 1, wherein pH adjusting agent is arginine and ethanolamine.
3. a kind of pharmaceutical composition according to claim 1, wherein ibuprofen 100 weight portions, arginine 83 weight portions, water for injection.
4. according to a kind of pharmaceutical composition described in claim 1 any one, wherein the weight ratio of arginine and ethanolamine is 1:0.2.
5. a kind of pharmaceutical composition according to claim 1, the pH value that wherein pH adjusting agent regulates is 7.4-7.8.
6. a kind of pharmaceutical composition according to claim 1, wherein the preparation method of aqueous injection is:
Getting temperature is 50~60 ℃, and 60% consumption water for injection, joins in airtight Agitation Tank, passes into nitrogen 15 minutes; Take arginine and add in water for injection 30 ℃ of insulated and stirred 30 minutes; Take ibuprofen and add in water for injection 30 ℃ of insulated and stirred 30 minutes; With pH adjusting agent adjusting pH value to 7.4~7.8, stir 30 minutes; Adding w/v is 0.1% needle-use activated carbon, stirs 30min at 50~60 ℃, filters de-charcoal, injects water to 100%; Through 0.22 μ m filtering with microporous membrane; Use neutral ampoule bottle being filled with embedding under nitrogen protection condition; Under 121.0 ℃ of conditions, sterilizing 15min, to obtain final product.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104288099A (en) * | 2014-09-25 | 2015-01-21 | 西安仁仁药业有限公司 | Ibuprofen injection |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104288099A (en) * | 2014-09-25 | 2015-01-21 | 西安仁仁药业有限公司 | Ibuprofen injection |
CN104288099B (en) * | 2014-09-25 | 2017-02-15 | 西安仁仁药业有限公司 | Preparation method of ibuprofen injection |
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Application publication date: 20140611 |