CN100346785C - Preparation of selective epoxide hydrolase II inhibitor - Google Patents
Preparation of selective epoxide hydrolase II inhibitor Download PDFInfo
- Publication number
- CN100346785C CN100346785C CN02819441.1A CN02819441A CN100346785C CN 100346785 C CN100346785 C CN 100346785C CN 02819441 A CN02819441 A CN 02819441A CN 100346785 C CN100346785 C CN 100346785C
- Authority
- CN
- China
- Prior art keywords
- preparation
- cox2 inhibitor
- pharmaceutical preparation
- celecoxib
- rofecoxib
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A transparent stable injection preparation of a new selective epoxide hydrolase II(cyclooxygenase II) inhibitor, is used for the treatment of pain and the inflammation that causes by cyclooxygenase II, especially the preparation is prepared by dissolving the selective active cyclooxygenase II inhibitor such as cyclooxygenase II inhibitor selected from example choose from celebrex, vioxx and their homologous compounds, into solvent such as isobide ester isosorbide as shown by the chemical formula I, wherein, R[1] and R[2] are hydrogen atom or the alkyl or acetic acid ester of 1 - 3 carbons; also disclosed is a simple and cost-rational preparation method of tha said new medicine preparation.
Description
Technical field:
The present invention relates to a kind of new medicinal preparation of transparent, stable selectivity cyclooxygenase 2 (CYCLOOXY GE NASEII is abbreviated as COX2) inhibitor, be applicable to injection for curing because pain and the inflammation symptom that cyclooxygenase 2 causes.
Background technology:
Selective COX2 inhibitor, be widely used for treating the imbalance of flesh bone such as celecoxib (Celecoxib), rofecoxib (Rofecoxib) and homologue thereof, such as rheumatic arthritis (rheumatoid arthritis), osteoarthritis (osteoarthritis), ankylosing spondylosis (ankylosing spondylitis) and acute pain.They also are used as the drug of first choice of treatment dysmenorrhea.In the life-time service plug former times cloth and the effective inflammation-inhibiting and do not have stomach toxicity (Simon etc., 1998,1999 of conventional nonselective NSAID (non-steroidal anti-inflammatory drug) (NSAID) of rofecoxib treatment; Bensen etc. 1999; Emery etc. 1999; Howaky etc. 2000; Schintzer etc. 1999; Ehlidrich etc. 1999; 1999 through Goodman ﹠amp such as Laine; Gilman ' s Thepharmacological basis of therapeutics 10
ThEdition, McGraw HillMedical Publication Division 2001).
WO 0145705 and WO 0145706 have disclosed the formula of oral preparation of celecoxib.
WO 0069434 and WO 0032189 have disclosed the solid dosage COX2 inhibitor formula of oral through admixed excipients (excipients).
The WO 0048583 that announces provides the rofecoxib oral agents that contains 5HT antagonist (antigonists) once more.
The WO 0032189 that announces further discloses the formula of oral that contains the celecoxib component and is used for treating the imbalance that Cycloxygenase causes as slow releasing pharmaceutical.
These existing selective COX2 inhibitoies or be made into oral tablets or oral liquid.Although convenient drug administration, peroral dosage form be because the matter of time in administration path, meeting the requirements of plasma concentration and drug treating time has delay.Therefore, selective COX2 inhibitor has tangible time lag when the performance therapeutic effect.In addition, the picked-up of food also can influence the absorption of medicine and postpone medicine and begin to play a role.Other has report to show that some selective COX2 inhibitoies and antacid are taken in simultaneously, and treatment concentration can reduce about 20%.
Because above-mentioned restriction is for realizing curative effect rapidly, the urgent now injection type of wishing to find selective COX2 inhibitor.In order to prepare the injection type of this compounds, the carrier/excipient (vehicle) of a suitable medicinal soluble is essential.Significantly, this carrier/excipient (vehicle) should be a safety non-toxic.Because the physicochemical property of this compounds, selective COX2 inhibitor is such as celecoxib, rofecoxib, penta ground former times cloth (Valdecoxib), the water solublity of Chinese mugwort tower former times cloth (Itacoxib) and SC 59046 (Deracoxib) is very poor, makes that preparation injection type medicine is very difficult.
Attempt to use ethanol, dimethyl sulfoxide, propylene glycol and glycerol to prepare the injection type of selective COX2 inhibitor such as celecoxib, rofecoxib or their homologue, but find it is unsuccessful, because solubility problem or because when they for example are dissolved in isopropyl alcohol acidic mixture, dimethyl sulfoxide and the propylene glycol solvent, because toxicity, said medicine does not allow to use these solvents by the muscle drug treatment with concentration range.
Because the problems referred to above also do not have the injectable agent of celecoxib, rofecoxib, penta ground former times cloth, Chinese mugwort tower former times cloth and SC 59046 now.Unique available injection is the precursor medicine parecoxib (Paracoxib) of penta ground former times cloth (Valdecoxib), and is to use with its sodium-salt form.Parecoxib enters the blood circulation posthydrolysis and becomes penta ground former times cloth.
As everyone knows, drug administration by injection can be brought into play drug effect rapidly and be used for antiinflammatory/pain relieving.This is because after the administration, finishes the blood Chinese medicine and reaches Cmax with the performance therapeutical effect, and injectable drug is faster than oral drugs.The time that arrives haemoconcentration after the oral drugs administration is after head crosses metabolism (first-passmetabolism).
Therefore because above-mentioned dissolubility and toxicity problem, prior art can't provide can direct injection COX2 inhibitor.
Summary of the invention:
The present invention aims to provide a kind of stable selectivity COX2 inhibitor such as rofecoxib, celecoxib or their the homologue pharmaceutical preparation with injection-type preparation performance drug effect, avoids the deficiency of above-mentioned existing COX2 inhibitor injection type.
Another object of the present invention is to provide a kind of simple and cost suitably to obtain the injectable drug preparation of selective COX2 inhibitor such as rofecoxib or celecoxib or its homologue.
Further aim of the present invention is to provide the injectable drug preparation of a kind of selective COX2 inhibitor such as rofecoxib or celecoxib or its homologue, said preparation is stable, transparent, limpid and easily muscle administration, and said preparation has the instant curative effect of safety with respect to the oral tablets/oral liquid of the selective COX2 inhibitor of present use.
The present invention also provides the gel of selective COX2 inhibitor such as rofecoxib or celecoxib or its homologue.
The invention provides Soquad (isosorbide) kind solvent shown in Formula I, only when selective COX2 inhibitor is dissolved in wherein, can make the injection of selective COX2 inhibitor provided by the present invention.
Formula I
R wherein
1And R
2Be the alkyl or the acetate of a hydrogen atom or 1-3 carbon, and R
1And R
2Can not be hydrogen atom simultaneously.
Therefore, the invention provides a kind of stabilised pharmaceutical, for example be dissolved in the COX2 inhibitor injection that celecoxib, rofecoxib have comprised the selective active COX2 inhibitor that is selected from as the described Soquad kind solvent of Formula I.
Formula I
R wherein
1And R
2Be the alkyl or the acetate of a hydrogen atom or 1-3 carbon, and R
1And R
2Can not be hydrogen atom simultaneously.
Above-mentioned prescription provided by the invention also can comprise water and/or one or more antioxidants.
This solution is transparent, limpid, and can be easily on demand therapeutic dose by the muscle administration.This prescription be stablize, safety, efficiently.In some cases, this medicine is than present widely used anti-inflammatory drug such as diclofenac sodium intramuscular dose better effects if.
An enforcement prescription of the present invention has been dissolved in active rofecoxib in water or the anhydrous Soquad kind solvent and has made.
Another prescription of the present invention is celecoxib to be dissolved in the Soquad class dissolving that contains antioxidant make.Added antioxidant improves the stability of celecoxib such as α vitamin E and/or its derivant.The concentration of celecoxib is that the concentration of 1-400mg/ml or rofecoxib is 1-25mg/ml in the pharmaceutical preparation provided by the present invention.
Preparation provided by the present invention also concentration be the celecoxib injection of 1-500mg/ml.
Another preparation of the present invention is that concentration is the rofecoxib injection of 1-50mg/ml.
Drug injection of the present invention can also contain antioxidant such as sodium bisulfate or vitamin E.
After the present invention comprises that also celecoxib and rofecoxib are dissolved in above-mentioned solvent, make the gel that concentration is 1-4%, be used for topical application, this dosage form can optionally contain carbomer (Carbomer) derivant, hydroxypropyl emthylcellulose [HPMC (Hydroxy propyl methylcellulose)], gelatin, sodium carboxymethyl cellulose (Sodium CMC), water and flavoring agent.
The present invention also provides a kind of preparation method of COX2 inhibitor injection, and step comprises:
I) from rofecoxib, celecoxib and homologue thereof, select COX2 inhibitor;
Ii) selected COX2 inhibitor is dissolved in the selected Soquad kind solvent shown in Formula I;
Formula I
R wherein
1And R
2Be the alkyl or the acetate of a hydrogen atom or 1-3 carbon, and R
1And R
2Can not be hydrogen atom simultaneously, water/and one or more antioxidants can also be arranged.
The present invention further provides the medicine of making by the mixture of active celecoxib, rofecoxib and homologue thereof and Formula I and be used for the treatment of rheumatic arthritis and osteoarthritis and treatment dysmenorrhea.
Formula I
R wherein
1And R
2Be the alkyl or the acetate of hydrogen or 1-3 carbon, and R
1And R
2Can not be hydrogen atom simultaneously, water/and one or more antioxidants can also be arranged.
The described chemical compound of Formula I is preferably 2, and 5-pair-the O-methyl isophthalic acid, 4:3,6 two dehydration-D-glucitols (2,5-di-O-methyl-1,4:3,6dianhydro-D-glucitol).
The specific embodiment:
The described chemical compound of Formula I is chosen to be the solvent of celecoxib, rofecoxib and homologue thereof.Wonderful discovery, selected shown in Formula I in the chemical compound celecoxib and rofecoxib dissolubility fairly good, can avoid the problem of the liquid state/injection type preparation of COX2 inhibitor.Celecoxib (also can contain antioxidant) and rofecoxib are dissolved in the injection in the chemical compound shown in the Formula I, are used for treating inflammation and because the disease that Cycloxygenase II causes because its printing effect can be by safety.
In above-mentioned rofecoxib injection, add and be no more than the stability that 20% water does not influence preparation reason, voltinism matter.
Equally, add antioxidant such as α vitamin E (being no more than 0.1%) in above-mentioned celecoxib injection, do not change its characteristic before the deadline.
To elaborate target of the present invention and advantage below, these illustrate and do not limit protection scope of the present invention.
Example 1
Rofecoxib with 3.976mmol joins 2 of 100ml while stirring, and 5-pair-the O-methyl isophthalic acid, 4:3 is in the 6 two dehydration-D-glucitols.Under aseptic condition, solution is continued to stir 15 minutes.Solution after the aseptic filtration seals the bottle/ampoule of packing into.
Example 2
Rofecoxib with 3.976mmol joins 2 of 80ml while stirring, and 5-pair-the O-methyl isophthalic acid, 4:3 is in the 6 two dehydration-D-glucitols.Continuation is stirred solution and adding 20ml water for injection at aseptic condition.Seal the bottle/ampoule of packing into after solution (with 2,5-is two-O-methyl isophthalic acid, 4:3,6 two dehydration-D-glucitols the are diluted to 100ml) aseptic filtration.
Example 3
Rofecoxib with 7.952mmol joins 2 of 80ml while stirring, and 5-pair-the O-methyl isophthalic acid, 4:3 is in the 6 two dehydration-D-glucitols.Solution continues to stir and add 20ml water for injection under aseptic condition.Seal the bottle/ampoule of packing into after solution (with 2,5-is two-O-methyl isophthalic acid, 4:3,6 two dehydration-D-glucitols the are diluted to 100ml) aseptic filtration.
Example 4
While stirring the 26.22mmol celecoxib is joined 2 of 100ml, 5-pair-the O-methyl isophthalic acid, 4:3 is in the 6 two dehydration-D-glucitols.Solution continues to stir 15 minutes under aseptic condition.Seal the bottle/ampoule of packing into after the aseptic filtration.
Example 5
While stirring 26.22mmol celecoxib and 0.116mmol (0.05%w/v) α vitamin E are joined 2 of 100ml, 5-pair-the O-methyl isophthalic acid, 4:3 is in the 6 two dehydration-D-glucitols.Solution continues to stir 15 minutes under aseptic condition.Seal the bottle/ampoule of packing into after the aseptic filtration.
Example 6
While stirring 26.22mmol celecoxib and 0.232mmol (0.1%w/v) α vitamin E are joined 2 of 100ml, 5-pair-the O-methyl isophthalic acid, 4:3 is in the 6 two dehydration-D-glucitols.Solution continues to stir 15 minutes under aseptic condition.Seal the bottle/ampoule of packing into after the aseptic filtration.
Example 7
While stirring 52.44mmol celecoxib and 0.116mmol (0.05w/v) α vitamin E are joined 2 of 100ml, 5-pair-the O-methyl isophthalic acid, 4:3 is in the 6 two dehydration-D-glucitols.Solution continues to stir 15 minutes under aseptic condition.Seal the bottle/ampoule of packing into after the aseptic filtration.
Example 8
While stirring 52.44mmol celecoxib and 0.232mmol (0.1%w/v) α vitamin E are joined 2 of 80ml, 5-pair-the O-methyl isophthalic acid, 4:3 is in the 6 two dehydration-D-glucitols.Solution continues to stir 15 minutes under aseptic condition.Sealing is packed into into bottle/ampoule after the aseptic filtration.
The effect of the injection type of COX2 inhibitor, pharmaco-kinetic properties and Study on Stability will be set forth below.
Experiment I
The effect of injection prescription provided by the present invention and conventional detailed comparison of irrigating profit (voveran) injection will be undertaken by following description of test.
Method: the Mus pawl edema that carrageenin brings out
Experimental animal: albino rat [(Albino rats) (Wistar)]
Quantity: 6 every group
Rofecoxib injected dose: 2.25mg/kg, celecoxib injected dose: 18mg/kg
Wo Wo profit contrast injected dose (diclofenac sodium): 4.5mg/kg
Administering mode: intramuscular injection.
Method:
Albino rat is divided into 3 groups every group 6, and male and female have.First group of injection fertile profit diclofenac sodium (4.5mg/kg) also regarded matched group.Second group of intramuscular injection rofecoxib is according to the dosed administration of 2.25mg/kg.The 3rd group of intramuscular injection celecoxib is according to the 18mg/kg dosed administration.
The rear solid end that carrageenin (0.1% alkali metal salt soln of 0.1ml) is injected into each mouse is after subcutaneous 15 minutes, the size of instant measuring claw.Carrageenin injection back size of measuring claw once more in the time of the 30th minute, 1,3,4 hour.Difference after record initial value and the edema of measuring in time subsequently between the value.Per hour suppression ratio separately can calculate with following formula:
V: hydrargyrum show value
Be listed among the edema value of decreased average Table A, B and the C below.
Table A
Observation (hydrargyrum shift value ml)
Average edema elimination factor
| The fertile profit of injection | 0hr | 0.5hr | 1hr | 3hr | 4hr |
| Dosage 4.5mg/kg | 6.74％ | 22.75％ | 27.87％ | 43.25％ | 43.58％ |
Table B
Average edema elimination factor
| The injection rofecoxib | 0hr | 0.5hr | 1hr | 3hr | 4hr |
| Dosage 2.25mg/kg | 5.18％ | 19.74％ | 25.78％ | 40.00％ | 35.35％ |
Table C
Average edema elimination factor
| The injection celecoxib | 0hr | 0.5hr | 1hr | 3hr | 4hr |
| Dose1.55mg/kg | 1.55％ | 18.45％ | 23.34％ | 37.5％ | 35.35％ |
Observe and find, the animal of diclofenac (Diclofenac) group average edema elimination factor after 3 hours is 43.25%, and the average edema elimination factor that rofecoxib of the same period and celecoxib preparation reach is respectively 40% and 37.5%.
Can conclude that rofecoxib intramuscular injection prescription provided by the present invention and celecoxib intramuscular injection prescription have good antiinflammatory action, on treating, irrigate profit good (diclofenac sodium 25mg/ml) than the conventional medicine in market with concentration
Experiment IIA
Relatively the celecoxib injection is with the capsular pharmaco-kinetic properties of celecoxib
Experimental program:
I) rabbit is accepted the pharmacokinetic studies of 100mg/ml celecoxib intramuscular injection
(n=3 begins experiment before by overnight fasted to rabbit in the morning, and the blood sample of fasting will be gathered (0hr).2 hours can not feeding.Each test rabbit is accepted the celecoxib of 1 dosage then.
Ensuing blood sample collection will be set according to the celecoxib intramuscular injection.
After administration the 10th minute, 15 minutes, 20 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours and 4 hours are gathered the blood of 5ml respectively.
Blood sample:
The centrifugalize 15 minutes under 3000RPM of the venous blood sample of 5ml is so that obtain blood plasma.Blood plasma is moved into then and is chilled in-20 ℃ in label 2054,23 * 75mm pipe up to beginning analysis.All samples are tested the acquisition time and the research label of label, the data of rabbit, the administration of being correlated with label.
Plasma analysis
The blood plasma of test is analyzed with anti-phase high performance liquid chromatography (reverse phase HPLC).Every milliliter of blood plasma Chinese medicine amount utilizes concentration-AUC standard chart to calculate according to the amount of the celecoxib of known adding.
Pharmacokinetic analysis:
Following pharmacokinetic parameters is evaluated:
1) C
Max: the maximal plasma concentration that reaches
2) T
Max: the time that reaches maximal plasma concentration
3) AUC: plasma concentration area under curve.
4) K
E1: on average drain constant
5) t
1/2: mean half-life
6) the relevant pharmacokinetic curve figure of use canonical reference
7) common point in external-body
II) rabbit is accepted the pharmacokinetic studies of 100mg/caps. celecoxib oral capsule
Experimental program:
Rabbit (n=3) begins experiment in the morning before by overnight fasted.The blood sample of fasting will be gathered (0hr).2 hours can not feeding.Each test rabbit is accepted the celecoxib of 1 dosage then.
Ensuing blood sample collection will be set according to the celecoxib oral capsule.
After administration the 0th minute, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 5 hours, 6 hours and 8 hours are gathered the blood of 5ml respectively.
Blood sample:
The centrifugalize 15 minutes under 3000RPM of the venous blood sample of 5ml is so that obtain blood plasma.Blood plasma is moved into then and is chilled in-20 ℃ in label 2054,23 * 75mm pipe up to beginning analysis.All samples are tested the acquisition time and the research label of label, the data of rabbit, the administration of being correlated with label.
Plasma analysis
The blood plasma of test is analyzed with the anti-phase high performance liquid chromatography.Every milliliter of blood plasma Chinese medicine amount utilizes concentration-AUC standard chart to calculate according to the amount of the celecoxib of known adding.
Pharmacokinetic analysis
Following pharmacokinetic parameters is evaluated:
1) C
Max: the maximal plasma concentration that reaches
2) T
Max: the time that reaches maximal plasma concentration
3) AUC: plasma concentration area under curve.
4) K
E1: on average drain constant
5) t
1/2: mean half-life
6) use the relevant pharmacokinetic curve figure experimental result of canonical reference in table D
Table D
(rabbit model)
| Celecoxib injection time-concentration value | Celecoxib capsule time-concentration value | |||
| Serial number | Time | Cmax value (ng) | Time | Cmax value (ng) |
| 1. | 0min | Do not detect | 0min | Do not detect |
| 2. | 15min | 4421(±70) | 15min | 185(±11) |
| 3. | 30min | 2583(±79) | 30min | 329(±17) |
| 4. | 1hr | 2144(±101) | 1hr | 823(±21) |
| 5. | 2hr | 1634(±93) | 2hr | 568(±11) |
| 6. | 3hr | 1007(±37) | 3hr | 509(±27) |
| 7. | 4hr | 915(±64) | 4hr | 435(±31) |
Experiment IIB
Relatively the rofecoxib injection is with the capsular pharmaco-kinetic properties of rofecoxib
I) rabbit is accepted the pharmacokinetic studies of 12.5mg/ml rofecoxib injection
Experimental program:
Rabbit (n=3) begins experiment in the morning before by overnight fasted.The blood sample of fasting will be gathered (0hr).2 hours can not feeding.Each test rabbit is accepted the rofecoxib of 1 dosage then.
Ensuing blood sample collection will be set according to the rofecoxib intramuscular dose.
After administration the 10th minute, 15 minutes, 20 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours are gathered the blood of 5ml respectively.
Blood sample:
The centrifugalize 15 minutes under 3000RPM of the venous blood sample of 5ml is so that obtain blood plasma.Blood plasma is moved into then and is chilled in-20 ℃ in label 2054,23 * 75mm pipe up to beginning analysis.All samples are tested the acquisition time and the research label of label, the data of rabbit, the administration of being correlated with label.
Plasma analysis
The blood plasma anti-phase efficient liquid phase chromatographic analysis of test.Every milliliter of blood plasma Chinese medicine amount utilizes concentration-AUC standard chart to calculate according to the amount of the rofecoxib of known adding.
Pharmacokinetic analysis
Following pharmacokinetic parameters is evaluated:
1) C
Max: the maximal plasma concentration that reaches
2) T
Max: the time that reaches maximal plasma concentration
3) AUC: plasma concentration area under curve.
4) K
E1: on average drain constant
5) t
1/2: mean half-life
6) the relevant pharmacokinetic curve figure of use canonical reference
7) common point in the external one
II) rabbit is accepted the pharmacokinetic studies of 12.5mg/caps. rofecoxib oral capsule
Experimental program:
Rabbit (n=3) begins experiment overnight fasted before in the morning.The blood sample of fasting will be gathered (0hr.).2 hours can not feeding.Each test rabbit is accepted 1 dosage rofecoxib then.
Ensuing blood sample collection will be set according to the rofecoxib oral capsule.
After administration the 0th minute, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 5 hours, 6 hours and 8 hours are gathered the blood of 5ml respectively.
Blood sample:
The centrifugalize 15 minutes under 3000RPM of the venous blood sample of 5ml is so that obtain blood plasma.Blood plasma is moved into then and is chilled in-20 ℃ in label 2054,23 * 75mm pipe up to beginning analysis.All samples are tested the acquisition time and the research label of label, the data of rabbit, the administration of being correlated with label.
Plasma analysis
The blood plasma anti-phase efficient liquid phase chromatographic analysis of test.Every milliliter of blood plasma Chinese medicine amount utilizes concentration-AUC standard chart to calculate according to the amount of the rofecoxib of known adding.
Pharmacokinetic analysis
Following pharmacokinetic parameters is evaluated:
1) C
Max: the maximal plasma concentration that reaches
2) T
Max: the time that reaches maximal plasma concentration
3) AUC: plasma concentration area under curve.
4) K
E1: on average drain constant
5) t
1/2: mean half-life
6) the relevant pharmacokinetic curve figure of use canonical reference
Experimental result is in table E
Table E
(rabbit model)
| Rofecoxib injection time-concentration value | Rofecoxib capsule time-concentration value | |||
| Serial number | Time | Cmax value (ng/ml) | Time | Cmax value (ng/ml) |
| 1. | 0min | Do not detect | 0min | Do not detect |
| 2. | 10min | 1240(±0.21) | 10min | 374(±0.09) |
| 3. | 15min | 2950(±0.33) | 15min | 431(±0.01) |
| 4. | 30min | 1020(±0.14) | 30min | 568(±0.12) |
| 5. | 1hr | 312(±0.05) | 1hr | 878(±0.08) |
| 6. | 2hr | 82(±0.009) | 2hr | 849(±0.18) |
| 7. | 3hr | 39(±0.04) | 3hr | 624(±0.02) |
| 8. | 4hr | 24(±0.001) | 4hr | 415(±0.065) |
Experiment IIIA
Celecoxib intramuscular dose of the present invention (100mg/ml) central analgesia Journal of Sex Research
Scheme
The albinism mouse (150-200g) that male and female all have is divided into 4 groups every group 6.Group I accepts excipient (vehicle) and organizes in contrast.Group II accepts standard drug [pentazocine (Pentazocin); Fu Ting (Fortwin) injection 30mg/ml].It is 200mg (4mg) that group III accepts the quite human dosage of testing drug celecoxib intramuscular dose (100mg/ml).
Animal is placed on the plate that maintains 55 ℃.Before using standard drug and the administration of testing drug muscle and the back recording reacting time (in order to the time of licking rear solid end be the response time).Before the administration, the time started that rear solid end licked in record is fundamental reaction time (BRT).Animal is placed on the plate administration in preceding 20 minutes of heat, spends 20 minutes then, in order to the time of licking rear solid end just hide the response time (LTR) be recorded.The response time enhancing rate is calculated as follows.
Promptly
Come the data of statistical analysis acquisition by Dunnet ' t ' check.
Dosage * 0.02 that the dosage that mouse is accepted=mankind accept
200mg * 0.02-4mg is 4000mcg
Table F
Average fundamental reaction time, the response time of hiding and response time enhancing rate (n=6)
| Serial number | Group | Fundamental reaction time (BRT) Sec | (LRT) Sec hides the response time | Response time enhancing rate (IRT) |
| 1 | Matched group | 6.83±0.75 | 6.83±0.75 | 0 |
| 2 | Standard drug group (pentazocine 20mcg/kg) | 6.33±0.41 | 11.66±1.60 | 92.85 |
| 3 | Test group (celecoxib intramuscular dose; 100mg/ml); 4000mcg | 5.66±0.79 | 15.83±2.20 | 184.4 |
Each meansigma methods (S.E.M.; P＜0.001, Dunnet ' t ' check.
Experiment IIIB
Rofecoxib intramuscular dose of the present invention (12.5mg/ml) central analgesia Journal of Sex Research
Scheme
The albinism mouse (150-200g) that male and female all have is divided into 4 groups every group 6.Group I accepts excipient and organizes in contrast.Group II accepts standard drug [pentazocine (Pentazocin); Fu Ting (Fortwin) injection 30mg/ml].It is 12.5mg (0.25mg) that group III accepts the quite human dosage of testing drug rofecoxib intramuscular dose (12.5mg/ml).
Animal is placed on the plate that maintains 55 ℃.Before using standard and testing drug by the muscle administration and after be recorded the response time (in order to the time of licking rear solid end be the response time).Before the administration, the initial time of licking rear solid end is to be recorded the fundamental reaction time (BRT).Animal is placed on the plate administration in preceding 20 minutes of heat, spends 20 minutes then, in order to lick the rear solid end time just hide the response time (LTR) be recorded.Response time promotes ratio and is calculated as follows.
Promptly
Come the data of statistical analysis acquisition by Dunnet ' t ' check.
Dosage * 0.02 that the dosage that mouse is accepted=mankind accept
12.5mg * 0.02=0.25mg is 250mcg
The result is provided by following table:
Table G
Average fundamental reaction time, the response time of hiding and response time enhancing rate (n=6)
| Serial number | Group | Fundamental reaction time (BRT) Sec | (LRT) Sec hides the response time | Response time enhancing rate (IRT) |
| 1 | Matched group | 6.83±0.75 | 6.83±0.75 | 0 |
| 2 | Standard drug group (pentazocine 20mcg/kg) | 6.33±0.41 | 11.66±1.60 | 92.85 |
| 3 | Test group (rofecoxib intramuscular dose; 100mg/ml); 4000mcg | 4.16±0.36 | 11.83±0.79 | 193.05 |
Each meansigma methods ± S.E.M.; P＜0.001, Dunnet ' t ' test
The result:
Above-mentioned table F and table G show that celecoxib injection provided by the present invention (100mg/ml) has been compared obvious central analgesia effect with rofecoxib injection (12.5mg/ml) with matched group.Celecoxib/rofecoxib prescription is proved to be than standard drug pentazocine more effective (P＜0.001).Use similar for analgesia metering (Analgesometer) demonstration of mouse on the plate of heat at central analgesia to Opium class analgesics (opioid analgesics).Celecoxib provided by the invention/rofecoxib prescription drug can be used in and the identical place of Opium class analgesics.Therefore, celecoxib provided by the present invention/rofecoxib prescription drug can be used for easing pain, and does not have the addiction of Opium class analgesics and the restriction of breathing problem.
Experiment IV
The stability study of injection provided by the present invention
Celecoxib
The celecoxib injection that makes according to step provided by the invention, (the sample A that in above-mentioned experiment 6, describes in detail, B and C), every 100mg celecoxib is dissolved in two methyl Soquads (dimethylisosorbide) of 1ml, one has been used antioxidant α vitamin E in these three samples, and other two samples do not add such antioxidant.
Carried out 3 months research by a definite date according to the ICH standard.Drug concentrations is by spectrophotometer (GBC), high performance liquid chromatography (HPLC) instrument, C under the situation such as degree such as grade
18Analytical column (C
18Column), analyze at 220nm and 20 μ l.The result is presented among table H and the I.
Table H
| Concentration 100mg/ml celecoxib injection pH 5.2 results that contain the 0.1%w/v vitamin E represent with theoretical concentration percent | |||
| Initially | 3 months, 25 ° ± 2 ℃/60% ± 5%RH | 3 months, 40 ° ± 2 ℃/75% ± 5%RH | |
| Sample A | 100.9％ | 100.3％ | 100.1％ |
| Sample B | 99.6％ | 99.3％ | 99.06％ |
| Sample C | 101.01％ | 100.1％ | 99.8％ |
| The RH-relative humidity | |||
Table I
| The celecoxib concentration 100mg/ml result who does not contain vitamin E represents pH 5.2 with theoretical concentration percent | |||
| Initially | 3 months, 25 ° ± 2 ℃/60% ± 5%RH | 3 months, 40 ° ± 2 ℃/75% ± 5%RH | |
| Sample A | 99.8％ | 99.3％ | 99％ |
| Sample B | 100.3％ | 100.0％ | 99％ |
| Sample C | 99％ | 98.3％ | 97.8％ |
Rofecoxib
According to rofecoxib injection (sample A provided by the invention, B and C) the test of stability, in the rofecoxib solution 20% water is arranged in each described sample, wherein the rofecoxib of 12mg is dissolved in two methyl Soquads (dimethylisosorbide), and 0.2ml is a water in just every 1ml solution.
Carried out 3 months research by a definite date according to the ICH standard.Drug concentrations is by GBC spectrophotometer, high performance liquid chromatograph, C under the situation such as degree such as grade
18Analytical column (C
18Column), analyze at 220nm and 20 μ l.The result is presented among the table J..
Table J
| Stability test | ||||||
| Rofecoxib injection notional result (%) concentration 12.5mg/ml rofecoxib total amount pH 5.20 | ||||||
| 20% water is arranged | There is not 20% water | |||||
| Initially | 6 months, 25 ° ± 2 ℃/60% ± 5% RH | 6 months, 40 ° ± 2 ℃/75% ± 5%RH | Initially | 6 months, 25 ° ± 2 ℃/60% ± 5% RH | 6 months, 40 ° ± 2 ℃/75% ± 5% RH | |
| Sample A | 100.3％ | 100.1％ | 99.98％ | 100.8％ | 100.3％ | 100.15％ |
| Sample B | 99.96％ | 99.35％ | 99.15％ | 100.75％ | 100.3％ | 99.9％ |
| Sample C | 99.6％ | 98.78％ | 99.0％ | 99.9％ | 99.75％ | 99.3％ |
The above results proof stability of drug of the present invention.
Claims (18)
1. the pharmaceutical preparation of a COX2 inhibitor is characterized in that and will be selected from the selective active COX2 inhibitor of celecoxib, rofecoxib, is dissolved in the Soquad kind solvent shown in the selected Formula I to make
Formula I
R wherein
1And R
2Be the alkyl or the acetate of a hydrogen atom or 1-3 carbon, and R
1And R
2Can not be hydrogen atom simultaneously.
2. the pharmaceutical preparation of a COX2 inhibitor according to claim 1 is characterized in that also comprising in the preparation other pharmaceutically acceptable additives.
3. the pharmaceutical preparation of a COX2 inhibitor according to claim 1 is characterized in that also containing in the preparation water and/or one or more antioxidants.
4. the pharmaceutical preparation of a COX2 inhibitor according to claim 1 is characterized in that the described chemical compound of described Formula I is selected from 2,5-pair-the O-methyl isophthalic acid, and 4:3,6 two dehydration-D-glucitols.
5. the pharmaceutical preparation of a COX2 inhibitor according to claim 1 and 2, the concentration that it is characterized in that the COX2 inhibitor celecoxib is 1-400mg/ml.
6. the pharmaceutical preparation of a COX2 inhibitor according to claim 1, the concentration that it is characterized in that the COX2 inhibitor rofecoxib is 1-25mg/ml.
7. the pharmaceutical preparation of a COX2 inhibitor according to claim 3 is characterized in that described antioxidant is selected from α vitamin E and other conventional antioxidant that uses.
8. pharmaceutical preparation according to arbitrary described COX2 inhibitor in the claim 1 to 3 is characterized in that pharmaceutical preparation is loaded in the ampoule of sealing, bottle, bottle, capsule, pipe or any other container.
9. pharmaceutical preparation according to arbitrary described COX2 inhibitor by drug administration by injection in the claim 1 to 3, described preparation is transparent, stable, is applied in preparation and is used for immediate treatment pain and because the medicine of the inflammation symptom that cyclooxygenase 2 causes.
10. the pharmaceutical preparation of a COX2 inhibitor according to claim 3 is characterized in that celecoxib concentration in described solvent is 1-500mg/ml.
11. the pharmaceutical preparation of a COX2 inhibitor according to claim 3 is characterized in that rofecoxib concentration in described solvent is 1-50mg/ml.
12. the pharmaceutical preparation according to claim 10 or 11 described COX2 inhibitor is characterized in that described antioxidant is selected from sodium sulfite or vitamin E.
13. the pharmaceutical preparation of a COX2 inhibitor according to claim 1 is characterized in that said preparation is a gelinite.
14. the pharmaceutical preparation of a COX2 inhibitor according to claim 13, it is characterized in that this gelinite is used for local the use, contain the active component that concentration is 1%-4%, this dosage form also comprises carbomer, hydroxypropyl emthylcellulose, gelatin, sodium carboxymethyl cellulose, water and flavor ingredients.
15. the preparation method by the COX2 inhibitor injection of drug administration by injection comprises the steps:
I) from rofecoxib, celecoxib, select COX2 inhibitor;
Ii) selected COX2 inhibitor is dissolved in the Soquad kind solvent shown in the selected Formula I;
Formula I
R wherein
1And R
2Be the alkyl or the acetate of a hydrogen atom or 1-3 carbon, and R
1And R
2Can not be hydrogen atom simultaneously, also have water/and one or more antioxidants.
16. a preparation method that requires 15 described COX2 inhibitor injections as requested is characterized in that also adding other known pharmaceutically acceptable additives.
17. a preparation method that requires 15 or 16 described COX2 inhibitor injections as requested is characterized in that the chemical compound shown in the described Formula I is selected from 2,5 pairs of O-methyl isophthalic acids, 4:3,6 two dehydration-D-glucitols.
18. utilize the preparation of the described COX2 inhibitor of claim 1, give mammal by the described preparation of administration/application, as the application process of preparation treatment by the diagonosis of disorder medicine of cyclooxygenase 2 initiation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN610/CAL/2001 | 2001-10-25 | ||
| IN610CA2001 | 2001-10-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1561210A CN1561210A (en) | 2005-01-05 |
| CN100346785C true CN100346785C (en) | 2007-11-07 |
Family
ID=34452215
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN02819441.1A Expired - Fee Related CN100346785C (en) | 2001-10-25 | 2002-05-14 | Preparation of selective epoxide hydrolase II inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100346785C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100434072C (en) * | 2006-06-19 | 2008-11-19 | 西安交通大学 | Medication of possessing function of anti inflammation, for improving rheological property of blood, and restraining thrombosis |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1161652A (en) * | 1994-10-26 | 1997-10-08 | 诺瓦蒂斯有限公司 | Pharmaceutical compositions |
| CN1240646A (en) * | 1998-01-12 | 2000-01-12 | 灵药生物技术有限公司 | Injectable composition of non-steroidal anti-inflammatory drugs |
| WO2000072884A1 (en) * | 1999-05-31 | 2000-12-07 | Dinesh Shantilal Patel | A novel formulation of n-(4-nitro-2-phenoxyphenyl)methanesulfonamide |
| WO2005000007A2 (en) * | 2003-05-30 | 2005-01-06 | Cargill, Incorporated | Methods of making plants that exhibit enhanced disease resistance |
-
2002
- 2002-05-14 CN CN02819441.1A patent/CN100346785C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1161652A (en) * | 1994-10-26 | 1997-10-08 | 诺瓦蒂斯有限公司 | Pharmaceutical compositions |
| CN1240646A (en) * | 1998-01-12 | 2000-01-12 | 灵药生物技术有限公司 | Injectable composition of non-steroidal anti-inflammatory drugs |
| WO2000072884A1 (en) * | 1999-05-31 | 2000-12-07 | Dinesh Shantilal Patel | A novel formulation of n-(4-nitro-2-phenoxyphenyl)methanesulfonamide |
| WO2005000007A2 (en) * | 2003-05-30 | 2005-01-06 | Cargill, Incorporated | Methods of making plants that exhibit enhanced disease resistance |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1561210A (en) | 2005-01-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1148186C (en) | Clonidine preparation | |
| CN1237106A (en) | Stable medicinal compositions containing 4,5-epoxymorphinane derivatives | |
| CN1212833C (en) | Orally administered pharmaceutical formulations of benzimidazole derivatives and the method of preparing the same | |
| CN1242991C (en) | Aporphine esters and their use in therapy | |
| CN1486690A (en) | Medicinal salt with local narcosis and antiphlogosis activity and its prepn process | |
| CN1767856A (en) | Pharmaceutical compositions for hepatitis C viral protease inhibitors | |
| CN1917859A (en) | Drug-loaded nanoparticles, method for producing same, and parenteral preparation containing same | |
| CN1358094A (en) | Method for treating chronic pain using MEK inhibitors | |
| CN1407887A (en) | Oral liquid compositions | |
| CN1735401A (en) | Microemulsion concentrate for oral administration of water-insoluble anti-cold drug and method for preparing same | |
| CN1094756C (en) | Combined antipyretic analgesic drug | |
| CN1762495A (en) | Long acting sustained-release formulation containing dopamine-receptor stimulant medicine and its preparation process | |
| CN1960974A (en) | Alkyl substituted piperidine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors | |
| CN1499968A (en) | Method of treatment of dopamine-related dysfuction | |
| CN1353990A (en) | Preparation for analgesia and anesthesia or curing drug dependence | |
| CN1931143A (en) | Orally taken control released trimetazidine medicine composition | |
| CN1092959C (en) | Pharmaceutical composition contg. tiagabine hydrochloride and process for its preparation | |
| CN1931167A (en) | Double layer osmotic pump controlled release felodipine medicine composition | |
| CN1527700A (en) | Compaction process for manufacture of sodium phenytoin dosage form | |
| CN100346785C (en) | Preparation of selective epoxide hydrolase II inhibitor | |
| CN1265838C (en) | Injectable veterinary composition for small animals | |
| CN1103782A (en) | Anti-allergic pharmaceutical composition for ophthalmic topical admini stration | |
| CN1489461A (en) | Triglyceride depressant composition | |
| CN1092074A (en) | Azepine derivatives | |
| CN1037653A (en) | The alcoholism preventive that medicine and drinking causes and the preparation method of therapeutic agent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20071107 |