CN1088600C - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
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- CN1088600C CN1088600C CN93107666A CN93107666A CN1088600C CN 1088600 C CN1088600 C CN 1088600C CN 93107666 A CN93107666 A CN 93107666A CN 93107666 A CN93107666 A CN 93107666A CN 1088600 C CN1088600 C CN 1088600C
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- ibuprofen
- beta
- cyclodextrin
- water
- solution
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Abstract
The present invention relates to a brufen-beta-cyclodextrin compound orally taken in the form of hot-water solution. The compound can be prepared in water solution by a crystallization process.
Description
The present invention relates to Pharmaceutical composition that contains ibuprofen and preparation method thereof, and relate to the good to eat preparation of its suitable for oral administration.Specifically, the present invention relates to be suitable in aqueous solution, being formulated as the ibuprofen-cyclodextrin clathrate complex of hot drink.
Ibuprofen--(±)-2-(to isobutyl phenenyl) propanoic acid belongs to non-steroidal anti-inflammatory agent class (NSAIDs), be widely used in the state of palliating a disease such as arthritic pain with inflammation and be used for the treatment of the symptom relevant with influenza with common cold, because its poorly water-soluble and tool penetrating odor and taste beastly, this medicine is mixed with the preparation of suitable for oral administration, particularly is mixed with the complicated operationization of the water-soluble form that is suitable for the liquid dosages administration thereby make.The purpose of this invention is to provide and contain ibuprofen and be for oral use good to eat Pharmaceutical composition of aqueous solution.
People just know before many years, and the drug-cyclodextrin coordination compound can increase water solublity and can cover taste beastly and abnormal smells from the patient.In this respect, proved already: ibuprofen is suitable for forming coordination compound with cyclodextrin very much.
Disclose the preparation method of ibuprofen-beta-schardinger dextrin-clathrate complex among the open JP 56-46837 (Kowa Yakuhin Kogyo) of Japan Patent, it comprises: under hot conditions ibuprofen and beta-schardinger dextrin-are mixed in water and spray-dried this clathrate of telling.It is reported, the percentage composition height of ibuprofen in the product that this method obtains, the mol ratio of its ibuprofen and beta-schardinger dextrin-exceeds 0.7.The water solublity of this medicine increases significantly, increases more than 8 times, and every 100ml 10.44mg increases to every 100ml 89.38mg during from 27 ℃.
Although make water solublity be able to remarkable improvement by forming coordination compound, also be not enough to ibuprofen is mixed with the liquid form oral soluble dosage forms of the content of ibuprofen in the water (120-250ml) of proper volume in therapeutic dose level (100-600mg) with beta-schardinger dextrin-.
European patent discloses 274444 (Bristol Myers) and has described with alpha-cyclodextrin, gamma-cyclodextrin or methylated beta-schardinger dextrin-and replace beta-schardinger dextrin-to prepare ibuprofen-beta-cyclodextrin composition.With these form of cyclodextrin the water solublity of ibuprofen-beta-cyclodextrin composition is further increased, reached the level of practical application, but these material cost height, therefore unlikely thereby improved the cost of the drug products that contains them, promoted it aspect analgesic, especially can be used for autotherapy with the lighter pain of treatment and alleviate extensive use aspect the product of cold and grippal symptom.
Open GB 2219585 (the Reckitt ﹠amp of British patent; Colman) coordination compound of sodium salt, potassium salt, ammonium salt, magnesium salt, calcium salt, arginine salt, glycinate or the lysinate of beta-schardinger dextrin-and ibuprofen is disclosed, the molar ratio of its ibuprofen and beta-schardinger dextrin-is in 1: 0.2 to 1: 0.75 scope and have a good water solublity, these coordination compounds and not exclusively suitable mixing in the oral liquid preparation of desire, this be because their aqueous solution is more or less beastly, as saponiform taste, be typical alkaline solution.
The invention provides suitable ibuprofen-beta-cyclodextrin composition of taking with the form of aqueous solution, this coordination compound is good to eat, and compares with the prior art of ibuprofen-beta-cyclodextrin composition, and its production is at present easier and inexpensive.
The invention provides ibuprofen-beta-cyclodextrin complex in the purposes of producing aspect the oral drugs of aqueous solution form, it is characterized in that: this coordination compound is taken with the solution form that contains hot water.
Have been found that preparing ibuprofen-beta-cyclodextrin complex under hot conditions in aqueous solution can increase 30 times of dissolubilities.Therefore in the liquid preparation of single agent, the ibuprofen in the solution can reach the dosage level of treatment.Ibuprofen-beta-cyclodextrin complex used in this invention can provide the concentration of ibuprofen to reach 600mg in the 200ml of single agent volume.
Can increase although people know with the dissolubility of the many materials of the increase of temperature in water, the fact that the heat of ibuprofen liquid is improved is astonishing.It is reported that the stability constant of beta-cyclodextrin composition raises with temperature and reduces (JACS, 101,1864 pages (1979) and JCSPerkin Trans., 2,15 pages (1984)) rapidly.Therefore can expect: because the stability constant of ibuprofen-beta-cyclodextrin complex reduces, can follow ibuprofen from coordination compound, to disengage, thereby do not wished the oily mixture that obtains with temperature its dissolving in water that raises.Yet opposite with this expectation, have been found that now: until 100 ℃, ibuprofen-beta-cyclodextrin complex is still evenly also stable in water.
Owing to utilize the water solublity that at high temperature increases ibuprofen-beta-cyclodextrin complex, so oral administration solution not necessarily must be at alkaline pH according to the beta-cyclodextrin composition described in the GB 2219585.According to the present invention, ibuprofen-beta-cyclodextrin complex can the pleasant solution form of the taste of pH in the 2.5-7.0 scope be taken.
The present invention provides the preparation method of ibuprofen-beta-schardinger dextrin-clathrate complex on the other hand.In recent years, ibuprofen-beta-schardinger dextrin-clathrate complex prepares with several method, and they comprise co-precipitation, lyophilization and neutralization precipitation method.These methods all need to use or alkali, and perhaps therefore organic solvent needs strict means of purification.The spray drying method of describing among the JP 56-46837 can avoid using these reagent; But spray drying is costliness but also time-consuming not only.Compare with the prior art method, the inventive method is for the not only easy but also effective production method of cost and only used water except that ibuprofen and beta-schardinger dextrin-.
Method of the present invention comprises: ibuprofen and beta-schardinger dextrin-are added thermosetting solution in water, suit to be heated to 100 ℃; Should the crystallization from the solution of formation like this of ibuprofen-beta-cyclodextrin complex be separated out by this solution being put-being placed in the 5-20 ℃ temperature range then.According to the inventive method, can obtain ibuprofen-beta-cyclodextrin complex, the molar ratio of its ibuprofen and beta-schardinger dextrin-is within 1: 1 to 1: 3 scope.
Obtaining ibuprofen-beta-cyclodextrin complex with crystalline method from aqueous solution is another aspect of the present invention.Although the ibuprofen-beta-schardinger dextrin-clathrate complex with the preparation of known technology method can be used in the preparation of the present invention, preferentially selected for use in oral liquid mentioned above with ibuprofen-beta-cyclodextrin complex that method for crystallising obtains from aqueous solution.
Coordination compound of the present invention can be mixed with any form easily as being used for the tablet of solution, perhaps make solution again again with powder or particulate form water, in addition, the invention provides the Pharmaceutical composition of forming with pharmaceutically acceptable carrier mixing by the ibuprofen-beta-cyclodextrin complex that from aqueous solution, obtains with crystallization process.
Purposes by the ibuprofen-beta-cyclodextrin complex of the inventive method preparation is not limited at high temperature oral with the form of aqueous solution.Coordination compound of the present invention can be mixed with any form easily for oral use, as swallows or masticable tablet, or liquid suspension.
The coordination compound that obtains from aqueous solution with crystallization process can or be suitable for the accessory drugs of selected dosage form-with preparing with any suitable carrier.For example, the present composition can comprise the antiseptic that for example is suitable for its form, suspending agent, correctives, filler, cement, binding agent, lubricant, disintegrating agent, coloring agent, sweeting agent, adsorbent, thickening agent and diluent.
The present composition that contains ibuprofen-beta-cyclodextrin complex can also comprise other medicament that other is suitable for taking simultaneously, for example comprises other analgesics, antiinflammatory and antipyretic and also comprises expectorant, hydryllin, Decongestant and anti-tussive agents for example cathine, phyenlephrinium, pseudoephedrine, dextromethorphan, caffeine, codeine and ascorbic acid.
Following examples are to illustrate of the present invention.Within the scope of the present invention embodiment 5 not included be used for contrast.
Unless otherwise mentioned, in an embodiment, abbreviation β CD is meant beta-schardinger dextrin-ten monohydrates.
Embodiment 1
The preparation of β CD/ ibuprofen clathrate (2.2: 1)
With β CD (146.5g 110mM) is dissolved in 100 ℃ the water (1000ml), add ibuprofen (10.3g, 50mM) and with the solution that obtains put in the tray in 60 ℃ in convection oven dry 16 hours.The white amorphous products that obtains is crossed 500 μ m sieve, get the Powdered β CD/ of 132g ibuprofen clathrate, it contains about 7.0% ibuprofen (every 5714mg clathrate 400mg ibuprofen).
Embodiment 2
The preparation of β CD/ ibuprofen clathrate (1.1: 1)
(146.6g 110mM) is dissolved in 100 ℃ the water (1000ml), and (20.6g 100mM) and with the solution that obtains is cooled to 1 ℃, obtains the white crystalline precipitation to add ibuprofen with β CD.With its with cold water washing and in 50 ℃ in convection oven dry 4 hours.White solid product is crossed 500 μ M sieve, get 125g β CD/ ibuprofen clathrate, it contains about 14% ibuprofen (every 2857mg clathrate 400mg ibuprofen).
Embodiment 3
Contain the preparation of the Pharmaceutical composition of ibuprofen/β CD clathrate heat supply water reuse (treatment
Following ingredients is crossed 500 μ m sieve and is mixed together into uniform white powder:
Ibuprofen/β CD clathrate (embodiment 1) 5714mg
Sucrose 1876mg
Sodium citrate 430mg
Citric acid 680mg
Saccharin sodium 40mg
Fructus Citri Limoniae edible essence 60mg
Sodium cyclamate 60mg
The powder that obtains is dissolved in the 150ml hot water, must clarifies, the pleasant solution of taste, contain the 400mg ibuprofen in every 150ml water.
Embodiment 4
Contain the preparation of the Pharmaceutical composition of ibuprofen/β CD clathrate heat supply water reuse (treatment
Ibuprofen/β CD clathrate (embodiment 2) 2857mg
Sucrose 1733mg
Sodium citrate 430mg
Citric acid 680mg
Saccharin sodium 40mg
Fructus Citri Limoniae edible essence 200mg
Sodium cyclamate 60mg
The powder that obtains is dissolved in the 200ml hot water, obtains clarification, the pleasant solution of taste contains the 400mg ibuprofen in every 200ml water.
Embodiment 5
Contain the preparation of the Pharmaceutical composition of ibuprofen heat supply water reuse (treatment
Following composition crossed 500 μ m sieve and mixes make uniform white powder:
Ibuprofen 400mg
Sucrose 3590mg
Sodium citrate 430mg
Citric acid 680mg
Saccharin sodium 40mg
Fructus Citri Limoniae edible essence 200mg
Sodium cyclamate 60mg
The powder that obtains is added in the 200ml hot water, get cloudy suspensions.This suspension tool bitterness/make oral mucosa produces the effect of numb sensation, thereby is considered to be in and sensuously is difficult to accept.
Claims (3)
1. in up to 100 ℃ hot water, still keep even, the stable purposes of ibuprofen-beta-cyclodextrin complex in producing oral drugs.
2. according to the purposes of claim 1, wherein, in single dosage unit solution, ibuprofen-beta-cyclodextrin complex provides the ibuprofen of 100-600mg therapeutic dose level.
3. according to the purposes of claim 1 or 2, wherein the pH of ibuprofen-beta-cyclodextrin complex solution is 2.5-7.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93107666A CN1088600C (en) | 1993-07-31 | 1993-07-31 | Pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93107666A CN1088600C (en) | 1993-07-31 | 1993-07-31 | Pharmaceutical composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1098288A CN1098288A (en) | 1995-02-08 |
| CN1088600C true CN1088600C (en) | 2002-08-07 |
Family
ID=4986791
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93107666A Expired - Lifetime CN1088600C (en) | 1993-07-31 | 1993-07-31 | Pharmaceutical composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1088600C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102488689B (en) * | 2011-12-12 | 2013-03-13 | 南京臣功制药股份有限公司 | Compound zinc gluconateand ibuprofen granule capable of curing cold and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0268215A1 (en) * | 1986-11-13 | 1988-05-25 | LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d. | Inclusion complex of ibuproxam with beta-cyclodextrin, a process for preparing the same and a pharmaceutical preparation containing the same |
| EP0274444A2 (en) * | 1987-01-09 | 1988-07-13 | Bristol-Myers Company | Solution inbuprofen complexes, compositions and processes for preparing the same |
| EP0346006A1 (en) * | 1988-06-09 | 1989-12-13 | Reckitt And Colman Products Limited | Pharmaceutical compositions containing ibuprofen-cyclodextrin complexes |
-
1993
- 1993-07-31 CN CN93107666A patent/CN1088600C/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0268215A1 (en) * | 1986-11-13 | 1988-05-25 | LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d. | Inclusion complex of ibuproxam with beta-cyclodextrin, a process for preparing the same and a pharmaceutical preparation containing the same |
| EP0274444A2 (en) * | 1987-01-09 | 1988-07-13 | Bristol-Myers Company | Solution inbuprofen complexes, compositions and processes for preparing the same |
| EP0346006A1 (en) * | 1988-06-09 | 1989-12-13 | Reckitt And Colman Products Limited | Pharmaceutical compositions containing ibuprofen-cyclodextrin complexes |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1098288A (en) | 1995-02-08 |
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Expiration termination date: 20130731 Granted publication date: 20020807 |