CN101269041A - Dexibuprofen sustained-release dropping pill and preparation method thereof - Google Patents
Dexibuprofen sustained-release dropping pill and preparation method thereof Download PDFInfo
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- CN101269041A CN101269041A CNA2008101118429A CN200810111842A CN101269041A CN 101269041 A CN101269041 A CN 101269041A CN A2008101118429 A CNA2008101118429 A CN A2008101118429A CN 200810111842 A CN200810111842 A CN 200810111842A CN 101269041 A CN101269041 A CN 101269041A
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Abstract
The invention discloses a pharmaceutical preparation used for resisting inflammation, alleviating pain and eliminating fever, and particularly relates to a prepared sustained-release oral formulation adopting dexibuprofen as the ingredient. The pharmaceutical preparation aims to supplement the deficiency of the prior art and provide a sustained-release dexibuprofen dropping pill. The sustained-release dexibuprofen dropping pill overcomes the defects in the prior art effectively, guarantees no occurrence of an obvious quality change for the drug during the effective storage period and has the advantages of controllable release time, full release and high bioavailability simultaneously.
Description
Technical field
The present invention relates to a kind of be used for antiinflammatory, analgesia, antipyretic pharmaceutical preparation, particularly is a kind of oral sustained release pharmaceutical preparation that feedstock production forms with the (S)-ibuprofen.
Background technology
(S)-ibuprofen is the nonsteroidal anti inflammatory medicine, mainly is to suppress the synthetic of Cycloxygenase and prostaglandin and reach antiinflammatory, analgesic activity, and plays refrigeration function by the hypothalamus center of body temperature regulation.Has application value.The clinically at present acute attack stage of various chronic arthritiss such as 1. alleviation rheumatoid arthritis, osteoarthritis, SpA, gouty arthritis, rheumatic arthritis or arthralgia condition of illness of persistence of being used for more, anosis because for the treatment of and control the effect of the course of disease; 2. treat non-arthrogenous various soft tissue rheumatism pain, as shoulder pain, tenosynovitis, bursitis, the damaging pain of myalgia and motion back etc.; 3. acute light, moderate pain as; After operation back, the wound, oldly decrease back, primary dysmenorrhea, toothache, headache etc.; 4. the heating to adult and child has refrigeration function.
At present, the (S)-ibuprofen of listing only has tablet, capsule and suppository, and oral formulations such as tablet and capsule exist and shortcoming such as absorb slowly, first pass effect is strong, bioavailability is low, the decrement when being not easy to special disease such as old people is taken.The subject matter of suppository is to take inconvenience, and its suitable crowd only is defined in pediatric patient.There is no any slow releasing preparation and be seen in report.
Solid dispersion (solid dispersion, SD) be the solid dispersion system of the high degree of dispersion that is mixed and made into by medicine and carrier, usually adopt the SD of rapid release solid dispersion carrier material such as water soluble polymer carrier acquisition, can reduce the granularity of insoluble drug significantly, increase its diffusion area, significantly increase its dissolubility and dissolution rate, thereby improve bioavailability of medicament.SD can further make drop pill, tablet etc.In recent years, for satisfying long-acting purpose, slow-releasing solid dispersion carrier material having occurred adopting is the SD that the slightly solubility carrier makes, can delay or control drug release, thereby the research that makes SD is used and have been entered new developmental stage, simultaneously for the preparation slow releasing preparation opened up a new way (Tang Chunfa. the development of silymarin sustained-release dropping pill and extracorporeal releasing characteristic thereof. the 273rd page of Chinese pharmacist 2005 the 8th the 4th phase of volume).
Utilize solid dispersions technique, adopting ease of solubility and/or slightly solubility material is carrier, and with the solid dispersion of technology such as fusion method or solvent fusion method preparation, promptly sustained-release dropping pill is a kind of solid-state liquid preparation in fact.Consider that from preparation process and cost angle sustained-release dropping pill and comparisons such as slow releasing tablet that uses in the market or slow releasing capsule: drop pill only need mix, molten material, drips the system process; Need not to make processes such as soft material, granulation, drying, granulate, tabletting or dress capsule, therefore, the technology of sustained-release dropping pill is simpler, operation still less, because drop pill is to prepare under the state of liquid, so pollution-free aborning, no dust, automaticity is higher, and cost is starkly lower than tablet and capsule.
The slow-release pill preparation that forms with prior art for preparing, though it is abundant to obtain release, the bioavailability height, characteristics such as cost is low, but prove through long-term experiment, if it is very unreasonable that the prescription of carrier and medicine or preparation method are selected, in long term store, will produce some unsettled phenomenon, i.e. catabiosis.As the Dexibuprofen sustained-release dropping pill that forms with prior art for preparing, related substance increases etc. under long-term room temperature storage condition.Analysis may be the influence of the factors such as characteristic, preparation method and external environment that are subjected to medicine itself, material crystal formation after making the structure of (S)-ibuprofen itself and forming drop pill produces variation, thereby the medicine related substance is increased, make drug release time out of control, declined bioavailability of oral administration, therefore, offset the peculiar superiority of drop pill to a certain extent.
Summary of the invention
The objective of the invention is to replenish the deficiencies in the prior art, a kind of Dexibuprofen sustained-release dropping pill preparation is provided.Dexibuprofen sustained-release dropping pill involved in the present invention, be in the component that adopts in prior art, added the stabilizing agent vitamin E, effectively overcome the defective of prior art, guarantee that the obvious change of its related substances can not take place in effective storage period medicine, it is abundant that the while also has release, and drug release time is controlled, the advantage that bioavailability is high, suitable clinical and family uses.
Adopt following preparation method can make Dexibuprofen sustained-release dropping pill involved in the present invention.
[main component]
Raw material: (S)-ibuprofen
Chemical name: S (+)-2 (4-isobutylphenyl) Propionic acid
English name: Dexibuprofen
Molecular formula: C
13H
18O
2
Molecular weight: 206.28
Structural formula:
[preparation method]
1. component constitutes: calculate according to percentage by weight, Dexibuprofen sustained-release dropping pill involved in the present invention is made up of substrate and the 0.5-5% stabilizing agent of 10-40% (S)-ibuprofen and 60-90%, and substrate comprises 40-80% hydrophilic framework material and 10-30% hydrophobic framework material.
2. in the said components, the hydrophilic framework material in the described substrate is made up of Polyethylene Glycol (PEG) 4000 or Polyethylene Glycol (PEG) 6000 or Polyethylene Glycol (PEG) 10000 or their mixture of polyoxyethylene stearate (40) ester (S-40).
3. in the said components, the hydrophobic framework material in the described substrate is made up of glyceryl monostearate or stearic acid or hydroxypropyl methylcellulose or their mixture.
4. in the said components, described stabilizing agent is made up of vitamin E.
5. preparation method: take by weighing described hydrophilic framework material and hydrophobic framework material earlier, place the heating container internal heating and stir and make it to dissolve, the (S)-ibuprofen that adds corresponding proportion, fully stir, add again after stabilizing agent stirs, under heat-retaining condition, the medicinal liquid of fusion or mixing is splashed in the condensation column that fills dimethicone, take out after being shaped, promptly.
6. in the above-mentioned preparation method, the temperature during described heating and melting is 55 ℃～85 ℃.
7. in the above-mentioned preparation method, described condensed fluid is the dimethicone greater than 150#.
8. in the above-mentioned preparation method, the temperature on described condensed fluid top is 20 ℃～30 ℃, and the temperature of bottom is-4 ℃～10 ℃.
Beneficial effect
Ibuprofen is made up of the (S)-ibuprofen and the left-handed ibuprofen of equivalent, has 30 years as antiinflammatory and analgesic clinical practice, is considered to safest nonsteroidal antiinflammatory drug (NSAID), and is a kind of nonprescription drugs.But ibuprofen still has multiple side reactions such as the gastrointestinal toxicity of comprising, water-sodium retention, renal perfusion reduction and anaphylaxis, and incidence rate reaches 15%～30%.For developing safer NSAID, two kinds of medicines are recommended: the pure space of Cycloxygenase-inhibitor 2 and NSAID corresponding body, especially (S)-ibuprofen.1996, (S)-ibuprofen begins to be widely used in the treatment rheumatoid arthritis in Austria, as a kind of new NSAID, because it is the corresponding body in pure space of ibuprofen, and people are to the existing a large amount of clinical experiences of ibuprofen, therefore be accepted very soon approval (Shen Hao. the clinical practice modern diagnosis of (S)-ibuprofen with treat .2003; 14 (3): 175).
(S)-ibuprofen is the nonsteroidal anti inflammatory medicine, mainly is to suppress the synthetic of Cycloxygenase and prostaglandin and reach antiinflammatory, analgesic activity, and plays refrigeration function by the hypothalamus center of body temperature regulation.Has application value.The clinically at present acute attack stage of various chronic arthritiss such as 1. alleviation rheumatoid arthritis, osteoarthritis, SpA, gouty arthritis, rheumatic arthritis or arthralgia condition of illness of persistence of being used for more, anosis because for the treatment of and control the effect of the course of disease; 2. treat non-arthrogenous various soft tissue rheumatism pain, as shoulder pain, tenosynovitis, bursitis, the damaging pain of myalgia and motion back etc.; 3. acute light, moderate pain as; After operation back, the wound, oldly decrease back, primary dysmenorrhea, toothache, headache etc.; 4. the heating to adult and child has refrigeration function.
According to the literature, the Dexibuprofen sustained-release capsule is a kind of held stationary blood drug level that helps, and the sustained-release oral dosage forms of the analgesic effect of remaining valid can reduce the side effect in taking, and reduces medicining times, and the compliance that improves the patient is had practical significance.But the complicated process of preparation of slow releasing capsule is to the requirement height of equipment.Generally will prepare blank pill earlier, make on this basis and contain pill core, further process such as coating, dress capsule also can be brought certain pollution, thereby impact for environment and direct labor's health again.Yet the slow releasing preparation that does not also still have (S)-ibuprofen at present both at home and abroad comes out.
The slow-release pill preparation that forms with prior art for preparing, though it is abundant to obtain release, the bioavailability height, characteristics such as cost is low, but prove through long-term experiment, if it is very unreasonable that the prescription of carrier and medicine or preparation method are selected, in long term store, will produce some unsettled phenomenon, i.e. catabiosis.As the Dexibuprofen sustained-release dropping pill that forms with prior art for preparing, related substance increases etc. under long-term room temperature storage condition.Analysis may be the influence of the factors such as characteristic, preparation method and external environment that are subjected to medicine itself, material crystal formation after making the structure of (S)-ibuprofen itself and forming drop pill produces variation, the medicine related substance increases, color and luster changes thereby make, make drug release time out of control, declined bioavailability of oral administration, therefore, offset the peculiar superiority of drop pill to a certain extent.
The objective of the invention is to replenish the deficiencies in the prior art, a kind of Dexibuprofen sustained-release dropping pill preparation is provided.Dexibuprofen sustained-release dropping pill involved in the present invention, be in the component that adopts in prior art, added vitamin E, effectively overcome the defective of prior art, guarantee that the obvious change of its related substances can not take place in effective storage period medicine, it is abundant that the while also has release, and drug release time is controlled, the advantage that bioavailability is high, suitable clinical and family uses.
Specific implementation method
First group:
In gross weight 100g, take by weighing substrate PEG4000 40%, PEG6000 10%, and PEG10000 10%, stearic acid 11%, glyceryl monostearate 17%, stabilizing agent vitamin E 2%, raw material (S)-ibuprofen 10%; Substrate is made it to dissolve in placing the heating container internal heating and stirring, the (S)-ibuprofen that adds corresponding proportion, fully stir, add again after the stabilizing agent vitamin E stirs, under heat-retaining condition, the medicinal liquid of fusion or mixing is splashed in the condensation column that fills dimethicone, wherein, temperature during heating and melting is 55 ℃, and the temperature on condensed fluid top is 20 ℃, and the temperature of bottom is-4 ℃; The back taking-up is shaped.
Products obtained therefrom, 2 hours cumulative release percentage rate are that 35～55%, 6 hours cumulative release percentage rate are that 62～82%, 10 hours cumulative release percentage rate are 75～95%, continuous 3 months no significant change of related substance examination, roundness is better.
Second group:
In gross weight 100g, take by weighing substrate PEG4000 10%, PEG6000 20%, and PEG10000 30%, stearic acid 11%, glyceryl monostearate 8.5%, stabilizing agent vitamin E 0.5%, raw material (S)-ibuprofen 20%; Substrate is made it to dissolve in placing the heating container internal heating and stirring, the (S)-ibuprofen that adds corresponding proportion, fully stir, add again after the stabilizing agent vitamin E stirs, under heat-retaining condition, the medicinal liquid of fusion or mixing is splashed in the condensation column that fills dimethicone, wherein, temperature during heating and melting is 65 ℃, and the temperature on condensed fluid top is 30 ℃, and the temperature of bottom is 0 ℃; The back taking-up is shaped.
Products obtained therefrom, 2 hours cumulative release percentage rate are that 48%～68%, 6 hours cumulative release percentage rate are that 75～95%, 10 hours cumulative release percentage rate are 80～100%, continuous 3 months no significant change of related substance examination, roundness is better.
The 3rd group:
In gross weight 100g, take by weighing substrate polyoxyethylene stearate (40) ester (S-40) 10%, PEG6000 10%, PEG1000020%, stearic acid 10%, hydroxypropyl methylcellulose 7%, stabilizing agent vitamin E 3%, raw material (S)-ibuprofen 40%; Substrate is made it to dissolve in placing the heating container internal heating and stirring, the (S)-ibuprofen that adds corresponding proportion, fully stir, add again after the stabilizing agent vitamin E stirs, under heat-retaining condition, the medicinal liquid of fusion or mixing is splashed in the condensation column that fills dimethicone, wherein, temperature during heating and melting is 75 ℃, and the temperature on condensed fluid top is 20 ℃, and the temperature of bottom is 0 ℃; The back taking-up is shaped.
Products obtained therefrom, 2 hours cumulative release percentage rate are that 35%～55%, 6 hours cumulative release percentage rate are that 60～80%, 10 hours cumulative release percentage rate are 70～90%, continuous 3 months no significant change of related substance examination, roundness is better.
The 4th group:
In gross weight 100g, take by weighing substrate polyoxyethylene stearate (40) ester (S-40) 10%, PEG6000 15%, PEG1000030%, glyceryl monostearate 2%, hydroxypropyl methylcellulose 8%, stabilizing agent vitamin E 5%, raw material (S)-ibuprofen 30%; Substrate is made it to dissolve in placing the heating container internal heating and stirring, the (S)-ibuprofen that adds corresponding proportion, fully stir, add again after the stabilizing agent vitamin E stirs, under heat-retaining condition, the medicinal liquid of fusion or mixing is splashed in the condensation column that fills dimethicone, wherein, temperature during heating and melting is 85 ℃, and the temperature on condensed fluid top is 30 ℃, and the temperature of bottom is 5 ℃; The back taking-up is shaped.
Products obtained therefrom, 2h cumulative release percentage rate is 39%～59%, and 6h cumulative release percentage rate is 64～84%, and 10h cumulative release percentage rate is 76～96%,, continuous 3 months no significant change of related substance examination, roundness is better.
The 5th group:
In gross weight 100g, take by weighing substrate polyoxyethylene stearate (40) ester (S-40) 10%, PEG4000 10%, PEG600030%, stearic acid 5%, glyceryl monostearate 3%, hydroxypropyl methylcellulose 10%, stabilizing agent vitamin E 2%, raw material (S)-ibuprofen 30%; Substrate is made it to dissolve in placing the heating container internal heating and stirring, the (S)-ibuprofen that adds corresponding proportion, fully stir, add again after the stabilizing agent vitamin E stirs, under heat-retaining condition, the medicinal liquid of fusion or mixing is splashed in the condensation column that fills dimethicone, wherein, temperature during heating and melting is 65 ℃, and the temperature on condensed fluid top is 20 ℃, and the temperature of bottom is 4 ℃; The back taking-up is shaped.
Products obtained therefrom, 2h cumulative release percentage rate is 42%～62%, and 6h cumulative release percentage rate is 69～89%, and 10h cumulative release percentage rate is 76～96%, continuous 3 months no significant change of related substance examination, roundness is better.
The 6th group:
In gross weight 100g, take by weighing substrate polyoxyethylene stearate (40) ester (S-40) 10%, PEG4000 20%, PEG600020%, PEG10000 20%, stearic acid 11%, glyceryl monostearate 7%, stabilizing agent vitamin E 2%, raw material (S)-ibuprofen 10%; Substrate is made it to dissolve in placing the heating container internal heating and stirring, the (S)-ibuprofen that adds corresponding proportion, fully stir, add again after the stabilizing agent vitamin E stirs, under heat-retaining condition, the medicinal liquid of fusion or mixing is splashed in the condensation column that fills dimethicone, wherein, temperature during heating and melting is 70 ℃, and the temperature on condensed fluid top is 30 ℃, and the temperature of bottom is 0 ℃; The back taking-up is shaped.
Products obtained therefrom, 2h cumulative release percentage rate is 40%～60%, and 6h cumulative release percentage rate is 70～88%, and 10h cumulative release percentage rate is 80～95%, continuous 3 months no significant change of related substance examination, roundness is better.
Claims (8)
1. a Dexibuprofen sustained-release dropping pill that is used for antipyretic-antalgic calculates according to percentage by weight, and Dexibuprofen sustained-release dropping pill involved in the present invention is made up of (S)-ibuprofen and substrate; Component constitutes: calculate according to percentage by weight, Dexibuprofen sustained-release dropping pill involved in the present invention is made up of the substrate and 0.5～5% stabilizing agent of 10～40% (S)-ibuprofens and 60～90%, and substrate comprises 40～80% hydrophilic framework materials and 10～30% hydrophobic framework materials.
2. Dexibuprofen sustained-release dropping pill as claimed in claim 1, it is characterized in that the hydrophilic framework material in the described substrate is made up of Polyethylene Glycol (PEG) 4000 or Polyethylene Glycol (PEG) 6000 or Polyethylene Glycol (PEG) 10000 or their mixture of polyoxyethylene stearate (40) ester (S-40).
3. Dexibuprofen sustained-release dropping pill as claimed in claim 1 is characterized in that, the hydrophobic framework material in the described substrate is made up of glyceryl monostearate or stearic acid or hydroxypropyl methylcellulose or their mixture.
4. Dexibuprofen sustained-release dropping pill as claimed in claim 1 is characterized in that described stabilizing agent is made up of vitamin E.
5. Dexibuprofen sustained-release dropping pill as claimed in claim 1, it is characterized in that preparation method is as follows: take by weighing described hydrophilic framework material and hydrophobic framework material earlier, place the heating container internal heating and stir and make it to dissolve, the (S)-ibuprofen that adds corresponding proportion fully stirs, and adds after stabilizing agent stirs again, under heat-retaining condition, the medicinal liquid of fusion or mixing is splashed in the condensation column that fills dimethicone, and take out the back that is shaped, promptly.
6. as the preparation method of Dexibuprofen sustained-release dropping pill as described in the claim 5, it is characterized in that: the temperature during described heating and melting is 55 ℃～85 ℃.
7. as the preparation method of Dexibuprofen sustained-release dropping pill as described in the claim 5, it is characterized in that: described condensed fluid is the dimethicone greater than 150#.
8. as the preparation method of (S)-ibuprofen drop pill as described in the claim 5, it is characterized in that: the temperature on described condensed fluid top is 20 ℃～30 ℃, and the temperature of bottom is-4 ℃～10 ℃.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2008101118429A CN101269041A (en) | 2008-05-16 | 2008-05-16 | Dexibuprofen sustained-release dropping pill and preparation method thereof |
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| CNA2008101118429A CN101269041A (en) | 2008-05-16 | 2008-05-16 | Dexibuprofen sustained-release dropping pill and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102526000A (en) * | 2012-02-02 | 2012-07-04 | 武汉长联来福制药股份有限公司 | Dexibuprofen slow-release capsule and production method thereof |
-
2008
- 2008-05-16 CN CNA2008101118429A patent/CN101269041A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102526000A (en) * | 2012-02-02 | 2012-07-04 | 武汉长联来福制药股份有限公司 | Dexibuprofen slow-release capsule and production method thereof |
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Open date: 20080924 |