CN1850080A - Oral dispersion domperidone coutrolled-release gel and its preparing method - Google Patents
Oral dispersion domperidone coutrolled-release gel and its preparing method Download PDFInfo
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- CN1850080A CN1850080A CN 200610056788 CN200610056788A CN1850080A CN 1850080 A CN1850080 A CN 1850080A CN 200610056788 CN200610056788 CN 200610056788 CN 200610056788 A CN200610056788 A CN 200610056788A CN 1850080 A CN1850080 A CN 1850080A
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Abstract
The present invention relates to a domperidone gel preparation for curing reflux esophagitis. Said preparation includes active component and matrix, in which the active component includes the solution made up by using domperidone, polyvinylpyrrolidone and water. Its taste is good, and its stability is better.
Description
Technical field
The present invention relates to a kind of oral gel, in particular, is a kind of domperidone gel that disperses build.
Background technology
Domperidone is a kind of specific periphery dopamine-receptor antagonist, mainly act on the gastrointestinal dopamine receptor, have stronger short stomach motion and antiemetic effect, can strengthen esophagus bottom sphincter tone, preventing effects such as stomach-esophageal reflux, is the medicine commonly used of treatment reflux esophagitis.But domperidone can not be resisted gastric acid, must with receptor acting after could onset, therefore oral back is difficult to rapidly upper digestive tract be shielded.
At present, domperidone mainly contains tablet and suspensoid, and need administration repeatedly every day, not only use inconvenience, and the fluctuating of the drug level in the blood is very big, causes " peak valley " phenomenon.When drug level is in the peak, surpassed optimum treatment concentration, just cause more side reaction, even poison; Otherwise, when drug level drops to low ebb, under desired concn, be difficult to play a role again.Simultaneously because tablet and suspensoid are shorter in the gastrointestinal tract holdup time, and can be destroyed by gastric acid under one's belt, be unfavorable for the absorption fully of medicine, bioavailability is lower.
The commercially available peroral dosage form of existing domperidone exists can not protect lower esophageal rapidly; short in the digestive tract holdup time; blood drug level rises and falls very big; technical problem and deficiencies such as oral absorption is bad, and because the domperidone water solubility is little, hydrophilic is poor; in gel, easily assemble in bulk; be difficult for homodisperse, since extremely unstable, utilize existing technology can't prepare the gel that meets the pharmaceutics requirement at all.Therefore, although the gel listing of multiple medications has been arranged, do not have any domperidone gel up to now and develop or go on the market.
Summary of the invention
The inventor is by studying intensively; invented and a kind ofly can directly protect the esophagus mucosa in short-term; and can be detained at gastrointestinal tract; effect is lasting rapidly; blood drug level is steady; absorb fully; can effectively treat the oral dispersion type gelling agent for controlling and releasing of reflux esophagitis; and unexpectedly,, domperidone is disperseed equably by special component and the preparation method that the inventor provided; thereby make this gel have advantages of excellent stability; pharmacokinetic property and activity; especially the effective blood drug concentration that has lasting stability after oral can reduce medicining times, increases compliance of patients.
The invention provides a kind of oral gel, comprise active component and substrate, wherein said active component comprises the aqueous solution of domperidone, polyvinylpyrrolidone, its part by weight is: the domperidone of 0.1-0.5%, the polyvinylpyrrolidone of 0.05-5%, the substrate of 0.1-1.0% and an amount of water, described " substrate " is selected from one or more in carbomer, hydroxypropyl emthylcellulose, methylcellulose and the hydroxypropyl cellulose, preferred carbomer.
Described " an amount of water " comprises the water yield that makes the complete swelling of substrate, and the last surplus water yield sum of supplying etc., that is to say, removes active component and substrate and other adjuvants in gel, as being the amount of water behind ethyl hydroxybenzoate, the sorbitol.And the present invention is for the not special restriction of the amount of water.
Described polyvinylpyrrolidone is selected from one or more among PVPK25, PVPK30, PVPK90 or the PVPK90D, and carbomer is selected from carbomer-P934, one or more among carbomer-P971 or the carbomer-P974.Selectable, any self-control or commercially available polyvinylpyrrolidone, carbomer may be used to the present invention and do not influence goal of the invention of the present invention.
Water comprises distilled water, deionized water etc., and only otherwise can have influence on the performance and the effect of medicament of the present invention, other self-control or commercially available water also can be selected.
In embodiment preferred of the present invention, contain domperidone, the polyvinylpyrrolidone of 1-3%, the substrate of 0.4-1.0% and an amount of water of 0.1-0.5% in the gel of the present invention.
Those skilled in the art can add other pharmacy acceptable auxiliary in above-mentioned preparation, as ethyl hydroxybenzoate, sorbitol and aromatic, flavoring agent or other adjuvants etc.In embodiment preferred of the present invention, gel comprises the domperidone of 0.1-0.5%, the polyvinylpyrrolidone of 0.05-5%, the ethyl hydroxybenzoate of 0.01-0.25%, the sorbitol of 0.5-2.0%, the substrate of 0.1-1.0% and an amount of water.
The pharmaceutically active substances that gel of the present invention can also add other is prepared into compound gel, and these pharmaceutically active substances and domperidone form synergism, superposition, strengthens the effect of treatment reflux esophagitis.Preferably, this pharmaceutically active substance is a ranitidine.In one embodiment of the invention, add an amount of ranitidine hydrochloride in the domperidone solution of active component, join the good matrix solution of swelling again, mix homogeneously, transfer PH to 7.0-9.0 with triethanolamine, obtain containing the compound gel of domperidone and ranitidine hydrochloride.
According to gel of the present invention, the domperidone gel that is mixed with promptly gets freeze-dried powder through lyophilization, adds an amount of water, reverts to the domperidone gel again.
Because the domperidone water solubility is little, hydrophilic is poor, easily assembles in bulk in gel, be difficult for homodisperse, therefore the present invention has carried out significant improvement to prior art, and a kind of special preparation technology is provided, and its key is domperidone is mixed with a kind of good hydrophilic property, finely dispersed solution.Therefore technical scheme of the present invention is that domperidone is made a kind of solid dispersion earlier, the solid dispersion liquid solution is mixed with gel again, domperidone is scattered in the gel equably, thereby makes this gel have very good stable.
The invention provides a kind of preparation technology of domperidone gel, comprising:
Substrate is sprinkled in an amount of distilled water, places 24 hours, makes its abundant swelling;
Get a certain amount of domperidone and polyvinylpyrrolidone, add an amount of dehydrated alcohol and make dissolving fully, distilling under reduced pressure under 50 ℃ of water-baths obtains solid dispersion;
The domperidone solid dispersion is added in the matrix solution that swelling is good, after the stirring, regulate pH to 7.0-9.0, add water to capacity and obtain gel with triethanolamine.
Gel after making is creamy white thick, and is even, fine and smooth.
During use, directly oral, each 10g once a day, early takes before the meal.
Be excellent characteristic and the effect of checking domperidone gel of the present invention to be had, we have done following investigations to this gel:
1. the mensuration of content of dispersion
Investigated the content of the domperidone in many groups gel with ultraviolet spectrophotometry, the result shows: the content of the domperidone in the gel is the 95%-105% of labelled amount, shows that preparation of the present invention and preparation method have good homogeneity and industrial applicibility.
2. centrifugal test
Domperidone is directly sneaked in the matrix solution, and re-adjustment pH makes a certain amount of suspendible gel.The present invention with suspendible gel, commercially available suspensoid and equivalent is simultaneously centrifugal then, and rotating speed is 3000r/min, and the time is 30min.The result shows: the medicine in suspendible gel and the commercially available suspensoid is sunken at the bottom of the centrifuge tube, and not sedimentation of medicine of the present invention still is uniform milky, illustrates that prepared gel is the pastille system of homogeneous, has dispersibility preferably.
3. stability test
Investigated the influence to domperidone gel stability of light, heat (40 ℃, 60 ℃), low temperature factors such as (20 ℃), the result shows: the every index of domperidone gel there is no significant change.
With room temperature accelerated test (40 ℃, RH75%) 3 months, every index had no significant change.
4. bioavailability test
In the bioavailability test, give the oral commercially available domperidone tablet of beasle dog, commercially available domperidone suspensoid and domperidone gel of the present invention respectively, blood drug level-time graph is referring to accompanying drawing 1.
The comparison of the oral domperidone gel of table 1 and marketed tablet and suspensoid blood drug level
| Administering mode | Pharmacokinetic parameters | ||
| Maximum plasma concentration C max | Peak time T max | AUC | |
| 10mg domperidone tablet oral administration | 35.92μg·L -1 | 1h | 247.16μg·h·L -1 |
| 10mg domperidone suspensoid oral administration | 165.02μg·L -1 | 1h | 431.15μg·h·L -1 |
| 10mg domperidone gel oral administration | 45.52μg·L -1 | 2h | 731.35μg·h·L -1 |
Shown by accompanying drawing 1 and table 1: the present invention compares with tablet or suspensoid, can delay peak time, blood drug level is stable lasting after reaching the peak, can keep effective blood drug concentration more than 12 hours, 30 hours AUC is respectively 3 times of marketed tablet, 1.7 times of suspensoid significantly improve the bioavailability of domperidone.
Compare with existing preparation, the advantage that preparation of the present invention has is very obvious and outstanding, gel of the present invention and general formulation commonly used such as oral or suspensoid etc. have been compared following advantage: gained gel character is stable, and content is even, separates out through placing no any precipitation; Gel can attach on the esophageal wall, and is slowly dirty along esophageal wall, forms the certain physical barrier at the esophagus mucous membrane surface, can protect the effect of esophagus bottom rapidly; Can the neutralize gastric acid of a part of gel reduces the acidity of epigastric and lower esophageal, has reduction acidity, the effect of protection mucosa; Gel enters in the gastric sour environment can form the solution shape, and the polyvinylpyrrolidone in the solid dispersion can promote the absorption of medicine; The oral back of the gel of making is rapid-action, long action time, and blood drug level is stable, and administration number of times was kept to once a day for three times from every day, improves compliance of patients; The gel of making is specious, and mouthfeel is good, has increased the compliance of child patient; Especially specifically, unexpectedly, because special formulation provided by the invention and preparation method, gel of the present invention has special advantages of excellent stability, so taking dose is accurate, shakes up before need not using, and uses more convenient.
Description of drawings
Accompanying drawing 1 is blood drug level-time plot behind the oral different dosage form.
The specific embodiment
The following examples are that the present invention is further specified and explains, rather than the present invention is carried out any restriction.
Embodiment 1
Take by weighing 0.1g carbomer-P934, be sprinkled in the 25ml distilled water, swelling 24 hours.Take by weighing 500mg domperidone and 5gPVPk30, after both are mixed, add the 100ml dehydrated alcohol, place 50 ℃ of water-baths to dissolve fully.Solid dispersion is made in distilling under reduced pressure in 50 ℃ of water-baths.Take by weighing the solid dispersion that 550mg makes, add in the good liquid of above-mentioned swelling, stir.Add the 2ml50% triethanolamine solution, regulate pH value to 9.Add distilled water again to 50g.
Embodiment 2
Take by weighing 0.1g carbomer-P971, remove in the 25ml distilled water, swelling 24 hours.Accurately take by weighing 500mg domperidone and 5gPVPk30, after both are mixed, add the 100ml dehydrated alcohol, place 50 ℃ of water-baths to dissolve fully.Solid dispersion is made in distilling under reduced pressure in 50 ℃ of water-baths.Take by weighing the solid dispersion that 550mg makes, add in the good liquid of above-mentioned swelling, stir.Add the 2ml50% triethanolamine solution, regulate pH value to 7.Add distilled water again to 50g.
Embodiment 3
Take by weighing 0.1g carbomer-P974, be sprinkled in the 25ml distilled water, swelling 24 hours.Take by weighing 500mg domperidone and 5gPVPk25, after both are mixed, add the 100ml dehydrated alcohol, place 50 ℃ of water-baths that it is dissolved fully.Solid dispersion is made in distilling under reduced pressure in 50 ℃ of water-baths.Accurately take by weighing the solid dispersion that 550mg makes, add in the good liquid of above-mentioned swelling, stir.Add the 2ml50% triethanolamine solution, regulate pH value to 9.Add distilled water again to 50g.
Embodiment 4
Take by weighing the 0.2g hydroxypropyl emthylcellulose, be sprinkled in the 25ml distilled water, swelling 24 hours.Take by weighing 500mg domperidone and 2gPVPk30, after both are mixed, add the 100ml dehydrated alcohol, place 50 ℃ of water-baths to dissolve fully.Solid dispersion is made in distilling under reduced pressure in 50 ℃ of water-baths.Take by weighing the solid dispersion that 550mg makes, add in the good liquid of above-mentioned swelling, stir.Add the 2ml50% triethanolamine solution, regulate pH value to 8.Add distilled water again to 50g.
Embodiment 5
Take by weighing the 0.2g methylcellulose, be sprinkled in the 25ml distilled water, swelling 24 hours.Take by weighing 500mg domperidone and 2gPVPk30, after both are mixed, add the 100ml dehydrated alcohol, place 50 ℃ of water-baths that it is dissolved fully.Solid dispersion is made in distilling under reduced pressure in 50 ℃ of water-baths.Take by weighing the solid dispersion that 550mg makes, add in the good liquid of above-mentioned swelling, stir.Add the 2ml50% triethanolamine solution, regulate pH value to 9.Add distilled water again to 50g.
Embodiment 6
Take by weighing the 0.5g hydroxypropyl cellulose, be sprinkled in the 25ml distilled water, swelling 24 hours.Take by weighing 500mg domperidone and 2gPVPk30, after both are mixed, add the 100ml dehydrated alcohol, place 50 ℃ of water-baths that it is dissolved fully.Solid dispersion is made in distilling under reduced pressure in 50 ℃ of water-baths.Take by weighing the solid dispersion that 550mg makes, add in the good liquid of above-mentioned swelling, stir.Add the 2ml50% triethanolamine solution, regulate pH value to 8.Add distilled water again to 50g.Through lyophilization, get pressed powder.Add distilled water again to 50g.
Be appreciated that those skilled in the art can add other pharmacy acceptable auxiliary separately or together in the active component of preparation of the present invention and substrate or the ratio of each component carried out minor alteration and do not influence the fundamental property of pharmaceutical preparation.But the pharmaceutical preparation and the preparation method that are obtained by these changes all do not break away from spirit of the present invention, drop in the protection domain of description of the present invention and claims yet.
Claims (10)
1. oral dispersion domperidone coutrolled gel, comprise active component and and substrate, wherein said active component comprises the aqueous solution of domperidone, polyvinylpyrrolidone, described substrate is selected from one or more in carbomer, hydroxypropyl emthylcellulose, methylcellulose and the hydroxypropyl cellulose, preferred carbomer, part by weight is: the domperidone of 0.1-0.5%, the polyvinylpyrrolidone of 0.05-5%, the substrate of 0.1-1.0% and an amount of water.
2. gel according to claim 1 also comprises ethyl hydroxybenzoate, sorbitol in active component.
3. gel according to claim 1 and 2 comprises domperidone, the polyvinylpyrrolidone of 0.05-5%, the ethyl hydroxybenzoate of 0.01-0.25%, the sorbitol of 0.5-2.0%, the substrate of 0.1-1.0% and an amount of water of 0.1-0.5%
4. gel according to claim 1 and 2, the ratio that it is characterized in that described active component and substrate is 1: 1～4.
5. gel according to claim 1 is characterized in that substrate is the earlier abundant good solution of swelling in water.
6. gel according to claim 1 is characterized in that after the lyophilization of gained gel, gets freeze-dried powder.After freeze-dried powder added suitable quantity of water, regain gel.
7. gel according to claim 1 or 5 is characterized in that the domperidone solution of active component adds an amount of H
2Receptor antagonist as ranitidine, cimetidine, famotidine and nizatidine, obtains containing the compound gel of domperidone and bisfentidine.
8. gel according to claim 1 or 5 is characterized in that the domperidone solution of active component adds an amount of antifungal drug, as ketoconazole, fluconazol, miconazole and itraconazole, obtains containing the compound gel of domperidone and antifungal drug.
9. according to the preparation method of the wherein any described gel of claims 1-8, it is characterized in that:
1) substrate is sprinkled in an amount of distilled water, placed 24 hours, make its abundant swelling;
2) take by weighing a certain amount of domperidone and polyvinylpyrrolidone, add an amount of dehydrated alcohol and make dissolving fully, distilling under reduced pressure under 50 ℃ of water-baths obtains solid dispersion;
3) the domperidone solid dispersion is added in the matrix solution that swelling is good, after the stirring, regulate pH to 7.0-9.0, add water to capacity and obtain gel with triethanolamine.
10. the described gel of claim 1-8 is used for the treatment of purposes in the medicine of reflux esophagitis in preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100567883A CN100490806C (en) | 2006-03-08 | 2006-03-08 | Oral dispersion domperidone coutrolled-release gel and its preparing method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100567883A CN100490806C (en) | 2006-03-08 | 2006-03-08 | Oral dispersion domperidone coutrolled-release gel and its preparing method |
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| CN1850080A true CN1850080A (en) | 2006-10-25 |
| CN100490806C CN100490806C (en) | 2009-05-27 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB2006100567883A Expired - Fee Related CN100490806C (en) | 2006-03-08 | 2006-03-08 | Oral dispersion domperidone coutrolled-release gel and its preparing method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104127390A (en) * | 2014-08-05 | 2014-11-05 | 孙丽华 | Domperidone tablet and preparation process thereof |
| CN105663055A (en) * | 2016-03-01 | 2016-06-15 | 山东司邦得制药有限公司 | Children domperidone dry suspension and preparation method of children domperidone dry suspension |
-
2006
- 2006-03-08 CN CNB2006100567883A patent/CN100490806C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104127390A (en) * | 2014-08-05 | 2014-11-05 | 孙丽华 | Domperidone tablet and preparation process thereof |
| CN104127390B (en) * | 2014-08-05 | 2016-05-11 | 孙丽华 | A kind of Domperidone Tablets and preparation technology thereof |
| CN105663055A (en) * | 2016-03-01 | 2016-06-15 | 山东司邦得制药有限公司 | Children domperidone dry suspension and preparation method of children domperidone dry suspension |
| CN105663055B (en) * | 2016-03-01 | 2018-07-06 | 山东司邦得制药有限公司 | A kind of children's domperidone dry suspensoid agent and preparation method thereof |
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| Publication number | Publication date |
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| CN100490806C (en) | 2009-05-27 |
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Granted publication date: 20090527 Termination date: 20140308 |