CN112704668A - Pramipexole dihydrochloride sustained-release composition - Google Patents
Pramipexole dihydrochloride sustained-release composition Download PDFInfo
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- CN112704668A CN112704668A CN202110038568.2A CN202110038568A CN112704668A CN 112704668 A CN112704668 A CN 112704668A CN 202110038568 A CN202110038568 A CN 202110038568A CN 112704668 A CN112704668 A CN 112704668A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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Abstract
The invention provides a pramipexole dihydrochloride sustained-release composition and a preparation method thereof, tablets prepared from the composition can have stable and similar release behaviors at low rotating speed and high rotating speed, the dissolution difference is small, the influence of gastrointestinal tract mechanical stress is avoided, the content uniformity of the tablets is obviously improved by controlling the granularity of raw materials, and the bioavailability problem caused by physiological difference of different patients can be effectively avoided.
Description
Technical Field
The invention belongs to the field of preparations, and particularly relates to a pramipexole dihydrochloride sustained-release composition.
Background
The pramipexole dihydrochloride sustained-release tablet is a medicament which is developed by Germany Brigg Yiger Han company and is used for treating the Parkinson disease. Pramipexole is a dopamine receptor agonist that selectively acts on dopamine D2And D3Receptors, which alleviate movement disorders in parkinson patients by stimulating striatal dopamine receptors.
The product is approved to be marketed in Europe at 10 months in 2009 with trade name
Marketed in the United states after approval by the FDA at 02 months 2010 under the name Mirapex
Sold in China in 2014 under the trade name of
According to the published product information of EMA, FDA and the like, the prescription of the original preparation comprises pramipexole dihydrochloride, hydroxypropyl methylcellulose, carbomer, corn starch, colloidal silicon dioxide and magnesium stearate.
The development and application of the oral sustained-release preparation bring great convenience to patients, and compared with the common oral preparation, the oral sustained-release preparation has large drug-loading rate, relatively long administration period and longer retention time in the gastrointestinal tract. But the gastrointestinal tract movement of human is very complicated, and the gastrointestinal tract movement is greatly different at different ages or different sexes. The slow release preparation has a long retention time in the gastrointestinal tract, so that the environment passing through the gastrointestinal tract has high variability, and therefore, the influence of factors such as gastrointestinal motility and the like on the release effect of the slow release preparation needs to be considered. The release behavior of the oral sustained-release preparation is ensured to be relatively stable under different conditions, and the medicament is not or less influenced by physiological factors after entering the gastrointestinal tract, thereby reducing possible individual difference and ensuring the effectiveness and the universality of the medicament in different crowds.
The influence of gastrointestinal peristalsis on drug dissolution is simulated by setting dissolution experiments at different rotating speeds, and the dissolution rates of the commercially available pramipexole dihydrochloride sustained release tablets at different rotating speeds are investigated. The results show that the dissolution difference of the commercial products is large under different rotating speeds (similar factor f)2Less than 50), indicating that the release characteristics of the commercial product are greatly influenced by mechanical external force, and different patients take the product due to gastrointestinal motility and the likePhysical differences may lead to different release behavior, which in turn leads to differences in bioavailability.
Disclosure of Invention
The invention provides a composition formula of a pramipexole dihydrochloride sustained-release preparation and a preparation method thereof, the prepared tablet can have stable and similar release behaviors at low rotating speed and high rotating speed, the dissolution difference is small, the influence of gastrointestinal tract mechanical stress is avoided, the content uniformity of the tablet is obviously improved by controlling the granularity of raw materials, and the bioavailability problem caused by physiological difference of different patients can be effectively avoided.
The invention provides a pramipexole dihydrochloride sustained-release composition which is characterized by comprising pramipexole dihydrochloride, a sustained-release material, a filler, a glidant and a lubricant, wherein the pramipexole dihydrochloride sustained-release composition accounts for the following weight percentage of the composition:
further, the pramipexole dihydrochloride sustained-release composition comprises the following components in percentage by weight:
further, the pramipexole dihydrochloride sustained-release composition comprises 36% of hydroxypropyl methylcellulose, 15% of sodium carboxymethyl cellulose and 3% of ethyl cellulose by weight.
Further, the particle diameter D of the pramipexole dihydrochloride90Is 19 to 125 μm, preferably 35 to 113 μm, and more preferably 38 to 113 μm.
Further, the filler is selected from one or more of corn starch, lactose, microcrystalline cellulose and mannitol; the glidant is selected from colloidal silicon dioxide, talcum powder, sodium aluminosilicate, calcium phosphate, hard paraffin, sodium lauryl sulfate, glyceryl monostearate and glyceryl monopalmitate, and the lubricant is selected from one or more of magnesium stearate, zinc stearate, calcium stearate, polyethylene glycol, sodium stearyl fumarate, zinc stearate and hydrogenated vegetable oil.
Further, the filler is corn starch, the glidant is colloidal silicon dioxide, and the lubricant is magnesium stearate.
Further, the composition is a solid preparation.
Further, the solid preparation is a tablet.
The method for preparing the tablet adopts a direct compression method.
The invention has the beneficial effects that:
1. the invention provides a novel sustained-release framework material for pramipexole dihydrochloride sustained-release tablets, and the hypromellose, sodium carboxymethylcellulose and ethylcellulose are jointly used, so that the preparation has similar release behaviors at different rotating speeds, and the drug is not influenced by the mechanical stress of the gastrointestinal tract after entering the gastrointestinal tract, thereby reducing possible individual difference and ensuring the effectiveness and safety of different crowds.
2. The invention obviously improves the content uniformity of the product by controlling the grain diameter of the raw materials, thereby ensuring that the quality of the medicine is more stable and improving the safety and the effectiveness of the medicine.
Detailed Description
The preparation method of pramipexole dihydrochloride sustained release tablets provided by the present invention is described in detail below with reference to some examples, but the present invention is not limited to the following examples. Any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are exemplary only.
The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
The method for measuring the content uniformity comprises the following steps:
1. preparation of the solution
Taking 1 tablet of the product, placing the tablet in a 25ml measuring flask, adding a proper amount of organic solvent, shaking for 10 minutes to disintegrate the tablet, adding a proper amount of phosphate buffer solution with pH3.0 and a proper amount of enzyme solution (amylase and cellulase are dissolved in phosphate buffer solution with pH 3.0), shaking for 1 hour, diluting to a scale with the phosphate buffer solution with pH3.0, shaking uniformly, standing overnight, shaking uniformly, filtering, and taking the subsequent filtrate as a sample solution.
2. Chromatographic conditions
The chromatographic column uses octadecylsilane chemically bonded silica as a filler and uses phosphate buffer solution-acetonitrile (75:25) with the pH value of 3.0 as a mobile phase; the detection wavelength was 262nm using a diode array detector.
The dissolution method comprises the following steps:
preparation of dissolution medium (ph6.8 phosphate buffer solution): mixing 250ml of 0.2mol/L potassium dihydrogen phosphate solution and 112ml of 0.2mol/L sodium hydroxide solution, adding water to dilute the mixture to 1000ml, and shaking up the mixture to obtain the potassium dihydrogen phosphate.
According to the determination method of dissolution rate and release rate (first method of 0931 of the four general rules of the 2020 edition of Chinese pharmacopoeia), 500ml of phosphate buffer solution with pH of 6.8 is used as dissolution medium, the rotation speed is 50rpm or 150rpm, the method is operated, and the filtrate is respectively taken as test solution through different time points (2h, 6h, 9h, 12h, 16h, 20h and 24h), and dissolution medium with the same volume and the same temperature is immediately supplemented in a dissolution cup. And accurately weighing a proper amount of pramipexole dihydrochloride reference substance, diluting with a dissolution medium, and shaking uniformly to obtain a reference substance solution. Measured by liquid chromatography in content uniformity.
Comparative example 1:
commercial product (original research) information: a pramipexole dihydrochloride sustained-release tablet,
china, 0.375mg specification, product batch number B97996.
TABLE 1 dissolution results of the original preparation
The results show a similar factor f for the dissolution of the commercial product at 50rpm and 150rpm2The dissolution rate is less than 50, which shows that the release characteristic of the commercial product is obviously influenced by mechanical external force. Meanwhile, the appearance of the surface of the commercially available preparation is rough, powder falls off by touching, the formability is poor, the content uniformity of the tablet is detected, and the A +2.2S is 10.8, which indicates that the content uniformity is poor.
Example 1:
tablets of different formulations were prepared and tested for dissolution using the formulations in tables 2 and 3, with a tablet size of 0.375mg and a tablet weight of 250 mg. Similar factor f of dissolution at different stirring speeds2In order to evaluate indexes, the release characteristics of pramipexole dihydrochloride sustained-release tablets prepared by different sustained-release materials are examined.
TABLE 2 tablet formulations of different sustained release materials
TABLE 3 tablet formulations in different proportions
The preparation method comprises the following steps:
(1) taking pramipexole dihydrochloride to be crushed, and the particle diameter D of the crushed pramipexole dihydrochloride90And 60 μm.
(2) And mixing the crushed pramipexole dihydrochloride with the hydroxypropyl methylcellulose to obtain a premix 1.
(3) And mixing the colloidal silicon dioxide and the corn starch, and then sieving the mixture by a 50-mesh sieve for dispersion to obtain a premix 2.
(4) Mixing the premix 1, the auxiliary materials except the magnesium stearate and the premix 2, and sieving by a 30-mesh sieve for dispersion.
(5) Magnesium stearate was added for total mixing.
(6) And (6) tabletting.
TABLE 4 dissolution rates of tablets of different sustained-release materials
TABLE 5 dissolution of tablets in different proportions
The inventor researches and discovers that when hypromellose and one or more of other different sustained-release materials (such as polyoxyethylene, carbomer, sodium carboxymethylcellulose, ethyl cellulose and the like) are jointly used for preparing the pramipexole dihydrochloride sustained-release tablet, the dissolution rates at the same sampling time point are greatly different under the conditions that the rotating speed of 50rpm and 150rpm is 1-6, and the f of a dissolution curve is larger2The values are all less than 50, which indicates that the release behavior of the sustained-release tablets is greatly influenced by mechanical external force.
When hypromellose, sodium carboxymethylcellulose and ethylcellulose are used jointly as the slow-release material, as in the formula 7, the improvement of the dissolution difference of the tablet at different rotating speeds is obviously influenced. And when the hydroxypropyl methylcellulose is in the range of 36-45%, 9-15% of sodium carboxymethyl cellulose and 3-9% of ethyl cellulose, similar release behaviors and dissolution curves f are shown under the rotating speed conditions of 50rpm and 150rpm2The values are all more than 50, which indicates that the release behavior of the sustained release tablet is less influenced by mechanical external force.
Example 2:
different formulations were prepared by the following preparation methods using formulation 7 of example 1, and the content uniformity of the resulting mixed powder (6 times of sampling) and the formulation (10 samples were measured), respectively, and the results are shown in tables 6 and 7.
The preparation method comprises the following steps:
(1) taking pramipexole dihydrochloride to be crushed, and the particle diameter D of the crushed pramipexole dihydrochloride9019 μm, 38 μm, 60 μm, 113 μm, 125 μm, respectively.
(2) And mixing the crushed pramipexole dihydrochloride with the hydroxypropyl methylcellulose to obtain a premix 1.
(3) And mixing the colloidal silicon dioxide and the corn starch, and then sieving the mixture by a 50-mesh sieve for dispersion to obtain a premix 2.
(4) And mixing the premix 1, the sodium carboxymethylcellulose, the ethyl cellulose and the premix 2, and sieving by a 30-mesh sieve for dispersion.
(5) Magnesium stearate was added for total mixing.
(6) And (6) tabletting.
Table 6 summary of blend uniformity data for blended powders
TABLE 7 summary of content uniformity data for tablets
Note: the 0941 content uniformity inspection method of the four general regulations of the 2020 edition of Chinese pharmacopoeia specifies that the content uniformity A +2.2S is less than or equal to 15.0.
According to tables 6 and 7, the particle size of the raw material affects the mixing uniformity of the mixed powder and the content uniformity of the tablets. When the granularity of the raw material is larger (125 mu m), the mixing uniformity of the mixed powder is poor, and the content uniformity A +2.2S of the obtained tablet is more than 15.8 and is unqualified.
When the particle size of the raw material is too small (19 mu m), the raw material is easy to adsorb on the surface of equipment, so that the content of mixed powder particles is low and is only 93.1%, and the content uniformity A +2.2S of the obtained tablet is 16.9-15, and the tablet is not qualified.
Only when the particle size of the raw material D90When the particle size is within the range of 35-113 mu m, the mixed powder is uniformly mixed, the content uniformity of the tablet is less than 15 within the range of 2.4-5.4, and the requirement is met.
Claims (9)
1. The pramipexole dihydrochloride sustained-release composition is characterized by comprising pramipexole dihydrochloride, a sustained-release material, a filling agent, a glidant and a lubricant, and the pramipexole dihydrochloride sustained-release composition accounts for the following weight percentages:
2. the pramipexole dihydrochloride sustained-release composition according to claim 1, wherein the pramipexole dihydrochloride, the sustained-release material, the filler, the glidant and the lubricant account for the following weight percentage of the composition:
3. the pramipexole dihydrochloride sustained release composition according to claim 2, wherein the hypromellose is 36% by weight of the composition, the sodium carboxymethylcellulose is 15% by weight of the composition, and the ethylcellulose is 3% by weight of the composition.
4. The pramipexole dihydrochloride sustained-release composition according to claim 1, wherein the pramipexole dihydrochloride particle size D90Is 30 to 120 μm, preferably 35 to 115 μm, and more preferably 38 to 113 μm.
5. The pramipexole dihydrochloride sustained release composition according to any one of claims 1 to 4, wherein the filler is selected from one or more of corn starch, lactose, microcrystalline cellulose and mannitol; the glidant is selected from colloidal silicon dioxide, talcum powder, sodium aluminosilicate, calcium phosphate, hard paraffin, sodium lauryl sulfate, glyceryl monostearate and glyceryl monopalmitate, and the lubricant is selected from one or more of magnesium stearate, zinc stearate, calcium stearate, polyethylene glycol, sodium stearyl fumarate, zinc stearate and hydrogenated vegetable oil.
6. The pramipexole dihydrochloride sustained release composition according to claim 5, wherein the filler is corn starch, the glidant is colloidal silicon dioxide, and the lubricant is magnesium stearate.
7. The pramipexole dihydrochloride sustained release composition according to claim 5, which is a solid preparation.
8. The pramipexole dihydrochloride sustained release composition according to claim 7, wherein the solid preparation is a tablet.
9. A process for preparing the pramipexole dihydrochloride sustained release composition according to claim 8 by a direct compression method.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114137130A (en) * | 2021-12-21 | 2022-03-04 | 南通联亚药业有限公司 | Method for detecting release degree of pramipexole dihydrochloride sustained-release tablets |
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| US4226849A (en) * | 1979-06-14 | 1980-10-07 | Forest Laboratories Inc. | Sustained release therapeutic compositions |
| CN101005830A (en) * | 2004-08-13 | 2007-07-25 | 贝林格尔·英格海姆国际有限公司 | Extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof, method for manufacturing the same and use thereof |
| CN104069502A (en) * | 2013-03-29 | 2014-10-01 | 北京罗诺强施医药技术研发中心有限公司 | Composite framework material and medicinal composition thereof |
| CN106983729A (en) * | 2016-01-21 | 2017-07-28 | 北京北大维信生物科技有限公司 | Pramipexole sustained release tablets and preparation method |
| CN107951853A (en) * | 2016-10-17 | 2018-04-24 | 四川海思科制药有限公司 | A kind of body of Pramipexole dihydrochloride sustained release pharmaceutical composition and preparation method thereof |
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2021
- 2021-01-12 CN CN202110038568.2A patent/CN112704668B/en active Active
Patent Citations (5)
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| US4226849A (en) * | 1979-06-14 | 1980-10-07 | Forest Laboratories Inc. | Sustained release therapeutic compositions |
| CN101005830A (en) * | 2004-08-13 | 2007-07-25 | 贝林格尔·英格海姆国际有限公司 | Extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof, method for manufacturing the same and use thereof |
| CN104069502A (en) * | 2013-03-29 | 2014-10-01 | 北京罗诺强施医药技术研发中心有限公司 | Composite framework material and medicinal composition thereof |
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| CN107951853A (en) * | 2016-10-17 | 2018-04-24 | 四川海思科制药有限公司 | A kind of body of Pramipexole dihydrochloride sustained release pharmaceutical composition and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114137130A (en) * | 2021-12-21 | 2022-03-04 | 南通联亚药业有限公司 | Method for detecting release degree of pramipexole dihydrochloride sustained-release tablets |
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