CN112704668B - Pramipexole dihydrochloride sustained-release composition - Google Patents

Pramipexole dihydrochloride sustained-release composition Download PDF

Info

Publication number
CN112704668B
CN112704668B CN202110038568.2A CN202110038568A CN112704668B CN 112704668 B CN112704668 B CN 112704668B CN 202110038568 A CN202110038568 A CN 202110038568A CN 112704668 B CN112704668 B CN 112704668B
Authority
CN
China
Prior art keywords
release
pramipexole dihydrochloride
sustained
tablet
dissolution
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.)
Active
Application number
CN202110038568.2A
Other languages
Chinese (zh)
Other versions
CN112704668A (en
Inventor
杜丹
司亚娟
崔巧利
王露露
刘雪静
牛方欣
陈欢欢
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Original Assignee
CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd filed Critical CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Priority to CN202110038568.2A priority Critical patent/CN112704668B/en
Publication of CN112704668A publication Critical patent/CN112704668A/en
Application granted granted Critical
Publication of CN112704668B publication Critical patent/CN112704668B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • 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
    • 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

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

Pramipexole dihydrochloride sustained-release composition
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 D 2 And D 3 Receptors, which alleviate movement disorders in parkinson patients by stimulating striatal dopamine receptors.
The product is approved to be marketed in Europe in 10 months in 2009 with trade name
Figure BDA0002894463840000011
After approval by FDA in 2010 at 02/US, the product is marketed in the United states under the name Mirapex
Figure BDA0002894463840000012
Sold in China in 2014 under the trade name of
Figure BDA0002894463840000013
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) 2 Less than 50), which indicates that the release characteristics of the commercial product are greatly influenced by mechanical external force, and different patients may have different release behaviors due to physiological differences such as gastrointestinal motility, and further causes the difference of bioavailability.
Disclosure of Invention
The invention provides a composition formula of a pramipexole dihydrochloride sustained release preparation and a preparation method thereof, wherein the prepared tablets can have stable and similar release behaviors at low rotating speed and high rotating speed, have small dissolution difference and are not influenced by mechanical stress of gastrointestinal tracts, 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.
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:
Figure BDA0002894463840000021
。
further, the pramipexole dihydrochloride sustained-release composition comprises the following components in percentage by weight:
Figure BDA0002894463840000022
。
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 size D of the pramipexole dihydrochloride 90 Is 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 by some examples below, 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 do not indicate any specific conditions, and are carried out 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 to which this invention belongs.
The content uniformity determination method 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 Ministry of the year 2020 edition of Chinese pharmacopoeia), 500ml of pH6.8 phosphate buffer solution is used as dissolution medium, the rotation speed is 50rpm or 150rpm, the operation is carried out according to the method, and through different time points (2h, 6h, 9h, 12h, 16h, 20h and 24h), filtrate is respectively taken as test solution, and dissolution medium with the same volume and the same temperature is instantly 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,
Figure BDA0002894463840000044
china, 0.375mg specification, product batch number B97996.
TABLE 1 dissolution results of the original preparation
Figure BDA0002894463840000041
The results show a similar factor f for the dissolution of the commercial product at 50rpm and 150rpm 2 The 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 speeds 2 In 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
Figure BDA0002894463840000042
TABLE 3 tablet formulations in different proportions
Figure BDA0002894463840000043
Figure BDA0002894463840000051
The preparation method comprises the following steps:
(1) taking pramipexole dihydrochloride to be crushed, and the particle diameter D of the crushed pramipexole dihydrochloride 90 And 60 μm.
(2) And mixing the crushed pramipexole dihydrochloride with the hydroxypropyl methylcellulose to obtain a premix 1.
(3) After mixing colloidal silicon dioxide and corn starch, the mixture is sieved by a 50-mesh sieve for dispersion, and a premix 2 is obtained.
(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
Figure BDA0002894463840000052
TABLE 5 dissolution of tablets in different proportions
Figure BDA0002894463840000053
Figure BDA0002894463840000061
The inventor researches to find that when hydroxypropyl methylcellulose and other different sustained-release materials (such as polyoxyethylene, carbomer, sodium carboxymethylcellulose, ethyl cellulose and the like) are adoptedOne or more of the pramipexole dihydrochloride sustained-release tablets are jointly used for preparation, under the conditions that the dissolution rates of the pramipexole dihydrochloride sustained-release tablets are 1-6 and the rotating speeds of 50rpm and 150rpm are higher, the dissolution rates at the same sampling time point are different greatly, and the f of a dissolution curve 2 The 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 150rpm 2 The 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 for crushing, and obtaining the particle size D after crushing 90 19 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) After mixing colloidal silicon dioxide and corn starch, the mixture is sieved by a 50-mesh sieve for dispersion, and a premix 2 is obtained.
(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
Figure BDA0002894463840000062
Figure BDA0002894463840000071
TABLE 7 summary of content uniformity data for tablets
Figure BDA0002894463840000072
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 D 90 When 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 (2)

1. The pramipexole dihydrochloride sustained-release tablet is characterized in that the particle size D of the pramipexole dihydrochloride 90 The particle size of the pramipexole dihydrochloride slow-release tablet is 35-115 mu m, the tablet is composed of pramipexole dihydrochloride, a slow-release material, a filling agent, a glidant and a lubricant, and the weight percentage of each component in the tablet is as follows:
Figure 988659DEST_PATH_IMAGE002
，
wherein the filler is corn starch, the glidant is colloidal silicon dioxide, the lubricant is magnesium stearate, and the tablet is prepared by a direct compression method.
2. The pramipexole dihydrochloride sustained-release tablet according to claim 1, wherein the pramipexole dihydrochloride particle size D 90 38 to 113 μm.
CN202110038568.2A 2021-01-12 2021-01-12 Pramipexole dihydrochloride sustained-release composition Active CN112704668B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110038568.2A CN112704668B (en) 2021-01-12 2021-01-12 Pramipexole dihydrochloride sustained-release composition

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110038568.2A CN112704668B (en) 2021-01-12 2021-01-12 Pramipexole dihydrochloride sustained-release composition

Publications (2)

Publication Number Publication Date
CN112704668A CN112704668A (en) 2021-04-27
CN112704668B true CN112704668B (en) 2022-09-30

Family

ID=75548903

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110038568.2A Active CN112704668B (en) 2021-01-12 2021-01-12 Pramipexole dihydrochloride sustained-release composition

Country Status (1)

Country Link
CN (1) CN112704668B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
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

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4226849A (en) * 1979-06-14 1980-10-07 Forest Laboratories Inc. Sustained release therapeutic compositions
KR101052436B1 (en) * 2004-08-13 2011-07-29 베링거 인겔하임 인터내셔날 게엠베하 Extended release tablet formulations containing pramipexole or pharmaceutically acceptable salts thereof, methods of preparation and uses thereof
CN104069502B (en) * 2013-03-29 2018-02-16 北京罗诺强施医药技术研发中心有限公司 Compound skeleton material and its pharmaceutical composition
CN106983729B (en) * 2016-01-21 2021-02-26 北京北大维信生物科技有限公司 Pramipexole sustained release tablet and preparation method thereof
CN107951853B (en) * 2016-10-17 2022-04-08 海思科制药(眉山)有限公司 Pramipexole dihydrochloride sustained-release pharmaceutical composition and preparation method thereof

Also Published As

Publication number Publication date
CN112704668A (en) 2021-04-27

Similar Documents

Publication Publication Date Title
CN105832713B (en) A kind of pharmaceutical composition and preparation method thereof comprising fluvoxamine maleate
CN114288257B (en) Fluvoxamine maleate tablet and preparation method thereof
JP2022538215A (en) Oral capsule and its preparation method
CN102988993A (en) Screening and composition of main auxiliary materials of compound acetaminophen tablet, and preparation method of compound acetaminophen tablet
CN104306344B (en) A kind of Azilsartan tablet and preparation technology thereof
CN110420192B (en) Isosorbide mononitrate sustained-release tablet and preparation method thereof
CN112704668B (en) Pramipexole dihydrochloride sustained-release composition
CN103610677A (en) Repaglinide troche and preparation method thereof
CN111973565A (en) Vonoprazan fumarate-containing tablet and dissolution rate determination method thereof
CN108066312B (en) Palbociclib pharmaceutical composition and preparation method thereof
Osman et al. Comparative Physicochemical Evaluation of Starch Extracted from Pearl millet seeds grown in Sudan as a Pharmaceutical Excipient against Maize and Potato Starch, using Paracetamol as a model drug
CN109908104B (en) Amoxicillin capsule and preparation method thereof
CN103385876A (en) Frovatriptan medicine composition and preparation method thereof
CN103301081B (en) A kind of Cefdinir dispersible tablet and preparation method thereof
CN115531327B (en) Irbesartan tablet and preparation method thereof
CN106265557A (en) Pharmaceutical composition containing ticagrelor
CN112691084B (en) Pharmaceutical composition and preparation method thereof
CN102106809B (en) Solid preparation of clopidogrel and preparation method thereof
CN110960501B (en) Norfloxacin capsule and preparation method thereof
CN102988372A (en) Screening and composition of main auxiliary materials of compound aspirin tablet, and preparation method of compound aspirin sheet
CN104414988B (en) A kind of Dasatinib tablet and its preparation process
CN112741819A (en) Fluoxetine hydrochloride capsule and preparation method thereof
CN103007286A (en) Solid medicine composition of tolvaptan
Peng et al. Data on the drug release profiles and powder characteristics of the ethyl cellulose based microparticles prepared by the ultra-fine particle processing system
JP2016536351A (en) Stable crystalline X-form agomelatine tablet and preparation method thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant