CN116370417A - Rasagiline granule composition and pharmaceutical composition thereof - Google Patents
Rasagiline granule composition and pharmaceutical composition thereof Download PDFInfo
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- CN116370417A CN116370417A CN202111580047.6A CN202111580047A CN116370417A CN 116370417 A CN116370417 A CN 116370417A CN 202111580047 A CN202111580047 A CN 202111580047A CN 116370417 A CN116370417 A CN 116370417A
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- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 title claims abstract description 27
- 229960000245 rasagiline Drugs 0.000 title claims abstract description 26
- 239000008202 granule composition Substances 0.000 title claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 6
- 239000000203 mixture Substances 0.000 claims abstract description 29
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000002245 particle Substances 0.000 claims abstract description 14
- 238000009478 high shear granulation Methods 0.000 claims abstract description 13
- 239000000314 lubricant Substances 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims abstract description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- 238000001035 drying Methods 0.000 claims abstract description 6
- 239000008213 purified water Substances 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 239000000080 wetting agent Substances 0.000 claims abstract description 5
- 238000003825 pressing Methods 0.000 claims abstract description 4
- 239000011230 binding agent Substances 0.000 claims description 7
- 239000008187 granular material Substances 0.000 claims description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 5
- 229920002261 Corn starch Polymers 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- 235000021355 Stearic acid Nutrition 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 239000008120 corn starch Substances 0.000 claims description 4
- 238000005520 cutting process Methods 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 4
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 239000008117 stearic acid Substances 0.000 claims description 4
- 239000000454 talc Substances 0.000 claims description 4
- 235000012222 talc Nutrition 0.000 claims description 4
- 229910052623 talc Inorganic materials 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 239000005426 pharmaceutical component Substances 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 239000003833 bile salt Substances 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000001506 calcium phosphate Substances 0.000 claims description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 2
- 235000011010 calcium phosphates Nutrition 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- 239000002738 chelating agent Substances 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 2
- 239000003623 enhancer Substances 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- -1 medium chain fatty acid salt Chemical class 0.000 claims description 2
- 239000003961 penetration enhancing agent Substances 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 229940069328 povidone Drugs 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims 2
- 229920002785 Croscarmellose sodium Polymers 0.000 claims 1
- 229960001681 croscarmellose sodium Drugs 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000000853 adhesive Substances 0.000 abstract description 5
- 230000001070 adhesive effect Effects 0.000 abstract description 5
- XJEVHMGJSYVQBQ-UHFFFAOYSA-N 2,3-dihydro-1h-inden-1-amine Chemical compound C1=CC=C2C(N)CCC2=C1 XJEVHMGJSYVQBQ-UHFFFAOYSA-N 0.000 abstract description 3
- 230000015556 catabolic process Effects 0.000 abstract description 2
- 238000006731 degradation reaction Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 17
- JDBJJCWRXSVHOQ-UTONKHPSSA-N methanesulfonic acid;(1r)-n-prop-2-ynyl-2,3-dihydro-1h-inden-1-amine Chemical compound CS(O)(=O)=O.C1=CC=C2[C@H](NCC#C)CCC2=C1 JDBJJCWRXSVHOQ-UTONKHPSSA-N 0.000 description 9
- 229960001956 rasagiline mesylate Drugs 0.000 description 9
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 230000001133 acceleration Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000007596 consolidation process Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000017 mucous membrane irritation Toxicity 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Images
Classifications
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a rasagiline granule composition and a pharmaceutical composition thereof, the preparation method of the composition comprises the following steps of mixing rasagiline or medicinal salt thereof, microcrystalline cellulose, a disintegrating agent, an adhesive and other excipients to obtain a mixture, carrying out high-shear wet granulation on the mixture by taking purified water as a wetting agent, drying to obtain the granule composition, or further mixing with a lubricant and pressing into tablets to obtain the pharmaceutical composition; the obtained tablet has good stability, and particularly, the content of main degradation impurities of 1-aminoindan and total impurities of rasagiline is obviously reduced; the obtained particles have better fluidity and higher bulk density, can improve commercial production batch, and have more advantages in production efficiency; the process is simple to operate, the process is easy to control, and the method is more suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a rasagiline composition and a preparation method thereof.
Background
Rasagiline has the chemical name of (1R) -2, 3-dihydro-N-2-propynyl-1H-inden-1-amine, and the structural formula is shown in formula I:
rasagiline mesylate tablets are suitable for monotherapy in primary parkinson's disease patients and for combination therapy (in combination with levodopa) in patients with agent-end fluctuations. When in use, the time of the off state can be obviously shortened, exhibit good tolerability.
The stability of rasagiline formulations remains a problem, and research and development of new rasagiline formulations to improve the quality of formulations have been carried out in the pharmaceutical community.
CN105496979 discloses a rasagiline preparation and a preparation method thereof, and a specific adhesive and a specific process are adopted to produce a product with stable quality. Wherein the adhesive is hydroxypropyl cellulose, EDTA-2Na and microcrystalline cellulose. And meanwhile, the rasagiline pharmaceutically acceptable salt is directly dissolved in the adhesive solution for preparation.
CN107753446 discloses a rasagiline preparation and a preparation method thereof, and polyethylene glycol aqueous solution with the concentration of 0.1% -30% is adopted as wetting agent for wet granulation, thereby improving the long-term stability of the product and the like. Wherein the polyethylene glycol has a molecular weight of 400-8000. However, polyethylene glycol with molecular weight lower than 2000 is easy to absorb moisture and has certain mucous membrane irritation; polyethylene glycol of high molecular weight can increase the effectiveness of the tablet binder, affecting the granule plasticity.
In the development process of the product, the inventor surprisingly found that the prepared product has good preparation stability and good particle fluidity and is suitable for industrial mass production by selecting microcrystalline cellulose as a filler and adopting a high-shear wet granulation process.
Disclosure of Invention
The invention aims to solve the technical problem of providing a rasagiline composition and a preparation method thereof, and a finished product of the rasagiline composition has the characteristics of simple prescription, easy operation, low cost and good stability.
In one aspect, the invention provides a rasagiline particle composition, characterized in that the particle composition consists of the following pharmaceutical components in weight percent:
the preparation method of the particle composition is characterized by comprising the following steps:
1) Mixing rasagiline or its medicinal salt, microcrystalline cellulose, disintegrating agent, binder and other excipient to obtain mixture;
2) Performing high-shear wet granulation and drying on the mixture obtained in the previous step by taking purified water as a wetting agent to obtain dry granules; wherein the rotation speed of the stirring paddle of the high-shear wet granulation method is 50-1000rpm, and the rotation speed of the cutting knife is 0-3000rpm.
In another aspect, the present invention also provides a pharmaceutical composition of rasagiline, which can be further mixed with a lubricant by the granular composition provided by the present invention, and compressed into tablets.
Preferably, the binder is selected from one or more of pregelatinized starch, povidone (PVP), hypromellose (HPMC), sodium carboxymethylcellulose (CMC-Na), more preferably pregelatinized starch.
Preferably, the lubricant is selected from one or more of sodium stearyl fumarate, hydrogenated castor oil, stearic acid, talc and magnesium stearate, preferably one or more of stearic acid and talc.
Preferably, the disintegrating agent is selected from one or more of corn starch, crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, and sodium croscarmellose, preferably corn starch.
Preferably, the other excipients are selected from one or more of glidants and permeation enhancers; wherein the glidant is selected from one or more of micropowder silica gel, talcum powder and calcium phosphate, and the penetration enhancer is selected from one or more of medium-chain fatty acid salt, bile salt and chelating agent.
Preferably, the rasagiline accounts for 0.7-2.5% of the total tablet weight, the microcrystalline cellulose accounts for 70-80% of the total tablet weight, the disintegrating agent accounts for 8-11% of the total tablet weight, the adhesive accounts for 8-11% of the total tablet weight, the lubricant accounts for 2-4% of the total tablet weight, and the other excipients account for 0.3-0.7% of the total tablet weight.
Preferably, the high shear wet granulation process described in the preparation of the composition is carried out with a stirring paddle rotation of 70-800rpm and a cutter rotation of 1000-2500rpm.
The invention has the positive progress effects that:
1. the tablet disclosed by the invention has very good stability, and particularly, the content of main degradation impurities of 1-aminoindane and total impurities of rasagiline is obviously reduced.
2. The particles prepared by the process have good fluidity and higher bulk density, can improve commercial production batch, and has higher production efficiency.
3. The tablet of the invention adopts a conventional high-shear wet granulation process, has simple operation and easy control of the process, and is more suitable for industrial production. And common and conventional pharmaceutic adjuvants are adopted, so that the cost is low, and the preparation method has commercial competitive advantages.
Description of the drawings:
FIG. 1 is a comparison of the flow function curves for dry particles of example 2 and comparative example 4, with the resultant consolidation force on the abscissa and the breaking strength on the ordinate, with the greater slope of the curve and poorer flowability of the particles.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments and the scope of the present invention are not limited thereto.
The amount of rasagiline mesylate used in the examples below was 1.56mg rasagiline mesylate, based on rasagiline, corresponding to approximately 1mg rasagiline mesylate.
Example 1:
example 1 rasagiline tablets were prepared as follows:
all auxiliary materials except the lubricant are uniformly mixed with rasagiline mesylate, purified water is added in a mixed state for high-shear wet granulation, the rotation speed of a stirring paddle is 500rpm, and the rotation speed of a cutting knife is 2000rpm. Drying the wet granules, granulating by a screen, adding a lubricant, uniformly mixing, and finally pressing the granules into tablets to obtain the rasagiline mesylate tablet finished product.
Example 1 the raw materials and proportions are shown in table 1 (unit: g):
table 1:
example 2:
example 2 using a high shear granulation process, the inner granulation section was granulated with the drug-containing solution in a mixed state, dried, then the outer granulation section was added and mixed well, and compressed into tablets.
Table 2:
comparative examples:
the preparation method of comparative examples 1 to 3 is the same as that of example 1
Comparative example 1 the raw materials and proportions are shown in table 3:
table 3:
comparative example 2 the raw materials and proportions are shown in table 4:
table 4:
comparative example 3 the raw materials and proportions are shown in table 5:
table 5:
comparative example 4:
comparative example 4 a fluid bed top spray granulation process was used. Dissolving rasagiline mesylate in purified water to prepare a drug solution, fully mixing an inner granulating part, performing fluid-bed top-spraying granulation, drying, adding an outer granulating part, uniformly mixing, and finally pressing into tablets.
Table 6:
example 1 and comparative examples 1-3 content and related substance stability investigation
1. Sample acceleration conditions: the finished products obtained in example 1 and comparative examples 1 to 3 were double-aluminum-packed, and the content of active ingredients and the percentage of impurities (%) were measured by an external standard method after being placed in a constant temperature and humidity box under forced acceleration conditions (60 ℃ + -2 ℃;75% + -5%) for 10 days.
The forced acceleration results of the examples are shown in Table 7:
table 7:
from the results, after the forced acceleration experiment is carried out for 10 days, the total impurity amount of the rasagiline mesylate tablet finished product prepared in the example 1 is less than or equal to 1.5 percent, and the 1-aminoindane amount of the main metabolite is less than or equal to 0.5 percent; the stability was better than in comparative examples 1-3. Therefore, the rasagiline mesylate tablet obtained according to the technical scheme of the invention can effectively control the impurity limit, has higher preparation stability and meets the requirements of relevant clinical medication regulations.
Example 2 comparison of particle Properties with comparative example 4
Taking mixed particles of the example 2 and the comparative example 4, carrying out flowability test by adopting a PET powder flow tester, drawing a rheological function, and comparing the flowability of the mixed particles; and simultaneously detecting the bulk density of the mixed particles. The results are shown in FIG. 1 and Table 8:
TABLE 8
| Examples | Bulk density/g.cm -3 | Flow index |
| Example 2 | 0.456 | 0.06 |
| Comparative example 4 | 0.398 | 0.11 |
FIG. 1 shows a flow function diagram of example 2 and comparative example 4. The abscissa represents the consolidation force, the ordinate represents the breaking strength, and the larger the slope of the curve is, the worse the fluidity of the particles is.
As can be seen from the results of fig. 1 and 8, the flowability of example 2 is superior to that of comparative example 4, and the bulk density is greater than that of comparative example 4, which is more advantageous in commercial production.
While the invention has been described with respect to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (8)
1. A rasagiline granule composition, characterized in that the granule composition consists of the following pharmaceutical components in weight percent:
the preparation method of the particle composition is characterized by comprising the following steps:
1) Mixing rasagiline or its medicinal salt, microcrystalline cellulose, disintegrating agent, binder and other excipient to obtain mixture;
2) Performing high-shear wet granulation and drying on the mixture obtained in the previous step by taking purified water as a wetting agent to obtain dry granules;
wherein the rotation speed of the stirring paddle of the high-shear wet granulation method is 50-1000rpm, and the rotation speed of the cutting knife is 0-3000rpm.
2. The rasagiline pharmaceutical composition is characterized by comprising the following pharmaceutical components in percentage by weight:
the preparation method of the composition is characterized by comprising the following steps:
1) Mixing rasagiline or its medicinal salt, microcrystalline cellulose, disintegrating agent, binder and other excipient to obtain mixture;
2) Performing high-shear wet granulation and drying on the mixture obtained in the previous step by taking purified water as a wetting agent to obtain dry granules;
3) Mixing the dry granules obtained in the previous step with a lubricant, and pressing into tablets;
wherein the rotation speed of the stirring paddle of the high-shear wet granulation method is 50-1000rpm, and the rotation speed of the cutting knife is 0-3000rpm.
3. Composition according to claim 1 or 2, wherein the binder is selected from one or more of pregelatinized starch, povidone (PVP), hypromellose (HPMC), sodium carboxymethylcellulose (CMC-Na), preferably pregelatinized starch.
4. A composition according to claim 1 or 2, wherein the lubricant is selected from one or more of sodium stearyl fumarate, hydrogenated castor oil, stearic acid, talc and magnesium stearate, preferably one or more of stearic acid, talc.
5. Composition according to claim 1 or 2, wherein the disintegrant is selected from one or more of corn starch, crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, croscarmellose sodium (CCMC-Na), preferably corn starch.
6. The composition according to claim 1 or 2, wherein the other excipients are selected from one or more of glidants, permeation enhancers; wherein the glidant is selected from one or more of micropowder silica gel, talcum powder and calcium phosphate; the penetration enhancer is one or more selected from medium chain fatty acid salt, bile salt and chelating agent.
7. The composition according to claim 1 or 2, wherein the rasagiline is present in an amount of 0.7 to 2.5% by weight of the total tablet, the microcrystalline cellulose is present in an amount of 70 to 80% by weight of the total tablet, the disintegrant is present in an amount of 8 to 11% by weight of the total tablet, the binder is present in an amount of 8 to 11% by weight of the total tablet, the lubricant is present in an amount of 2 to 4% by weight of the total tablet, and the other excipients are present in an amount of 0.3 to 0.7% by weight of the total tablet.
8. Composition according to claim 1 or 2, characterized in that the high shear wet granulation is carried out in the preparation of the composition with a stirring paddle rotation of 70-800rpm and a cutter rotation of 1000-2500rpm.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111580047.6A CN116370417A (en) | 2021-12-22 | 2021-12-22 | Rasagiline granule composition and pharmaceutical composition thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111580047.6A CN116370417A (en) | 2021-12-22 | 2021-12-22 | Rasagiline granule composition and pharmaceutical composition thereof |
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| CN116370417A true CN116370417A (en) | 2023-07-04 |
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