CN116549402A - Pirenpazide fine particle composition, preparation method and application - Google Patents
Pirenpazide fine particle composition, preparation method and application Download PDFInfo
- Publication number
- CN116549402A CN116549402A CN202310840588.0A CN202310840588A CN116549402A CN 116549402 A CN116549402 A CN 116549402A CN 202310840588 A CN202310840588 A CN 202310840588A CN 116549402 A CN116549402 A CN 116549402A
- Authority
- CN
- China
- Prior art keywords
- solution
- preparation
- lactose
- mannitol
- binder
- 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.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 239000010419 fine particle Substances 0.000 title claims abstract description 9
- 239000000853 adhesive Substances 0.000 claims abstract description 38
- 230000001070 adhesive effect Effects 0.000 claims abstract description 38
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 28
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 28
- 229930195725 Mannitol Natural products 0.000 claims abstract description 28
- 239000008101 lactose Substances 0.000 claims abstract description 28
- 239000000594 mannitol Substances 0.000 claims abstract description 28
- 235000010355 mannitol Nutrition 0.000 claims abstract description 28
- 239000011230 binding agent Substances 0.000 claims abstract description 25
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims abstract description 21
- 239000002994 raw material Substances 0.000 claims abstract description 16
- 239000000463 material Substances 0.000 claims abstract description 12
- 238000001035 drying Methods 0.000 claims abstract description 8
- 238000005469 granulation Methods 0.000 claims abstract description 6
- 230000003179 granulation Effects 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 28
- 239000002245 particle Substances 0.000 claims description 21
- 238000005086 pumping Methods 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 11
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 9
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 9
- 238000007873 sieving Methods 0.000 claims description 6
- 238000000889 atomisation Methods 0.000 claims description 5
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000009477 fluid bed granulation Methods 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 239000001961 anticonvulsive agent Substances 0.000 claims description 3
- 239000003086 colorant Substances 0.000 claims description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 3
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 3
- 229960003943 hypromellose Drugs 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 229940069328 povidone Drugs 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- 239000004408 titanium dioxide Substances 0.000 claims description 2
- 229960003965 antiepileptics Drugs 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 17
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 abstract description 7
- 229960004633 pirenzepine Drugs 0.000 abstract description 7
- 239000004480 active ingredient Substances 0.000 abstract description 6
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 4
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 37
- 238000009472 formulation Methods 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 11
- 230000006399 behavior Effects 0.000 description 9
- 239000008187 granular material Substances 0.000 description 7
- 239000013078 crystal Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000004503 fine granule Substances 0.000 description 6
- 238000011161 development Methods 0.000 description 5
- 235000019640 taste Nutrition 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000005550 wet granulation Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000004530 micro-emulsion Substances 0.000 description 4
- 239000006191 orally-disintegrating tablet Substances 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010013911 Dysgeusia Diseases 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 235000019629 palatability Nutrition 0.000 description 3
- 230000002572 peristaltic effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- MMWRGWQTAMNAFC-UHFFFAOYSA-N 1,2-dihydropyridine Chemical class C1NC=CC=C1 MMWRGWQTAMNAFC-UHFFFAOYSA-N 0.000 description 1
- 102000003678 AMPA Receptors Human genes 0.000 description 1
- 108090000078 AMPA Receptors Proteins 0.000 description 1
- 229940098747 AMPA receptor antagonist Drugs 0.000 description 1
- 239000000775 AMPA receptor antagonist Substances 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 235000020980 bad eating habits Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 230000001339 gustatory effect Effects 0.000 description 1
- 208000007386 hepatic encephalopathy Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 238000003475 lamination Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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
- A61K9/14—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
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pirenzepine fine particle composition, a preparation method and application. The raw materials of the composition comprise: pirenzeneb or a hydrate thereof, lactose, mannitol, a binder and a glidant; the mass ratio of lactose to mannitol is 1:3-3:1. The preparation method comprises preparing binder solution 1 from part of binder, preparing solution from the rest binder, and adding raw materials except mannitol and lactose into the solution to obtain binder solution 2; finally, mannitol and lactose are mixed as a base material, firstly, the adhesive solution 1 is pumped, then the adhesive solution 2 is pumped, and the mixture is subjected to fluidized bed granulation and drying to obtain the finished product. The lactose mannitol with a specific proportion and the preparation method are adopted, so that the active ingredient has dissolution behavior which is not inferior to that of a reference preparation, and particularly can be quickly and completely dissolved in an API indissolvable medium with pH of 4.0.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pirenzepine fine particle composition, a preparation method and application.
Background
The pirenzenenaphthalene is a high-selectivity and non-competitive AMPA receptor antagonist, can reduce the hyperexcitability of neurons related to epileptic seizures by targeted inhibition of the glutamate activity of postsynaptic membrane AMPA receptors, and has different action mechanisms with other antiepileptic drugs, so that the pirenzenenaphthalene can be combined with other common antiepileptic drugs to better control epileptic seizures.
The pirenzenepamine only has tablets on the market in China, but the granules have better compliance for epileptics and are convenient to take, so the invention is the pirenzenepamine fine granule which has stable product quality, reliable curative effect, reasonable dissolution rate and simple preparation process, and has great economic and social benefits.
The fine granule is a formulation developed in developed countries such as western europe and japan in the last 80 th century. According to the definition of Chinese pharmacopoeia 2020 edition, the granule is prepared by mixing the raw material medicines with proper auxiliary materials to prepare a dry granular preparation with certain granularity. Usually, the preparation method adopts dry granulation, wet granulation and other methods. The sum of the particles which cannot pass through the first sieve (2000 μm) and the particles which can pass through the fifth sieve (180 μm) is not more than 15% as determined by the particle size and particle size distribution determination method (general rule 0982 second double sieving method). According to the definition of Japanese pharmacopoeia (JP 18), fine granules are granules which pass through a 850 μm sieve and which have a material content of less than 10% retained on a 500 μm sieve. In japan, fine-grained formulations are generally developed using complex and expensive formulation equipment, and the process difficulty is extremely great.
Compared with the conventional dosage forms, the fine granule (1) is easy to swallow (compared with dry suspension, tablets, powder and the like); (2) the effect is rapid; (3) the dosage is easy to adjust; (4) easy to mix (compared to other dosage forms); (5) bitter taste suppression (compared with powder) and the like. Fine particles are a patient friendly formulation since they ensure compliance with the administration, especially welcome by patients who may have dysphagia (e.g. elderly and children).
The pirrennet fine granule is initially developed by a guard (Eisai) company, has very strict requirements on production equipment and production process, and has fine control of process parameters; laboratory techniques are also in the development stage, and industrial production is more difficult. The pH-solubility research of the pirenzenenaphthalene shows that the API dissolution has pH dependency, the dissolution is quick and complete in a pH1.2 hydrochloric acid solution, but the dissolution is slow in a weak acid or neutral medium, and the research of the original development agent of the product further shows that the original development product has quick dissolution of active ingredients in a pH1.2 hydrochloric acid solution and quick dissolution behavior in a pH4.0 acetate buffer solution and a pH6.8 phosphate buffer solution.
The prior art is mostly the development of compounds, crystalline forms, compositions, components, preparation methods and product applications. The Chinese patent application CN1942443A describes "crystals of 1, 2-dihydropyridine compounds and methods for producing the same", which are disclosed by the guard R & D management Co., ltd., and relates to a method for producing hydrate crystals and anhydrous crystal forms (I, III, V) and uses thereof (a therapeutic or prophylactic agent for epilepsy, hepatic encephalopathy, etc.).
The Chinese patent application CN104292153A describes a 'Pirenpananel crystal form A and a preparation method thereof' disclosed by Suzhou crystal cloud pharmaceutical technology Co., ltd, wherein the preparation method of the crystal form A is realized by dissolving solid of the Pirenpananel in a mixed solvent system of acetic acid and water, crystallizing by a slow volatilization or slow cooling method at room temperature.
In chinese patent application CN109106696a, "pirenzepine oral film and method for preparing the same" published by beijing primibos investment limited is described, which relates to a pirenzepine oral film comprising pirenzepine particles having a particle size (D90) of less than 35 μm, a film former and a disintegrant, and uses thereof: can be used for treating epilepsy.
The Chinese patent application CN106860409A describes a 'Pirenpananel orally disintegrating tablet and a preparation method thereof' disclosed by the Buddha Hongtai medicine research and development limited company, wherein the orally disintegrating tablet is a pharmaceutical composition containing Pirenpananel, a filler, a disintegrating agent, a wetting agent, an adhesive, a flavoring agent and a lubricant, and is prepared by adopting wet granulation and tabletting.
In Chinese patent applications CN105640900A and CN104644592A, "a pharmaceutical composition of pirenzenenaphthalene and a preparation method thereof", disclosed by Tianjin Han kang medical biotechnology Co., ltd, are described, wherein the pharmaceutical composition of pirenzenenaphthalene and different auxiliary materials is described, and the pharmaceutical composition is prepared by adopting a powder direct compression or wet granulation method.
The Chinese patent application CN106692106A describes a 'self-microemulsion preparation of pirenzenepamil and a preparation method thereof' disclosed by the drug development limited company of Hongtai in Buddha, and describes a method for forming the liquid self-microemulsion preparation from the pirenzenepamil, an oil phase, an emulsifying agent and a co-emulsifying agent, or further preparing the obtained liquid self-microemulsion preparation into a solid self-microemulsion preparation by the excipient.
In the chinese patent application CN104706604a, "a freeze-dried orally disintegrating tablet of pirenzenepamil and its preparation method" invented by beijing star pharmaceutical company limited is described, which describes that the freeze-dried orally disintegrating tablet of pirenzenepamil includes: 1 to 20 parts of framework propping agent, 1 to 50 parts of adhesive, 0.1 to 8 parts of freeze-drying protective agent and 2 to 12 parts of pirenzenepamil, and is prepared by a method of coating a film after freeze drying.
In the Chinese patent application CN105287411A, "a pirenzenene dispersible tablet and a preparation method thereof" disclosed by Meijis pharmaceutical (Xiamen) limited company, the method is described that the raw material medicine of the pirenzenene is required to be micronized, D90 is less than 50 mu m, preferably D90 is less than 10 mu m, and the raw material medicine is combined with other auxiliary materials and prepared by adopting a wet granulation method.
At present, the problems of prescriptions and processes for stable quality, consistent particle size distribution and dissolution behavior of the pirenzenepeanel fine granules with the original developing agent and industrial production are not solved yet.
Disclosure of Invention
In order to overcome the defects, the invention provides a pirenzepine fine particle composition, a preparation method and application.
The technical scheme adopted is as follows:
a fine particle composition of pirenzenepraline, the raw materials of which comprise: pirenzeneb or a hydrate thereof, lactose, mannitol, a binder and a glidant; the mass ratio of lactose to mannitol is 1:3-3:1.
Preferably, the raw materials of the composition comprise, in parts by weight: 0.5-2 parts of pirenzenenaphthalene or hydrate thereof, 20-60 parts of lactose, 20-60 parts of mannitol, 1-10 parts of adhesive and 0.1-2 parts of glidant.
Preferably, the binder is selected from at least one of povidone, hypromellose, hydroxypropyl cellulose, and polyethylene glycol.
Preferably, the binder is hydroxypropyl cellulose.
Preferably, the binder is 3-10 parts by weight of hydroxypropyl cellulose.
Preferably, the glidant is selected from silicon dioxide.
Preferably, the composition further comprises a colorant and a light shielding agent in parts by weight.
Preferably, the colorant is selected from yellow iron oxide and the light-shielding agent is selected from titanium dioxide.
It is still another object of the present invention to provide a method for preparing the above composition, comprising the steps of:
(1) Firstly, taking part of adhesive to prepare adhesive solution 1;
(2) Then the residual adhesive is prepared into a solution, and raw materials except mannitol and lactose are added into the solution to prepare an adhesive solution 2;
(3) Finally, mixing mannitol and lactose as a base material, pumping into a binder solution 1, performing fluidized bed granulation, pumping into a binder solution 2, continuously performing fluidized bed granulation, and drying to obtain the finished product.
Preferably, the part in the step (1) is 45-55%, the mass concentration of the binder solution 1 is 1.4-1.6%, and the mass concentration of the solution in the step (2) is 2.8-3.2%.
Preferably, the initial pump speed is 8-16rpm when the binder solution 1 is pumped in step (3), and then 5rpm is increased every 10min until it remains unchanged after 35-42 rpm.
Preferably, the process parameters of the two fluid bed granulation in step (3) include: air inlet temperature: 55-65 ℃, the temperature of a heater is 80-100 ℃, the frequency of a fan is 20-28Hz, the atomization pressure is 0.10-0.20mPa, and the temperature of the bed charge in the fluidized bed is 28-32 ℃.
Preferably, the process parameters of the drying in step (3) include: the fan frequency is 28-35Hz, and the heater temperature is 65-75 ℃.
Preferably, the particles dried in the step (3) are obtained by sieving with a 450-550 μm sieve.
It is a further object of the present invention to provide the use of the above composition or method of preparation for the preparation of a medicament for the treatment of epilepsy.
Compared with the prior art, the invention has the positive beneficial effects that:
(1) The invention adopts lactose and mannitol with specific proportion, so that the active ingredients have dissolution behavior which is not inferior to that of the reference preparation, and particularly the active ingredients are quickly and completely dissolved in the pH4.0 medium with indissolvable API.
(2) The invention adopts the hydroxypropyl cellulose as the adhesive, and the dosage is in a reasonable range, which is helpful for the rapid and complete dissolution of the API, and the taste is better by adopting the proper raw material dosage.
(3) The invention adopts a specific granulating process and a unique laminated step-by-step granulating mode, and uses adhesive solutions with different concentrations to granulate for two times, wherein the first 3% adhesive solution solves the problem that powder is not easy to fluidize, and the second 1.5% adhesive solution solves the problems of fine particle forming and medicine lamination; the choice of the particular binder solution ensures that the cascade granulation of the layer is carried out. Compared with the conventional fine granule, the self-developing agent can be easily prepared by adopting complicated and expensive imported special granulating equipment and selecting the traditional fluidized bed equipment based on process innovation, has lower production cost and is easy to be commercialized and implemented.
Detailed Description
The present invention will be described in further detail with reference to the following examples, which are not intended to limit the present invention, but are merely illustrative of the present invention. The experimental methods used in the following examples are not specifically described, but the experimental methods in which specific conditions are not specified in the examples are generally carried out under conventional conditions, and the materials, reagents, etc. used in the following examples are commercially available unless otherwise specified.
The prescription compositions of examples 1-3 and comparative example 1 are shown in Table 1 below:
TABLE 1
The preparation method of example 1 is as follows:
(1) Adding water into 50% of adhesive to prepare an adhesive solution 1 with the mass concentration of 1.5%;
(2) Preparing the residual adhesive into a solution with the mass concentration of 3%, adding raw materials except mannitol and lactose into the solution, and continuously stirring until the mixture is uniformly suspended to prepare an adhesive solution 2;
(3) Mannitol and lactose were used as primers: granulating by using DPL-II type fluidized bed of Chongqing fine worker, and setting parameters as follows: air inlet temperature: placing lactose and mannitol in a fluidized bed for granulating when the temperature of the material is 30 ℃ and the temperature of a heater is 60 ℃, the temperature of the heater is 90 ℃, the frequency of a fan is 25Hz, the atomization pressure is 0.15mPa, and the temperature of the preheated fluidized bed is shown as 30 ℃;
(4) Setting the peristaltic pump at 8rpm, starting granulating, pumping the adhesive solution 1, increasing the initial pump speed to 12rpm every 10min, increasing the speed to 5rpm, keeping the speed constant after the speed is 38rpm, keeping the equipment parameters constant after the pumping is finished, and continuously pumping the adhesive solution 2 until the pumping is finished.
(5) Raising the frequency of a fan to 30Hz, setting the temperature of a heater to 70 ℃, starting drying until the LOD of the particles is less than or equal to 1.0%, and sieving the particles obtained after granulating by a 500 mu m screen.
The preparation method of example 2 is as follows:
(1) Adding water into 50% of adhesive to prepare an adhesive solution 1 with the mass concentration of 1.5%;
(2) Preparing the residual adhesive into a solution with the mass concentration of 3%, adding raw materials except mannitol and lactose into the solution, and continuously stirring until the mixture is uniformly suspended to prepare an adhesive solution 2;
(3) Mannitol and lactose were used as primers: granulating by using DPL-II type fluidized bed of Chongqing fine worker, and setting parameters as follows: air inlet temperature: the method comprises the steps of (1) preheating a fluidized bed to a material temperature of about 28 ℃ when the temperature of a heater is 60 ℃, the temperature of the heater is 80 ℃, the frequency of a fan is 28Hz, the atomization pressure is 0.20mPa, and placing lactose and mannitol in the fluidized bed for granulating;
(4) Setting the peristaltic pump at 8rpm, starting granulating, pumping the adhesive solution 1, increasing the initial pump speed to 8rpm every 10min, increasing the speed to 5rpm, keeping the speed constant after the speed is 35rpm, keeping the equipment parameters unchanged after the pumping is finished, and continuously pumping the adhesive solution 2 until the pumping is finished.
(5) Raising the frequency of a fan to 28Hz, setting the temperature of a heater to 70 ℃, starting drying until the LOD of the particles is less than or equal to 1.0%, and sieving the particles obtained after granulating by a 500 mu m screen.
The preparation method of example 3 is as follows:
(1) Adding water into 50% of adhesive to prepare an adhesive solution 1 with the mass concentration of 1.5%;
(2) Preparing the residual adhesive into a solution with the mass concentration of 3%, adding raw materials except mannitol and lactose into the solution, and continuously stirring until the mixture is uniformly suspended to prepare an adhesive solution 2;
(3) Mannitol and lactose were used as primers: granulating by using DPL-II type fluidized bed of Chongqing fine worker, and setting parameters as follows: air inlet temperature: placing lactose and mannitol in a fluidized bed for granulating when the temperature of the material is 32 ℃ and the temperature of the material is 60 ℃ and the temperature of a heater is 100 ℃, the frequency of a fan is 20Hz, the atomization pressure is 0.10mPa, and preheating the fluidized bed;
(4) Setting the peristaltic pump at 8rpm, starting granulating, pumping the adhesive solution 1, increasing the initial pump speed to 16rpm every 10min, increasing the speed to 5rpm, keeping the speed constant after the speed is 42rpm, keeping the equipment parameters constant after the pumping is finished, and continuously pumping the adhesive solution 2 until the pumping is finished.
(5) Raising the frequency of a fan to 35Hz, setting the temperature of a heater to 70 ℃, starting drying until the LOD of the particles is less than or equal to 1.0%, and sieving the particles obtained after granulating by a 500 mu m screen.
Comparative example 1 was prepared in the same manner as in example 1.
The granules obtained in examples 1-3 and comparative example 1 were subjected to an tasting experiment to evaluate the palatability of the active ingredient, the relevant experiment and results being as follows:
experiment design: each of 9 healthy male and female subjects (no bad eating habits such as smoking, drinking, etc.) tasted the above-mentioned 4 kinds of particles with different content of pirenzepine, and each sample was subjected to evaluation of the next sample after rinsing with clear water at 1 hour interval after tasting. A scoring table is designed for the taste of the product, and the scoring table is divided into very bad taste (0 score), bad taste (0-20 score), bad taste (20-50 score), good taste (50-80 score) and very good taste (80-100 score) and the taste description type gustatory vocabulary is selected for statistics.
(3) The results of the study are summarized in table 2 below:
TABLE 2
Conclusion: it can be seen from experiments that examples 1,2,3 all have good palatability, which represents acceptable palatability of the formulation at an active ingredient ratio of 0.5-2% in the formulation, preferably 1%, more suitable for development as target product particles.
Examples 4-6 and comparative example 2 were formulated as follows in table 3:
TABLE 3 Table 3
Based on the dissolution behavior of the self-grinding formulation and the reference formulation RLD tested in highly differential ph4.0 medium, the product dissolution behavior was evaluated with a similar factor f2, with the results as shown in table 4 below:
TABLE 4 Table 4
As can be seen from the dissolution behavior, the composition of the invention, in a medium at ph4.0, when lactose and mannitol ratio is at 1:3-3: within 1, the product dissolves rapidly, similar to the reference formulation, with lactose: mannitol = 48.25:46.60 the similarity factor is highest. Lactose and mannitol ratio to 1:5, the product is difficult to dissolve completely.
Examples 7 to 13
The prescription is shown in Table 5.
TABLE 5
Dissolution behavior in pH4.0 medium compared to the reference formulation, with the reference formulation as an evaluation index, the results are shown in Table 6 below:
TABLE 6
From the dissolution behavior, it can be seen that, in the binder category, polyethylene glycol, hypromellose, povidone and hydroxypropyl cellulose are selected to give a dissolution behavior of the self-grinding product similar to that of the reference formulation (f 2 > 50) at a level of 3%, wherein the hydroxypropyl cellulose is preferably fitted to the dissolution in a range of 1-10%, in particular in a range of 3-5%. Therefore, the binder type is preferably hydroxypropyl cellulose, and the amount is 3-5%.
Example 1 and comparative examples 3 to 7
Comparative examples 3-7 were prepared in the same manner as in example 1 and the preparation method is shown in Table 7.
TABLE 7
The particle size results obtained are given in Table 8 below:
TABLE 8
The raw materials used in comparative examples 3 to 7 were the same as in example 1 except that the preparation process was different, the dry granulation was used in comparative example 3, the wet granulation was used in comparative example 4, the single binder solvents of different mass concentrations were used in comparative examples 5 to 6 for fluid bed granulation, and the mass concentration of the binder solution of comparative example 7 was not within the appropriate range. From the particle size distribution data, it can be seen that when the fluid bed granulation process of the present invention is used, the mass concentration of the binder solution 1 and the binder solution 2 is within a suitable range to meet the fine granule requirements, and the specific layered layer-by-layer granulation of the present invention has the particle size closest to that of the reference formulation and the particle size is the most excellent.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (13)
1. A fine particle composition of pirenzeneb characterized in that the raw materials of the composition comprise: pirenzeneb or a hydrate thereof, lactose, mannitol, a binder and a glidant; the mass ratio of lactose to mannitol is 1:3-3:1.
2. The composition according to claim 1, wherein the raw materials of the composition comprise, in parts by weight: 0.5-2 parts of pirenzenenaphthalene or hydrate thereof, 20-60 parts of lactose, 20-60 parts of mannitol, 1-10 parts of adhesive and 0.1-2 parts of glidant.
3. The composition of claim 2, wherein the binder is selected from at least one of povidone, hypromellose, hydroxypropyl cellulose, and polyethylene glycol.
4. The composition according to claim 2, wherein the binder is 3-10 parts by weight of hydroxypropyl cellulose.
5. The composition according to any one of claims 1 to 4, wherein the glidant is selected from the group consisting of silicon dioxide.
6. The composition according to any one of claims 1 to 4, further comprising a colorant selected from the group consisting of iron oxide yellow and a light-shielding agent selected from the group consisting of titanium dioxide, in parts by weight.
7. A process for the preparation of a composition as claimed in any one of claims 1 to 6, comprising the steps of:
(1) Firstly, taking part of adhesive to prepare adhesive solution 1;
(2) Then the residual adhesive is prepared into a solution, and raw materials except mannitol and lactose are added into the solution to prepare an adhesive solution 2;
(3) Finally, mannitol and lactose are mixed as a base material, firstly, the adhesive solution 1 is pumped, then the adhesive solution 2 is pumped, and the mixture is subjected to fluidized bed granulation and drying to obtain the finished product.
8. The preparation method according to claim 7, wherein the part in the step (1) is 45-55%, the mass concentration of the binder solution 1 is 1.4-1.6%, and the mass concentration of the solution in the step (2) is 2.8-3.2%.
9. The preparation method according to claim 7, wherein the initial pumping speed is 8-16rpm when the binder solution 1 is pumped in step (3), and then 5rpm is increased every 10min until it is maintained after 35-42 rpm.
10. The method of claim 7, wherein the process parameters of fluid bed granulation in step (3) include: air inlet temperature: 55-65 ℃, the temperature of a heater is 80-100 ℃, the frequency of a fan is 20-28Hz, the atomization pressure is 0.10-0.20mPa, and the temperature of the bed charge in the fluidized bed is 28-32 ℃.
11. The method of claim 7, wherein the process parameters of the drying in step (3) include: the fan frequency is 28-35Hz, and the heater temperature is 65-75 ℃.
12. The method according to claim 7, wherein the dried particles in the step (3) are obtained by sieving with a 450-550 μm sieve.
13. Use of a composition according to any one of claims 1 to 6 or a method of preparation according to any one of claims 7 to 12 for the preparation of an antiepileptic drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310840588.0A CN116549402B (en) | 2023-07-11 | 2023-07-11 | Pirenpazide fine particle composition, preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310840588.0A CN116549402B (en) | 2023-07-11 | 2023-07-11 | Pirenpazide fine particle composition, preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116549402A true CN116549402A (en) | 2023-08-08 |
| CN116549402B CN116549402B (en) | 2023-09-19 |
Family
ID=87493269
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310840588.0A Active CN116549402B (en) | 2023-07-11 | 2023-07-11 | Pirenpazide fine particle composition, preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116549402B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105287411A (en) * | 2015-09-22 | 2016-02-03 | 美吉斯制药（厦门）有限公司 | Perampanel dispersible tablet and preparation method thereof |
| CN105640900A (en) * | 2014-11-11 | 2016-06-08 | 天津市汉康医药生物技术有限公司 | Perampanel medicinal composition |
| WO2016172333A1 (en) * | 2015-04-21 | 2016-10-27 | Teva Pharmaceuticals International Gmbh | A solid state form of perampanel |
| CN106389367A (en) * | 2016-11-16 | 2017-02-15 | 杭州朱养心药业有限公司 | Perampanel coated tablet pharmaceutical composition |
| US20170173039A1 (en) * | 2014-04-02 | 2017-06-22 | Yale University | Compositions and methods to treat addiction |
-
2023
- 2023-07-11 CN CN202310840588.0A patent/CN116549402B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170173039A1 (en) * | 2014-04-02 | 2017-06-22 | Yale University | Compositions and methods to treat addiction |
| CN105640900A (en) * | 2014-11-11 | 2016-06-08 | 天津市汉康医药生物技术有限公司 | Perampanel medicinal composition |
| WO2016172333A1 (en) * | 2015-04-21 | 2016-10-27 | Teva Pharmaceuticals International Gmbh | A solid state form of perampanel |
| CN105287411A (en) * | 2015-09-22 | 2016-02-03 | 美吉斯制药（厦门）有限公司 | Perampanel dispersible tablet and preparation method thereof |
| CN106389367A (en) * | 2016-11-16 | 2017-02-15 | 杭州朱养心药业有限公司 | Perampanel coated tablet pharmaceutical composition |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116549402B (en) | 2023-09-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI795462B (en) | Pharmaceutical preparation excellent in light stability and dissolution property | |
| CN102905707A (en) | Pharmaceutical preparation comprising phenylalanine derivative | |
| CN105193763B (en) | A kind of hydrobromic acid Vortioxetine piece and preparation method thereof | |
| CN103393617B (en) | Febustat tablet and preparation method thereof | |
| EP3733167A1 (en) | Novel fine particle coating (drug-containing hollow particle and method for manufacturing same) | |
| TWI788557B (en) | Solid dosage form having excellent stability | |
| CN104523686A (en) | Acotiamide hydrochloride medicinal preparation and preparation method thereof | |
| CN102228450B (en) | Nicergoline capsule and production method thereof | |
| CN116549402B (en) | Pirenpazide fine particle composition, preparation method and application | |
| JPWO2012036078A1 (en) | Drug-containing film-coated particles with unpleasant taste masked | |
| CN114129528B (en) | Novel sildenafil citrate preparation with clinical advantages and preparation process and application thereof | |
| TWI344376B (en) | Pharmaceutical composition having improved solubility and fluidity | |
| CN109700773B (en) | Ticagrelor preparation composition and preparation method thereof | |
| KR101761983B1 (en) | Fast dissolving oral thin film composite and preparing method thereof | |
| CN107080741A (en) | Pirfenidone sustained release preparation and preparation method | |
| CN105287412A (en) | Aripiprazole dispersible tablet and preparation method thereof | |
| CN113041231A (en) | Tebipenem pivoxil fine granule composition and preparation method thereof | |
| CN107613978B (en) | Pharmaceutical composition of mek inhibitor and preparation method thereof | |
| CN104337783B (en) | A kind of capecitabine tablet and preparation method thereof | |
| CN113599366B (en) | Tenofovir disoproxil fumarate granules and preparation method thereof | |
| CN106913535A (en) | A kind of DDP-4 inhibitor medicaments oral disintegrating tablet and preparation method thereof | |
| WO2022042646A1 (en) | Lurasidone hydrochloride composition and preparation method therefor | |
| CN112704740B (en) | Montelukast resin compound and preparation method and application thereof | |
| CN117695255A (en) | Production process of loratadine oral instant film agent | |
| CN117442573A (en) | Eszopiclone pharmaceutical composition |
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 | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20231024 Address after: 201815 building 16, No. 66, Huiyuan Road, Jiading District, Shanghai Patentee after: Zezheng (Shanghai) Biotechnology Co.,Ltd. Patentee after: SHANDONG HI-QUAL PHARMATECH CO.,LTD. Address before: Floor 4, Building D, Biomedical Innovation Park, No. 1, Lutai Avenue, High tech Zone, Zibo City, Shandong Province 255,035 Patentee before: SHANDONG HI-QUAL PHARMATECH CO.,LTD. |
|
| CP03 | Change of name, title or address |
Address after: 201815 building 16, No. 66, Huiyuan Road, Jiading District, Shanghai Patentee after: Shanghai Zezheng Pharmaceutical Technology Co.,Ltd. Country or region after: China Patentee after: SHANDONG HI-QUAL PHARMATECH CO.,LTD. Address before: 201815 building 16, No. 66, Huiyuan Road, Jiading District, Shanghai Patentee before: Shanghai Zezheng Biopharmaceutical Co.,Ltd. Country or region before: China Patentee before: SHANDONG HI-QUAL PHARMATECH CO.,LTD. Address after: 201815 building 16, No. 66, Huiyuan Road, Jiading District, Shanghai Patentee after: Shanghai Zezheng Biopharmaceutical Co.,Ltd. Country or region after: China Patentee after: SHANDONG HI-QUAL PHARMATECH CO.,LTD. Address before: 201815 building 16, No. 66, Huiyuan Road, Jiading District, Shanghai Patentee before: Zezheng (Shanghai) Biotechnology Co.,Ltd. Country or region before: China Patentee before: SHANDONG HI-QUAL PHARMATECH CO.,LTD. |