CN113750070A - Phencyclamate dimedone capsule - Google Patents
Phencyclamate dimedone capsule Download PDFInfo
- Publication number
- CN113750070A CN113750070A CN202010504385.0A CN202010504385A CN113750070A CN 113750070 A CN113750070 A CN 113750070A CN 202010504385 A CN202010504385 A CN 202010504385A CN 113750070 A CN113750070 A CN 113750070A
- Authority
- CN
- China
- Prior art keywords
- phenmetyl
- capsule
- mannitol
- sulfonic acid
- microcrystalline cellulose
- 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.)
- Pending
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- 239000002775 capsule Substances 0.000 title claims abstract description 36
- BADXJIPKFRBFOT-UHFFFAOYSA-N dimedone Chemical compound CC1(C)CC(=O)CC(=O)C1 BADXJIPKFRBFOT-UHFFFAOYSA-N 0.000 title claims description 18
- 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 46
- 229930195725 Mannitol Natural products 0.000 claims abstract description 36
- 239000000594 mannitol Substances 0.000 claims abstract description 36
- 235000010355 mannitol Nutrition 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000009826 distribution Methods 0.000 claims abstract description 9
- 108010010803 Gelatin Proteins 0.000 claims abstract description 3
- 239000008273 gelatin Substances 0.000 claims abstract description 3
- 229920000159 gelatin Polymers 0.000 claims abstract description 3
- 235000019322 gelatine Nutrition 0.000 claims abstract description 3
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 3
- 239000011812 mixed powder Substances 0.000 claims abstract description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 29
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 28
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 28
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 28
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 28
- 239000000945 filler Substances 0.000 claims description 14
- 238000011049 filling Methods 0.000 claims description 13
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
- 239000000835 fiber Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 23
- 238000004090 dissolution Methods 0.000 abstract description 17
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 abstract description 10
- 239000002245 particle Substances 0.000 abstract description 9
- 235000019359 magnesium stearate Nutrition 0.000 abstract description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 abstract 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 abstract 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 abstract 1
- 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 abstract 1
- 230000000052 comparative effect Effects 0.000 description 32
- 239000002994 raw material Substances 0.000 description 16
- 238000002156 mixing Methods 0.000 description 14
- 239000007903 gelatin capsule Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 239000011265 semifinished product Substances 0.000 description 8
- 239000012085 test solution Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000008187 granular material Substances 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 239000012088 reference solution Substances 0.000 description 5
- 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 description 4
- 229920000881 Modified starch Polymers 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229950002475 mesilate Drugs 0.000 description 4
- 238000007873 sieving Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000005465 B01AC22 - Prasugrel Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- -1 mesilate ketone Chemical class 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical compound C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 description 3
- 229960004197 prasugrel Drugs 0.000 description 3
- 230000000750 progressive effect Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 239000005594 Phenmedipham Substances 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 2
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 229960000913 crospovidone Drugs 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 235000013345 egg yolk Nutrition 0.000 description 2
- 210000002969 egg yolk Anatomy 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- FPLYNRPOIZEADP-UHFFFAOYSA-N octylsilane Chemical group CCCCCCCC[SiH3] FPLYNRPOIZEADP-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- IDOWTHOLJBTAFI-UHFFFAOYSA-N phenmedipham Chemical compound COC(=O)NC1=CC=CC(OC(=O)NC=2C=C(C)C=CC=2)=C1 IDOWTHOLJBTAFI-UHFFFAOYSA-N 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- HOIIHACBCFLJET-SFTDATJTSA-N 4-((6br,10as)-3-methyl-2,3,6b,9,10,10a-hexahydro-1h-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxalin-8-(7h)-yl)-1-(4-fluorophenyl)-1-butanone Chemical compound C([C@@H]1N2CCN(C=3C=CC=C(C2=3)[C@@H]1C1)C)CN1CCCC(=O)C1=CC=C(F)C=C1 HOIIHACBCFLJET-SFTDATJTSA-N 0.000 description 1
- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 description 1
- 108010072564 5-HT2A Serotonin Receptor Proteins 0.000 description 1
- 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 description 1
- 102000004980 Dopamine D2 Receptors Human genes 0.000 description 1
- 108090001111 Dopamine D2 Receptors Proteins 0.000 description 1
- 102000019208 Serotonin Plasma Membrane Transport Proteins Human genes 0.000 description 1
- 108010012996 Serotonin Plasma Membrane Transport Proteins Proteins 0.000 description 1
- FPWNQPQTICPCOM-UHFFFAOYSA-N acetonitrile;propan-2-ol Chemical compound CC#N.CC(C)O FPWNQPQTICPCOM-UHFFFAOYSA-N 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- CSVGEMRSDNSWRF-UHFFFAOYSA-L disodium;dihydrogen phosphate Chemical compound [Na+].[Na+].OP(O)([O-])=O.OP(O)([O-])=O CSVGEMRSDNSWRF-UHFFFAOYSA-L 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 229960004396 famciclovir Drugs 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000000742 histaminergic effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229950003467 lumateperone Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000013081 microcrystal Substances 0.000 description 1
- 230000003551 muscarinic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- 229960003243 phenformin Drugs 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000005550 wet granulation Methods 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a capsule of phencyclamate famethione. Wherein the capsule shell is a non-gelatin hollow capsule, the content is mixed powder of phenmetyl-sulfonic acid pantone and cross-linked sodium carboxymethyl cellulose, magnesium stearate, mannitol and talcum powder, the water content of the content is less than or equal to 0.5%, and the particle size distribution D90 of the phenmetyl-sulfonic acid pantone is less than or equal to 30 mu m. The capsule prepared by the invention has the advantages of high dissolution rate, good stability, high safety and simple preparation process.
Description
Technical Field
The invention relates to the field of medicinal preparations, in particular to a capsule of phencyclamate famethicone.
Background
Dimedone mesylate can have high binding affinity (Ki = 0.54 nM) for the 5-hydroxytryptamine 5-HT2A receptor by binding, and moderate binding affinity (Ki = 32 nM) for the dopamine D2 receptor. Phenmetidine mesylate has a moderate binding affinity for the serotonin transporter (Ki = 33 nM). Lumateperone also has moderate binding affinity for dopamine D1 (41 nM) and D4 and the alpha1A and alpha1B receptors of epinephrine (Ki predicted <100 nM), but low binding affinity for muscarinic and histaminergic receptors (inhibition less than 50% at 100 nM), and is useful in the treatment of schizophrenia. The phenmetidone mesylate is an oily sticky solid, has poor solubility in water, hygroscopicity and poor stability, so the invention relates to a capsule of the phenmetidone mesylate. The prepared capsule has the advantages of high dissolution rate, good stability, high safety and simple preparation process.
Disclosure of Invention
In order to develop a more stable and effective pharmaceutical preparation of the phenmedipham mesylate pantone, the inventor screens and prepares a more stable capsule preparation with better bioequivalence and higher safety on the basis of a large number of tests by carrying out long-time intensive research on the physicochemical properties of the phenmedipham mesylate pantone.
The invention adopts the following technical scheme: a capsule of phenmetyl sulfhydrate dimedone is provided, wherein the capsule shell is a non-gelatin hollow capsule, and the filling material is mixed powder of phenmetyl sulfhydrate, mannitol and microcrystalline cellulose. The amount of the phenmetyl sulfonic acid phenmetione is 1.216-60.8 mg.
The weight ratio of the mannitol to the microcrystalline cellulose in the filler is 1: 0-1, preferably 1: 0.1-0.5, and most preferably 1: 0.3.
The water content of the filler is less than or equal to 0.5 percent.
The granularity distribution of the phenmetyl sulfenate dimedone in the filler is that D90 is less than or equal to 30 mu m.
The grain size of the mannitol in the filler ranges from 60 to 150 mu m, and the grain size of the microcrystalline cellulose ranges from 100 to 200 mu m.
The microcrystalline fibers in the filler are silicified microcrystals of 100-200 mu m, and the mannitol is spray-dried mannitol of 60-150 mu m.
The content of the phenmetyl mesilate ketone in each capsule filling of the capsule preparation is preferably 3.04-24.32 mg.
The preparation process of the phencyclamate dimedone capsule comprises the following steps: micronizing phenmetyl sulfonic acid dimedone, uniformly mixing the prescription dose of phenmetyl sulfonic acid dimedone with the prescription dose of mannitol and microcrystalline cellulose according to an equivalent progressive method, detecting the content of a semi-finished product, and filling capsules to obtain the phenmetyl sulfonic acid dimedone.
The phencyclamate dimedone capsule has fewer selected auxiliary materials and better medication safety; more stable, better bioequivalence and simple preparation process; the problem of the increase of related substances of the phenmetyl sulfhydrate famethione in the wet granulation process is avoided. As can be seen from the test example 1, the capsule provided by the invention has good stability and high dissolution rate. The test example 2 shows that the phenmetrazone hydrochloride capsule has good bioavailability and is superior to a comparative example, so that the phenmetrazone hydrochloride capsule has outstanding advantages, is simple in process and is suitable for large-scale production.
[Microsof1]
The dimedone capsules of the present invention are further illustrated by the following examples, but the present invention is not limited to the following examples.
Example 1
Dosage of raw materials (mg)
Phenmetyl sulfonic acid famethione 3.04
Mannitol 100
The preparation method comprises the following steps: micronizing phenmetyl sulfonic acid and ensuring that the particle size distribution D90 is less than or equal to 30 mu m; controlling the water content of the pregelatinized starch to be less than or equal to 0.5 percent; taking the prescription amount of the phenmetyl sulfenate famidone and the prescription amount of the mannitol, uniformly mixing according to an equivalent gradual addition method, detecting the content of a semi-finished product, and filling a non-gelatin capsule to obtain the pharmaceutical composition.
Example 2
Dosage of raw materials (mg)
Phenmetyl sulfonic acid phenmetin 6.08
Mannitol 100
Silicified microcrystalline cellulose 10
The preparation method comprises the following steps: micronizing phenmetyl sulfonic acid and ensuring that the particle size distribution D90 is less than or equal to 30 mu m; controlling the water content of mannitol and microcrystalline cellulose to be less than or equal to 0.5 percent; taking the prescription dose of the phenmetyl sulfhydrate famidone, the prescription dose of the mannitol and the silicified microcrystalline cellulose, uniformly mixing according to an equivalent progressive method, detecting the content of a semi-finished product, and filling a non-gelatin capsule to obtain the pharmaceutical composition.
Example 3
Dosage of raw materials (mg)
Phenmetyl sulfonic acid phenmetin 6.08
Spray-dried mannitol (100 SD) 100
Microcrystalline cellulose (PH 112) 25
The preparation method comprises the following steps: the same as in example 2.
Example 4
Dosage of raw materials (mg)
Phenmetyl sulfonic acid phenmetin 6.08
Spray-dried mannitol (100 SD) 100
Microcrystalline cellulose (pH 113) 30
The preparation method comprises the following steps: the same as in example 2.
Example 5
Dosage of raw materials (mg)
Phenmetyl sulfonic acid famethione 12.16
Spray-dried mannitol (100 SD) 100
Microcrystalline cellulose (pH 103) 40
The preparation method comprises the following steps: the same as in example 2.
Example 6
Dosage of raw materials (mg)
Phenmetyl sulfonic acid phenmetin 6.08
Spray-dried mannitol (100 SD) 100
Microcrystalline cellulose (M102 QD) 50
The preparation method comprises the following steps: the same as in example 2.
Example 7
Dosage of raw materials (mg)
Phenmetyl sulfonic acid famethione 12.16
Mannitol 100
Microcrystalline cellulose (pH 200) 50
The preparation method comprises the following steps: the same as in example 2.
Comparative example 1
Dosage of raw materials (mg)
Phenmetyl sulfonic acid phenmetin 6.08
Pregelatinized starch 66.9
Microcrystalline cellulose 44
Low-substituted hydroxypropylcellulose 10
Hydroxypropyl methylcellulose 1.7
Magnesium stearate 1.3
Appropriate amount of Opadry
Preparation method
1. Adding phenmetyl phencyclamate, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and hydroxypropyl methylcellulose in equal amount, and mixing uniformly to obtain a mixture 1;
2. dry granulating the mixture 1 to obtain granules 1;
3. adding magnesium stearate into the obtained granule 1, and mixing
4. Tabletting and coating the mixed granules.
Comparative example 2
Dosage of raw materials (mg)
Phenmetyl sulfonic acid phenmetin 6.08
Egg yolk phosphatidyl glycerol 40
Cholesterol 150
Glycocholic acid sodium salt 25
Starch 20
Lactose 50
Crospovidone 20
Hydroxypropyl methylcellulose 2
Silica gel micropowder 10
Magnesium stearate 4
Preparation process
1. Dissolving 40g of egg yolk phosphatidyl glycerol, 150g of cholesterol and 25g of sodium glycocholate in 500ml of mixed solvent of isopropanol and acetone in a volume ratio of 5:2, uniformly mixing, and removing the mixed solvent on a rotary film evaporator under reduced pressure to obtain a phospholipid membrane;
2. adding 300ml of phosphoric acid-disodium hydrogen phosphate buffer solution with pH value of 5.2, shaking, stirring to make phospholipid membrane completely hydrated, homogenizing at high speed, emulsifying, and filtering to obtain blank liposome suspension;
3. dispersing 5g of prasugrel in 100ml of water, adding the blank liposome suspension, keeping the temperature at 50 ℃, stirring for 60 minutes, and performing spray drying to obtain liposome solid
4. Mixing the solid phenmetyl sulfonate pantone liposome with starch, lactose and crospovidone, sieving with 60 mesh sieve, mixing well, adding 2% hydroxypropyl methylcellulose 20% ethanol solution to make soft mass, sieving with 20 mesh sieve, granulating, and drying;
5. mixing the dry granules with silica gel micropowder and magnesium stearate, and sieving with 18 mesh sieve
6. Tabletting;
7. coating gastric soluble film coat, and increasing weight by 2.1%.
Comparative example 3
Dosage of raw materials (mg)
Phenmetyl sulfonic acid famethione 12.16
Mannitol 50
Microcrystalline cellulose 100
The preparation method comprises the following steps: micronizing phenmetyl sulfhydrate, mixing phenmetyl sulfhydrate with mannitol and microcrystalline cellulose, detecting semi-finished product content, and filling into non-gelatin capsule.
The particle size distribution D90 of the phenmetyl sulfonic acid phenmetidone is 26.79 mu m, and the water content is 0.49 percent.
Comparative example 4
Dosage of raw materials (mg)
Phenmetyl sulfonic acid phenmetin 6.08
Spray-dried mannitol (100 SD) 100
Microcrystalline cellulose (PH 112) 25
The preparation method comprises the following steps: pulverizing phenmetyl sulfonic acid phenmethyl ketone, mixing with spray dried mannitol (100 SD) and microcrystalline cellulose, detecting semi-finished product content, and filling into non-gelatin capsule.
The particle size distribution D90 of the phenmetyl sulfonic acid phenmetione is 78.19 mu m, and the water content is 0.44 percent.
Comparative example 5
Dosage of raw materials (mg)
Phenmetyl sulfonic acid famethione 12.16
Spray-dried mannitol (100 SD) 100
Microcrystalline cellulose (pH 103) 40
The preparation method comprises the following steps: micronizing phenmetyl sulfonic acid dimedone, mixing the phenmetyl sulfonic acid dimedone with spray-dried mannitol (100 SD) and microcrystalline cellulose according to equivalent progressive method, detecting semi-finished product content, and filling into non-gelatin capsule.
The particle size distribution D90 of the phenmetyl sulfonic acid phenmetione is 27.56 μm, and the water content is 2.52%.
Comparative example 6
Dosage of raw materials (mg)
Phenmetyl sulfonic acid phenmetin 6.08
Spray-dried mannitol (100 SD) 100
Microcrystalline cellulose (pH 113) 30
The preparation method comprises the following steps: micronizing phenmetyl sulfonic acid and ensuring that the particle size distribution D90 is less than or equal to 30 mu m; spray drying mannitol (100 SD), microcrystalline cellulose with water content not more than 0.5%; taking the prescription amount of the phenmetyl sulfhydrate famidone, the prescription amount of the spray-dried mannitol (100 SD) and the microcrystalline cellulose, adding the components in equal amount gradually, mixing uniformly, detecting the content of a semi-finished product, and filling a gelatin capsule to obtain the pharmaceutical composition.
Comparative example 7
Dosage of raw materials (mg)
Phenmetyl sulfonic acid phenmetin 6.08
Lactose 100
Pregelatinized starch 30
The preparation method comprises the following steps: pulverizing and sieving; mixing the formula amount of phenmetyl sulfenate phenformin, the formula amount of lactose and pregelatinized starch uniformly according to an equivalent gradual addition method, detecting the content of a semi-finished product, and filling gelatin capsules to obtain the gelatin capsules
Experimental example 1 an example of the invention has the following technical characteristics:
1 dissolution rate
The dissolution rate of the capsules prepared according to the examples of the invention is compared with that of the comparative example
And (3) measuring by a self-built dissolution measuring method. Taking 6 samples of examples 1-7 and comparative examples 1-6 of the invention, taking 900ml of hydrochloric acid with pH of 1.2 as a dissolution medium, rotating at 50 r/min, and taking appropriate amount of solution at 5min, 10 min, 15 min, 30 min and 45min respectively, and filtering to obtain a test solution; and precisely weighing a proper amount of the phenmetyl-sulfonic acid famethione, placing the weighed phenmetyl-sulfonic acid famethione into a measuring flask, adding a proper amount of acetonitrile into the measuring flask for ultrasonic dissolution, and diluting the solution to a proper concentration by using a dissolution medium to be used as a reference solution. 20. mu.l of each of the test solution and the control solution was measured accurately and injected into a liquid chromatograph, and the measurement was carried out by the following method. Octyl silane bonded silica gel is used as a filling agent, acetonitrile-isopropanol-0.01 mol/L trifluoroacetic acid (30: 20: 50) is used as a mobile phase, and the detection wavelength is 220 nm. The theoretical plate number is not less than 3000 according to prasugrel. The results are shown in Table 1.
TABLE 1 dissolution comparison study of famciclovir mesylate in hydrochloric acid pH1.2
It can be seen from table 1 that the capsules prepared according to the examples of the present invention are significantly superior in dissolution to the comparative examples; and most preferably embodiment 4 is superior to the other embodiments. Comparative example 1 using dry granulation, the granules were harder and disintegrated slowly after tablet coating, resulting in slower dissolution. Compared with the liposome prepared by the comparative example 2, the hydrophilicity of the phenmetyl mesilate famethione is reduced, and the dissolution of the phenmetyl mesilate famethione is reduced. The ratio of mannitol to microcrystalline cellulose in comparative example 3 is outside the range of the present invention, and the dissolution is inferior to that of example, but slightly better than that of comparative examples 1 and 2. In comparative example 4, the particle size of the raw material alone was out of the range of the present invention, and the dissolution was inferior to that of example. Comparative example 5 the filler was higher in moisture; comparative example 6 a gelatin capsule was used, and the high shell moisture had a relatively small effect on dissolution, superior to other comparative examples but slightly inferior to the examples. The auxiliary materials selected in comparative example 7 are not in the range of the present invention, and the dissolution is poor.
2. Related substances
The related substance detection method comprises the following steps: self-research establishment
Chromatographic conditions and system adaptability test use octyl silane bonded silica gel as filler, acetonitrile-isopropanol 0.01mol/L trifluoroacetic acid (20: 10: 70) as mobile phase, and the detection wavelength is 220 nm. The theoretical plate number is not less than 5000 in terms of prasugrel.
Measuring to obtain appropriate amount (about 10 mg) of fine powder, placing in 10ml measuring flask, ultrasonic dissolving with acetonitrile, cooling, diluting to scale, shaking, filtering with 0.45 μm filter membrane, and collecting the filtrate as sample solution; precisely measuring 1ml of a test solution, placing the test solution into a 100ml measuring flask, adding acetonitrile to dilute the test solution to a scale, and taking the test solution as a reference solution; measuring 20 mul of reference solution, injecting into a liquid chromatograph, adjusting detection sensitivity to make the peak height of the main component peak be 25% of the full range of the recorder, precisely measuring 20 mul of test solution and reference solution, respectively injecting into the liquid chromatograph, recording chromatogram until the retention time of the phenmetyl mesilate dimedone peak is 3 times, if an impurity peak appears in the chromatogram of the test solution, the sum of the peak areas of each impurity peak should not be larger than the main peak area (1.0%) of the reference solution.
The results of the comparative study on the substances are shown in Table 2.
TABLE 2 comparative study results of related substances of phencyclamate
As can be seen from Table 2, the stability of the relevant substances of the capsules prepared according to the examples of the present invention is significantly better than that of the comparative examples. Comparative example 1 water or other non-aqueous solvent is inevitably used during the coating process and heating is required, and the solvent used is also left, which accelerates the hydrolysis and oxidation of phenmetyl amine sulfonate, and thus is poor in stability. In comparative example 2, water and some organic solvents were used, and heating was required during the preparation process to accelerate hydrolysis and oxidation of phenmetyl amine sulfonate, resulting in poor stability. The ratio of mannitol to microcrystalline cellulose in comparative example 3 is outside the range of the present invention, and the stability is inferior to that of example, but better than comparative examples 1 and 2. In comparative example 4, only the particle size of the raw material was different from that of the present invention, and the influence on the dissolution was small. Comparative example 5 the filler was higher in moisture; comparative example 6 adopts gelatin capsule, and the water content of the capsule shell is high; the auxiliary materials selected in comparative example 7 are out of the range of the present invention, and the stability is poor.
The results show that the capsule prepared according to the invention has better dissolution rate, stability and the like than the comparative examples, and the preparation process is simple and is suitable for industrial mass production.
The above-mentioned embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of the present invention is not limited thereto. The equivalent substitution or change made by the technical personnel in the technical field on the basis of the invention is all within the protection scope of the invention.
Claims (5)
1. A capsule of phenmetyl sulfhydrate dimedone comprises a capsule shell and a filler, and is characterized in that the capsule shell is a non-gelatin hollow capsule, and the filler is mixed powder of phenmetyl sulfhydrate, mannitol and microcrystalline cellulose; the amount of the phenmetyl sulfonic acid famethione is 1.216-60.8 mg; the weight ratio of mannitol to microcrystalline cellulose in the filler is 1: 0-1; the water content of the filler is less than or equal to 0.5 percent; the granularity distribution of the phenmetyl sulfonic acid dimedone in the filler is that D90 is less than or equal to 30 mu m, the grain size range of mannitol is 60-150 mu m, and the grain size range of microcrystalline cellulose is 100-200 mu m.
2. The phenmetyl sulfenate dimedone capsule as claimed in claim 1, wherein the microcrystalline fiber is silicified microcrystalline 100-200 μm, and the mannitol is spray-dried mannitol 60-150 μm.
3. The phenmetyl sulfenate dimedone capsule as claimed in claim 1, wherein the weight ratio of mannitol to microcrystalline cellulose in the filling is 1: 0.1-0.5.
4. The phenmettanone mesylate capsule according to claim 2, wherein the weight ratio of mannitol to microcrystalline cellulose in the filling is 1: 0.3.
5. The phenmetrafenone mesylate capsule according to claim 1, wherein the content of phenmetrafenone mesylate in each capsule filling is 3.04-24.32 mg.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010504385.0A CN113750070A (en) | 2020-06-05 | 2020-06-05 | Phencyclamate dimedone capsule |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010504385.0A CN113750070A (en) | 2020-06-05 | 2020-06-05 | Phencyclamate dimedone capsule |
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| CN113750070A true CN113750070A (en) | 2021-12-07 |
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|---|---|---|---|
| CN202010504385.0A Pending CN113750070A (en) | 2020-06-05 | 2020-06-05 | Phencyclamate dimedone capsule |
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| CN (1) | CN113750070A (en) |
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