CN116942619A - Lurasidone hydrochloride pharmaceutical composition and preparation method thereof - Google Patents
Lurasidone hydrochloride pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN116942619A CN116942619A CN202210416519.2A CN202210416519A CN116942619A CN 116942619 A CN116942619 A CN 116942619A CN 202210416519 A CN202210416519 A CN 202210416519A CN 116942619 A CN116942619 A CN 116942619A
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- lurasidone hydrochloride
- microcrystalline cellulose
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- lurasidone
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- 229960002863 lurasidone hydrochloride Drugs 0.000 title claims abstract description 31
- NEKCRUIRPWNMLK-SCIYSFAVSA-N lurasidone hydrochloride Chemical compound Cl.C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 NEKCRUIRPWNMLK-SCIYSFAVSA-N 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 title description 3
- 239000000203 mixture Substances 0.000 claims abstract description 45
- 239000003826 tablet Substances 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000000945 filler Substances 0.000 claims abstract description 9
- 239000007935 oral tablet Substances 0.000 claims abstract description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 15
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 15
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 15
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 15
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 15
- 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 description 13
- 229930195725 Mannitol Natural products 0.000 claims description 13
- 239000000594 mannitol Substances 0.000 claims description 13
- 235000010355 mannitol Nutrition 0.000 claims description 13
- 229960001855 mannitol Drugs 0.000 claims description 13
- 239000008187 granular material Substances 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- 239000000853 adhesive Substances 0.000 claims description 7
- 230000001070 adhesive effect Effects 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 238000009472 formulation Methods 0.000 claims description 7
- 239000013022 formulation composition Substances 0.000 claims description 7
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 6
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 3
- 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 description 2
- 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 description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 229960001375 lactose Drugs 0.000 claims description 2
- 229940096978 oral tablet Drugs 0.000 claims description 2
- 238000003825 pressing Methods 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims 1
- 229940095672 calcium sulfate Drugs 0.000 claims 1
- 235000019700 dicalcium phosphate Nutrition 0.000 claims 1
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 26
- 238000000338 in vitro Methods 0.000 abstract description 5
- 238000000227 grinding Methods 0.000 abstract description 4
- 239000011248 coating agent Substances 0.000 description 21
- 238000000576 coating method Methods 0.000 description 21
- 239000000463 material Substances 0.000 description 18
- 239000002245 particle Substances 0.000 description 10
- PQXKDMSYBGKCJA-CVTJIBDQSA-N lurasidone Chemical compound C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 PQXKDMSYBGKCJA-CVTJIBDQSA-N 0.000 description 9
- 238000007922 dissolution test Methods 0.000 description 8
- 238000005469 granulation Methods 0.000 description 7
- 230000003179 granulation Effects 0.000 description 7
- 229960001432 lurasidone Drugs 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 238000010828 elution Methods 0.000 description 5
- 239000007888 film coating Substances 0.000 description 5
- 238000009501 film coating Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 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
- 230000008569 process Effects 0.000 description 4
- 238000005507 spraying Methods 0.000 description 4
- 230000004584 weight gain Effects 0.000 description 4
- 235000019786 weight gain Nutrition 0.000 description 4
- 229920000881 Modified starch Polymers 0.000 description 3
- 239000007891 compressed tablet Substances 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 201000000980 schizophrenia Diseases 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- 208000020925 Bipolar disease Diseases 0.000 description 2
- 239000004821 Contact adhesive Substances 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000012669 compression test Methods 0.000 description 2
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 2
- 229940084026 sodium valproate Drugs 0.000 description 2
- 239000000243 solution Substances 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
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 241000846171 Cremastra Species 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000011362 coarse particle Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 229940036674 latuda Drugs 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Molecular Biology (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 provides a lurasidone hydrochloride preparation composition and a preparation method thereof, wherein the tablet weight difference and dissolution individual difference can be reduced by optimizing a prescription, particularly controlling the selection and the dosage of a filling agent in the composition, so that a more uniform tablet is prepared and is consistent with the dissolution in vitro of an original grinding body; in addition, the composition can be prepared into oral tablets by adopting a conventional granulating method, including wet granulating and one-step granulating, and is more suitable for industrialized application.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a lurasidone hydrochloride pharmaceutical composition and a preparation method thereof.
Background
Lurasidone (lurasidone) is an atypical antipsychotic developed by Sumitomo pharmaceutical company, which has been marketed in the United states as film coated tablets (20 mg, 40mg, 80mg, 120 mg/tablet). The United states Food and Drug Administration (FDA) approved Latuda (lurasidone hydrochloride) for the treatment of schizophrenia, 10 months, 28 days 2010; two new indications approved by the FDA, day 28 of 6 of 2013, are used as monotherapy and as adjuvant therapy for lithium or sodium valproate, in major depressive episodes associated with bipolar I disorder in adult patients.
Lurasidone has obvious curative effect on patients with schizophrenia compared with placebo. The lurasidone has no sex, age and race difference in the aspect of treating the schizophrenia, and has remarkable treatment effect. Whereas for bipolar disorder, lurasidone group single drug treatment has significant differences compared to placebo; although data were not statistically analyzed when used as adjuvant to lithium or sodium valproate for the treatment of bipolar disorders, relevant reports have demonstrated their effectiveness.
Currently, lurasidone tablets are clinically used in patients. In order to exert the desired efficacy of lurasidone with a short onset of action and a sustained action, the preparation is expected to have quick release and rapid dissolution characteristics. However, since lurasidone is a poorly soluble drug, sufficient immediate release and solubility cannot be obtained under many formulation conditions.
In the FDA marketing instruction, a preparation containing part of pregelatinized starch is adopted, part of pregelatinized starch is starch modified auxiliary material, has the characteristic of starch but has stronger viscosity, is used as a filling agent in the wet granulation process, and can lead to that materials with more contact adhesive are aggregated into large particles and agglomerate under the shearing force along with the continuous addition of the adhesive, and the particles formed by materials with less contact adhesive are smaller or not formed into particles, so that the particles are nonuniform, and the particles are nonuniform for a while, thereby causing trouble to granule finishing, drying, tabletting and the like.
In order to solve the problems, researchers generally crush the raw materials to control the particle size of the raw materials and then mix the raw materials with other auxiliary materials for granulation in the preparation process of the lurasidone hydrochloride preparation, but in experiments, the situation that the raw materials are crushed, especially micronized, and have larger static electricity, larger loss in the processing process of the raw materials and uneven granulation is more likely to occur in the preparation production is found.
Therefore, there is still a need for a lurasidone hydrochloride formulation composition with uniform granulation and small individual difference in tablet weight in industrial production, which is suitable for industrial production.
Disclosure of Invention
In order to solve the problems, the invention provides a lurasidone hydrochloride preparation composition and a preparation method thereof.
A lurasidone hydrochloride preparation composition, which comprises a filler, wherein the filler is one or more selected from mannitol, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, lactose, calcium hydrophosphate and calcium sulfate, and is preferably a mixture of mannitol, low-substituted hydroxypropyl cellulose and microcrystalline cellulose.
In particular, the low substituted hydroxypropylcellulose is 15% to 25%, preferably 16% to 20%, most preferably 17% by weight of the composition.
In particular, the microcrystalline cellulose is 5% to 20%, preferably 5% to 10%, most preferably 7% by weight of the composition. More specifically, the weight ratio of the low-substituted hydroxypropyl cellulose to the microcrystalline cellulose in the composition ranges from 0.75 to 5:1.
specifically, the mannitol is 5% to 70%, preferably 20% to 60%, more preferably 43% by weight of the composition.
The composition further comprises a disintegrant, preferably croscarmellose sodium, which is 0.5% to 5%, preferably 1% to 3%, most preferably 2% by weight of the composition.
Specifically, the lurasidone hydrochloride preparation composition comprises lurasidone hydrochloride as an active ingredient, filler mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and also comprises a disintegrating agent, an adhesive and a lubricant.
In particular, the disintegrant is preferably croscarmellose sodium, the binder is preferably hypromellose, and the lubricant is preferably magnesium stearate.
Specifically, the lurasidone hydrochloride preparation composition comprises the following components in percentage by weight:
further preferably, the lurasidone hydrochloride preparation composition comprises, in weight percent:
more preferably, the lurasidone hydrochloride preparation composition comprises the following components in percentage by weight:
examples of further preferred prescriptions include:
the composition can further comprise a coating material, wherein the coating material is a conventional coating material, preferably a gastric-soluble film coating premix, and the coating weight gain is 0.5-8%, preferably 2-4%.
The composition can be further prepared into lurasidone hydrochloride oral preparations, including tablets, capsules, granules and the like, preferably tablets.
Specifically, the preparation method of the composition for preparing the oral tablet comprises the following steps:
(1) Crushing the raw material medicaments, wherein the granularity range of the crushing is controlled to be D90 less than or equal to 50 mu m;
(2) Granulating, adding adhesive, drying, adding adjuvants, and making into granule;
(3) And (5) pressing and forming by adopting a tablet press.
Wherein the granulating in the step (2) can be carried out by adopting one-step granulating or wet granulating, the coating operation can be carried out after the tabletting in the step (3), and concretely, a coating pan and other similar coating equipment can be selected to coat the compressed tablet to obtain a final coated tablet, wherein the coating material is a film coating premix, preferably a gastric-soluble film coating premix, and the coating weight gain is controlled to be 2-4%.
The invention has the beneficial effects that:
the invention provides a lurasidone hydrochloride preparation composition and a preparation method thereof, wherein the tablet weight difference and dissolution individual difference can be reduced by optimizing a prescription, particularly controlling the selection and the dosage of a filling agent in the composition, so that a more uniform tablet is prepared and is consistent with the dissolution in vitro of an original grinding body; in addition, the composition can be prepared into oral tablets by adopting a conventional granulating method, including wet granulating and one-step granulating, and is more suitable for industrialized application.
Description of the drawings:
FIG. 1 is a graph showing comparison of elution curves of examples 1 to 3 and a crude preparation (Suzhou Co., ltd., suzhou Suyou, 40mg, lot Q0659830P)
FIG. 2 is a graph showing comparison of elution curves of examples 4 to 6 and a crude preparation (Suzhou Co., suzhou Suyou, suzhou Co., ltd., 40mg, lot number Q0659830P)
FIG. 3 is a graph showing comparison of elution curves of examples 9 to 12 and a crude preparation (Suzhou Co., ltd., suzhou Suyou, 40mg, lot Q0659830P)
The specific embodiment is as follows:
the present invention will be described in detail with reference to the following specific embodiments, but the scope of the present invention is not limited thereto.
In the following examples, reagents and apparatus used, unless specifically indicated, are those commonly used in the art and are commercially available; the methods used are conventional in the art, and one skilled in the art will know how to implement the methods specifically and achieve the corresponding results based on the description of the embodiments.
The lurasidone hydrochloride drug substance used in the examples was Jiangsu sea Cremastra biopharmaceutical industry Co., ltd (production lot number 19060501).
1. Examples 1 to 3
With reference to the prescribed amounts (10000 tablets in batch) of each example of table 1 below, lurasidone hydrochloride tablets were prepared as follows:
(1) Pretreating raw materials, and crushing the raw materials until D90 is less than or equal to 50 mu m for later use;
(2) Preparing an adhesive, and preparing 5% (w/w) aqueous solution of hydroxypropyl methylcellulose (HPMC) with a prescription amount for later use;
(3) Mixing and granulating, namely placing the lurasidone hydrochloride, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and croscarmellose sodium with the prescription amount into a wet mixing granulator, starting stirring, mixing for 3-10 min, adding an adhesive, and continuously stirring to form wet granules;
(4) Drying, namely adopting a fluidized bed drying process, beginning spraying slurry after the temperature of the material is more than or equal to 25 ℃, controlling the temperature of the fluidized material to be 30-50 ℃, and drying until the moisture is lower than 5% after the spraying slurry is finished;
(5) Finishing, namely finishing the granules by a 20-30-mesh screen;
(6) Finally mixing, adding magnesium stearate, and mixing for 2-15 min;
(7) Tabletting, controlling the hardness to be 30N-90N, tabletting the mixture to obtain tablets;
(8) And coating, namely coating the compressed tablet by using coating equipment such as a coating pot and the like to obtain a final coated tablet, wherein the coating material is a film coating premix, and the coating weight gain is controlled to be 2-4%.
TABLE 1 consumption of raw materials and auxiliary materials of examples 1-3 (10000 tablets in batch, unit: g)
In the granulation process, it was found that the wet granules prepared according to the prescription of example 1 (mannitol and microcrystalline cellulose as filler) had agglomerated, had localized over-wetting, had uneven granulation, and had more coarse particles in the particle size distribution after granulation (see table 2 below), in contrast to the granules obtained according to the prescription of examples 2 and 3.
TABLE 2 statistical particle size distribution of the particles in examples 1-3
| Particle size distribution | Example 1 | Example 2 | Example 3 |
| 24 mesh (%) | 2.12 | 0 | 0 |
| 24-40 mesh (%) | 12.34 | 3.4 | 1.25 |
| 40-60 mesh (%) | 41.25 | 46.98 | 18.57 |
| 60-80 mesh (%) | 17.28 | 20.19 | 38.96 |
| 80-100 mesh (%) | 22.49 | 16.79 | 30.96 |
| Less than 100 mesh (%) | 4.52 | 12.64 | 10.26 |
After the above pellets were compressed by a rotary tablet press, samples were taken to determine the difference in tablet weight and the uniformity of content, wherein the tablets obtained in example 1 were found to have a poor difference in tablet weight and uniformity of content (see table 3 below), and the tablets obtained in examples 2 and 3 were found to have a good quality.
TABLE 3 examination of examples 1 to 3 tabletting
1* The Chinese pharmacopoeia 2020 edition four general rules 0941 should be met: A+2.2S is less than or equal to 15.0
The dissolution test was performed in examples 1 to 3, the dissolution method was the second method (paddle method) of dissolution and release measurement according to the rule 0931 of the fourth edition of the 2020 edition of chinese pharmacopoeia, the dissolution curve test was performed by selecting an acetate buffer solution having a ph of 4.0 and a medium volume of 900mL and rotating at 50rpm, and the detection method was the high performance liquid chromatography according to the rule 0512 of the fourth edition of the 2020 edition of chinese pharmacopoeia (the dissolution measurement method in each example described below).
Contrast to original developer(Suzhou Co., suzhou Suyou, 40mg, lot number Q0659830P), the dissolution results of each example are shown in Table 4 below (dissolution curve see FIG. 1), wherein the dissolution results of example 1 were slower than those of the original reagents, and the in vitro dissolution was inconsistent (f 2 <50 While examples 2, 3 represent f2 values > 50 for similarity of dissolution characteristics, resulting in a formulation with similar dissolution characteristics.
TABLE 4 dissolution test results for examples 1-3
| Dissolution time/min | Original developer | Example 1 | Example 2 | Example 3 |
| 5 | 27 | 10 | 23 | 22 |
| 10 | 58 | 25 | 54 | 51 |
| 15 | 69 | 37 | 65 | 62 |
| 30 | 81 | 60 | 76 | 74 |
| 45 | 86 | 71 | 84 | 82 |
| 60 | 89 | 81 | 91 | 90 |
| 90 | 93 | 87 | 94 | 93 |
| Similarity factor f 2 | / | 30.29 | 69.63 | 60.34 |
2. Examples 4 to 6
With reference to the prescribed amounts (10000 tablets in batch) of each example of table 5 below, lurasidone hydrochloride tablets were prepared as follows:
(1) Pretreating raw materials, and crushing the raw materials until D90 is less than or equal to 50 mu m for later use;
(2) Preparing adhesive, namely preparing 5% (w/w) aqueous solution of HPMC with a prescription amount for later use;
(3) Granulating in one step, namely placing the lurasidone hydrochloride, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and croscarmellose sodium with the prescription amount into a one-step granulator, starting air inlet, spraying after the material temperature is more than or equal to 30 ℃, controlling the temperature of fluidized material to be 30-50 ℃, and drying until the water content is lower than 4% after the spraying is finished;
(4) Finishing, namely finishing the granules by a 20-30-mesh screen;
(5) Finally mixing, adding auxiliary materials such as magnesium stearate and the like, and mixing for 2-10 min;
(6) Tabletting, controlling the hardness to be 30N-90N, tabletting the mixture to obtain tablets;
(7) And coating, namely coating the compressed tablet by using coating equipment such as a coating pot and the like to obtain a final coated tablet, wherein the coating material is a film coating premix, and the coating weight gain is controlled to be 2-4%.
TABLE 5 examples 4 to 6 raw and auxiliary materials used (batch 10000 tablets, unit: g)
Granulating by adopting the one-step granulating process, tabletting, and measuring the weight difference and content uniformity of tablets. The test results show that the prescription in the example 4 (mannitol and low-substituted hydroxypropyl cellulose are adopted as the filling agent) has a tablet weight difference of more than 5% in the tabletting after the granulating, and the intermediate granules obtained by the prescription in the examples 5 and 6 and the finished tablet after the tabletting are in accordance with the four-part rule of the 2020 edition of Chinese pharmacopoeia in terms of weight difference and content uniformity.
TABLE 6 tabletting test results for examples 4-6
The rule 0941 of the fourth edition of the Chinese pharmacopoeia 2020 version prescribes that A+2.2S is less than or equal to 15.0
The dissolution test of examples 4 to 6 was performed by referring to the dissolution test methods of examples 1 to 3, and the dissolution results of each example are shown in the following Table 7 (dissolution curve is shown in FIG. 2), wherein the dissolution results of example 4 are slower than those of the original grinding reagent, and the dissolution of example 6 is faster than that of the original grinding for 5min, becomes slower after 30min, and is inconsistent in vitro dissolution (f 2 <50 While example 5 shows similar elution characteristics in the f2 value > 50 range of the similarity of elution characteristics.
TABLE 7 dissolution test results for examples 4-6
Examples 7 to 8
Examples 7 and 8 lurasidone hydrochloride tablets (10000 tablets in batch) were prepared according to the following formulation in table 8 with reference to the wet granulation process used in examples 1 to 3 and the one-step granulation process used in examples 4 to 6, respectively, and were tabletted, sampled, and the tablet weight difference and content uniformity were determined. The test results show that the granules are agglomerated and nonuniform by adopting the prescription in table 8, and the problems of tablet weight difference of more than 5% and content uniformity failing to meet the regulation exist in tabletting (see table 9 below).
TABLE 8 EXAMPLES 7/8 prescription information form
| Names of raw and auxiliary materials | Single dose (mg) |
| Lurasidone hydrochloride | 40 |
| Mannitol (mannitol) | 70.4 |
| Partially pregelatinized starch | 16 |
| Hydroxypropyl methylcellulose | 4.8 |
| Croscarmellose sodium | 3.2 |
| Magnesium stearate | 1.6 |
TABLE 9 compression test results for examples 7 and 8
The rule 0941 of the fourth edition of the Chinese pharmacopoeia 2020 version prescribes that A+2.2S is less than or equal to 15.0
Examples 9 to 12
Lurasidone hydrochloride tablets (10000 tablets in batch) were prepared according to the prescription in table 10 by referring to the wet granulation process adopted in examples 1 to 3, and after tabletting, samples were taken to determine the tablet weight difference and content uniformity.
The test results showed that the formulation of example 12 (low substituted hydroxypropyl cellulose/microcrystalline cellulose=6:1) resulted in agglomeration and harder granules, the tablet weight difference in the tablet was > 5%, and the content uniformity was not in compliance with the specified conditions, while the formulation of example 9 (low substituted hydroxypropyl cellulose/microcrystalline cellulose=0.4:1) was examined for the presence of non-compliance (see table 11 below).
Table 10. Table 9-12 prescription information (batch 10000 tablets, unit: g)
TABLE 11 compression test results for examples 9-12
The rule 0941 of the fourth edition of the Chinese pharmacopoeia 2020 version prescribes that A+2.2S is less than or equal to 15.0
The dissolution test of examples 9 to 12 was performed by referring to the dissolution test methods of examples 1 to 3, and the dissolution results of each example are shown in Table 12 below (dissolution curve is shown in FIG. 3), wherein the dissolution results of examples 9 and 12 are slower than those of the original reagent, and the dissolution in vitro is inconsistent (f 2 <50 While example 10 and example 11 represent f2 values > 50 for similarity of dissolution characteristics, resulting in a formulation with similar dissolution characteristics.
TABLE 12 dissolution test results for examples 9-12
While the invention has been described in terms of the various embodiments described above, it is not intended to limit the scope of the invention. Therefore, based on the innovative concepts of the present invention, alterations and modifications to the embodiments described herein, or equivalent structures or equivalent flow transformations made by utilizing the content of the present description, apply the above technical solutions directly or indirectly to other relevant technical fields, all of which are included in the scope of the invention.
Claims (10)
1. A lurasidone hydrochloride formulation composition comprising a filler selected from one or more of mannitol, low-substituted hydroxypropylcellulose, microcrystalline cellulose, lactose, dibasic calcium phosphate, calcium sulfate, preferably a mixture of mannitol, low-substituted hydroxypropylcellulose and microcrystalline cellulose.
2. The composition according to claim 1, wherein the low substituted hydroxypropylcellulose is 15% to 25%, preferably 16% to 20%, most preferably 17% by weight of the composition.
3. Composition according to claim 1, characterized in that the microcrystalline cellulose is present in an amount of 5% to 20%, preferably 5% to 10%, most preferably 7% by weight of the composition.
4. A composition according to claim 3, wherein the ratio of low substituted hydroxypropylcellulose to microcrystalline cellulose in the composition is in the range of 0.75 to 5 by weight: 1.
5. the composition of any one of claims 1 to 4, wherein the lurasidone hydrochloride formulation composition comprises lurasidone hydrochloride, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and further comprises a disintegrant, a binder, and a lubricant;
the disintegrating agent is preferably croscarmellose sodium;
the binder is preferably hypromellose;
the lubricant is preferably magnesium stearate.
6. The composition of claim 5, wherein the lurasidone hydrochloride formulation composition comprises, in weight percent:
7. the composition of claim 6, wherein the lurasidone hydrochloride formulation composition comprises, in weight percent:
8. the composition of claim 7, wherein the lurasidone hydrochloride formulation composition comprises, in weight percent:
9. the composition of claim 8, wherein the lurasidone hydrochloride formulation composition formulation comprises:
10. a method of preparing a composition according to any one of claims 1 to 9 into an oral tablet, comprising the steps of:
1) Crushing the raw material medicaments, wherein the granularity range of the crushing is controlled to be D90 less than or equal to 50 mu m;
2) Granulating, adding adhesive, drying, adding adjuvants, and making into granule;
3) And (5) pressing and forming by adopting a tablet press.
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