CN114903867A - RAF kinase inhibitor capsule composition - Google Patents

RAF kinase inhibitor capsule composition Download PDF

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CN114903867A
CN114903867A CN202110186564.9A CN202110186564A CN114903867A CN 114903867 A CN114903867 A CN 114903867A CN 202110186564 A CN202110186564 A CN 202110186564A CN 114903867 A CN114903867 A CN 114903867A
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dihydro
composition
microcrystalline cellulose
silicified microcrystalline
lubricant
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Inventor
范文源
吴建设
王刚
于佳
陈辉
杜争鸣
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Baiji Shenzhou Suzhou Biotechnology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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Abstract

The invention belongs to the field of pharmaceutical formulation and relates to a RAF kinase inhibitor particle composition, which comprises the following components in part by weight: (1) 5- (((1R, 1aS, 6bR) -1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) -1a, 6 b-dihydro-1H-cyclopropa [ b ] benzofuran-5-yl) oxy) -3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one, or a pharmaceutically acceptable salt thereof, (2) silicified microcrystalline cellulose, and (3) optionally other pharmaceutically acceptable excipients, aS active ingredients, and the particulate composition is prepared by roller compaction granulation. The invention adopts the mode of directly filling the dry granules into capsules without adding auxiliary materials (such as silicified microcrystalline cellulose) and controlling the content of the silicified microcrystalline cellulose, thereby solving the problem of poor stability of small-size (such as 5mg) capsules. The obtained capsule composition with small specification (such as 5mg) has good preparation stability, the production process is suitable for amplification, and the content of each batch is uniform.

Description

RAF kinase inhibitor capsule composition
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation containing RAF kinase inhibitor 5- (((1R, 1aS, 6bR) -1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazole-2-yl) -1a, 6 b-dihydro-1H-cyclopropa [ b ] benzofuran-5-yl) oxy) -3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one or pharmaceutically acceptable salts thereof.
Background
RAS/RAF/MEK/ERK are important pathways for regulating tumor cell growth, and are involved in regulating various biological processes in cells, such as cell growth, differentiation, apoptosis and the like. RAF is a family of serine/threonine-specific kinases including a-RAF, B-RAF and C-RAF, in which the B-RAF gene is found to be mutated in numerous malignancies such as melanoma (40-50%), thyroid (27%), ovarian (15%), colorectal (5-14%), non-small cell lung (2-4%). Two first generation B-RAF inhibitors have been approved by FDA and EMA for the treatment of B-RAF mutated melanoma, which are vemurafenib from roche and dabrafenib from grazing, respectively. However, these two first generation B-RAF inhibitors have limitations and deficiencies with respect to drug resistance, side effects and indications. Therefore, there is still a great need for safer, more effective and more indicated B-RAF inhibitors for tumor patients.
WO2013/097224a1 discloses that the second generation B-RAF inhibitor 5- (((1R, 1aS, 6bR) -1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) -1a, 6B-dihydro-1H-cyclopropa [ B ] benzofuran-5-yl) oxy) -3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one, which has been demonstrated to have potent inhibitory effect on the RAF family of serine/threonine kinases, has now formed a second generation of entirely new molecularly oral targeted antineoplastic agents under development against the B-RAF gene target for B-RAF or K-RAS mutated solid tumors, including melanoma, colorectal cancer, non-small cell lung cancer, etc. The preclinical development has shown that the compound has significant safety and efficacy advantages compared with two first-generation B-RAF inhibitors with the same target just approved in the United states. WO2016/165626 further discloses a sesquimaleate salt of 5- (((1R, 1aS, 6bR) -1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) -1a, 6 b-dihydro-1H-cyclopropa [ b ] benzofuran-5-yl) oxy) -3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one (known aS Lifirafenib) which is very stable to heat and is hardly hygroscopic and has a better bioavailability.
However, the flowability of the Lifirafenib is poor, the agglomeration is easy, the electrostatic effect exists, and the solubility is low, which provides some challenges for the formulation development of the Lifirafenib. The inventors have attempted to prepare capsule fillings by direct mixing with dry powders of conventional fillers such as lactose, especially for formulations of high dosage specifications, which still do not solve the problem of poor flowability due to electrostatic effects, and the powders obtained by direct mixing of dry powders cannot be subjected to automated or semi-automated capsule filling, greatly limiting the development of Lifirafenib formulations. The technical problems of the present invention could not be solved by various attempts of granulation methods such as wet granulation and general dry granulation, and the inventors have determined the development direction of roller compaction granulation as a production process of capsule contents.
In developing the roller compaction granulation process, the inventors have found that when the filler is silicified microcrystalline cellulose, the resulting ribbon from roller compaction has better properties, is suitable for subsequent size reduction granulation and can result in a granular composition suitable for further use. In the study on the formulation of small dose (5mg size), the inventors further found that when silicified microcrystalline cellulose is added or the content of silicified microcrystalline cellulose is relatively high, the content of impurities is increased in the accelerated test, and the formulation is unstable. Thus, the inventors have further developed formulations at specific ratios aimed at improving the stability of small dose (5mg gauge) formulations.
Disclosure of Invention
The invention aims to provide a preparation containing a RAF kinase inhibitor and a preparation process thereof, wherein the RAF kinase inhibitor is 5- (((1R, 1aS, 6bR) -1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) -1a, 6 b-dihydro-1H-cyclopropa [ b ] benzofuran-5-yl) oxy) -3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one or a pharmaceutically acceptable salt thereof; the silicified microcrystalline cellulose is used, a rolling and granulating technology is adopted, granules with good fluidity are obtained, and the stability of a small-dose (5mg) specification preparation is improved by adjusting the proportion of the silicified microcrystalline cellulose.
In order to achieve the above purpose, the invention provides the following technical scheme:
in one aspect, the invention relates to a small format (5mg) capsule composition of a RAF kinase inhibitor, the composition comprising: (1) 5- (((1R, 1aS, 6bR) -1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) -1a, 6 b-dihydro-1H-cyclopropa [ b ] benzofuran-5-yl) oxy) -3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one, or a pharmaceutically acceptable salt thereof, (2) silicified microcrystalline cellulose, and (3) optionally other pharmaceutically acceptable excipients, aS active ingredient, wherein the particulate composition is prepared by roller compaction granulation, wherein silicified microcrystalline cellulose is not added during the preparation process, and the total content of silicified microcrystalline cellulose in the formulation does not exceed 90%.
The other pharmaceutically acceptable excipient comprises one or more of a disintegrant, a lubricant, and a filler.
The active ingredient of the invention is preferably a pharmaceutically acceptable salt of 5- (((1R, 1aS, 6bR) -1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) -1a, 6 b-dihydro-1H-cyclopropa [ b ] benzofuran-5-yl) oxy) -3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one, said salt being selected from the group consisting of hydrochloride, methanesulfonate, 2-hydroxyethanesulfonate, maleate and oxalate.
The salt is a solid, more preferably the salt is in crystalline form.
Preferably, the salt is a maleate salt.
Most preferably, the active ingredient is a crystalline sesquimaleate salt of 5- (((1R, 1aS, 6bR) -1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) -1a, 6 b-dihydro-1H-cyclopropa [ b ] benzofuran-5-yl) oxy) -3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one having the following structure:
Figure BDA0002942627430000031
this compound is also known as Lifirafenib.
The weight percentage of the active ingredient is from 5% to 50%, preferably from 10% to 30%, more preferably from 13% to 20%, based on the total weight of the solids of the particulate composition contained within the capsule.
The silicified microcrystalline cellulose is present in an amount of not more than 85% by weight, preferably not more than 83% by weight, calculated on the total weight of the solids of the particulate composition.
Preferably, the granule composition further comprises one or more of a disintegrant and a lubricant.
Preferably, the granule composition further contains a disintegrant and a lubricant.
Based on the total weight of the solid of the granular composition, the weight percentage of the disintegrating agent is 0.1 to 15 percent; preferably 1% to 5%.
The lubricant is present in an amount of 0.1 to 10% by weight, preferably 0.5 to 5% by weight, based on the total weight of the solids of the particulate composition.
The disintegrating agent is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose. Preferably, the disintegrant is croscarmellose sodium.
The lubricant is selected from one or more of magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, superfine silica gel powder, talcum powder, polyethylene glycol and glyceryl monostearate. Preferably, the lubricant is micro-powder silica gel and/or sodium stearyl fumarate.
In a preferred embodiment, the granule composition further comprises a disintegrant and a lubricant, wherein the disintegrant is croscarmellose sodium, and the lubricant is at least one of aerosil and sodium stearyl fumarate.
In another preferred embodiment, the present invention relates to a RAF kinase inhibitor particle composition comprising: (1) 5-50% by weight of a crystalline sesquimaleate salt of 5- (((1R, 1aS, 6bR) -1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) -1a, 6 b-dihydro-1H-cyclopropa [ b ] benzofuran-5-yl) oxy) -3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one, (2) 50-89% silicified microcrystalline cellulose, (3) 1-5% disintegrant and (4) 0.5-5% lubricant, wherein the particulate composition is prepared by roller compaction granulation, the granulation being directly used for capsule filling.
In addition to the silicified microcrystalline cellulose, the granular composition may optionally contain other fillers selected from one or more of microcrystalline cellulose, lactose, sucrose, mannitol, starch, pregelatinized starch, dextrin, algal polysaccharide, chitosan, monocalcium phosphate, and calcium sulfate.
In a second aspect, the present invention relates to a method of preparing a small format (5mg) capsule of a RAF kinase inhibitor, the method comprising the steps of:
(1) mixing: mixing a prescribed amount of active ingredient, the entire amount of silicified microcrystalline cellulose, a disintegrant, and the entire or partial amount of a lubricant;
(2) and (3) dry granulation: adding the mixture into a granulator, rolling to prepare a belt-shaped object, and crushing the belt-shaped object to pass through a screen to obtain granules;
(3) lubrication: when only part of the lubricant is added in the step (1), adding the rest lubricant into the obtained particles, and mixing;
(4) and (3) filling capsules: and (3) filling the granules prepared in the step (2) or (3) into a capsule shell to prepare a capsule preparation with the specification of 5 mg.
The types and amounts of the active ingredient, disintegrant, lubricant, silicified microcrystalline cellulose are as defined above.
Preferably, said step (4) uses an automatic capsule filling machine.
In a third aspect, the invention also relates to a method of treating and/or preventing a RAF kinase associated disease or disorder, said method comprising administering an oral formulation prepared using a small format (5mg) capsule as described herein.
The invention also relates to application of the particle composition or an oral preparation prepared from the particle composition in preparation of a medicament for treating and/or preventing RAF kinase related diseases or symptoms.
The disease or disorder is cancer. The cancer is selected from: brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, breast cancer, head and neck cancer, ovarian cancer, melanoma, skin cancer, adrenal cancer, cervical cancer, colorectal cancer, lymphoma, or thyroid tumor and complications thereof.
Preferably wherein the disease is selected from BRAF, NRAS and KRAS mutated brain, lung, kidney, bone, liver, bladder, breast, head and neck, ovary, melanoma, skin, adrenal, cervix, colorectal, lymphoma or thyroid tumours and complications thereof.
As used herein, the terms "comprises," "comprising," or any other variation thereof, mean that the compositions and methods described, etc., include the recited elements and do not exclude others.
The compositions of the present invention comprise a mixture of the active ingredient with other chemical ingredients.
Optionally, the term "optionally" as used herein means optionally with or without the addition of excipients, such as optionally with the addition of excipients means with or without the addition of excipients.
The invention solves the problem of poor stability of the small-specification (5mg) capsule by optimizing the prescription and the process and adopting a mode of controlling the content of silicified microcrystalline cellulose without adding silicified microcrystalline cellulose when the small-specification (5mg) capsule is filled. The obtained capsule composition with small specification (5mg) has good preparation stability, the production process is suitable for amplification, and the content of each batch is uniform.
Detailed Description
The capsules containing the RAF kinase inhibitor particle composition of the present invention are further illustrated by the following examples, which are not intended to limit the invention in any way.
Example 1: preparation of Lifirafenib granules, per 100g of formulation:
Figure BDA0002942627430000051
wherein the Lifiafenib is prescribed in terms of the crystalline sesquimaleate salt of 5- (((1R, 1aS, 6bR) -1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) -1a, 6 b-dihydro-1H-cyclopropa [ b ] benzofuran-5-yl) oxy) -3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one.
The preparation process comprises the following steps:
(1) mixing: a prescribed amount of Lifirafenib drug substance, a prescribed amount of silicified microcrystalline cellulose, a prescribed amount of croscarmellose sodium, and a prescribed amount of sodium stearyl fumarate were mixed.
(2) And (3) dry granulation: adding the mixture into a Freund Vector granulator (TFC-LAB Micro), feeding at the speed of 20-40 RPM, rolling to prepare a belt, and grinding and screening the belt through a 35-mesh screen to obtain granules.
(3) Lubrication: additional sodium stearyl fumarate was added to the granules obtained above and mixed to obtain a granular composition.
Example 2: a small size (5mg) capsule of Lifirafenib, each capsule being formulated as:
lifiafenib granules (product of example 1) 50mg
Total 50mg
Specification 5mg is calculated aS 5- (((1R, 1aS, 6bR) -1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) -1a, 6 b-dihydro-1H-cyclopropa [ b ] benzofuran-5-yl) oxy) -3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one.
The preparation process comprises the following steps:
(1) filling: the mixture granules of example 1 were filled into empty capsules by an automatic capsule filling machine according to the content of the raw material in the capsule contents and the weight of the contents to obtain capsules of 5mg size.
Repeat 2 batches.
Comparative example 1: a small-size (5mg) capsule of Lifiafenib, the prescription of each capsule is as follows:
lifiafenib granules (product of example 1) 50mg
Silicified microcrystalline cellulose 70mg
Total 120mg
Specification 5mg is based on 5- (((1R, 1aS, 6bR) -1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) -1a, 6 b-dihydro-1H-cyclopropa [ b ] benzofuran-5-yl) oxy) -3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one.
The preparation process comprises the following steps:
(1) external mixing of a filling agent: the mixture granules of example 1 were measured as prescribed and silicified microcrystalline cellulose was applied as prescribed.
(2) Filling: the final blend granules are filled into empty capsules by an automatic capsule filling machine according to the content of the raw drug in the capsule contents and the weight of the contents.
Repeat 4 batches.
Test example 1 accelerated test
The Lifiafenib capsules prepared in example 2 and comparative example 1 were subjected to quality inspection while performing accelerated tests (test conditions 40 ℃/75% RH for 6 months). The results are shown in table 1.
TABLE 1 Lifiafenib Capsule accelerated test results
Figure BDA0002942627430000061
Figure BDA0002942627430000071
As shown in table 1, the amount of impurities, the content of each batch of comparative example 1 is significantly higher than that of example 2. The stability of the Lifirafenib capsule can be significantly improved by omitting the addition of silicified microcrystalline cellulose while controlling the content of silicified microcrystalline cellulose.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, so that any simple modification, equivalent change or modification made to the above embodiment according to the technical spirit of the present invention will still fall within the scope of the technical solution of the present invention without departing from the content of the technical solution of the present invention.

Claims (8)

1. A 5mg format RAF kinase inhibitor capsule composition, comprising: (1) 5- (((1R, 1aS, 6bR) -1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) -1a, 6 b-dihydro-1H-cyclopropa [ b ] benzofuran-5-yl) oxy) -3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one or a pharmaceutically acceptable salt thereof, (2) silicified microcrystalline cellulose and (3) optionally other pharmaceutically acceptable excipients aS active ingredients, wherein the particulate composition is prepared by roller compaction granulation, characterized in that the silicified microcrystalline cellulose is not added during the preparation process and the total content of silicified microcrystalline cellulose in the preparation does not exceed 90%.
2. The composition of claim 1, the other pharmaceutically acceptable excipients comprising one or more of a disintegrant, a lubricant, a filler.
3. A composition according to claim 1 or 2, wherein the active ingredient is a pharmaceutically acceptable salt of 5- (((1R, 1aS, 6bR) -1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) -1a, 6 b-dihydro-1H-cyclopropa [ b ] benzofuran-5-yl) oxy) -3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one selected from the group consisting of hydrochloride, methanesulfonate, 2-hydroxyethanesulfonate, maleate and oxalate; more preferably, the active ingredient has the following structure:
Figure FDA0002942627420000011
4. a composition according to any of claims 1 to 3, wherein the weight percentage of active ingredient is from 5% to 50%, preferably from 10% to 30%, more preferably from 13% to 20%, calculated on the total weight of the solids of the particulate composition contained in the capsule; the silicified microcrystalline cellulose is present in a percentage by weight not exceeding 85%, preferably not exceeding 83%.
5. The composition according to any one of claims 1 to 4, wherein the granular composition further comprises a disintegrant and a lubricant, wherein the weight percentage of the disintegrant is 0.1% to 15% based on the total weight of the solids of the granular composition; preferably 1 to 5 percent; and/or the weight percentage of the lubricant is 0.1-10%, preferably 0.5-5%.
6. The composition according to any one of claims 1 to 5, wherein the disintegrating agent is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose; preferably, the disintegrant is croscarmellose sodium; and/or the lubricant is selected from one or more of magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, superfine silica powder, talcum powder, polyethylene glycol and glyceryl monostearate; preferably, the lubricant is micro-powder silica gel and/or sodium stearyl fumarate.
7. The composition of any one of claims 1-6, comprising: (1) 5-50% by weight of a crystalline sesquimaleate salt of 5- (((1R, 1aS, 6bR) -1- (6- (trifluoromethyl) -1H-benzo [ d ] imidazol-2-yl) -1a, 6 b-dihydro-1H-cyclopropa [ b ] benzofuran-5-yl) oxy) -3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one, (2) 50-89% silicified microcrystalline cellulose, (3) 1-5% disintegrant and (4) 0.5-5% lubricant, wherein the particulate composition is prepared by roller compaction granulation, the granulation being directly used for capsule filling.
8. Use of a particulate composition according to claims 1-7 in the manufacture of a medicament for the treatment and/or prevention of a RAF kinase associated disease or disorder.
CN202110186564.9A 2021-02-10 2021-02-10 RAF kinase inhibitor capsule composition Pending CN114903867A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111184693A (en) * 2019-05-29 2020-05-22 百济神州(苏州)生物科技有限公司 RAF kinase inhibitor preparation and preparation method thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111184693A (en) * 2019-05-29 2020-05-22 百济神州(苏州)生物科技有限公司 RAF kinase inhibitor preparation and preparation method thereof

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