WO2020239097A1 - 一种parp抑制剂微丸制剂及其制备工艺 - Google Patents

一种parp抑制剂微丸制剂及其制备工艺 Download PDF

Info

Publication number
WO2020239097A1
WO2020239097A1 PCT/CN2020/093438 CN2020093438W WO2020239097A1 WO 2020239097 A1 WO2020239097 A1 WO 2020239097A1 CN 2020093438 W CN2020093438 W CN 2020093438W WO 2020239097 A1 WO2020239097 A1 WO 2020239097A1
Authority
WO
WIPO (PCT)
Prior art keywords
pellet
pellets
drug
active ingredient
pellet composition
Prior art date
Application number
PCT/CN2020/093438
Other languages
English (en)
French (fr)
Inventor
郭远静
王亦平
范文源
杜争鸣
仇罡
徐铄
吕会茹
Original Assignee
百济神州有限公司
郭远静
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to CN202210604782.4A priority Critical patent/CN115105484A/zh
Priority to US17/613,662 priority patent/US20220233550A1/en
Priority to JP2021570181A priority patent/JP2022534093A/ja
Priority to AU2020282478A priority patent/AU2020282478A1/en
Application filed by 百济神州有限公司, 郭远静 filed Critical 百济神州有限公司
Priority to CN202080015196.5A priority patent/CN113438944A/zh
Priority to SG11202112924RA priority patent/SG11202112924RA/en
Priority to CA3141770A priority patent/CA3141770A1/en
Priority to BR112021018847A priority patent/BR112021018847A2/pt
Priority to EP20812784.5A priority patent/EP3977984A4/en
Priority to EA202192272A priority patent/EA202192272A1/ru
Priority to MX2021014339A priority patent/MX2021014339A/es
Priority to KR1020217030646A priority patent/KR20220016028A/ko
Publication of WO2020239097A1 publication Critical patent/WO2020239097A1/zh
Priority to ZA2021/09635A priority patent/ZA202109635B/en
Priority to IL288467A priority patent/IL288467A/en

Links

Images

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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the disclosure belongs to the field of medicine, and relates to a PARP inhibitor pellet preparation and a preparation method thereof, and specifically relates to (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro -5,6,7a,11-Tetraazacycloheptatrieno[def]cyclopenta[a]fluorene-4(5H)-one and its pharmaceutically acceptable salt or hydrate pellet preparation And its preparation method.
  • Adenosine diphosphate ribose polymerase (Poly (ADP-Ribose) Polymerase, PARP) is a class of proteases with important physiological functions. Exist in the nucleus of eukaryotic cells. The PARP family contains a variety of PARP enzymes, the most important of which is PARP-1. On the one hand, PARP-1 is an abundant DNA gap-sensitive protease. Once the molecule binds to the DNA gap, it activates PARP to cleave NAD+ into nicotinamide and ADP-ribose and polymerize the latter to include histones, transcription factors and PARP On its own nuclear receptor protein.
  • Adenosine diphosphate ribose multimerization plays an important role in DNA repair and genome stability.
  • the over-activation of PARP induced by oxidative stress consumes NAD+, which in turn consumes ATP, resulting in accumulation of cell dysfunction or necrosis.
  • This intracellular suicide mechanism is contained in the pathological mechanisms of many diseases, such as stroke, myocardial infarction, diabetes, diabetes-related cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, enteritis, allergic cerebrospinal cord Inflammation and various other forms of inflammation.
  • PARP as a target for the treatment of malignant tumors has attracted worldwide attention.
  • Olabprib is the world's first PARP inhibitor, and the drug has been marketed in Europe and the United States.
  • WO2013/097225A1 discloses as poly(ADP-ribosyl)transferase (PARPs) inhibitors, and specifically discloses compounds Namely (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclo[def]cyclopentan Dieno[a]fluorene-4(5H)-one, this compound is an inhibitor of adenosine polydiphosphate (ADP) ribose polymerase (PARP), which has high selectivity to PARP-1/2, And can effectively inhibit the proliferation of cell lines with BRCA1/2 mutations or other HR defects.
  • PARPs poly(ADP-ribosyl)transferase
  • WO2017/032289A1 discloses (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatrieno[ def]cyclopenta[a]fluorene-4(5H)-one sesquihydrate, which has the following structure: This sesquihydrate has excellent chemical stability and is called Pamiparib.
  • Pamiparib has significant advantages in safety and effectiveness compared with olaparib and other PARP inhibitors (such as Veliparib) that have entered clinical phase III by the US FDA: it has stronger DNA capture activity; in vitro with BRCA mutations In the experiment of xenotransplantation model, Pamiparib is about 16 times more active than olaparib; and it has good PARP1/2 selectivity. Rodents have good tolerance to Pamiparib and have about 10 times the treatment Window; In addition, the drug has no CYP inhibitory activity and exhibits strong combined drug activity and excellent pharmacokinetic properties: it has excellent DMPK properties and significant brain permeability.
  • PARP inhibitors such as Veliparib
  • Pamiparib has poor fluidity, and it is difficult to directly fill the product during the preparation process. Therefore, it is necessary to develop a formulation that overcomes the poor fluidity of Pamiparib and is suitable for mass production.
  • the inventors have made a lot of attempts in the development of Pamiparib formulations, and found that the development of Pamiparib into pellets has successfully reduced the amount of APIs.
  • the difficulty of the formulation improves the fluidity and stability of the product, and makes mass commercial production possible, convenient for transportation and storage, simple preparation process, no special requirements for equipment, and the final product has good stability and is suitable for large-scale production. produce.
  • the inventors unexpectedly discovered that mixing the prepared pellets with a certain amount of lubricant such as talc effectively reduces the electrostatic interaction between the pellets, thereby enabling the industrial production of pellet preparations.
  • the inventors of the present invention succeeded in improving the fluidity of the bulk drug powder after preparing Pamiparib into pellets; and after mixing the pellets with a lubricant such as talc, the electrostatic effect between the pellets was prevented. , Thereby facilitating the packaging of capsules.
  • the inventor also found through a large number of creative experiments that the D 90 of the raw material drug Pamiparib has a certain impact on the quality attributes of the final product. As an unexpected surprise, when D 90 is less than 30 ⁇ m, the ideal quality attributes can be obtained. The final product.
  • the invention relates to a PARP inhibitor pellet composition and a preparation method thereof; a preparation prepared using the pellet composition; and the use of the pellet composition and the preparation for treating/preventing diseases or disorders related to PARP.
  • the present invention relates to a PARP inhibitor pellet composition, said composition comprising: pellets and optional additional excipients, said pellets comprising (1) pellet core; (2) containing The drug layer and (3) an optional protective layer; the drug-containing layer contains (a) the active ingredient and (b) the binder; when the composition contains a protective layer, the protective layer contains (c ) Coating material; the active ingredient is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraaza Cycloheptatrieno[def]cyclopenta[a]fluorene-4(5H)-one, its pharmaceutically acceptable salts and hydrates thereof.
  • the present invention relates to a PARP inhibitor pellet composition, said composition comprising: pellets and optional additional excipients, said pellets comprising (1) pellet cores; (2) ) Drug-containing layer;
  • the drug-containing layer includes (a) an active ingredient and (b) an adhesive; (3) an optional protective layer; the active ingredient is (R)-2-fluoro-10a- Methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclo[def]cyclopenta[a]fluorene-4(5H )-Ketone, its pharmaceutically acceptable salt and its hydrate.
  • the present invention relates to a PARP inhibitor pellet composition, said composition comprising: pellets and optional additional excipients, said pellets comprising (1) pellet cores; (2) ) A drug-containing layer and (3) an optional protective layer; the drug-containing layer includes (a) an active ingredient and (b) a binder; the protective layer includes (c) a coating material; the The active ingredient is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazaheptatrieno[def] Cyclopenta[a]fluorene-4(5H)-one, its pharmaceutically acceptable salt and its hydrate.
  • the pellets are (1) pellet core, (2) drug-containing layer and (3) optional protective layer from the inside to the outside.
  • the optional external excipients include, but are not limited to, fillers, lubricants and other conventionally used excipients.
  • the external excipient contains one or more of a filler and a lubricant, and more preferably, the external excipient contains a lubricant.
  • the additional excipient is mixed with the pellets comprising (1) pellet core; (2) drug-containing layer and (3) optional protective layer.
  • the pellet core is a blank pellet core, selected from one or more of sucrose pellet core, microcrystalline cellulose pellet core, and starch pellet core.
  • the weight percentage of the pellet core to the total weight of the pellet composition is 50% to 90%, preferably 60% to 85% (w/w).
  • the active ingredient is preferably (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11- Tetraazacyclo[def]cyclopenta[a]fluorene-4(5H)-one AL crystal form or (R)-2-fluoro-10a-methyl-7,8,9 ,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclo[def]cyclopenta[a]fluorene-4(5H)-one hydrate.
  • the active ingredient is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptane Trieno[def]cyclopenta[a]fluorene-4(5H)-one crystal form C.
  • the A-L crystal form can be prepared with reference to WO2017/032289A1.
  • the active ingredient is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptane Trieno[def]cyclopenta[a]fluorene-4(5H)-one sesquihydrate, which has the following structure:
  • the inventors discovered that the D 90 of the active ingredient Pamiparib has an impact on the quality attributes of the final product.
  • the D 90 of the active ingredient is less than 100 ⁇ m, preferably D 90 is less than 50 ⁇ m.
  • the D 90 of the active ingredient is most preferably less than 30 ⁇ m. .
  • the weight percentage of the active ingredient to the total weight of the pellet composition is 5%-50%, preferably 10%-25%, further preferably 10-20% (w/w).
  • the active ingredient is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraaza heterocycle
  • the crystal form C of tropo[def]cyclopenta[a]fluorene-4(5H)-one, the particle size D 90 is less than 30 ⁇ m, and the active ingredient accounts for the weight percentage of the total weight of the pellet composition It is 10%-25% (w/w), more preferably 10%-20%.
  • the active ingredient is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraaza heterocycle Heptatrieno[def]cyclopenta[a]fluorene-4(5H)-one sesquihydrate, with a particle size D 90 of less than 30 ⁇ m, and the active ingredient accounts for the weight of the total weight of the pellet composition
  • the percentage is 10%-25% (w/w), more preferably 10%-20%.
  • the binder includes, but is not limited to, one or more of carbomer, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose, and povidone .
  • the weight percentage of the binder to the total weight of the pellet composition is 1%-20%, preferably 1%-10%, more preferably 3%-8%, most preferably 3% % ⁇ 6%(w/w).
  • the binder is selected from hypromellose, sodium hypromellose and povidone.
  • the binder is hypromellose and sodium hypromellose with a weight percentage of 3%-8% (w/w) based on the total weight of the pellet composition.
  • the coating material includes but not limited to one or more of carbomer, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose, and povidone .
  • the coating material accounts for 1% to 25% by weight of the total weight of the pellet composition, preferably 1% to 10%, more preferably 1.5% to 8%, most preferably 3% ⁇ 6% (w/w).
  • the coating material is selected from hypromellose and sodium hypromellose.
  • the coating material is hypromellose and hypromellose sodium with a weight percentage of 1.5%-8% (w/w) of the total weight of the pellet composition.
  • the lubricant includes but is not limited to one of calcium stearate, magnesium stearate, zinc stearate, stearic acid, sodium stearyl fumarate, talc or Several kinds.
  • the weight percentage of the lubricant in the total weight of the pellet composition is 0.1% to 5.0%, preferably 0.1% to 2%. More preferably, it is 0.5% to 1.5% (w/w).
  • the pellets After preparing Pamiparib into pellets, the pellets successfully improved the fluidity of the bulk drug powder, which was sufficient to meet the preparation requirements, without the need for additional lubricants to improve material fluidity. Moreover, the inventor unexpectedly discovered that an electrostatic effect was generated between the pellets, which had a certain impact on the filling of the capsule. In order to avoid the electrostatic problem, the inventor surprisingly found that mixing a certain lubricant in the pellets, especially talc, can effectively reduce the electrostatic effect of the pellets, making it possible for the preparations to be mass-produced commercially. Therefore, preferably, the lubricant is selected from talc.
  • the lubricant is selected from talc powder with a weight percentage of 0.1% to 2% based on the total weight of the pellet composition.
  • the present invention also relates to a PARP inhibitor pellet composition, which comprises: (1) an active ingredient, and the active ingredient is (R)-2-fluoro-10a-methyl-7 ,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclo[def]cyclopenta[a]fluorene-4(5H)-one, Pharmaceutically acceptable salts and hydrates thereof; (2) pellet cores; (3) binders; (4) optional coating materials; and (5) optional external excipients.
  • the present invention relates to a PARP inhibitor pellet composition, the composition comprising: (1) an active ingredient, and the active ingredient is (R)-2-fluoro-10a-methyl- 7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazaheptatrieno[def]cyclopenta[a]fluorene-4(5H)-one , Its pharmaceutically acceptable salt and its hydrate; (2) pellet core; (3) binder; and (4) optional external excipients.
  • the present invention relates to a PARP inhibitor pellet composition, the composition comprising: (1) an active ingredient, and the active ingredient is (R)-2-fluoro-10a-methyl -7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclo[def]cyclopenta[a]fluorene-4(5H)- Ketones, their pharmaceutically acceptable salts and their hydrates; (2) pellet cores; (3) binders; (4) coating materials; and (5) optional external excipients.
  • pellet composition the types, contents and characteristics of the active ingredients, pellet cores, binders, coating materials and additional excipients are as defined above.
  • the present invention relates to a preparation method of the pellet composition.
  • a method for preparing a pellet composition comprising the following steps:
  • step 2) Spray the drug-containing suspension described in step 1) on the surface of the pellet core to form a drug-containing layer to prepare drug-loaded pellets;
  • step 4 Mix the pellets obtained in step 2) or step 3) with external excipients to prepare a total mixed pellets, and this step is optionally performed.
  • the present invention relates to a method for preparing a pellet composition, the method comprising the following steps:
  • step 2) Spray the drug-containing suspension described in step 1) on the surface of the pellet core to form a drug-containing layer to prepare drug-loaded pellets;
  • the present invention relates to a method for preparing a pellet composition, the method comprising the following steps:
  • step 2) Spray the drug-containing suspension described in step 1) on the surface of the pellet core to form a drug-containing layer to prepare drug-loaded pellets;
  • step 3 Mix the pellets obtained in step 2) with external excipients to prepare a total mixed pellets to obtain a pellet composition.
  • the present invention relates to a method for preparing a pellet composition, the method comprising the following steps:
  • step 2) Spray the drug-containing suspension described in step 1) on the surface of the pellet core to form a drug-containing layer to prepare drug-loaded pellets;
  • step 4) Mix the pellets obtained in step 3) with external excipients to prepare a total mixed pellets to obtain a pellet composition.
  • the method of the present invention further includes encapsulating the total mixed pellets into capsules.
  • pellet composition the types, contents and characteristics of the active ingredients, pellet cores, binders, coating materials and additional excipients are as defined above.
  • the present invention relates to an oral formulation of a PARP inhibitor, which is prepared from the above-mentioned pellet composition.
  • a PARP inhibitor oral preparation said oral preparation is prepared from the aforementioned pellet composition, said oral preparation is tablet, capsule, granule, preferably capsule.
  • the capsule When the oral preparation is a capsule, the capsule includes a capsule shell.
  • the capsule shell is selected from gelatin hollow capsule shells, hypromellose hollow capsule shells, preferably gelatin hollow capsule shells.
  • capsules of different specifications can be filled according to the content of the raw material in the pellets and the weight of the pellets.
  • the specifications include but are not limited to each capsule containing (R)-2-fluoro-10a-methyl -7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclo[def]cyclopenta[a]fluorene-4(5H)- Based on the weight of ketone, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 100mg active ingredient.
  • the present invention relates to a method for treating and/or preventing diseases related to PARP.
  • the method uses the pellet composition of the present invention or an oral preparation prepared with the pellet composition.
  • the present invention also relates to the use of the pellet composition or the oral preparation prepared from the pellet composition in the preparation of a medicine for treating and/or preventing mammalian PARP related diseases.
  • the PARP-related diseases of the present invention include but are not limited to: tumor angiogenesis; chronic inflammatory diseases such as rheumatoid arthritis and atherosclerosis; skin diseases such as psoriasis and scleroderma; diabetes induction Skin diseases, diabetic retinopathy, retinopathy of prematurity, age-related degeneration, cancer, hemangioma, glioma, Kaposi's sarcoma, ovarian cancer, breast cancer; lung cancer, including small cell lung cancer; pancreatic cancer , Lymphoma, prostate cancer, colon cancer and skin tumors, and their complications.
  • the disease is preferably selected from BRCA1 and BRCA2 mutant tumors, such as BRCA1 and BRCA2 mutant breast cancer, ovarian cancer and their complications.
  • TMZ temozolomide
  • docetaxel a chemotherapy for example, temozolomide (TMZ) and docetaxel
  • biological therapy for example, radiation therapy.
  • composition and method include the listed elements and do not exclude others.
  • composition of the present invention includes a mixture of active ingredients and other chemical ingredients.
  • the optional (of) in the present invention means that it can be selected or not.
  • the optional additional excipient means that it contains or does not contain additional excipients.
  • the lubricants described in the present invention include conventional lubricants and/or conventional glidants.
  • the invention provides a PARP inhibitor pellet composition, a preparation process and an oral preparation (such as a capsule) prepared by using the pellet composition.
  • the (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatrieno[def] Cyclopenta[a]fluorene-4(5H)-one active ingredient is prepared into drug-loaded pellets, which successfully improves the physical and chemical properties of the raw material drug, and improves the fluidity and stability of the product, making mass commercial production Possibly, it is easy to transport and store, the preparation process is simple, and the final and intermediate products have good stability.
  • the intermediate product pellets have high drug loading, which can be adjusted to different dosages according to clinical indications, which is convenient for patients to take.
  • FIG. 1 Electron microscope image of Pamiparib API.
  • Drug-containing layer Pamiparib 12.08g; Povidone 4.02g
  • Pamiparib is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatrieno[def]
  • capsules of different specifications are filled. Specifications include, but are not limited to, each capsule contains 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg based on the weight of the compound anhydrous. , 70mg, 80mg, 100mg active ingredients.
  • Figure 1 of the specification is an electron microscope image of Pamiparib bulk drug. Because BGB290 bulk drug contains crystal water, it is very easy to agglomerate and has poor fluidity, which is not conducive to capsule filling and affects the large-scale production of the preparation.
  • Figure 2 of the specification is an electron microscope picture of the pellets of Example 1. It can be seen from the picture that the pellets are round in shape, can be evenly spread under the electron microscope field of view, and have good fluidity. Can satisfy the filling of the capsule.
  • Drug-containing layer Pamiparib 11.60g; Hypromellose 7.73g
  • Pamiparib is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatrieno[def]
  • capsules of different specifications are filled. Specifications include, but are not limited to, each capsule contains 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg based on the weight of the compound anhydrous. , 70mg, 80mg, 100mg active ingredients.
  • Drug-containing layer Pamiparib 12.08g; Hypromellose 4.02g
  • Pamiparib is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatrieno[def]
  • capsules of different specifications are filled.
  • the specifications include but are not limited to each capsule containing 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg based on the weight of the compound , 70mg, 80mg, 100mg active ingredients.
  • Medicated layer Pamiparib 12.13g; sodium hydroxymethyl cellulose 4.04g
  • Pamiparib is represented by (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatrieno[def] The total weight of cyclopenta[a]fluorene-4(5H)-one sesquihydrate.
  • capsules of different specifications are filled.
  • the specifications include but are not limited to each capsule containing 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg based on the weight of the compound , 70mg, 80mg, 100mg active ingredients.
  • Medicinal layer Pamiparib 12.08g; sodium hydroxymethyl cellulose 4.02g
  • Pamiparib is represented by (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatrieno[def] The total weight of cyclopenta[a]fluorene-4(5H)-one sesquihydrate.
  • capsules of different specifications are filled.
  • the specifications include but are not limited to each capsule containing 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg based on the weight of the compound , 70mg, 80mg, 100mg active ingredients.
  • Drug-containing layer Pamiparib 20.53g; Povidone 6.84g
  • Pamiparib is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatrieno[def]
  • capsules of different specifications are filled.
  • the specifications include but are not limited to each capsule containing 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg based on the weight of the compound , 70mg, 80mg, 100mg active ingredients.
  • Drug-containing layer Pamiparib 5.16g; Hydroxypropyl cellulose 1.72g
  • Pamiparib is represented by (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatrieno[def] The total weight of cyclopenta[a]fluorene-4(5H)-one sesquihydrate.
  • capsules of different specifications are filled. Specifications include, but are not limited to, each capsule contains 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg based on the weight of the compound anhydrous. , 70mg, 80mg, 100mg active ingredients.
  • Drug-containing layer Pamiparib 12.19g; Hypromellose 4.06g
  • Pamiparib is represented by (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatrieno[def] The total weight of cyclopenta[a]fluorene-4(5H)-one sesquihydrate.
  • capsules of different specifications are filled. Specifications include, but are not limited to, each capsule contains 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg based on the weight of the compound anhydrous. , 70mg, 80mg, 100mg active ingredients.
  • Drug-containing layer Pamiparib 11.85g; Povidone 3.95g
  • Pamiparib is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatrieno[def]
  • capsules of different specifications are filled.
  • the specifications include but are not limited to each capsule containing 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg based on the weight of the compound , 70mg, 80mg, 100mg active ingredients.
  • Example 10- The effect of the particle size of the raw material drug on the active ingredient content of Pamiparib pellets
  • Drug-containing layer Pamiparib 12.08g; Povidone 4.02g
  • Pamiparib is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatrieno[def]
  • Example 3 According to the method described in Example 3, a 20 mg capsule was prepared.
  • the D90 is measured by a Malvern Laser Particle Sizer 3000 using laser diffraction method.
  • Assay determination Weigh 225mg of capsule contents pellets (allowable weighing range: 158-292mg), dilute the contents pellets 250 times with diluent, mix well, use 0.45 ⁇ m PTFE syringe filter, discard 3ml, The collected filtrate was detected by UV method at a wavelength of 297nm/or determined by HPLC, and the analysis results were as follows.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (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)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Ophthalmology & Optometry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种PARP抑制剂微丸组合物及其制备工艺，所述微丸组合物包含：微丸和任选地的外加赋形剂，所述的微丸包含(1)微丸丸芯；(2)含药层以及(3)任选地保护层；含药层包含(a)活性成分和(b)粘合剂；当所述组合物包含保护层时，所述的保护层包含(c)包衣材料；所述的活性成分为(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮、其药物上可接受的盐及其水合物。

Description

一种PARP抑制剂微丸制剂及其制备工艺 技术领域
本披露属于药物领域，涉及了一种PARP抑制剂微丸制剂及其制备方法，具体涉及(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮及其药学可接受的盐或水合物的微丸制剂及其制备方法。
背景技术
二磷酸腺苷核糖多聚酶(Poly(ADP-Ribose)Polymerase，PARP)是一类具有重要生理功能的蛋白酶。存在于真核细胞的核中。PARP家族包含多种PARP酶，其中较为重要的是PARP-1。一方面，PARP-1是丰富的DNA缺口敏感的蛋白酶，该分子一旦结合到DNA缺口，便激活PARP将NAD+切割为烟酰胺和ADP-核糖并将后者聚合到包括组蛋白，转录因子和PARP本身的核受体蛋白上。二磷酸腺苷核糖多聚化对DNA修复和基因组稳定性起着重要作用。另一方面，氧化压力诱导的PARP过激活消耗了NAD+，随之又消耗了ATP,累积造成细胞功能失调或坏死。这种细胞内的自杀机制蕴涵在许多疾病的病理机制中，如中风、心肌梗死、糖尿病、糖尿病相关的心血管功能失调、休克、创伤性中枢神经系统损伤、关节炎、肠炎、过敏性脑脊髓炎和各种其他形式的炎症。PARP作为恶性肿瘤治疗的靶标引起了世界范围的广泛关注。奥拉帕尼(Olabprib)是全球第一个PARP抑制剂，该药物已经在欧洲和美国上市。
WO2013/097225A1公开了作为聚(ADP-核糖基)转移酶(PARPs)抑制剂，并具体公开了化合物
Figure PCTCN2020093438-appb-000001
即(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮，该化合物是一种聚二磷酸腺苷(ADP)核糖聚合酶(PARP)的抑制剂，其对PARP-1/2具有高选择性，并能有效抑制具有BRCA1/2突变或其它HR缺陷的细胞系的增殖。WO2017/032289A1公开了(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮的倍半水合物，其具有如下结构：
Figure PCTCN2020093438-appb-000002
该倍半水合物具有优良的化学稳定性，被称为Pamiparib。临床前研究表明Pamiparib与奥拉帕尼和美国FDA进入临床III期的其他PARP抑制剂(比如Veliparib)相比安全性和有效性有显著优势：具有更强的DNA捕获活性；在BRCA变异的体外异种移植模型的实验中，Pamiparib比奥拉帕尼的活性强约16倍；且具有较好的PARP1/2选择性，啮齿类动物对Pamiparib有很好的耐受性并有约10 倍的治疗窗；此外，该药物没有CYP抑制活性并表现出较强的联合用药活性和优异的药物代谢动力学性质：具有卓越的DMPK性质和显著的脑渗透性。
然而，Pamiparib的流动性较差，在制剂生产过程中，难以直接灌装生产。因此，需要开发出克服Pamiparib流动性差而且适合大规模生产的制剂。
发明内容
为了克服Pamiparib原料药在制备制剂时所遇到的理化性质方面的不足，发明人在Pamiparib制剂开发方面进行了大量的尝试，并发现，将Pamiparib开发为微丸制剂，成功地降低了原料药在制剂方面的难度，提高了产品的流动性和稳定性，使得大批量商业生产成为可能，便于运输和贮藏，制备工艺简便，对设备无特殊要求，并且最终获得的成品稳定性良好，适合规模化生产。此外，发明人意料不到地发现，将所制备的微丸与一定量的润滑剂如滑石粉混合，有效地降低了微丸之间的静电作用，从而能够工业化生产微丸制剂。
因此，本发明的发明人在将Pamiparib制备为微丸后，成功地改善了原料药粉末的流动性；而且将微丸与润滑剂如滑石粉混合后，防止了微丸之间产生的静电作用，从而有利于胶囊剂的封装。
在此基础上，发明人还通过大量创造性实验研究发现，原料药Pamiparib的D 90对最终产品的质量属性有一定的影响，作为意外的惊喜，当D 90小于30μm时，能获得理想质量属性的终产品。
本发明涉及一种PARP抑制剂微丸组合物及其制备方法；使用微丸组合物制备的制剂；以及使用微丸组合物及其制剂用于治疗/预防与PARP相关的疾病或病症的用途。
第一方面，本发明涉及一种PARP抑制剂微丸组合物，所述组合物包含：微丸和任选的外加赋形剂，所述的微丸包含(1)微丸丸芯；(2)含药层以及(3)任选的保护层；所述的含药层包含(a)活性成分和(b)粘合剂；当所述组合物包含保护层时，所述的保护层包含(c)包衣材料；所述的活性成分为(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮、其药物上可接受的盐及其水合物。
在一些实施方式中，本发明涉及一种PARP抑制剂微丸组合物，所述组合物包含：微丸和任选的外加赋形剂，所述的微丸包含(1)微丸丸芯；(2)含药层；所述的含药层包含(a)活性成分和(b)粘合剂；(3)任选的保护层；所述的活性成分为(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮、其药物上可接受的盐及其水合物。
在一些实施方式中，本发明涉及一种PARP抑制剂微丸组合物，所述组合物包含：微丸和任选的外加赋形剂，所述的微丸包含(1)微丸丸芯；(2)含药层以及(3)任选的保护层；所述的含药层包含(a)活性成分和(b)粘合剂；所述的保护层包含(c)包衣材料；所述的活性成分为(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮、其药物上可接受的盐及其水合物。
优选地，所述微丸从内至外依次为(1)微丸丸芯，(2)含药层和(3)任选的保护层。
在上述微丸组合物中，所述任选的外加赋形剂包含包括但不限于填充剂、润滑剂及其他常规使用的赋形剂。优选地所述的外加赋形剂包含填充剂、润滑剂中的一种或几种，更优选地所述的外加赋形剂包含润滑剂。
任选地，所述外加赋形剂与包含(1)微丸丸芯；(2)含药层以及(3)任选的保护层的微丸混合在一起。
在上述微丸组合物中，所述的微丸丸芯为空白丸芯，选自蔗糖微丸丸芯、微晶纤维素微丸丸芯，淀粉微丸丸芯中的一种或几种。
在上述微丸组合物中，所述的微丸丸芯占微丸组合物总重的重量百分比为50％～90％，优选60％～85％(w/w)。
在上述微丸组合物中，所述的活性成分优选(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮的A-L晶型或(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮的水合物。
优选地，所述的活性成分为(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮的C晶型。
所述的A-L晶型可参照WO2017/032289A1制备。
优选地，所述的活性成分为(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮的倍半水合物，其具有如下结构：
Figure PCTCN2020093438-appb-000003
作为本发明额外的部分，发明人发现活性成分Pamiparib的D 90对最终产品的质量属性有影响。
优选地，所述的活性成分的D 90小于100μm，优选为D 90小于50μm。
作为意外的惊喜，当D 90小于30μm，最终产品将获得理想的终产品含量(99％以上)，因此，最优选地活性成分的D 90小于30μm。。
优选地，所述的活性成分占微丸组合物总重的重量百分比为5％-50％，优选10％-25％，进一步优选为10-20％(w/w)。
作为优选地，所述的活性成分为(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮的C晶型，粒径D 90小于30μm，所述的活性成分占微丸组合物总重的重量百分比为10％-25％(w/w)，更优选10％～20％。
作为优选地，所述的活性成分为(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮的倍半水合物，粒径D 90小于30μm，所述的活性成分占微丸组合物总重的重量百分比为10％-25％(w/w)，更优选10％～20％。
在上述微丸组合物中，所述的粘合剂包含但不限于卡波姆、羧甲基纤维素钠、羟丙纤维素、羟丙甲纤维素、聚维酮中的一种或多种。
在上述微丸组合物中，所述的粘合剂占微丸组合物总重的重量百分比为1％～20％，优选1％～10％，更优选3％～8％，最优选地3％～6％(w/w)。
优选地，所述的粘合剂选自羟丙甲纤维素，羟丙甲纤维素钠以及聚维酮。
更优选地，所述的粘合剂为占微丸组合物总重的重量百分比为3％～8％(w/w)的羟丙甲纤维素、羟丙甲纤维素钠。
在上述微丸组合物中，所述的包衣材料包含但不限于卡波姆、羧甲基纤维素钠、羟丙纤维素、羟丙甲纤维素、聚维酮中的一种或几种。
在上述微丸组合物中，所述的包衣材料占微丸组合物总重的重量百分比为1％～25％，优选1％～10％，更优选1.5％～8％，最优选3％～6％(w/w)。
优选地，所述的包衣材料选自羟丙甲纤维素、羟丙甲纤维素钠。
更优选地，所述的包衣材料为占微丸组合物总重的重量百分比为1.5％～8％(w/w)的羟丙甲纤维素、羟丙甲纤维素钠。
在上述微丸组合物中，所述的润滑剂包括但不限于硬脂酸钙、硬脂酸镁、硬脂酸锌、硬脂酸、硬脂酰富马酸钠、滑石粉的一种或几种。
在上述微丸组合物中，所述的润滑剂占微丸组合物总重的重量百分比为0.1％～5.0％，优选0.1％～2％。更优选0.5％～1.5％(w/w)。
在将Pamiparib制备为微丸后，该微丸成功改善了原料药粉末的流动性，该流动性足以满足制备需求，而无需再额外使用润滑剂来改善物料流动性。而且发明人始料未及地发现微丸之间产生了静电作用，该作用对胶囊剂的灌装产生一定的影响。为了避免静电问题的产生，发明人惊喜地发现在微丸中混入一定的润滑剂，特别是滑石粉可有效降低微丸的静电作用，使得制剂大批量商业生产成为可能。因此，优选地，所述润滑剂选自滑石粉。
优选地，所述的润滑剂选自占微丸组合物总重的重量百分比为0.1％～2％的滑石粉。
第二方面，本发明还涉及一种PARP抑制剂微丸组合物，所述组合物包含：(1)活性成分，所述的活性成分为(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮、药物上可接受的盐及其水合物；(2)微丸丸芯；(3)粘合剂；(4)任选的包衣材料；以及(5)任选的外加赋形剂。
在一些实施方式中，本发明涉及一种PARP抑制剂微丸组合物，所述组合物包含：(1)活性成分，所述的活性成分为(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮、其药物上可接受的盐及其水合物；(2)微丸丸芯；(3)粘合剂；以及(4)任选的外加赋形剂。
在另一些实施方式中，本发明涉及一种PARP抑制剂微丸组合物，所述组合物包含：(1)活性成分，所述的活性成分为(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂 环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮、其药物上可接受的盐及其水合物；(2)微丸丸芯；(3)粘合剂；(4)包衣材料；以及(5)任选的外加赋形剂。
在上述微丸组合物中，所述的活性成分、微丸丸芯、粘合剂、包衣材料以及外加赋形剂的种类、含量及特性如前述所定义。
第三方面，本发明涉及微丸组合物的制备方法。
一种微丸组合物的制备方法，所述方法包括以下步骤：
1)将活性成分分散于粘合剂溶液中，制备含药混悬液；
2)将步骤1)所述的含药混悬液喷于微丸丸芯表面形成含药层，制备成载药微丸；
3)制备包衣材料溶液，将所述包衣材料溶液喷于载药微丸表面作为保护层，制备成保护层微丸，该步骤任选执行；
4)将步骤2)或步骤3)所得到的微丸与外加赋形剂混合，制备成总混微丸，该步骤任选执行。
在一些实施方式中，本发明涉及一种微丸组合物的制备方法，所述方法包括以下步骤：
1)将活性成分分散于粘合剂溶液中，制备含药混悬液；
2)将步骤1)所述的含药混悬液喷于微丸丸芯表面形成含药层，制备成载药微丸；
3)制备包衣材料溶液，将所述包衣材料溶液喷于载药微丸表面作为保护层，制备成保护层微丸即得微丸组合物。
在一些实施方式中，本发明涉及一种微丸组合物的制备方法，所述方法包括以下步骤：
1)将活性成分分散于粘合剂溶液中，制备含药混悬液；
2)将步骤1)所述的含药混悬液喷于微丸丸芯表面形成含药层，制备成载药微丸；
3)将步骤2)所得到的微丸与外加赋形剂混合，制备成总混微丸即得微丸组合物。
在一些实施方式中，本发明涉及一种微丸组合物的制备方法，所述方法包括以下步骤：
1)将活性成分分散于粘合剂溶液中，制备含药混悬液；
2)将步骤1)所述的含药混悬液喷于微丸丸芯表面形成含药层，制备成载药微丸；
3)制备包衣材料溶液，将所述包衣材料溶液喷于载药微丸表面作为保护层，制备成保护层微丸；
4)将步骤3)所得到的微丸与外加赋形剂混合，制备成总混微丸，即得微丸组合物。
本发明的方法进一步包括将所述总混微丸封装为胶囊。
在上述微丸组合物中，所述的活性成分、微丸丸芯、粘合剂、包衣材料以及外加赋形剂的种类、含量及特性如前述所定义。
第四方面，本发明涉及一种PARP抑制剂口服制剂，所述的口服制剂由上述微丸组合物制备。
一种PARP抑制剂口服制剂，所述的口服制剂由前述微丸组合物制备，所述口服制剂为片剂、胶囊、颗粒剂，优选胶囊。
当所述口服制剂为胶囊时，所述胶囊包括胶囊壳。所述胶囊壳选自明胶空心胶囊壳、羟丙甲纤维素空心胶囊壳，优选明胶空心胶囊壳。
当口服制剂为胶囊时，可根据微丸中原料药的含量以及微丸的重量来填充不同规格的胶囊，规格包括但不限于每粒胶囊含有以(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮重量计，5mg、10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、100mg活性成分。
第五方面，本发明涉及一种治疗和/或预防对PARP相关的疾病的方法，所述的方法使用本发明所述的微丸组合物或有所述微丸组合物制备的口服制剂。
本发明还涉及所述微丸组合物或微丸组合物制备的口服制剂在制备用于治疗和/或预防哺乳动物PARP相关疾病的药物中的用途。
本发明所述的与PARP相关的疾病包括但不限于：肿瘤血管发生；慢性炎性疾病，诸如类风湿性关节炎、动脉粥样硬化；皮肤病，诸如银屑病和硬皮病；糖尿病诱导的皮肤病、糖尿病性视网膜病、早产儿视网膜病、年龄相关的变性色斑、癌症，血管瘤、胶质瘤、卡波西肉瘤、卵巢癌、乳腺癌；肺癌，包括小细胞肺癌；胰腺癌、淋巴瘤、前列腺癌、结肠癌和皮肤肿瘤，以及它们的并发症。
在本申请提及的哺乳动物中，优选人类。
所述疾病优选自BRCA1和BRCA2突变体肿瘤，诸如BRCA1和BRCA2突变体乳腺癌、卵巢癌以及它们的并发症。
上述预防或治疗疾病的方法还可与任何化学疗法(例如，替莫唑胺(temozolomide,TMZ)和多西他赛(docetaxel))、生物疗法或放射疗法联合使用。
技术术语
除非另有定义，本发明所使用的技术和科学术语具有所属技术领域人员通常理解的相同的含义。
本发明所用的单数形式“一(a/an)”和“这(the)”包括复数指示物。
本发明所使用的术语“包含“、”包括“或其语法变型表示所述组合物和方法等包括所列举的要素且不排除其它。
本发明所述的组合物包括活性成分与其他化学成分的混合物。
本发明所述的任选地(的)，表示可以选择或不选择，如任选的外加赋形剂表示含有外加赋形剂或不含有外加赋形剂。
本发明所述的润滑剂，包括常规使用的润滑剂和/或常规使用的助流剂。
本发明提供一种PARP抑制剂微丸组合物和制备工艺以及使用该微丸组合物制备的口服制剂(如胶囊剂)。其中，将(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮活性成分制备成载药微丸，成功地改善原料药的理化性质不足，提高了产品的流动性和稳定性使得大批量商业生产成为可能，便于运输和贮藏，制备工艺简便，最终成品和中间产品稳定性良好。并且，中间产品微丸载药量高可根据临床适应症调节不同的给药剂量，方便患者服用。
在微丸中混入一定量的润滑剂如滑石粉可有效降低微丸的静电作用，使得制剂大批量商业生产成为可能。
当D 90小于30μm，最终产品将获得理想质量属性的终产品。
附图说明
图1.是Pamiparib原料药电子显微镜图。
图2.为实施例1微丸的电子显微镜图
具体实施方式
下面的实施例可以帮助本领域的技术人员更全面地理解本发明，但不以任何方式限制本发明。所属原料均可市售获得。
实施例1
100g微丸制剂的处方：
微晶纤维素微丸丸芯 80.50g
含药层：Pamiparib 12.08g；聚维酮 4.02g
保护层：羟丙甲纤维素 2.90g
滑石粉 0.50g
其中Pamiparib以(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮倍半水合物总重计。
制备工艺：
1)称取处方量(4.02g)的聚维酮配制为5％浓度的粘合剂溶液，将12.08g Pamiparib均匀分散在所述粘合剂溶液中，制备含药层包衣混悬液。
2)取处方量的微晶纤维素微丸丸芯，将所述含药层包衣混悬液喷于微丸丸芯表面形成含药层，制备成载药微丸。取处方量(2.90g)的包衣材料羟丙甲纤维素配制5％浓度的包衣材料溶液，将所述包衣材料溶液喷于载药微丸表面作为保护层，制备成含保护层的载药微丸。
3)将上述步骤所获得载药微丸(含保护层)和处方量的滑石粉混合，制备成总混微丸。
4)将所述总混微丸填充胶囊。
根据微丸中原料药的含量以及微丸的重量来填充不同规格的胶囊，规格包括但不限于每粒胶囊含有以化合物无水物重量计，5mg、10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、100mg活性成分。
说明书附图1为Pamiparib原料药的电子显微镜图，由于BGB290原料药含有结晶水，极容易聚团，流动性很差，不利于胶囊填充，影响制剂的工艺化大生产。而说明书附图2为实施例1的微丸电子显微镜图片，由图片可知，微丸形状圆整，可均匀地平铺在电子显微镜视野之下，流动性良好。可满足胶囊的填充。
实施例2
100g微丸制剂的处方：
蔗糖微丸丸芯 77.28g
含药层：Pamiparib 11.60g；羟丙甲纤维素 7.73g
保护层：聚维酮 2.90g
滑石粉 0.50g
其中Pamiparib以(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮倍半水合物总重计。
制备工艺：
1)称取处方量(7.73g)的羟丙甲纤维素配制为5％浓度的粘合剂溶液，将11.60g Pamiparib均匀分散在所述粘合剂溶液中，制备含药层包衣混悬液。
2)取处方量的蔗糖微丸丸芯，将所述含药层包衣混悬液喷于微丸丸芯表面形成含药层，制备成载药微丸。取处方量(2.90g)的包衣材料聚维酮配制5％浓度的包衣材料溶液，将所述包衣材料溶液喷于载药微丸表面作为保护层，制备成含保护层的载药微丸。
3)将上述步骤所获得载药微丸(含保护层)和处方量的滑石粉混合，制备成总混微丸。
4)将所述总混微丸填充胶囊。
根据微丸中原料药的含量以及微丸的重量来填充不同规格的胶囊，规格包括但不限于每粒胶囊含有以化合物无水物重量计，5mg、10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、100mg活性成分。
实施例3
100g微丸制剂的处方：
微晶纤维素微丸丸芯 80.50g
含药层：Pamiparib 12.08g；羟丙甲纤维素 4.02g
保护层：羟丙甲纤维素 2.90g
滑石粉 0.50g
其中Pamiparib以(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮倍半水合物总重计。
制备工艺：
1)称取处方量(4.02g)羟丙甲纤维素配制为5％浓度的粘合剂溶液，将12.08g Pamiparib均匀分散在所述粘合剂溶液中，制备含药层包衣混悬液。
2)取处方量的微晶纤维素微丸丸芯，将所述含药层包衣混悬液喷于微丸丸芯表面形成含药层，制备成载药微丸。取处方量(2.90g)的包衣材料羟丙甲纤维素配制5％浓度的包衣材料溶液，将所述包衣材料溶液喷于载药微丸表面作为保护层，制备成含保护层的载药微丸。
3)将上述步骤所获得载药微丸(含保护层)和处方量的滑石粉混合，制备成总混微丸。
4)将所述总混微丸填充胶囊。
根据微丸中原料药的含量以及微丸的重量来填充不同规格的胶囊，规格包括但不限于每粒胶囊含有以化合物无水物重量计，5mg、10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、100mg活性成分。
实施例4
100g微丸制剂的处方：
微晶纤维素微丸丸芯 79.91g
含药层：Pamiparib 12.13g；羟甲基纤维素钠 4.04g
保护层：羟甲基纤维素钠 2.42g
滑石粉 1.50g
其中Pamiparib以(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮倍半水合物总重计。
制备工艺：
1)称取处方量(4.04g)的羟甲基纤维素钠配制为5％浓度的粘合剂溶液，将12.13g Pamiparib均匀分散在所述粘合剂溶液中，制备含药层包衣混悬液。
2)取处方量的微晶纤维素微丸丸芯，将所述含药层包衣混悬液喷于微丸丸芯表面形成含药层，制备成载药微丸。取处方量(2.42g)的包衣材料羟甲基纤维素钠配制5％浓度的包衣材料溶液，将所述包衣材料溶液喷于载药微丸表面作为保护层，制备成含保护层的载药微丸。
3)将上述步骤所获得载药微丸(含保护层)与处方量的滑石粉混合，制备成总混微丸。
4)将所述总混微丸填充胶囊。
根据微丸中原料药的含量以及微丸的重量来填充不同规格的胶囊，规格包括但不限于每粒胶囊含有以化合物无水物重量计，5mg、10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、100mg活性成分。
实施例5
100g微丸制剂的处方：
蔗糖微丸丸芯 80.50g
含药层：Pamiparib 12.08g；羟甲基纤维素钠 4.02g
保护层：卡波姆 2.90g
滑石粉 0.50g
其中Pamiparib以(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮倍半水合物总重计。
制备工艺：
1)称取处方量(4.02g)的羟甲基纤维素钠配制为5％浓度的粘合剂溶液，将12.08g Pamiparib均匀分散在所述粘合剂溶液中，制备含药层包衣混悬液。
2)取处方量的蔗糖微丸丸芯，将所述含药层包衣混悬液喷于微丸丸芯表面形成含药层，制备成载药微丸。取处方量(2.90g)的包衣材料卡波姆配制5％浓度的包衣材料溶液，将所述包衣材料溶液喷于载药微丸表面作为保护层，制备成含保护层的载药微丸。
3)将上述步骤所获得载药微丸(含保护层)与处方量的滑石粉混合，制备成总混微丸。
4)将所述总混微丸填充胶囊。
根据微丸中原料药的含量以及微丸的重量来填充不同规格的胶囊，规格包括但不限于每粒胶囊含有以化合物无水物重量计，5mg、10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、100mg活性成分。
实施例6
100g微丸制剂的处方：
微晶纤维素微丸丸芯 68.43g
含药层：Pamiparib 20.53g；聚维酮 6.84g
保护层：羟甲基纤维素钠 3.70g
滑石粉 0.50g
其中Pamiparib以(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮倍半水合物总重计。
制备工艺：
1)称取处方量(6.84g)聚维酮配制为5％浓度的粘合剂溶液，将20.53g Pamiparib均匀分散在所述粘合剂溶液中，制备含药层包衣混悬液。
2)取处方量的微晶纤维素微丸丸芯，将所述含药层包衣混悬液喷于微丸丸芯表面形成含药层，制备成载药微丸。取处方量(3.70g)的包衣材料羟甲基纤维素钠配制5％浓度的包衣材料溶液，将所述包衣材料溶液喷于载药微丸表面作为保护层，制备成含保护层的载药微丸。
3)将上述步骤所获得载药微丸(含保护层)与处方量的滑石粉混合，制备成总混微丸。
4)将所述总混微丸填充胶囊。
根据微丸中原料药的含量以及微丸的重量来填充不同规格的胶囊，规格包括但不限于每粒胶囊含有以化合物无水物重量计，5mg、10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、100mg活性成分。
实施例7
100g微丸制剂的处方：
微晶纤维素微丸丸芯 89.40g
含药层：Pamiparib 5.16g；羟丙基纤维素 1.72g
保护层：羟丙甲纤维素 3.22g
滑石粉 0.50g
其中Pamiparib以(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮倍半水合物总重计。
制备工艺：
1)称取处方量(1.72g)羟丙纤维素配制为5％浓度的粘合剂溶液，将5.16g Pamiparib均匀分散在所述粘合剂溶液中，制备含药层包衣混悬液。
2)取处方量的微晶纤维素微丸丸芯，将所述含药层包衣混悬液喷于微丸丸芯表面形成含药层，制备成载药微丸。取处方量(3.22g)的包衣材料羟丙甲纤维素配制5％浓度的包衣材料溶液，将所述包衣材料溶液喷于载药微丸表面作为保护层，制备成含保护层的载药微丸。
3)将上述步骤所获得载药微丸(含保护层)与处方量的滑石粉混合，制备成总混微丸。
4)将所述总混微丸填充胶囊。
根据微丸中原料药的含量以及微丸的重量来填充不同规格的胶囊，规格包括但不限于每粒胶囊含有以化合物无水物重量计，5mg、10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、100mg活性成分。
实施例8
100g微丸制剂的处方：
蔗糖微丸丸芯 81.30g
含药层：Pamiparib 12.19g；羟丙甲纤维素 4.06g
保护层：羟甲基纤维素钠 1.95g
滑石粉 0.50g
其中Pamiparib以(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮倍半水合物总重计。
制备工艺：
1)称取处方量(4.06g)羟丙甲纤维素配制为5％浓度的粘合剂溶液，将12.19g Pamiparib均匀分散在所述粘合剂溶液中，制备含药层包衣混悬液。
2)取处方量的蔗糖微丸丸芯，将所述含药层包衣混悬液喷于微丸丸芯表面形成含药层，制备成载药微丸。取处方量(1.95g)的包衣材料羟甲基纤维素钠配制5％浓度的包衣材料溶液，将所述包衣材料溶液喷于载药微丸表面作为保护层，制备成含保护层的载药微丸。
3)将上述步骤所获得载药微丸(含保护层)与处方量的滑石粉混合，制备成总混微丸。
4)将所述总混微丸填充胶囊。
根据微丸中原料药的含量以及微丸的重量来填充不同规格的胶囊，规格包括但不限于每粒胶囊含有以化合物无水物重量计，5mg、10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、100mg活性成分。
实施例9
100g微丸制剂的处方：
微晶纤维素微丸丸芯 78.97g
含药层：Pamiparib 11.85g；聚维酮 3.95g
保护层：羟丙甲纤维素 4.74g
滑石粉 0.50g
其中Pamiparib以(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮倍半水合物总重计。
制备工艺：
1)称取处方量(3.95g)聚维酮配制为5％浓度的粘合剂溶液，将11.85g Pamiparib均匀分散在所述粘合剂溶液中，制备含药层包衣混悬液。
2)取处方量的微晶纤维素微丸丸芯，将所述含药层包衣混悬液喷于微丸丸芯表面形成含药层，制备成载药微丸。取处方量(4.74g)的包衣材料羟丙甲纤维素配制5％浓度的包衣材料溶液，将所述包衣材料溶液喷于载药微丸表面作为保护层，制备成含保护层的载药微丸。
3)将上述步骤所获得载药微丸(含保护层)与处方量的滑石粉混合，制备成总混微丸。
4)将所述总混微丸填充胶囊。
根据微丸中原料药的含量以及微丸的重量来填充不同规格的胶囊，规格包括但不限于每粒胶囊含有以化合物无水物重量计，5mg、10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、100mg活性成分。
实施例10——原料药粒径对Pamiparib微丸胶囊活性成分含量的影响
发明人在制剂开发过程中意外地发现，Pamiparib原料药的D 90值对微丸胶囊制剂最终产品的活性成分的含量具有一定影响。采用实施例3相同的处方:
100g微丸制剂的处方：
微晶纤维素微丸丸芯 80.50g
含药层：Pamiparib 12.08g；聚维酮 4.02g
保护层：羟丙甲纤维素 2.90g
滑石粉 0.50g
其中Pamiparib以(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮倍半水合物总重计。
实验组1：Pamiparib D 90＝7.87μm
实验组2：Pamiparib D 90＝21.9μm
实验组3：Pamiparib D 90＝35.6μm
实验组4：Pamiparib D 90＝45.5μm
按照实施例3所述的方法制备20mg含量的胶囊。所述D90采用马尔文激光粒度仪3000，使用激光衍射法测定。
含量测定：称取胶囊内容物微丸225mg(允许称量范围：158-292mg)，将内容物微丸用稀释剂稀释250倍，混匀，用0.45μm PTFE针式过滤器，弃去3ml，收集滤液使用UV方法在波长297nm处检测/或使用HPLC测定，分析含量结果如下。
表1.不同粒径原料药制备的产品的含量结果
实验组别 含量％
实验组1(D 90＝7.87μm) 99.2％
实验组2(D 90＝21.9μm) 99.9％
实验组3(D 90＝35.6μm) 91.5％
实验组4(D 90＝45.5μm) 90.6％
由实验结果可知，当D 90小于30μm时，最终的产品具有较高的含量结果。
上文中已经用一般性说明、具体实施方式和试验对本发明做了详尽的描述，在不偏离本发明精神的基础上所做的修改或改进，均属于本发明要求保护的范围。

Claims (15)

  1. 一种PARP抑制剂微丸组合物，所述组合物包含：微丸和任选的外加赋形剂，所述的微丸包含(1)微丸丸芯；(2)含药层以及(3)任选的保护层；所述的含药层包含(a)活性成分和(b)粘合剂；当所述组合物包含保护层时，所述的保护层包含(c)包衣材料；所述的活性成分为(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮、其药物上可接受的盐及其水合物。
  2. 一种PARP抑制剂微丸组合物，所述组合物包含：(1)活性成分，所述的活性成分为(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮、其药物上可接受的盐及其水合物；(2)微丸丸芯；(3)粘合剂；(4)任选的包衣材料；以及(5)任选的外加赋形剂。
  3. 根据权利要求1或2所述的微丸组合物，所述外加赋形剂包含填充剂、润滑剂中的一种或几种，更优选地所述的外加赋形剂包含润滑剂。
  4. 根据权利要求1或2所述的微丸组合物，所述的微丸丸芯为空白丸芯，选自蔗糖微丸丸芯、微晶纤维素微丸丸芯，淀粉微丸丸芯中的一种或几种；和/或
    所述的微丸丸芯占微丸组合物总重的重量百分比为50％～90％，优选60％～85％(w/w)。
  5. 根据权利要求1或2所述的微丸组合物，所述的活性成分为A-L晶型或水合物；优选地，所述的活性成分为C晶型；优选地，所述的活性成分为倍半水合物，其具有如下结构：
    Figure PCTCN2020093438-appb-100001
  6. 根据权利要求5所述的微丸组合物，所述的活性成分的粒径的D 90小于100μm之间，优选为D 90小于50μm，更优选小于30μm；和/或所述的活性成分占微丸组合物总重的重量百分比为5％-50％，优选10％-25％，进一步优选为10-20％(w/w)。
  7. 根据权利要求1或2所述的微丸组合物，所述的活性成分为(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮的C晶型和/或倍半水合物，粒径为D 90小于30μm，所述的活性成分占微丸组合物总重的重量百分比为10％-25％。
  8. 根据权利要求1或2所述的微丸组合物，所述的粘合剂选自卡波姆、羧甲基纤维素钠、羟丙纤维素、羟丙甲纤维素、羟丙甲纤维素钠、聚维酮中的一种或多种；优选地，所述的粘合剂选自羟丙甲纤维素、羟丙甲纤维素钠、聚维酮；和/或所述的粘合 剂占微丸组合物总重的重量百分比为1％～20％，优选1％～10％，更优选3％～8％，最优选地3％～6％(w/w)。
  9. 根据权利要求1或2所述的微丸组合物，所述的包衣材料选自卡波姆、羧甲基纤维素钠、羟丙纤维素、羟丙甲纤维素、羟丙甲纤维素钠、聚维酮中的一种或几种；优选羟丙甲纤维素、羟丙甲纤维素钠；和/或所述的包衣材料占微丸组合物总重的重量百分比为1％～25％，优选1％～10％，更优选1.5％～8％，最优选3％～6％(w/w)。
  10. 根据权利要求3所述的微丸组合物，所述的润滑剂包括但不限于硬脂酸钙、硬脂酸镁、硬脂酸锌、硬脂酸、硬脂酰富马酸钠、滑石粉的一种或几种，优选滑石粉；和/或所述的润滑剂占微丸组合物总重的重量百分比为0.1％～5.0％，优选0.1％～2％。更优选0.5％～1.5％(w/w)。
  11. 权利要求1-2任一项所述的微丸组合物的制备方法，所述方法包括以下步骤：
    1)将活性成分分散于粘合剂溶液中，制备含药混悬液；
    2)将步骤1)所述的含药混悬液喷于微丸丸芯表面形成含药层，制备成载药微丸；
    3)制备包衣材料溶液，将所述包衣材料溶液喷于载药微丸表面作为保护层，制备成保护层微丸，该步骤任选执行；
    4)将步骤2)或步骤3)所得到的微丸与外加赋形剂混合，制备成总混微丸，该步骤任选执行。
  12. 一种PARP抑制剂口服制剂，所述的口服制剂由前述权利要求1-10任一项所述的微丸组合物制备，所述口服制剂为片剂、胶囊、颗粒剂，优选胶囊。
  13. 根据权利要求12所述的口服制剂，所述的所述胶囊包括胶囊壳；所述胶囊壳选自明胶空心胶囊壳、羟丙甲纤维素空心胶囊壳，优选明胶空心胶囊壳；和/或根据微丸中活性成分的含量以及微丸的重量来填充不同规格的胶囊，规格选自每粒胶囊含有以(R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚三烯并[def]环戊二烯并[a]芴-4(5H)-酮重量计，5mg、10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、100mg活性成分。
  14. 一种治疗PARP相关疾病的方法，所述方法包括向患者施用治疗有效量的权利要求1-11任一项所述的微丸组合物或权利要求12-13任一项所述的口服制剂。
  15. 根据权利要求14所述的方法，所述PARP相关疾病选自肿瘤血管发生、慢性炎性疾病、类风湿性关节炎、动脉粥样硬化、皮肤病，银屑病和硬皮病、糖尿病诱导的皮肤病、糖尿病性视网膜病、早产儿视网膜病、年龄相关的变性色斑、癌症，血管瘤、胶质瘤、卡波西肉瘤、卵巢癌、乳腺癌；肺癌、小细胞肺癌、胰腺癌、淋巴瘤、前列腺癌、结肠癌和皮肤肿瘤，以及它们的并发症。
PCT/CN2020/093438 2019-05-31 2020-05-29 一种parp抑制剂微丸制剂及其制备工艺 WO2020239097A1 (zh)

Priority Applications (14)

Application Number Priority Date Filing Date Title
SG11202112924RA SG11202112924RA (en) 2019-05-31 2020-05-29 Parp inhibitor pellet preparation and preparation process therefor
JP2021570181A JP2022534093A (ja) 2019-05-31 2020-05-29 Ｐａｒｐ阻害剤ペレット製剤及びその調製方法
AU2020282478A AU2020282478A1 (en) 2019-05-31 2020-05-29 PARP inhibitor pellet preparation and preparation process therefor
BR112021018847A BR112021018847A2 (pt) 2019-05-31 2020-05-29 Composições de pélete, método para preparar uma composição de pélete, formulação oral de inibidor de parp, método para tratar uma doença associada à parp
CN202080015196.5A CN113438944A (zh) 2019-05-31 2020-05-29 一种parp抑制剂微丸制剂及其制备工艺
US17/613,662 US20220233550A1 (en) 2019-05-31 2020-05-29 Parp inhibitor pellet preparation and preparation process therefor
CA3141770A CA3141770A1 (en) 2019-05-31 2020-05-29 Parp inhibitor pellet preparation and preparation process therefor
CN202210604782.4A CN115105484A (zh) 2019-05-31 2020-05-29 一种parp抑制剂微丸制剂及其制备工艺
EP20812784.5A EP3977984A4 (en) 2019-05-31 2020-05-29 PREPARATION OF PARP INHIBITOR TABLET AND METHOD OF PREPARATION THEREOF
EA202192272A EA202192272A1 (ru) 2019-05-31 2020-05-29 Гранулированный препарат ингибитора parp и способ его получения
MX2021014339A MX2021014339A (es) 2019-05-31 2020-05-29 Preparacion de granulo inhibidor de parp y proceso de preparacion del mismo.
KR1020217030646A KR20220016028A (ko) 2019-05-31 2020-05-29 Parp 억제제 펠릿 제조 및 이의 제조방법
ZA2021/09635A ZA202109635B (en) 2019-05-31 2021-11-26 Parp inhibitor pellet preparation and preparation process therefor
IL288467A IL288467A (en) 2019-05-31 2021-11-28 Preparation of a parp inhibitor pill and a method for its preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2019089618 2019-05-31
CNPCT/CN2019/089618 2019-05-31

Publications (1)

Publication Number Publication Date
WO2020239097A1 true WO2020239097A1 (zh) 2020-12-03

Family

ID=73553507

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/093438 WO2020239097A1 (zh) 2019-05-31 2020-05-29 一种parp抑制剂微丸制剂及其制备工艺

Country Status (15)

Country Link
US (1) US20220233550A1 (zh)
EP (1) EP3977984A4 (zh)
JP (1) JP2022534093A (zh)
KR (1) KR20220016028A (zh)
CN (2) CN113438944A (zh)
AU (1) AU2020282478A1 (zh)
BR (1) BR112021018847A2 (zh)
CA (1) CA3141770A1 (zh)
EA (1) EA202192272A1 (zh)
IL (1) IL288467A (zh)
MX (1) MX2021014339A (zh)
SG (1) SG11202112924RA (zh)
TW (1) TW202110455A (zh)
WO (1) WO2020239097A1 (zh)
ZA (1) ZA202109635B (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013097225A1 (en) 2011-12-31 2013-07-04 Beigene, Ltd. Fused tetra or penta-cyclic dihydrodiazepinocarbazolones as parp inhibitors
WO2017032289A1 (en) 2015-08-25 2017-03-02 Beigene, Ltd. Process for preparing parp inhibitor, crystalline forms, and uses thereof
CN106619567A (zh) * 2017-01-02 2017-05-10 佛山市腾瑞医药科技有限公司 一种琥珀酸曲格列汀速释微丸制剂与制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108201536A (zh) * 2016-12-16 2018-06-26 中国科学院上海药物研究所 一种奥拉帕尼口服缓控释药物组合物及其用途
WO2019090141A1 (en) * 2017-11-02 2019-05-09 Vicus Therapeutics, Llc Combination drug therapies for cancer and methods of making and using them

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013097225A1 (en) 2011-12-31 2013-07-04 Beigene, Ltd. Fused tetra or penta-cyclic dihydrodiazepinocarbazolones as parp inhibitors
CN103703004A (zh) * 2011-12-31 2014-04-02 百济神州有限公司 作为parp抑制剂的稠合的四环或五环的二氢二氮杂*并咔唑酮
WO2017032289A1 (en) 2015-08-25 2017-03-02 Beigene, Ltd. Process for preparing parp inhibitor, crystalline forms, and uses thereof
CN106619567A (zh) * 2017-01-02 2017-05-10 佛山市腾瑞医药科技有限公司 一种琥珀酸曲格列汀速释微丸制剂与制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3977984A4

Also Published As

Publication number Publication date
BR112021018847A2 (pt) 2021-11-30
AU2020282478A1 (en) 2021-09-16
CA3141770A1 (en) 2020-12-03
JP2022534093A (ja) 2022-07-27
MX2021014339A (es) 2022-01-06
US20220233550A1 (en) 2022-07-28
EA202192272A1 (ru) 2022-03-02
IL288467A (en) 2022-01-01
CN115105484A (zh) 2022-09-27
EP3977984A4 (en) 2023-01-11
EP3977984A1 (en) 2022-04-06
SG11202112924RA (en) 2021-12-30
TW202110455A (zh) 2021-03-16
ZA202109635B (en) 2023-03-29
CN113438944A (zh) 2021-09-24
KR20220016028A (ko) 2022-02-08

Similar Documents

Publication Publication Date Title
JP2023036772A (ja) ブルトンチロシンキナーゼの阻害剤を含む剤形組成物
JP2009073854A (ja) Ｎｆ−カッパｂ阻害剤としてのフマル酸誘導体
EP3630726B1 (en) Crystalline solid forms of salts of n-{4-[(6,7-dimethoxyquinolin-4-yl) oxy]phenyl}-n'-(4-fluorphenyl) cyclopropane-1,1-dicarboxamide, processes for making, and methods of use
WO2018190294A1 (ja) エスシタロプラム医薬組成物
CA2993363A1 (en) Naphthofuran compounds and compositions for targeting cancer stem cells
CN107530304A (zh) Olig2活性的抑制
JP2018513863A (ja) ブロモドメイン阻害剤
KR20140129164A (ko) 히스톤 데아세틸라아제 억제제 및 파조파닙의 조합물 및 이의 용도
KR20190041509A (ko) Olig2 활성의 억제
WO2014056396A1 (zh) 甲磺酸氟马替尼晶型及其制备方法和用途
WO2020239097A1 (zh) 一种parp抑制剂微丸制剂及其制备工艺
CN106102744A (zh) 用于治疗异常细胞生长的组合物和方法
Diggikar et al. Formulation of modified release pellets of Montelukast sodium
TWI794214B (zh) 包含5-氯-n4-[2-(二甲基磷醯基)苯基]-n2-{2-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯基}嘧啶-2,4-二胺之醫藥調配物
KR20130078147A (ko) 일정한 입도를 갖는 ４，５―디아릴―３（２ｈ）―퓨라논 유도체를 포함하는 약학 조성물
KR102481517B1 (ko) 약제학적 제제
CN112007011B (zh) 一种parp抑制剂微丸胶囊及其制备工艺
CN114727965B (zh) 一种jak激酶抑制剂药物组合物
CN107820424A (zh) Mu类鸦片受体拮抗剂与类鸦片药剂的组合剂型
WO2023186031A1 (zh) 多靶点蛋白激酶抑制剂的药物组合物及其用途和制备方法
CN114845723B (zh) 包含喹唑啉衍生物或其盐的药物组合物
WO2022087763A1 (zh) 含有索拉非尼游离碱和5-氟尿嘧啶的共晶体、药物组合物及其用途
TWI843838B (zh) 激酶抑制劑之多晶型、含有該化合物之醫藥組成物、製備方法、及應用
TW201127826A (en) Solid dispersion comprising an anti-HIV agent
Trivedi et al. Nintedanib as the First Treatment for Group of Progressive Interstitial Lung Diseases: A Review of Patent Literature

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20812784

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2020282478

Country of ref document: AU

Date of ref document: 20200529

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112021018847

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 3141770

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2021570181

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 112021018847

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20210922

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020812784

Country of ref document: EP

Effective date: 20220103