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CN112007011B - PARP inhibitor pellet capsule and preparation process thereof - Google Patents

PARP inhibitor pellet capsule and preparation process thereof Download PDF

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Publication number
CN112007011B
CN112007011B CN201910468662.4A CN201910468662A CN112007011B CN 112007011 B CN112007011 B CN 112007011B CN 201910468662 A CN201910468662 A CN 201910468662A CN 112007011 B CN112007011 B CN 112007011B
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pellet
weight
drug
capsule
composition
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CN112007011A (en
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郭远静
王亦平
范文源
杜争鸣
仇罡
徐铄
吕会茹
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Baiji Shenzhou Suzhou Biotechnology Co ltd
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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
    • A61K9/48—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
    • 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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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

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Abstract

The invention relates to a PARP inhibitor pellet capsule and a preparation process thereof, wherein the pellet capsule comprises a pellet composition, and the composition comprises the following components: (1) An active ingredient which is (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one, pharmaceutically acceptable salts thereof and hydrates thereof; (2) a pellet core; (3) an adhesive; (4) an optional coating material; and (5) optionally, additional excipients.

Description

PARP inhibitor pellet capsule and preparation process thereof
Technical Field
The disclosure belongs to the field of medicines, relates to a PARP inhibitor pellet capsule and a preparation method thereof, and in particular relates to a pellet capsule of (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one and pharmaceutically acceptable salts or hydrates thereof and a preparation method thereof.
Background
Adenosine diphosphate ribose Polymerase (Poly (ADP-Ribose) Polymerase, PARP) is a class of proteases with important physiological functions. Is present in the nucleus of eukaryotic cells. The PARP family comprises a variety of PARP enzymes, of which PARP-1 is important. In one aspect, PARP-1 is a rich DNA gap sensitive protease that, once bound to a DNA gap, activates PARP to cleave nad+ into nicotinamide and ADP-ribose and polymerize the latter onto nuclear receptor proteins including histones, transcription factors, and PARP itself. Adenosine diphosphate ribose multimerization plays an important role in DNA repair and genomic stability. On the other hand, oxidative stress induced PARP overactivation consumes nad+ and in turn ATP, and accumulation causes cell dysfunction or necrosis. This intracellular suicide mechanism is implicated in the pathological mechanisms of many diseases, such as stroke, myocardial infarction, diabetes-related cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, enteritis, allergic encephalomyelitis, and various other forms of inflammation. PARP has attracted worldwide attention as a target for malignant tumor treatment. Olaparib (Olabprib) is the first PARP inhibitor worldwide and has been marketed in Europe and the United states.
WO2013/097225A1 discloses compounds as inhibitors of poly (ADP-ribosyl) transferase (PARPs), and in particularI.e., (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one, is an inhibitor of poly (adenosine diphosphate) (ADP) ribose polymerase (PARP), has high selectivity for PARP-1/2, and is effective in inhibiting proliferation of cell lines with BRCA1/2 mutations or other HR defects. WO 2017/032889 A1 discloses sesquihydrates of (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one having the following structure: The sesquihydrate has excellent chemical stability and is called Pamiparib. Preclinical studies have shown that Pamiparib has significant advantages in safety and efficacy over olaparib and other PARP inhibitors that the FDA enters clinical stage III in the united states (such as Veliparib): has stronger DNA capturing activity; pamiparib was about 16-fold more active than olaparib in experiments with in vitro xenograft models of BRCA variation; and has better PARP1/2 selectivity, rodents have good tolerance to Pamiparib and have about 10 times of treatment window; in addition, the drug has no CYP inhibitory activity and shows strong combined drug activity and excellent pharmacokinetic properties: has excellent DMPK properties and remarkable brain permeability.
However, pamiparib is poor in fluidity and difficult to directly fill in the process of manufacturing the formulation.
Therefore, there is a need to develop formulations that overcome Pamiparib's poor flowability and are suitable for large-scale production.
Disclosure of Invention
In order to overcome the defects of Pamiparib in physicochemical properties encountered when the bulk drug is prepared into a preparation, the inventor makes a great deal of attempts in Pamiparib preparation development, and discovers that Pamiparib is developed into a pellet preparation, so that the difficulty in preparing the bulk drug is successfully reduced, the fluidity and stability of the product are improved, the mass commercial production is possible, the transportation and the storage are convenient, the preparation process is simple and convenient, no special requirement is required on equipment, and the finally obtained finished product has good stability and is suitable for large-scale production. Furthermore, the inventors have unexpectedly found that mixing the prepared pellets with a certain amount of a lubricant such as talc effectively reduces the electrostatic effect between the pellets, thereby enabling industrial production of pellet formulations.
Therefore, the inventor of the present invention successfully improved the fluidity of the drug substance powder after Pamiparib was prepared as pellets; and after the pellets are mixed with a lubricant such as talcum powder, the electrostatic effect generated between the pellets is prevented, thereby being beneficial to the encapsulation of the capsule.
Based on this, the inventors have also found through a great deal of creative experimental study that D 90 of bulk drug Pamiparib has a certain influence on the quality properties of the final product, and as an unexpected surprise, when D 90 is less than 30 μm, the final product with desirable quality properties can be obtained.
The invention relates to a PARP inhibitor pellet capsule and a preparation method thereof; and the use of the formulation for the treatment/prevention of diseases or conditions associated with PARP.
In a first aspect, the present invention relates to a PARP inhibitor pellet capsule comprising a pellet composition comprising: micropellets and optionally additional excipients, said micropellets comprising (1) a micropellet core; (2) a drug-containing layer and (3) an optional protective layer; the drug-containing layer comprises (a) an active ingredient and (b) a binder; when the composition comprises a protective layer, the protective layer comprises (c) a coating material; the active ingredient is (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one, pharmaceutically acceptable salts and hydrates thereof.
In some embodiments, the present invention relates to a PARP inhibitor pellet capsule comprising a pellet composition comprising: micropellets and optionally additional excipients, said micropellets comprising (1) a micropellet core; (2) a drug-containing layer; the drug-containing layer comprises (a) an active ingredient and (b) a binder; (3) an optional protective layer; the active ingredient is (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one, pharmaceutically acceptable salts and hydrates thereof.
In some embodiments, the present invention relates to a PARP inhibitor pellet capsule comprising a pellet composition comprising: micropellets and optionally additional excipients, said micropellets comprising (1) a micropellet core; (2) a drug-containing layer and/or (3) a protective layer; the drug-containing layer comprises (a) an active ingredient and (b) a binder; the protective layer comprises (c) a coating material; the active ingredient is (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one, pharmaceutically acceptable salts and hydrates thereof.
Preferably, the pellets are (1) pellet cores, (2) drug-containing layers and (3) optional protective layers in sequence from inside to outside.
In the pellet compositions described above, the optional additional excipients include excipients including, but not limited to, fillers, lubricants and other conventionally used excipients. Preferably the additional excipient comprises one or more of a filler, a lubricant, more preferably the additional excipient comprises a lubricant.
In the micropill composition, the micropill core is blank one or more selected from sucrose micropill core, microcrystalline cellulose micropill core and starch micropill core.
In the pellet composition, the pellet core accounts for 50-90% of the total weight of the pellet composition, and preferably 60-85% (w/w).
In the pellet composition, the active ingredient is preferably (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one in the form of A-L or (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one in the form of hydrate.
Preferably, the active ingredient is the C crystal form of (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one.
The A-L crystal form can be prepared by referring to WO 2017/032889A 1.
Preferably, the active ingredient is a sesquihydrate of (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one, having the following structure:
As an additional part of the invention, the inventors found that D 90 of the active ingredient Pamiparib has an effect on the quality attributes of the final product.
Preferably, the active ingredient has a D 90 of less than 100. Mu.m, preferably a D 90 of less than 50. Mu.m.
As a surprise, when D 90 is less than 30 μm, the final product will achieve the desired final product content (above 99%), and therefore most preferably D 90 of the active ingredient is less than 30 μm. .
Preferably, the active ingredient comprises 5% to 50%, preferably 10% to 25%, more preferably 10% to 20% (w/w) of the total weight of the pellet composition.
Preferably, the active ingredient is (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluorene-4 (5H) -one in the C crystal form, the particle size D 90 is less than 30 μm, and the weight percentage of the active ingredient in the total weight of the pellet composition is 10% -25% (w/w), more preferably 10% -20%.
Preferably, the active ingredient is (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one sesquihydrate, the particle size D 90 is less than 30 μm, and the weight percentage of the active ingredient accounting for the total weight of the pellet composition is 10% -25% (w/w), more preferably 10% -20%.
In the pellet composition, the binder comprises one or more of Yu Kabo m, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose and povidone.
In the pellet composition, the binder accounts for 1 to 20 weight percent of the total weight of the pellet composition, preferably 1 to 10 weight percent, more preferably 3 to 8 weight percent, and most preferably 3 to 6 weight percent (w/w).
Preferably, the binder is selected from hypromellose, sodium hypromellose, and povidone.
More preferably, the binder is hypromellose or hypromellose sodium, which is 3% -8% (w/w) of the total weight of the pellet composition.
In the pellet composition, the coating material comprises one or more of Yu Kabo mu, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose and povidone.
In the pellet composition, the coating material accounts for 1 to 25 percent of the total weight of the pellet composition, preferably 1 to 10 percent, more preferably 1.5 to 8 percent, and most preferably 3 to 6 percent (w/w).
Preferably, the coating material is selected from hypromellose and hypromellose sodium.
More preferably, the coating material is hydroxypropyl methylcellulose and hydroxypropyl methylcellulose sodium which account for 1.5-8% (w/w) of the total weight of the pellet composition.
In the pellet composition, the lubricant comprises one or more of calcium stearate, magnesium stearate, zinc stearate, stearic acid, sodium stearyl fumarate and talcum powder.
In the pellet composition, the lubricant accounts for 0.1 to 5.0 percent, preferably 0.1 to 2 percent of the total weight of the pellet composition. More preferably 0.5% to 1.5% (w/w).
After Pamiparib is prepared into pellets, the pellets successfully improve the flowability of the bulk drug powder, which is sufficient to meet the preparation requirements, without the need of additionally using a lubricant to improve the flowability of the material. Furthermore, the inventors have found, unexpectedly, that an electrostatic effect is generated between the pellets, which effect has a certain effect on the filling of the capsules. In order to avoid the generation of static problems, the inventor surprisingly found that the mixing of a certain lubricant, especially talcum powder, into the pellets can effectively reduce the static effect of the pellets, so that the mass commercial production of the preparation is possible. Thus, preferably, the lubricant is selected from talc.
Preferably, the lubricant is selected from talc in an amount of 0.1% to 2% by weight based on the total weight of the pellet composition.
In a second aspect, the present invention also relates to a PARP inhibitor pellet capsule comprising a pellet composition comprising: (1) The active ingredient is (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluorene-4 (5H) -one, pharmaceutically acceptable salts and hydrates thereof; (2) a pellet core; (3) an adhesive; (4) an optional coating material; and (5) optionally, additional excipients.
In some embodiments, the present invention relates to a PARP inhibitor pellet capsule comprising a pellet composition comprising: (1) An active ingredient which is (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one, pharmaceutically acceptable salts thereof and hydrates thereof; (2) a pellet core; (3) an adhesive; and (4) optionally additional excipients.
In other embodiments, the present invention relates to a PARP inhibitor pellet capsule comprising a pellet composition comprising: (1) An active ingredient which is (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one, pharmaceutically acceptable salts thereof and hydrates thereof; (2) a pellet core; (3) an adhesive; (4) a coating material; and (5) optionally, additional excipients.
In the pellet composition, the types, contents and characteristics of the active ingredients, pellet cores, binders, coating materials and additional excipients are defined as above.
In a third aspect, the present invention relates to a method of preparing a pellet composition.
A method of preparing a pellet composition, the method comprising the steps of:
1) Dispersing the active ingredient in a binder solution to prepare a drug-containing suspension;
2) Spraying the drug-containing suspension in the step 1) on the surface of a pellet core to form a drug-containing layer, and preparing into drug-carrying pellets;
3) Preparing a coating material solution, spraying the coating material solution on the surface of the drug-loaded pellets to serve as a protective layer, and preparing protective layer pellets, wherein the step is optionally executed;
4) Mixing the pellets obtained in step 2) or step 3) with an additional excipient to prepare a total mixed pellet, and optionally performing the step.
In some embodiments, the present invention relates to a method of preparing a pellet composition, the method comprising the steps of:
1) Dispersing the active ingredient in a binder solution to prepare a drug-containing suspension;
2) Spraying the drug-containing suspension in the step 1) on the surface of a pellet core to form a drug-containing layer, and preparing into drug-carrying pellets;
3) And (3) preparing a coating material solution, spraying the coating material solution on the surface of the drug-loaded pellets to serve as a protective layer, and preparing protective layer pellets to obtain the pellet composition.
In some embodiments, the present invention relates to a method of preparing a pellet composition, the method comprising the steps of:
1) Dispersing the active ingredient in a binder solution to prepare a drug-containing suspension;
2) Spraying the drug-containing suspension in the step 1) on the surface of a pellet core to form a drug-containing layer, and preparing into drug-carrying pellets;
3) Mixing the pellets obtained in the step 2) with an external excipient to prepare total mixed pellets, thus obtaining the pellet composition.
In some embodiments, the present invention relates to a method of preparing a pellet composition, the method comprising the steps of:
1) Dispersing the active ingredient in a binder solution to prepare a drug-containing suspension;
2) Spraying the drug-containing suspension in the step 1) on the surface of a pellet core to form a drug-containing layer, and preparing into drug-carrying pellets;
3) Preparing a coating material solution, and spraying the coating material solution on the surface of the drug-loaded pellets to serve as a protective layer, so as to prepare protective layer pellets;
4) Mixing the pellets obtained in the step 3) with an external excipient to prepare total mixed pellets, and obtaining the pellet composition.
In the pellet composition, the types, contents and characteristics of the active ingredients, pellet cores, binders, coating materials and additional excipients are defined as above.
In a fourth aspect, the present invention relates to the preparation of a PARP inhibitor pellet capsule.
The capsule comprises a capsule shell. The capsule shell is selected from gelatin hollow capsule shell and hydroxypropyl methylcellulose hollow capsule shell, preferably gelatin hollow capsule shell.
Capsules of different specifications, including but not limited to 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 100mg of active ingredient by weight of (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one are filled depending on the content of the drug substance in the pellets and the weight of the pellets.
In a fifth aspect, the present invention relates to a method for the treatment and/or prophylaxis of diseases associated with PARP using the pellet capsules of the present invention.
The invention also relates to the application of the oral preparation prepared by the pellet capsule in preparing a medicament for treating and/or preventing the PARP related diseases of mammals.
PARP-related diseases described herein include, but are not limited to: tumor angiogenesis; chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis; skin disorders such as psoriasis and scleroderma; diabetes-induced skin diseases, diabetic retinopathy, retinopathy of prematurity, age-related degenerative spots, 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 complications thereof.
Among the mammals mentioned in the present application, humans are preferred.
The disease is preferably selected from BRCA1 and BRCA2 mutant tumors, such as BRCA1 and BRCA2 mutant breast cancer, ovarian cancer, and complications thereof.
The above methods of preventing or treating a disease may also be used in combination with any chemotherapy (e.g., temozolomide (TMZ) and docetaxel), biological therapy, or radiation therapy.
Technical terminology
Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
The terms "comprising," "including," or grammatical variants thereof, as used herein, mean that the compositions and methods, 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 (as used herein) means optionally or not, as optional additional excipients means with additional excipients or without additional excipients.
The lubricant comprises a conventionally used lubricant and/or a conventionally used glidant.
The invention provides a PARP inhibitor pellet capsule. Wherein, the (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluorene-4 (5H) -ketone active ingredient is prepared into drug-loaded pellets, which successfully improves the physicochemical property of the bulk drug, improves the fluidity and stability of the product, enables mass commercial production to be possible, is convenient for transportation and storage, has simple preparation process, and has good stability of the final product and intermediate product. In addition, the pellet drug loading amount of the intermediate product is high, and different drug dosage can be adjusted according to clinical indications, so that the pellet drug is convenient for patients to take.
The mixing of a certain amount of lubricant such as talcum powder into the pellets can effectively reduce the electrostatic effect of the pellets, so that the mass commercial production of the preparation is possible.
When D 90 is less than 30 μm, the final product will achieve the desired quality attributes of the final product.
Drawings
Fig. 1 is an electron microscope image of Pamiparib drug substances.
FIG. 2 is an electron micrograph of the pellets of example 1
Detailed Description
The following examples will assist those skilled in the art in a more complete understanding of the invention, but are not intended to limit the invention in any way. All the raw materials are commercially available.
Example 1
Prescription of 100g pellet formulation:
Microcrystalline cellulose micropill core 80.50g
Drug-containing layer: pamiparib 12.08.08 g; povidone 4.02g
And (3) a protective layer: hydroxypropyl methylcellulose 2.90g
Talc powder 0.50g
Wherein Pamiparib is based on the total weight of (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one sesquihydrate.
The preparation process comprises the following steps:
1) The prescribed amount (4.02 g) of povidone was weighed to prepare a 5% strength binder solution in which 12.08g Pamiparib was uniformly dispersed to prepare a drug-containing layer coating suspension.
2) Taking the microcrystalline cellulose pellet core with the prescription amount, spraying the coating suspension of the drug-containing layer on the surface of the pellet core to form a drug-containing layer, and preparing the drug-carrying pellet. And preparing 5% concentration coating material solution from the coating material hydroxypropyl methylcellulose with the prescription dosage (2.90 g), and spraying the coating material solution on the surface of the drug-loaded pellets to prepare the drug-loaded pellets containing the protective layer.
3) Mixing the drug-carrying micropill (containing protective layer) obtained in the above steps with the prescribed amount of talcum powder to prepare the total mixed micropill.
4) And filling the total mixed micropellets into capsules.
Capsules of different specifications are filled according to the content of the bulk drug in the pellets and the weight of the pellets, and the specifications include, but are not limited to, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg and 100mg of active ingredient per capsule based on the anhydrous weight of the compound.
Fig. 1 of the specification is an electron microscope image of Pamiparib raw materials, and Pamiparib raw materials contain crystal water, so that the raw materials are extremely easy to agglomerate, have poor fluidity, are not beneficial to capsule filling, and influence the technological mass production of the preparation. In contrast, fig. 2 of the specification is a picture of the electron microscope of the pellets of example 1, and it is clear from the picture that the pellets are round in shape and can be uniformly spread under the field of view of the electron microscope, and have good fluidity. Can satisfy the filling of capsules.
Example 2
Prescription of 100g pellet formulation:
sucrose micropill core 77.28g
Drug-containing layer: pamiparib 11.60.60 g; hydroxypropyl methylcellulose 7.73g
And (3) a protective layer: povidone 2.90g
Talc powder 0.50g
Wherein Pamiparib is based on the total weight of (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one sesquihydrate.
The preparation process comprises the following steps:
1) The prescribed amount (7.73 g) of hypromellose was weighed to prepare a 5% strength binder solution, and 11.60g Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.
2) Taking the sucrose pellet core with the prescription dosage, spraying the coating suspension of the drug-containing layer on the surface of the pellet core to form a drug-containing layer, and preparing the drug-carrying pellet. Coating material povidone with the prescription amount (2.90 g) is taken to prepare coating material solution with the concentration of 5%, and the coating material solution is sprayed on the surface of the drug-loaded pellets to be used as a protective layer, so that the drug-loaded pellets containing the protective layer are prepared.
3) Mixing the drug-carrying micropill (containing protective layer) obtained in the above steps with the prescribed amount of talcum powder to prepare the total mixed micropill.
4) And filling the total mixed micropellets into capsules.
Capsules of different specifications are filled according to the content of the bulk drug in the pellets and the weight of the pellets, and the specifications include, but are not limited to, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg and 100mg of active ingredient per capsule based on the anhydrous weight of the compound.
Example 3
Prescription of 100g pellet formulation:
Microcrystalline cellulose micropill core 80.50g
Drug-containing layer: pamiparib 12.08.08 g; hydroxypropyl methylcellulose 4.02g
And (3) a protective layer: hydroxypropyl methylcellulose 2.90g
Talc powder 0.50g
Wherein Pamiparib is based on the total weight of (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one sesquihydrate.
The preparation process comprises the following steps:
1) The prescribed amount (4.02 g) of hypromellose was weighed to prepare a 5% strength binder solution, and 12.08g Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.
2) Taking the microcrystalline cellulose pellet core with the prescription amount, spraying the coating suspension of the drug-containing layer on the surface of the pellet core to form a drug-containing layer, and preparing the drug-carrying pellet. And preparing 5% concentration coating material solution from the coating material hydroxypropyl methylcellulose with the prescription dosage (2.90 g), and spraying the coating material solution on the surface of the drug-loaded pellets to prepare the drug-loaded pellets containing the protective layer.
3) Mixing the drug-carrying micropill (containing protective layer) obtained in the above steps with the prescribed amount of talcum powder to prepare the total mixed micropill.
4) And filling the total mixed micropellets into capsules.
Capsules of different specifications are filled according to the content of the bulk drug in the pellets and the weight of the pellets, and the specifications include, but are not limited to, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg and 100mg of active ingredient per capsule based on the anhydrous weight of the compound.
Example 4
Prescription of 100g pellet formulation:
microcrystalline cellulose micropill core 79.91g
Drug-containing layer: pamiparib 12.13.13 g; sodium hydroxymethylcellulose 4.04g
And (3) a protective layer: sodium hydroxymethylcellulose 2.42g
Talc powder 1.50g
Wherein Pamiparib is based on the total weight of (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one sesquihydrate.
The preparation process comprises the following steps:
1) The prescribed amount (4.04 g) of sodium hydroxymethyl cellulose was weighed to prepare a 5% strength binder solution, and 12.13g Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.
2) Taking the microcrystalline cellulose pellet core with the prescription amount, spraying the coating suspension of the drug-containing layer on the surface of the pellet core to form a drug-containing layer, and preparing the drug-carrying pellet. Coating material sodium hydroxymethyl cellulose with the prescription amount (2.42 g) is taken to prepare coating material solution with the concentration of 5 percent, and the coating material solution is sprayed on the surface of the drug-carrying micropills to be used as a protective layer, so as to prepare the drug-carrying micropills containing the protective layer.
3) Mixing the drug-carrying micropill (containing protective layer) obtained in the above steps with the prescribed amount of talcum powder to prepare the total mixed micropill.
4) And filling the total mixed micropellets into capsules.
Capsules of different specifications are filled according to the content of the bulk drug in the pellets and the weight of the pellets, and the specifications include, but are not limited to, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg and 100mg of active ingredient per capsule based on the anhydrous weight of the compound.
Example 5
Prescription of 100g pellet formulation:
80.50g of sucrose micropill core
Drug-containing layer: pamiparib 12.08.08 g; sodium hydroxymethylcellulose 4.02g
And (3) a protective layer: carbomer 2.90g
Talc powder 0.50g
Wherein Pamiparib is based on the total weight of (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one sesquihydrate.
The preparation process comprises the following steps:
1) The prescribed amount (4.02 g) of sodium hydroxymethyl cellulose was weighed to prepare a 5% strength binder solution, and 12.08g Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.
2) Taking the sucrose pellet core with the prescription dosage, spraying the coating suspension of the drug-containing layer on the surface of the pellet core to form a drug-containing layer, and preparing the drug-carrying pellet. Coating material carbomer with the prescription amount (2.90 g) is taken to prepare coating material solution with the concentration of 5 percent, and the coating material solution is sprayed on the surface of the drug-carrying micropills to be used as a protective layer, so as to prepare the drug-carrying micropills containing the protective layer.
3) Mixing the drug-carrying micropill (containing protective layer) obtained in the above steps with the prescribed amount of talcum powder to prepare the total mixed micropill.
4) And filling the total mixed micropellets into capsules.
Capsules of different specifications are filled according to the content of the bulk drug in the pellets and the weight of the pellets, and the specifications include, but are not limited to, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg and 100mg of active ingredient per capsule based on the anhydrous weight of the compound.
Example 6
Prescription of 100g pellet formulation:
Microcrystalline cellulose micropill core 68.43g
Drug-containing layer: pamiparib 20.53.53 g; povidone 6.84g
And (3) a protective layer: sodium hydroxymethylcellulose 3.70g
Talc powder 0.50g
Wherein Pamiparib is based on the total weight of (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one sesquihydrate.
The preparation process comprises the following steps:
1) The prescribed amount (6.84 g) of povidone was weighed to prepare a 5% strength binder solution and 20.53g Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.
2) Taking the microcrystalline cellulose pellet core with the prescription amount, spraying the coating suspension of the drug-containing layer on the surface of the pellet core to form a drug-containing layer, and preparing the drug-carrying pellet. Coating material sodium hydroxymethyl cellulose with the prescription amount (3.70 g) is taken to prepare coating material solution with the concentration of 5 percent, and the coating material solution is sprayed on the surface of the drug-carrying micropills to be used as a protective layer, so as to prepare the drug-carrying micropills containing the protective layer.
3) Mixing the drug-carrying micropill (containing protective layer) obtained in the above steps with the prescribed amount of talcum powder to prepare the total mixed micropill.
4) And filling the total mixed micropellets into capsules.
Capsules of different specifications are filled according to the content of the bulk drug in the pellets and the weight of the pellets, and the specifications include, but are not limited to, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg and 100mg of active ingredient per capsule based on the anhydrous weight of the compound.
Example 7
Prescription of 100g pellet formulation:
Microcrystalline cellulose micropill core 89.40g
Drug-containing layer: pamiparib 5.16.16 g; hydroxypropyl cellulose 1.72g
And (3) a protective layer: hydroxypropyl methylcellulose 3.22g
Talc powder 0.50g
Wherein Pamiparib is based on the total weight of (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one sesquihydrate.
The preparation process comprises the following steps:
1) The prescribed amount (1.72 g) of hydroxypropylcellulose was weighed to prepare a 5% strength binder solution, and 5.16g Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.
2) Taking the microcrystalline cellulose pellet core with the prescription amount, spraying the coating suspension of the drug-containing layer on the surface of the pellet core to form a drug-containing layer, and preparing the drug-carrying pellet. And preparing 5% concentration coating material solution from the coating material hydroxypropyl methylcellulose with the prescription dosage (3.22 g), and spraying the coating material solution on the surface of the drug-loaded pellets to prepare the drug-loaded pellets containing the protective layer.
3) Mixing the drug-carrying micropill (containing protective layer) obtained in the above steps with the prescribed amount of talcum powder to prepare the total mixed micropill.
4) And filling the total mixed micropellets into capsules.
Capsules of different specifications are filled according to the content of the bulk drug in the pellets and the weight of the pellets, and the specifications include, but are not limited to, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg and 100mg of active ingredient per capsule based on the anhydrous weight of the compound.
Example 8
Prescription of 100g pellet formulation:
81.30g of sucrose micropill core
Drug-containing layer: pamiparib 12.19.19 g; hydroxypropyl methylcellulose 4.06g
And (3) a protective layer: 1.95g of sodium hydroxymethyl cellulose
Talc powder 0.50g
Wherein Pamiparib is based on the total weight of (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one sesquihydrate.
The preparation process comprises the following steps:
1) The prescribed amount (4.06 g) of hypromellose was weighed to prepare a 5% strength binder solution, and 12.19g Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.
2) Taking the sucrose pellet core with the prescription dosage, spraying the coating suspension of the drug-containing layer on the surface of the pellet core to form a drug-containing layer, and preparing the drug-carrying pellet. Coating material sodium hydroxymethyl cellulose with the prescription amount (1.95 g) is taken to prepare coating material solution with the concentration of 5 percent, and the coating material solution is sprayed on the surface of the drug-carrying micropills to be used as a protective layer, so as to prepare the drug-carrying micropills containing the protective layer.
3) Mixing the drug-carrying micropill (containing protective layer) obtained in the above steps with the prescribed amount of talcum powder to prepare the total mixed micropill.
4) And filling the total mixed micropellets into capsules.
Capsules of different specifications are filled according to the content of the bulk drug in the pellets and the weight of the pellets, and the specifications include, but are not limited to, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg and 100mg of active ingredient per capsule based on the anhydrous weight of the compound.
Example 9
Prescription of 100g pellet formulation:
microcrystalline cellulose micropill core 78.97g
Drug-containing layer: pamiparib 11.85.85 g; povidone 3.95g
And (3) a protective layer: hydroxypropyl methylcellulose 4.74g
Talc powder 0.50g
Wherein Pamiparib is based on the total weight of (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one sesquihydrate.
The preparation process comprises the following steps:
1) The prescribed amount (3.95 g) of povidone was weighed to prepare a 5% strength binder solution, and 11.85g Pamiparib was uniformly dispersed in the binder solution to prepare a drug-containing layer coating suspension.
2) Taking the microcrystalline cellulose pellet core with the prescription amount, spraying the coating suspension of the drug-containing layer on the surface of the pellet core to form a drug-containing layer, and preparing the drug-carrying pellet. And preparing 5% concentration coating material solution from the coating material hydroxypropyl methylcellulose with the prescription dosage (4.74 g), and spraying the coating material solution on the surface of the drug-loaded pellets to prepare the drug-loaded pellets containing the protective layer.
3) Mixing the drug-carrying micropill (containing protective layer) obtained in the above steps with the prescribed amount of talcum powder to prepare the total mixed micropill.
4) And filling the total mixed micropellets into capsules.
Capsules of different specifications are filled according to the content of the bulk drug in the pellets and the weight of the pellets, and the specifications include, but are not limited to, 5mg, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg and 100mg of active ingredient per capsule based on the anhydrous weight of the compound.
Example 10 Effect of drug substance particle size on Pamiparib Capsule active ingredient content
The inventors have unexpectedly found during the formulation development process that the D 90 value of Pamiparib drug substance has a certain effect on the content of active ingredient in the final product of the pellet capsule formulation. The same recipe as in example 3 was used:
prescription of 100g pellet formulation:
Microcrystalline cellulose micropill core 80.50g
Drug-containing layer: pamiparib 12.08.08 g; povidone 4.02g
And (3) a protective layer: hydroxypropyl methylcellulose 2.90g
Talc powder 0.50g
Wherein Pamiparib is based on the total weight of (R) -2-fluoro-10 a-methyl-7, 8,9,10 a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one sesquihydrate.
Experiment group 1: pamiparib D 90 = 7.87 μm
Experiment group 2: pamiparib D 90 = 21.9 μm
Experiment group 3: pamiparib D 90 = 35.6 μm
Experiment group 4: pamiparib D 90 = 45.5 μm
Capsules with 20mg content were prepared as described in example 3. The D90 was measured using a laser diffraction method using a malvern laser particle sizer 3000.
And (3) content measurement: 225mg (allowable weighing range: 158-292 mg) of the capsule content pellets were weighed, the content pellets were diluted 250 times with a diluent, mixed well, 3ml was discarded with a 0.45 μm PTFE needle filter, and the filtrate was collected and detected at a wavelength of 297nm using a UV method and/or measured using HPLC, and the analysis content results were as follows.
TABLE 1 content results of products prepared from crude drugs of different particle sizes
Group of experiments Content%
Experiment group 1 (D 90 =7.87 μm) 99.2％
Experiment group 2 (D 90 =21.9 μm) 99.9％
Experiment group 3 (D 90 =35.6 μm) 91.5％
Experiment group 4 (D 90 =45.5 μm) 90.6％
From the experimental results, it is found that when D 90 is less than 30. Mu.m, the final product has a higher content.
The invention has been described in detail in the foregoing general description, embodiments and experiments, and modifications or improvements can be made without departing from the spirit of the invention, which falls within the scope of the invention as claimed.

Claims (19)

1. A PARP inhibitor pellet capsule, said pellet capsule comprising a pellet composition comprising:
(1) An active ingredient which is a crystalline sesquihydrate of (R) -2-fluoro-10 a-methyl-7, 8,9, 10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one, having the structure:
(2) Microcrystalline cellulose micropellet cores;
(3) The adhesive is hydroxypropyl methylcellulose;
(4) Optionally, a coating material, wherein the coating material is hypromellose; and
(5) Optionally, an additional excipient, wherein the additional excipient is talcum powder;
Wherein the active ingredient has a particle size D 90 of less than 30 μm; and
The weight percentage of the active ingredient accounting for the total weight of the pellet composition is 5% -50% (w/w).
2. The micropellet capsule of claim 1, wherein said microcrystalline cellulose micropellet core comprises 50% to 90% (w/w) by weight of the total weight of the micropellet composition.
3. The micropellet capsule of claim 2, wherein the microcrystalline cellulose micropellet core comprises 60% to 85% (w/w) by weight of the total weight of the micropellet composition.
4. The pellet capsule of claim 1, wherein the active ingredient is a-L crystalline form or a hydrate.
5. The pellet capsule of claim 4, wherein the active ingredient is in form C.
6. The pellet capsule of claim 1, wherein the active ingredient comprises 10% to 25% (w/w) by weight of the total weight of the pellet composition.
7. The pellet capsule of claim 6, wherein the active ingredient comprises 10-20% (w/w) by weight of the total weight of the pellet composition.
8. The pellet capsule of claim 1, wherein the binder comprises 1% to 20% (w/w) by weight of the total weight of the pellet composition.
9. The pellet capsule of claim 8, wherein the binder comprises 1% to 10% (w/w) by weight of the total weight of the pellet composition.
10. The pellet capsule of claim 9, wherein the binder comprises 3% to 8% (w/w) by weight of the total weight of the pellet composition.
11. The pellet capsule of claim 10, wherein the binder comprises 3% to 6% (w/w) by weight of the total weight of the pellet composition.
12. The pellet capsule of claim 1, wherein the coating material comprises 1% to 25% (w/w) by weight of the total weight of the pellet composition.
13. The pellet capsule of claim 12, wherein the coating material comprises 1% to 10% (w/w) by weight of the total weight of the pellet composition.
14. The pellet capsule of claim 13, wherein the coating material comprises 1.5% to 8% (w/w) by weight of the total weight of the pellet composition.
15. The pellet capsule of claim 14, wherein the coating material comprises 3% to 6% (w/w) by weight of the total weight of the pellet composition.
16. The pellet capsule of claim 1, wherein the additional excipient comprises 0.1% to 5.0% (w/w) by weight of the total weight of the pellet composition.
17. The pellet capsule of claim 16, wherein the additional excipient comprises 0.1% to 2% (w/w) by weight of the total weight of the pellet composition.
18. The pellet capsule of claim 17, wherein the additional excipient comprises 0.5% to 1.5% (w/w) by weight of the total weight of the pellet composition.
19. A process for preparing a pellet capsule as claimed in claim 1, the process comprising the steps of:
1) Dispersing the active ingredient in a binder solution to prepare a drug-containing suspension;
2) Spraying the drug-containing suspension in the step 1) on the surface of a microcrystalline cellulose pellet core to form a drug-containing layer, and preparing into drug-carrying pellets;
3) Preparing a coating material solution, spraying the coating material solution on the surface of the drug-loaded pellets to serve as a protective layer, and preparing protective layer pellets, wherein the step is optionally executed;
4) Mixing the pellets obtained in step 2) or step 3) with an additional excipient to prepare total mixed pellets, wherein the step is optionally executed;
5) And filling the micropills into capsules.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101032464A (en) * 2007-04-01 2007-09-12 杨喜鸿 Combination containing rimonabant and polyvinyl pyrrolidone, solid dispersion and the preparing and medicine application thereof
CN106619567A (en) * 2017-01-02 2017-05-10 佛山市腾瑞医药科技有限公司 Trelagliptin succinate rapid-release pellet preparation and preparation method thereof
CN107922425A (en) * 2015-08-25 2018-04-17 百济神州有限公司 Method for preparing PARP inhibitor, crystal form and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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 (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101032464A (en) * 2007-04-01 2007-09-12 杨喜鸿 Combination containing rimonabant and polyvinyl pyrrolidone, solid dispersion and the preparing and medicine application thereof
CN107922425A (en) * 2015-08-25 2018-04-17 百济神州有限公司 Method for preparing PARP inhibitor, crystal form and application thereof
CN106619567A (en) * 2017-01-02 2017-05-10 佛山市腾瑞医药科技有限公司 Trelagliptin succinate rapid-release pellet preparation and preparation method thereof

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