PARP inhibitor child preparation and preparation process thereof

Abstract

The invention belongs to the field of medicines, and relates to a PARP inhibitor pellet preparation and a preparation method thereof, in particular to a children preparation of (R)-2-fluoro-10a-methyl-7, 8, 9, 10, 10a, 11-hexahydro-5, 6, 7a, 11-tetraazacycloheptatrieno [def] cyclopenta [a] fluorene-4 (5H)-ketone and pharmaceutically acceptable salt or hydrate thereof and a preparation method of the children preparation of the (R)-2-fluoro-10a-methyl-7, 8, 9, 10, 10a, 11-hexahydro-5, 6, 7a, 11-tetraazacycloheptatrieno [def] cyclopenta [a] fluorene-4 (5H)-ketone and the pharmaceutically acceptable salt or hydrate thereof. The pamipalide children preparation can be suitable for different patient weights, the taste can meet patient compliance, and the pamipalide children preparation has the advantages of being convenient to prepare, having certain stability and being capable of being used in a common production line with adult pellet compositions to reduce the cost.

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to a PARP inhibitor pellet preparation and a preparation method thereof, and specifically relates to a children's preparation of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one and a pharmaceutically acceptable salt or hydrate thereof and a preparation method thereof. Background Art

[0002] Poly (ADP-Ribose) Polymerase (PARP) is a class of proteases with important physiological functions. It exists in the nucleus of eukaryotic cells. The PARP family contains a variety of PARP enzymes, among which PARP-1 is more important. On the one hand, PARP-1 is an abundant DNA nick-sensitive protease. Once the molecule binds to the DNA nick, it activates PARP to cut NAD+ into nicotinamide and ADP-ribose and polymerize the latter to nuclear receptor proteins including histones, transcription factors and PARP itself. ADP-ribose polymerization plays an important role in DNA repair and genome stability. On the other hand, oxidative stress-induced PARP overactivation consumes NAD+, which in turn consumes ATP, and the 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, 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 is the world's first PARP inhibitor, which has been marketed in Europe and the United States.

[0003] WO2013 / 097225A1 discloses a poly(ADP-ribosyl) transferase (PARPs) inhibitor, and specifically discloses a compound That is, (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one, which is an inhibitor of poly adenosine diphosphate (ADP) ribose polymerase (PARP) that is highly selective for PARP-1 / 2 and can effectively inhibit the proliferation of cell lines with BRCA1 / 2 mutations or other HR defects.

[0004] WO2017 / 032289A1 discloses a sesquihydrate of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one, which has 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 compared with Olaparib and other PARP inhibitors that have entered Phase III clinical trials by the US FDA (such as Veliparib): it has stronger DNA capture activity; in experiments on in vitro xenograft models of BRCA mutations, Pamiparib is about 16 times more active than Olaparib; and has good PARP1 / 2 selectivity, rodents have good tolerance to Pamiparib and have about 10 times the therapeutic window; in addition, the drug has no CYP inhibitory activity and exhibits strong combination drug activity and excellent pharmacokinetic properties: it has excellent DMPK properties and significant brain permeability. WO2020 / 239097A1 discloses compounds That is, a micropellet composition of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one.

[0005] However, there is no pediatric formulation of pamiparib on the market at present. The dosage of pediatric formulations is directly related to the weight of the child, and the taste of pediatric formulations has a great impact on patient compliance. Summary of the invention

[0006] In order to fill the gap in pamiparib in children's preparations and prepare a pamiparib children's preparation that is suitable for the needs of patients with different weights and has strong compliance, the inventors have made a lot of attempts in the development of pamiparib preparations, and developed the original micro-pellet composition of pamiparib into a children's preparation. The pamiparib children's preparation is not only suitable for different patient weights and has a taste that can meet patient compliance, but also has the advantages of easy preparation, certain stability, and can share a production line with adult micro-pellet compositions to reduce costs.

[0007] On this basis, the inventors also found through a large number of creative experimental studies that the API pamiparib has high stability after being prepared into a micro-pellet composition and then mixed with semi-solid food, and there is no micro-pellet disintegration within 2 hours at room temperature, which is suitable for preparation and use under family conditions. In addition, the inventors found that pamiparib has a greater solubility in acid. In order to improve the dissolution of pamiparib in the stomach, the inventors creatively designed the use of weakly acidic semi-solid food mixed with the pamiparib micro-pellet composition to prepare a children's preparation.

[0008] The present invention relates to a PARP inhibitor children's preparation composition and a preparation method thereof; and use of the children's preparation composition and the preparation thereof for treating / preventing diseases or disorders associated with PARP.

[0009] The present invention relates to a pamiparib children's preparation, which comprises a pamiparib micropellet composition and semisolid food.

[0010] The semi-solid food is an acidic semi-solid food;

[0011] Preferably, the semi-solid food is fruit puree, vegetable puree, jam, pectin, honey, syrup, yogurt;

[0012] Further preferably, the semi-solid food is apple puree, apple jam, apple pectin, strawberry puree, strawberry jam, strawberry pectin, carrot puree, tomato sauce, honey, maple syrup, yogurt;

[0013] More preferably, the semi-solid food is ketchup or strawberry jam.

[0014] The pamiparib children's preparation is prepared by quantitatively mixing the micropellet particles in the pamiparib capsule with semi-solid food;

[0015] Preferably, the pamiparib children's preparation is prepared by combining the pamiparib pellets in the pamiparib capsule into a quantitative mixture and mixing with semi-solid food within 2 hours before administration;

[0016] Further preferably, the mass ratio of the combination of semi-solid food and pamiparib microcapsules is 2500-10000:180; preferably, the mass ratio of the combination of semi-solid food and pamiparib microcapsules is 4000-6000:180; preferably, the mass ratio of the combination of semi-solid food and pamiparib microcapsules is 5000:180.

[0017] The pamiparib micropellet composition comprises (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-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one, its pharmaceutically acceptable salts and hydrates thereof.

[0018] Preferably, the micropellets are composed of (1) a micropellet core, (2) a drug-containing layer, and (3) an optional protective layer from the inside to the outside.

[0019] In the above pellet composition, optional additional excipients may also be included, including but not limited to fillers, lubricants and other conventionally used excipients. Preferably, the additional excipients include one or more of fillers and lubricants, and more preferably, the additional excipients include lubricants.

[0020] Optionally, the additional excipients are mixed with the pellets comprising (1) a pellet core; (2) a drug-containing layer; and (3) an optional protective layer.

[0021] In the above-mentioned pellet composition, the pellet core is a blank pellet core, which is selected from one or more of a sucrose pellet core, a microcrystalline cellulose pellet core, and a starch pellet core.

[0022] In the above-mentioned pellet composition, the pellet core accounts for 50% to 90% by weight of the total weight of the pellet composition, preferably 60% to 85% (w / w).

[0023] In the above-mentioned micropellet composition, the active ingredient is preferably the AL crystal form of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene [def] cyclopenta [a] fluorene-4(5H)-one or the hydrate of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene [def] cyclopenta [a] fluorene-4(5H)-one.

[0024] Preferably, the active ingredient is the C crystalline form of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one.

[0025] The AL crystal form can be prepared with reference to WO2017 / 032289A1.

[0026] Preferably, the active ingredient is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one sesquihydrate, which has the following structure:

[0027]

[0028] As an additional part of the present invention, the inventors have found that the D of the active ingredient pamiparib 90 Have an impact on the quality attributes of the final product.

[0029] Preferably, the active ingredient D 90 Less than 100 μm, preferably D 90 Less than 50μm.

[0030] As an unexpected surprise, when D 90 Less than 30 μm, the final product will obtain the ideal final product content (more than 99%), therefore, the most preferred active ingredient D 90 Less than 30μm.

[0031] Preferably, the weight percentage of the active ingredient in the total weight of the micropellet composition is 5%-50%, preferably 10%-25%, and more preferably 10-20% (w / w).

[0032] Preferably, the active ingredient is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-

[0033] 5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one, crystal form C, particle size D 90 The active ingredient accounts for 10% to 25% (w / w) of the total weight of the micro-pellet composition, and more preferably 10% to 20%.

[0034] Preferably, the active ingredient is (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-

[0035] 5,6,7a,11-Tetraazacycloheptatrien[def]cyclopenta[a]fluoren-4(5H)-one sesquihydrate, particle size D 90 The active ingredient accounts for 10% to 25% (w / w) of the total weight of the micro-pellet composition, and more preferably 10% to 20%.

[0036] In the above-mentioned micro-pellet composition, the binder includes but is not limited to one or more of carbomer, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose, and povidone.

[0037] In the above-mentioned pellet composition, the weight percentage of the binder to the total weight of the pellet composition is 1% to 20%, preferably 1% to 10%, more preferably 3% to 8%, and most preferably 3% to 6% (w / w).

[0038] Preferably, the binder is selected from hypromellose, hypromellose sodium and povidone.

[0039] More preferably, the binder is 3% to 8% (w / w) of hypromellose or hypromellose sodium based on the total weight of the pellet composition.

[0040] In the above-mentioned micro-pellet composition, the coating material includes but is not limited to one or more of carbomer, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose, and povidone.

[0041] In the above-mentioned pellet composition, the weight percentage of the coating material to the total weight of the pellet composition is 1% to 25%, preferably 1% to 10%, more preferably 1.5% to 8%, and most preferably 3% to 6% (w / w).

[0042] Preferably, the coating material is selected from hypromellose and hypromellose sodium.

[0043] More preferably, the coating material is 1.5% to 8% (w / w) of hypromellose or hypromellose sodium based on the total weight of the pellet composition.

[0044] In the above-mentioned micro-pill composition, the lubricant includes but is not limited to one or more of calcium stearate, magnesium stearate, zinc stearate, stearic acid, sodium stearyl fumarate, and talc.

[0045] In the above micro-pellet composition, the weight percentage of the lubricant to the total weight of the micro-pellet composition is 0.1% to 5.0%, preferably 0.1% to 2%, and more preferably 0.5% to 1.5% (w / w).

[0046] After Pamiparib was prepared as a micropill, the micropill successfully improved the fluidity of the raw material powder, which was sufficient to meet the preparation requirements without the need to use an additional lubricant to improve the fluidity of the material. Moreover, the inventor unexpectedly found that electrostatic effects were generated between the micropills, which had a certain impact on the filling of the capsules. In order to avoid the generation of static electricity problems, the inventor was pleasantly surprised to find that mixing a certain lubricant into the micropill, especially talcum powder, can effectively reduce the electrostatic effect of the micropills, making it possible to commercially produce the preparation in large quantities. Therefore, preferably, the lubricant is selected from talcum powder.

[0047] Preferably, the lubricant is selected from talc powder accounting for 0.1% to 2% by weight of the total weight of the micropill composition.

[0048] The preparation method of the micropill composition of the present invention is as follows:

[0049] A method for preparing a micropellet composition, the method comprising the following steps:

[0050] 1) dispersing the active ingredient in the binder solution to prepare a drug-containing suspension;

[0051] 2) Spraying the drug-containing suspension described in step 1) onto the surface of the micro-pellet core to form a drug-containing suspension.

[0052] layer to prepare drug-loaded pellets;

[0053] 3) preparing a coating material solution, spraying the coating material solution on the surface of the drug-loaded pellets as a protective layer to prepare protective layer pellets, which step is optional;

[0054] 4) The pellets obtained in step 2) or step 3) are mixed with an external excipient to prepare total mixed pellets. This step is optional.

[0055] In some embodiments, the present invention relates to a method for preparing a micropellet composition, the method comprising the following steps:

[0056] 1) dispersing the active ingredient in the binder solution to prepare a drug-containing suspension;

[0057] 2) spraying the drug-containing suspension described in step 1) onto the surface of the pellet core to form a drug-containing layer to prepare drug-loaded pellets;

[0058] 3) preparing a coating material solution, spraying the coating material solution on the surface of the drug-loaded micropellets as a protective layer, and preparing protective layer micropellets to obtain a micropellet composition.

[0059] In some embodiments, the present invention relates to a method for preparing a micropellet composition, the method comprising the following steps:

[0060] 1) dispersing the active ingredient in the binder solution to prepare a drug-containing suspension;

[0061] 2) Spraying the drug-containing suspension described in step 1) onto the surface of the micro-pellet core to form a drug-containing suspension.

[0062] layer to prepare drug-loaded pellets;

[0063] 3) The pellets obtained in step 2) are mixed with an external excipient to prepare a total mixed pellet to obtain a pellet composition.

[0064] In some embodiments, the present invention relates to a method for preparing a micropellet composition, the method comprising the following steps:

[0065] 1) dispersing the active ingredient in the binder solution to prepare a drug-containing suspension;

[0066] 2) Spraying the drug-containing suspension described in step 1) onto the surface of the micro-pellet core to form a drug-containing suspension.

[0067] layer to prepare drug-loaded pellets;

[0068] 3) preparing a coating material solution, spraying the coating material solution on the surface of the drug-loaded pellets as a protective layer to prepare protective layer pellets;

[0069] 4) The pellets obtained in step 3) are mixed with an external excipient to prepare a total mixed pellet, that is, a pellet composition.

[0070] The total mixed pellets can be encapsulated into capsules.

[0071] In the above-mentioned micropellet composition, the types, contents and characteristics of the active ingredients, micropellet cores, binders, coating materials and additional excipients are as defined above.

[0072] The present invention also relates to a method for preparing a pamiparib children's preparation, characterized in that the pamiparib children's preparation is prepared by quantitatively mixing micropellets in pamiparib capsules with semi-solid food; preferably, the pamiparib children's preparation is prepared by quantitatively mixing micropellets in pamiparib capsules with semi-solid food within 2 hours before taking. The micropellets of pamiparib are quantified according to the patient's weight by a quantitative device.

[0073] The present invention also relates to a method for treating and / or preventing PARP-related diseases, wherein the method uses the pamiparib children's preparation of the present invention.

[0074] The present invention also relates to the use of the pamiparib children's preparation in preparing a drug for treating and / or preventing PARP-related diseases in mammals.

[0075] Based on actual measurements or public information, the pH values ​​of common foods are as follows:

[0076] Food Types pH Food Types pH Apple(puree) 3.34–3.90 Honey 3.70–4.20 apple 3.35–4.00 Infant formula 5.70–6.00 Apple Jam 3.10–3.60 Maple Syrup 4.60–5.15 Banana (puree) 4.50–5.20 milk 6.40–6.80 Buttermilk 4.41–4.83 Orange juice 3.30–4.19 Carrot (purée) 5.88–6.40 Orange Marmalade 3.00–3.33 Chocolate Pudding 5.50–6.00 Peanut Butter 6.28 Coconut milk 6.10–7.00 Pineapple juice 3.30–3.60 Cranberry Juice 2.30–2.52 Rice Pudding 4.00–5.00 drinking water 6.50–8.50 Soy milk 7.00 Fruit jelly 3.00–3.50 strawberry 3.00–3.90 jam 3.50–4.50 Strawberry Jam 3.00–3.40 Grapefruit juice 2.90–3.25 yogurt 4.40–5.00

[0077] Based on the public information of patent document CN107922425B, it is known that the solubility of pamiparib in low pH aqueous media such as simulated gastric fluid (SGF, for example, about 4.5 mg / mL, pH=1.2) makes rapid dissolution in the stomach possible and good drug absorption can be obtained in animals and humans. Based on actual measurements, it is quite surprising that when the pH value is ≤2, the solubility of pamiparib is greatly increased, so the prepared children's preparation will disintegrate rapidly before use. When the pH value is between 3.0-5.5, the solubility of pamiparib does not increase significantly, and the prepared children's preparation is relatively stable. In addition, semi-solid food has a certain viscosity, which can maintain the state of micro-pellets well, and is a better choice of food types, such as puree, vegetable puree, jam, pectin, honey, syrup, and yogurt. More preferably, the semi-solid food is apple puree, apple jam, apple pectin, strawberry puree, strawberry jam, strawberry pectin, carrot puree, tomato sauce, honey, maple syrup, yogurt; even more preferably, the semi-solid food is tomato sauce or strawberry jam.

[0078] As shown in the accompanying drawings, in some embodiments, the pediatric preparation of pamiparib is prepared by quantitatively obtaining the micropellet particles in the pamiparib capsule based on the child's weight and then mixing the micropellet particles with semi-solid food.

[0079] In some embodiments, the pediatric preparation of pamiparib is prepared by quantitatively mixing the micropellet particles in the pamiparib capsule with semi-solid food; preferably, the pediatric preparation of pamiparib is prepared by quantitatively mixing the micropellet particles in the pamiparib capsule with semi-solid food within 2 hours before taking.

[0080] In some embodiments, the pediatric formulation of pamiparib is prepared by mixing the micropellet particles in the pamiparib capsule with semi-solid food after quantitatively obtaining the micropellet particles based on the child's weight.

[0081] The PARP-related diseases described in 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-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 their complications.

[0082] Among the mammals mentioned in the present application, humans are preferred.

[0083] The disease is preferably selected from BRCA1 and BRCA2 mutant tumors, such as BRCA1 and BRCA2 mutant breast cancer, ovarian cancer and complications thereof.

[0084] The above-mentioned method for preventing or treating a disease may also be used in combination with any chemotherapy (eg, temozolomide (TMZ) and docetaxel), biological therapy or radiotherapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0085] Instructions attached Figure 1 :Pamiparib pellet quantitative device

[0086] Instructions attached Figure 2 :Preparation process of pamiparib children's preparation

[0087] Technical terms

[0088] Unless defined otherwise, technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0089] As used herein, the singular forms "a," "an," and "the" include plural referents.

[0090] The terms "comprising", "including" or grammatical variations thereof used herein mean that the compositions and methods, etc. include the listed elements and do not exclude others.

[0091] The composition of the present invention comprises a mixture of active ingredients and other chemical ingredients.

[0092] The term "optionally" in the present invention means that the compound can be selected or not selected, such as the optional additional excipient means that the compound contains an additional excipient or does not contain an additional excipient.

[0093] The lubricant described in the present invention includes a conventionally used lubricant and / or a conventionally used glidant.

[0094] The present invention provides a PARP inhibitor pellet composition and a preparation process, as well as an oral preparation (such as a capsule) prepared using the pellet composition. Among them, the (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene and [def] cyclopentadiene and [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, improves the fluidity and stability of the product, makes large-scale commercial production possible, is easy to transport and store, has a simple preparation process, and has good stability of the final product and intermediate product. In addition, the intermediate product pellet has a high drug loading capacity and can adjust different dosages according to clinical indications, which is convenient for patients to take.

[0095] Mixing a certain amount of lubricant such as talcum powder into the micropellets can effectively reduce the electrostatic effect of the micropellets, making large-scale commercial production of the preparation possible.

[0096] When D 90 Less than 30μm, the final product will have the desired quality attributes. DETAILED DESCRIPTION

[0097] The following examples may help those skilled in the art to more fully understand the present invention, but are not intended to limit the present invention in any way. All raw materials are commercially available.

[0098] Example 1

[0099] Prescription for 100g pellet preparation:

[0100] Microcrystalline cellulose pellets 80.50g

[0101] Drug-containing layer: Pamiparib 12.08g; Povidone 4.02g

[0102] Protective layer: Hydroxypropyl methylcellulose 2.90g

[0103] Talc 0.50g

[0104] The amount of pamiparib is calculated based on the total weight of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one sesquihydrate.

[0105] Preparation process:

[0106] 1) Weigh the prescribed amount (4.02 g) of povidone to prepare a 5% concentration binder solution, and evenly disperse 12.08 g of pamiparib in the binder solution to prepare a drug-containing coating suspension.

[0107] 2) Take the prescribed amount of microcrystalline cellulose pellet cores, spray the drug-containing layer coating suspension on the surface of the pellet cores to form a drug-containing layer, and prepare drug-loaded pellets. Take the prescribed amount (2.90 g) of coating material hypromellose to prepare a 5% concentration coating material solution, spray the coating material solution on the surface of the drug-loaded pellets as a protective layer, and prepare drug-loaded pellets containing a protective layer.

[0108] 3) The drug-loaded pellets (including the protective layer) obtained in the above step are mixed with a prescribed amount of talcum powder to prepare total mixed pellets.

[0109] 4) Filling the total mixed pellets into capsules.

[0110] Capsules of different specifications are filled according to the content of the raw material in the micropills and the weight of the micropills. The specifications include but are not limited to each capsule containing 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, and 100 mg of active ingredient based on the weight of the anhydrous compound.

[0111] Instructions attached Figure 1 This is an electron microscope image of the pamiparib API. Since the BGB290 API contains crystalline water, it is very easy to aggregate and has poor fluidity, which is not conducive to capsule filling and affects the large-scale production of the preparation. Figure 2 This is an electron microscope picture of the micro-pellets of Example 1. It can be seen from the picture that the micro-pellets are round in shape, can be evenly spread under the electron microscope field of view, and have good fluidity, which can meet the needs of capsule filling.

[0112] Example 2

[0113] Prescription for 100g pellet preparation:

[0114] Sucrose micropellets core 77.28g

[0115] Drug-containing layer: Pamiparib 11.60g; Hydroxypropyl methylcellulose 7.73g

[0116] Protective layer: Povidone 2.90g

[0117] Talc 0.50g

[0118] The amount of pamiparib is calculated based on the total weight of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one sesquihydrate.

[0119] Preparation process:

[0120] 1) Weigh the prescribed amount (7.73 g) of hypromellose to prepare a 5% concentration binder solution, and evenly disperse 11.60 g of pamiparib in the binder solution to prepare a drug-containing coating suspension.

[0121] 2) Take the prescribed amount of sucrose pellet cores, spray the drug-containing layer coating suspension on the surface of the pellet cores to form a drug-containing layer, and prepare drug-loaded pellets. Take the prescribed amount (2.90 g) of coating material povidone to prepare a 5% concentration coating material solution, spray the coating material solution on the surface of the drug-loaded pellets as a protective layer, and prepare drug-loaded pellets containing a protective layer.

[0122] 3) The drug-loaded pellets (including the protective layer) obtained in the above step are mixed with a prescribed amount of talcum powder to prepare total mixed pellets.

[0123] 4) Filling the total mixed pellets into capsules.

[0124] Capsules of different specifications are filled according to the content of the raw material in the micropills and the weight of the micropills. The specifications include but are not limited to each capsule containing 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, and 100 mg of active ingredient based on the weight of the anhydrous compound.

[0125] Example 3

[0126] Prescription for 100g pellet preparation:

[0127] Microcrystalline cellulose pellets 80.50g

[0128] Drug-containing layer: Pamiparib 12.08g; Hydroxypropyl methylcellulose 4.02g

[0129] Protective layer: Hydroxypropyl methylcellulose 2.90g

[0130] Talc 0.50g

[0131] The amount of pamiparib is calculated based on the total weight of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one sesquihydrate.

[0132] Preparation process:

[0133] 1) Weigh the prescribed amount (4.02 g) of hypromellose to prepare a 5% concentration binder solution, and evenly disperse 12.08 g of pamiparib in the binder solution to prepare a drug-containing coating suspension.

[0134] 2) Take the prescribed amount of microcrystalline cellulose pellet cores, spray the drug-containing layer coating suspension on the surface of the pellet cores to form a drug-containing layer, and prepare drug-loaded pellets. Take the prescribed amount (2.90 g) of coating material hypromellose to prepare a 5% concentration coating material solution, spray the coating material solution on the surface of the drug-loaded pellets as a protective layer, and prepare drug-loaded pellets containing a protective layer.

[0135] 3) The drug-loaded pellets (including the protective layer) obtained in the above step are mixed with a prescribed amount of talcum powder to prepare total mixed pellets.

[0136] 4) Filling the total mixed pellets into capsules.

[0137] Capsules of different specifications are filled according to the content of the raw material in the micropills and the weight of the micropills. The specifications include but are not limited to each capsule containing 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, and 100 mg of active ingredient based on the weight of the anhydrous compound.

[0138] Example 4

[0139] Prescription for 100g pellet preparation:

[0140] Microcrystalline cellulose pellets 79.91g

[0141] Drug-containing layer: Pamiparib 12.13g; Sodium hydroxymethylcellulose 4.04g

[0142] Protective layer: 2.42g sodium hydroxymethylcellulose

[0143] Talc 1.50g

[0144] The amount of pamiparib is calculated based on the total weight of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one sesquihydrate.

[0145] Preparation process:

[0146] 1) Weigh the prescribed amount (4.04 g) of sodium hydroxymethylcellulose to prepare a 5% concentration binder solution, and evenly disperse 12.13 g of pamiparib in the binder solution to prepare a drug-containing coating suspension.

[0147] 2) Take the prescribed amount of microcrystalline cellulose pellet cores, spray the drug-containing layer coating suspension on the surface of the pellet cores to form a drug-containing layer, and prepare drug-loaded pellets. Take the prescribed amount (2.42 g) of coating material sodium hydroxymethyl cellulose to prepare a 5% concentration coating material solution, spray the coating material solution on the surface of the drug-loaded pellets as a protective layer, and prepare drug-loaded pellets containing a protective layer.

[0148] 3) The drug-loaded pellets (including the protective layer) obtained in the above step are mixed with a prescribed amount of talcum powder to prepare total mixed pellets.

[0149] 4) Filling the total mixed pellets into capsules.

[0150] Capsules of different specifications are filled according to the content of the raw material in the micropills and the weight of the micropills. The specifications include but are not limited to each capsule containing 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, and 100 mg of active ingredient based on the weight of the anhydrous compound.

[0151] Example 5

[0152] Prescription for 100g pellet preparation:

[0153] Sucrose micropellets 80.50g

[0154] Drug-containing layer: Pamiparib 12.08g; Sodium hydroxymethylcellulose 4.02g

[0155] Protective layer: Carbomer 2.90g

[0156] Talc 0.50g

[0157] The amount of pamiparib is calculated based on the total weight of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one sesquihydrate.

[0158] Preparation process:

[0159] 1) Weigh the prescribed amount (4.02 g) of sodium hydroxymethylcellulose to prepare a 5% concentration binder solution, and evenly disperse 12.08 g of pamiparib in the binder solution to prepare a drug-containing coating suspension.

[0160] 2) Take the prescribed amount of sucrose pellet cores, spray the drug-containing layer coating suspension on the surface of the pellet cores to form a drug-containing layer, and prepare drug-loaded pellets. Take the prescribed amount (2.90 g) of the coating material carbomer to prepare a 5% concentration coating material solution, spray the coating material solution on the surface of the drug-loaded pellets as a protective layer, and prepare drug-loaded pellets containing a protective layer.

[0161] 3) The drug-loaded pellets (including the protective layer) obtained in the above step are mixed with a prescribed amount of talcum powder to prepare total mixed pellets.

[0162] 4) Filling the total mixed pellets into capsules.

[0163] Capsules of different specifications are filled according to the content of the raw material in the micropills and the weight of the micropills. The specifications include but are not limited to each capsule containing 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, and 100 mg of active ingredient based on the weight of the anhydrous compound.

[0164] Example 6

[0165] Prescription for 100g pellet preparation:

[0166] Microcrystalline cellulose pellets 68.43g

[0167] Drug-containing layer: Pamiparib 20.53g; Povidone 6.84g

[0168] Protective layer: 3.70g sodium hydroxymethylcellulose

[0169] Talc 0.50g

[0170] The amount of pamiparib is calculated based on the total weight of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one sesquihydrate.

[0171] Preparation process:

[0172] 1) Weigh the prescribed amount (6.84 g) of povidone to prepare a 5% concentration binder solution, and evenly disperse 20.53 g of pamiparib in the binder solution to prepare a drug-containing coating suspension.

[0173] 2) Take the prescribed amount of microcrystalline cellulose pellet cores, spray the drug-containing layer coating suspension on the surface of the pellet cores to form a drug-containing layer, and prepare drug-loaded pellets. Take the prescribed amount (3.70 g) of coating material sodium hydroxymethyl cellulose to prepare a 5% concentration coating material solution, spray the coating material solution on the surface of the drug-loaded pellets as a protective layer, and prepare drug-loaded pellets containing a protective layer.

[0174] 3) The drug-loaded pellets (including the protective layer) obtained in the above step are mixed with a prescribed amount of talcum powder to prepare total mixed pellets.

[0175] 4) Filling the total mixed pellets into capsules.

[0176] Capsules of different specifications are filled according to the content of the raw material in the micropills and the weight of the micropills. The specifications include but are not limited to each capsule containing 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, and 100 mg of active ingredient based on the weight of the anhydrous compound.

[0177] Example 7

[0178] Prescription for 100g pellet preparation:

[0179] Microcrystalline cellulose pellets 89.40g

[0180] Drug-containing layer: Pamiparib 5.16g; Hydroxypropyl cellulose 1.72g

[0181] Protective layer: Hydroxypropyl methylcellulose 3.22g

[0182] Talc 0.50g

[0183] The amount of pamiparib is calculated based on the total weight of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one sesquihydrate.

[0184] Preparation process:

[0185] 1) Weigh the prescribed amount (1.72 g) of hydroxypropyl cellulose to prepare a 5% concentration binder solution, and evenly disperse 5.16 g of pamiparib in the binder solution to prepare a drug-containing coating suspension.

[0186] 2) Take the prescribed amount of microcrystalline cellulose pellet cores, spray the drug-containing layer coating suspension on the surface of the pellet cores to form a drug-containing layer, and prepare drug-loaded pellets. Take the prescribed amount (3.22 g) of coating material hypromellose to prepare a 5% concentration coating material solution, spray the coating material solution on the surface of the drug-loaded pellets as a protective layer, and prepare drug-loaded pellets containing a protective layer.

[0187] 3) The drug-loaded pellets (including the protective layer) obtained in the above step are mixed with a prescribed amount of talcum powder to prepare total mixed pellets.

[0188] 4) Filling the total mixed pellets into capsules.

[0189] Capsules of different specifications are filled according to the content of the raw material in the micropills and the weight of the micropills. The specifications include but are not limited to each capsule containing 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, and 100 mg of active ingredient based on the weight of the anhydrous compound.

[0190] Example 8

[0191] Prescription for 100g pellet preparation:

[0192] Sucrose micropellets 81.30g

[0193] Drug-containing layer: Pamiparib 12.19g; Hydroxypropyl methylcellulose 4.06g

[0194] Protective layer: 1.95g sodium hydroxymethylcellulose

[0195] Talc 0.50g

[0196] The amount of pamiparib is calculated based on the total weight of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one sesquihydrate.

[0197] Preparation process:

[0198] 1) Weigh the prescribed amount (4.06 g) of hypromellose to prepare a 5% concentration binder solution, and evenly disperse 12.19 g of pamiparib in the binder solution to prepare a drug-containing coating suspension.

[0199] 2) Take the prescribed amount of sucrose pellet cores, spray the drug-containing coating suspension on the surface of the pellet cores to form a drug-containing layer, and prepare drug-loaded pellets. Take the prescribed amount (1.95 g) of coating material sodium hydroxymethyl cellulose to prepare a 5% concentration coating material solution, spray the coating material solution on the surface of the drug-loaded pellets as a protective layer, and prepare drug-loaded pellets containing a protective layer.

[0200] 3) The drug-loaded pellets (including the protective layer) obtained in the above step are mixed with a prescribed amount of talcum powder to prepare total mixed pellets.

[0201] 4) Filling the total mixed pellets into capsules.

[0202] Capsules of different specifications are filled according to the content of the raw material in the micropills and the weight of the micropills. The specifications include but are not limited to each capsule containing 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, and 100 mg of active ingredient based on the weight of the anhydrous compound.

[0203] Example 9

[0204] Prescription for 100g pellet preparation:

[0205] Microcrystalline cellulose pellets 78.97g

[0206] Drug-containing layer: Pamiparib 11.85g; Povidone 3.95g

[0207] Protective layer: Hydroxypropyl methylcellulose 4.74g

[0208] Talc 0.50g

[0209] The amount of pamiparib is calculated based on the total weight of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one sesquihydrate.

[0210] Preparation process:

[0211] 1) Weigh the prescribed amount (3.95 g) of povidone to prepare a 5% concentration binder solution, and evenly disperse 11.85 g of pamiparib in the binder solution to prepare a drug-containing coating suspension.

[0212] 2) Take the prescribed amount of microcrystalline cellulose pellet cores, spray the drug-containing layer coating suspension on the surface of the pellet cores to form a drug-containing layer, and prepare drug-loaded pellets. Take the prescribed amount (4.74 g) of coating material hypromellose to prepare a 5% concentration coating material solution, spray the coating material solution on the surface of the drug-loaded pellets as a protective layer, and prepare drug-loaded pellets containing a protective layer.

[0213] 3) The drug-loaded pellets (including the protective layer) obtained in the above step are mixed with a prescribed amount of talcum powder to prepare total mixed pellets.

[0214] 4) Filling the total mixed pellets into capsules.

[0215] Capsules of different specifications are filled according to the content of the raw material in the micropills and the weight of the micropills. The specifications include but are not limited to each capsule containing 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, and 100 mg of active ingredient based on the weight of the anhydrous compound.

[0216] Example 10 - Effect of API Particle Size on Active Ingredient Content of Pamiparib Micropellets

[0217] The inventors unexpectedly discovered during the formulation development process that the D 90 The value has a certain influence on the content of active ingredients in the final product of micro-pill capsule preparation. Using the same prescription as Example 3:

[0218] Prescription for 100g pellet preparation:

[0219] Microcrystalline cellulose pellets 80.50g

[0220] Drug-containing layer: Pamiparib 12.08g; Povidone 4.02g

[0221] Protective layer: Hydroxypropyl methylcellulose 2.90g

[0222] Talc 0.50g

[0223] Pamiparib is calculated based on the total weight of (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one sesquihydrate.

[0224] Experimental Group 1: Pamiparib D 90 =7.87μm

[0225] Experimental Group 2: Pamiparib D 90 =21.9μm

[0226] Experimental Group 3: Pamiparib D 90 =35.6μm

[0227] Experimental Group 4: Pamiparib D 90 =45.5μm

[0228] Capsules with a content of 20 mg were prepared according to the method described in Example 3. The D90 was measured using Malvern Laser Particle Sizer 3000 by laser diffraction method.

[0229] Content determination: Weigh 225 mg of capsule content pellets (allowable weighing range: 158-292 mg), dilute the content pellets 250 times with diluent, mix well, use 0.45μm PTFE needle filter, discard 3 ml, collect the filtrate and use UV method to detect at a wavelength of 297nm / or use HPLC to determine the content. The analysis results are as follows.

[0230] Table 1. Content results of products prepared from APIs with different particle sizes

[0231] Experimental groups content% <![CDATA[Experimental group 1 (D 90 = 7.87 μm)]]> 99.2％ <![CDATA[Experimental group 2 (D 90 = 21.9 μm)]]> 99.9％ <![CDATA[Experimental group 3 (D 90 = 35.6 μm)]]> 91.5％ <![CDATA[Experimental group 4 (D 90 = 45.5 μm)]]> 90.6％

[0232] From the experimental results, we can see that when D 90 When the particle size is less than 30 μm, the final product has a higher content result.

[0233] Example 11 Preparation of Pamiparib Tomato Sauce Children's Preparation

[0234] Pamiparib tomato paste children's preparation prescription:

[0235] Tomato paste: 5g

[0236] Pamiparib pellets: 180 mg

[0237] The pamiparib ketchup children's preparation is prepared by mixing ketchup with pamiparib micropellets. After being placed at room temperature for 2 hours after preparation, the preparation has no obvious shape change, and the pamiparib particles do not disintegrate or dissolve. The smell and taste of the preparation are the same as ketchup.

[0238] Example 12 Preparation of Pamiparib Strawberry Jam Children's Preparation

[0239] Prescription for Pamiparib Strawberry Jam Children's Preparation:

[0240] Strawberry jam: 5g

[0241] Pamiparib pellets: 180 mg

[0242] The pamiparib strawberry jam children's preparation is prepared by mixing strawberry jam with pamiparib micropellets. After being placed at room temperature for 2 hours after preparation, the preparation did not change significantly in shape, and the pamiparib particles did not disintegrate or dissolve. The smell and taste of the preparation are the same as those of strawberry jam.

[0243] Example 13 Preparation of Pamiparib Milk Children's Preparation

[0244] Prescription of Pamiparib milk preparation for children:

[0245] Milk: 5g

[0246] Pamiparib pellets: 180 mg

[0247] The pamiparib milk children's preparation is prepared by mixing milk with pamiparib micropellets. After being placed at room temperature for 2 hours after preparation, the pamiparib micropellets in the preparation disintegrate and dissolve.

[0248] Based on the comparison of Examples 11, 12, and 13, it can be seen that the children's preparation of pamiparib is not suitable for mixing with liquid food. Using semi-solid food to mix with it can effectively prevent the disintegration and dissolution of the pamiparib microcapsules before entering the human body, and has a certain storage time, which is suitable for short-term storage when the patient compliance is not high.

[0249] The present invention has been described in detail above by means of general explanations, specific implementation methods and experiments. Any modifications or improvements made without departing from the spirit of the present invention shall fall within the scope of protection claimed by the present invention.

Claims

1. A pamiparib children's preparation, characterized in that The pamiparib children's preparation comprises a pamiparib micropellet composition and semisolid food.

2. The pamiparib children's preparation according to claim 1, characterized in that The pamiparib micropellet composition comprises (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-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacycloheptatriene[def]cyclopenta[a]fluorene-4(5H)-one, its pharmaceutically acceptable salts and hydrates thereof.

3. The pamiparib children's preparation according to claim 2, characterized in that The pellet core of the pellet composition is a blank pellet core, selected from one or more of a sucrose pellet core, a microcrystalline cellulose pellet core, and a starch pellet core; and / or The weight percentage of the active ingredient in the total weight of the pellet composition is 5%-50%, preferably 10%-25%, and more preferably 10-20% (w / w); and / or The binder is selected from one or more of carbomer, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose, sodium hypromellose, and povidone; preferably, the binder is selected from hypromellose, sodium hypromellose, and povidone; and / or the binder accounts for 1% to 20% by weight of the total weight of the pellet composition, preferably 1% to 10%, more preferably 3% to 8%, and most preferably 3% to 6% (w / w); and / or The coating material is selected from one or more of carbomer, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose, sodium hypromellose, and povidone; preferably hypromellose and sodium hypromellose; and / or the weight percentage of the coating material to the total weight of the pellet composition is 1% to 25%, preferably 1% to 10%, more preferably 1.5% to 8%, and most preferably 3% to 6% (w / w).

4. The pamiparib children's preparation according to claims 1-3, characterized in that The semi-solid food is an acidic semi-solid food; Preferably, the semi-solid food is fruit puree, vegetable puree, jam, pectin, honey, syrup, yogurt; Further preferably, the semi-solid food is apple puree, apple jam, apple pectin, strawberry puree, strawberry jam, strawberry pectin, carrot puree, tomato sauce, honey, maple syrup, yogurt; More preferably, the semi-solid food is ketchup or strawberry jam.

5. The pamiparib children's preparation according to claims 1-3, characterized in that The pamiparib children's preparation is prepared by quantitatively mixing the micropellets in the pamiparib capsule with semi-solid food; preferably, the pamiparib children's preparation is prepared by quantitatively mixing the pamiparib micropellets in the pamiparib capsule with semi-solid food within 2 hours before taking; Further preferably, the mass ratio of the combination of semi-solid food and pamiparib microcapsules is 2500-10000:180; preferably, the mass ratio of the combination of semi-solid food and pamiparib microcapsules is 4000-6000:180; preferably, the mass ratio of the combination of semi-solid food and pamiparib microcapsules is 5000:

180.

6. The pamiparib children's preparation according to claim 5, characterized in that The pamiparib children's preparation is prepared by quantitatively obtaining micropellet particles in pamiparib capsules based on the weight of children and then mixing the micropellet particles with semi-solid food.

7. The method for preparing the pamiparib children's preparation according to claims 1-5, characterized in that The pamiparib children's preparation is prepared by quantitatively mixing the micropellet particles in the pamiparib capsule with semi-solid food; preferably, the pamiparib children's preparation is prepared by quantitatively mixing the micropellet particles in the pamiparib capsule with semi-solid food within 2 hours before taking.

8. The method for preparing the pamiparib children's preparation according to claim 7, characterized in that The pamiparib children's preparation is prepared by quantitatively obtaining micropellet particles in pamiparib capsules based on the weight of children and then mixing the micropellet particles with semi-solid food.

9. A method for preparing a drug for treating PARP-related diseases using the pamiparib children's preparation according to claims 1-5, characterized in that The PARP-related disease is selected from chronic inflammatory diseases, rheumatoid arthritis, atherosclerosis, psoriasis and scleroderma, diabetes-induced skin diseases, diabetic retinopathy, retinopathy of prematurity, age-related degenerative macules, hemangiomas, gliomas, Kaposi's sarcoma, ovarian cancer, breast cancer, lung cancer, small cell lung cancer, pancreatic cancer, lymphoma, prostate cancer, colon cancer and skin tumors, and their complications.

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