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WO2020249001A1 - 一种含有布鲁顿氏酪氨酸激酶抑制剂的口服固体片剂及其制备方法 - Google Patents

一种含有布鲁顿氏酪氨酸激酶抑制剂的口服固体片剂及其制备方法 Download PDF

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WO2020249001A1
WO2020249001A1 PCT/CN2020/095352 CN2020095352W WO2020249001A1 WO 2020249001 A1 WO2020249001 A1 WO 2020249001A1 CN 2020095352 W CN2020095352 W CN 2020095352W WO 2020249001 A1 WO2020249001 A1 WO 2020249001A1
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Prior art keywords
oral solid
solid tablet
tablet according
zebutinib
cellulose
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PCT/CN2020/095352
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English (en)
French (fr)
Inventor
仇罡
沈一唯
范文源
徐铄
吕会茹
卞佳琳
杜争鸣
Original Assignee
百济神州瑞士有限责任公司
仇罡
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Application filed by 百济神州瑞士有限责任公司, 仇罡 filed Critical 百济神州瑞士有限责任公司
Priority to JP2021572296A priority Critical patent/JP2022538214A/ja
Priority to CN202080042382.8A priority patent/CN113939289A/zh
Priority to EP20822605.0A priority patent/EP3981399A4/en
Priority to US17/617,530 priority patent/US20220249491A1/en
Publication of WO2020249001A1 publication Critical patent/WO2020249001A1/zh
Priority to US18/388,898 priority patent/US12233069B2/en
Priority to US19/026,988 priority patent/US20250152594A1/en
Priority to JP2025049435A priority patent/JP2025085845A/ja

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to an inhibitor containing Bruton's Tyrosine Kinase (BTK), in particular (S)-7-[4-(1-acryloylpiperidine)]-2-(4- Phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide oral solid tablet and its preparation method.
  • BTK Bruton's Tyrosine Kinase
  • Bruton's Tyrosine Kinase (BTK), more specifically (S)-7-[4-(1-acryloylpiperidine)]-2- (4-Phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (common name zebutinib (Zanubrutinib)), which The chemical structure is as follows:
  • Zebutinib belongs to the second-generation BTK inhibitor, which irreversibly inactivates the enzyme by covalently binding with tyrosine kinase. It is used as a single agent or in combination with other drugs for the treatment of B lymphocyte tumors, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM ), follicular lymphoma (FL), non-germinal center subtype diffuse large B-cell lymphoma (non-GCB DLBCL), etc.
  • CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma
  • MCL mantle cell lymphoma
  • WM Waldenstrom's macroglobulinemia
  • FL follicular lymphoma
  • non-GCB DLBCL non-germinal center subtype diffuse large B-cell lymphoma
  • the raw material of Zebutinib is slightly hygroscopic. DSC results show that the compound has a clear endothermic peak when it melts, and its starting temperature and peak temperature are 139°C and 144°C, respectively.
  • the melting point of the bulk drug is 145°C, which is lower than the ideal melting point of 150°C for tablet development, and the material is relatively viscous. This has brought huge challenges to the development and large-scale industrial production of Zebutinib tablets.
  • the solubility of zebutinib is pH-dependent and belongs to the class II (low solubility, high permeability) drug of the biopharmaceutical classification system. Therefore, there is an urgent need to develop a zebutinib tablet in which the active ingredient It can dissolve quickly from the preparation, so as to maintain the rapid release of the drug in the whole intestinal tract with good bioavailability.
  • the present invention provides a method containing Bruton's tyrosine Oral solid tablet of acid kinase inhibitor Zebutinib and its preparation method.
  • the inventor of the present invention unexpectedly discovered that a certain amount of colloidal silica as a glidant and other excipients has a significant contribution to improving the viscosity of the drug and ensuring a good dissolution rate of the drug.
  • the oral solid tablet of zebutinib of the present invention can be released relatively quickly in a medium containing sodium lauryl sulfate at pH 1.2 (HCl).
  • the dissolution rate can be within 30-60 minutes when the proportion of some prescription excipients is It can reach more than 80%; preferably, the dissolution of zebutinib can reach more than 95% within 30 minutes in the proportion of some prescription excipients.
  • the zebutinib oral solid tablet of the present invention has no special requirements for production equipment, simple preparation process, stable product, and low production cost.
  • an oral solid tablet containing Zebutinib which contains: (1) Zebutinib 20% to 70% (mass percentage), preferably 30% to 50% (Mass percentage); (2) One or more pharmaceutically acceptable excipients.
  • the zebutinib can be in any solid form, such as crystal form (such as crystal form A disclosed in WO2018033853A), amorphous, or a mixture of crystal form and amorphous form.
  • the zebutinib is crystal form A, amorphous, or a mixture of crystal form A and amorphous.
  • the particle size of the zebutinib is below 40 ⁇ m.
  • the X-ray powder diffraction pattern of Form A includes diffraction peaks having angle values independently selected from the following 2 ⁇ angle values: about 14.8 ⁇ 0.2°, 15.6 ⁇ 0.2°, 16.4 ⁇ 0.2°, and 21.4 ⁇ 0.2°. In some embodiments, the X-ray powder diffraction pattern of Form A includes diffraction peaks having 2 ⁇ angle values independently selected from: about 12.2 ⁇ 0.2°, 12.9 ⁇ 0.2°, 14.8 ⁇ 0.2°, 15.6 ⁇ 0.2°, 16.4 ⁇ 0.2° and 21.4 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form A includes diffraction peaks having 2 ⁇ angle values independently selected from: about 12.2 ⁇ 0.2°, 12.9 ⁇ 0.2°, 14.8 ⁇ 0.2°, 15.6 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.7 ⁇ 0.2°, 18.5 ⁇ 0.2°, 20.7 ⁇ 0.2° and 21.4 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form A is substantially consistent with FIG. 1.
  • the excipient is arbitrarily selected from fillers, binders, disintegrants, wetting agents, glidants, lubricants, and any combination thereof.
  • the filler is selected from starch, sucrose, microcrystalline cellulose, mannitol, lactose, pregelatinized starch, glucose, maltodextrin, cyclodextrin, cellulose, siliconized micro Crystal cellulose and any combination thereof.
  • the filler is lactose, and its content is about 20% to 70%, preferably about 40% to 60%, all in mass percentage.
  • the filler is microcrystalline cellulose
  • microcrystalline cellulose is an internal filler
  • the content of microcrystalline cellulose filler is about 10% to 50%, preferably about 30% to 50% are all mass percentages.
  • the content of lactose and microcrystalline cellulose is about 0% to 70% and about 0% to 50%, respectively, preferably About 40% to 60% and about 4% to 10% are mass percentages.
  • the binder is selected from starch, hypromellose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose , Gelatin, sucrose and any combination of them.
  • the binder is hypromellose, and the content of hypromellose is about 0-10%, preferably about 0-5%, all in mass percentage .
  • the binder is croscarmellose sodium, and its content is about 0% to 10%, preferably about 0% to 5%, all in mass percentage.
  • the disintegrant is selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, croscarmellose Cellulose, methyl cellulose, pregelatinized starch, sodium alginate and any combination thereof.
  • the disintegrant is croscarmellose sodium
  • the content of croscarmellose sodium is about 0.5% to 5%, preferably about 1% to about 1%.
  • 3% is the mass percentage.
  • the wetting agent is sodium lauryl sulfate (SLS), and the content of the sodium lauryl sulfate is about 0% to 5%, preferably 0.5% to 1.0% , Are the mass percentage.
  • SLS sodium lauryl sulfate
  • the glidant is selected from powdered cellulose, magnesium trisilicate, colloidal silicon dioxide, talc, and any combination thereof.
  • the glidant is colloidal silica
  • the content of colloidal silica is about 0.1%-20%, which is a mass percentage.
  • the content of colloidal silica is less than 0.1% (mass percentage)
  • the colloidal silica cannot effectively disperse the API, so that the rapid disintegration of the tablet and the dissolution of the API cannot be guaranteed;
  • the content is greater than 20% (mass percentage)
  • the content of colloidal silica is about 4%-8%, which is a mass percentage.
  • the lubricant is selected from zinc stearate, glyceryl monostearate, glyceryl palmitate stearate, magnesium stearate, sodium stearate fumarate and their random combination.
  • the lubricant is preferably magnesium stearate, and its content is about 0.1% to 2%, preferably about 0.3% to 1%, all in mass percentage.
  • the oral solid tablet of Zebutinib provided by the present invention further contains a coating agent.
  • the coating agent is selected from Opadry film coating powder, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol and any combination thereof. Preferably it is Opadry film coating powder.
  • the present invention provides a method for preparing the zebutinib oral solid preparation, the granulation process is selected from powder direct pressing, dry granulation, wet granulation, preferably wet granulation.
  • the present invention provides a preparation method of the zebutinib oral solid tablet, which comprises the following steps:
  • step (3) if step (3) is not performed, the whole grain obtained in step (2) is compressed into a plain tablet.
  • the organic reagent in step (2) is selected from ethanol, acetone, and combinations thereof.
  • the additional excipients described in step (3) are selected from fillers (such as microcrystalline cellulose), lubricants (such as magnesium stearate), glidants (such as colloidal two Silicon oxide) and any combination thereof.
  • the "mixing" in the above preparation step (1) is performed by a commonly used mixing method.
  • Use equipment such as a hopper mixer, a vertical granulator, FLO-5M, a V-type mixer, a drum mixer, etc., for "mixing".
  • the granulation in the above-mentioned preparation step (2) can be carried out by using a usual granulation method.
  • Use equipment such as a wet granulator for granulation.
  • Use a conventional tablet press such as ZP10A for compression. After making the tablet, if necessary, it can be "dried".
  • any method used for drying formulations such as vacuum drying, fluidized bed drying, etc., can be used. The following terms that can be used herein are used according to the following definitions.
  • ranges cited herein are inclusive; that is, the ranges include the values of the upper and lower limits of the range and all values in between.
  • temperature ranges, percentages, equivalent ranges, etc. described herein include the upper and lower limits of the range and any value in the continuous interval in between.
  • mass percentage describes the content of the bulk drug zebutinib and various excipients, which is calculated relative to the total mass of the oral solid tablet.
  • formulation refers to a mixture, aggregate, solution, or other combination of substances including an active pharmaceutical ingredient (API), the formulation is suitable for a particular route of administration, for example, is suitable for compression to be designed for use It is a formulation of a tablet that is orally administered in the treatment, management, prevention, etc. of a patient's disease state or condition.
  • API active pharmaceutical ingredient
  • the “coating” used herein is not limited to the case of coating the entire surface of the coated object (a plain tablet containing zebutinib), and can also refer to the partial coating of the coated object and the coating on the coated object.
  • the subject absorbs or adsorbs enteric-coated components or plain tablets coated with the inner core.
  • the oral solid tablet prepared according to the present invention has a hardness of 60N-220N, and the dissolution rate exceeds 85% within 30 minutes.
  • the content of zebutinib in the solid oral tablet is usually about 70 mg to about 400 mg zebutinib per tablet, preferably about 80 mg, 160 mg or 320 mg of zebutinib. Butinib.
  • the solid oral tablet may also contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to provide a pharmaceutically beautiful and palatable preparation.
  • the solid oral tablet can be prepared in a variety of possible shapes (ellipsoid, capsule, circular lamp with two convex sides).
  • Figure 1 is an X-ray powder diffraction pattern of the crystal form A of Zebutinib.
  • Figure 2 is a schematic diagram of the cumulative drug dissolution (in vitro dissolution) of the oral solid tablets of Zebutinib in Example 1.
  • Figure 3 is a schematic diagram of cumulative drug dissolution (in vitro dissolution) of the oral solid tablets of Zebutinib in Example 8 and Example 9. Among them, the drug dissolution rate of Example 8 is significantly better than that of Example 9.
  • the temperature is in °C.
  • Reagents are purchased from commercial providers such as Sigma-Aldrich, Alfa Aesar or TCI, and can be used without further purification unless otherwise specified.
  • the prescription is (per 100g plain tablets):
  • Preparation process Add 53.2g of lactose, 2g of croscarmellose sodium, 1g of sodium lauryl sulfate and 34.8g of zebutinib into a high-shear granulator (MYCROMIX, manufactured by BOSCH) After mixing for 5 minutes, add appropriate amount of purified water for granulation, dry and sizing, then add 4.5 g of colloidal silicon dioxide, 4 g of microcrystalline cellulose and 0.5 g of magnesium stearate and mix. After mixing, press tablets to obtain plain tablets. The above-mentioned plain tablets were coated with 2.4 g of Opadry to obtain oral solid tablets containing Zebutinib.
  • MYCROMIX high-shear granulator
  • in vitro dissolution test is determined by automatic sampling dissolution apparatus (model: 708+850DS, purchased from AGILENT), using USP ⁇ 711> "dissolution” using basket method, setting automatic sampling dissolution apparatus The temperature of the water bath is 37 ⁇ 0.5°C, the rotation speed is 100rpm, the pH 1.2(HCl)+0.5%SLS dissolution medium is selected, and the volume is 900mL. Samples were taken at 10min, 15min, 30min, 45min, and 60min respectively, and all samples were passed through a 0.45 ⁇ m filter membrane, and the samples were measured and analyzed according to the method of sample dissolution.
  • the zebutinib oral solid tablet of the present invention is in a pH 1.2 (HCl) + 0.5% SLS medium, and more than 90% of zebutinib is dissolved within 30 minutes, which can meet the requirements of rapid release Claim.
  • Example 2-12 were all measured according to the method of Example 1 to determine the cumulative dissolution rate (in vitro dissolution) of the drug.
  • the prescription is (per 100g plain tablets):
  • Preparation process Add 55.6g of lactose, 2.2g of croscarmellose sodium, 1.1g of sodium lauryl sulfate, 4.3g of colloidal silicon dioxide and 36.2g of zebutinib into high shear Mix in a cutting granulator for 5 minutes, add an appropriate amount of purified water for granulation, dry and granulate, then add 0.5 g of magnesium stearate and mix. After mixing, tableting is obtained to obtain plain tablets, which are oral solid tablets containing zebutinib.
  • Drug cumulative dissolution (in vitro dissolution) test about 90% of Zebutinib was dissolved at 30 min.
  • the prescription is (per 100g plain tablets):
  • Preparation process add 49.2g of lactose, 2g of croscarmellose sodium, 1g of sodium lauryl sulfate and 33.3g of zebutinib into a high-shear granulator and mix for 5 minutes, then add 2g The hypromellose aqueous solution was granulated, dried and sized, and then 4g of colloidal silicon dioxide, 8g of microcrystalline cellulose and 0.5g of magnesium stearate were added and mixed. After mixing, tableting is obtained to obtain plain tablets, which are oral solid tablets containing zebutinib.
  • the prescription is (per 100g plain tablets):
  • Preparation process After sieving 50g of Zebutinib, 4g of croscarmellose sodium, 12.0g of colloidal silicon dioxide, 1g of sodium lauryl sulfate, and 32.5g of microcrystalline cellulose Mix in a high shear granulator, then add 0.5 g of magnesium stearate and mix well. The mixed powder is directly pressed into tablets to obtain plain tablets. The above plain tablets were coated with a coating liquid containing 2.4 g of Opadry to obtain oral solid tablets containing Zebutinib.
  • Drug cumulative dissolution rate (in vitro dissolution) test the drug dissolution rate (%) in 30 minutes is about 80%.
  • the prescription is (per 100g plain tablets):
  • Preparation process 23.8g of lactose, 40g of microcrystalline cellulose, 2g of croscarmellose sodium, 1g of sodium lauryl sulfate, 4g of colloidal silicon dioxide and 26.7g of zebuty
  • spray an aqueous solution containing 2g of hypromellose for granulation dry the magnesium stearate and mix.
  • press tablets to obtain plain tablets.
  • the above plain tablets were coated with a coating liquid containing 1.5 g of Opadry to obtain oral solid tablets containing zebutinib.
  • the prescription is (per 100g plain tablets):
  • Preparation process 26.7g of Zebutinib, 2g of croscarmellose sodium, 4g of colloidal silicon dioxide, 1g of sodium lauryl sulfate, 35.8g of lactose and 30g of silicified microcrystals After sieving the cellulose, it is mixed in a high-shear granulator, and 0.5 g of magnesium stearate is added and mixed uniformly. The powder is directly compressed and coated with Opadry coating solution to obtain oral solid tablets containing Zebutinib.
  • the prescription is (per 100g plain tablets):
  • Preparation process After sieving 50.0g of zebutinib, 4g of croscarmellose sodium, 8g of colloidal silicon dioxide, 1g of sodium lauryl sulfate and 36.5g of lactose, sieving Mix in a cutting granulator, then add 0.5 g of magnesium stearate and mix well. The powder is directly compressed to obtain plain tablets, which are oral solid tablets containing Zebutinib.
  • Drug cumulative dissolution (in vitro dissolution) test The drug is about 40% in 30 minutes.
  • the prescription is (per 100g plain tablets):
  • Preparation process After sieving 50.0g of Zebutinib, 36.5g of microcrystalline cellulose, 4g of croscarmellose sodium, 8g of colloidal silicon dioxide, and 1g of sodium lauryl sulfate Mix in a high shear granulator, then add 0.5 g of magnesium stearate and mix well. The powder is directly compressed to obtain plain tablets, which are oral solid tablets containing Zebutinib.
  • Drug cumulative dissolution (in vitro dissolution) test The dissolution curve of the drug is shown in Figure 3. It can be seen that the dissolution is greater than 80% in 30 minutes.
  • the prescription is (per 100g plain tablets):
  • Preparation process After sieving 60g of Zebutinib, 33.7g of microcrystalline cellulose, 4g of croscarmellose sodium, 0.8g of colloidal silicon dioxide, and 1g of sodium lauryl sulfate Mix in a high shear granulator, then add 0.5 g of magnesium stearate and mix well. The powder is directly compressed to obtain plain tablets, which are oral solid tablets containing Zebutinib.
  • Drug cumulative dissolution (in vitro dissolution) test The dissolution curve of the drug is shown in Figure 3. It can be seen that the dissolution is less than 60% in 30 minutes
  • the prescription is (per 100g plain tablets):
  • Preparation process Add 53.2g of lactose, 2g of croscarmellose sodium, 1g of sodium lauryl sulfate and 34.8g of zebutinib into a high-shear granulator (MYCROMIX, manufactured by BOSCH) After mixing for 5 minutes, add appropriate amount of purified water for granulation, dry and sizing, then add 4.5 g of colloidal silicon dioxide, 4 g of microcrystalline cellulose and 0.5 g of magnesium stearate and mix. After mixing, press tablets to obtain plain tablets, even oral solid tablets containing zebutinib.
  • MYCROMIX high-shear granulator
  • Drug cumulative dissolution rate (in vitro dissolution) test the drug dissolution rate (%) in 60 minutes is about 80%.
  • the prescription is (per 100g plain tablets):
  • Drug cumulative dissolution rate (in vitro dissolution) test the drug dissolution rate (%) in 60 minutes is less than 80%.
  • the prescription is (per 100g plain tablets):

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Abstract

提供了一种含有(S)-7-[4-(1-丙烯酰基哌啶)]-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺的口服固体片剂及其制备方法。所述口服固体片剂具有良好的药物释放特性，且用药方便，释放迅速高效，对设备无特殊要求，制剂工艺简单，能够保证制剂稳定性，便于运输和储藏，适合规模化生产。

Description

一种含有布鲁顿氏酪氨酸激酶抑制剂的口服固体片剂及其制备方法 技术领域
本发明涉及一种含有布鲁顿氏酪氨酸激酶(Bruton’s Tyrosine Kinase,BTK)抑制剂，尤其是(S)-7-[4-(1-丙烯酰基哌啶)]-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺的口服固体片剂及其制备方法。
背景技术
国际申请WO2014173289A公开了一种新型的布鲁顿氏酪氨酸激酶(Bruton’s Tyrosine Kinase,BTK)，更具地为(S)-7-[4-(1-丙烯酰基哌啶)]-2-(4-苯氧基苯基)-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺(通用名为泽布替尼(Zanubrutinib))，其化学结构如下：
Figure PCTCN2020095352-appb-000001
泽布替尼属于第二代BTK抑制剂，其通过与酪氨酸激酶共价结合，使酶不可逆失活。其单药或与其它药物联合用于B淋巴细胞肿瘤的治疗，包括慢性淋巴细胞白血病/小淋巴细胞淋巴瘤(CLL/SLL)、套细胞淋巴瘤(MCL)、华氏巨球蛋白血症(WM)、滤泡性淋巴瘤(FL)、非生发中心亚型弥漫性大B细胞淋巴瘤(non-GCB DLBCL)等。
泽布替尼的原料药物略有吸湿性。DSC结果表明，该化合物熔化时具有明确的吸热峰，其起始温度和峰值温度分别为139℃和144℃。该原料药的熔点为145℃，低于片剂开发的理想熔点150℃，且物料粘性较大，这对泽布替尼的片剂开发、大规模工业化生产带来了巨大的挑战。另外，泽布替尼的溶解度具有pH依赖性，属于生物药剂学分类系统II类(低溶解性、高渗透性)药物，因此，迫切需要开发出一种泽布替尼片剂，其中活性成分能够快速地从制剂中溶出，从 而保持药物在全肠道中快速释放以具有良好的生物利用度。
发明内容
为了克服泽布替尼原料药(API)在理化性质方面的不足，如粘性大、流动性差、溶解度差等，并且保证药物的良好溶出度，本发明提供了一种含有布鲁顿氏酪氨酸激酶抑制剂泽布替尼的口服固体片剂及其制备方法。本发明的发明人意料不到地发现，一定量的胶态二氧化硅作为助流剂以及其它赋形剂对改善药物粘冲问题、保证药物良好的溶出速度具有显著贡献。本发明的泽布替尼口服固体片剂能够在pH 1.2(HCl)的含十二烷基硫酸钠的介质中较为快速的释放，例如在一些处方辅料配比时在30～60min内溶出度能够达到80％以上；优选地在一些处方辅料配比时泽布替尼在30分钟内溶出达到95％以上。并且，本发明的泽布替尼口服固体片剂对生产设备无特殊要求，制剂工艺简单、产品稳定、生产成本低。
在本发明的一个方面中，提供了一种含有泽布替尼的口服固体片剂，其含有：(1)泽布替尼20％～70％(质量百分比)，优选为30％～50％(质量百分比)；(2)一种或多种药学上可接受的赋形剂。
在本发明的一些实施方案中，所述泽布替尼可以为其任意固体形态，如晶型(如WO2018033853A中公开的晶型A)、无定形、或晶型与无定形的混合物。优选地，所述泽布替尼为晶型A、无定形、或晶型A与无定形的混合物。在本发明的一些具体实施方案中，所述泽布替尼的粒径在40μm以下。
在一些实施方案中，晶型A的X射线粉末衍射图包含具有独立选自以下2θ角度值的衍射峰：约14.8±0.2°、15.6±0.2°、16.4±0.2°和21.4±0.2°。在一些实施方案中，晶型A的X射线粉末衍射图包含具有独立选自以下2θ角度值的衍射峰：约12.2±0.2°、12.9±0.2°、14.8±0.2°、15.6±0.2°、16.4±0.2°和21.4±0.2°。在一些实施方案中，晶型A的X射线粉末衍射图包含具有独立选自以下2θ角度值的衍射峰：约12.2±0.2°、12.9±0.2°、14.8±0.2°、15.6±0.2°、16.4±0.2°、17.7±0.2°、18.5±0.2°、20.7±0.2°和21.4±0.2°。在一些实施方案中，晶型A的X射线粉末衍射图基本上与图1一致。
在本发明的一些实施方案中，所述赋形剂任意地选自填充剂、粘合剂、崩解剂、润湿剂、助流剂、润滑剂以及它们的任意组合。
在本发明的一些具体实施方案中，所述填充剂选自淀粉、蔗糖、微晶纤维素、甘露醇、乳糖、预胶化淀粉、葡萄糖、麦芽糊精、环糊精、纤维素、硅化微晶纤 维素以及它们的任意组合。
在本发明的一些具体实施方案中，所述填充剂为乳糖，其含量为约20％～70％，优选为约40％～60％，均为质量百分比。
在本发明的一些具体实施方案中，所述填充剂为微晶纤维素，微晶纤维素为內加填充剂，并且微晶纤维素填充剂的含量为约10％～50％，优选为约30％～50％，均为质量百分比。
在本发明的一些具体实施方案中，所述填充剂为乳糖和微晶纤维素的组合时，乳糖和微晶纤维素的含量分别为约0％～70％和约0％～50％，优选为约40％～60％和约4％～10％，均为质量百分比。
在本发明的一些实施方案中，所述粘合剂选自淀粉、羟丙甲纤维素、聚乙烯吡咯烷酮、羧甲基纤维素钠、羟丙基纤维素、甲基纤维素、乙基纤维素、明胶、蔗糖以及它们的任意组合。
在本发明的一些具体实施方案中，所述粘合剂为羟丙甲纤维素，所述羟丙甲纤维素的含量为约0～10％，优选为约0～5％，均为质量百分比。
在本发明的一些具体实施方案中，所述粘合剂为交联羧甲基纤维素钠，其含量为约0％～10％，优选为约0％～5％，均为质量百分比。
在本发明的一些实施方案中，所述崩解剂选自羧甲基淀粉钠、低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、交联羧甲基纤维素、甲基纤维素、预胶化淀粉、海藻酸钠以及它们的任意组合。
在本发明的一些具体实施方案中，所述崩解剂为交联羧甲基纤维素钠，所述交联羧甲基纤维素钠含量为约0.5％～5％，优选为约1％～3％，均为质量百分比。
在本发明的一些实施方案中，所述润湿剂为十二烷基硫酸钠(SLS)，所述十二烷基硫酸钠的含量为约0％～5％，优选为0.5％～1.0％，均为质量百分比。
在本发明的一些实施方案中，所述助流剂选自粉状纤维素、三硅酸镁、胶态二氧化硅、滑石粉的以及它们的任意组合。
在本发明的一些具体实施方案中，所述助流剂为胶态二氧化硅，所述胶态二氧化硅含量为约0.1％～20％，为质量百分比。当胶态二氧化硅的含量小于0.1％(质量百分比)时，胶态二氧化硅不能有效地分散API，从而不能保证片剂的快速崩散和API的溶出；而当胶态二氧化硅的含量大于20％(质量百分比)时，由于体积巨大导致对于商业化生产不利。更优选地，胶态二氧化硅的含量为约4％～8％，为质量百分比。
在本发明的一些实施方案中，所述润滑剂选自硬脂酸锌、单硬脂酸甘油酯、硬脂酸棕榈酸甘油酯、硬脂酸镁、硬脂酸富马酸钠以及它们的任意组合。
在本发明的一些具体实施方案中，所述润滑剂优选为硬脂酸镁，其含量为约0.1％～2％，优选为约0.3％～1％，均为质量百分比。
更进一步地，在本发明所提供的泽布替尼口服固体片剂还进一步含有包衣剂。
在本发明的一些实施方案中，所述包衣剂选自欧巴代薄膜包衣粉、聚乙烯醇、羟丙基纤维素、聚乙二醇以及它们的任意组合。优选为欧巴代薄膜包衣粉。
本发明的一个方面中，本发明提供了一种制备所述泽布替尼口服固体制剂的方法，其制粒工艺选自粉末直压、干法制粒、湿法制粒，优选湿法制粒。
在本发明的一个方面中，本发明提供了所述泽布替尼口服固体片剂的制备方法，其包括以下步骤：
(1)混合泽布替尼原料药和赋形剂(包括但并不限于，填充剂、粘合剂、崩解剂、润湿剂、助流剂和润滑剂)；
(2)将所述泽布替尼原料药和赋形剂的混合物用纯化水、或有机试剂(包括但不限于乙醇、丙酮)、或含有粘合剂的水溶液或有机溶液进行湿法制粒，干燥并整粒；
(3)任选地，将所述整粒后颗粒与外加赋形剂(包括但不限于填充剂、润滑剂、助流剂)混合，并压制成素片；
(4)任选地，对素片进行包衣，
其中，如果未进行步骤(3)，则将步骤(2)中获得的所述整粒压制成素片。
在本发明的一些实施方案中，步骤(2)中所述有机试剂选自乙醇、丙酮以及它们的组合。
在本发明的一些实施方案中，步骤(3)中所述外加赋形剂选自填充剂(如微晶纤维素)、润滑剂(如硬脂酸镁)、助流剂(如胶态二氧化硅)以及它们的任意组合。
在上述制备方法中，填充剂、粘合剂、崩解剂、润湿剂、助流剂、润滑剂和包衣的具体实例和含量如上所述。
在上述制备方法中，通过通常使用的混合法，进行上述制备步骤(1)中的“混合”。使用设备，例如，料斗混合机、垂直造粒机、FLO-5M、V型混合机、转鼓混合机等，进行“混合”。
在上述制备方法中，可以使用通常的造粒方法进行上述制备步骤(2)中的制粒。使用设备，例如湿法制粒机等进行制粒。使用常规的压片机，如ZP10A进行压 制。制片之后，在必要时，可以进行“干燥”。对于干燥来说，通常可以使用干燥制剂所使用的任何方法，例如，真空干燥、流态化床干燥，等。本文中可使用的下面的术语根据下述定义来使用。
除非明确地有相反指示，否则本文中引用的所有范围都是包含性质的；即，所述范围包括所述范围的上限和下限的值以及在中间的所有值。例如，本文描述的温度范围、百分比、当量范围等包括所述范围的上限和下限以及在其中间的连续区间的任何值。
如本文所使用术语“质量百分比”描述要原料药泽布替尼及各种赋形剂的含量，其是以相对于所述口服固体片剂的总质量计算。
如本文所使用的术语“制剂”是指包括活性药物成份(API)的物质的混合物、聚集体、溶液或其它组合，所述制剂适合于特定的施用途径，例如，适合于压缩成被设计用于在患者的疾病状态或病症的治疗、管理、预防等中口服施用的片剂的制剂。
本文使用的“包衣”不局限于涂覆所包衣的对象(含有泽布替尼的素片)的整个表面的情形，还可以指部分涂覆所包衣的对象、在所包衣的对象吸收或吸附肠溶衣组分、或者涂覆内核的素片的情形。根据本发明所制备的口服固体片剂的硬度在60N-220N，并且在30分钟内的溶出度超过85％。
在本发明的一些实施方案中，所述固体口服片剂中泽布替尼的含量通常为每个片剂含有约70mg～约400mg的泽布替尼，优选含有约80mg，160mg或320mg的泽布替尼。
在本发明的一些实施方案中，所述固体口服片剂中还可以包含一种或多种选自甜味剂、矫味剂、着色剂和防腐剂的试剂，以提供药学上美观和适口的制剂。
在本发明的一些实施方案中，所述固体口服片剂可以采用多种可能的形状(椭圆体、胶囊、两面凸的圆形灯)来制备。
附图说明
图1为泽布替尼的晶型A的X射线粉末衍射图。
图2为实施例1的泽布替尼口服固体片剂的药物累积溶出度(体外溶出)示意图。
图3为实施例8和实施例9的泽布替尼口服固体片剂的药物累积溶出度(体外溶出)示意图。其中，实施例8的药物溶出速度显著优于实施例9。
具体实施方式：
下面的实施例可以帮助本领域的技术人员更全面地理解本发明，但不以任何方式限制本发明。下文中，除非另作说明，否则温度以℃计。试剂购自商业提供商例如Sigma-Aldrich、Alfa Aesar或TCI，且无需进一步纯化即可使用，除非另作说明。
实施例1
泽布替尼口服固体片剂的制备，规格160mg
处方为(每100g素片)：
Figure PCTCN2020095352-appb-000002
制备工艺：将53.2g的乳糖、2g的交联羧甲基纤维素钠、1g的十二烷基硫酸钠和34.8g的泽布替尼加入高剪切制粒机(MYCROMIX，由BOSCH制造)中混合5分钟，加入适量纯化水进行制粒，干燥后整粒，再加入4.5g的胶态二氧化硅、4g的微晶纤维素和0.5g的硬脂酸镁并进行混合。混合后压片，得到素片。用2.4g的欧巴代对上述素片进行包衣，得到含有泽布替尼的口服固体片剂。
药物累积溶出度(体外溶出)测试：体外溶出实验通过自动取样溶出仪(型号：708+850DS，购自AGILENT)测定，选用USP<711>“溶出度”采用篮法，设定自动取样溶出仪水浴温度37±0.5℃，转速100rpm，选用pH 1.2(HCl)+0.5％SLS溶出介质，体积为900mL。分别于10min、15min、30min、45min、60min取样，将所有样品过0.45μm滤膜，按样品溶出度测定方法测定分析。如图2所示，本发明的泽布替尼口服固体片剂在pH 1.2(HCl)+0.5％SLS介质中，在30min时即有大于90％的泽布替尼被溶出，能满足快速释放要求。
如下实施例2-12均按照实施例1的方法测定药物累积溶出度(体外溶出)。
实施例2
泽布替尼口服固体片剂的制备，规格160mg
处方为(每100g素片)：
Figure PCTCN2020095352-appb-000003
制备工艺：将55.6g的乳糖、2.2g的交联羧甲基纤维素钠、1.1g的十二烷基硫酸钠、4.3g的胶态二氧化硅和36.2g的泽布替尼加入高剪切制粒机中混合5分钟，加入适量纯化水进行制粒，干燥后整粒，再加入0.5g的硬脂酸镁并进行混合。混合后压片，得到素片，即为含有泽布替尼的口服固体片剂。
药物累积溶出度(体外溶出)测试：在30min时约90％的泽布替尼被溶出。
实施例3
泽布替尼口服固体片剂的制备，规格160mg
处方为(每100g素片)：
Figure PCTCN2020095352-appb-000004
制备工艺：将49.2g的乳糖、2g的交联羧甲基纤维素钠、1g的十二烷基硫酸钠和33.3g的泽布替尼加入高剪切制粒机中混合5分钟，加入2g的羟丙甲纤维素水溶液进行制粒，干燥后整粒，再加入4g的胶态二氧化硅、8g的微晶纤维素和0.5g的硬脂酸镁并进行混合。混合后压片，得到素片，即为含有泽布替尼的口服固体片剂。
实施例4
泽布替尼口服固体片剂的制备，规格320mg
处方为(每100g素片)：
Figure PCTCN2020095352-appb-000005
制备工艺：将50g的泽布替尼、4g的交联羧甲基纤维素钠、12.0g的胶态二氧化硅、1g的十二烷基硫酸钠、32.5g的微晶纤维素过筛后在高剪切制粒机中混合，再加入0.5g硬脂酸镁并混合均匀。将混合后的粉末直接压片，得到素片。用包含2.4g的欧巴代的包衣液对上述素片进行包衣，得到含有泽布替尼的口服固体片剂。
药物累积溶出度(体外溶出)测试：药物在30min的溶出度(％)约为80％。
实施例5
泽布替尼口服固体片剂的制备，规格80mg
处方为(每100g素片)：
Figure PCTCN2020095352-appb-000006
制备工艺：将23.8g的乳糖、40g的微晶纤维素、2g的交联羧甲基纤维素钠、 1g的十二烷基硫酸钠、4g的胶态二氧化硅和26.7g的泽布替尼加入流化床后，喷入含有2g羟丙甲纤维素的水溶液进行制粒，干燥后加入的硬脂酸镁并进行混合。混合后进行压片，得到素片。用包含1.5g的欧巴代的包衣液对上述素片进行包衣，得到含有泽布替尼的口服固体片剂。
实施例6
泽布替尼口服固体片剂的制备，规格80mg
处方为(每100g素片)：
Figure PCTCN2020095352-appb-000007
制备工艺：将26.7g的泽布替尼、2g的交联羧甲基纤维素钠、4g的胶态二氧化硅、1g的十二烷基硫酸钠、35.8g的乳糖和30g的硅化微晶纤维素过筛后在高剪切制粒机中混合，再加入0.5g硬脂酸镁并混合均匀。粉末直接压片，欧巴代包衣液包衣，得到含有泽布替尼的口服固体片剂。
实施例7
泽布替尼口服固体片剂的制备，规格320mg
处方为(每100g素片)：
Figure PCTCN2020095352-appb-000008
制备工艺：将50.0g的泽布替尼、4g的交联羧甲基纤维素钠、8g的胶态二氧化硅、1g的十二烷基硫酸钠、36.5g的乳糖过筛后在高剪切制粒机中混合，再加 入0.5g的硬脂酸镁并混合均匀。粉末直接压片，得到素片，即为含有泽布替尼的口服固体片剂。
药物累积溶出度(体外溶出)测试：药物在30min约为40％。
实施例8
泽布替尼口服固体片剂的制备，规格320mg
处方为(每100g素片)：
Figure PCTCN2020095352-appb-000009
制备工艺：将50.0g的泽布替尼、36.5g的微晶纤维素、4g的交联羧甲基纤维素钠、8g的胶态二氧化硅、1g的十二烷基硫酸钠过筛后在高剪切制粒机中混合，再加入0.5g的硬脂酸镁并混合均匀。将粉末直接压片，得到素片，即为含有泽布替尼的口服固体片剂。
药物累积溶出度(体外溶出)测试：药物的溶出曲线见图3，可以看出，溶出在30min大于80％。
实施例9
泽布替尼口服固体片剂的制备，规格320mg
处方为(每100g素片)：
Figure PCTCN2020095352-appb-000010
制备工艺：将60g的泽布替尼、33.7g的微晶纤维素、4g的交联羧甲基纤维素钠、0.8g的胶态二氧化硅、1g的十二烷基硫酸钠过筛后在高剪切制粒机中混 合，再加入0.5g的硬脂酸镁并混合均匀。将粉末直接压片，得到素片，即为含有泽布替尼的口服固体片剂。
药物累积溶出度(体外溶出)测试：药物的溶出曲线见图3，可以看出，溶出在30min小于60％
实施例10
泽布替尼口服固体片剂的制备，规格320mg
处方为(每100g素片)：
Figure PCTCN2020095352-appb-000011
制备工艺：将53.2g的乳糖、2g的交联羧甲基纤维素钠、1g的十二烷基硫酸钠和34.8g的泽布替尼加入高剪切制粒机(MYCROMIX，由BOSCH制造)中混合5分钟，加入适量纯化水进行制粒，干燥后整粒，再加入4.5g的胶态二氧化硅、4g的微晶纤维素和0.5g的硬脂酸镁并进行混合。混合后压片，得到素片，即使含有泽布替尼的口服固体片剂。
药物累积溶出度(体外溶出)测试：药物在60min的溶出度(％)约为80％。
实施例11
泽布替尼口服固体片剂的制备，规格320mg
处方为(每100g素片)：
Figure PCTCN2020095352-appb-000012
Figure PCTCN2020095352-appb-000013
制备工艺：按照实施例10类似的方法，可以制备含有泽布替尼的口服固体片剂。
药物累积溶出度(体外溶出)测试：药物在60min的溶出度(％)小于80％。
实施例12
泽布替尼口服固体片剂的制备，规格320mg
处方为(每100g素片)：
Figure PCTCN2020095352-appb-000014
制备工艺：按照实施例10类似的方法，可以制备含有泽布替尼的口服固体片剂。
尽管前述说明书教导了本发明的原理，并为了举例说明的目的提供了实施例，但是本发明的实践包括在下述权利要求的范围内的所有常见变化、适应和/或修饰。本公开所涉及的文献通过引用并入本文中。

Claims (21)

  1. 一种含有泽布替尼的口服固体片剂，其含有：(1)泽布替尼20％～70％，优选为30％～50％，均为质量百分比；(2)一种或多种药学上可接受的赋形剂。
  2. 根据权利要求1所述的口服固体片剂，其中，所述泽布替尼为晶型A、无定形、或晶型A与无定形的混合物。
  3. 根据权利要求1或2所述的口服固体片剂，其中，所述赋形剂选自填充剂、粘合剂、崩解剂、润湿剂、助流剂、润滑剂以及它们的任意组合。
  4. 根据权利要求3所述的口服固体片剂，其中，所述填充剂选自淀粉、蔗糖、微晶纤维素、甘露醇、乳糖、预胶化淀粉、葡萄糖、麦芽糊精、环糊精、纤维素、硅化微晶纤维素以及它们的任意组合。
  5. 根据权利要求4所述的口服固体片剂，其中，所述填充剂为乳糖，所述乳糖的含量为20％～70％，优选为40％～60％，均为质量百分比。
  6. 根据权利要求4所述的口服固体片剂，其中，所述填充剂为微晶纤维素，所述微晶纤维素的含量为10％～50％，优选为30％～50％，均为质量百分比。
  7. 根据权利要求4所述的口服固体片剂，其中，所述填充剂为乳糖和微晶纤维素的组合，所述乳糖和所述微晶纤维素的含量分别为0％～70％和0％～50％，优选为40％～60％和4％～10％，均为质量百分比。
  8. 根据权利要求3所述的口服固体片剂，其中，所述粘合剂选自淀粉、羟丙甲纤维素、聚乙烯吡咯烷酮、羧甲基纤维素钠、羟丙基纤维素、甲基纤维素、乙基纤维素、明胶、蔗糖以及它们的任意组合。
  9. 根据权利要求8所述的口服固体片剂，其中，所述粘合剂为羟丙甲纤维素，所述羟丙甲纤维素的含量为0～10％，优选为0～5％，均为质量百分比。
  10. 根据权利要求3所述的口服固体片剂，其中，所述崩解剂选自羧甲基淀粉钠、低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、交联羧甲基纤维素、甲基纤维素、预胶化淀粉、海藻酸钠以及它们的任意组合。
  11. 根据权利要求10所述的口服固体片剂，其中，所述崩解剂为交联羧甲基纤维素钠，所述交联羧甲基纤维素钠的含量为0.5％～5％，优选为1％～3％，均为质量百分比。
  12. 根据权利要求3所述的口服固体片剂，其中，所述润湿剂为十二烷基硫酸钠，所述十二烷基硫酸钠的含量为0％～5％，优选为0.5％～1.0％，均为质量百分比。
  13. 根据权利要求3所述的口服固体片剂，其中，所述助流剂选自粉状纤维素、三硅酸镁、胶态二氧化硅、滑石粉以及它们的任意组合。
  14. 根据权利要求13所述的口服固体片剂，其中，所述助流剂为胶态二氧化硅，所述胶态二氧化硅的含量为0.1％～20％，优选为4％～8％，均为质量百分比。
  15. 根据权利要求3所述的口服固体片剂，其中，所述润滑剂选自硬脂酸锌、单硬脂酸甘油酯、硬脂酸棕榈酸甘油酯、硬脂酸镁、硬脂酸富马酸钠以及它们的任意组合。
  16. 根据权利要求15所述的口服固体片剂，其中，所述润滑剂为硬脂酸镁，所述硬脂酸镁的含量为0.1％～2％，优选为0.3％～1％，均为质量百分比。
  17. 根据权利要求1至16中任一项所述的口服固体片剂，其中，所述口服固体片剂还进一步含有包衣剂，所述包衣剂选自欧巴代薄膜包衣粉、聚乙烯醇、羟丙基纤维素、聚乙二醇以及它们的任意组合，优选为欧巴代薄膜包衣粉。
  18. 一种制备权利要求1-17中任一项所述的口服固体片剂的方法，其中，所述口服固体片剂的制粒方法选自粉末直压、干法制粒、湿法制粒，优选湿法制粒。
  19. 一种制备权利要求1-17中任一项所述的口服固体片剂的方法，其包括以下步骤：
    (1)混合所述泽布替尼和一种或多种赋形剂；
    (2)将所述泽布替尼和一种或多种赋形剂的混合物用纯化水、或有机试剂、或含有粘合剂的水溶液或有机溶液进行湿法制粒，干燥并整粒；
    (3)任选地，将所述整粒后颗粒与外加赋形剂混合，并压制成素片；
    (4)任选地，对素片进行包衣，
    其中，如果未进行步骤(3)，则将步骤(2)中获得的所述整粒后颗粒压制成素片。
  20. 根据权利要求19所述的方法，其中，步骤(2)中所述有机试剂选自乙醇、丙酮以及它们的组合。
  21. 根据权利要求19或20所述的方法，其中，步骤(3)中所述外加赋形剂选自填充剂、润滑剂、助流剂以及它们的任意组合。
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