WO2019101150A1 - 一种海泽麦布片剂及其制备方法 - Google Patents

一种海泽麦布片剂及其制备方法 Download PDF

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WO2019101150A1
WO2019101150A1 PCT/CN2018/117086 CN2018117086W WO2019101150A1 WO 2019101150 A1 WO2019101150 A1 WO 2019101150A1 CN 2018117086 W CN2018117086 W CN 2018117086W WO 2019101150 A1 WO2019101150 A1 WO 2019101150A1
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haize
wheat
cloth
wheat cloth
sheet according
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PCT/CN2018/117086
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English (en)
French (fr)
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丁立
代军
冯春荣
代常亮
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浙江海正药业股份有限公司
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Priority to CN201880073252.3A priority Critical patent/CN111601590A/zh
Priority to US16/766,292 priority patent/US11622939B2/en
Publication of WO2019101150A1 publication Critical patent/WO2019101150A1/zh

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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
    • A61K9/20—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
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams

Definitions

  • the invention belongs to the field of medicine, and particularly relates to a haize wheat cloth tablet and a preparation process thereof.
  • Haize Maibu (HS-25) is a cholesterol-lowering drug, disclosed in WO2011017907, having the following structural formula:
  • Heze Metz reduces plasma sterol levels by inhibiting cholesterol absorption protein NPCILI of intestinal epithelial cells to reduce cholesterol, phytosterol absorption, and bile cholesterol reabsorption.
  • This product is used clinically: 1. Primary hypercholesterolemia; 2. Homozygous familial hypercholesterolemia (HoFH); 3. Treatment of homozygous glutathione (or phytosterolemia).
  • Heze Metz is a poorly soluble drug.
  • a surfactant such as Tween or sodium lauryl sulfate can usually be added to the preparation.
  • sodium lauryl sulfate can be added as a surfactant. Since Heze methane is unstable to alkali, the amount of sodium lauryl sodium is generally controlled to be less than 5% by weight of the tablet.
  • Micronization of the drug substance is a common method for improving drug dissolution and increasing the bioavailability of the drug.
  • the particle size of the raw material after micronization is too small, which will increase the electrostatic adsorption and increase the contact area with water and air, which leads to product instability; Larger, it will lead to slower dissolution of the product and lower bioavailability.
  • the invention provides a suitable particle size range of the raw material medicine, in which the high-performance raw material of the haize wheat cloth can be processed, the prepared product has good bioavailability, the crystal form and the related substance are stable, and has good commercial production value.
  • solid dispersion technology is another way to increase the bioavailability of poorly soluble drugs.
  • the risk of this technology is that the drug may undergo a crystal form transition from a high energy amorphous form to a stable crystalline form. This may pose a hidden danger to the stability and solubility of the drug.
  • the Heze wheat cloth piece made of water granules is not added with anti-oxidant in the prescription, and it is stable under the condition of long-term accelerated placement.
  • the moisture content of the Heze wheat cloth prepared by ethanol granulation is not increased when the antioxidant is not added in the prescription.
  • the main reason is that the amorphous Heze wheat cloth has higher energy and is in contact with the moisture and oxidizing substances in the preparation. The probability is large, and the degradation is easy under the influence of temperature.
  • the invention adds an appropriate amount of an antioxidant such as butylated hydroxytoluene to the water or organic solvent prescription, which can effectively reduce the degradation impurities, and the appropriate amount of butylated hydroxytoluene is added to the Heze wheat cloth tablet. It contributes to the stability of the product, and the amount of addition can be adjusted in combination with the process.
  • This patent describes in detail the wet granulation process of Haize Maibu tablets.
  • the appearance of the tablets obtained by water or ethanol granulation is smooth, rapid release in vitro, uniform in content and content, and no degradation of impurities.
  • the crystal form is stable, the production process is simple, and the related problems in industrial production are better handled.
  • the present invention provides a haize wheat cloth tablet and a preparation process thereof, which have the advantages of high bioavailability, good stability, high yield, and easy commercial production.
  • the haize wheat cloth sheet according to the present invention contains an auxiliary material such as a granule, a filler, a binder, a disintegrating agent and a lubricant, and the granules of the sieving sheet are 1-20% by weight of the tablet.
  • the Heyze wheat cloth tablet preferably further contains a stabilizer and/or a surfactant.
  • the filler is at least one of lactose, microcrystalline cellulose, and pregelatinized starch; preferably, at least one of lactose and microcrystalline cellulose; more preferably, 30 to 60% The weight of lactose, at least one of 20-60% by weight of microcrystalline cellulose.
  • the binder is at least one of hydroxypropylcellulose and povidone; preferably, povidone; more preferably, from 1 to 5% by weight of povidone; most preferably It is 1 to 5% by weight of povidone K30.
  • the disintegrant is at least one of crospovidone and croscarmellose sodium; preferably, it is 1 to 10% by weight of crospovidone or 1 to 10% by weight.
  • Cross-linked sodium carboxymethyl cellulose is preferred.
  • the stabilizer is at least one of butylated hydroxyanisole and butylated hydroxytoluene; preferably, butylated hydroxytoluene; more preferably, 0.005 to 0.1% by weight of butylated hydroxytoluene.
  • the surfactant is at least one of sodium lauryl sulfate and polysorbate; preferably, sodium lauryl sulfate; more preferably, 1 to 5% by weight of dodecane Sodium sulfate.
  • the lubricant is at least one of magnesium stearate and talc; preferably, magnesium stearate; more preferably, 0.5 to 2% by weight of magnesium stearate.
  • the Heyze Mai cloth sheet may be granulated with water, alcohol, acetone, or the like, and a mixture thereof, and then compressed into tablets.
  • the inventors have unexpectedly found through a large number of experiments that the Heze Metz is dissolved in an organic solvent containing povidone and then poured or sprayed into the excipient to prepare a solid dispersion thereof.
  • This aspect can solve the electrostatic adsorption problem of the drug substance, and can also inhibit the crystal form transformation.
  • the present invention provides, in one aspect, a Heyze Maimb Solid Dispersion Composition comprising Heze Met and Povidone.
  • the present invention provides a Heyze Mai Mai sheet comprising the Hazelmeat solid dispersion composition of the present invention.
  • the present invention also provides the use of the Hazelmeat solid dispersion composition of the present invention for the preparation of a solid preparation of Heze wheat cloth.
  • the solid preparation is preferably selected from the group consisting of a tablet, a capsule, a granule, and a powder.
  • the present invention also provides a process for the preparation of the Hazel malt solid dispersion composition of the present invention comprising the steps of dissolving Heze Metz in an organic solvent containing povidone.
  • the method of preparing a Hazel malt solid dispersion composition further optionally includes pouring or spraying the Heze Metz solution obtained in the above step into the excipient, and optionally Whole and/or drying steps.
  • the organic solvent may be selected from organic solvents such as alcohols, ethers, ketones, esters, and the like, including but not limited to methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, n-pentanol, and iso Pentanol, n-hexanol, cyclohexanol, tetrahydrofuran, diethyl ether, methyl ethyl ether, ethyl acetate, ethyl formate or a mixture thereof; preferably, the organic solvent is selected from the group consisting of ethanol, isopropanol and a mixed solvent thereof with water .
  • organic solvents such as alcohols, ethers, ketones, esters, and the like, including but not limited to methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, n-pentan
  • the haize wheat cloth sheet of the present invention can be prepared by wet granulation and tableting by water. More preferably, the haize wheat cloth sheet can be prepared by the following method:
  • the Heze wheat cloth used in the above preparation process is Heze Met Crystal Form I.
  • the Hezemeer cloth used in the above preparation process has a particle size ranging from 1 ⁇ m ⁇ D90 ⁇ 100 ⁇ m, preferably 1 ⁇ m ⁇ D90 ⁇ 50 ⁇ m.
  • the granules of the invention can also be prepared by a method of wet granulation and tableting with an organic solvent and a solution thereof, wherein the organic solvent and the solution thereof are preferably an alcohol solvent and a solution thereof, more preferably ethanol and
  • the solution, more preferably an ethanol solution can be prepared by the following method:
  • the ethanol solution is an aqueous ethanol solution, more preferably, the concentration of the aqueous ethanol solution is ⁇ 60% (w/w); more preferably, the concentration of the aqueous ethanol solution is ⁇ 75% (w/w); Preferably, the concentration of the aqueous ethanol solution is 80-90% (w/w).
  • the ethanol solution is used in an amount of 30% to 50% (w/w) of the prescribed amount; more preferably, the ethanol solution is used in an amount of 35% to 45% (w/w) of the prescribed amount.
  • the weight ratio of Heze Metz to povidone ranges from 10:1 to 1:1; more preferably, the weight ratio ranges from 5:1 to 5:3.
  • the granulation method comprises high-speed agitation granulation mechanism granulation or fluidized bed granulation.
  • the Haize Maibu sheet prepared by the method of the present invention 90% or more of the Haize Maibu is present in an amorphous form.
  • the Heyze Mai Mai sheet according to the present invention preferably contains 5 to 20 mg of Heze Maid cloth per drug dosage unit; more preferably, the dosage of Hai Ze Mai cloth contained in each medicine dosage unit is 5 mg, 10 mg Or 20mg.
  • the haize wheat cloth tablet further comprises 20 to 250 mg of lactose, 20 to 200 mg of microcrystalline cellulose, 1 to 10 mg of croscarmellose sodium or 5 to 30 mg per drug dosage unit.
  • Cross-linked povidone 1 to 15 mg of povidone K30, 0 to 0.2 mg of butylated hydroxytoluene, 0 to 15 mg of sodium lauryl sulfate, and 0.5 to 10 mg of magnesium stearate.
  • Haze Maibu raw material drug has large electrostatic adsorption and poor self-flowability; it has poor solubility in water and poor absorption in the body.
  • the present invention provides two methods for preparing Heze Maibu tablets.
  • One of the preparation methods comprises the following steps: preparing the Heze gauze raw material medicine by micronizing and then directly mixing with the auxiliary material, and then adopting water for wet granulation to obtain the Heze wheat cloth piece, and preferably selecting a suitable particle size range of the raw material medicine.
  • Another preparation method comprises the steps of: dissolving the Hazel malt raw material by an organic solvent, preferably dissolving the Hazel malt raw material in an organic solvent containing povidone, and then optionally pouring the obtained solution into Or spray into the excipients for granulation.
  • the problem of electrostatic adsorption can be solved, and on the other hand, as a simple solid dispersion technology, it is beneficial to improve bioavailability, and the optimal amount of povidone is preferably used, and the sea is better solved.
  • the electrostatic adsorption problem of the Zemak raw material drug solves the risk of crystal transformation, and the obtained Heze wheat cloth sheet still exists in an amorphous state during the stability placement process.
  • the preparation method provided by the invention improves the bioavailability of the haize wheat cloth, is easy to be commercialized, and has high economic value.
  • Figure 3 XRD pattern of a mixture of Haize Maibu Placebo and Haize Maibu API (Form I)
  • Figure 4 XRD pattern of Heze Maibu tablets with an API concentration of 20% for 0 months
  • Haize Maibu raw material medicine according to the present invention is provided by Zhejiang Haizheng Pharmaceutical Co., Ltd., and the crystal form of Haize Maibu raw material medicine is crystalline form I, and its preparation is described in WO2014036956.
  • Example 1 Heze Metz (water granulation), specification: 10 mg, each weighing 100 mg.
  • the composition of the prescription (unit: g) is composed as follows:
  • step 3 The povidone K30 solution of step 2 was added to the mixture of step 1, granulated, and the wet granules were sized using a 1.0 mm sieve.
  • Example 2 Haze Maibu tablets (water granulation), specification: 10 mg, each tablet weighing 100 mg.
  • the composition of the prescription (unit: g) is composed as follows:
  • the Haze Maibu bulk drug was pulverized by a jet mill, and the preparation method was the same as in Example 1.
  • Example 3 Heze Metz tablets (alcohol granulation prescription), specification 10 mg, each weighing 200 mg.
  • the prescription composition (unit: g) is as follows:
  • step 3 The binder solution of step 2 was added to the mixture of step 1, granulated, and the wet granules were sized using a 1.0 mm sieve.
  • Example 4 Heze Metz tablets, specification: 5 mg, each weighing 100 mg.
  • the prescription composition (unit: g) is as follows:
  • Example 5 Heze Metz tablets, specification: 5 mg, each weighing 100 mg.
  • the prescription composition (unit: g) is as follows:
  • Example 6 Heze Metz tablets, specification: 5 mg, 100 mg per tablet.
  • the prescription composition (unit: g) is as follows:
  • Example 7 Heze Metz tablets, specification: 5 mg, 100 mg per tablet.
  • the prescription composition (unit: g) is as follows:
  • step 3 The binder solution of step 2 was added to the mixture of step 1, granulated, and the wet granules were sized using a 1.0 mm sieve.
  • Example 8 Heze Metz tablets, specification: 10 mg, 200 mg per tablet.
  • the prescription composition (unit: g) is as follows:
  • Example 9 Heze Metz tablets, specification: 20 mg, 400 mg per tablet.
  • the prescription composition (unit: g) is as follows:
  • Example 10 Heze Metz tablets, specification: 20 mg, 400 mg per tablet.
  • the prescription composition (unit: g) is as follows:
  • Povidone K30 and Haize Maibu were dissolved in 85% (w/w) aqueous ethanol solution (35% of the prescribed amount), and used as a binder solution.
  • step 3 The binder solution of step 2 was added to the mixture of step 1, granulated, and the wet granules were sized using a 1.0 mm sieve.
  • Example 11 Heze Metz tablets, specification: 20 mg, 100 mg per tablet.
  • the prescription composition (unit: g) is as follows:
  • step 3 The binder solution of step 2 was added to the mixture of step 1, granulated, and the wet granules were sized using a 1.0 mm sieve.
  • Example 12 Heze Metz Placebo, 400 mg per tablet.
  • the prescription composition (unit: g) is as follows:
  • step 3 The binder solution of step 2 was added to the mixture of step 1, granulated, and the wet granules were sized using a 1.0 mm sieve.
  • Example 1 and Example 2 were orally administered to male Beagle dogs, and the pharmacokinetic characteristics of the dogs were examined.
  • the experimental data of the animals are shown in Table 1 and Table 2.
  • Example 2 micronized treatment of HS-25 drug substance
  • HS-25 drug substance can significantly improve the bioavailability of HS-25 in vivo.
  • Example 3 After the tablets prepared in Example 3 were orally administered to male Beagle dogs, the pharmacokinetic characteristics of the dogs were examined. The experimental data of the animals are shown in Table 3.
  • Example 3 Comparing the tablets of Examples 1 and 2 (both in Heze's Maibu water granulation formulation), the tablet of Example 3 (alcohol granulation formulation) allows HS-25 to achieve higher bioavailability in vivo.
  • Test Example 3 Stability study of Heze Metz tablets (10 mg specification)
  • Example 3 The tablet prepared in Example 3 was plasticized by aluminum, packaged in a blank envelope (containing 2 g of desiccant), and placed at a temperature of 25 ° C ⁇ 2 ° C and a humidity (RH) of 60% ⁇ 5%. Stability study, the test results are shown in Table 4.
  • Example 6 The tablet prepared in Example 6 was plasticized by aluminum, packaged in a blank middle bag (containing 2 g of desiccant), and placed at a temperature of 25 ° C ⁇ 2 ° C and a humidity (RH) of 60% ⁇ 5%. Stability study, the test results are shown in Table 5.
  • Test Example 5 Stability data of Heze Met sheet stability study (10 mg specification)
  • Example 8 The tablet prepared in Example 8 was plasticized by aluminum, packaged in a blank envelope (containing 2 g of desiccant), and placed at a temperature of 25 ° C ⁇ 2 ° C and a humidity (RH) of 60% ⁇ 5%. Stability study, the test results are shown in Table 6.
  • Example 9 The tablet prepared in Example 9 was plasticized by aluminum, packaged in a blank envelope (containing 2 g of desiccant), and placed at a temperature of 25 ° C ⁇ 2 ° C and a humidity (RH) of 60% ⁇ 5%. Stability study, the test results are shown in Table 7.
  • Test Example 7 Stability data of Heze wheat cloth without BHT
  • Example 9 and Example 10 were plastically molded, packaged in a blank envelope (containing 2 g of desiccant), and placed at a temperature of 40 ° C ⁇ 2 ° C and a humidity (RH) of 75% ⁇ 5%. , Stability study, the test results are shown in Table 8.
  • Test Example 8 Effect of sodium dodecyl sulfate (SDS) on dissolution of Heze wheat sheet
  • Dissolution method paddle method, dissolution medium: 0.1N hydrochloric acid solution containing 0.5% SDS, rotation speed: 50 rpm, medium volume: 900 mL
  • the Haize Maibu placebo and the Haize Maibu API (Form I) were mixed at a weight ratio of 98:2, and the obtained mixture was subjected to X-ray diffraction (XRD) to obtain a Haize Maibu placebo and XRD pattern of a mixture of Hazel malt raw material (Form I) (see Figure 3), followed by an XRD pattern of Figure 3 and Haize Maibu placebo (see Figure 1) and Haze Maibu raw material (Form I)
  • the XRD pattern was compared. At the 18° position in Figure 3, the characteristic peak of Heze Met Crystal Form I was detected, and the detection limit of XRD detection equipment for Heze Met Crystal Form I was determined. It is 2%.
  • the crystal form I in the tablet accounts for more than 2% of the total tablet weight, the crystal form I can be detected.
  • the Xerox film of 20% of the content obtained in Example 11 was subjected to XRD measurement, and it was found that no peak appeared at 18° (see Fig. 4), indicating that the tablet prepared by the method of Example 11 was crystallized.
  • the amount of the drug substance present is at least 2% by weight of the tablet, that is, the tablet of Example 11 has a tablet weight of 18% or more of the drug substance in an amorphous form, and the tablet of Example 11 is judged.
  • the content of amorphous in Zhonghaize Maibu accounts for more than 90% of the total amount of raw materials.
  • Example 11 Hai Ze Mai cloth 20 mg, alcohol granule tablet
  • accelerated conditions temperature 40 ° C ⁇ 2 ° C, humidity (RH) 75% ⁇ 5%
  • Figure 5 shows that the amorphous content is still above 90% under accelerated conditions of 3 months.
  • Figure 6 shows that the amorphous content is still above 90% under 9 months of accelerated conditions.

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Abstract

海泽麦布片剂、海泽麦布固体分散体组合物及其制备方法和用途。采用海泽麦布与辅料进行湿法制粒，干燥，整粒，压片得到海泽麦布片剂。

Description

一种海泽麦布片剂及其制备方法
交叉引用
本申请要求发明名称为“一种海泽麦布片剂及其制备方法”于2017年11月23日提交到中国专利局的中国专利申请201711183388.3的优先权，其内容通过引用以整体并入本文。
技术领域
本发明属于医药领域，具体涉及海泽麦布片剂及其制备工艺。
背景技术
海泽麦布(HS-25)是降胆固醇药，公开于WO2011017907中，具有以下的结构式：
Figure PCTCN2018117086-appb-000001
海泽麦布通过抑制肠上皮细胞的胆固醇吸收蛋白NPCILI减少胆固醇、植物固醇的吸收以及胆汁胆固醇的再吸收，从而降低血浆固醇水平。本品临床用于：1、原发性高胆固醇血症；2、纯合子家族性高胆固醇血症(HoFH)；3、纯合子谷甾醇血症(或植物甾醇血症)的治疗。
海泽麦布原料药静电吸附大，导致自身流动性较差；在水中溶解性较差，从而在体内吸收较差；而且，该化合物对温湿度较敏感。由于海泽麦布在稳定性和吸收方面存在上述问题，需要采用合适的制备工艺将海泽麦布制备成稳定、体内吸收良好的制剂。
海泽麦布属于难溶性药物，为了提高药物在体内的生物利用度，通常可以在制剂中加入适量表面活性剂，例如吐温或十二烷基硫酸钠等。在本发明的片剂处方中，可以加入十二烷基硫酸钠作为表面活性剂。由于海泽麦布对碱不稳定，因此十二烷基钠的用量一般控制在片重的5％以下。
将原料药进行微粉化，是提高药物溶出、增加药物生物利用度的一种常用方法。然而，由于海泽麦布原料药静电吸附大，微粉化后的原料药粒径过小会 加剧静电吸附，增加与水分、空气的接触面积，从而导致产品不稳定；另一方面，粒径过大又会导致成品溶出偏慢、生物利用度偏低。本发明提供了原料药合适的粒径范围，在该范围内海泽麦布原料药可加工性强，制备的成品生物利用度好、晶型及有关物质稳定，具有较好的商业化生产价值。
采用固体分散技术是提高难溶性药物生物利用度的另外一种方法。然而，该技术存在的风险是药物有可能发生晶型转变，从高能态的无定型转变为稳定的晶型。这可能为药物的稳定性和溶解性带来隐患。
采用水制粒制成的海泽麦布片，处方中未添加抗氧化剂，其长期加速放置条件下较稳定。而采用乙醇制粒制备的海泽麦布片，处方中未添加抗氧化剂则杂质增长较快，其主要原因是无定型的海泽麦布能量较高，与制剂中的水分、氧化物质接触的概率大，在温度的影响下容易发生降解，本发明在水或有机溶剂处方中加入适量的抗氧化剂例如丁羟甲苯，可有效的减少降解杂质，海泽麦布片中加入适量的丁羟甲苯有助于产品的稳定性，其加入量可以结合工艺进行调整。
本专利详细描述了海泽麦布片湿法制粒工艺过程，无论采用水或者乙醇制粒制得的片剂外观光洁、体外快速释放、含量及含量均匀度合格、降解杂质均未超过限度要求、晶型稳定、生产工艺简单，较好的处理了工业生产中相关难题。
发明内容
为了解决上述技术问题，本发明提供了一种海泽麦布片剂及其制备工艺，该片剂具有生物利用度高，稳定性好，收率高、易于商业化生产等优点。
本发明所述的海泽麦布片，其含有海泽麦布、填充剂、粘合剂、崩解剂和润滑剂等辅料，其中，海泽麦布占片重的1-20％。所述海泽麦布片剂优选还含有稳定剂和/或表面活性剂。
优选地，所述填充剂为乳糖、微晶纤维素、预胶化淀粉中的至少一种；优选地，为乳糖、微晶纤维素中的至少一种；更优选地，为30～60％重量的乳糖，20-60％重量的微晶纤维素中的至少一种。
优选地，所述粘合剂为羟丙基纤维素、聚维酮中的至少一种；优选地，为聚维酮；更优选地，为1～5％重量的聚维酮；最优选地，为1～5％重量的聚维酮K30。
优选地，所述崩解剂为交联聚维酮、交联羧甲基纤维素钠中的至少一种；优选地，为1～10％重量的交联聚维酮或1～10％重量的交联羧甲基纤维素钠。
优选地，所述稳定剂为丁羟茴醚、丁羟甲苯中的至少一种；优选地，为丁羟甲苯；更优选地，为0.005～0.1％重量的丁羟甲苯。
优选地，所述表面活性剂为十二烷基硫酸钠、聚山梨酯中的至少一种；优选地，为十二烷基硫酸钠；更优选地，为1～5％重量的十二烷基硫酸钠。
优选地，所述润滑剂为硬脂酸镁、滑石粉中的至少一种；优选地，为硬脂酸镁；更优选地，为0.5～2％重量的硬脂酸镁。
所述海泽麦布片可以用水、醇、丙酮、或类似溶剂、以及它们的混合物进行制粒，然后压制成片。
本发明人经过大量实验，出乎意料地发现：将海泽麦布通过含有聚维酮的有机溶剂溶解，然后倒入或喷雾至辅料中，从而制得其固体分散体。这一方面可以解决原料药的静电吸附问题，同时也可以抑制晶型转变。
基于此发现，本发明在一方面提供了一种海泽麦布固体分散体组合物，其包含海泽麦布和聚维酮。
在另一方面，本发明提供了一种海泽麦布片，其包含本发明所述的海泽麦布固体分散体组合物。
在又一方面，本发明还提供了本发明所述的海泽麦布固体分散体组合物在制备海泽麦布固体制剂中的用途。所述固体制剂优选选自片剂、胶囊、颗粒剂、粉剂。
本发明还提供了制备本发明所述的海泽麦布固体分散体组合物的方法，包括以下步骤：将海泽麦布溶解在含有聚维酮的有机溶剂中。在一些具体的实施方案中，所述制备海泽麦布固体分散体组合物的方法还任选地包括将上述步骤所得的海泽麦布溶液倒入或喷雾至辅料中，以及任选地进行整粒和/或烘干的步骤。所述有机溶剂可选自醇类、醚类、酮类、酯类等有机溶剂，包括但不限于甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、正戊醇、异戊醇、正己醇、环己醇、四氢呋喃、乙醚、甲乙醚、乙酸乙酯、甲酸乙酯或它们的混合物；优选地，所述有机溶剂选自乙醇、异丙醇及其与水的混合溶剂。
本发明的海泽麦布片可采用水进行湿法制粒后压片的方法制备得到，更优选地，所述海泽麦布片可通过以下方法制备：
(1)将海泽麦布和乳糖、微晶纤维素、十二烷基硫酸钠以及交联羧甲基纤维素钠混合均匀；
(2)将聚维酮溶于水中；
(3)将步骤(2)得到的聚维酮溶液加入步骤(1)得到的混合物中进行制粒，烘干，整粒；
(4)将步骤(3)整粒后的颗粒与硬脂酸镁混合均匀，压片。
优选地，上述制备过程中使用的海泽麦布为海泽麦布晶型Ⅰ。
优选地，上述制备过程中使用的海泽麦布粒径范围为1μm≤D90≤100μm，优选1μm≤D90≤50μm。
本发明的海泽麦布片还可采用有机溶剂及其溶液进行湿法制粒后压片的方法制备得到，其中，所述有机溶剂及其溶液优选为醇溶剂及其溶液，更优选为乙醇及其溶液，更优选为乙醇溶液，所述海泽麦布片可通过以下方法制备：
(1)将乳糖、微晶纤维素、十二烷基硫酸钠以及交联聚维酮混合均匀，或者将乳糖、微晶纤维素以及交联聚维酮混合均匀；
(2)将海泽麦布、聚维酮、丁羟甲苯(BHT)溶于醇溶剂中，或者将海泽麦布、聚维酮溶于醇溶剂中；
(3)将步骤(2)所得溶液加入步骤(1)所得的混合物中进行制粒，烘干，整粒；
(4)将步骤(3)得到的颗粒与硬脂酸镁混合均匀，压片。
优选地，所述乙醇溶液为乙醇水溶液，更优选地，所述乙醇水溶液的浓度≥60％(w/w)；更优选地，所述乙醇水溶液的浓度≥75％(w/w)；最优选地，所述乙醇水溶液的浓度为80-90％(w/w)。
优选地，所述乙醇溶液的用量为处方量的30％～50％(w/w)；更优选地，乙醇溶液的用量为处方量的35％～45％(w/w)。
优选地，在本发明的制备方法中，海泽麦布与聚维酮的重量比范围为10:1-1:1；更优选地，重量比范围为5:1-5:3。
优选地，在本发明的制备方法中，制粒方式包括高速搅拌制粒机制粒或流化床制粒。
优选地，在本发明的制备方法中，采用本发明方法制备的海泽麦布片，海泽麦布90％以上以无定型形式存在。
本发明所述的海泽麦布片，优选其中每药物剂量单元中含有5～20mg的海泽麦布；更优选地，其中每药物剂量单元中含有的海泽麦布的剂量为5mg，10mg或20mg。
优选地，所述的海泽麦布片，其中每药物剂量单元还含有20～250mg的乳糖，20～200mg的微晶纤维素，1～10mg的交联羧甲基纤维素钠或5～30mg的交联聚维酮，1～15mg的聚维酮K30，0～0.2mg的丁羟甲苯，0～15mg的十二烷基硫酸钠，0.5～10mg的硬脂酸镁。
海泽麦布原料药静电吸附大，自身流动性较差；在水中溶解性较差，在体内吸收较差。本发明提供了海泽麦布片的两种制备方法。其中一种制备方法为将海泽麦布原料药进行微粉化处理后与辅料直接混合后，采用水进行湿法制粒的方法制得海泽麦布片，并优选了合适的原料药粒径范围；另外一种制备方法包括以下步骤：将海泽麦布原料药通过有机溶剂溶解，优选将海泽麦布原料药溶解在含有聚维酮的有机溶剂中，然后任选地将所得溶液倒入或喷雾至辅料中进行制粒。通过上述方法，一方面可以解决静电吸附问题，另外一方面作为一种简单的固体分散体技术，有利于提高生物利用度，并优选了最佳的聚维酮使用量，较好的解决了海泽麦布原料药的静电吸附问题，解决了晶型转变的风险，得到的海泽麦布片在稳定性放置过程中仍然以无定型存在。本发明提供的制备方法提高了海泽麦布的生物利用度，易于商业化生产，具有较高的经济价值。
附图说明
图1：海泽麦布安慰剂的XRD图谱
图2：海泽麦布原料药(晶型I)的XRD图谱
图3：海泽麦布安慰剂与海泽麦布原料药(晶型I)混合物的XRD图谱
图4：API浓度为20％的海泽麦布片0月的XRD图谱
图5：API浓度为20％的海泽麦布片3月的XRD图谱
图6：API浓度为20％的海泽麦布片9月的XRD图谱
具体实施方式
以下结合实施例对本发明进行详细说明，必须指出，以下实施例只用于说明本发明，而不是对本发明的限制。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
本发明所述的海泽麦布原料药是由浙江海正药业股份有限公司提供，海泽麦布原料药的晶型为晶型Ⅰ，其制备参见WO2014036956。
实施例1：海泽麦布片(水制粒)，规格：10mg，每片重100mg。处方组成(单位：g)组成如下：
Figure PCTCN2018117086-appb-000002
制备方法：
1.将海泽麦布原料药(未微粉化)、单水乳糖200目、微晶纤维素101、十二烷基硫酸钠、交联羧甲基纤维素钠过40目筛后，预混合。
2.将聚维酮K30溶于纯化水(处方量的30％)中，备用。
3.将步骤2的聚维酮K30溶液加入步骤1的混合物中，制粒，湿颗粒采用1.0mm筛网整粒。
4.将湿颗粒置于流化床中，设置流化床进风温度55-65℃，开始干燥，烘干。
5. 1.0mm筛网整粒。
6.加入硬脂酸镁混合。
7.压片。
实施例2海泽麦布片(水制粒)，规格：10mg，每片重100mg。处方组成(单 位：g)组成如下：
Figure PCTCN2018117086-appb-000003
制备方法：
将海泽麦布原料药采用气流粉碎机粉碎，制备方法同实施例1。
实施例3：海泽麦布片(醇制粒处方)，规格10mg，每片重200mg。处方组成(单位：g)如下：
Figure PCTCN2018117086-appb-000004
制备方法：
1.单水乳糖200目、微晶纤维素101、交联聚维酮XL过40目筛后，预混合。
2.将丁羟甲苯、聚维酮K30、海泽麦布溶于85％(w/w)乙醇水溶液(处方量的35％)中，作为粘合剂溶液备用。
3.将步骤2的粘合剂溶液加入步骤1的混合物中，制粒，湿颗粒采用1.0mm筛网整粒。
4.将湿颗粒置于烘箱中，设置温度40-50℃，开始干燥，烘干。
5. 1.0mm筛网整粒。
6.加入硬脂酸镁混合。
7.压片。
实施例4：海泽麦布片，规格：5mg，每片重100mg。处方组成(单位：g)如下：
Figure PCTCN2018117086-appb-000005
制备方法：同实施例3
实施例5：海泽麦布片，规格：5mg，每片重100mg。处方组成(单位：g)如下：
Figure PCTCN2018117086-appb-000006
Figure PCTCN2018117086-appb-000007
制备方法：同实施例3。
实施例6：海泽麦布片，规格：5mg，每片100mg。处方组成(单位：g)如下：
Figure PCTCN2018117086-appb-000008
制备方法：同实施例3。
实施例7：海泽麦布片，规格：5mg，每片100mg。处方组成(单位：g)如下：
Figure PCTCN2018117086-appb-000009
Figure PCTCN2018117086-appb-000010
制备方法：
1.单水乳糖200目、微晶纤维素101、交联聚维酮XL、十二烷基硫酸钠过40目筛后，预混合。
2.将丁羟甲苯、聚维酮K30、海泽麦布溶于85％(w/w)乙醇水溶液(处方量的35％)中，作为粘合剂溶液备用。
3.将步骤2的粘合剂溶液加入步骤1的混合物中，制粒，湿颗粒采用1.0mm筛网整粒。
4.将湿颗粒置于烘箱中，设置温度40-50℃，开始干燥，烘干。
5. 1.0mm筛网整粒。
6.加入硬脂酸镁混合。
7.压片。
实施例8：海泽麦布片，规格：10mg，每片200mg。处方组成(单位：g)如下：
Figure PCTCN2018117086-appb-000011
制备方法：同实施例7。
实施例9：海泽麦布片，规格：20mg，每片400mg。处方组成(单位：g)如下：
Figure PCTCN2018117086-appb-000012
制备方法：同实施例7。
实施例10：海泽麦布片，规格：20mg，每片400mg。处方组成(单位：g)如下：
Figure PCTCN2018117086-appb-000013
制备方法：
1.单水乳糖200目、微晶纤维素101、交联聚维酮XL、十二烷基硫酸钠过40目筛后，预混合。
2.将聚维酮K30、海泽麦布溶于85％(w/w)乙醇水溶液(处方量的35％)中， 作为粘合剂溶液备用。
3.将步骤2的粘合剂溶液加入步骤1的混合物中，制粒，湿颗粒采用1.0mm筛网整粒。
4.将湿颗粒置于烘箱中，设置温度40-50℃，开始干燥，烘干。
5. 1.0mm筛网整粒。
6.加入硬脂酸镁混合。
7.压片。
实施例11：海泽麦布片，规格：20mg，每片100mg。处方组成(单位：g)如下：
Figure PCTCN2018117086-appb-000014
制备方法：
1.单水乳糖200目、微晶纤维素101、交联聚维酮XL过40目筛后，预混合。
2.将丁羟甲苯、聚维酮K30、海泽麦布溶于85％(w/w)乙醇水溶液中，作为粘合剂溶液备用。
3.将步骤2的粘合剂溶液加入步骤1的混合物中，制粒，湿颗粒采用1.0mm筛网整粒。
4.将湿颗粒置于烘箱中，设置温度40-50℃，开始干燥，烘干。
5. 1.0mm筛网整粒。
6.加入硬脂酸镁混合。
7.压片。
实施例12：海泽麦布安慰剂，每片400mg。处方组成(单位：g)如下：
Figure PCTCN2018117086-appb-000015
制备方法：
1.单水乳糖200目、微晶纤维素101、交联聚维酮XL、十二烷基硫酸钠过40目筛后，预混合。
2.将丁羟甲苯、聚维酮K30溶于85％(w/w)乙醇水溶液(处方量的35％)中，作为粘合剂溶液备用。
3.将步骤2的粘合剂溶液加入步骤1的混合物中，制粒，湿颗粒采用1.0mm筛网整粒。
4.将湿颗粒置于烘箱中，设置温度40-50℃，开始干燥，烘干。
5. 1.0mm筛网整粒。
6.加入硬脂酸镁混合。
7.压片。
试验例1：
将实施例1和实施例2制备得到的片剂给雄性比格犬口服后，考察犬体内的药物动力学特征，动物实验数据见表1及表2。
表1雄性比格犬口服给予10mg/kg实施例1的HS-25片剂后(水制粒)HS-25的药动学参数
Figure PCTCN2018117086-appb-000016
表2雄性比格犬口服给予10mg/kg实施例2的HS-25片剂(微粉化水制粒处方)后HS-25的药动学参数
Figure PCTCN2018117086-appb-000017
结论：实施例2的片剂(将HS-25原料药微粉化处理)可明显提高HS-25在体内的生物利用度。
试验例2：
将实施例3制备得到的片剂给雄性比格犬口服后，考察犬体内的药物动力学特征，动物实验数据见表3。
表3雄性比格犬口服给予10mg/kg实施例3的HS-25片剂(醇制粒处方)后HS-25的药动学参数
Figure PCTCN2018117086-appb-000018
Figure PCTCN2018117086-appb-000019
对比实施例1和2的片剂(均为海泽麦布水制粒处方)，实施例3的片剂(醇制粒处方)可以使HS-25在体内得到更高的生物利用度。
试验例3：海泽麦布片稳定性研究(10mg规格)
将实施例3制备得到的片剂铝塑后，包装于空白中封袋中(内含2g干燥剂)，放置于温度25℃±2℃、湿度(RH)60％±5％条件下，进行稳定性研究，试验结果见表4。
表4.海泽麦布片(10mg规格)的稳定性数据
Figure PCTCN2018117086-appb-000020
结果显示，在储存条件为25℃±2℃、RH60％±5％放置24个月后，海泽麦布片(10mg)的含量和溶出度均无明显变化，杂质略有上升，表明样品较为稳定。
试验例4：海泽麦布片稳定性研究(5mg规格)的稳定性数据
将实施例6制备得到的片剂铝塑后，包装于空白中封袋中(内含2g干燥剂)，放置于温度25℃±2℃、湿度(RH)60％±5％条件下，进行稳定性研究，试验结果见表5。
表5.海泽麦布片(5mg规格)的稳定性数据
Figure PCTCN2018117086-appb-000021
结果显示，在储存条件为25℃±2℃、RH60％±5％放置24个月后，海泽麦布片(5mg)的含量和溶出度均无明显变化，杂质略有上升，表明样品较为稳定。
试验例5：海泽麦布片稳定性研究(10mg规格)的稳定性数据
将实施例8制备得到的片剂铝塑后，包装于空白中封袋中(内含2g干燥剂)，放置于温度25℃±2℃、湿度(RH)60％±5％条件下，进行稳定性研究，试验结果见表6。
表6海泽麦布片(10mg规格)的稳定性数据
Figure PCTCN2018117086-appb-000022
结果显示，在储存条件为25℃±2℃、RH60％±5％放置36个月后，海泽麦布片(10mg)的含量和溶出度均无明显变化，杂质略有上升，表明样品较为稳定。
试验例6：海泽麦布片稳定性研究(20mg规格)的稳定性数据
将实施例9制备得到的片剂铝塑后，包装于空白中封袋中(内含2g干燥剂)，放置于温度25℃±2℃、湿度(RH)60％±5％条件下，进行稳定性研究，试验结果见表7。
表7.海泽麦布片(20mg规格)的稳定性数据
Figure PCTCN2018117086-appb-000023
结果显示，在储存条件为25℃±2℃、RH60％±5％放置36个月后，海泽麦布片(20mg)的含量和溶出度均无明显变化，杂质略有上升，表明样品较为稳定。
试验例7：不含BHT的海泽麦布片稳定性数据
将实施例9和实施例10的片剂铝塑后，包装于空白中封袋中(内含2g干燥剂)，放置于温度40℃±2℃、湿度(RH)75％±5％条件下，进行稳定性研究，试验结果见表8。
表8.海泽麦布片(20mg规格)的稳定性数据
Figure PCTCN2018117086-appb-000024
试验例8：十二烷基硫酸钠(SDS)对海泽麦布片溶出的影响
溶出度测定方法：桨法，溶出介质：含0.5％SDS的0.1N盐酸溶液，转速：50rpm，介质体积：900mL
分别测定实施例3和实施例8的片剂的溶出度，结果如表9
表9.海泽麦布片(10mg规格)的溶出数据对比
时间(min) 5 10 15 20 30 45 60 90
实施例3(％) 40 62 73 79 84 89 91 95
实施例8(％) 55 73 81 86 90 93 95 96
结果显示，海泽麦布在实施例8的片剂中的溶出比实施例3的片剂快，表明处方中含有十二烷基硫酸钠能够促进海泽麦布的溶出。
试验例9：海泽麦布晶型研究
将海泽麦布安慰剂及海泽麦布原料药(晶型I)按照重量为98:2的比例混合，将所得的混合物进行X射线衍射(XRD)检测，得到海泽麦布安慰剂与海泽麦布原料药(晶型I)混合物的XRD图(见图3)，而后将图3与海泽麦布安慰剂的XRD图谱(见图1)及海泽麦布原料(晶型I)的XRD图谱(见图2)进行对比，在图3中的18°的位置，检测到海泽麦布晶型I的特征峰，判断XRD检测设备对海泽麦布晶型I的检测限为2％。即表明当片剂中的晶型I占总片重的2％以上时，晶型I可被检测出来。将实施例11制得的含量为20％的海泽麦布片进行XRD检测，发现在18°处未出峰(见图4)，则表明按照实施例11的方法制备的片剂中以晶型I的形式存在的原料药至少少于片重的2％，即实施例11的片剂中有片重的18％以上的原料药以无定型的形式存在，则判断实施例11的片剂中海泽麦布无定型的含量占原料药总量的90％以上。将实施例11的片剂(海泽麦布20mg，醇制粒片剂)在加速条件下(温度40℃±2℃、湿度(RH)75％±5％)，考察稳定性，结果如图5和图6所示：
图5显示，在3个月的加速条件下无定型的含量仍在90％以上。
图6显示，在9个月的加速条件下无定型的含量仍在90％以上。

Claims (28)

  1. 一种海泽麦布片，其含有海泽麦布、填充剂、粘合剂、崩解剂和润滑剂等辅料，其中，海泽麦布占片重的1-20％。
  2. 根据权利要求1中所述的海泽麦布片，其中，所述填充剂为乳糖、微晶纤维素、预胶化淀粉中的至少一种，所述粘合剂为羟丙基纤维素、聚维酮中的至少一种，所述崩解剂为交联聚维酮、交联羧甲基纤维素钠中的至少一种，所述润滑剂为硬脂酸镁、滑石粉中的至少一种。
  3. 根据权利要求1或2中所述的海泽麦布片，其中还含有稳定剂和/或表面活性剂。
  4. 根据权利要求3中所述的海泽麦布片，所述稳定剂为丁羟茴醚、丁羟甲苯中的至少一种，所述表面活性剂为十二烷基硫酸钠、聚山梨酯中的至少一种。
  5. 根据权利要求1-4中任一项所述的海泽麦布片，其特征在于，含有30～60％重量的乳糖，20～60％重量的微晶纤维素，1～5％重量的聚维酮，1～10％重量的交联聚维酮或交联羧甲基纤维素钠，0～0.1％重量的丁羟甲苯，0～5％重量的十二烷基硫酸钠，0.5～2％重量的硬脂酸镁。
  6. 根据权利要求5的海泽麦布片，其中含有0.005～0.1％重量的丁羟甲苯。
  7. 根据权利要求5的海泽麦布片，其中十二烷基硫酸钠的含量为1～5％重量。
  8. 根据权利要求1-7中任一项所述的海泽麦布片，其特征在于，其可以用水、醇、丙酮、或类似溶剂、以及它们的混合物进行制粒，然后压制成片。
  9. 根据权利要求1至8中任一项所述的海泽麦布片，其包含含有海泽麦布和聚维酮的海泽麦布固体分散体。
  10. 一种海泽麦布固体分散体组合物，其包含海泽麦布和聚维酮。
  11. 一种海泽麦布片，其包含权利要求10所述的海泽麦布固体分散体组合物。
  12. 权利要求10所述的海泽麦布固体分散体组合物在制备海泽麦布固体制剂中的用途。
  13. 根据权利要求12所述的用途，其中所述固体制剂选自片剂、胶囊、颗粒剂、粉剂。
  14. 制备权利要求10所述的海泽麦布固体分散体组合物的方法，包括以下步骤：
    将海泽麦布溶解在含有聚维酮的有机溶剂中。
  15. 根据权利要求14所述的制备方法，还包括将所得的海泽麦布溶液倒入或喷雾至辅料中。
  16. 根据权利要求14或15的制备方法，其中所述有机溶剂选自乙醇、异丙醇及其与水的混合溶剂。
  17. 制备权利要求8所述的海泽麦布片的方法，包括以下步骤：
    (1)将海泽麦布和乳糖、微晶纤维素、十二烷基硫酸钠以及交联羧甲基纤维素钠混合均匀；
    (2)将聚维酮溶于水中；
    (3)将步骤(2)的聚维酮溶液加入步骤(1)的混合物中进行制粒，烘干，整粒；
    (4)将步骤(3)整粒后的颗粒与硬脂酸镁混合均匀，压片。
  18. 根据权利17所述的海泽麦布片制备方法，其中制备过程中使用的海泽麦布为海泽麦布晶型Ⅰ。
  19. 根据权利17所述的海泽麦布片制备方法，其中制备过程中使用的海泽麦布粒径范围为1μm≤D90≤100μm，优选1μm≤D90≤50μm。
  20. 制备权利要求8或9所述的海泽麦布片的方法，包括以下步骤：
    (1)将乳糖、微晶纤维素、十二烷基硫酸钠以及交联聚维酮混合均匀，或者将乳糖、微晶纤维素以及交联聚维酮混合均匀；
    (2)将海泽麦布、聚维酮、丁羟甲苯溶于醇溶剂中，或者将海泽麦布、聚维酮溶于醇溶剂中；
    (3)将步骤(2)所得溶液加入步骤(1)所得的混合物中进行制粒，烘干，整粒；
    (4)将步骤(3)得到的颗粒与硬脂酸镁混合均匀，压片。
  21. 根据权利要求20所述的海泽麦布片制备方法，其中制备方法中溶解海泽麦布的醇溶剂为乙醇水溶液，优选地，所述乙醇水溶液的浓度≥60％(w/w)，更优选地，所述乙醇水溶液的浓度≥75％(w/w)，最优选地，所述乙醇水溶液 的浓度为80-90％(w/w)；所述乙醇溶液的用量为处方量的30％～50％(w/w)，更优选地，为处方量的35％～45％(w/w)。
  22. 根据权利要求20或21所述的海泽麦布片制备方法，其特征在于，制备方法中海泽麦布与聚维酮的重量比范围为10:1-1:1；更优选地，重量比范围为5:1-5:3。
  23. 根据权利20所述的海泽麦布片制备方法，其特征在于，制备方法中制粒方式包括高速搅拌制粒机制粒或流化床制粒。
  24. 根据权利20所述的海泽麦布片制备方法，其特征在于，制备方法中采用该方法制备的海泽麦布片，海泽麦布90％以上以无定型形式存在。
  25. 根据权利要求17至24中任一项所述的制备方法制备得到的海泽麦布片。
  26. 根据权利要求1-9和25中任一项所述的海泽麦布片，其中每药物剂量单元中含有5～20mg的海泽麦布。
  27. 根据权利要求26所述的海泽麦布片，其中每药物剂量单元中含有的海泽麦布的剂量为5mg，10mg或20mg。
  28. 根据权利要求26或27所述的海泽麦布片，其中每药物剂量单元含有20～250mg的乳糖，20～200mg的微晶纤维素，1～10mg的交联羧甲基纤维素钠或5～30mg的交联聚维酮，1～15mg的聚维酮K30，0～0.2mg的丁羟甲苯，0～15mg的十二烷基硫酸钠，0.5～10mg的硬脂酸镁。
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