WO2023039989A1 - 悬浮的胶囊片 - Google Patents

悬浮的胶囊片 Download PDF

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WO2023039989A1
WO2023039989A1 PCT/CN2021/124821 CN2021124821W WO2023039989A1 WO 2023039989 A1 WO2023039989 A1 WO 2023039989A1 CN 2021124821 W CN2021124821 W CN 2021124821W WO 2023039989 A1 WO2023039989 A1 WO 2023039989A1
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tablet
capsule
water
capsule according
hypromellose
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PCT/CN2021/124821
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English (en)
French (fr)
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邓彬
夏怡然
严俊
黄大伟
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江苏万邦生化医药集团有限责任公司
上海复星星泰医药科技有限公司
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Publication of WO2023039989A1 publication Critical patent/WO2023039989A1/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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • the invention relates to a capsule which contains a suspension tablet and belongs to the field of preparations.
  • Patents US8580303 and US8333991 report a dosage form comprising (a) at least one component containing a gas generating agent and gabapentin, and (b) at least one hydrophilic film covering (a). In it, the hydrophilic membrane expands by swelling, floats on the gastric juice, and the gastric juice is permeable therein.
  • Patents US8529955, US8440232 and US8475813 propose a dosage form comprising: gabapentin and a pharmaceutically acceptable tablet core containing excipients, and a semipermeable membrane surrounding the tablet core, the semipermeable membrane comprising a plasticizer, gastric juice Permeable, but essentially impermeable to undissolved gabapentin.
  • Nilesh Desai et al. (AAPS PharmSciTech 2017Oct; 18(7):2626-2638) and Jin Guan et al. (Int.J.Pharm.383(2010)30-36) also introduced the use of osmotic tablets in gastric retention dosage forms. application.
  • the drug since drug release needs to pass through the porous channels of the coating membrane, the drug must be molecularly dissolved in the medium. Insoluble drug particles cannot be released through the film, and the release rate of this technology will be low when applied to this type of drug.
  • Sheng-Feng Hung et al. (PLoS One. 2014:9(6):e100321) applied a plasticizer-containing polymer coating to a multi-unit floating drug delivery system.
  • Vinay Kumar Katakam et al. (Trop.J.Pharm.Res.April 2014; 13(4):489-496) taught a technique for implementing a three-layer coating on the tablet surface, including a barrier layer, a blister Teng layer (gas-generating layer, not gas-generating inside the core) and outer polymer film layer.
  • coating on the outside of the tablet core will delay tablet blooming time. At the same time, the gas generated at the periphery of the tablet core will hinder drug release and further lead to fluctuations in dissolution between batches.
  • Ampanart Huanbuta et al. (PharmSciTech, Vol. 17, No. 3, June 2016) introduced a new floating system in which the tablet core is surrounded by a semipermeable membrane.
  • the tablet core contains a high proportion of water-insoluble microcrystalline cellulose or gas generating agent.
  • the generated gas is uniformly distributed in the tablet core (see Figure 4 and Figure 8 of the article). Uniform distribution of this gas within the tablet core or around the film coat will impede drug release and cause fluctuations in drug release.
  • Zulfequar A. Khan et al. (AAPS Pharmsitech, Vol. 12, No. 4, Dec. 2011) describe a floating tablet that wraps a drug-loaded core with a gas-generating layer and a polymer layer.
  • the polymer membrane can act as a shield to prevent gastric juice from penetrating into the membrane instantaneously, thereby delaying the conversion of sodium bicarbonate to carbon dioxide.
  • the drug is released through the drug release hole.
  • Rania A.H.Ishak ((J Pharm Pharm Sci,18(1)77-100, 2015) believes that the preferred drug candidates for gastric retention preparations are those that are easily soluble in the acidic environment of the stomach.
  • the present invention provides a suspension capsule tablet
  • the suspension capsule tablet includes a capsule shell
  • one or more suspension tablets are contained in the capsule shell
  • the suspension tablet includes the following components by weight percentage: drug 2%-30 %, water-soluble swelling polymer 10-70%, caprylic acid macrogolglyceride 0.1%-5%, gas generating agent 8-50%, excipient 10-50%, glidant 0.1%-6 %, lubricant 0.1%-5%, penetration enhancer 0-7%, the sum of each component is 100%.
  • the adjuvant of the present invention is evenly distributed in the tablet core.
  • the surface of the tablet disintegrates rapidly at the initial stage, resulting in a sudden release of the drug, and then a sustained release of the drug .
  • a capsule was added (tablet in capsule; capsule tablet)
  • the capsule immediately floated and began to dissolve, the disintegration of the tablet surface was greatly reduced, and some capsules
  • the drug dissolution profile of tablet formulations, especially HPMC capsules is more linear in the first few hours (Example 2).
  • the invention is suitable for poorly soluble drugs, which require a stable drug dissolution rate and an ideal dissolution curve effect.
  • the suspension tablet includes the following ingredients in weight percentage: 3%-15% of drug, 30-70% of water-soluble swelling polymer, and 0.2%-5% of caprylic macrogolglyceride , penetration enhancer 0.2-6%, gas generating agent 8-30%, excipient 15-40%, glidant 0.1%-6%, lubricant 0.5%-5%, the sum of each component is 100% .
  • the capsule shell of the present invention is an HPMC capsule shell (hypromellose capsule shell), which can be purchased in the market; the capsule shell needs to be larger than the tablet size.
  • HPMC capsule shell hyperromellose capsule shell
  • the medicine of the present invention can be applicable to the medicine of any solubility, especially, it can be more suitable for the medicine of little solubility in the acid, and the medicine of the little solubility in the acid of the present invention refers to the hydrochloric acid that pH is 1.2
  • Drugs with a solubility of less than 1 mg/ml, such as cabozantinib malate, can also be used for drugs with better solubility in acid, such as lenvatinib mesylate.
  • the dosage form of the present invention can reduce the risk of drug burst release in the early stage, and then release the drug continuously, which can not only meet the release requirement, but also prevent excessive disintegration in the early stage, resulting in drug burst release.
  • drugs with low solubility in acid include but are not limited to cabozantinib or its salt, crizotinib or its salt; drugs with relatively good solubility in acid, such as lenvatinib mesylate; In some embodiments, the preferred weight ratio is 2%-15%.
  • Drugs according to the invention may be milled or dispersed in a substance prior to forming dosage forms to improve their rate of dissolution.
  • the solid drug can be pulverized to the micron or nanometer level, for example, the average particle size can be 0.1 micron to 20 micron.
  • techniques such as solid dispersion and clathrate can also be used to improve the dissolution rate. These means can be the common means in this field, for example Zhi Hui Loh et al. (Asian Sciences (Asian Sciences), volume 10, the 4th period, July 2015, 255-274.) described for improving insoluble Dissolution rate of drug in water by different milling techniques. Vincent Caron et al.
  • the weight percentage of caprylic capric acid macrogol glyceride is 3-5%.
  • Caprylic capric acid polyethylene glycol glyceride (labrosal) is a mixture of a certain proportion of mono-, di-, tri-glycerides and mono-, di-fatty acid polyethylene glycol esters, a small part of caprylic acid (C8) and capric acid (C10 ) mono, bis, triglycerides and most PEG-8 (molecular weight 400) mono- and di-esters, which can be obtained commercially.
  • the water absorption of the tablet can be increased and the formation of the gel skeleton can be promoted by adding caprylic capric acid macrogol glyceride.
  • the gas generating agent is sodium bicarbonate; in some specific embodiments, the weight ratio of the gas generating agent is 8-25%; in some specific embodiments, the gas generating agent The weight ratio is 9-12%.
  • the water-soluble swelling polymer is selected from hydroxypropyl methylcellulose (hypromellose), carbomer, polyethylene oxide, methylcellulose, gelatin And other water-soluble polymers with similar high viscosity; in some embodiments, the weight ratio of water-soluble swelling polymer is 35-70% In some embodiments, the weight ratio of water-soluble swelling polymer is 40- 50%.
  • the water-soluble swelling polymer is selected from hypromellose (HPMC) with a viscosity range of 15mPa.s-4000mPa.s, such as hypromellose E15LV, hypromellose E50 , hypromellose K100LV or hypromellose K4M.
  • Hypromellose (METHOCEL TM ) is the preferred excipient for hydrophilic gel matrix formulations.
  • METHOCEL TM pharmaceutical grade hypromellose has multiple optional viscosity specifications to meet the release requirements of drugs with different solubility . Commonly used CR specifications include E50LV, K100LV, K4M, K15M, K100M, etc.
  • the combination of primary water-soluble swelling polymers is hypromellose E series and K series, such as K4M, K15M and K100M, or a water-soluble swelling polymer having similar properties to K series.
  • the combination of primarily water-soluble swelling polymers is hydroxypropylmethylcellulose K100LV.
  • At least two water-soluble swelling polymers are included.
  • excipients described in the present invention include but are not limited to mannitol, fructose, sucrose, lactose, xylitol, sorbitol, microcrystalline cellulose, calcium carbonate, calcium hydrogen phosphate, tribasic calcium or calcium sulfate, etc.
  • the added amount of the excipient is 18-35%. In some embodiments, the added amount of the excipient is 19-26%.
  • the penetration enhancer of the invention includes but not limited to water-soluble salts of inorganic acids, such as potassium chloride, potassium sulfate, potassium hydrogen phosphate, sodium hydrogen phosphate and sodium chloride and other organic acids, such as citric acid, tartaric acid wait.
  • a preferred penetration enhancer is citric acid.
  • the weight ratio of the penetration enhancer is 0.5-6%.
  • Glidants of the invention include, but are not limited to, silicon dioxide, magnesium trisilicate, tribasic calcium phosphate, calcium silicate, magnesium silicate, and other materials known to those of ordinary skill in the art.
  • the added amount of the glidant is 5-6%.
  • the lubricant described in the present invention can be selected from but not limited to those conventionally known in the art, such as sodium stearyl fumarate, magnesium stearate, aluminum stearate or calcium stearate or zinc stearate, poly Ethylene glycol, glyceryl monostearate, glyceryl monostearate, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil or talc.
  • the lubricant is added in an amount of 0.5-2.5%. In some embodiments, the lubricant is added in an amount of 0.5-1.5%.
  • the disintegrants described in the present invention can be selected from but not limited to those conventionally known in the art, such as croscarmellose sodium.
  • a disintegrant may or may not be added.
  • the suspension tablet of the present invention can be coated or uncoated, preferably no coating is required, but if it is coated, in some embodiments of the present invention, the coating includes 10%-85% of a water-insoluble polymer and The water-soluble polymer is 20%-80%, and the sum of each component is 100%.
  • the range of coating ingredients has little influence on the effect of the present invention, and adjustments within this range can achieve the effects of the present invention. Described water-insoluble polymer is cationic polymethyl methacrylate (commercial product, such as EUDRAGIT and EUDRAGIT ), the preferred dosage range is 10%-50%.
  • Water soluble polymers include, but are not limited to, polysaccharides such as maltodextrin, alkylcelluloses such as methylcellulose or ethylcellulose, cellulose acetates, hydroxyalkylcelluloses such as hydroxypropylcellulose or hydroxypropyl methylcellulose), polyvinylpyrrolidone, gum arabic, sucrose, gelatin, shellac, cellulose acetate, phthalates, lipids, synthetic resins, acrylic polymers, Coating systems, polyvinyl alcohol (PVA), copolymers of vinylpyrrolidone and vinyl acetate (e.g. in sold under the trade name) or methacrylic acid-based polymers (as in those sold under the trade name).
  • PVA polyvinyl alcohol
  • copolymers of vinylpyrrolidone and vinyl acetate e.g. in sold under the trade name
  • methacrylic acid-based polymers as in those sold under the trade name
  • additives can include plasticizers, channel forming agents, anti-adhesive (anti-stick) agents, fillers, polishing agents or opacifying agents, etc., which can be commonly used in this field.
  • plasticizers can be phthalic acid di Butyl ester, triethyl citrate, polyethylene glycol (PEG) etc.
  • Channel forming agent can be surfactant, short-chain water-soluble polymer, salt etc.
  • Antisticking (antisticking) agent can be talcum powder, hard Fatty acid, magnesium stearate and colloidal silicon dioxide, etc.
  • fillers can be talcum powder, precipitated calcium carbonate, etc.
  • polishing agents can be beeswax, carnauba wax, synthetic chlorinated wax, etc.
  • opacifying agents such as titanium dioxide, etc. All these additives can be used at levels well known to those skilled in the art.
  • the present invention also discloses a method for preparing the suspension tablet of the present invention.
  • the caprylic capric acid macrogol glyceride is first mixed with a glidant to form particles, or the caprylic caproic acid macrogol glyceride is first mixed with The drug and glidant are mixed to form granules, which are mixed with other core materials and compressed, with or without coating.
  • the tablet cores of the present invention may be formed by direct compression, granulation-compression, pellet-compression or equivalent methods.
  • direct compression the ingredients are intimately mixed and placed in a compression mold, which is compressed to form a tablet.
  • granulation a formulation solution is sprayed onto a mixture of "granules" and excipients to form granules. The granules are dried and ground to the desired particle size distribution. The granules are then mixed with other excipients and placed in a compression mold and compressed to form tablets.
  • the medicine of the present invention can be applicable to the medicine of any solubility, especially, it can be more suitable for the medicine of little solubility in the acid, and the medicine of the little solubility in the acid of the present invention refers to the hydrochloric acid that pH is 1.2
  • Drugs with a solubility of less than 1 mg/ml, such as cabozantinib malate, can also be used for drugs with better solubility in acid, such as lenvatinib mesylate.
  • Consisting of is a transitional phrase used in the claims of the present invention. "Consisting of” excludes any element, step or ingredient not specified in a claim.
  • carbonate is interchangeable with “bicarbonate”, which can be carbonate or bicarbonate (bicarbonate).
  • suspension tablet refers to the suspension tablet placed in a capsule.
  • % in the present invention represents weight percentage.
  • Fig. 1 is the result data of embodiment 1, wherein: Fig. 1 a is the drug dissolution comparison of prescription 1 suspension tablet and gelatin capsule tablet of embodiment 1. Fig. 1b is the drug dissolution comparison of the prescription HPMC capsule tablet of Example 1.
  • Fig. 2 is the result data of embodiment 2, wherein: Fig. 2a is the drug dissolution contrast of prescription 2a HPMC capsule sheet and gelatin capsule sheet of embodiment 2. Fig. 2b is the drug dissolution contrast of prescription 2a HPMC capsule tablet and gelatin capsule tablet of embodiment 2. Fig. 2c is the drug dissolution contrast of prescription 2c HPMC capsule tablet and gelatin capsule tablet of embodiment 2.
  • test materials in the following examples are conventional methods unless otherwise specified.
  • the test materials used in the following examples, unless otherwise specified, were purchased from conventional biochemical reagent stores.
  • Tablet core Caprylic caprate polyethylene glycol glyceride is quickly mixed with silicon dioxide to form granules according to the prescription quantity, and then mixed with other materials, and the uniformly mixed tablet is compressed with a rotary tablet machine. Complete the core of prescription one.
  • Capsule filling Put the tablet core of prescription 1 into capsules of different sizes.
  • the supplier of the capsules is Suzhou Capsules.
  • the standard specifications of the capsules are selected from large to small as No. 000, No. 00 and No. 0, and there are also extra-long specifications for transverse diameter capsules.

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Abstract

一种悬浮的胶囊片，胶囊壳内含有一个悬浮片，悬浮片包括以下重量百分比的成分：药物2％-30％、水溶性溶胀聚合物10-70％、辛酸癸酸聚乙二醇甘油酯0.1％-5％、产气剂8-50％、赋形剂10-50％、助流剂0.1％-6％、润滑剂0.1％-5％，促渗剂0-7％，各组分相加为100％。该胶囊在浸入酸溶液之后，立即漂浮并开始逐渐溶解，水分渗入后，片剂表面也随着慢慢崩解，片芯继续漂浮。

Description

悬浮的胶囊片 技术领域
本发明涉及一种胶囊，胶囊内含有一个悬浮片，属于制剂领域。
背景技术
由于胃漂浮制剂要求水快速渗透从而快速产气，因此大多数泡腾漂浮系统没有采用膜包衣技术，但这种泡腾漂浮系统往往因为漏气导致悬浮力不足。因此有一些文献提出了薄膜包衣漂浮技术。
专利US8580303和US8333991报道了一种剂型，其包含(a)至少一种含有产气剂和加巴喷丁的组分，以及(b)至少有一种包裹(a)的亲水性薄膜。其中，该亲水性膜通过膨胀而扩大，漂浮在胃液上，胃液可渗透其中。专利US8529955、US8440232和US8475813提出了一种剂型，该剂型包含：加巴喷丁和药学上可接受的含赋形剂的片芯，以及围绕片芯的半透膜，该半透膜包含增塑剂，胃液可渗透，但对于不溶解的加巴喷丁基本上不可渗透。Nilesh Desai等人(AAPS PharmSciTech 2017Oct；18(7)：2626-2638)以及Jin Guan等人(Int.J.Pharm.383(2010)30-36)还介绍了渗透片剂在胃滞留剂型中的应用。但是，由于药物释放需要透过包衣膜的多孔通道，因此药物必须以分子状态溶解在介质中。难溶性药物颗粒无法通过薄膜释放，该技术应用于这类药物时会存在释放速率低的问题。
Sheng-Feng Hung等人(PLoS One.2014：9(6)：e100321)将含增塑剂的聚合物包衣应用于多单元漂浮药物递送系统。Vinay Kumar Katakam等人(Trop.J.Pharm.Res.4月2014；13(4)：489-496)传授了一种在片剂表面实施三层包衣的技术，包括一个隔离层、一个泡腾层(产气层，不在片芯内部产气)和外部聚合物膜层。然而，在片芯外部包衣会延迟片剂起漂时间。同时，在该片芯外围产生的气体将阻碍药物释放，并进一步导致批间溶出的波动。
Ampanart Huanbuta等人(PharmSciTech，第17卷，第3期，2016年6月)介绍了一种新的漂浮系统，其片芯被一层半透膜包围。片芯含高比例的水不溶性微晶纤维素或产气剂。在溶出过程中，生成的气体均匀分布在片芯中(参考制品的图 4和图8)。这种气体在片芯内或在薄膜包衣周围的均匀分布将阻碍药物释放并引起药物释放的波动。
Zulfequar A.Khan等人(AAPS Pharmsitech，第12卷，第4期，2011年12月)介绍了一种漂浮片剂，该片剂将载药片芯包上产气层和聚合物层。这样聚合物膜可以起到屏蔽的作用，防止胃液瞬间渗透进入膜内，从而延迟碳酸氢钠转化为二氧化碳。药物通过释药孔释放。Rania A.H.Ishak((J Pharm Pharm Sci,18(1)77-100，2015)认为胃滞留制剂的优选候选药物是易溶于胃酸性环境的药物。与Khan的观点相同，Raina也认为聚合物包衣应该能够承受二氧化碳产生的压力，以避免破裂。Sadhana Shahi等人(Asian Journal of Pharmaceutical Technology&Innovation,03(15)；2015；32-49)认为药物需要从片剂聚合物膜上的释药孔释放，释药孔尺寸从600微米到1毫米。他们还认为，对于基础渗透泵片(单层渗透泵片)，首选水溶性药物。这些文献均一致的认为包衣需要保持完整，不能破裂，因为一旦破裂会导致漏气，悬浮力出现问题；但是由于释药孔尺寸是有限制的，为了实现所需的释药效果，这类剂型适用的通常为有良好水溶性或者胃酸溶性的药物，对于难溶性的药物，并不适用。因为，包衣悬浮片是极难释放难溶性的药物。我们早前发明了包衣崩解悬浮片技术和快速胶成的悬浮片来应用于难溶性的药物。(中国专利申请号：20110978396.7)但两者都出现了再初期片剂表面快速崩解和药物释放的情况。
发明内容
因为大多文献和在市场上的悬浮片处方都需要包衣的，包衣后，片剂只可以应用于水溶性好的药物。我们早前发明了包衣崩解悬浮片技术和快速成胶的悬浮片来应用于难溶性的药物。(中国专利申请号：20110978396.7)但两者都有初期片剂表面快速崩解和药物释放的情况。在一项研究中，我们意外地发现，通过胶囊的配合，调节片芯组分，可以有效克服前述问题。基于此，本发明提供一种悬浮胶囊片，所述悬浮胶囊片包括胶囊壳，所述胶囊壳内含有一个或多个悬浮片，所述悬浮片包括以下重量百分比的成分：药物2％-30％、水溶性溶胀聚合物10-70％、辛酸葵酸聚乙二醇甘油酯0.1％-5％、产气剂8-50％、赋形剂10-50％、助流剂0.1％-6％、润滑剂0.1％-5％，促渗剂0-7％，各组分相加为100％。
除了胶囊，本发明所述的辅料均匀分布在片芯中，在0.1N的HCl中，片剂单独在浸入酸溶液之后，片剂的表面初段快速崩解，导致药物突释，而后缓释药物。但当加了个胶囊后(片剂在胶囊内；胶囊片)，令人惊讶的是：在溶出实验的初期，胶囊立即漂浮并开始溶解，片剂表面的崩解情况大幅度降低，一些胶囊片处方，特别是HPMC胶囊，的药物溶出曲线的首数小时更接近直线(实施例2)。该发明适用于难溶性药物，需要平稳药物溶出速率，达到理想的溶出曲线效果的产品。
在一些具体的实施例中，所述悬浮片包括以下重量百分比的成分：药物3％-15％、水溶性溶胀聚合物30-70％、辛酸葵酸聚乙二醇甘油酯0.2％-5％、促渗剂0.2-6％、产气剂8-30％、赋形剂15-40％、助流剂0.1％-6％、润滑剂0.5％-5％，各组分相加为100％。
本发明所述的胶囊壳为HPMC胶囊壳(羟丙甲纤维素胶囊壳)，可通过市面进行购买；胶囊壳需大于片剂大小。
本发明所述的药物可以适用于任何溶解度的药物，特别的是，它可以更适用于酸中溶解度小的药物，本发明所述的酸中溶解度小的药物是指在pH为1.2的盐酸中溶解度小于1mg/ml的药物，例如苹果酸卡博替尼，也可以用于酸中溶解性比较好的药物，例如甲磺酸仑伐替尼。本发明所述的剂型可以降低早段药物突释风险然后，持续释放药物，既可以实现释放需求，又不会发生早段崩解过量，导致药物突释。在一些实施例中，酸中溶解度小的药物包括但不限于卡博替尼或其盐、克唑替尼或其盐；酸中溶解性比较好的药物，例如甲磺酸仑伐替尼；在一些实施例中，优选的重量比为2％-15％。
本发明所述的药物可以在形成剂型之前研磨或分散在一种物质中，以改善其溶解速率。在一些实施例中，可以将固体药物粉碎至微米或纳米级，例如平均粒径可以为0.1微米至20微米。在另一些实施例中，也可以采用固体分散体、包合物等技术改善其溶解速率。这些手段可以为本领域的常用手段，例如Zhi Hui Loh等人(亚洲科学(Asian Sciences)，第10卷，第4期，2015年7月，255-274.)描述了用于改进难溶于水的药物的溶解速率的不同的研磨技术。Vincent Caron等人(Mixer Mill MM400，Retsch GmbH&Co.，Germany)在室温下用PM 100高能行星式研磨机(Retsch，Germany)进行研磨，在振荡球磨机中进行冷冻研磨。在许 多科学文章中也描述了分子分散(此处，它相当于固体分散剂)的方法(如：AAPS PharmSci Tech.2013Mar；14(1)：464–474.)。Francimary L.Guedes等人(AAPS PharmSci Tech.2011Mar；12(1)：401-410.)使用聚乙烯吡咯烷酮(PVP)和聚乙二醇(PEG)制备新型药物的固体分散剂。将药物和聚合物溶解在甲醇/氯仿混合物中，然后通过蒸发、冷冻干燥去除溶剂。该药物是处于无定形状态。Lili Fitriani等人(J Adv.Pharm Technol.).Res.2016Jul-Sep；7(3)：105-109)，通过溶剂蒸发法以2：1、1：1和1：2的比例制备依法韦仑-PVP K30分散剂，并使用冷冻干燥器干燥。Abhishek Singh等人(先进药物递送综述，第100卷，2016年5月1日，27-50)通过喷雾干燥制备无定形固体分散剂。
在本发明的一些实施例中，辛酸葵酸聚乙二醇甘油酯的重量百分比为3-5％。辛酸癸酸聚乙二醇甘油酯(labrosal)是由一定比例的单、双、三甘油酯与单、双脂肪酸聚乙二醇酯组成的混合物，一小部分辛酸(C8)和癸酸(C10)的单，双，三甘油酯和绝大多数PEG-8(分子量400)单、双酯组成，可通过市售获得。本发明通过加入辛酸葵酸聚乙二醇甘油酯可以增加片剂的吸水性，促进凝胶骨架的形成。
在本发明的一些实施例中，所述的产气剂为碳酸氢钠；在一些具体实施例中，产气剂的重量比为8-25％；在一些具体实施例中，产气剂的重量比为9-12％。
在本发明的一些实施例中，所述的水溶性溶胀聚合物选自羟丙基甲基纤维素(羟丙甲纤维素)、卡波姆、聚环氧乙烷、甲基纤维素、明胶及其它具有类似高粘度的水溶性聚合物；在一些具体实施例中，水溶性溶胀聚合物的重量比为35-70％在一些具体实施例中，水溶性溶胀聚合物的重量比为40-50％。
在一些实施例中，所述的水溶性溶胀聚合物选自粘度范围为15mPa.s-4000mPa.s的羟丙甲纤维素(HPMC)，例如羟丙甲纤维素E15LV,羟丙甲纤维素E50、羟丙甲纤维素K100LV或羟丙甲纤维素K4M。羟丙甲纤维素(美多秀 TM)是亲水凝胶骨架配方的首选辅料，美多秀 TM药用级羟丙甲纤维素具有多个可选黏度规格，可以满足不同溶解度药物的释放需求。常用CR规格包括E50LV,K100LV,K4M,K15M,K100M等。在一些实施例中，主要水溶性溶胀聚合物的组合是羟丙甲纤维素E系列和K系列，例如K4M,K15M和K100M，或和K系列有类似特质的水溶性溶胀 聚合物。在一些实施例中，主要水溶性溶胀聚合物的组合是羟丙基甲基纤维素K100LV。
在一些实施例中，包含了至少两种水溶性溶胀聚合物。
本发明所述的赋形剂包括但不限于甘露醇、果糖、蔗糖、乳糖、木糖醇、山梨糖醇、微晶纤维素、碳酸钙、磷酸氢钙、三元钙或硫酸钙等。在一些实施例中，所述赋形剂的加入量18-35％。在一些实施例中，所述赋形剂的加入量19-26％。
发明所述的促渗剂，其包括但不限于无机酸的水溶性盐，如氯化钾、硫酸钾、磷酸氢钾、磷酸氢钠和氯化钠和其他有机酸，例如枸橼酸、酒石酸等。优选的促渗剂是枸橼酸。在一些具体实施例中，促渗剂的重量比为0.5-6％。
发明所述的助流剂包括但不限于二氧化硅、三硅酸镁、三碱式磷酸钙、硅酸钙、硅酸镁和本领域普通技术人员已知的其他材料。在一些实施例中，所述助流剂的加入量5-6％。
本发明所述的润滑剂可以选自但不限于本领域常规已知的那些，例如硬脂富马酸钠、硬脂酸镁、硬脂酸铝或硬脂酸钙或硬脂酸锌、聚乙二醇、单硬脂酸甘油酯、单硬脂酸甘油酯、山嵛酸甘油酯、矿物油、硬脂酰富马酸钠、硬脂酸、氢化植物油或滑石粉。在一些实施例中，所述润滑剂的加入量0.5-2.5％。在一些实施例中，所述润滑剂的加入量0.5-1.5％。
本发明所述的崩解剂可以选自但不限于本领域常规已知的那些，例如交联羧甲基纤维素钠。崩解剂可以添加也可以不添加。
本发明所述的悬浮片可以包衣或不包衣，优选不需要包衣，但包衣的话，在本发明的一些实施例中，所述包衣包括水不溶性聚合物10％-85％和水溶性聚合物20％-80％，各组分相加为100％，包衣的配料范围对本发明效果影响较小，在该范围内调整均可实现本发明所述的效果。所述的水不溶性聚合物是阳离子聚甲基丙烯酸甲酯(商业产品，例如EUDRAGIT
Figure PCTCN2021124821-appb-000001
和EUDRAGIT
Figure PCTCN2021124821-appb-000002
)，优选的用量范围为10％-50％。水溶性聚合物包括但不限于多糖(如麦芽糖糊精)、烷基纤维素(如甲基纤维素或乙基纤维素)、乙酸纤维素、羟烷基纤维素(例如羟丙基纤维素或羟丙基甲基纤维素)、聚乙烯吡咯烷酮、阿拉伯胶、蔗糖、明胶、虫胶、乙酸纤维素、酞酸盐、脂质、合成树脂、丙烯酸聚合物、
Figure PCTCN2021124821-appb-000003
包衣系统、聚乙烯醇(PVA)、乙烯基吡咯 烷酮和乙酸乙烯酯的共聚物(例如在
Figure PCTCN2021124821-appb-000004
商标名下销售的)或者基于甲基丙烯酸的聚合物(如在
Figure PCTCN2021124821-appb-000005
商标名下销售的那些)。这些可以从水性或非水性体系或水性和非水性体系的组合(视情况而定)施用。也可与添加剂和成膜剂一起包含以得到更令人满意的膜。这些添加剂可包括增塑剂、通道形成剂、抗粘(抗粘)剂、填料、抛光剂或不透明剂等，这些均可以为本领域常用的选择，例如增塑剂可以为邻苯二甲酸二丁酯、柠檬酸三乙酯、聚乙二醇(PEG)等；通道形成剂可以为表面活性剂、短链水溶性聚合物、盐等；抗粘(抗粘)剂可以为滑石粉，硬脂酸、硬脂酸镁和胶态二氧化硅等；填料可以为滑石粉，沉淀碳酸钙等；抛光剂可以为蜂蜡、巴西棕榈蜡、合成氯化蜡等；不透明剂如二氧化钛等。所有这些添加剂可以以本领域技术人员熟知的水平使用。
本发明还公开一种制备本发明所述的悬浮片的方法，将辛酸葵酸聚乙二醇甘油酯先与助流剂混合形成粒子，或者先将辛酸葵酸聚乙二醇甘油酯先与药物和助流剂混合形成粒子，再与其他片芯物料混合后进行压片，进行或不进行包衣。
本发明所述的制备方法中涉及的具体操作可以按照本领域的常规方法。例如，本发明所述片芯可通过直接压制、制粒-压制、丸粒-压制或等同方法形成。在直接压片中，将原料充分混合并置于压模中，压制形成片剂。在制粒中，将配方溶液喷雾到“颗粒”和赋形剂的混合物上以形成颗粒。将颗粒干燥并研磨至所需的粒度分布。然后，将颗粒与其他赋形剂混合，并置于压模中，压制形成片剂。用于制备片剂的技术描述于Remington”s Pharmaceutical Sciences，(Arthur Osol，editor)，1553-1593(1980)中。使用流化床的颗粒包衣报道于U.S.美国专利号8,282,957，其描述了使用喷雾干燥方法的颗粒喷涂。美国专利号8,911,766描述了使用溶剂蒸发技术的颗粒喷涂。一些其他替代方法也可用于本发明中的颗粒或微粒包衣。用包衣锅、流化床或类似的等同设备包衣的片剂芯。盘包衣可以是对片芯进行薄膜包衣的方便方法。将片芯置于盘中，旋转盘，并将半渗透性聚合物溶液喷雾到片芯上。还可以考虑其他喷涂技术，例如空气悬浮法(流化床)。在流化床中，将片芯悬浮在空气中，实际上通过Wurster柱的循环，用聚合物溶液喷雾片芯。锅包衣程序可以在美国找到。专利申请No.20060099262。空气悬浮程序描述于U.S. 美国专利号2，799，241.Am.Pharm.Assoc.，第48卷，第451-459页(1959)；以及出处同上，第49卷，第82-84页(1960)。
本发明的有益效果：
市面上大多数的悬浮片产品是需要包衣的，只能适合于水溶性良好的药物。我们早前发明了包衣崩解悬浮片技术和快速成胶的悬浮片来应用于难溶性的药物。(中国专利申请号：20110978396.7)在溶出实验中，两者都有初期片剂表面快速崩解和药物释放的情况。但当加了个胶囊后(片剂在胶囊内；胶囊片)，令人惊讶的是：在溶出实验的初期，胶囊立即漂浮并开始逐渐溶解，片剂表面的崩解情况大幅度降低，一些胶囊片处方的药物溶出曲线的首数小时更接近直线(实施例2)。本发明所述的药物可以适用于任何溶解度的药物，特别的是，它可以更适用于酸中溶解度小的药物，本发明所述的酸中溶解度小的药物是指在pH为1.2的盐酸中溶解度小于1mg/ml的药物，例如苹果酸卡博替尼，也可以用于酸中溶解性比较好的药物，例如甲磺酸仑伐替尼。
如果没有特别说明，本发明的名称按照以下定义：
“任选的”或“任选地”是指随后描述的情况可以发生或可以不发生，这样使得该描述包括其中该情况发生的实例以及其中它不发生的实例。
除非明确陈述或上下文另外明确指示，否则权利要求书中所包含的单数形式(如“一个”、“一种”和“该”)包括复数参考。另一方面，单数形式“ONE”不包括复数引用。
“由...组成”是在本发明的权利要求中使用的过渡短语。“由……组成”排除权利要求中未指定的任何要素、步骤或成分。
术语“碳酸盐”可交换为“碳酸氢盐”，它可以是碳酸盐或碳酸氢盐(碳酸氢盐)。
若无特别说明，本发明所述的“悬浮片”“片剂”“片芯”均表示置于胶囊内的悬浮片。
若无特别说明，本发明的％表示重量百分比。
附图说明
图1为实施例1的结果数据，其中：图1a为将实施例1处方1悬浮片剂和明胶胶囊片剂的药物溶出对比。图1b为将实施例1的处方HPMC胶囊片剂的药物溶出对比。
图2为实施例2的结果数据，其中：图2a为将实施例2的处方2a HPMC胶囊片和明胶胶囊片的药物溶出对比。图2b为将实施例2的处方2a HPMC胶囊片和明胶胶囊片的药物溶出对比。图2c为将实施例2的处方2c HPMC胶囊片和明胶胶囊片的药物溶出对比。
具体实施方式
前述实例为本发明的说明性实施例且仅为示例性的。在不脱离本发明的精神和范围的情况下，本领域技术人员可以做出变化和修改。所有这样的修改和变化旨在被包括在本发明的范围内。
下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为自常规生化试剂商店购买得到的。
实施例1
制备了1批次。片芯处方如下表1(％表示质量百分比)所示：
【表1】
处方号 处方一
药物含量，mg 60
苹果酸卡博替尼,％ 11.12
羟丙甲纤维素E50LV,％ 43.88
辛酸葵酸聚乙二醇甘油酯，％ 4.00
碳酸氢钠,％ 9.00
微晶纤维素102,％ 24.50
二氧化硅，％ 6.00
枸橼酸,％ 0.50
硬脂酸镁,％ 1.00
片重,mg 540
片芯：按处方量称辛酸葵酸聚乙二醇甘油酯先与二氧化硅快速混合形成粒子，然后，与其他物料混合，将混合均匀的片剂用旋转压片机压片。完成处方一的片芯。
胶囊填充：把处方一的片芯放进不同规格大小的胶囊。胶囊的供应商是苏州胶囊。根据片芯尺寸选择胶囊标准规格由大到小分别为000号、00号和0号，同样横径胶囊还有特长规格。
结果：
采用中国药典桨法50rpm溶出条件，溶出介质0.1NHCl+0.2％吐温80，体积900mL，一分钟内悬浮片开始漂浮，而胶囊片一开始就漂浮。测定溶出数据，结果见表3；图1a和1b所示：可见本发明选用的HPMC胶囊壳可以在溶出实验的初期，可以有效降低片剂表面的崩解情况。
【表2】溶出数据
Figure PCTCN2021124821-appb-000006
实施例2
制备了3批次。处方如下表3所示：
【表3】
Figure PCTCN2021124821-appb-000007
Figure PCTCN2021124821-appb-000008
工艺和实施例1一样。
结果：
采用中国药典桨法50rpm溶出条件，溶出介质0.1NHCl+0.2％吐温80，体积900mL，一分钟内悬浮片开始漂浮，而胶囊片一开始就漂浮。测定溶出数据，结果见表5；图2a，图2b和2c：可见本发明选用的HPMC胶囊壳可以在溶出实验的初期，可以有效降低片剂表面的崩解情况。
【表4】溶出数据
Figure PCTCN2021124821-appb-000009

Claims (12)

  1. 一种胶囊，特征在于，包括胶囊壳，所述胶囊壳内含有一个或多个悬浮片，悬浮片包括以下重量百分比的成分：药物2％-30％、水溶性溶胀聚合物10-70％、辛酸葵酸聚乙二醇甘油酯0.1％-5％、产气剂8-50％、赋形剂10-50％、助流剂0.1％-6％、润滑剂0.1％-5％，促渗剂0-7％，各组分相加为100％；优选的悬浮片包括以下重量百分比的成分：药物3％-15％、水溶性溶胀聚合物30-70％、辛酸葵酸聚乙二醇甘油酯0.2％-5％、促渗剂0.2-6％、产气剂8-30％、赋形剂15-40％、助流剂0.1％-6％、润滑剂0.5％-5％，各组分相加为100％。
  2. 根据权利要求1所述的胶囊，其特征在于，所述胶囊壳为HPMC胶囊壳，且胶囊壳大于片剂大小。
  3. 根据权利要求1所述的胶囊，其特征在于，所述悬浮片不包衣。
  4. 根据权利要求1所述的胶囊，其特征在于，所述的药物为卡博替尼或其盐、仑伐替尼或其盐、克唑替尼或其盐；优选的药物的重量百分比为2％-15％。
  5. 根据权利要求1所述的胶囊，其特征在于，辛酸葵酸聚乙二醇甘油酯的重量百分比为3％-5％。
  6. 根据权利要求1所述的胶囊，其特征在于，所述的产气剂为碳酸氢钠；优选的产气剂的重量比为8-25％，更优选为9-12％。
  7. 根据权利要求1所述的胶囊，其特征在于，所述的水溶性溶胀聚合物选自羟丙甲纤维素、卡波姆、聚环氧乙烷、甲基纤维素或明胶；优选的，所述的水溶性溶胀聚合物选自粘度范围为15mPa.s-4000mPa.s的羟丙甲纤维素；更优选的所述的水溶性溶胀聚合物选自羟丙甲纤维素E15、羟丙甲纤维素E50、羟丙甲纤维素K100LV或羟丙甲纤维素K4M；优选的，水溶性溶胀聚合物的重量比为35-70％，更优选为40-50％。
  8. 根据权利要求1所述的胶囊，其特征在于，所述的赋形剂包括甘露醇、果糖、蔗糖、乳糖、木糖醇、山梨糖醇、微晶纤维素、碳酸钙、磷酸氢钙、三元钙或硫酸钙；优选的所述赋形剂的加入量18-35％，更优选的为19-26％。
  9. 根据权利要求1所述的胶囊，其特征在于，所述的促渗剂包括无机酸的水溶性盐或有机酸；优选的，所述的无机酸的水溶性盐包括氯化钾、硫酸钾、磷酸氢 钾、磷酸氢钠或氯化钠；所述有机酸包括枸橼酸或酒石酸；优选的，促渗剂的重量比为0.5-6％。
  10. 根据权利要求1所述的胶囊，其特征在于，所述的助流剂包括二氧化硅、三硅酸镁、三碱式磷酸钙、硅酸钙或硅酸镁；优选的所述助流剂的加入量5-6％。
  11. 根据权利要求1所述的胶囊，其特征在于，所述的润滑剂包括硬脂富马酸钠、硬脂酸镁、硬脂酸铝、硬脂酸钙、硬脂酸锌、聚乙二醇、单硬脂酸甘油酯、单硬脂酸甘油酯、山嵛酸甘油酯、矿物油、硬脂酰富马酸钠、硬脂酸、氢化植物油或滑石粉；优选的，所述润滑剂的加入量0.5％-2.5％，更优选的为0.5-1.5％。
  12. 根据权利要求1所述的胶囊，其特征在于，所述悬浮片制备方法为：将辛酸葵酸聚乙二醇甘油酯先与助流剂混合形成粒子，或者先将辛酸葵酸聚乙二醇甘油酯先与药物和助流剂混合形成粒子，再与其他片芯物料混合后进行压片。
PCT/CN2021/124821 2021-09-14 2021-10-20 悬浮的胶囊片 WO2023039989A1 (zh)

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