WO2023024185A1 - 一种悬浮片剂 - Google Patents
一种悬浮片剂 Download PDFInfo
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- WO2023024185A1 WO2023024185A1 PCT/CN2021/118158 CN2021118158W WO2023024185A1 WO 2023024185 A1 WO2023024185 A1 WO 2023024185A1 CN 2021118158 W CN2021118158 W CN 2021118158W WO 2023024185 A1 WO2023024185 A1 WO 2023024185A1
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- tablet
- water
- tablet according
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Images
Classifications
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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
- A61K31/435—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
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- 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
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention relates to 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 there will be a problem of low release rate when this technology is 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 preparation). 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 inventors found that the combination of excipients of the prescription is an effective method for releasing insoluble drugs from the suspension tablet, and the tablet developed based on this, surprisingly, after the disintegration of the tablet surface, the remaining tablet remains It can continue to float without completely disintegrating the medicine.
- the present invention provides a tablet, wherein the composition includes the following weight percentage: drug 2%-30%, water-soluble swelling polymer 10-70%, caprylic capric acid macrogolglyceride 0.1%- 5%, gas generating agent 8-50%, excipient 10-50%, glidant 0.1%-5%, lubricant 0.1%-5%, penetration enhancer 0-7%, the sum of each component is 100%.
- the tablet of the present invention may or may not be coated, and if coated, the weight gain of the coating shall not be greater than 5%. Regardless of whether the tablet is coated or not, the tablet of the invention can achieve a good floating effect, and the preparation process is simpler and more controllable.
- the auxiliary material of the present invention is evenly distributed in the tablet core, the tablet core is a single-layer tablet, and in 0.1N HCl, the tablet swells and floats on the surface.
- the surface of the tablet core disintegrates quickly, releasing part of the drug quickly, and then the tablet core continues to float to release the drug slowly.
- this suspension tablet exhibits a two-stage release pattern - fast followed by sustained release. The inventor thinks that it is because the water-soluble swelling polymer in the tablet core first disintegrates the surface quickly and then continues to float.
- caprylic caprate macrogolglyceride can increase the water absorption of the tablet, and at the same time, in the dissolution process, reduce Initial tablet disintegration rate.
- rapid tablet surface disintegration occurs within 30 minutes of immersion of the tablet in hydrochloric acid, while rapidly dissolving at least 5% of the drug.
- the tablet of the present invention after being immersed in an acidic medium, the tablet floats quickly within a few seconds to a few minutes, effectively avoiding the risk of entering the small intestine, the surface of the tablet disintegrates and dissolves part of the drug quickly, and then continues to expand and continue to float Sustained drug release can be achieved over several hours.
- the tablet includes the following ingredients in weight percentage: 3%-15% of drug, 30-70% of water-soluble swelling polymer, 0.2%-5% of caprylic acid macrogolglyceride , penetration enhancer 0-5%, gas generating agent 8-30%, excipient 15-40%, glidant 0.1%-5%, lubricant 0.5%-5%, the sum of each component is 100% .
- 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 meet the large amount of sustained release of this type of drug after rapid release, and can realize the release requirement without disintegration and excessive release.
- drugs with low solubility in acid include but are not limited to cabozantinib or a salt thereof, lenvatinib or a salt thereof, or crizotinib or a salt thereof; drugs with better 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 0.5%-2%.
- 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%.
- 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%.
- the water-soluble swelling polymer is selected from hypromellose with a viscosity range of 15mPa.s-4000mPa.s, such as hypromellose E15, hypromellose E50, hypromellose Methylcellulose 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. In some embodiments, the added amount of the excipient is 18-35%.
- 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.
- 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 0.5-2%.
- 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. In some embodiments, the lubricant is added in an amount of 1-2.5%.
- 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 coating includes 10%-85% of water-insoluble polymer and 20%-80% of water-soluble polymer, and the sum of each component is 100%.
- the effect has little influence, and adjustments within this range can all achieve the effects described in the present invention.
- Described water-insoluble polymer is cationic polymethyl methacrylate (commercial product, such as and ), 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.
- Antistick (antistick) 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 invention also discloses a method for preparing the 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 pharmaceutical dosage form of the present invention is a suspension tablet, which is particularly suitable for drugs that are difficult to dissolve in water.
- the tablet When the dosage form is immersed in acid, the tablet generates gas, thereby floating, and the surface of the tablet disintegrates, which accelerates the drug in the initial stage. Dissolution, the disintegration of the tablet slows down, continues to float, and releases the drug slowly.
- This technology can be used for drugs with high solubility and poorly soluble drugs, such as cabozantinib malate.
- This invention can also be used for drugs with better solubility in acid, such as lenvatinib mesylate.
- caprylic capric acid macrogol glyceride can significantly improve the water absorption capacity of the tablet, and after being immersed in the acid solution, slow down the initial disintegration of the tablet, and quickly form a stable gel, so it is expected that after taking the tablet, it can Quickly and stably float in the gastric juice, and fully moisten and release the drug.
- 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).
- Fig. 1 is that the coated tablet of prescription 2 of embodiment 1 is immersed in 0.1N HCl, begins to float within 3 minutes, and the surface of the tablet begins to disintegrate.
- Fig. 2 is that two kinds of tablets of embodiment 4 are placed in 37 DEG C of 0.1N HCl solution, and about 5min observes to contain Labrasol sample (Fig. 2 left LY) surface rapid gelation, does not contain the sample of Labrasol (Fig. 2 right LNO ) surface disintegration faster than the gelation speed.
- Fig. 3 is after two kinds of tablets of embodiment 4 are placed in 37 DEG C of 0.1N HCl solution 4h, observe that the sample that contains Labrasol sample (Fig. 2 left LY) is still stable floating, does not contain the sample of Labrasol (Fig. 2 right LNO ) sinks to the bottom.
- Fig. 4 is that two kinds of tablets of Example 4 are placed in 37 DEG C 0.1N HCl solution, after 4 hours, the tablet is cut in half, and it is found that the tablet core containing Labrasol (right sample LY in Fig. 2) is completely gelled, However, the tablet cores without Labrasol (left sample LN in Figure 2) were mostly in the form of dry powder, and the solution was not infiltrated.
- 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 according to the prescription quantity. First mix with silicon dioxide quickly to form granules, then mix with other materials, and press the uniformly mixed tablet with a rotary tablet press.
- Coating Add ethanol to Eudragit RL 5% and Opadry 95%, the solid content is 10%, stir and mix evenly, filter (60 mesh).
- the prepared tablet cores were coated with a high-efficiency coating pan, and the weight gain of the coating was 2.0%.
- the tablet is placed in 0.1N HCl at 37°C until it starts to float as shown in Table 5:
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Abstract
一种悬浮片剂，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％-5％、润滑剂0.1％-5％，促渗剂0-7％，各组分相加为100％。该片剂在浸入酸溶液之后，表面崩解，片芯继续漂浮，缓释药物。同时，辛酸癸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。
Description
本发明涉及一种悬浮片剂，属于制剂领域。
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。同时，文献描述的单层悬浮片或包衣悬浮片的溶出多为线性释放。此外，现有技术中的漂浮片剂均需要包衣，通过包衣来达到漂浮和溶出的目的，制备工艺相对难以控制。
发明内容
在实验中，发明人发现处方的辅料组合是对于悬浮片释放难溶性药物的有效方法，并且据此研发的片剂，令人惊讶的是，在片剂表面崩解后，余下的片剂仍然可以继续漂浮，并且不会发生彻底崩解释药的情况。
根据一些文献的处方进行研究，我们发现当产气片芯处方不包衣或普通的单层包衣，浸入0.1N的HCl中会快速释放气体和崩解，无法稳定漂浮和持续释放，或其漂浮力不太好。在一项研究中，我们意外地发现，通过调节片芯组分，可以有效克服前述问题。基于此，本发明提供一种片剂，其中所述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％-5％、润滑剂0.1％-5％，促渗剂0-7％，各组分相加为100％。
本发明所述的片剂可以包衣也可以不包衣，如果包衣，所述包衣增重不大于5％。本发明所述的片剂无论是否包衣，均可以实现很好的漂浮效果，制备工艺更加简单可控。
本发明所述的辅料均匀分布在片芯中，片芯是单层片，在0.1N的HCl中，片剂膨胀并漂浮在表面上。片芯的表面快速崩散，快速释出部分药物，随后片芯继续漂浮，缓释药物。令人惊讶的是，这种悬浮片表现形成两阶段的释放形式-快速然后缓释。发明人认为是因为片芯中的水溶性溶胀聚合物首先快速把表面崩解然后继续漂浮，同时，辛酸葵酸聚乙二醇甘油酯可以增加片剂的吸水性，同时在溶出过程中，降低刚开始的片剂崩解速度。从而有利于片剂快速凝胶化，稳定起漂，并持续水化至良好的凝胶状态，使之可以实现片剂先快速释药，随后缓释药物，特别适合难溶性药物，达到理想的溶出曲线效果。
在本发明的一些实施例中，快速片剂表面崩散是在片剂沉浸在盐酸30分钟内产生的，而快速溶出至少5％药物。
本发明所述的片剂，浸入酸性介质后，片剂在数秒到数分钟时间内快速漂浮，有效避免了进入小肠的风险，片剂表面崩解快速溶出部分药物，然后继续膨胀并可继续漂浮数小时以上，可实现药物的持续释放。
在一些具体的实施例中，所述片剂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0-5％、产气剂8-30％、赋形剂15-40％、助流剂0.1％-5％、润滑剂0.5％-5％，各组分相加为100％。
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在快速释放后满足这类药物的大量持续释放，既可以实现释放需求，又不会发生崩解过量释放。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、乐伐替尼或其盐或克唑替尼或其盐；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.2013 Mar；14(1)：464–474.)。Francimary L.Guedes等人(AAPS PharmSci Tech.2011 Mar；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0.5％-2％。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，例如羟丙甲纤维素E15、羟丙甲纤维素E50、羟丙甲纤维素K100LV或羟丙甲纤维素K4M。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％。
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。
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0.5-2％。
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1-2.5％。
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。
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
和
)，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、
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
商标名下销售的)或者基于甲基丙烯酸的聚合物(如在
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片剂的方法，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：
本发明所述的药物剂型为悬浮片，特别适合难溶于水的药物，当所述剂型浸入酸中时，所述片剂产生气体，从而漂浮，片剂表面崩解，加速药物在初期的溶出，片剂的崩解慢下来，继续漂浮，缓释药物，此技术可用于溶解度高的药物和难溶性药物，例如苹果酸卡博替尼。此发明也可以用于酸中溶解度较好的药物，例如甲磺酸仑伐替尼。在实验中，令人惊讶的是，在片剂表面少量崩解后，剩余片芯快速水化形成凝胶，维持良好的完整性和漂浮力。在处方中加入
即辛酸葵酸聚乙二醇甘油酯，可以显著改善片剂的吸水能力，以及在浸入酸溶液后，减缓片剂初期的崩解，快速形成稳定的凝胶，从而预期在服用药片后，能够快速而稳定地漂浮在胃液中，并充分润湿和释药。研究人员分别将含和不含
的片剂放进37℃0.1N HCl溶液中，前者快速凝胶化稳定漂浮，但后者初期有明显崩解(见图2)；且含有
的片剂完整性较好，漂浮更稳定，时长明显多于
的片剂(图3)。浸润4h后取出药片，沿中线切成两半,发现含有
的片剂完全凝胶化，无
的片剂片芯大多是干粉，溶液无法充分渗透(图4)。
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)。
图1为实施例1处方2包衣片浸入0.1N HCl，3分钟内开始浮动，片剂表面开始崩解。
图2为将实施例4两种片剂置于37℃0.1N HCl溶液中，5min左右观察到含Labrasol样品(图2左LY)表面快速凝胶化，不含Labrasol的样品(图2右LNO)表面崩解快于凝胶化速度。
图3为将实施例4两种片剂置于37℃0.1N HCl溶液中4h后，观察到含Labrasol样品(图2左LY)的样品仍稳定漂浮，不含Labrasol的样品(图2右LNO)则沉底。
图4为将实施例4两种片剂置于37℃0.1N HCl溶液中，4小时后将片剂切成两半，发现含有Labrasol(图2右样品LY)的片芯完全凝胶化，而不含Labrasol(图2左样品LN)的片芯大多呈干粉状，溶液未渗透。
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8批次。处方如下表1：
【表1】
片芯：按处方量称。
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，压片。
包衣：Eudragit RL 5％和Opadry 95％加入乙醇，固含量为10％，搅拌混合均匀,过滤(60目)。将制备的片芯用高效包衣锅进行包衣，包衣增重2.0％。
结果：
1、片剂被放置在0.1N HCl，在37℃下至开始漂浮的时间如下表2：
【表2】
| 处方号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 时间至漂浮，秒 | 20s | 20s | 20s | 20s | 30s | 35s | 30s |
所有片剂在刚开始实验时，都出现片剂表面崩解的情况(图1)，所述片剂均可呈现很好的漂浮效果。
2、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，测定溶出数据，结果见表3：
【表3】
| 处方号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 0.5h | 36 | 25 | 56 | 17 | 39 | 26 | 58 |
| 1h | 64 | 30 | 62 | 20 | 67 | 32 | 64 |
| 2h | 72 | 38 | 65 | 23 | 77 | 44 | 68 |
| 4h | 77 | 51 | 68 | 28 | 83 | 57 | 73 |
| 6h | 79 | 62 | 69 | 33 | 86 | 69 | 75 |
| 8h | 80 | 72 | 70 | 36 | 88 | 78 | 78 |
| 12h | 83 | 82 | 72 | 43 | 90 | 87 | 80 |
实施例2
制备了4批次。处方如下表4：
【表4】
| 处方号 | 8 | 9 | 10 | 11 |
| 药物含量，mg | 30 | 30 | 30 | 30 |
| 苹果酸卡博替尼,％ | 5.6 | 5.6 | 5.6 | 5.6 |
| 羟丙甲纤维素K4M,％ | 10.0 | 10.0 | 10.0 | 10.0 |
| 羟丙甲纤维素E50LV,％ | 25.0 | 35.0 | 25.0 | 35.0 |
| 辛酸葵酸聚乙二醇甘油酯，％ | 2.0 | 2.0 | 2.0 | 2.0 |
| 碳酸氢钠,％ | 20.0 | 20.0 | 20.0 | 20.0 |
| 微晶纤维素102,％ | 34.3 | 24.3 | 34.3 | 24.3 |
| 二氧化硅，％ | 1.0 | 1.0 | 1.0 | 1.0 |
| 滑石粉,％ | 1.0 | 1.0 | 1.0 | 1.0 |
| 硬脂酸镁,％ | 1.1 | 1.1 | 1.1 | 1.1 |
| 片重,mg | 540 | 540 | 540 | 540 |
| 包衣，％(增重) | 0 | 0 | 2 | 2 |
工艺和实施例1一样。
结果：
1、片剂被放置在0.1N HCl，在37℃下至开始漂浮的时间如下表5：
【表5】
所有片剂在刚开始实验时，都出现片剂表面崩解的情况。
2、溶出实验(900mL，0.1NHCl+0.2％吐温80)桨法50rpm，测得结果如下表6：
【表6】
| 处方号 | 8 | 9 | 10 | 11 |
| 0 | 0 | 0 | 0 | 0 |
| 0.5h | 26 | 15 | 11 | 7 |
| 1h | 32 | 19 | 15 | 9 |
| 2h | 39 | 25 | 19 | 13 |
| 4h | 49 | 36 | 26 | 19 |
| 6h | 58 | 45 | 31 | 24 |
| 8h | 67 | 53 | 37 | 30 |
| 12h | 78 | 64 | 47 | 39 |
实施例3
利用与实施例1相同的工艺制备了3批次。处方和起漂时间观察如下表7：
【表7】
可实现同实施例1和实施例2类似的释放效果。
实施例4
利用与实施例1相同的工艺制备了2批次。处方和起漂时间观察如下表8：
【表8】
| 批次 | LNO | LY |
| 药物含量，mg | 60 | 60 |
| 苹果酸卡博替尼,％ | 10.10 | 10.10 |
| 羟丙甲纤维素K100LV，％ | 30.18 | 30.18 |
| 羟丙甲纤维素E50LV，％ | 30.18 | 30.18 |
| 辛酸葵酸聚乙二醇甘油酯，％ | 0 | 0.45 |
| 微晶纤维素102，％ | 9.55 | 9.1 |
| 碳酸氢钠,％ | 18.18 | 18.18 |
| 枸橼酸,％ | 0.45 | 0.45 |
| 二氧化硅(mg),％ | 0.45 | 0.45 |
| 硬脂酸镁,％ | 0.91 | 0.91 |
| 合计 | 100 | 100 |
| 片重,mg | 594.00 | 594.00 |
| 时间至漂浮，秒 | 60s | 20s |
| 漂浮时间 | 4h | ＞6h |
将两种片剂置于37℃0.1N HCl溶液中，在片剂接触溶液的初期，含有Labrasol的片子崩解相对缓和(图2)，且漂浮状态稳定，维持时间更长(图3)。4小时后将片剂切成两半，含有Labrasol的片芯完全凝胶化，而不含Labrasol的片芯大多呈干粉状，溶液未渗透(图4右样品为LY，左样品为LNO)。
Claims (14)
- 一种片剂，其特征在于，其中所述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％-5％、润滑剂0.1％-5％，促渗剂0-7％，各组分相加为100％；优选的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0-5％、产气剂8-30％、赋形剂15-40％、助流剂0.1％-5％、润滑剂0.5％-5％，各组分相加为100％。
- 根据权利要求1所述的片剂，其特征在于，所述片剂包衣或不包衣，当包衣时，所述包衣增重不大于5％。
- 根据权利要求2所述的片剂，其特征在于，所述片剂不包衣。
- 根据权利要求1所述的片剂，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、乐伐替尼或其盐或克唑替尼或其盐；优选的药物的重量百分比为2％-15％。
- 根据权利要求1所述的片剂，其特征在于，辛酸葵酸聚乙二醇甘油酯的重量百分比为0.5％-2％。
- 根据权利要求1所述的片剂，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％。
- 根据权利要求1所述的片剂，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％。
- 根据权利要求1所述的片剂，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％。
- 根据权利要求1所述的片剂，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。
- 根据权利要求1所述的片剂，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0.5-2％。
- 根据权利要求1所述的片剂，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1-2.5％。
- 根据权利要求1所述的片剂，其特征在于，所述的崩解剂为交联羧甲基纤维素钠。
- 根据权利要求2所述的片剂，其特征在于，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％；所述的水不溶性聚合物是阳离子聚甲基丙烯酸甲酯；水溶性聚合物包括多糖、烷基纤维素、乙酸纤维素、羟烷基纤维素、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、包衣系统、聚乙烯醇)、乙烯基吡咯烷酮和乙酸乙烯酯的共聚物、或者基于甲基丙烯酸的聚合物。
- 权利要求1～13任一项所述的片剂的制备方法，其特征在于，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。
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