WO2021134647A1 - 一种持续释放组合物及其制备方法 - Google Patents

一种持续释放组合物及其制备方法 Download PDF

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WO2021134647A1
WO2021134647A1 PCT/CN2019/130866 CN2019130866W WO2021134647A1 WO 2021134647 A1 WO2021134647 A1 WO 2021134647A1 CN 2019130866 W CN2019130866 W CN 2019130866W WO 2021134647 A1 WO2021134647 A1 WO 2021134647A1
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Prior art keywords
sustained
altn
release composition
release
sodium
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PCT/CN2019/130866
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English (en)
French (fr)
Inventor
谭晓峰
梁文伟
周伟杰
赖树挺
刘锋
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广州帝奇医药技术有限公司
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Priority to CN201980032345.6A priority Critical patent/CN112218626B/zh
Priority to PCT/CN2019/130866 priority patent/WO2021134647A1/zh
Publication of WO2021134647A1 publication Critical patent/WO2021134647A1/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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention belongs to the field of medicine. Specifically, the present invention relates to a sustained-release composition and a preparation method, in particular to a preparation for oral administration and a preparation method thereof.
  • the prescription of this product contains lactose monohydrate, hydroxypropyl cellulose, sodium lauryl sulfate, magnesium stearate and carmellose calcium, as well as a vegetable capsule shell.
  • SLS sodium lauryl sulfate
  • the main reason for using such a high amount of SLS is the poor solubility of ALTN, which requires a larger amount of surfactant to promote the dissolution of the drug and increase the bioavailability to meet the needs of clinical use, but nevertheless, according to Roche's drug application data
  • the data shows that its bioavailability in the human body is still only 37%.
  • the above data is obtained under the conditions of best absorption after a high-fat meal.
  • the bioavailability is lower in the fasting state, which is about the same as that after a high-fat meal. Around 35%.
  • ALTN hydrochloride has the best solubility under acidic conditions (4.5mg/mL at pH 2), and very low under alkaline conditions (simulated fasting intestinal fluid (FaSSIF) at pH 6.5 It is 0.023mg/ml, and the simulated feeding intestinal fluid (FeSSIF) is 0.077mg/ml at pH 6.5).
  • FaSSIF simulated fasting intestinal fluid
  • FeSSIF simulated feeding intestinal fluid
  • the low bioavailability may be due to the fact that it is emptied by the stomach into the intestine in an alkaline environment without being fully dissolved after taking it, resulting in insufficient release and incomplete absorption.
  • CN106456651 proposes a high-content ALTN preparation.
  • a large number of disintegrants are used in the invention. Crystallize sodium lauryl sulfate to improve the dissolution of high-content ALTN formulations. None of the embodiments of the present invention has made more improvements in the drug loading per unit formulation of the existing marketed products, and there is uncertainty as to whether the drug loading per unit formulation can be increased.
  • CN101330907 mentions a pregabalin sustained-release solid pharmaceutical composition, which includes a matrix forming agent and a swelling agent, and is taken orally once a day.
  • the invention uses size exclusion technology to achieve gastric retention and sustained release, thereby reducing the number of daily medications and improving patient compliance; reducing or avoiding potential and undesirable dose-related effects by reducing the maximum content (Cmax) in the blood
  • Cmax maximum content
  • the side effects of the drug can also increase the efficacy of the drug by increasing the minimum concentration (Cmin) in the plasma.
  • pregabalin immediate-release capsule preparations Compared with the bioavailability of pregabalin immediate-release capsule preparations in the prior art as high as 90% or more, CN101330907 this invention claims to increase the absorption window of pregabalin sustained-release preparations, but the advantage of improving the bioavailability is only Compared with other sustained-release preparations of pregabalin, in fact, the bioavailability of pregabalin immediate-release capsules is not significantly improved.
  • pregabalin in the present invention is water-soluble and easily absorbed by itself, which is very different from the active ingredient ALTN and its salt in the present invention, which are poorly soluble drugs and have low bioavailability.
  • the general sustained-release preparation technology usually will Missing the active compound's most suitable dissolution environment or the absorption window of the gastrointestinal tract will also lead to incomplete dissolution or incomplete absorption, which will affect the bioavailability; on the other hand, general sustained-release preparations need to have a larger amount of high
  • the combination of molecular materials or other excipients achieves a sustained release effect. Within the acceptable tablet weight range of the patient, a large proportion of the amount of excipients will affect the drug loading.
  • the ALTN sustained-release composition prepared by the present invention not only solves the above-mentioned problems, but also has a significant improvement in bioavailability compared with an immediate-release capsule.
  • the inventors found that the phenomenon mentioned in CN106456651 does exist, that is, ALTN or its salt will gel and agglomerate and is not easy to disintegrate and dissolve, even when combined with a large amount of surfactants. Or it can be prepared into a solid dispersion, this phenomenon still exists. Based on this, it can be considered that ALTN or its salt is not conducive to the development of sustained-release preparations.
  • the present invention cleverly combines the unique properties of ALTN or its salt, which is gelled and agglomerated and is not easy to disintegrate and dissolve, ingeniously combined with slow-release technology, and uses its characteristics of gelling and agglomerating in contact with water to improve the strength of the sustained-release matrix.
  • the dosage of the morphological carrier also increases the drug loading capacity of the drug.
  • the solubility of ALTN or its salt is pH-dependent, and the solubility is best under acidic conditions. Based on this feature, the inventor combined with gastric retention slow-release technology to make ALTN or its salt in its dominant dissolution environment for a long time. More sufficient dissolution and release, solving the problem of insufficient dissolution under high drug loading.
  • the present invention combines corresponding solubilization technology and slow-release technology, especially gastric retention slow-release technology, which has a complementary effect and effectively solves the problem of developing ALTN or its salt into a sustained-release preparation This problem.
  • An object of the present invention is to provide a sustained release composition of inhibitor composition, which has the following characteristics:
  • the preparation can maintain a sustained release for more than 8 hours, reduce the peak concentration of the drug, thereby reducing the side effects of the drug;
  • the present invention uses the ALTN solubilizing complex, combined with slow-release technology, to obtain a sustained-release composition capable of sustained and slow release of the active ingredient ALTN.
  • the sustained-release composition reduces the peak concentration of the drug, thereby reducing the side effects of the drug.
  • the present invention uses ALTN solubilization complex combined with size exclusion retention sustained-release preparation technology to achieve a larger drug loading per unit preparation.
  • the invention not only greatly increases the drug loading, but also keeps the active ingredient ALTN to be continuously released for more than 8 hours, reduces the number of daily administrations, and even reduces the number of preparations for each administration.
  • the present invention uses the ALTN solubilizing complex combined with the size exclusion retention sustained-release preparation technology containing enteric materials to achieve the prolonged residence of the ALTN composition in the stomach, which is beneficial to improve the weak alkaline and poorly soluble drug ALTN.
  • the dissolution rate keeps the active ingredient ALTN continuously released for more than 8 hours, increasing the absorption of the drug by extending the residence time of the drug in the digestive tract, and improving the bioavailability of the drug.
  • the composition containing the enteric material is gradually eroded in a high pH environment after entering the intestinal tract, so that the insoluble ALTN drug is released more fully, thereby further improving the bioavailability of the drug.
  • the present invention provides a sustained-release composition of an ALK inhibitor, the sustained-release composition containing the solubilizing complex of the ALK inhibitor and a swelling agent, the sustained-release composition can be maintained for more than 8 hours
  • the release rate within 8 hours is less than 80%; preferably, the sustained-release composition can maintain a sustained release for more than 8 hours, and the release rate is 20% to 35% in 4 hours, and the release rate is 50% to 80% in 8 hours.
  • the solubilized complex of the ALK inhibitor is a mixture of an ALK inhibitor and a surfactant, or a solid dispersion of an ALK inhibitor, or a solid dispersion of an ALK inhibitor containing a surfactant.
  • the solubilizing complex of the inhibitor can make the poorly soluble drug ALK inhibitor, such as ALTN, better release, and cooperate with the adopted slow-release technology to achieve the purpose of fully releasing the inhibitor, so as to avoid the occurrence of inadequate release. Completely caused the problem of low bioavailability.
  • the weight ratio of surfactant to ALTN is 1:1 to 4.
  • the weight ratio of surfactant to ALTN is 1:1 ⁇ 4.
  • the mixture of the inhibitor and surfactant may also contain a pharmaceutically acceptable carrier to facilitate mixing and dispersion
  • the soluble components are lactose and mannitol. , Povidone, sodium chloride, hypromellose, etc.
  • the insoluble components are starch, micronized silica gel, talc and so on.
  • the term "pharmaceutically acceptable carrier” refers to more than one suitable solid excipient diluent, and is a substance suitable for administration to mammals, including humans.
  • the surfactant is selected from monoalkyl sulfate, polyoxy(40) stearate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) two Alcohol, polyoxyethylene hydrogenated castor oil 60, castor oil polyoxyester (35), polycinnamyl alcohol, dioctyl succinate sodium sulfonate, sodium lauroyl sarcosinate, sodium dodecyl benzene sulfonate, One or more of sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, preferably polyoxyethylene (105) polyoxypropylene (5) two One or both of alcohol and sodium lauryl sulfate, most preferably sodium lauryl sulfate.
  • the sodium lauryl sulfate is prepared by spray drying or crystallization.
  • the preparation method of the mixture of ALTN and surfactant includes: mixing the surfactant, ALTN and optional pharmaceutically acceptable carrier by grinding, ball milling, pulverizing and other physical means to obtain the mixture, or using ethanol, tetrahydrofuran, Solvents such as dimethyl sulfoxide are dissolved or partially dissolved and dried to obtain a mixture.
  • the solid dispersion of ALTN comprises ALTN and solid polymer material, and preferably, the weight ratio of ALTN to solid polymer material is 1:0.5-3.
  • the solid polymer material is polyethylene caprolactam-polyethylene acetic acid-polyethylene glycol graft copolymer, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate , Or one or more of methacrylic acid copolymer L.
  • the preparation method of the solid dispersion containing ALTN is obtained by dissolving the ALTN and the solid polymer material in tetrahydrofuran and then drying it, or by hot melting the ALTN and the solid polymer material and then cooling it.
  • the sustained-release composition of the present invention may also include a swelling agent, and the swelling agent is one or more of crospovidone, polyethylene oxide, carbomer, and hydroxypropyl methylcellulose, Preferably, the swelling agent accounts for 4.5-30% of the total weight of the sustained-release composition.
  • the swelling agent is a substance that swells rapidly and/or continuously after absorbing water, and is soluble or insoluble in water.
  • the presence of the swelling agent can increase the volume of the sustained-release composition preparation of the present invention and increase the residence time in the stomach .
  • the swelling agent may be crospovidone, polyethylene oxide, carbomer, hydroxypropyl methyl cellulose, alginic acid and salts thereof.
  • the sustained-release composition of the present invention may further include an enteric material.
  • the enteric material may be an acrylic resin compound, preferably, a copolymer of methacrylic acid and ethyl acrylate, methacrylic acid and acrylic acid. One or a mixture of methyl ester copolymer, methacrylic acid and methyl methacrylate copolymer.
  • the enteric material accounts for 0-20% of the total weight of the sustained-release composition.
  • the enteric material is an acrylic resin compound, such as a copolymer of methacrylic acid and ethyl acrylate (1:1 (molar ratio)), methacrylic acid and methyl acrylate (1:1 (molar ratio)) Copolymer, methacrylic acid and methyl methacrylate (1:2 (molar ratio)) copolymer.
  • acrylic resin compound such as a copolymer of methacrylic acid and ethyl acrylate (1:1 (molar ratio)), methacrylic acid and methyl acrylate (1:1 (molar ratio)) Copolymer, methacrylic acid and methyl methacrylate (1:2 (molar ratio)) copolymer.
  • enteric materials varies with the pH value. As enteric materials, it needs to meet the requirements of being insoluble in acidic gastric juice, but quickly disintegrating or dissolving in neutral or alkaline intestinal juice.
  • the inhibitor of the present invention is ALTN, or a pharmaceutically acceptable salt thereof, especially the hydrochloride salt of ALTN.
  • the dissolution of the inhibitor of the present invention is pH-dependent and has high solubility in an acidic environment. The use of gastric retention technology will be more beneficial to improve the dissolution of the drug, thereby increasing the bioavailability.
  • the sustained-release composition may further comprise a pore-forming matrix.
  • the presence of the porogen will form different release channels to facilitate adjustment of the release of the drug.
  • the pore-forming matrix is a water-soluble substance, such as lactose, sucrose, One or a mixture of mannitol, xylitol and sorbitol, or a water-insoluble cellulosic substance, such as microcrystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium One or a mixture of several.
  • the sustained-release composition can be prepared into a once-daily dosage form, which contains 150-600 mg of ALTN (ALTN hydrochloride as ALTN), preferably, contains 300-600 mg of ALTN (ALTN salt).
  • ALTN ALTN hydrochloride
  • ALTN salt 300-600 mg of ALTN (ALTN salt).
  • the acid salt is calculated as ALTN).
  • sustained-release composition of the present invention may further include a pharmaceutically acceptable carrier, a lubricant, and a glidant to facilitate the smooth progress of the preparation process, and to shape the preparation to obtain a tablet core.
  • a pharmaceutically acceptable carrier e.g., a lubricant, and a glidant to facilitate the smooth progress of the preparation process, and to shape the preparation to obtain a tablet core.
  • the outer layer of the tablet core can also be coated with a non-functional coating layer.
  • the present invention provides a sustained release composition of a high drug-loaded inhibitor, the composition comprising a mixture of ALTN and sodium lauryl sulfate, a swelling agent, an enteric material, a pore-forming matrix, and
  • the unit preparation of the sustained-release composition contains 300-600 mg of ALTN (ALTN hydrochloride is calculated as ALTN).
  • the sustained release composition of the present invention can maintain a sustained release for more than 8 hours, preferably, the release rate within 8 hours is less than 80%, and it is taken once a day.
  • the weight ratio of sodium lauryl sulfate to ALTN in the mixture of ALTN and sodium lauryl sulfate is 1:1 ⁇ 4.
  • the swelling agent is crospovidone or polyethylene oxide, wherein crospovidone accounts for 0-15% of the total weight of the sustained release composition, and polyethylene oxide accounts for 1.5% of the total weight of the sustained release composition. ⁇ 30%;
  • the swelling agent is a mixture of cross-linked povidone and polyethylene oxide, and cross-linked povidone and polyethylene oxide account for 1.5% to 30% of the total weight of the sustained-release composition;
  • the enteric material is one or a mixture of methacrylic acid and ethyl acrylate copolymer, methacrylic acid and methyl acrylate copolymer.
  • the pore-forming matrix is one of lactose and microcrystalline cellulose or a mixture of the two.
  • the sustained release composition of the inhibitor is in the form of an oral preparation.
  • the sustained release composition of the inhibitor of the present invention can be prepared into a tablet, and the preparation method includes: solubilizing the ALK inhibitor complex, a swelling agent, and further, enteric materials, pore-forming matrix and other pharmaceutically acceptable
  • the accepted carrier, lubricant, glidant, etc. are mixed in powder form and then compressed directly to obtain a tablet core.
  • the method for preparing a tablet includes the steps of using wet granulation processes such as high-shear granulation and fluidized bed granulation to granulate and dry to obtain ALTN granules, and then prepare tablet cores through mixing and tableting.
  • wet granulation processes such as high-shear granulation and fluidized bed granulation to granulate and dry to obtain ALTN granules
  • the method for preparing a tablet includes the steps of granulating through a process such as dry granulation to obtain granules containing ALTN, and then preparing a tablet core through mixing and tableting.
  • the method for preparing a tablet further includes: performing a gastric-dissolving non-functional coating operation on the outer layer of the tablet core, or performing a film coating operation with a certain sustained-release function to obtain a package with further sustained-release function. Coating preparations.
  • the ALTN sustained-release composition prepared by the present invention has a significant increase in bioavailability even compared to an immediate-release capsule.
  • the ALTN sustained-release composition prepared by the present invention can maintain a sustained release for more than 8 hours, especially the release rate within 8 hours is less than 80%, specifically, it can achieve a 4h release rate of 20% to 35%, and an 8h release rate of 50%. % ⁇ 80%, therefore, it can be prepared into a once-daily dosage form, which greatly improves the patient's medication compliance.
  • the unexpected effect of improving the bioavailability and sustained release of the poorly soluble drug ALTN is achieved.
  • the ALTN sustained-release composition prepared by the present invention has a significant improvement in bioavailability compared to commercially available immediate-release capsules.
  • the release measurement conditions used are pH 1.2, simulated gastric juice containing 6% polyoxyethylene [10] octyl phenyl ether but without pepsin (0.2% (w/v) sodium chloride and 0.7% (v/v) hydrochloric acid), 900 mL, paddle method (2015 Chinese Pharmacopoeia), rotating 100 times per minute.
  • the release completely means that the release degree of the sustained-release preparation can reach more than 80%.
  • the following examples are mainly used for the test in the form of ALTN hydrochloride.
  • the corresponding weight is calculated as ALTN.
  • the tablet weight is for the convenience of calculation and expression.
  • the weight of hydrochloric acid in the form of ALTN hydrochloride is not included.
  • the actual tablet weight should be added The weight of this part.
  • ALTN hydrochloride for Examples 1-18, ALTN hydrochloride, surfactants, and pharmaceutically acceptable carriers were mixed in a certain proportion and then subjected to physical mixing treatment, thereby obtaining various combinations of ALTN and surfactants as shown in Table 1. mixture.
  • the weight of ALTN hydrochloride is calculated as ALTN, and the weight of ALTN is taken as a reference, and it is counted as 1 part.
  • the ALTN hydrochloride (2.5 g as ALTN) and the solid polymer material (5.60 g) shown in Table 2 were placed in a container, the corresponding solvent was added, and the mixture was stirred until dissolved. The obtained solution is spray-dried at about 100° C., and then dried under reduced pressure to obtain a solid dispersion of ALTN.
  • the ALTN solubilizing complex (containing ALTN 2g) obtained in Examples 1-18 and the single ALTN hydrochloride (Form I) of Comparative Example 1 were added to pH 1.2, containing 6% polyoxyethylene [10] octyl phenyl In 900 mL of simulated gastric juice medium containing ether but no pepsin, the paddle method was used to rotate 100 times per minute. After stirring for 30 minutes, the concentration was measured with a high performance liquid chromatograph.
  • Examples 27-30 are the combination of the ALTN solubilizing complex (the ratio of surfactant to ALTN is 1:1 to 4) obtained by using Examples 14-17 and other components in a certain ratio (see Table 5 below).
  • the sustained release composition preparation is obtained by the following preparation process. Preparation process: According to the prescription ingredient list corresponding to the embodiment, the ALTN solubilizing compound, swelling agent, enteric material, and pore-forming matrix are cast into a high-shear granulator for pre-mixing, and an appropriate amount of purified water is sprayed to continue wet mixing.
  • the granules are then dried in a fluidized bed and granulated to obtain dry granules, and then lubricants and glidants are added to lubricate in a mixer to obtain total mixed granules, and the total mixed granules are compressed on a rotary tablet machine to obtain tablets.
  • Example 27 Example 28
  • Example 29 Example 30 2h 6 7 7 12 4h 20 25 30 33 6h 40 48 53 60 8h 55 65 73 78 12h 72 81 85 88 16h 78 85 89 93 20h 81 86 92 95
  • Examples 31-34 are the combination of the ALTN solubilizing complex (ALTN to solid polymer material ratio 1:0.5-3) obtained by using Examples 23-26 and other components in a certain ratio (see Table 7 below),
  • the sustained release composition preparation is obtained through the following preparation process.
  • Preparation process According to the prescription ingredient list corresponding to the embodiment, the ALTN solubilizing compound, swelling agent, enteric material, and pore-forming matrix are cast into a high-shear granulator for pre-mixing, and an appropriate amount of purified water is sprayed to continue wet mixing.
  • the granules are dried in a fluidized bed and sizing to obtain dry granules, and then lubricants and glidants are added to lubricate in a mixer to obtain total mixed granules, and the total mixed granules are compressed on a rotary tableting machine to obtain tablets.
  • Example 31 Example 32
  • Example 33 Example 34 2h 6 7 8 13 4h 25 27 30
  • 34 6h 40 45 50 59 8h 55 63 69 75 12h 70 80 85 88 16h 79 89 90 95 20h 84 94 92 98
  • the ALTN solubilized complex obtained in Example 10 is combined with other components in a certain proportion (see Table 9-11 below), and the sustained release composition preparation is obtained through the following preparation process.
  • Preparation process According to the prescription ingredient list corresponding to the embodiment, the ALTN solubilizing compound, swelling agent, enteric material, and pore-forming matrix are cast into a high-shear granulator for pre-mixing, and an appropriate amount of purified water is sprayed to continue wet mixing.
  • the granules are then dried in a fluidized bed and granulated to obtain dry granules, and then lubricants and glidants are added to lubricate in a mixer to obtain total mixed granules, and the total mixed granules are compressed on a rotary tablet machine to obtain tablets.
  • Example 35 Example 36
  • Example 37 Example 38 2h 6 6 12 6 4h 25 25 30 twenty one 6h 47 40 60 42 8h 66 52 76 58 12h 81 67 88 74 16h 86 75 93 82 20h 88 80 97 86
  • Example 40 Example 41
  • Example 42 2h 6 6 6 8 4h twenty three twenty two twenty one 28 6h 45
  • 43 8h 62 63 62 75 12h 75 78 77 86 16h 80
  • 83 84 90 20h 84 88 89 92
  • Examples 43-47 are the ALTN solubilizing complex obtained in Example 18 (the ratio of ALTN to the surfactant sodium lauryl sulfate is 1:0.25) and other components are combined in a certain ratio (see Table 14 below) ,
  • the sustained-release composition preparation is obtained through the following preparation process. Preparation process: According to the prescription ingredient list corresponding to the embodiment, the ALTN solubilizing compound, swelling agent, enteric material, and pore-forming matrix are cast into a high-shear granulator for pre-mixing, and an appropriate amount of purified water is sprayed to continue wet mixing.
  • the granules are then dried in a fluidized bed and granulated to obtain dry granules, and then lubricants and glidants are added to lubricate in a mixer to obtain total mixed granules, and the total mixed granules are compressed on a rotary tablet machine to obtain tablets.
  • Example 44 Example 45
  • Example 46 Example 47 2h 6 6 5 5 6 4h 28 25 25 twenty four twenty four 6h 48
  • 42 40 42 8h 69 63 61 58 61 12h 85 78 75
  • 72 74 16h 90
  • 80 78 80 20h 91 87 85
  • Example 46 and Example 47 were tested using the aforementioned release determination method, and the results obtained in Table 16 showed no significant difference.
  • the applicant adjusted the aforementioned release measurement method, using the replacement medium release measurement method, that is, at pH 1.2 in the first 12 hours, 900 mL of simulated gastric juice (0.2% (w/v) sodium chloride and 0.7% (v/v) hydrochloric acid) medium containing 6% polyoxyethylene [10] octyl phenyl ether but without pepsin, after 12 hours
  • the release test was carried out in a pH 6.8, 900 mL phosphate buffer medium containing 6% polyoxyethylene [10] octyl phenyl ether, paddle method (2015 version of the Chinese Pharmacopoeia), 150 rotations per minute, the results are as follows Table 16 shows.
  • Example 46 Judging from the measurement results of the release rate method of changing the medium, the release rate of Example 46 was significantly faster than that of Example 47 after 12 hours, and the dissolution was more sufficient in 24 hours, indicating that the addition of enteric materials in the prescription will be more conducive to the drug release of the sample in the intestinal environment. .
  • Example 26 of CN106456651 a capsule containing ALTN was prepared, and The results of the capsule dissolution comparison are as follows.
  • the dissolution method is:
  • Example 44 and Example 46 Use the listed ALTN capsules
  • the 150 mg tablets obtained in Example 44 and Example 46 were compared in animal experiments to investigate the differences in the bioavailability of several formulations.
  • Specific plan Select 9 male beagle dogs and divide them into A/B/C 3 groups, each with 3 dogs, a three-cycle three-crossing design, the drug will be administered within 30 minutes after high-fat eating, the first cycle A/B/C3 group Give separately The capsule, the tablet of Example 46, the tablet of Example 47, the second cycle A/B/C 3 groups were given the tablet of Example 46, the tablet of Example 47, Capsules, the third cycle A/B/C 3 groups were given Example 47 tablets, Capsules, tablets of Example 46, of which The capsules are administered twice a day, 2 capsules each time, the tablet of Example 46 is administered once a day, 1 capsule each time, and the tablet of Example 47 is administered once a day, 1 capsule each time. From 0.5 hour to 48 hours after administration, blood was collected on time to detect the
  • Example 44 Use the listed ALTN capsules
  • the 150 mg tablets obtained in Example 44 and Example 46 were compared in animal experiments to investigate the difference in bioavailability of several formulations.
  • Specific plan Select 9 male beagle dogs and divide them into A/B/C3 groups, each with 3 dogs. A three-cycle three-over design is carried out.
  • Example 46 tablets, Example 47 tablets, the second cycle A/B/C 3 groups were given Example 46 tablets, Example 47 tablets, Capsules, the third cycle A/B/C 3 groups were given Example 47 tablets, Capsules, tablets of Example 46, of which The capsules were administered twice a day, 2 capsules each time, the Example 46 tablets were administered once a day, 1 capsule each time, and the Example 47 tablets were administered once a day, 1 capsule each time. From 0.5 hour to 48 hours after administration, blood was collected on time to detect the concentration of ALTN in plasma. The statistical data is shown in Table 19 below.
  • the ratios of the fasting AUC of the capsule (150mg*4), the tablet of Example 46 (600mg) and the tablet obtained in Example 47 (600mg) to the high-fat meal AUC were 37.43%, 85.47%, and 83.48%, respectively, indicating the present invention Compared with the tablet (600mg) obtained in Example 46 and the tablet (600mg) obtained in Example 47 The bioavailability of the capsule (150mg*4) after taking it is less affected by food.
  • the ALTN composition prepared by the present invention has the effects of sustained sustained release and increased bioavailability.
  • the ALTN sustained release composition prepared by the present invention has a significant increase in bioavailability compared to immediate release capsules. .
  • the process of clinical use under the condition of reaching the same blood drug exposure as the Anshengsha capsule, it has the potential to reduce the dose, and at the same time, it can reduce the number of medications and the number of tablets taken each time.

Abstract

一种持续释放组合物，所述组合物可保持8h以上的持续释放，降低了药物达峰浓度，降低了药物的副作用，减少了每日给药次数，甚至减少了每次给药制剂的数量。同时，所述持续释放组合物具有胃滞留作用，有利于提高弱碱性难溶性药物的溶出度，能够保持8h以上的持续释放，通过延长药物在消化道的停留时间来增加药物的吸收，有利于提高药物的生物利用度。

Description

一种持续释放组合物及其制备方法 技术领域
本发明属于医药领域，具体而言，本发明涉及一种持续释放组合物及制备方法，特别涉及经口给药用制剂及其制备方法。
背景技术
9-乙基-6,6-二甲基-8-(4-吗啉-4-基-哌啶-1-基)-11-氧代-6,11-二氢-5H-苯并[b]咔唑-3-甲腈(在本发明中简称ALTN)或其盐为难溶性药物，是一种抑制剂。已上市胶囊制剂(商品名称
Figure PCTCN2019130866-appb-000001
)，是由罗氏公司研制用于治疗间变性淋巴瘤激酶(anaplastic lymphoma kinase，ALK)阳性的局部晚期或转移性非小细胞肺癌。规格为150mg，每颗胶囊内容物重量约为330mg，每次需服用4粒，每天服用两次，临床服用剂量大且每日服用次数多。
该产品处方中含有乳糖一水合物，羟丙纤维素，十二烷基硫酸钠，硬脂酸镁和羧甲纤维素钙，以及植物胶囊壳。根据公开信息，处方中十二烷基硫酸钠(SLS)用量占到20％以上。使用如此高用量的SLS的主要原因是ALTN的溶解性差，从而需要较大的表面活性剂用量以促进药物溶出和提高生物利用度来满足临床使用的需求，但尽管如此，根据罗氏的药品申报资料数据显示，其在人体的生物利用度仍然只有37％，上述数据还是在高脂餐后具备最好吸收的条件下获得的，在空腹状态其生物利用度更低，约为高脂餐后的35％左右。
ALTN或其盐的溶解度属于pH依赖型，ALTN盐酸盐在酸性条件下溶解度最佳(pH2时为4.5mg/mL)，偏碱性条件下非常低(模拟空腹肠液(FaSSIF)pH6.5时为0.023mg/ml，模拟进食肠液(FeSSIF)pH6.5时为0.077mg/ml)。
Figure PCTCN2019130866-appb-000002
的生物利用度低的原因很大可能是服用后还未充分溶解即被胃排空进入碱性环境的肠道中，导致释放不充分，吸收不完全。
CN106456651中提出了一种高含量的ALTN制剂，为解决该ALTN或其盐凝集而不崩解导致溶出性降低这一现象，该发明中使用了大量的崩解剂，通过配合制剂制备工艺以及加入晶析十二烷基硫酸钠来提高高含量ALTN制剂的溶出。该发明实施例均未针对现有上市产品在单位制剂的载药量方面做更多改善，对于是否可以提高单位制剂载药量具有不确定性。
TW201613906中提出采用ALTN非晶形状态以及制备成非晶形固体分散体可显著提高药物的溶解性，该专利技术未使用表面活性剂，应用该技术手段可以一定程度提高药物的载药量，有利于提高药物的生物利用度。然而，单纯采用该技术依然无法解决药物在消化道内停留时间有限的问题，服用后很可能快速被胃排空进入低溶解度的高pH值环境，不利于药物 生物利用度的提高。
CN101330907中提及了一种普瑞巴林缓释固体药物组合物，包括基质形成剂和溶胀剂，每日口服一次。该发明采用尺寸排阻技术实现胃滞留缓释作用，从而减少每日服药次数，改善患者的顺从性；通过减少在血液中的最高含量(Cmax)而减轻或避免潜在、不希望的与剂量有关的副作用，还可通过增加在血浆中的最低浓度(Cmin)而增加药物功效。相比于现有技术中普瑞巴林速释胶囊制剂的生物利用度高达90％以上，CN101330907这项发明声称提高了普瑞巴林缓释制剂的吸收窗，但是有利于提高生物利用度的优势只是与普瑞巴林其它缓释制剂相比较而言的，实际上相对于普瑞巴林速释胶囊剂的生物利用度并无明显改善。而且该发明中普瑞巴林是水易溶性的，本身就容易被吸收，与本发明中活性成分ALTN及其盐为难溶性药物、生物利用度低的性质有极大的差异。
由于ALTN或其盐存在难溶性和生物利用度低的问题，临床服用剂量大，开发成缓释制剂的难度相当大，一方面是一般缓释制剂技术通常会减少药物的溶出程度，甚至出现溶出不完全的现象，对于难溶性药物来说影响更大，很容易出现缓释材料包埋化合物导致最后一部分药物无法释放，进而会影响到生物利用度；另一方面是一般缓释制剂技术通常会错过活性化合物最适合溶出环境或胃肠道的吸收窗口段，也会导致溶出不完全或吸收不完全，进而会影响到生物利用度；另一方面，一般的缓释制剂需要有较大量的高分子材料或其它辅料组合实现缓释效果，在患者可接受的片重范围内，辅料的大比例用量会影响到载药量。直至目前尚无采用缓释技术的ALTN产品的公开信息和技术。本发明制备的ALTN缓释组合物不仅解决以上述问题，而且相比速释胶囊剂在生物利用度上有显著的提高。
发明内容
本发明人在开发以高用量包含ALTN或其盐的制剂过程中发现确实存在CN106456651所提及的现象，即ALTN或其盐会胶化凝集而不易崩散溶出，即使是结合大量的表面活性剂或将其制备成固体分散体，这一现象仍然存在，基于此，可以认为ALTN或其盐并不利于开发成缓释制剂。
本发明却将ALTN或其盐的胶化凝集而不易崩散溶出这一独特性质巧妙结合缓释技术，利用其遇水胶化凝集的特性来提高缓释骨架的强度，一方面减少了维持骨架形态载体的用量，另一方面也提高了药物的载药量。另外，ALTN或其盐的溶解度属于pH依赖型，在酸性条件下溶解度最佳，本发明人根据这一特性，结合胃滞留缓释技术，使ALTN或其盐在其优势溶解环境中长时间的较充分的溶解释放，解决了高载药量下溶解不充分的问题。本发明根据 ALTN或其盐的理化性质，结合相应的增溶技术和缓释技术，特别是胃滞留缓释技术，起到了相得益彰的效果，有效的解决了将ALTN或其盐开发成缓释制剂这一难题。
本发明的一个目的是提供一种抑制剂组合物的持续释放组合物，具有以下特征：
(1)该制剂可保持8h以上的持续释放，降低药物的达峰浓度，从而降低药物的副作用；
(2)进一步地，减少每日的给药次数，甚至减少每次给药制剂的数量；以及
(3)进一步地，具有胃滞留作用，提高了弱碱性难溶性药物ALTN的溶出度，能够保持8h以上的持续释放，通过延长药物在消化道的停留时间来增加药物的吸收，提高药物的生物利用度。
本发明利用ALTN增溶复合物，结合缓释技术，获得了能够持续缓慢释放活性成分ALTN的持续释放组合物，与已公开及上市的制剂，尤其是速释处方的胶囊相比，本发明的持续释放组合物降低了药物的达峰浓度，从而降低了药物的副作用。
尤其是，本发明利用ALTN增溶复合物结合尺寸排阻滞留缓释制剂技术实现了单位制剂的较大载药量，与已公开及上市的制剂，尤其是速释处方的胶囊相比，本发明不仅极大提高了载药量，而且使活性成分ALTN保持了8h以上的持续释放，减少了每日给药次数，甚至减少了每次给药制剂的数量。
更进一步，本发明利用ALTN增溶复合物结合含肠溶材料的尺寸排阻滞留缓释制剂技术，实现了ALTN组合物在胃部的延长停留，有利于提高弱碱性难溶性药物ALTN的溶出度，使活性成分ALTN保持了8h以上的持续释放，通过延长药物在消化道的停留时间来增加药物的吸收，以及提高药物的生物利用度。同时，含肠溶材料的组合物进入肠道后在高pH环境中逐渐被溶蚀，使难溶性的ALTN药物更充分的释放，从而进一步提高了药物的生物利用度。
第一方面，本发明提供了一种ALK抑制剂的持续释放组合物，所述持续释放组合物含有ALK抑制剂的增溶复合物和溶胀剂，所述持续释放组合物可保持8h以上的持续释放，且8h内释放度小于80％；优选地，所述持续释放组合物可保持8h以上的持续释放，且4h释放度为20％～35％，8h释放度为50％～80％。
优选地，所述ALK抑制剂的增溶复合物为ALK抑制剂与表面活性剂的混合物，或者是ALK抑制剂的固体分散体，或者是含有表面活性剂的ALK抑制剂的固体分散体。
所述的抑制剂的增溶复合物可以使难溶性药物ALK抑制剂，例如ALTN，更好的释放，与所采用的缓释技术相配合达到充分释放抑制剂的目的，从而避免出现由于释放不完全所导致的生物利用度低的问题。
优选地，在抑制剂的增溶复合物为ALTN与表面活性剂的混合物的情况下，表面活性剂与ALTN的重量比为1:1～4。例如，表面活性剂与ALTN的重量比为1:1～4。
优选地，所述抑制剂与表面活性剂的混合物，尤其是ALTN与表面活性剂的混合物，还可以含有药学上可接受的载体以便于辅助混合、分散，比如可溶性的组分为乳糖、甘露醇、聚维酮、氯化钠、羟丙甲基纤维素等，不溶性的组分为淀粉、微粉硅胶、滑石粉等。
本发明中，术语“药学上可接受的载体”是指一种以上合适的固体赋形稀释剂，并且是适于对哺乳类动物，包括人，给药的物质。
优选地，所述表面活性剂选自单烷基硫酸盐、硬脂酸聚烃氧(40)酯、三油酸失水山梨糖醇酯、聚氧乙烯(105)聚氧丙烯(5)二醇、聚氧乙烯氢化蓖麻油60、蓖麻油聚烃氧酯(35)、聚桂醇、丁二酸二辛酯磺酸钠、月桂酰肌氨酸钠、十二烷基苯磺酸钠、十二烷基硫酸钠、十四烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠中的一种或多种，优选为聚氧乙烯(105)聚氧丙烯(5)二醇及十二烷基硫酸钠中的一种或两种，最优选为十二烷基硫酸钠。所述十二烷基硫酸钠为经喷雾干燥或晶析等制备而成。
所述ALTN与表面活性剂的混合物的制备方法包括：将表面活性剂与ALTN以及任选的药学上可接受的载体，通过研磨、球磨、粉碎等物理手段混合获得混合物，或采用乙醇、四氢呋喃、二甲基亚砜等溶剂溶解或部分溶解后干燥获得混合物。
优选地，ALTN的固体分散体包含ALTN和固体高分子材料，优选地，ALTN与固体高分子材料的重量比为1：0.5～3。
优选地，所述固体高分子材料为聚乙烯己内酰胺-聚乙烯醋酸-聚乙二醇接枝共聚物、羟丙基甲基纤维素酞酸酯、羟丙基甲基纤维素醋酸酯琥珀酸酯、或甲基丙烯酸共聚物L中的一种或几种。
所述含有ALTN的固体分散体的制备方法为采用四氢呋喃溶解ALTN与固体高分子材料后再经干燥制得，或者通过热熔ALTN与固体高分子材料再经冷却后获得。
更优选地，本发明的持续释放组合物还可以包含溶胀剂，所述溶胀剂为交联聚维酮、聚氧化乙烯、卡波姆、羟丙甲基纤维素中的一种或几种，优选地，所述溶胀剂占持续释放组合物总重量的4.5～30％。
所述溶胀剂为吸水后迅速和/或持续膨胀的物质，可溶于水或不溶于水，溶胀剂的存在可以使本发明的持续释放组合物制剂的体积增加，提高在胃内的滞留时间。优选地，所述溶胀剂可以为交联聚维酮、聚氧化乙烯、卡波姆、羟丙甲基纤维素、海藻酸及其盐等。
更优选地，本发明的持续释放组合物还可包含肠溶材料，所述肠溶材料可以为丙烯酸树脂类化合物，优选地，可以为甲基丙烯酸和丙烯酸乙酯共聚物、甲基丙烯酸和丙烯酸甲酯共聚物、甲基丙烯酸和甲基丙烯酸甲酯共聚物中的一种或几种的混合物。优选地，所述肠溶材料占持续释放组合物总重量的0～20％。
优选地，所述肠溶材料为丙烯酸树脂类化合物，例如甲基丙烯酸和丙烯酸乙酯(1：1(摩尔比))共聚物、甲基丙烯酸和丙烯酸甲酯(1：1(摩尔比))共聚物、甲基丙烯酸和甲基丙烯酸甲酯(1：2(摩尔比))共聚物。
肠溶材料的溶解度随pH值的不同而不同，作为肠溶材料需要满足在酸性胃液中不溶，而在中性或偏碱性的肠液中能迅速崩解或溶解的要求。
本发明所述的抑制剂为ALTN，或其药学可接受的盐，尤其是ALTN的盐酸盐。本发明的抑制剂的溶解属于pH依赖型，在酸性环境中溶解度高，采用胃滞留技术将更加有利于提高药物溶解，进而提高生物利用度。
更优选地，所述持续释放组合物还可包含致孔基质，致孔剂的存在会形成不同的释放通道会便于调整药物的释放，其中致孔基质为水溶性物质，例如为乳糖、蔗糖、甘露醇、木糖醇和山梨糖醇中一种或几种的混合物，或者为水不溶性的纤维素物质，例如为微晶纤维素、低取代羟丙基纤维素、交联羧甲基纤维素钠中一种或几种的混合物。
更优选地，所述持续释放组合物，可制备成每日服用一次的剂型，其中含有150～600mg的ALTN(ALTN盐酸盐以ALTN计)，优选地，含有300～600mg的ALTN(ALTN盐酸盐以ALTN计)。
此外，本发明的持续释放组合物还可进一步包含药学上可接受的载体、润滑剂、助流剂以便于制备工艺的顺利进行，以及将制剂成型得到片芯。进一步地，所述片芯的外层还可包覆非功能性的包衣层。
优选地，本发明提供了一种高载药量的抑制剂的持续释放组合物，所述组合物包含ALTN与十二烷基硫酸钠的混合物、溶胀剂、肠溶材料、致孔基质，所述持续释放组合物的单位制剂含有300～600mg的ALTN(ALTN盐酸盐以ALTN计)。本发明的持续释放组合物可保持8h以上的持续释放，优选地，8h内释放度小于80％，每日服用一次。优选地，ALTN与十二烷基硫酸钠的混合物中十二烷基硫酸钠与ALTN的重量比为1:1～4。优选地，所述溶胀剂为交联聚维酮或聚氧化乙烯中其中交联聚维酮占持续释放组合物总重量的0～15％，聚氧化乙烯占持续释放组合物总重量的1.5％～30％；优选地，所述溶胀剂为交联聚维酮与聚氧化乙烯 的混合物，交联聚维酮与聚氧化乙烯占持续释放组合物总重量的1.5％～30％；。优选地，所述肠溶材料为甲基丙烯酸和丙烯酸乙酯共聚物、甲基丙烯酸和丙烯酸甲酯共聚物中的一种或几种的混合物。优选地，所述致孔基质为乳糖、微晶纤维素中的一种或为二者的混合物。
本发明中，抑制剂的持续释放组合物为口服制剂形式。
本发明的抑制剂的持续释放组合物可以制备成片剂，所述制备方法包括：将ALK抑制剂增溶复合物、溶胀剂，进一步的还有肠溶材料、致孔基质以及其它药学上可接受的载体、润滑剂、助流剂等，以粉末形式混合后直接压片获得片芯的步骤。
可选的，制备片剂的方法包括：采用高剪切制粒、流化床制粒等湿法制粒工艺进行造粒、干燥获得ALTN颗粒，再经过混合、压片制备获得片芯的步骤。
可选的，制备片剂的方法包括：通过干法制粒等工艺造粒获得含有ALTN的颗粒，再经过混合、压片制备获得片芯的步骤。
优选地，制备片剂的方法还进一步包括：对片芯外层进行胃溶型非功能性的包衣操作，或进行具有一定缓释功能的薄膜包衣操作，得到具有进一步缓释功能的包衣制剂。
本发明的抑制剂组合物，具有以下有益效果：
(1)可保持8h以上的持续释放，减少每日给药次数，降低药物达峰浓度，降低药物的副作用；
(2)提高单位制剂的载药量，甚至减少每次给药制剂的数量；
(3)通过延长药物在消化道的停留时间来增加药物的吸收，从而提高药物的生物利用度。
尤其是，本发明制备的ALTN缓释组合物即使相比速释胶囊剂在生物利用度上也有显著的提高。而且，本发明制备的ALTN缓释组合物可保持8h以上的持续释放，尤其是8h内释放度小于80％，具体而言，可以实现4h释放度为20％～35％，8h释放度为50％～80％，因此，可以制备成每日服用一次的剂型，极大改善了患者的用药依从性。同时实现了提高难溶性药物ALTN的生物利用度以及缓释的预料之外的效果。而且，本发明制备的ALTN缓释组合物相比市售的速释胶囊剂在生物利用度上有显著的提高。
具体实施方式
本发明中，所采用的释放度测定条件为pH1.2，含6％聚氧乙烯[10]辛基苯基醚但不含胃蛋白酶的模拟胃液(0.2％(w/v)氯化钠和0.7％(v/v)盐酸)，900mL，桨法(2015版中国药典)，每分钟旋转100次。
在本发明中，所述释放完全是指所述缓释制剂释放度可达到80％以上。
以下所述的是本发明的优选实施方式，本发明所保护的不限于以下优选实施方式。应当指出，对于本领域的技术人员来说在此发明创造构思的基础上，做出的若干变形和改进，都属于本发明的保护范围。所用试剂未注明生产商者，均为可以通过市购获得的常规产品。
以下举出实施例中主要以ALTN盐酸盐形式进行试验，相应重量以ALTN计，片剂的片重为方便计算表达，未计入ALTN盐酸盐形式中盐酸的重量，实际片重应加入该部分重量。
实施例1～18
对于实施例1～18，是将ALTN盐酸盐、表面活性剂、药学上可接受的载体按照一定比例混合后进行物理混合处理，由此得到表1所示的ALTN与表面活性剂的各种混合物。其中ALTN盐酸盐重量以ALTN计，将ALTN重量作为基准，计为1份。
表1
Figure PCTCN2019130866-appb-000003
Figure PCTCN2019130866-appb-000004
实施例19～22
对于实施例19～22，是将ALTN盐酸盐(以ALTN计2.5g)及表2中所示固体高分子材料(5.60g)放于容器中，加入相应溶剂，将混合物搅拌至溶解。将所获得溶液在约100℃下进行喷雾干燥，后续进行减压干燥，可获得ALTN的固体分散体。
表2
Figure PCTCN2019130866-appb-000005
实施例23～26
对于实施例23～26，是将ALTN盐酸盐及表3中所示固体高分子材料的不同用量放于容器中，加入相应溶剂，将混合物搅拌至溶解。将所获得溶液在约100℃下进行喷雾干燥，后续进行减压干燥，可获得ALTN固体分散体。
表3
Figure PCTCN2019130866-appb-000006
对比例1
ALTN盐酸盐(晶型I)不做任何处理。
溶解改善测试
将实施例1～18所得ALTN增溶复合物(含ALTN 2g)和对比例1的单独ALTN盐酸盐(晶型I)分别加入pH 1.2，含有6％聚氧乙烯[10]辛基苯基醚但不含胃蛋白酶的模拟胃液介质900mL中，桨法，以每分钟旋转100次，分别搅拌30分钟后，用高效液相色谱仪测量浓度。
表4
Figure PCTCN2019130866-appb-000007
Figure PCTCN2019130866-appb-000008
从实施例1～18和对比例1的溶解情况来看，含表面活性剂的ALTN混合物中烷基硫酸钠(C 12～18)表现出来的溶解改善表现好于其他表面活性剂，其中十二烷基硫酸钠市场上易得，优先考虑选择使用；实施例19～26中由固体高分子制备所得的ALTN固体分散体均表现出溶解改善。
实施例27～30
实施例27～30为采用实施例14～17获得的ALTN增溶复合物(表面活性剂与ALTN比例为1:1～4)与其它组分按照一定比例的组合(参见下表5)，通过如下制备工艺获得持续释放组合物制剂。制备工艺：按照实施例对应的处方成分表，将ALTN增溶复合物与溶胀剂、肠溶材料、致孔基质投至高剪切制粒机中进行预混合，喷洒适量的纯化水继续湿搅拌制粒，再进行流化床干燥、整粒获得干燥颗粒，再外加润滑剂、助流剂在混合机中进行润滑获得总混颗粒，将总混颗粒在旋转压片机进行压片获得片剂。
表5
Figure PCTCN2019130866-appb-000009
采用前述的释放度测定方法对实施例27～30所得片剂进行检测，表6的结果表明缓释效果良好，释放完全。
表6
溶出度％ 实施例27 实施例28 实施例29 实施例30
2h 6 7 7 12
4h 20 25 30 33
6h 40 48 53 60
8h 55 65 73 78
12h 72 81 85 88
16h 78 85 89 93
20h 81 86 92 95
实施例31～34
实施例31～34为采用实施例23～26获得的ALTN增溶复合物(ALTN与固体高分子材料比例为1:0.5～3)与其它组分按照一定比例的组合(参见下表7)，通过如下制备工艺获得持续释放组合物制剂。制备工艺：按照实施例对应的处方成分表，将ALTN增溶复合物与溶胀剂、肠溶材料、致孔基质投至高剪切制粒机中进行预混合，喷洒适量的纯化水继续湿搅拌制粒，再进行流化床干燥、整粒获得干燥颗粒，再外加润滑剂、助流剂在混合机中进行润滑获得总混颗粒，将总混颗粒在旋转压片机进行压片获得片剂。
表7
Figure PCTCN2019130866-appb-000010
Figure PCTCN2019130866-appb-000011
采用前述的释放度测定方法对实施例31～34所得片剂进行检测，表8的结果表明缓释效果良好，释放完全。
表8
溶出度％ 实施例31 实施例32 实施例33 实施例34
2h 6 7 8 13
4h 25 27 30 34
6h 40 45 50 59
8h 55 63 69 75
12h 70 80 85 88
16h 79 89 90 95
20h 84 94 92 98
实施例35～42
实施例35～42为采用实施例10获得的ALTN增溶复合物再与其它种类组分按照一定比例组合(参见下表9-11)，通过如下制备工艺获得持续释放组合物制剂。制备工艺：按照实施例对应的处方成分表，将ALTN增溶复合物与溶胀剂、肠溶材料、致孔基质投至高剪切制粒机中进行预混合，喷洒适量的纯化水继续湿搅拌制粒，再进行流化床干燥、整粒获得干燥颗粒，再外加润滑剂、助流剂在混合机中进行润滑获得总混颗粒，将总混颗粒在旋转压片机进行压片获得片剂。
表9
Figure PCTCN2019130866-appb-000012
Figure PCTCN2019130866-appb-000013
表10
Figure PCTCN2019130866-appb-000014
表11
Figure PCTCN2019130866-appb-000015
Figure PCTCN2019130866-appb-000016
采用前述的释放度测定方法对实施例35～42所得片剂进行检测，表12-13的结果表明缓释效果良好，释放较为完全。
表12
溶出度％ 实施例35 实施例36 实施例37 实施例38
2h 6 6 12 6
4h 25 25 30 21
6h 47 40 60 42
8h 66 52 76 58
12h 81 67 88 74
16h 86 75 93 82
20h 88 80 97 86
表13
溶出度％ 实施例39 实施例40 实施例41 实施例42
2h 6 6 6 8
4h 23 22 21 28
6h 45 44 43 53
8h 62 63 62 75
12h 75 78 77 86
16h 80 83 84 90
20h 84 88 89 92
实施例43～47
实施例43～47为采用实施例18获得的ALTN增溶复合物(ALTN与表面活性剂十二烷基硫酸钠比例为1:0.25)与其它组分按照一定的比例组合(参见下表14)，通过如下制备工艺获得持续释放组合物制剂。制备工艺：按照实施例对应的处方成分表，将ALTN增溶复合物与溶胀剂、肠溶材料、致孔基质投至高剪切制粒机中进行预混合，喷洒适量的纯化水继续湿搅拌制粒，再进行流化床干燥、整粒获得干燥颗粒，再外加润滑剂、助流剂在混合机中进行润滑获得总混颗粒，将总混颗粒在旋转压片机进行压片获得片剂。
表14
Figure PCTCN2019130866-appb-000017
Figure PCTCN2019130866-appb-000018
采用前述的释放度测定方法对实施例43～47所得片剂进行检测，表15的结果表明缓释效果良好，释放较为完全。
表15
溶出度％ 实施例43 实施例44 实施例45 实施例46 实施例47
2h 6 6 5 5 6
4h 28 25 25 24 24
6h 48 44 42 40 42
8h 69 63 61 58 61
12h 85 78 75 72 74
16h 90 83 80 78 80
20h 91 87 85 83 85
24h 92 89 86 85 87
采用前述的释放度测定方法对实施例46、实施例47所得片剂进行检测，表16的所得结果显示无明显差别。为更好的模拟体内释放环境对这两个实施例样品释放的影响差别，申请人对前述的释放度测定方法进行了调整，利用更换介质释放度测定方法，即，前12小时在pH 1.2，900mL含有6％聚氧乙烯[10]辛基苯基醚但不含胃蛋白酶的模拟胃液(0.2％(w/v)氯化钠和0.7％(v/v)盐酸)介质中，之后12小时在pH6.8，900mL含有6％聚氧乙烯[10]辛基苯基醚的磷酸盐缓冲液介质中进行释放度检测，桨法(2015版中国药典)，以每分钟旋转150次，结果如下表16所示。
表16
溶出度％ 实施例46 实施例47
2h 6 6
4h 25 24
6h 40 43
8h 57 60
12h 73 74
16h 86 82
20h 93 85
24h 99 88
从更换介质释放度方法测定结果来看，实施例46在12h后释放速度较实施例47明显加快，24h溶出更加充分，说明处方中加入肠溶材料会更有利于样品在肠道环境的药物释放。
对比例2
采用CN106456651中实施例26公开的技术和处方，制备获得含有ALTN的胶囊剂，与
Figure PCTCN2019130866-appb-000019
胶囊进行溶出对比结果如下。溶出方法为：
采用pH 1.2，900mL不含胃蛋白酶但含有6％聚氧乙烯[10]辛基苯基醚的模拟胃液(0.2％(w/v)氯化钠和0.7％(v/v)盐酸)介质，桨法(2015版中国药典)，以每分钟旋转100次。表17的结果表明，对比例2的溶出效果与
Figure PCTCN2019130866-appb-000020
胶囊相当，没有缓释的效果。而从两者公开的处方来看，辅料种类也相同，可以预测两者服用后临床效果会较为相近。
表17
Figure PCTCN2019130866-appb-000021
实施例48动物实验生物利用度的研究
(1)进食影响研究：
采用已上市的ALTN胶囊
Figure PCTCN2019130866-appb-000022
150mg与实施例44、实施例46所得的片剂进行动物实验对比考察几种制剂的生物利用度的差异。具体方案：选取9只雄性比格犬，分成A/B/C 3组，每组3只，进行三周期三交叉设计，高脂进食后30min内给药，第一周期A/B/C3组分别给予
Figure PCTCN2019130866-appb-000023
胶囊、实施例46的片剂、实施例47的片剂，第二周期A/B/C 3组分别给予实施例46片剂、实施例47片剂、
Figure PCTCN2019130866-appb-000024
胶囊，第三周期A/B/C 3组分别给予实施例47片剂、
Figure PCTCN2019130866-appb-000025
胶囊、实施例46片剂，其中
Figure PCTCN2019130866-appb-000026
胶囊为每日给药两次，每次2粒，实施例46的片剂每日给药一次，每次1粒，实施例47片剂为每日给药一次，每次1粒。给药后0.5小时到48小时内按时取血检测血浆中ALTN的浓度，统计数据如下表18所示。
表18
Figure PCTCN2019130866-appb-000027
从
Figure PCTCN2019130866-appb-000028
胶囊(150mg*4)与实施例46的片剂(600mg)、实施例47所得的片剂(600mg)动物生物利用度的考察数据可知，从Cmax方面，实施例46所得片剂(600mg)、实施例47 所得片剂(600mg)的Cmax值均低于
Figure PCTCN2019130866-appb-000029
胶囊的65％，有明显的降低；而且从AUC方面看，实施例46所得片剂(600mg)、实施例47所得片剂(600mg)的Cmax值均为
Figure PCTCN2019130866-appb-000030
Figure PCTCN2019130866-appb-000031
胶囊的177％以上，差不多为2倍，说明ALTN的生物利用度大幅度提高。其中，处方中含有肠溶材料的实施例46相比不含肠溶材料的实施例47的生物利用度更高，说明肠溶材料的加入更有利于提高ALTN的生物利用度。
(2)空腹影响研究：
采用已上市的ALTN胶囊
Figure PCTCN2019130866-appb-000032
150mg与实施例44、实施例46所得片剂进行动物实验对比考察几种制剂的生物利用度差异。具体方案：选取9只雄性比格犬，分成A/B/C3组，每组3只，进行三周期三交叉设计，进食2h后给药，第一周期A/B/C 3组分别给予
Figure PCTCN2019130866-appb-000033
胶囊、实施例46片剂、实施例47片剂，第二周期A/B/C 3组分别给予实施例46片剂、实施例47片剂、
Figure PCTCN2019130866-appb-000034
胶囊，第三周期A/B/C 3组分别给予实施例47片剂、
Figure PCTCN2019130866-appb-000035
Figure PCTCN2019130866-appb-000036
胶囊、实施例46片剂，其中
Figure PCTCN2019130866-appb-000037
胶囊为每日给药两次，每次2粒，实施例46片剂每日给药一次，每次1粒，实施例47片剂为每日给药一次，每次1粒。给药后0.5小时到48小时内按时取血检测血浆中ALTN的浓度，统计数据如下表19所示。
表19
Figure PCTCN2019130866-appb-000038
Figure PCTCN2019130866-appb-000039
胶囊(150mg*4)与实施例46片剂(600mg)、实施例47所得片剂(600mg)动物空腹AUC与高脂餐后AUC的比值分别为37.43％、85.47％、83.48％，可知本发明实施例46所得片剂(600mg)、实施例47所得片剂(600mg)相比
Figure PCTCN2019130866-appb-000040
胶囊(150mg*4)在服用后的生物利用度更少受到食物的影响。
上述结果说明，本发明制备的ALTN组合物具有持续缓释和提高生物利用度的效果，尤其是，本发明制备的ALTN缓释组合物相比速释胶囊剂在生物利用度上有显著的提高。临床使用过程中，在达到与安圣莎胶囊相同血药暴露量的情况下，具有减少给药剂量的潜力，同时可以减少服药的次数及每次服用片剂的数量。

Claims (10)

  1. 一种持续释放组合物，其特征在于所述持续释放组合物含有ALK抑制剂的增溶复合物和溶胀剂，所述持续释放组合物能保持8h以上的持续释放，且8h内释放度小于80％；优选地，所述持续释放组合物可保持8h以上的持续释放，且4h释放度为20％～35％，8h释放度为50％～80％。
  2. 根据权利要求1所述的持续释放组合物，其特征在于所述ALK抑制剂的增溶复合物为ALK抑制剂与表面活性剂的混合物，或是ALK抑制剂的固体分散体；优选地，所述表面活性剂与ALK抑制剂的重量比为1:1～4；优选地，所述表面活性剂为单烷基硫酸盐、硬脂酸聚烃氧(40)酯、三油酸失水山梨糖醇酯、聚氧乙烯(105)聚氧丙烯(5)二醇、聚氧乙烯氢化蓖麻油60、蓖麻油聚烃氧酯(35)、聚桂醇、丁二酸二辛酯磺酸钠、月桂酰肌氨酸钠、十二烷基苯磺酸钠、十二烷基硫酸钠、十四烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠中的一种或多种；优选为聚氧乙烯(105)聚氧丙烯(5)二醇及十二烷基硫酸钠中的一种或两种，最优选为十二烷基硫酸钠；优选地，所述ALK抑制剂的固体分散体包含ALTN抑制剂和固体高分子材料，所述固体高分子材料为聚乙烯己内酰胺-聚乙烯醋酸-聚乙二醇接枝共聚物、羟丙基甲基纤维素酞酸酯、羟丙基甲基纤维素醋酸酯琥珀酸酯、或甲基丙烯酸共聚物L中的一种或多种，优选地，ALTN抑制剂与固体高分子材料的重量比为1：0.5～3。
  3. 根据权利要求2所述的持续释放组合物，其特征在于所述ALK抑制剂与表面活性剂的混合物还含有药学上可接受的载体，所述药学上可接受的载体选自乳糖、甘露醇、聚维酮、氯化钠、羟丙甲基纤维素、淀粉、微粉硅胶和滑石粉。
  4. 根据权利要求1-3任一项所述的持续释放组合物，其特征在于所述持续释放组合物还包含溶胀剂，所述溶胀剂为交联聚维酮、聚氧化乙烯、卡波姆、羟丙甲基纤维素，海藻酸及其盐中的一种或几种，优选地，所述溶胀剂的用量以重量计为4.5～30％。
  5. 根据权利要求1-4任一项所述的持续释放组合物，其特征在于所述持续释放组合物还包含肠溶材料，所述肠溶材料为丙烯酸树脂类化合物，优选地，为甲基丙烯酸和丙烯酸乙酯共聚物、甲基丙烯酸和丙烯酸甲酯共聚物、甲基丙烯酸和甲基丙烯酸甲酯共聚物中的一种或几种的混合物，更优选地，所述肠溶材料的含量以重量计为0～20％。
  6. 根据权利要求1-5任一项所述的持续释放组合物，其特征在于所述持续释放组合物还包含水溶性致孔基质，所述致孔基质为乳糖、蔗糖、甘露醇、木糖醇和山梨糖醇中一种或多种，或者为水不溶性的纤维素物质，优选地，所述纤维素物质为微晶纤维素、低取代羟丙 基纤维素、交联羧甲基纤维素钠中一种或多种。
  7. 根据权利要求1-6任一项所述的持续释放组合物，其特征在于所述ALK抑制剂为ALTN，或其药学可接受的盐，优选为ALTN的盐酸盐。
  8. 根据权利要求7所述的持续释放组合物，其特征在于所述持续释放组合物能制备成每日服用一次的制剂，所述每日服用一次的制剂含有150～600mg的ALTN，优选地，含有300～600mg的ALTN。
  9. 一种高载药量的ALTN的持续释放组合物，其特征在于所述持续释放组合物包含ALTN与十二烷基硫酸钠的混合物、溶胀剂、肠溶材料、致孔基质，所述持续释放组合物的单位制剂含有300～600mg的ALTN；优选地，ALTN与十二烷基硫酸钠的混合物中十二烷基硫酸钠与ALTN重量比为1:1～4；优选地，所述溶胀剂为交联聚维酮或聚氧化乙烯中其中交联聚维酮占持续释放组合物总重量的0～15％，聚氧化乙烯占持续释放组合物总重量的1.5％～30％；优选地，所述溶胀剂为交联聚维酮与聚氧化乙烯的混合物，交联聚维酮与聚氧化乙烯占持续释放组合物总重量的1.5％～30％；优选地，所述肠溶材料为甲基丙烯酸和丙烯酸乙酯共聚物、甲基丙烯酸和丙烯酸甲酯共聚物中的一种或几种的混合物；优选地，所述致孔基质为乳糖、微晶纤维素中的一种或为二者的混合物。
  10. 权利要求1-9任一项的持续释放组合物的制备方法，所述制备方法选自：
    (1)将ALK抑制剂增溶复合物、溶胀剂，肠溶材料，致孔基质以粉末形式混合后直接压片获得片芯；
    (2)采用高剪切制粒或流化床制粒的湿法制粒进行造粒、干燥获得抑制剂颗粒，再经过混合、压片制备获得片芯；和
    (3)通过干法制粒进行造粒获得抑制剂颗粒，再经过混合、压片制备获得片芯；
    优选地，所述制备方法还包括对片芯外层进行胃溶型非功能性的包衣，或对片芯外层进行薄膜包衣。
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