WO2019218576A1 - 一种来那度胺胃滞留缓释片及其制备方法 - Google Patents

一种来那度胺胃滞留缓释片及其制备方法 Download PDF

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WO2019218576A1
WO2019218576A1 PCT/CN2018/108771 CN2018108771W WO2019218576A1 WO 2019218576 A1 WO2019218576 A1 WO 2019218576A1 CN 2018108771 W CN2018108771 W CN 2018108771W WO 2019218576 A1 WO2019218576 A1 WO 2019218576A1
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release
lenalidomide
sustained
sustained release
gastric retention
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PCT/CN2018/108771
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English (en)
French (fr)
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刘锋
罗华锋
何静瑜
谭晓峰
赖树挺
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广州帝奇医药技术有限公司
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Priority to EP18918993.9A priority Critical patent/EP3766494B1/en
Priority to US17/041,635 priority patent/US12226530B2/en
Priority to JP2020555458A priority patent/JP6990470B2/ja
Publication of WO2019218576A1 publication Critical patent/WO2019218576A1/zh

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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
    • A61K31/44—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
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a lenalidomide gastric retention sustained release tablet and a preparation method thereof.
  • Lenalidomide is an anti-tumor immunomodulator that is now widely used clinically in multiple myeloma (MM), developed by Celgene and marketed in capsule form.
  • MM multiple myeloma
  • lenalidomide capsules are rapidly absorbed in the gastrointestinal tract after oral administration, and the peak time of blood medicine is 0.5 to 1.5 hours, and the half-life is about 3 hours.
  • the dose is between 5 and 50 mg, the maximum plasma concentration (Cmax) and the area under the blood concentration time curve (AUC) can be proportionally increased with increasing dose.
  • Cmax maximum plasma concentration
  • AUC area under the blood concentration time curve
  • the blood drug concentration fluctuated greatly, and the toxic and side effects were obvious, which significantly reduced the number of neutrophils and the number of platelets. Therefore, it is necessary to prepare a slow-release preparation with a small fluctuation in blood concentration to reduce the peak-to-valley difference of blood concentration, achieve a relatively stable blood concentration, and reduce toxic side effects.
  • An oral sustained release preparation refers to a preparation which can continuously release a drug for a long period of time after administration.
  • the drug in the sustained-release preparation is slowly released at an appropriate rate, which reduces the peak-to-valley phenomenon of the blood drug concentration exhibited by the common dosage form, and maintains the blood drug concentration within a relatively stable and long-lasting effective range, thereby improving the safety of the drug.
  • a sustained-release preparation of a drug having a short biological half-life or requiring frequent administration can reduce the number of administrations and improve the compliance of the medication.
  • Patent CN103610658A provides a lenalidomide sustained release agent and a preparation method thereof, and the lenalidomide sustained release tablet of the invention can release the drug slowly and uniformly by using the sustained release skeleton material, thereby reducing the release rate and delaying the peak time. Extend the action time of lenalidomide to provide a uniform and constant blood concentration.
  • the conventional slow-release preparation has a shorter residence time in the upper digestive tract (stomach, duodenum) of the human body, and some drugs have not been released or absorbed completely from the tablet. It has been transported to the lower digestive tract and missed the optimal absorption site, resulting in a decrease in the area under the curve of blood concentration (AUC) and a decrease in bioavailability, which affects the therapeutic effect of the drug.
  • AUC area under the curve of blood concentration
  • the gastric retention sustained-release preparation belongs to the category of sustained-release preparations, and has the characteristics of localized release in the stomach, which can prolong the release time of the medicine in the gastrointestinal tract (mainly the stomach), thereby increasing the absorption degree of the medicine in the gastrointestinal tract.
  • the sustained release of the drug in the stomach reduces the effect of body fluid pH on the drug release rate and improves the bioavailability or efficacy of certain drugs.
  • the stability of some active substances decreases with the increase of pH in the intestinal environment (such as lenalidomide, captopril).
  • the active ingredient can be released and absorbed in a lower pH environment. Bioavailability. For drugs that only exert activity locally (such as L-dopa or riboflavin in the upper intestinal tract), it is important to extend the residence time in the stomach.
  • the solubility of lenalidomide in pH 1.2 hydrochloric acid buffer is about 18 mg/ml, and when the solution medium pH is greater than 4.6, the solubility is less than 0.6 mg/ml.
  • the stability of lenalidomide is related to the pH of the solvent, and the degradation is exacerbated when the pH is increased. The concentration was unchanged in the solvent of pH 1.2 for 6 hours, decreased by 6% in the solvent of pH 4.5 for 6 hours, and decreased by 16% in the solvent of pH 6.8 for 6 hours. Under normal physiological conditions, the pH value in the stomach ranges from 1 to 4, and the pH value of the intestine ranges from 5 to 8. The stability and solubility of lenalidomide in the stomach is better than that in the intestine. Therefore, it has gastric retention. Compared with the conventional sustained-release tablets, the lenalidomide sustained-release tablets can ensure the stability of the active ingredients after release, improve the bioavailability and reduce the toxic side effects of the degradation products while maintaining the sustained release effect.
  • the retention principle of gastric retention preparations is mainly bioadhesion, size rejection and floating.
  • the bioadhesive gastric retention sustained release preparation can adhere to the gastric contents due to its non-selective adhesion, and is discharged from the stomach by gastric motility;
  • the size exclusion type gastric retention sustained release preparation is not conducive to the patient due to its large size.
  • the service also has the risk of blocking the gastric pylorus, affecting the normal work of gastric peristalsis;
  • the floating gastric retention release preparation is made of a light waxy material (a bleaching aid) or a gas-producing carbonate (foaming agent). composition.
  • Commonly used bleaching agents are stearyl alcohol, stearic acid, glyceryl monostearate, glyceryl behenate, carnauba wax, white wax, hydrogenated vegetable oil, etc. These materials have poor stability and low melting point. Conducive to the stability of the formulation, but also not conducive to production. Commonly used blowing agents are alkaline carbonates or hydrogencarbonates, and are not suitable for drugs that are unstable to alkali.
  • the present invention provides a lenalidomide gastric retention sustained-release tablet and a preparation method thereof, and the sustained release tablet can be quickly floated and floated in a stomach environment.
  • the characteristics of the stomach are long, and it is not easy to be removed with the contents of the stomach.
  • the bioavailability of the drug is high and the side effects are small.
  • a lenalidomide gastric retention sustained release tablet characterized in that the sustained release tablet comprises 3 to 14% by weight of lenalidomide and 14 to 68% by weight of low bulk density.
  • a release-promoting agent 23 to 70% by weight of a sustained-release material having a low bulk density, and the balance of other pharmaceutically acceptable excipients, wherein preferably, the release-promoting agent is used in an amount of 40% to 68% by weight of the prescription.
  • the bulk release agent has a bulk density of 0.24 to 0.52 g/cm 3 ; preferably, the sustained release material is used in an amount of 30% to 50% by weight of the formulation, and the bulk density of the sustained release material is 0.29 0.51 g/cm 3 .
  • the crystalline form of lenalidomide comprises crystal form A, crystal form B, crystal form E, form F, form H, form I, form II, form IV, form X, and crystal
  • the type ⁇ is preferably a crystal form B, a crystal form IV, a crystal form ⁇ , a crystal form I, a crystal form II, and more preferably a crystal form B.
  • Form A its X-ray diffraction pattern, the 2 ⁇ expressed in degrees has characteristic absorption peaks at about 8, 14.5, 16, 17.5, 20.5, 24 and 26, and the melting point is about 270 °C.
  • Form B is a hemihydrate having an X-ray diffraction pattern.
  • the 2 ⁇ expressed in degrees has characteristic absorption peaks at about 16, 18, 22 and 27, and the melting point is about 267 °C.
  • Form H has a melting point of about 269 ° C.
  • the DSC thermogram shows an endotherm at about 50 ° C to about 125 ° C and an endotherm at about 269 ° C.
  • the X-ray diffraction pattern is expressed in degrees of 2 ⁇ . 12.5, 15.2, 26 and 31 have characteristic absorption peaks.
  • Form E its X-ray diffraction pattern, the 2 ⁇ expressed in degrees has characteristic absorption peaks at about 20, 24.5 and 29.
  • Form F Its X-ray diffraction pattern, 2 ⁇ in degrees, has characteristic absorption peaks at about 19, 19.5 and 25.
  • Form X X-ray diffraction pattern, the diffraction peaks of 2 ⁇ in degrees of about 12.0, 14.3, 14.8, 16.2, 17.6, 21.5, 22.6, 23.8, 24.0, 26.0, 28.3, 29.8, 31.9, 32.6, and 33.5 .
  • Form I X-ray diffraction pattern, 2 ⁇ in degrees 7.9, 8.6, 14.2, 14.5, 15.8, 17.0, 18.0, 18.4, 18.8, 19.6, 21.6, 22.0, 22.9, 23.3, 24.0, 24.4, 25.4 26.8, 29.1, 29.6, 30.2, 31.0, 32.0 have diffraction peaks and a melting point of 267 to 269 °C.
  • Crystal form ⁇ its X-ray diffraction pattern, the 2 ⁇ in degrees shows diffraction peaks at 10.1, 12.4, 17.3, 18.1, 18.4, 19.7, 21.5, 22.9, 24.5, 25.6, 26.6, 27.9, 32.4.
  • Form II X-ray diffraction pattern, 2 ⁇ in degrees 12.0, 12.5, 13.2, 13.6, 15.2, 15.7, 17.1, 18.0, 18.9, 19.5, 19.9, 25.6, 28.6, 29.1, 30.2, 30.6, 31.0 31.9, 34.1, and 34.5 have diffraction peaks and a melting point of 267 to 269 °C.
  • Form IV its X-ray diffraction pattern, the 2 ⁇ expressed in degrees is 7.7 ⁇ 0.2, 11.9 ⁇ 0.2, 25.8 ⁇ 0.2, 15.6 ⁇ 0.2, 16.4 ⁇ 0.2, 17.6 ⁇ 0.2, 20.4 ⁇ 0.2, 21.2 ⁇ 0.2, 24.0 ⁇ 0.2, 24.7 ⁇ 0.2, 27.4 ⁇ 0.2, and 29.0 ⁇ 0.2 have diffraction peaks.
  • the DSC scan has a range of 115 to 142 °C in the first endothermic peak and a range of 261 to 271 °C in the second endothermic peak. between.
  • the release-promoting agent is insoluble in water, and its volume expansion after contact with water can further expand the volume of the tablet, increase the contact area between the tablet and the gastric juice, and promote the release of the drug; meanwhile, due to the volume expansion of the tablet To further reduce its density, it can remain floating in the gastric juice, prolonging the time of release of the tablet in the stomach.
  • the release-promoting agent is any one or a combination of crospovidone, microcrystalline cellulose, low-substituted hydroxypropylcellulose, and croscarmellose sodium.
  • the release promoting agent is one or a combination of crospovidone and microcrystalline cellulose.
  • the ratio of the crospovidone to the microcrystalline cellulose is from 1:9 to 4:1.
  • the sustained-release material is any one or a combination of hydroxypropylmethylcellulose, polyethylene oxide, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose.
  • the sustained release material is hydroxypropylmethylcellulose.
  • the sustained release material is hydroxypropylmethylcellulose having a weight average molecular weight of 200,000 or more.
  • the 2% aqueous solution of sodium carboxymethylcellulose, hydroxypropylcellulose and hydroxyethylcellulose has a viscosity greater than 3000 mPa-s.
  • the lenalidomide gastric retention sustained release tablet has a hardness of 3 to 10 kg/cm 2 .
  • the lenalidomide gastric retention sustained release tablet is prepared into a sustained release tablet having a hardness of 5 to 6 kg/cm 2 .
  • the lenalidomide gastric retention sustained release tablet has a density of 0.755 to 0.991 g/cm 3 .
  • the other pharmaceutically acceptable excipients include lubricants, glidants.
  • the glidant is selected from one or a combination of the following: silica, talc, and the like, preferably silica.
  • the amount of the flow aid is from 0.6% to 2.5% of the weight ratio of the prescription.
  • the lubricant is selected from one or a combination of magnesium stearate, sodium stearyl fumarate, talc, and the like, preferably magnesium stearate.
  • the lubricant is used in an amount of from 0.6% to 4.0% by weight of the formulation.
  • the invention further provides a preparation method of the above lenalidomide gastric retention sustained release tablet, comprising the following steps:
  • the compressed tablet has a hardness of from 3 to 10 kg/cm 2 and a density of from 0.755 to 0.991 g/cm 3 .
  • the prepared tablets can be further coated in accordance with a conventional method.
  • the coating agent used for the coating is preferably gastric-soluble Opadry.
  • an appropriate amount of lenalidomide may be added to make the coated tablet coating layer contain lenalidomide to form a package.
  • the instant release layer of the garment achieves the effect of immediate release and sustained release of lenalidomide.
  • the lenalidomide gastric retention sustained release tablet of the present invention contains 5 to 30 mg of lenalidomide per tablet and is administered every 24 hours.
  • the lenalidomide gastric retention sustained release tablet of the present invention is used for treating bone marrow that has received at least one therapy due to a 5q chromosome deletion, presence or absence of other cytogenetic abnormalities, low risk or moderate-1 risk Transfusion-dependent anemia caused by hyperplasia syndrome (MSD); combined with dexamethasone for the treatment of multiple myeloma (MM); also for the treatment of two treatments that have received one dose of bortezomib Post-recurrent and progressive mantle cell lymphoma (MCL).
  • MSD hyperplasia syndrome
  • MCL progressive mantle cell lymphoma
  • the lenalidomide gastric retention sustained-release tablet has the following characteristics: rapid floating in the stomach environment, floating state; moderate size, no difficulty in swallowing, high patient compliance; stomach Long residence time, not easy to be removed with stomach contents; no bleaching agent with low melting point (such as waxy material), high storage stability, long shelf life; no alkaline foaming agent, suitable for Alkali-labile drugs; high bioavailability and low side effects.
  • the bulk density of the sustained-release material and the release-promoting agent is determined by taking a 100 ml measuring cylinder, filling a 100 ml volume of a sustained-release material or a release-promoting agent, and weighing the 100 ml volume of the sustained-release material or the release-promoting agent.
  • the weight of the 100 ml sustained release material or the release promoting agent divided by the volume is the bulk density.
  • the density of the tablets in the present invention was measured using a JT-1200EN type multifunctional solid visual density tester (Mazhi Huck, Taiwan).
  • the in vitro floating performance and in vitro release effect of the lenalidomide gastric retention sustained release tablet of the present invention are determined by referring to the second method of the Chinese Pharmacopoeia 2015 edition four general rules ⁇ 0931>.
  • the specific method of in vitro floating performance is to observe how long the sustained release tablet can be floated after being placed in a dissolution cup containing the dissolution medium, and how long it can float in the liquid.
  • the specific conditions for in vitro release were as follows: 500 ml of a pH 1.2 hydrochloric acid solution was used as the dissolution medium, and the speed of the dissolution apparatus was 100 rpm, which was operated according to law. 5 ml of the solution was taken at the specified time point, filtered, and 5 ml of the same solvent at the same temperature was immediately added to the operating container. The filtrate was assayed for content and tablet release was calculated.
  • Lenalidomide is B crystal form, and hydroxypropylmethylcellulose K200M has a weight average molecular weight of about 1,200,000.
  • Preparation method of the tablet Weigh the above-mentioned raw materials except magnesium stearate, and mix them evenly after passing through a 60 mesh sieve. Further, magnesium stearate was added and appropriately mixed, and then compressed into tablets, and the tablet had a hardness of 9 to 10 kg/cm 2 and a tablet density of 0.991 g/cm 3 .
  • Example 1 Floating performance of gastric floating sustained-release tablets: The tablets were quickly floated after being placed in a dissolution cup, and were continuously floated in the dissolution medium for at least 24 hours.
  • the test results showed that the lenalidomide gastric sustained-release tablets had a remarkable sustained-release characteristics, and the time required for the drug to release 80% was about 16 hours.
  • Lenalidomide is A crystal form, and hydroxypropylmethyl cellulose K250 has a weight average molecular weight of about 200,000.
  • Preparation method Weigh the above-mentioned raw materials except sodium stearyl fumarate, and mix them evenly after passing through a 60 mesh sieve. The stearyl fumarate was further mixed and compressed into tablets, and the tablet had a hardness of 3 to 4 kg/cm 2 and a tablet density of 0.755 g/cm 3 .
  • Example 2 Floating performance of gastric floating sustained-release tablets: The tablets were quickly floated after being placed in a dissolution cup, and were continuously floated in the dissolution medium for at least 24 hours.
  • test results showed that lenalidomide gastric sustained-release tablets had a significant sustained-release characteristics, and the time required for drug release of 80% was about 14 hours.
  • Lenalidomide is a crystalline form of II, and the weight average molecular weight of hydroxypropylmethylcellulose K750 is about 250,000.
  • Preparation method The above-mentioned raw materials other than talcum powder are weighed, mixed separately after 60 mesh sieve, and then added with talc. The powder was appropriately mixed and compressed into tablets having a tablet hardness of 5 to 6 kg/cm 2 and a tablet density of 0.949 g/cm 3 .
  • Example 3 Floating performance of gastric floating sustained-release tablets: The tablets were quickly floated after being placed in a dissolution cup, and were continuously floated in the dissolution medium for at least 24 hours.
  • the test results showed that the lenalidomide gastric sustained-release tablets had a remarkable sustained-release characteristics, and the time required for the drug to release 80% was about 16 hours.
  • Lenalidomide is E crystal form, preparation method: weigh the above-mentioned raw materials except magnesium stearate, respectively, after 60 mesh sieve and mix evenly, and then add magnesium stearate to mix properly and then compress into tablets, tablet hardness 3 to 4 kg/cm 2 and a tablet density of 0.836 g/cm 3 .
  • Example 4 Floating performance of gastric floating sustained release tablets: The tablets were quickly floated after being placed in a dissolution cup, and were continuously floated in the dissolution medium for at least 24 hours.
  • the test results showed that the lenalidomide gastric sustained-release tablets had a remarkable sustained-release characteristics, and the time required for the drug to release 80% was about 16 hours.
  • Lenalidomide is a crystalline form of IV, and the weight average molecular weight of hydroxypropylmethylcellulose K100M is about 1000000.
  • Preparation method the above-mentioned raw materials other than magnesium stearate are weighed and mixed uniformly after passing through a 60 mesh sieve. Magnesium stearate was appropriately mixed and compressed into tablets, and the tablet had a hardness of 7 to 8 kg/cm 2 and a tablet density of 0.966 g/cm 3 .
  • Example 5 Floating performance of gastric floating sustained-release tablets: The tablets were quickly floated after being placed in a dissolution cup, and were continuously floated in the dissolution medium for at least 24 hours.
  • the test results showed that the lenalidomide gastric sustained-release tablets had a remarkable sustained-release characteristics, and the time required for the drug to release 80% was about 16 hours.
  • Lenalidomide is X crystal form, preparation method: weigh the above-mentioned raw materials except magnesium stearate, respectively, after 60 mesh sieve and mix evenly, and then add magnesium stearate to mix properly and then compress into tablets, tablet hardness 6 to 7 kg/cm 2 , and the tablet density was 0.977 g/cm 3 .
  • Example 6 Floating performance of gastric floating sustained-release tablets: The tablets were quickly floated after being placed in a dissolution cup, and were continuously floated in the dissolution medium for at least 24 hours.
  • the test results showed that the lenalidomide gastric sustained-release tablets had a remarkable sustained-release characteristics, and the time required for the drug to release 80% was about 18 hours.
  • Lenalidomide is a crystalline form of I, and the weight average molecular weight of hydroxypropylmethylcellulose K4M is about 400,000.
  • Preparation method the above-mentioned raw materials other than magnesium stearate are weighed and mixed uniformly after passing through a 60 mesh sieve. Magnesium stearate was appropriately mixed and compressed into tablets, and the tablet had a hardness of 5 to 6 kg/cm 2 and a tablet density of 0.930 g/cm 3 .
  • Example 7 Floatability of gastric floating sustained-release tablets: The tablets were quickly floated after being placed in a dissolution cup, and were continuously floated in the dissolution medium for at least 24 hours.
  • test results showed that lenalidomide gastric sustained-release tablets had a significant sustained-release characteristics, and the time required for drug release of 80% was about 14 hours.
  • Lenalidomide is ⁇ crystal form, and hydroxypropylmethyl cellulose K1500 has a weight average molecular weight of about 300,000.
  • Preparation method Weigh out the above-mentioned raw materials except stearyl fumarate, and mix them evenly after 60 mesh sieve. Further, the stearyl fumarate was further mixed and compressed into tablets, and the tablet had a hardness of 4 to 5 kg/cm 2 and a tablet density of 0.871 g/cm 3 .
  • Example 8 Floating performance of gastric floating sustained-release tablets: The tablets were quickly floated after being placed in a dissolution cup, and were continuously floated in the dissolution medium for at least 24 hours.
  • test results showed that lenalidomide gastric sustained-release tablets had a significant sustained-release characteristics, and the time required for drug release of 80% was about 14 hours.
  • Lenalidomide is B crystal form, tablet preparation method: Weigh out the above-mentioned raw materials except magnesium stearate, respectively, after 60 mesh sieve and mix well, then add magnesium stearate to mix properly and then compress into tablets and tablets.
  • the hardness of the agent was 5 to 6 kg/cm 2 and the tablet density was 0.967 g/cm 3 .
  • Example 9 Floating performance of gastric floating sustained-release tablets: The tablets were quickly floated after being placed in a dissolution cup, and were continuously floated in the dissolution medium for 24 hours.
  • the test results showed that the lenalidomide gastric sustained-release tablets had a remarkable sustained-release characteristics, and the time required for the drug to release 80% was about 18 hours.
  • Lenalidomide is F crystal form, preparation method: weigh the above-mentioned raw materials except magnesium stearate, respectively, after 60 mesh sieve and mix evenly, and then add magnesium stearate and mix well to form into tablets, tablet hardness 5 to 6 kg/cm 2 , and the tablet density is 0.975 g/cm 3 .
  • Example 10 Floating performance of gastric floating sustained-release tablets: The tablets were quickly floated after being placed in a dissolution cup, and were continuously floated in the dissolution medium for at least 24 hours.
  • test results show that the lenalidomide gastric sustained-release tablets have a remarkable sustained-release characteristics, and the time required for the drug to release 80% is about 10 hours.
  • Lenalidomide is B crystal form, and hydroxypropylmethylcellulose K200M has a weight average molecular weight of about 1,200,000.
  • Preparation method of the tablet Weigh the above-mentioned raw materials except magnesium stearate, and mix them evenly after passing through a 60 mesh sieve. Further, magnesium stearate was added and appropriately mixed, and then compressed into tablets, and the tablet had a hardness of 7 to 8 kg/cm 2 and a tablet density of 0.968 g/cm 3 .
  • Example 11 Floatability of gastric floating sustained-release tablets: The tablets were quickly floated after being placed in a dissolution cup, and were continuously floated in the dissolution medium for at least 24 hours.
  • the test results showed that the lenalidomide gastric sustained-release tablets had a remarkable sustained-release characteristics, and the time required for the drug to release 80% was about 12 hours.
  • a lenalidomide sustained release tablet was prepared as a comparative example of a conventional sustained release tablet (Example 12). 5. The difference is that the microcrystalline cellulose in Example 5 is replaced with a bulky lactose (lactose and microcrystalline cellulose are used in the original capsule preparation).
  • the formulation of the conventional sustained-release tablet (Example 13) was referred to Example 8, except that the sustained-release material of Example 13 was replaced with a higher bulk density of hydroxyethylcellulose.
  • Lenalidomide is B crystal form, tablet preparation method: Weigh out the above-mentioned raw materials except magnesium stearate, respectively, after 60 mesh sieve and mix well, then add magnesium stearate to mix properly and then compress into tablets and tablets.
  • the hardness of the agent was 7 to 8 kg/cm 2 and the tablet density was 1.158 g/cm 3 .
  • Floating performance of ordinary sustained-release tablets The tablets sinked after being placed in a dissolution cup, and no floating phenomenon occurred within 24 hours.
  • test results show that the lenalidomide sustained-release tablets have a remarkable sustained-release characteristics, and the time required for the drug to release 80% is about 18 hours, but the ordinary sustained-release tablets have no floating performance and cannot achieve the gastric retention effect.
  • Lenalidomide is ⁇ crystal form, preparation method: weigh the above-mentioned raw materials except stearyl fumarate, and then mix them evenly after 60 mesh sieve, and then add stearyl fumarate and mix them properly to form tablets.
  • the tablet has a hardness of 4 to 5 kg/cm 2 and a tablet density of 1.098 g/cm 3 .
  • Example 13 Floatability of gastric floating sustained-release tablets: no bleaching was observed within 24 hours after the tablets were placed in the dissolution cup.
  • test results show that lenalidomide gastric sustained-release tablets have a significant sustained-release characteristics, and the time required for drug release of 80% is about 20 hours.
  • Eight Beagle dogs were randomly divided into three groups, and one unit preparation of each of the commercially available lenalidomide immediate release capsules, lenalidomide sustained-release tablets and the lenalidomide gastric retention sustained-release tablets of the present invention was administered.
  • the concentration of lenalidomide in plasma at different time points after administration was determined by high performance liquid chromatography, and the pharmacokinetic parameters were calculated.
  • the lenalidomide gastric retention sustained release tablet of the present invention has better stability than the ordinary gastric floating tablets to which the bleaching agent or the foaming agent is added, the addition of a foaming agent and the addition of a bleaching agent (wax) are prepared.
  • the ordinary gastric floating tablets of the material were subjected to an accelerated stability comparison study of the ordinary gastric floating tablets of the genus and the gastric retention sustained-release tablets of the present invention.
  • Example 14 Adding a bleaching agent (octadecyl alcohol) of lenalidomide ordinary gastric floating tablets:
  • Lenalidomide is B crystal form, tablet preparation method: Weigh out the above-mentioned raw materials except magnesium stearate, respectively, after 60 mesh sieve and mix well, then add magnesium stearate to mix properly and then compress into tablets and tablets.
  • the hardness of the agent was 7 to 8 kg/cm 2 and the tablet density was 0.928 g/cm 3 .
  • Example 15 Addition of a foaming agent (calcium carbonate) of lenalidomide ordinary gastric floating tablets:
  • Lenalidomide is B crystal form, tablet preparation method: Weigh out the above-mentioned raw materials except magnesium stearate, respectively, after 60 mesh sieve and mix well, then add magnesium stearate to mix properly and then compress into tablets and tablets.
  • the hardness of the agent is 7-8 kg/cm 2
  • the density of the tablet is 1.098 g/cm 3
  • Accelerated stability test conditions temperature 40 ° C ⁇ 2 ° C, relative humidity 75% ⁇ 5%, before the stakeout sample test for 0 months, sampling after the first, 2, 3, 6 months sampling test.
  • the results of stability investigation showed that the content of common gastric floating tablets with foaming agent decreased significantly during the accelerated test, and the related substances increased significantly.
  • the content of ordinary gastric floating tablets with added bleaching agent was also significantly reduced, and the related substances increased significantly.
  • the stabilized change of the gastric retention sustained-release tablets of the invention is not obvious, and the related substances are slightly increased.
  • the stability of the lenalidomide gastric retention sustained release tablet of the invention is obviously better than that of the ordinary gastric floating tablet prepared by adding a bleaching aid or a foaming agent.

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Abstract

本发明公开了一种来那度胺胃滞留缓释片及其制备方法，所述缓释片包含3～14wt％的来那度胺、14～68wt％的松密度低的促释剂、23～70wt％的松密度低的缓释材料以及余量的其它药学上可接受的辅料，其中，所述促释剂的松密度为0.24～0.52g/cm 3；所述缓释材料的松密度为0.29～0.51g/cm 3。本发明的缓释片在胃环境中呈漂浮状态，不因胃排空而直接从胃排除，具有胃滞留的效果，且不容易随胃内容物排走，药物生物利用度高，副作用小。

Description

一种来那度胺胃滞留缓释片及其制备方法 技术领域
本发明属于医药技术领域，具体地涉及一种来那度胺胃滞留缓释片及其制备方法。
背景技术
来那度胺是一种抗肿瘤免疫调节剂，现在临床上已被广泛应用于多发性骨髓瘤(MM)，由新基公司(Celgene)研发并以胶囊剂型上市。
市售来那度胺胶囊口服后在胃肠道快速吸收，血药达峰时间为0.5～1.5h，半衰期约3h。给药剂量在5～50mg时，最大血浆浓度(Cmax)和血药浓度时间曲线下面积(AUC)均可随剂量的增加而成比例地增加。但其血药浓度波动较大，毒副作用明显，使中性粒细胞数量及血小板数量明显减少。因此，有必要制成血药浓度波动小的缓控释制剂，以降低血药浓度峰谷差值，实现较平稳的血药浓度，降低毒副反应。
口服缓释制剂是指用药后能在较长时间内持续释放药物的制剂。缓释制剂中的药物按适当的速度缓慢释放，减少了普通剂型给药所呈现血药浓度的峰谷现象，使血药浓度保持在比较平稳持久的有效范围内，提高了药物的安全性。生物半衰期短或需要频繁给药的药物制成缓释制剂可减少给药次数，改善用药的依从性。
专利CN103610658A提供了一种来那度胺缓释剂及其制备方法，该发明的来那度胺缓释片利用缓释骨架材料可缓慢均匀的释放药物，达到降低释放速度，推迟达峰时间，延长来那度胺的作用时间，提供均匀恒定的血药浓度。但由于受胃排空和肠道转运的影响，常规的缓控释制剂在人体上消化道(胃、十二指肠)内的停留时间较短，部分药物尚未从片剂中释放或吸收完全就已被转运至下消化道，错失最佳的吸收部位，从而导致血药浓度时间曲线下面积(AUC)下降，生物利用度降低，影响到药物的治疗效果。
胃滞留缓释制剂属于缓释制剂范畴，具有在胃中定位释放的特点，能延长药物在胃肠道(主要是胃)的释药时间，从而增加药物在胃肠道的吸收程度。药物在胃内持续释放，降低了体液酸碱度对药物释放速率的影响，提高了某些药物的生物利用度或疗效。有些活性物质的稳定性随肠道环境pH升高而降低(如来 那度胺、卡托普利)，当制备成胃滞留缓释制剂，可使活性成分在较低pH环境中释放吸收，提高了生物利用度。对于仅在局部发挥活性的药物(如L-多巴或核黄素在上肠道有吸收窗)，延长其在胃中的停留时间是非常重要的。
来那度胺在pH1.2盐酸缓冲液中的溶解度约为18mg/ml，当溶液介质pH大于4.6时，其溶解度小于0.6mg/ml。来那度胺的稳定性与溶媒pH有关，pH增加时，降解加剧。在pH1.2的溶媒中6小时浓度不变，在pH4.5的溶媒中6小时下降6％，在pH6.8的溶媒中6小时下降16％。正常生理条件下，胃内pH值范围在1～4左右，肠道pH值范围为5～8左右，来那度胺在胃内稳定性与溶解性比肠道内好，因此，具有胃滞留作用的来那度胺缓释片比普通缓释片相比，在保持缓释效果的同时，更能保证释放后活性成分的稳定，提高生物利用度，降低降解物可能带来的毒副作用。
目前，胃滞留制剂的滞留原理主要为生物黏附、尺寸排斥和漂浮。其中，生物黏附型胃滞留缓释制剂因其黏附的无选择性，可黏附于胃内容物而受胃蠕动作用排出胃部；尺寸排斥型胃滞留缓释制剂因其尺寸大，不利于患者吞服，同时有阻塞胃幽门的风险，影响胃部蠕动的正常工作；漂浮型胃滞留缓释制剂由轻质的蜡质材料(助漂剂)或能产生气体的碳酸盐(发泡剂)组成。常用的助漂剂有十八醇、硬脂酸、单硬脂酸甘油酯、山嵛酸甘油酯、巴西棕榈蜡、白蜡、氢化植物油等，这类物质稳定性较差，熔点较低，不利于制剂的稳定性，也不利于生产。常用的发泡剂为偏碱性的碳酸盐或碳酸氢盐，不适用于对碱不稳定的药物。
发明内容
发明目的：为解决现有技术中存在的技术问题，本发明提供一种来那度胺胃滞留缓释片及其制备方法，提供的缓释片在胃环境中能快速起漂，呈漂浮状态的特点，胃滞留时间长，不容易随胃内容物排走，药物生物利用度高，副作用小。
技术方案：为实现上述技术目的，一种来那度胺胃滞留缓释片，其特征在于,所述缓释片包含3～14wt％的来那度胺、14～68wt％的松密度低的促释剂、23～70wt％的松密度低的缓释材料以及余量的其它药学上可接受的辅料，其中，优选地,所述促释剂的用量占处方重量比例的40％～68％；所述促释剂的松密度为0.24～0.52g/cm 3；优选地,所述缓释材料的用量占处方重量比例的30％～50％，所述缓释材料的松密度为0.29～0.51g/cm 3。
其中，所述来那度胺的晶型包括晶型A、晶型B、晶型E、晶型F、晶型H、晶型Ⅰ、晶型Ⅱ、晶型Ⅳ、晶型Ⅹ、和晶型α，优选为晶型B、晶型Ⅳ、晶型α、晶型Ⅰ、晶型Ⅱ，更优选为晶型B。
来那度胺不同晶型的物理性质如下：
晶型A：其X-射线衍射图，以度表示的2θ在约8、14.5、16、17.5、20.5、24和26有特征吸收峰，熔点约为270℃。
晶型B：是一种半水合物，其X-射线衍射图，以度表示的2θ在约16、18、22和27有特征吸收峰，熔点约为267℃。
晶型H：其熔点约为269℃，DSC热分析图显示在约50℃到约125℃具有吸热和在约269℃具有吸热，其X-射线衍射图，以度表示的2θ在约12.5、15.2、26和31有特征吸收峰。
晶型E：其X-射线衍射图，以度表示的2θ在约20、24.5和29有特征吸收峰。
晶型F：其X-射线衍射图，以度表示的2θ在约19、19.5和25有特征吸收峰。
晶型Ⅹ:其X-射线衍射图，以度表示的2θ在约12.0、14.3、14.8、16.2、17.6、21.5、22.6、23.8、24.0、26.0、28.3、29.8、31.9、32.6和33.5有衍射峰。
晶型Ⅰ:其X-射线衍射图，以度表示的2θ在7.9、8.6、14.2、14.5、15.8、17.0、18.0、18.4、18.8、19.6、21.6、22.0、22.9、23.3、24.0、24.4、25.4、26.8、29.1、29.6、30.2、31.0、32.0有衍射峰，熔点为267～269℃。
晶型α：其X-射线衍射图，以度表示的2θ在10.1、12.4、17.3、18.1、18.4、19.7、21.5、22.9、24.5、25.6、26.6、27.9、32.4有衍射峰。
晶型Ⅱ：其X-射线衍射图，以度表示的2θ在12.0、12.5、13.2、13.6、15.2、15.7、17.1、18.0、18.9、19.5、19.9、25.6、28.6、29.1、30.2、30.6、31.0、31.9、34.1、34.5有衍射峰，熔点为267～269℃。
晶型Ⅳ：其X-射线衍射图，以度表示的2θ在7.7±0.2、11.9±0.2、25.8±0.2、15.6±0.2、16.4±0.2、17.6±0.2、20.4±0.2、21.2±0.2、24.0±0.2、24.7±0.2、27.4±0.2和29.0±0.2有衍射峰，其DSC扫描在第一个吸热峰的范围在115～142℃之间，第二吸热峰的范围在261～271℃之间。
所述促释剂不溶于水，其与水接触后发生体积膨胀，可使片剂的体积进一步膨胀，增大片剂与胃液的接触面积，促进药物的释放；同时，由于片剂的体积膨胀，使其密度进一步降低，可以在胃液中保持漂浮状态，延长片剂在胃内释药的时间。
具体地,所述促释剂为交联聚维酮、微晶纤维素、低取代羟丙基纤维素、交联羧甲基纤维素钠中的任意一种或几种的组合。优选地，所述促释剂为交联聚维酮与微晶纤维素之一或组合。当缓释剂为所述交联聚维酮与微晶纤维素的组合时，交联聚维酮与微晶纤维素的比例为1:9～4:1。所述缓释材料为羟丙甲基纤维素、聚环氧乙烷、羟丙基纤维素、羟乙基纤维素、羧甲基纤维素钠中的任意一种或几种的组合。优选地，所述缓释材料为羟丙甲基纤维素。
在一种优选的实施方式中,所述缓释材料为羟丙甲基纤维素，其重均分子量大于或等于200000。优选地,所述羧甲基纤维素钠、羟丙基纤维素和羟乙基纤维素的2％水溶液黏度大于3000mPa·s。
所述来那度胺胃滞留缓释片的硬度为3～10kg/cm 2。优选地，将所述来那度胺胃滞留缓释片制备成硬度为5～6kg/cm 2的缓释片。
优选地，所述来那度胺胃滞留缓释片的密度为0.755～0.991g/cm 3。
具体地，所述的其它药学上可接受的辅料包括润滑剂、助流剂。
所述助流剂选自下列之一或组合：二氧化硅、滑石粉等，优选为二氧化硅。助流剂的用量占处方重量比例的0.6％～2.5％。
所述润滑剂选自下列之一或组合：硬脂酸镁、硬脂富马酸钠、滑石粉等，优选为硬脂酸镁。润滑剂的用量占处方重量比例的0.6％～4.0％。
本发明进一步提出了上述来那度胺胃滞留缓释片的制备方法，包括如下步骤：
(1)将各原辅料分别过筛，优选地，过60目筛；
(2)将处方量的原料药与除润滑剂之外的所有辅料共同混合成均匀的共混物；
(3)在共混物中加入处方量的润滑剂进行适当的混合，得到总混物；
(4)将总混物压制成片剂。
优选地，压制成的片剂硬度为3～10kg/cm 2，密度为0.755～0.991g/cm 3。
进一步地，制备成的片剂可以进一步按照常规方法进行包衣。
所述包衣使用的包衣剂首选胃溶型欧巴代，在配置包衣液过程中，可以添加适量的来那度胺，以使包衣片包衣层含有来那度胺，构成包衣速释层，实现来那度胺速释与缓释的效果。
本发明的来那度胺胃滞留缓释片，其中每片含有5～30mg来那度胺，每24小时服用一次。
本发明的来那度胺胃滞留缓释片，用于治疗已接受过至少一种疗法，因有5q染色体缺失、存在或不存在其他细胞遗传学异常的低风险或中度-1风险的骨髓增生异常综合征(MSD)所致的输血依赖型贫血；与地塞米松联合使用，可用于治疗多发性骨髓瘤(MM)；也可用于治疗已接受过包含一次硼替佐米疗法的两次治疗后的复发和进展性套细胞淋巴瘤(MCL)。
与现有技术相比，所述来那度胺胃滞留缓释片具有以下特点：在胃环境中能快速起漂，呈漂浮状态的特点；尺寸适中，无吞咽困难，患者顺应性高；胃滞留时间长，不容易随胃内容物排走；不含低熔点的助漂剂(如蜡质材料)，贮存稳定性高，货架期长；不含偏碱性的发泡剂，适用于对碱不稳定的药物；药物生物利用度高，副作用小。
具体实施方式
下面结合实施例对本发明做进一步的详细说明。
本发明中缓释材料与促释剂的松密度测定方法为：取100ml量筒，装入100ml体积的缓释材料或促释剂，再对该100ml体积的缓释材料或促释剂进行称重，100ml缓释材料或促释剂的重量除以体积即为其松密度。
本发明中片剂的密度使用JT-1200EN型多功能固体视密度测试仪(台湾玛芝哈克)进行测定。
本发明的来那度胺胃滞留缓释片的体外漂浮性能及体外释放效果参考中国药典2015年版四部通则〈0931〉第二法进行测定。
体外漂浮性能的具体考察方法是观察缓释片投入盛有溶出介质的溶出杯后于多长时间能起漂，以及能在液体中漂浮多长时间。
体外释放度的具体考察条件为以pH1.2盐酸溶液500ml作为溶出介质，溶出装置转速为100转/分钟，依法操作。在规定时间点分别取溶液5ml，滤过，并即时在操作容器中补充同温度的相同溶剂5ml。滤液进行含量测定，计算片剂释放 度。
实施例1
Figure PCTCN2018108771-appb-000001
促释剂与缓释材料信息：
品名 类别 型号 松密度(g/cm 3)
羧甲基纤维素钠 缓释材料 SJJ-H 0.51
微晶纤维素 促释剂 101 0.39
羟丙甲基纤维素 缓释材料 K200M 0.29
交联聚维酮 促释剂 XL 0.32
来那度胺为B晶型，羟丙甲基纤维素K200M的重均分子量约为1200000，片剂制备方法：称取上述除硬脂酸镁外的原辅料，分别过60目筛后混合均匀，再加硬脂酸镁适当混合后压制成片，片剂硬度9～10kg/cm 2，片剂密度0.991g/cm 3。
实施例1胃漂浮缓释片的漂浮性能：片剂投入溶出杯后快速起漂，在溶出介质中持续漂浮至少24小时。
根据实施例1制备的来那度胺胃滞留缓释片的释放度测定结果：
时间(h) 2 4 8 12 16 20 24
累积释放度(％) 10.3 20.9 42.6 63.5 79.8 91.9 94.2
测试结果表明，来那度胺胃滞留缓释片具有显著的缓释特征，药物释放80％所需时间约16小时。
实施例2
Figure PCTCN2018108771-appb-000002
Figure PCTCN2018108771-appb-000003
促释剂与缓释材料信息：
品名 类别 型号 松密度(g/cm 3)
羟丙甲基纤维素 缓释材料 K250 0.29
交联聚维酮 促释剂 SL-10 0.24
来那度胺为A晶型，羟丙甲基纤维素K250的重均分子量约为200000，制备方法：称取上述除硬脂富马酸钠外的原辅料，分别过60目筛后混合均匀，再加硬脂富马酸钠适当混合后压制成片，片剂硬度3～4kg/cm 2，片剂密度0.755g/cm 3。
实施例2胃漂浮缓释片的漂浮性能：片剂投入溶出杯后快速起漂，在溶出介质中持续漂浮至少24小时。
根据实施例2制备的来那度胺胃滞留缓释片的释放度测定结果：
时间(h) 2 4 8 12 16 20 24
累积释放度(％) 16.3 28.9 52.6 74.5 90.1 95.8 96.6
测试结果表明，来那度胺胃滞留缓释片具有显著的缓释特征，药物释放80％所需时间约14小时。
实施例3
促释剂与缓释材料信息：
品名 类别 型号 松密度(g/cm 3)
羧甲基纤维素钠 缓释材料 7HXF 0.48
交联羧甲基纤维素钠 促释剂 SD 711 0.52
羟丙甲基纤维素 缓释材料 K750 0.29
来那度胺为Ⅱ晶型，羟丙甲基纤维素K750的重均分子量约为250000，制备方法：称取上述除滑石粉外的原辅料，分别过60目筛后混合均匀，再加滑石粉适当混合后压制成片，片剂硬度5～6kg/cm 2，片剂密度0.949g/cm 3。
实施例3胃漂浮缓释片的漂浮性能：片剂投入溶出杯后快速起漂，在溶出介质中持续漂浮至少24小时。
根据实施例3制备的来那度胺胃滞留缓释片的释放度测定结果：
时间(h) 2 4 8 12 16 20 24
累积释放度(％) 14 26.3 47.6 67.6 84.9 90.1 93.7
测试结果表明，来那度胺胃滞留缓释片具有显著的缓释特征，药物释放80％所需时间约16小时。
实施例4
Figure PCTCN2018108771-appb-000005
促释剂与缓释材料信息：
品名 类别 型号 松密度(g/cm 3)
羟丙基纤维素 缓释材料 MF 0.41
低取代羟丙基纤维素 促释剂 102 0.36
来那度胺为E晶型，制备方法：称取上述除硬脂酸镁外的原辅料，分别过60目筛后混合均匀，再加硬脂酸镁适当混合后压制成片，片剂硬度3～4kg/cm 2，片剂密度0.836g/cm 3。
实施例4胃漂浮缓释片的漂浮性能：片剂投入溶出杯后快速起漂，在溶出介质中持续漂浮至少24小时。
根据实施例4制备的来那度胺胃滞留缓释片的释放度测定结果：
时间(h) 2 4 8 12 16 20 24
累积释放度(％) 15.7 27.6 49.3 69 83.2 94.5 94.9
测试结果表明，来那度胺胃滞留缓释片具有显著的缓释特征，药物释放80％所需时间约16小时。
实施例5
Figure PCTCN2018108771-appb-000006
促释剂与缓释材料信息：
品名 类别 型号 松密度(g/cm 3)
羟丙甲基纤维素 缓释材料 K100M 0.29
微晶纤维素 促释剂 102 0.36
来那度胺为Ⅳ晶型，羟丙甲基纤维素K100M的重均分子量约为1000000，制备方法：称取上述除硬脂酸镁外的原辅料，分别过60目筛后混合均匀，再加硬脂酸镁适当混合后压制成片，片剂硬度7～8kg/cm 2，片剂密度0.966g/cm 3。
实施例5胃漂浮缓释片的漂浮性能：片剂投入溶出杯后快速起漂，在溶出介质中持续漂浮至少24小时。
根据实施例5制备的来那度胺胃滞留缓释片的释放度测定结果：
时间(h) 2 4 8 12 16 20 24
累积释放度(％) 17 28.9 49.4 67.1 80.8 91.9 95.6
测试结果表明，来那度胺胃滞留缓释片具有显著的缓释特征，药物释放80％所需时间约16小时。
实施例6
Figure PCTCN2018108771-appb-000007
促释剂与缓释材料信息：
品名 类别 型号 松密度(g/cm 3)
羟丙甲基纤维素 缓释材料 K100M 0.29
微晶纤维素 促释剂 102 0.36
羟乙基纤维素 缓释材料 HHW 0.51
来那度胺为Ⅹ晶型，制备方法：称取上述除硬脂酸镁外的原辅料，分别过60目筛后混合均匀，再加硬脂酸镁适当混合后压制成片，片剂硬度6～7kg/cm 2，片剂密度0.977g/cm 3。
实施例6胃漂浮缓释片的漂浮性能：片剂投入溶出杯后快速起漂，在溶出介质中持续漂浮至少24小时。
根据实施例6制备的来那度胺胃滞留缓释片的释放度测定结果：
时间(h) 2 4 8 12 16 20 24
累积释放度(％) 18.3 30.1 52.3 67.4 80.9 92.7 95.1
测试结果表明，来那度胺胃滞留缓释片具有显著的缓释特征，药物释放80％所需时间约18小时。
实施例7
Figure PCTCN2018108771-appb-000008
Figure PCTCN2018108771-appb-000009
促释剂与缓释材料信息：
品名 类别 型号 松密度(g/cm 3)
羟丙甲基纤维素 缓释材料 K4M 0.32
微晶纤维素 促释剂 102 0.36
聚环氧乙烷 缓释材料 470 0.45
来那度胺为Ⅰ晶型，羟丙甲基纤维素K4M的重均分子量约为400000，制备方法：称取上述除硬脂酸镁外的原辅料，分别过60目筛后混合均匀，再加硬脂酸镁适当混合后压制成片，片剂硬度5～6kg/cm 2，片剂密度0.930g/cm 3。
实施例7胃漂浮缓释片的漂浮性能：片剂投入溶出杯后快速起漂，在溶出介质中持续漂浮至少24小时。
根据实施例7制备的来那度胺胃滞留缓释片的释放度测定结果：
时间(h) 2 4 8 12 16 20 24
累积释放度(％) 19.6 32.9 58.7 75.4 89.4 94.7 95.8
测试结果表明，来那度胺胃滞留缓释片具有显著的缓释特征，药物释放80％所需时间约14小时。
实施例8
Figure PCTCN2018108771-appb-000010
促释剂与缓释材料信息：
品名 类别 型号 松密度(g/cm 3)
羟丙甲基纤维素 缓释材料 K1500 0.29
交联聚维酮 促释剂 XL 0.32
来那度胺为α晶型，羟丙甲基纤维素K1500的重均分子量约为300000，制备方法：称取上述除硬脂富马酸钠外的原辅料，分别过60目筛后混合均匀，再 加硬脂富马酸钠适当混合后压制成片，片剂硬度4～5kg/cm 2，片剂密度0.871g/cm 3。
实施例8胃漂浮缓释片的漂浮性能：片剂投入溶出杯后快速起漂，在溶出介质中持续漂浮至少24小时。
根据实施例8制备的来那度胺胃滞留缓释片的释放度测定结果：
时间(h) 2 4 8 12 16 20 24
累积释放度(％) 19.5 33.9 59.4 76.1 88.2 94.9 94.7
测试结果表明，来那度胺胃滞留缓释片具有显著的缓释特征，药物释放80％所需时间约14小时。
实施例9
Figure PCTCN2018108771-appb-000011
促释剂与缓释材料信息：
品名 类别 型号 松密度(g/cm 3)
羧甲基纤维素钠 缓释材料 SJJ-H 0.51
微晶纤维素 促释剂 101 0.39
羟丙基纤维素 缓释材料 HF 0.42
来那度胺为B晶型，片剂制备方法：称取上述除硬脂酸镁外的原辅料，分别过60目筛后混合均匀，再加硬脂酸镁适当混合后压制成片，片剂硬度5～6kg/cm 2，片剂密度0.967g/cm 3。
实施例9胃漂浮缓释片的漂浮性能：片剂投入溶出杯后快速起漂，在溶出介质中持续漂浮24小时。
根据实施例9制备的来那度胺胃滞留缓释片的释放度测定结果：
时间(h) 2 4 8 12 16 20 24
累积释放度(％) 18.9 28.9 47.2 65 77.9 88.6 94.2
测试结果表明，来那度胺胃滞留缓释片具有显著的缓释特征，药物释放80％所需时间约18小时。
实施例10
Figure PCTCN2018108771-appb-000012
促释剂与缓释材料信息：
品名 类别 型号 松密度(g/cm 3)
羟丙甲基纤维素 缓释材料 K750 0.29
微晶纤维素 促释剂 101 0.39
羟乙基纤维素 缓释材料 HHW 0.51
来那度胺为F晶型，制备方法：称取上述除硬脂酸镁外的原辅料，分别过60目筛后混合均匀，再加硬脂酸镁适当混合后压制成片，片剂硬度5～6kg/cm 2，片剂密度0.975g/cm 3。
实施例10胃漂浮缓释片的漂浮性能：片剂投入溶出杯后快速起漂，在溶出介质中持续漂浮至少24小时。
根据实施例10制备的来那度胺胃滞留缓释片的释放度测定结果：
时间(h) 2 4 8 12 16 20 24
累积释放度(％) 29.8 43.5 68 85.4 94.7 95.2 95.8
测试结果表明，来那度胺胃滞留缓释片具有显著的缓释特征，药物释放80％所需时间约10小时。
实施例11
Figure PCTCN2018108771-appb-000013
促释剂与缓释材料信息：
品名 类别 型号 松密度(g/cm 3)
羧甲基纤维素钠 缓释材料 SJJ-H 0.51
微晶纤维素 促释剂 101 0.39
羟丙甲基纤维素 缓释材料 K200M 0.29
交联聚维酮 促释剂 XL 0.32
来那度胺为B晶型，羟丙甲基纤维素K200M的重均分子量约为1200000，片剂制备方法：称取上述除硬脂酸镁外的原辅料，分别过60目筛后混合均匀，再加硬脂酸镁适当混合后压制成片，片剂硬度7～8kg/cm 2，片剂密度0.968g/cm 3。
实施例11胃漂浮缓释片的漂浮性能：片剂投入溶出杯后快速起漂，在溶出介质中持续漂浮至少24小时。
根据实施例1制备的来那度胺胃滞留缓释片的释放度测定结果：
时间(h) 2 4 8 12 16 20 24
累积释放度(％) 25.7 40.1 62.9 79.0 88.8 94.9 97.2
测试结果表明，来那度胺胃滞留缓释片具有显著的缓释特征，药物释放80％所需时间约12小时。
为了进一步说明本发明的来那度胺胃滞留缓释片具有胃滞留的有益效果，制备了来那度胺普通缓释片作为对比例，普通缓释片(实施例12)的处方参考实施例5，不同之处为将实施例5中的微晶纤维素用松密度较大的乳糖替代(原研胶囊制剂中使用了乳糖与微晶纤维素)。普通缓释片(实施例13)的处方参 考实施例8，不同之处为将实施例13的缓释材料用松密度较高的羟乙基纤维素替代。
实施例12来那度胺普通缓释片：
Figure PCTCN2018108771-appb-000014
来那度胺为B晶型，片剂制备方法：称取上述除硬脂酸镁外的原辅料，分别过60目筛后混合均匀，再加硬脂酸镁适当混合后压制成片，片剂硬度7～8kg/cm 2，片剂密度1.158g/cm 3。
普通缓释片的漂浮性能：片剂投入溶出杯后下沉，在24小时内未见漂浮现象。
来那度胺普通缓释片的释放度测定结果：
时间(h) 2 4 8 12 16 20 24
累积释放度(％) 15 25.9 43.4 58.1 73.8 84.7 93.6
测试结果表明，来那度胺普通缓释片具有显著的缓释特征，药物释放80％所需时间约18小时，但是普通缓释片并没有漂浮性能，不能达到胃滞留的效果。
实施例13来那度胺普通缓释片：
Figure PCTCN2018108771-appb-000015
促释剂与缓释材料信息：
品名 类别 型号 松密度(g/cm 3)
羟乙基纤维素 缓释材料 HX 0.55
交联聚维酮 促释剂 XL 0.32
来那度胺为α晶型，制备方法：称取上述除硬脂富马酸钠外的原辅料，分别过60目筛后混合均匀，再加硬脂富马酸钠适当混合后压制成片，片剂硬度4～5kg/cm 2，片剂密度1.098g/cm 3。
实施例13胃漂浮缓释片的漂浮性能：片剂投入溶出杯后24小时内未见起漂。
根据实施例13制备的来那度胺胃滞留缓释片的释放度测定结果：
时间(h) 2 4 8 12 16 20 24
累积释放度(％) 14.6 24.2 42.4 59.0 72.6 84.3 92.7
测试结果表明，来那度胺胃滞留缓释片具有显著的缓释特征，药物释放80％所需时间约20小时。
来那度胺制剂药代动力学参数对比试验
试验样品：
(1)速释胶囊：美国Celgene生物制药公司生产的来那度胺胶囊(瑞复美，规格：25mg)；
(2)普通缓释片：实施例12(规格：25mg)；
(3)胃滞留缓释片：实施例5(规格：25mg)。
试验方法：
Beagle犬18只，随机分为3组，给予市售来那度胺速释胶囊、来那度胺普通缓释片和本发明来那度胺胃滞留缓释片各一个单位制剂。采用高效液相色谱法测定给药后不同时间点血浆中来那度胺的浓度，计算药代动力学参数，详见下表：
药代动力学参数 速释胶囊 普通缓释片 胃滞留缓释片
Tmax(hr) 1.5 2.6 4.6
Cmax(ng/mL) 388±95 145±35 155±32
t 1/2(hr) 2.7 4.9 8.8
AUC ∞(ng·hr/mL) 1527±201 1106±131 1506±125
结果表明，相对于来那度胺速释胶囊，来那度胺胃滞留缓释片有效地延迟了来那度胺的达峰时间(Tmax)，显著的降低了峰浓度(Cmax)；胃滞留缓释片的生物利用度(AUC ∞)明显高于普通缓释片。
为了进一步说明本发明的来那度胺胃滞留缓释片比添加助漂剂或发泡剂的普通胃漂浮片具有更好的稳定性，制备了添加发泡剂和添加助漂剂(蜡质材料)的普通胃漂浮片，对来那度普通胃漂浮片与本发明的胃滞留缓释片进行了加速稳定性对比研究。
实施例14添加助漂剂(十八醇)的来那度胺普通胃漂浮片：
Figure PCTCN2018108771-appb-000016
来那度胺为B晶型，片剂制备方法：称取上述除硬脂酸镁外的原辅料，分别过60目筛后混合均匀，再加硬脂酸镁适当混合后压制成片，片剂硬度7～8kg/cm 2，片剂密度0.928g/cm 3。
实施例15添加发泡剂(碳酸钙)的来那度胺普通胃漂浮片：
Figure PCTCN2018108771-appb-000017
来那度胺为B晶型，片剂制备方法：称取上述除硬脂酸镁外的原辅料，分别过60目筛后混合均匀，再加硬脂酸镁适当混合后压制成片，片剂硬度7～8kg/cm 2，片剂密度1.098g/cm 3
加速稳定性试验条件：温度40℃±2℃，相对湿度75％±5％，放样前进行0月样品检验，放样后于第1、2、3、6个月取样检验。
稳定性试验考察结果：
样品中来那度胺含量变化结果：
Figure PCTCN2018108771-appb-000018
样品中总有关物质含量变化结果：
Figure PCTCN2018108771-appb-000019
稳定性考察结果表明，添加发泡剂的普通胃漂浮片在加速试验过程中含量显著降低，有关物质显著增加；添加助漂剂的普通胃漂浮片含量亦明显降低，有关物质明显增加；而本发明的胃滞留缓释片则含量稳定变化不明显，有关物质略有增加。本发明的来那度胺胃滞留缓释片稳定性明显优于添加助漂剂或发泡剂制备的普通胃漂浮片。

Claims (10)

  1. 一种来那度胺胃滞留缓释片，其特征在于,所述缓释片包含3～14wt％的来那度胺、14～68wt％的松密度低的促释剂、23～70wt％的松密度低的缓释材料以及余量的其它药学上可接受的辅料，其中，所述促释剂的松密度为0.24～0.52g/cm 3；所述缓释材料的松密度为0.29～0.51g/cm 3。
  2. 根据权利要求1所述的来那度胺胃滞留缓释片，其特征在于,所述促释剂为交联聚维酮、微晶纤维素、低取代羟丙基纤维素、交联羧甲基纤维素钠中的任意一种或几种的组合。
  3. 根据权利要求1所述的来那度胺胃滞留缓释片，其特征在于,所述缓释材料为羟丙甲基纤维素、聚环氧乙烷、羟丙基纤维素、羟乙基纤维素、羧甲基纤维素钠中的任意一种或几种的组合。
  4. 根据权利要求1所述的来那度胺胃滞留缓释片，其特征在于，所述缓释材料为羟丙甲基纤维素，其重均分子量大于或等于200000。
  5. 根据权利要求3所述的来那度胺胃滞留缓释片，其特征在于,所述羧甲基纤维素钠、羟丙基纤维素和羟乙基纤维素的2％水溶液黏度大于3000mPa·s。
  6. 根据权利要求1所述的来那度胺胃滞留缓释片，其特征在于,所述来那度胺胃滞留缓释片的硬度为3～10kg/cm 2。
  7. 根据权利要求1所述的来那度胺胃滞留缓释片，其特征在于,所述来那度胺胃滞留缓释片的密度为0.755～0.991g/cm 3。
  8. 根据权利要求1所述的来那度胺胃滞留缓释片，其特征在于,所述的其它药学上可接受的辅料包括润滑剂、助流剂。
  9. 权利要求1-7任一项所述的来那度胺胃滞留缓释片的制备方法，其特征在于，包括如下步骤：
    (1)将各原辅料分别过筛；
    (2)将处方量的原料药与除润滑剂之外的所有辅料共同混合成均匀的共混物；
    (3)在共混物中加入处方量的润滑剂进行适当的混合，得到总混物；
    (4)将总混物压制成片剂。
  10. 根据权利要求9所述的方法，其特征在于，所述片剂硬度为3～10kg/cm 2，密度为0.755～0.991g/cm 3。
PCT/CN2018/108771 2018-05-17 2018-09-29 一种来那度胺胃滞留缓释片及其制备方法 WO2019218576A1 (zh)

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JP6990470B2 (ja) 2022-01-13
CN108514560A (zh) 2018-09-11
JP2021517586A (ja) 2021-07-26
EP3766494B1 (en) 2023-03-29
US12226530B2 (en) 2025-02-18
CN108514560B (zh) 2020-07-03
EP3766494A1 (en) 2021-01-20

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