WO2022267169A1 - 一种含有利伐沙班的药物组合物及其应用 - Google Patents

一种含有利伐沙班的药物组合物及其应用 Download PDF

Info

Publication number
WO2022267169A1
WO2022267169A1 PCT/CN2021/108796 CN2021108796W WO2022267169A1 WO 2022267169 A1 WO2022267169 A1 WO 2022267169A1 CN 2021108796 W CN2021108796 W CN 2021108796W WO 2022267169 A1 WO2022267169 A1 WO 2022267169A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
rivaroxaban
microcrystalline cellulose
hypromellose
prescription
Prior art date
Application number
PCT/CN2021/108796
Other languages
English (en)
French (fr)
Inventor
侯朋
卢恩先
刘建军
朱韬
Original Assignee
上海奥全生物医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海奥全生物医药科技有限公司 filed Critical 上海奥全生物医药科技有限公司
Publication of WO2022267169A1 publication Critical patent/WO2022267169A1/zh

Links

Classifications

    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the invention belongs to the field of medicine, in particular to a pharmaceutical composition containing rivaroxaban and its application.
  • Rivaroxaban tablets were jointly developed by Bayer and Janssen. It was first approved for marketing by the European Medicines Agency (EMA) on September 30, 2008, and was approved by the FDA for marketing in the United States on July 1, 2011. It is mainly used to treat adult patients undergoing elective hip or knee replacement surgery to prevent venous thrombosis (VTE). Domestically, rivaroxaban tablets were approved for marketing by the State Food and Drug Administration in March 2009, and were successfully included in the 2009 National Medical Insurance List in the same year. XARELTO is an immediate-release tablet.
  • the US XARELTO original research patent US9415053B PCT to the Chinese patent CN1886120B discloses a fluidized bed wet granulation process, dissolving hypromellose and sodium lauryl sulfate in water, and rivaroxaban is dispersed in the above solution , to form a suspended granulation solution, spray on microcrystalline cellulose, lactose monohydrate and croscarmellose sodium, pass through a 0.8mm sieve after drying, add magnesium stearate and mix to obtain the mixture
  • the raw material rivaroxaban must be fully mixed with a wetting agent, a hydrophilic filler or low-viscosity hypromellose to improve the solubility of rivaroxaban, thereby achieving a rapid release effect, such as Chinese patent CN107773548A discloses a preparation method of apixaban tablets, mixing rivaroxaban and lactose monohydrate at a ratio of 1:2, passing through a 60-mesh sieve twice, and crushing with airflow until the particle size (D90) is less than 10 ⁇ m, to improve the solubility of rivaroxaban, this method is sieved multiple times, using jet milling, the process is complex and difficult to control;
  • CN105267169B discloses a rivaroxaban immediate-release preparation, especially in Examples 5 and 6. Although a wet granulation process is adopted, in the process, all hypromellose is dissolved in water for granulation, which is easy to affect Disintegration time, and about 4% colloidal silicon dioxide is added to the internal phase, and a large amount of fine powder is produced during the drying process. The inventors found in the process research and development process that this will significantly affect the content of intermediate particles and tablets. Therefore, This process often leads to lower content and longer disintegration time, so it is not suitable for the development of dispersible tablets.
  • Chinese patents CN104337787B and CN105232488A disclose a rivaroxaban immediate-release preparation, both of which adopt a wet granulation process, and both disperse or dissolve the raw material in a solvent, and then granulate, the purpose of which is to improve the rivaroxaban
  • rivaroxaban has an unstable amide group, which may cause hydrolysis and affect stability if it exists in a solvent for a long time.
  • Chinese patents CN104721142B and CN101321517B disclose a new type of granulation process, which adopts a melting method to prepare amorphous rivaroxaban, thereby improving its solubility. Because the melting method requires high temperature, generally greater than 100 ° C, for rivaroxaban There is a potential impact on the stability of the class, and it consumes a lot of energy and costs.
  • the purpose of the present invention is to provide a pharmaceutical composition containing rivaroxaban, preferably dispersible tablets, easy to carry, simple preparation process, high dissolution rate and rapid dispersion in water, rivaroxaban does not need to be dispersed in a solvent during the preparation process Medium or melt granulation.
  • a pharmaceutical composition containing rivaroxaban comprising the following components: by weight percentage, including rivaroxaban 1.0%-30.0%, hypromellose 1.0%-8.0%, sodium lauryl sulfate 0.1- 1%, crospovidone 5%-15.0%, colloidal silicon dioxide 0.5%-3.0% and lubricant 0.5%-5%, and the lubricant is sodium stearyl fumarate or magnesium stearate; The remainder is filler, which is microcrystalline cellulose and lactose monohydrate.
  • the hypromellose is used as a binder, which can prevent material inhomogeneity in the preparation process, resulting in a reduction in the content of intermediates and finished products.
  • Microcrystalline cellulose and lactose are fillers that have a direct impact on tablet hardness and dispersion.
  • Cross-linked povidone is a disintegrant, which is helpful for the disintegration of the product. This is the preferred disintegrant after screening the types of disintegrants, which is conducive to the characteristics of rapid dispersion in the later stage.
  • colloidal silicon dioxide The role of colloidal silicon dioxide is to aid flow, and at the same time it is beneficial to the disintegration speed of dispersible tablets, but its prescription amount and addition method will also affect the later tablet content, disintegration time and dissolution. (This is a technical advantage and caveat first discovered during the development of this tablet.)
  • Lubricants include sodium stearyl fumarate or magnesium stearate. Among them, sodium stearyl fumarate is preferred (see R&D section).
  • the present invention provides a pharmaceutical composition, which includes the following ingredients: by weight percentage, including rivaroxaban 1.5%-25.0%, hypromellose 1.0%-5.0%, lauryl sulfate Sodium 0.2-0.8%, crospovidone 6.0%-12.0%, colloidal silicon dioxide 0.6%-2.0% and sodium stearyl fumarate 1.0%-3.0%, the rest is filler, said filler is Microcrystalline Cellulose and Lactose Monohydrate.
  • the present invention provides a pharmaceutical composition, which includes the following ingredients: by weight percentage, including rivaroxaban 1.8%-22.0%, hypromellose 1.5%-3.5%, lauryl sulfate Sodium 0.2-0.8%, crospovidone 6.0%-12%, colloidal silicon dioxide 0.7%-1.5% and sodium stearyl fumarate 1.1%-2.5%, the rest is filler, said filler is Microcrystalline Cellulose and Lactose Monohydrate.
  • the present invention provides a pharmaceutical composition, which includes the following ingredients: by weight percentage, including rivaroxaban 2.0%-18.0%, hypromellose 2.0%-3.0%, lauryl sulfate Sodium 0.2-0.6%, crospovidone 6.0%-10.0%, colloidal silicon dioxide 0.8-1.2% and sodium stearyl fumarate 1.3%-2.2%,; the remainder is filler, said filler is Microcrystalline Cellulose and Lactose Monohydrate.
  • microcrystalline cellulose and lactose in the above pharmaceutical composition the weight ratio of microcrystalline cellulose and lactose is 1:1-2:1, preferably 1.5:1-1.8:1, preferably 1.60:1.
  • the present invention provides a pharmaceutical composition, which includes the following ingredients: by weight percentage, including 2.2%-18.0% of rivaroxaban, 2.7% of hypromellose, and 0.4% of sodium lauryl sulfate , crospovidone 8.8%, colloidal silicon dioxide 1.0% and sodium stearyl fumarate 1.8%, the rest is filler, said filler is microcrystalline cellulose and lactose monohydrate, microcrystalline cellulose: The ratio of lactose monohydrate is 1.5-1.7:1, including all prescriptions of embodiment 1.
  • the above-mentioned pharmaceutical composition is preferably a dispersible tablet, and the dosage range is preferably 2.5mg-20mg/tablet, and the amount of the filler can be adjusted according to the change of the tablet.
  • the pharmaceutical composition has an internal and external structure, and the internal additions are rivaroxaban, hydroxypropylmethylcellulose, sodium lauryl sulfate, 70-95% of the prescription amount of microcrystalline cellulose, lactose monohydrate and Crospovidone, plus remaining microcrystalline cellulose, colloidal silicon dioxide and lubricant.
  • the results of the small test show that adding a small amount of colloidal silicon dioxide to the internal phase contributes to the improvement of the uniformity of dispersion, but through the enlargement of the small test (1000 pieces) to the enlarged production (10000 pieces), the inventors found that the added colloidal silica Colloidal silica can easily lead to a reduction in the content of intermediates, so choose to reduce or not add colloidal silica, and the added silica can be unchanged or adjusted appropriately.
  • step (3) the mixture obtained in step (2) is sieved through comil;
  • step (3) mixing and granulating the mixture obtained in step (3) with microcrystalline cellulose and crospovidone of 70%-95% quality;
  • step (1) spray the granulation liquid in step (1) on the above mixture, wet granulate, dry, dry granulate, add lubricant, remaining microcrystalline cellulose, colloidal silicon dioxide and mix, measure intermediate content , compressed into tablets to obtain the pharmaceutical composition.
  • the amount of hypromellose added in water is 1/4-1/2 of its prescription amount.
  • the hardness of the tablet prepared therein is preferably 40 ⁇ 5N.
  • composition containing rivaroxaban is prepared by the following method:
  • the material obtained above is added to the high-shear wet granulator, and the added amount of microcrystalline cellulose and crospovidone are mixed for 3-8min, the stirring blade speed is 120-400rpm, and the cutting pulp speed is 300rpm -600rpm;
  • wet granules are wet sized, the sized sieve is 6350 ⁇ m, and the rotating speed is 1750 rpm;
  • step 6 dry the wet granules in step 6 in a fluidized bed, the fan frequency is set to 20-40HZ, the material temperature is 40-60°C, and the moisture content is controlled ⁇ 3.0%;
  • the dosage specifications of rivaroxaban in each tablet are 2.5mg, 10mg, 15mg and 20mg/tablet.
  • the hypromellose is hypromellose E3, hypromellose E5, hypromellose E6, hypromellose E15, hypromellose E50 One or more, preferably hypromellose E5.
  • the rivaroxaban dispersible tablet prepared by the method of the present invention has the advantages of fast disintegration and high dissolution rate.
  • the rivaroxaban dispersible tablet prepared by the method of the present invention is convenient to take. It can be taken as a common tablet or taken after being quickly dispersed in water, which greatly improves the compliance of clinical medication.
  • the rivaroxaban dispersible tablet prepared by the method of the present invention has a simple process, does not need to disperse or dissolve rivaroxaban in a solution, and improves the potential stability of rivaroxaban.
  • Suitable prescriptions of the present invention have been verified by 10,000 pieces of products, and the results of small tests, such as dispersion uniformity and dissolution rate, will fluctuate greatly when expanding production, which is also a common and unique situation in the development of dispersible tablets.
  • dispersion uniformity of 3min more stringent than the disintegration time, the reason is that the solubility of rivaroxaban itself is low, the disintegration time uses a 2mm sieve, and the dispersion uniformity uses a 710 ⁇ m sieve, so the disintegration time alone is fast , cannot reflect the uniformity of dispersion of the dispersible tablet, or even fail to meet the requirements of the Pharmacopoeia for uniformity of dispersion
  • the small test needs to be controlled within 90 seconds, and based on the difference of individual prescriptions, the expansion of production may require adjustment of the content of other excipients.
  • rivaroxaban is supplied by Zhejiang Supor, D90 ⁇ 35 ⁇ m; crospovidone is supplied by BASF, the model is KollidonCL-F; croscarmellose sodium (VIVASOL), carboxymethyl starch Sodium (VIVASTAR P) and sodium stearyl fumarate (PRUV) were supplied by JRS, hypromellose was supplied by Colorcon, microcrystalline cellulose was supplied by FMC, model PH101, lactose monohydrate was supplied by MEGGLE, model It is GranuLac 200; sodium lauryl sulfate is supplied by BASF, model is Kolliphor SLS Fine; colloidal silicon dioxide is supplied by EVONIK, model is AEROSIL200 Pharma; magnesium stearate is supplied by FACI, model is Eur Phar.
  • disintegrant directly affects the disintegration time and dispersion state of the tablet.
  • croscarmellose sodium and carboxymethyl starch sodium will gel during the disintegration process and affect the uniformity of dispersion property, crospovidone will not produce gelation, and has the best dispersion uniformity in existing dispersants (such as croscarmellose sodium or carboxymethyl starch sodium); in order to achieve the best Excellent dispersion uniformity, we also switched the hydrophobic lubricant magnesium stearate to hydrophilic sodium stearyl fumarate, and added a small amount of colloidal silicon dioxide to the internal phase and external phase of the formulation to form a preliminary target formulation 1 (10mg/tablet), the next step is to verify whether crospovidone has optimal dispersion uniformity compared with other disintegrants, see example 1.
  • Microcrystalline cellulose has good water absorption characteristics and compressibility, but if all microcrystalline cellulose is put into the inner phase for granulation, its disintegration and compressibility will be reduced, and if it is all put into the outer phase, the compressibility will be enhanced and the water absorption performance will be weak. To achieve good compressibility and water absorption properties, we granulate about 10% of the total tablet weight in the external phase and the rest in the internal phase.
  • the direct mixing process is as follows:
  • Table 3 summarizes the evaluation results of the basic items in the prescription in Table 2
  • the disintegration time limit inspection method (general rule 0921)
  • the inner diameter of the stainless steel wire mesh is 710 ⁇ m
  • the water temperature is 15-25 °C
  • take 6 pieces of the test product and they should all disintegrate within 3 minutes If there is a small amount that cannot pass through the sieve, but has been softened into a light float and has no hard core, it meets the requirements, the same below.
  • the data shows that the purpose of this test is to screen out the optimal disintegrant, and only evaluate the dispersion uniformity, without examining the content and dissolution rate.
  • the order of dispersion effect is crospovidone > sodium carboxymethyl starch > cross-linked Sodium methylcellulose has verified the initial conjecture. Therefore, other factors in this patent are investigated with crospovidone with better disintegration effect.
  • the next step is to investigate the effect of different crospovidone amounts on the basis of prescription 3. influences.
  • crospovidone Although crospovidone has the best disintegration effect on tablets, too much crospovidone may adsorb the main drug and affect the dissolution rate, and too little disintegration effect is not obvious.
  • crospovidone The optimal range of ketones, based on prescription 3, selected cross-linked povidone accounted for 6.18%, 8.8% and 11.5% of the prescription volume.
  • the impact on the basic items of the tablet, the process adopts wet granulation, and the composition of the prescription is shown in Table 4 .
  • Prescription 4-6 uses the following process:
  • the above-mentioned obtained material is added in the high-shear wet granulator, and microcrystalline cellulose and polyvinylpolypyrrolidone are added and mixed for 3 minutes, the rotating speed of the stirring paddle is 150 rpm, and the rotating speed of the cutting pulp is 300 rpm;
  • wet granules are wet sized, the sized sieve is 6350 ⁇ m, and the rotating speed is 1750 rpm;
  • the wet granules in step 6 are dried in a fluidized bed, the fan frequency is set to 20HZ, the material temperature is 50°C, and the moisture content is controlled ⁇ 3.0%;
  • Table 5 summarizes the evaluation results of the basic items in the prescription in Table 4.
  • the dispersion uniformity after scale-up (for example, 10,000-piece process) will be slower than the small-scale test data, which may be higher than the 3 minutes of the Pharmacopoeia standard.
  • the internal control standard for dispersion uniformity is set to be less than 90 seconds. Simply increasing the amount of disintegrant does not significantly improve the dispersion uniformity of rivaroxaban.
  • the next step is to optimize the process on the basis of prescription 4, see examples 3.
  • Example 2 all the binders were added (dissolved in water for granulation) and the dispersion uniformity was close to 2 minutes. This may be due to excessive granulation and increased hardness of the material, resulting in slower dispersion uniformity.
  • two additional process changes were selected. ; Process change 1: half of the adhesive is added and half is added internally (internal addition means that only half of the adhesive is added to water to prepare the adhesive liquid, and the remaining half is directly dry mixed with other internal phase components), process change 2: All the binders are added internally, directly add water to granulate, and the formula 4 with the cross-linked povidone amount in the middle value in Example 2 is selected as the model formula for research, and the formula composition is shown in Table 6.
  • Prescription 7 uses half of the hypromellose internally plus half of it externally, and prescription 8 uses all hypromellose internally, and the rest of the steps are the same as the process descriptions of prescriptions 4-6.
  • Table 7 summarizes the evaluation results of the basic items in the prescription in Table 6
  • Example 3 The granulation of half of the binder hypromellose plus half of the inside has good dispersion uniformity and content. Because of the low solubility of rivaroxaban, the amount of the binder can significantly increase the solubility of rivaroxaban , but too much binder will lead to slow disintegration of the tablet, and the dissolution rate may also be reduced, and the maximum size of the FDA-listed tablet is 20mg. In order to fully reflect the influence of different binder amounts on the dispersion uniformity, we choose a size of 20mg For investigation, Table 8 examines the influence of binder hypromellose E50%, 1%, 2% and 3.5%.
  • Table 9 summarizes the basic item evaluation results of the prescription in Table 8.
  • Microcrystalline cellulose is a plastic auxiliary material, and lactose monohydrate is a brittle auxiliary material. The optimal combination of the two often has good dispersion effect and compressibility.
  • Table 10 examines that microcrystalline cellulose/lactose monohydrate is about 1.96:1, 1.54 :1, 1:1 and 1:1.54 the impact on the basic items of the tablet, in which prescription 13 added part of microcrystalline in the external phase, prescription 14 added part of microcrystalline cellulose in the external phase and added retention aid colloidal II silicon oxide.
  • Table 11 summarizes the evaluation results of the basic items in the prescription in Table 10
  • prescription 14 can increase the amount of colloidal silicon dioxide and microcrystalline cellulose in the external phase, which can improve the uniformity of dispersion.
  • the ratio of microcrystalline cellulose/lactose monohydrate is greater than 1.54:1, the uniformity of dispersion is less than 60 seconds, so this patent is preferred
  • the ratio of microcrystalline cellulose/lactose monohydrate is 1:1-1.96:1, preferably 1.5-1.8:1.
  • Example 5 concluded that the addition of colloidal silicon dioxide to the external phase of the prescription has a positive effect on the dispersion effect of the tablet, so in this test we investigated the impact of the internal phase adding 0%, 0.5% and 1.0% on the basic items of the tablet, The composition of the prescription is shown in Table 12.
  • the prescription composition of table 12 different colloidal silicon dioxide amounts
  • Table 13 summarizes the evaluation results of the basic items in the prescription in Table 12
  • the original research prescription has no colloidal silica as a retention agent.
  • the test results show that: with the addition of 1.0% or no colloidal silica in the internal phase, the tablets disintegrate within 90 seconds, and the dissolution rate of 30 minutes All are greater than 85%, but adding 1.0% silicon dioxide has the best dispersion effect. Since the conventional content of externally added content is 0.5%-1.5%, the total amount of colloidal silicon dioxide in this patent is preferably 0.5%-3%.
  • the lubricant used in the original research prescription is magnesium stearate, magnesium stearate is a hydrophobic lubricant, and sodium stearyl fumarate is a hydrophilic lubricant.
  • magnesium stearate is a hydrophobic lubricant
  • sodium stearyl fumarate is a hydrophilic lubricant.
  • two types were investigated. The influence of different lubricants on rivaroxaban dispersible tablets was selected, and the lubricant with better dispersion effect was selected, and the influence of different amounts was investigated.
  • the composition of the prescription is shown in Table 14.
  • Table 15 summarizes the basic item evaluation results in the example 7 prescription
  • the dispersion uniformity of magnesium stearate prescription is obviously slower than that of sodium stearyl fumarate prescription, 1.3%-2.2% sodium stearyl fumarate has no difference in dispersion uniformity, and the dissolution rate of 30min meets the requirements, which is preferred
  • the amount of sodium stearyl fumarate is 1.3%-2.2%. It is preliminarily determined that prescription 7 is the optimal prescription, and the next step is to enlarge prescription 7, and the batch is 10,000 tablets/batch.
  • Example 8 investigates the impact of 10,000 scale-ups on tablets
  • Prescription 7 was changed to another prescription 23, and the screening process was simplified.
  • the adhesive is miscible with water, and then sprayed into the internal addition granules; for internal addition, the adhesive is directly mixed with other internal additions.
  • the content of colloidal silicon dioxide becomes 0.5-2%, preferably 0.5-1%, and preferably the prescription does not contain the prescription of adding silicon dioxide.
  • Table 17 summarizes the evaluation results of the basic items in the prescription in Table 16
  • the final forming process is as follows:
  • the material obtained above is added in the high-shear wet granulator, and microcrystalline cellulose and polyvinylpolypyrrolidone are added and mixed for 5 minutes, the stirring blade rotating speed is 150 rpm, and the cutting pulp rotating speed is 300 rpm;
  • wet granules are wet sized, the sized sieve is 6350 ⁇ m, and the rotating speed is 1750 rpm;
  • the wet granules in step 6 are dried in a fluidized bed, the fan frequency is set to 20HZ, the material temperature is 50°C, and the moisture content is controlled ⁇ 3.0%;
  • composition of prescription 2.5mg, 10mg, 15mg, and 20mg is shown in the table below (the following prescriptions are available for small-scale trials and expanded production)
  • the preparation method is:
  • the material obtained above is added in the high-shear wet granulator, and the internal phase microcrystalline cellulose and crospovidone are added and mixed for 5 minutes, the stirring blade speed is 150rpm, and the cutting pulp speed is 300rpm;
  • wet granules are wet sized, the sized sieve is 6350 ⁇ m, and the rotating speed is 1750 rpm;
  • the wet granules in step 6 are dried in a fluidized bed, the fan frequency is set to 20HZ, the material temperature is 50°C, and the moisture content is controlled ⁇ 3.0%;
  • Example 1 The hypromellose in said Example 1 is replaced by E3, E6, E50, etc., and the preparation method is the same as in Example 1, and corresponding technical effects can also be achieved.
  • Sodium stearyl fumarate in described embodiment 1 is replaced by magnesium stearate, and preparation method is the same as embodiment 1, also can reach corresponding technical effect.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

提供一种含有利伐沙班的药物组合物，其中，包括利伐沙班1.0％-30.0％，羟丙甲纤维素1.0％-8.0％，十二烷基硫酸钠0.1-1％，交联聚维酮5％-15.0％，胶态二氧化硅0.5％-3.0％和润滑剂0.5％-5％，所述润滑剂为硬脂富马酸钠或硬脂酸镁；剩余为填充剂，所述填充剂为微晶纤维素和一水乳糖，采用特殊的湿法制粒工艺，药物组合物具有利伐沙班稳定的快速溶出和快速崩解的特性，另外调整了粘合剂的加入工艺，使得小试和中试的技术效果达到一致，适合工业化生产。

Description

一种含有利伐沙班的药物组合物及其应用 技术领域
本发明属于药物领域，具体涉及含有利伐沙班的药物组合物及其应用。
背景技术
利伐沙班片由拜耳(Bayer)和杨森(Janssen)联合开发，最早于2008年9月30日获欧洲药物管理局(EMA)批准上市，2011年7月1日获FDA批准在美国上市，主要用于治疗择期髋关节或膝关节置换手术成年患者，以预防静脉血栓形成(VTE)。在国内，利伐沙班片在2009年3月获国家药监局批准上市，同年顺利纳入2009年国家医保目录，XARELTO是速释片。目前没有可商购的利伐沙班的液体制剂，因此，对于儿科患者和不能吞咽片剂的患者(例如需要通过药物治疗的重症患者)，经常需要药剂师使用利伐沙班片研碎来配制液体制剂经胃管或鼻饲管给药，因此急需一种在水中快速分散的剂型，优选分散片，分散片相对于混悬剂更加稳定，便于携带，生产成本低，且不容易产生用药错误。
而限于利伐沙班原料药的特点，即低溶解度，在药品片剂研发时，不同生产厂家采用不同的研究策略：
1、美国XARELTO原研专利US9415053B PCT至中国专利CN1886120B公开了一种流化床湿法制粒工艺，将羟丙甲纤维素和十二烷基硫酸钠溶解在水中，利伐沙班分散在上述溶液中，形成一个混悬的制粒液，喷在微晶纤维素、一水乳糖和交联羧甲基纤维素钠上，干燥之后过0.8mm筛网，加硬脂酸镁总混，得到的混合物用6mm的圆形冲模压片，硬度为50N-100N。
所存在的缺点是：流化床制粒，耗时长，且流化床制粒相对高剪切混合制粒难度高，易产生细粉损失，导致含量降低，另一方面，利伐沙班长期分散在溶剂中，可能导致利伐沙班稳定性和晶型的改变,此外，XARELTO崩解时间长，分散均匀性差。
因此，开发利伐沙班分散片需要同时克服以下技术难点：
1)快速溶出；2)良好的分散均匀性。
为实现目的1)，必须将原料药利伐沙班和润湿剂、亲水性填充剂或低粘度的羟丙甲充分混合，提高利伐沙班的溶解度，从而达到快速释放的效果，例如中国专利CN107773548A公开了一种阿哌沙班片的制备方法，将利伐沙班和一水乳糖以1:2的比例混合后过60目筛2次，用气流粉碎至粒径(D90)小于10μm，改善利伐沙班的溶解度，该方法多次过筛，采用气流粉碎，工艺复杂且较难控制；
中国专利CN105078997A处方中加入2.5％的十二烷基硫酸钠增溶，而一般人体摄入2％的量就可导致腹胀，腹痛，常规用量小于1％，因此这一方法制成的片剂具有副作用大的缺点；
CN105267169B公开了一种利伐沙班速释制剂，尤其是实施例5和6，虽然采用湿法制粒工艺，但工艺中，将羟丙甲纤维素全部溶于水制粒，这种方法容易影响崩解时间，且内相加入约4％的胶态二氧化硅，干燥过程中产生大量的细粉，本发明人在工艺研发过程发现，这会显著影响中间颗粒和片剂的含量，因此，这种工艺常常会引起含量降低和崩解时间的延长，所以不适合分散片的开发。
中国专利CN104337787B，和CN105232488A公开了一种利伐沙班速释制剂，均采用湿法制粒工艺，且均是将原料药分散或者溶解在溶剂中，而后制粒，其目的是提高利伐沙班的溶解度，但是利伐沙班具有不稳定的酰胺基，长时间存在溶剂中可能会导致水解，影响稳定性。
中国专利CN104721142B，CN101321517B公开了一种新型制粒工艺，采用熔融的方法，制备无定型的利伐沙班，从而提高其溶解度，因熔融的方法需要高温，一般需要大于100℃，对利伐沙班的稳定性有潜在的影响，且耗能大，成本高。
综上所述，目前市场或现有技术中没有一种利伐沙班的分散片，究其原因，是因为利伐沙班本身具有难溶于水的特性，无法兼备分散均匀度好和溶出度高两大特点，且小试的结果和中试容易出现不一致的结果，因此必须和各种辅料进行配合，且需要和合适制备工艺进行结合才能得到合适的分散片。
发明内容
本发明的目的在于提供一种含有利伐沙班的药物组合物，优选分散片，便于携带，制备工艺简单，溶出度高且在水中快速分散，制备工艺中利伐沙班不需要分散在溶剂中或者 熔融制粒。
一种含有利伐沙班的药物组合物，包括以下成分：按照重量百分比，包括利伐沙班1.0％-30.0％，羟丙甲纤维素1.0％-8.0％，十二烷基硫酸钠0.1-1％，交联聚维酮5％-15.0％，胶态二氧化硅0.5％-3.0％和润滑剂0.5％-5％，所述润滑剂为硬脂富马酸钠或硬脂酸镁；剩余为填充剂，所述填充剂为微晶纤维素和一水乳糖。
本发明中羟丙甲纤维素为粘合剂，能够防止制备过程中物料不均匀，造成中间体和成品检测结果含量的降低。
微晶纤维素和乳糖(或一水乳糖)属于填充剂，对于片剂的硬度和分散具有直接的影响。
交联聚维酮为崩解剂，有助于产品的崩解，这是经过崩解剂种类筛选后的优选崩解剂，有利于后期快速分散的特点。
胶态二氧化硅的作用为助流作用，同时有利于分散片崩解速度，但其处方量和加入方式也会影响到后期的片剂含量、崩解时间和溶出。(这是本片剂开发过程中首次发现的技术优点和注意项。)
润滑剂包括硬脂富马酸钠或硬脂酸镁。其中优选硬脂富马酸钠(见研发部分)。
进一步地，本发明提供了一种药物组合物，其中，包括以下成分：按照重量百分比，包括利伐沙班1.5％-25.0％，羟丙甲纤维素1.0％-5.0％，十二烷基硫酸钠0.2-0.8％，交联聚维酮6.0％-12.0％，胶态二氧化硅0.6％-2.0％和硬脂富马酸钠1.0％-3.0％，剩余为填充剂，所述填充剂为微晶纤维素和一水乳糖。
进一步地，本发明提供了一种药物组合物，其中，包括以下成分：按照重量百分比，包括利伐沙班1.8％-22.0％，羟丙甲纤维素1.5％-3.5％，十二烷基硫酸钠0.2-0.8％，交联聚维酮6.0％-12％，胶态二氧化硅0.7％-1.5％和硬脂富马酸钠1.1％-2.5％，剩余为填充剂，所述填充剂为微晶纤维素和一水乳糖。
进一步地，本发明提供了一种药物组合物，其中，包括以下成分：按照重量百分比，包括利伐沙班2.0％-18.0％，羟丙甲纤维素2.0％-3.0％，十二烷基硫酸钠0.2-0.6％，交联聚维酮6.0％-10.0％，胶态二氧化硅0.8-1.2％和硬脂富马酸钠1.3％-2.2％，；剩余为填充剂，所述填充剂为微晶纤维素和一水乳糖。
在上述药物组合物中所述微晶纤维素和乳糖，微晶纤维素和乳糖的重量比例为1:1-2:1，优选1.5:1-1.8:1，优选1.60:1。
进一步地，本发明提供了一种药物组合物，其中，包括以下成分：按照重量百分比，包括利伐沙班2.2％-18.0％，羟丙甲纤维素2.7％，十二烷基硫酸钠0.4％，交联聚维酮8.8％，胶态二氧化硅1.0％和硬脂富马酸钠1.8％，剩余为填充剂，所述填充剂为微晶纤维素和一水乳糖，微晶纤维素：一水乳糖的比例为1.5-1.7:1，包括了实施例1的所有处方。
上述药物组合物优选分散片，剂量范围优选2.5mg-20mg/片，可以根据片剂的变化，调整填充剂的量。
所述药物组合物为内加和外加结构，内加为利伐沙班、羟丙甲基纤维素、十二烷基硫酸钠、70-95％处方量的微晶纤维素、一水乳糖和交联聚维酮，外加为剩余微晶纤维素、胶态二氧化硅和润滑剂。
这是本发明的发明人根据利伐沙班的特性，即其水难溶性，需要控制其硬度、崩解速度和溶出度以及中间控制时，中间体含量各个参数时的处方优化。(具体见研究部分)。
小试结果显示，内相加入少量的胶态二氧化硅，有助于分散均匀性的提高，但通过小试(1000片)到扩大生产(10000片)的放大，发明人发现内加的胶态二氧化硅容易导致中间体的含量降低，所以选择降低或不加胶态二氧化硅，外加的二氧化硅可以不变或做适当调整。
针对上述的内加和外加结构，发明人开发了一种湿法制粒的制备方法，所述制备方法由以下步骤组成：
(1)、称取处方量1/4-1/2羟丙甲纤维素和十二烷基硫酸钠溶解到内加物质总重量的30-50％水中，形成澄清制粒液，备用；
(2)、称取处方量的利伐沙班、一水乳糖和剩余的羟丙甲纤维素混合；
(3)、将步骤(2)得到的混合物经comil过筛；
(4)、将步骤(3)得到的混合物与70％-95％质量的微晶纤维素和交联聚维酮混合制粒；
(5)、将步骤(1)中制粒液喷在上述混合物，湿整粒，干燥，干整粒，加入润滑剂、剩余微晶纤维素、胶态二氧化硅总混，测定中间体含量，压片，即得所述药物组合物。
申请人发现，在高剪切湿法制粒过程中，所需的水量远远小于流化床制粒所需的水量，如果粘合剂全部加入水中，制粒液会粘度很高，无法进行制粒；如果粘合剂不加入水中，则制粒效果不好，容易引起产品含量的损失。必须将一部分粘合剂加入水中，制成制粒液，剩余部分与其他内加成分一起加入到制粒机中进行混合，才能制备得到符合药典规定的药 品，这也是本发明中在制备工艺上的创新点。
其中加入水中的羟丙甲基纤维素量为其处方量的1/4-1/2。
其中制备的片剂硬度优选为40±5N。
其中更具体地，所述含有利伐沙班的药物组合物通过下述方法制备：
(1)、称取处方量1/4-1/2羟丙甲纤维素E5和十二烷基硫酸钠溶解内相颗粒30％-50％
水中，形成澄清制粒液，备用；
(2)、称取处方量的利伐沙班，一水乳糖和剩余的羟丙甲纤维素E5在混合料斗机混合22min，转速14rpm；
(3)、上述混合物经comil过筛，筛孔1016μm，转速1750-3000rpm；
(4)、上述得到的物料加入高剪切湿法制粒机中，并加入内加量的微晶纤维素和交联聚维酮混合3-8min，搅拌桨转速120-400rpm，切割浆转速300-600rpm；
(5)、将1中制粒液喷在上述混合物中，3-8分钟内加完，并继续粘合0.5-1.5min；
(6)、将上述的湿颗粒进行湿整粒，整粒筛孔6350μm，转速1750rpm；
(7)、将步骤6中湿颗粒在流化床中干燥，风机频率设为20-40HZ，物料温度为40-60℃，控制水份＜3.0％；
(8)、将步骤7的干颗粒进行干整粒，整粒筛孔1016μm-1575μm，转速1750-4000转；
(9)、称取外相所有的量并全部通过40-60目筛，和步骤8得到的混合物进行总混，转速14rpm，混合5-14min；
(10)、根据中间体含量采用6mm的圆形冲模进行压片，平均硬度控制在40±5N。
所述每片中利伐沙班的剂量规格为2.5mg，10mg，15mg和20mg/片。
在上述药物组合物中其中，所述羟丙甲纤维素为羟丙甲纤维素E3，羟丙甲纤维素E5，羟丙甲纤维素E6，羟丙甲纤维素E15，羟丙甲纤维素E50的一种或多种，优选羟丙甲纤维素E5。
本发明具有以下有益效果：
1、采用本发明的方法制备的利伐沙班分散片具有崩解快、溶出度高的优点。
2、采用本发明的方法制备的利伐沙班分散片服用方便，既可以作为普通片服用，又可放入水中迅速分散后服用，大大提高了临床用药的顺应性。
3、采用本发明的方法制备的利伐沙班分散片工艺简单，不需要将利伐沙班分散或者溶解在溶液中，改善利伐沙班潜在的稳定性。
发明人所检索到的最接近的技术文献为：XARELTO原研专利CN1886120B，其实例中列出原研利伐沙班速释片的处方组成，见表1，
表1 XARELTO原研处方组成
Figure PCTCN2021108796-appb-000001
原研工艺：将羟丙甲纤维素和十二烷基硫酸钠溶解在水中，利伐沙班分散在上述溶液中，形成一个混悬的制粒液，在流化床中喷在微晶纤维素、一水乳糖和交联羧甲基纤维素上，干燥之后过0.8mm筛网，加硬脂酸镁总混，得到的混合物用6mm的圆形冲模压片，硬度为50N-100N。(与本发明的差异在于，这一处方不适合作为分散片，结果达不到分散片的要求崩解时间超过3min，因此对于分散片的开发不具有参考性)
具体实施方式
本发明适宜的处方均经过10000片产品的验证，发现小试的结果，例如分散均匀度和溶出度会在扩大生产时出现较大浮动，这也是分散片剂开发中常见又个例的情况，基于中试分散均匀度为3min(比崩解时间更严格，原因在于利伐沙班本身的溶解度低，崩解时间采用2mm筛网，而分散均匀度采用710μm筛网，所以单独崩解时间快，不能反映分散片的分散均匀度，甚至达不到分散均匀度的药典要求)为限，则小试需要控制在90s以内，基于个体处方的不同，扩大生产可能还需要调整其他辅料的含量。
研究部分：
在这些实施例中，利伐沙班由浙江苏泊尔供应，D90＜35μm；交联聚维酮由BASF供应，型号为KollidonCL-F；交联羧甲基纤维素钠(VIVASOL)，羧甲基淀粉钠(VIVASTAR  P)和硬脂富马酸钠(PRUV)由JRS供应，羟丙甲纤维素由卡乐康供应，微晶纤维素由FMC供应，型号为PH101，一水乳糖由MEGGLE供应，型号为GranuLac 200；十二烷基硫酸钠由BASF供应，型号为Kolliphor SLS Fine；胶态二氧化硅由EVONIK供应，型号为AEROSIL200 Pharma；硬脂酸镁由FACI供应，型号为Eur Phar。
崩解剂的类型直接影响片剂的崩解时间和分散状态，根据ASHLAND内部培训可知，交联羧甲基纤维素钠和羧甲基淀粉钠在崩解的过程中会凝胶化影响分散均匀性，交联聚维酮不会产生凝胶化，在现有的分散剂(例如交联羧甲基纤维素钠或羧甲基淀粉钠)中，具有最好的分散均匀性；为了达到最优的分散均匀性，我们还将疏水性润滑剂硬脂酸镁切换成亲水性的硬脂富马酸钠，并将处方内相和外相同时加入少量的胶态二氧化硅，形成初步的目标处方1(10mg/片剂)，下一步验证交联聚维酮相比其它崩解剂是否具有最优的分散均匀性，见实例1。微晶纤维素具有良好吸水特征和可压性能，但是微晶纤维素全部放入内相制粒，其崩解和可压性能降低，全部放入外相可压性能增强，吸水性能较弱，为了达到良好的可压性和吸水特性，我们将约总片重的10％的微晶放入外相，其余放入内相制粒。
实例1-不同的崩解剂种类
根据药品研发常用崩解剂的类型，选择了交联羧甲基纤维素钠，羧甲基淀粉钠和交联聚维酮进行同步研究，因该实验仅仅考察分散均匀性，为了节约资源，我们采用直混工艺，处方组成见表2
表2不同崩解剂类型处方组成
Figure PCTCN2021108796-appb-000002
Figure PCTCN2021108796-appb-000003
直混工艺如下：
A)称取批量的内相辅料过40目，在干净的自封袋中混合4min；
B)称取批量的外相辅料过40目在A步骤的自封袋中，混合1min；
C)用6mm圆冲按照理论片重压片，考察各参数。
表3概括了表2处方中基本项目评价结果
Figure PCTCN2021108796-appb-000004
a：照中国药典2020版，崩解时限检查法(通则0921)检查，不锈钢丝网的筛孔内径为710μm，水温为15-25℃，取供试品6片，应在3分钟内全部崩解并通过筛网，如有少量不能通过筛网，但已软化成轻质上漂且无硬心者，符合要求，下同。
b：采用进口注册标准JX20160225的方法，pH4.5醋酸盐缓冲液加0.4％SLS，900ml溶出介质，转速75转/min，经30min取样测溶出度，下同。
无特别声明，本专利分散均匀性和溶出度检查均按照a，b方法检测。
数据显示：本次试验的目的是筛选出最优的崩解剂，仅评价分散均匀性，未考察含量和溶出度，分散效果依次为交联聚维酮＞羧甲基淀粉钠＞交联羧甲基纤维素钠，验证了初始的猜想，因此本专利其它因素考察均采用崩解效果较好的交联聚维酮，下一步在处方3的基础上，考察不同交联聚维酮量的影响。
实例2不同交联聚维酮量的评估
交联聚维酮虽然对片剂的崩解效果最优，但过多的交联聚维酮可能会吸附主药，影响溶出度，太少崩解效果不明显，为了筛选出交联聚维酮最佳的范围，处方3的基础上，选择了交联聚维酮占处方量的6.18％，8.8％和11.5％对片剂基本项目的影响，工艺采用湿法制粒，处方组成见表4。
表4不同交联聚维酮量的处方组成
Figure PCTCN2021108796-appb-000005
处方4-6采用工艺如下：
(1)称取处方量的羟丙甲纤维素E5和十二烷基硫酸钠溶解内相颗粒总重40％水中，形成澄清制粒液，备用；
(2)、称取处方量的利伐沙班，一水乳糖和胶态二氧化硅在混合料斗机混合22min，转速14rpm；
(3)、上述混合物经comil混合，筛孔1016μm，转速1750rpm；
(4)、上述得到的物料加入高剪切湿法制粒机中，并加入微晶纤维素和交联聚维酮混合3min，搅拌桨转速150rpm，切割浆转速300rpm；
(5)、将1中制粒液喷在上述混合物中，5分钟内加完，并继续粘合1min；
(6)、将上述的湿颗粒进行湿整粒，整粒筛孔6350μm，转速1750rpm；
(7)、将步骤6中湿颗粒在流化床中干燥，风机频率设为20HZ，物料温度为50℃，控制水分＜3.0％；
(8)、将步骤7的干颗粒进行干整粒，整粒筛孔1016μm，转速2996转；
(9)、称取外相的量并全部通过40目筛，和步骤8得到的混合物进行总混，转速14rpm，混合8min；
(10)、根据中间体含量采用6mm的圆形冲模进行压片，平均硬度控制在40±5N。
表5概括了表4处方中基本项目评价结果
Figure PCTCN2021108796-appb-000006
数据显示：将粘合剂全部外加(溶于水制粒)崩解剂交联聚维酮范围在6.18％-11.5％的分散均匀性均相似，但分散均匀性均约在2分钟，根据经验放大(例如10000片工艺)后的分散均匀性相比小试数据会更慢，可能会高于药典标准的3分钟，为了保证放大后有更宽的调整空间，降低放大风险，我们将小试的分散均匀性内控标准定为小于90秒，因单纯的增加崩解剂的量并没有显著提高利伐沙班的分散均匀性，下一步在处方4的基础上，进行工艺的优化，见实例3。
实例3工艺优化
实例2中将粘合剂全部外加(溶于水制粒)分散均匀性接近2分钟，可能是因为制粒过度，物料硬度增加导致的分散均匀性变慢，本次试验选择额外2种工艺变化；工艺变化1：粘合剂一半外加一半内加(内加的意思是，只有一半粘合剂加入水中，制备粘合剂液，剩下一半直接与其他内相成分直接干混合)，工艺变化2：粘合剂全部内加，直接加水制粒，选择实例2中交联聚维酮量为中间值的处方4为模型处方进行研究，处方组成见表6。
表6不同工艺的处方组成
Figure PCTCN2021108796-appb-000007
Figure PCTCN2021108796-appb-000008
处方7采用羟丙甲纤维素一半内加一半外加，处方8采用羟丙甲纤维素全部内加，剩余步骤同处方4-6工艺描述。
表7概括了表6处方中基本项目评价结果
Figure PCTCN2021108796-appb-000009
数据显示：惊讶的发现，粘合剂羟丙甲纤维素一半外加一半内加相对于粘合剂全部外加，可显著提高片剂的分散均匀性(33秒VS.114秒)
且粘合剂羟丙甲纤维素一半外加一半内加相对于粘合剂全部内加制粒，可显著提高片剂的含量(99.4％VS.93.7％)，初步确定处方7为最优工艺下的处方。
实例4-不同粘合剂量的评估
在解决了工艺带来的不稳定因素后，发明人进一步调整其他成分。
实例3粘合剂羟丙甲纤维素一半外加一半内加制粒具有良好的分散均匀性和含量，因利伐沙班低溶解的特点，粘合剂的量可显著增加利伐沙班的溶解度，但是过多的粘合剂导致片剂崩解慢，溶出度也可能降低，且FDA上市片剂最大规格为20mg，为了充分体现不同粘合剂量对分散均匀性的影响，我们选择规格为20mg进行考察，表8考察了粘合剂羟丙甲纤维素E50％，1％，2％和3.5％的影响。
表8不同粘合剂的量处方组成
Figure PCTCN2021108796-appb-000010
参照实例3处方7的工艺，处方10将粘合剂0.75份外加，0.25份内加，处方11将0.75份外加，1.25份内加，处方12将0.75份外加，2.75份内加。
表9概括表8处方的基本项目评价结果
Figure PCTCN2021108796-appb-000011
结果显示：处方中无粘合剂时，分散均匀性最快，但是溶出度很慢，粘合剂为1％时，30min的溶出度为94％，含量略低，将粘合剂增至2％时，30min的溶出度明显增加，将粘合剂增至3.5％时，对于20mg规格分散均匀性为86秒小于90秒，因此粘合剂的量控制在1％-3.5％。
实例5-微晶纤维素/一水乳糖不同比例的评估
微晶纤维素是塑性辅料，一水乳糖是脆性辅料，两者最优结合往往具有良好的分散效 果和可压性，表10考察了微晶纤维素/一水乳糖约为1.96:1，1.54:1，1:1和1:1.54对片剂基本项目的影响，其中处方13在外相额外加入部分微晶，处方14在外相额外加入部分微晶纤维素的同时加入了助留剂胶态二氧化硅。
表10微晶纤维素/一水乳糖不同比例处方组成
Figure PCTCN2021108796-appb-000012
参照实例3处方7的工艺。
表11概括了表10处方中基本项目评价结果
Figure PCTCN2021108796-appb-000013
NA：未检测，下同
结果显示：处方14相对于处方13和处方15可知，外相增加胶态二氧化硅和微晶纤维素的量可提高分散均匀性，微晶纤维素/一水乳糖越小，分散均匀性越慢，微晶纤维素/一水乳糖的比例为1.54:1时分散均匀性为64秒，微晶纤维素/一水乳糖的比例为1:1时分散均匀性为83秒，微晶纤维素/一水乳糖的比例为1:1.54时分散均匀性为103秒，大于内 控90秒，微晶纤维素/一水乳糖的比例为大于1.54:1时，分散均匀性小于60秒，因此本专利优选微晶纤维素/一水乳糖的比例为1:1-1.96:1，优选1.5-1.8:1。
实例6-不同胶态二氧化硅量的考察
实例5得到结论，处方中外相加入胶态二氧化硅对片剂的分散效果具有正作用，因此本次试验我们考察了内相加入0％，0.5％和1.0％对片剂基本项目的影响，处方组成见表12。
表12不同胶态二氧化硅量的处方组成
Figure PCTCN2021108796-appb-000014
参照实例3处方7的工艺进行制备。
表13概括了表12处方中基本项目评价结果
Figure PCTCN2021108796-appb-000015
从原研处方可知，原研处方组成无助留剂胶态二氧化硅，试验结果显示：内相加入1.0％或不加胶态二氧化硅，片剂均在90秒内崩解，30min的溶出度均大于85％，但内加1.0％ 的二氧化硅分散效果最好，由于外加含量常规含量为0.5％-1.5％，本专利胶态二氧化硅总量优选0.5％-3％。
实例7-不同润滑剂种类和量的考察
原研处方采用的润滑剂是硬脂酸镁，硬脂酸镁是疏水性润滑剂，硬脂富马酸钠是亲水性润滑剂，为了达到最优的片剂分散效果，考察了两种类型的润滑剂对利伐沙班分散片的影响，同时选择分散效果较好的润滑剂，考察了不同量的影响，处方组成见表14。
表14不同润滑剂种类和量的处方组成
Figure PCTCN2021108796-appb-000016
参照实例3处方7的工艺
表15概括了实例7处方中基本项目评价结果
Figure PCTCN2021108796-appb-000017
结果分析：硬脂酸镁处方分散均匀性明显慢于硬脂富马酸钠处方，1.3％-2.2％的硬脂 富马酸钠，分散均匀性无区别，30min的溶出度均满足要求，优选硬脂富马酸钠的量为1.3％-2.2％。初步确定处方7为最优处方，下一步对处方7进行放大，批量为10000片/批。
实例8考察10000片放大对片剂的影响
10000片放大工艺验证发现，10mg/片剂，等比例扩大了二氧化硅的含量，会影响到利伐沙班在片剂中的含量(中间颗粒含量降低到90％左右)，因此，去除内相二氧化硅，调整粘合剂的含量，发现扩大生产产品符合了药典要求。见表16。
处方7改为另外一种处方23，筛选过程简化。
表16 10000片放大后组成
Figure PCTCN2021108796-appb-000018
注：外加即将粘合剂与水混溶后，喷入内加颗粒中，内加即将粘合剂直接与其他内加组分混合。
由此，胶态二氧化硅的含量就变为0.5-2％，优选0.5-1％，优选处方中不含有内加二氧化硅的处方。
参照实例7的工艺
关键步骤的含量数据如下表
惊讶的发现内相去掉二氧化硅，并增加粘合剂的量(见处方23)可显著提高中间体中利伐沙班含量，避免主药和辅料不均匀的损失，我们将处方23压成片剂，考察片剂的基本项目，如下表
表17概括了表16处方中基本项目评价结果
  处方23
是否粘冲 否
外观 光洁
可压性 好
分散均匀性 55秒
30min溶出度 100.4％
在研发中：外加7.5g羟丙甲纤维素E5溶于水制粒，内加12.5-22.5g，(发明人注，之所以不是调整外加的量，是因为制粒液所需水的量不宜太多，所以配置的制粒液浓度需要稳定在一定限度，所以发明人选择调整内加量)分散均匀性均小于60秒，30min溶出度均达到85％以上，因粘合剂的增加可显著改善片剂的含量，为降低更大批量的风险，选择外加7.5g内加22.5g的处方为最优处方，因此确定处方23为最终处方，后期注册批26万片均可完美的重现。
最终形成的工艺如下：
(1)、称取处方量1/4羟丙甲纤维素E5和十二烷基硫酸钠溶解内相颗粒总质量的40％水中，形成澄清制粒液，备用；
(2)、称取处方量的利伐沙班，一水乳糖和剩余3/4的羟丙甲纤维素E5在混合料斗机混合22min，转速14rpm；
(3)、上述混合物经comil混合，筛孔1016μm，转速1750rpm；
(4)、上述得到的物料加入高剪切湿法制粒机中，并加入微晶纤维素和交联聚维酮混合5min，搅拌桨转速150rpm，切割浆转速300rpm；
(5)、将1中制粒液喷在上述混合物中，5分钟内加完，并继续粘合1min；
(6)、将上述的湿颗粒进行湿整粒，整粒筛孔6350μm，转速1750rpm；
(7)、将步骤6中湿颗粒在流化床中干燥，风机频率设为20HZ，物料温度为50℃，控制水份＜3.0％；
(8)、将步骤7的干颗粒进行干整粒，整粒筛孔1016μm，转速2996转；
(9)、将外相辅料过40-60目筛，和步骤8得到的混合物进行总混，转速14rpm，混合8min；
(10)、根据中间体含量采用6mm的圆形冲模进行压片，平均硬度控制在40±5N
以上所述仅是本发明的优选实施方式，应该指出，对于本技术领域的普通技术人员说，在不脱离本发明原理的前提下，还可做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
实施例1：
处方2.5mg，10mg，15mg，20mg组成见下表(下列处方小试和扩大生产均可以)
Figure PCTCN2021108796-appb-000019
制备方法为：
(1)、称取处方量1/4羟丙甲纤维素E5和十二烷基硫酸钠溶解内相颗粒总质量的40％水中，形成澄清制粒液，备用；
(2)、称取处方量的利伐沙班，一水乳糖和剩余3/4的羟丙甲纤维素E5在混合料斗机混合22min，转速14rpm；
(3)、上述混合物经comil混合，筛孔1016μm，转速1750rpm；
(4)、上述得到的物料加入高剪切湿法制粒机中，并加入内相微晶纤维素和交联聚维酮混合5min，搅拌桨转速150rpm，切割浆转速300rpm；
(5)、将1中制粒液喷在上述混合物中，5分钟内加完，并继续粘合1min；
(6)、将上述的湿颗粒进行湿整粒，整粒筛孔6350μm，转速1750rpm；
(7)、将步骤6中湿颗粒在流化床中干燥，风机频率设为20HZ，物料温度为50℃，控制水份＜3.0％；
(8)、将步骤7的干颗粒进行干整粒，整粒筛孔1016μm，转速2996转；
(9)、将外相辅料过40-60目筛，和步骤8得到的混合物进行总混，转速14rpm，混合8min；
(10)、根据中间体含量采用6mm的圆形冲模进行压片，平均硬度控制在40±5N。
实施例2
所述实施例1中的羟丙甲纤维素更换为E3、E6、E50等，制备方法同实施例1，也能达到相应的技术效果。
实施例3
所述实施例1中的硬脂富马酸钠更换为硬脂酸镁，制备方法同实施例1，也能达到相应的技术效果。

Claims (11)

  1. 一种含有利伐沙班的药物组合物，其特征在于，包括以下成分：按照重量百分比，包括利伐沙班1.0％-30.0％，羟丙甲纤维素1.0％-8.0％，十二烷基硫酸钠0.1-1％，交联聚维酮5％-15.0％，胶态二氧化硅0.5％-3.0％和润滑剂0.5％-5％，所述润滑剂为硬脂富马酸钠或硬脂酸镁；剩余为填充剂，所述填充剂为微晶纤维素和一水乳糖。
  2. 根据权利要求1所述的药物组合物，其特征在于，包括以下成分：按照重量百分比，包括利伐沙班1.5％-25.0％，羟丙甲纤维素1.0％-5.0％，十二烷基硫酸钠0.2-0.8％，交联聚维酮6.0％-12.0％，胶态二氧化硅0.6％-2.0％和硬脂富马酸钠1.0％-3.0％，剩余为填充剂，所述填充剂为微晶纤维素和一水乳糖。
  3. 根据权利要求2所述的药物组合物，其特征在于，包括以下成分：按照重量百分比，包括利伐沙班1.8％-22.0％，羟丙甲纤维素1.5％-3.5％，十二烷基硫酸钠0.2-0.8％，交联聚维酮6.0％-12％，胶态二氧化硅0.7％-1.5％和硬脂富马酸钠1.1％-2.5％，剩余为填充剂，所述填充剂为微晶纤维素和一水乳糖。
  4. 根据权利要求3所述的药物组合物，其特征在于，包括以下成分：按照重量百分比，包括利伐沙班2.0％-18.0％，羟丙甲纤维素2.0％-3.0％，十二烷基硫酸钠0.2-0.6％，交联聚维酮6.0％-10.0％，胶态二氧化硅0.8-1.2％和硬脂富马酸钠1.3％-2.2％，；剩余为填充剂，所述填充剂为微晶纤维素和一水乳糖。
  5. 根据权利要求1-4任一项所述的药物组合物，其特征在于，所述药物组合物为分散片，剂量范围为2.5mg-20mg/片。
  6. 根据权利要求1所述的药物组合物，其特征在于，所述药物组合物为内加和外加结构，内加为利伐沙班、羟丙甲基纤维素、十二烷基硫酸钠、70-95％处方量的微晶纤维素、一水乳糖和交联聚维酮，外加为剩余微晶纤维素、胶态二氧化硅和润滑剂。
  7. 根据权利要求6所述的药物组合物，其特征在于，所述微晶纤维素与一水乳糖重量比例为1:1-2:1，优选1.5-1.8：1。
  8. 根据权利要求1所述的药物组合物，其特征在于，所述药物组合物由以下方法制得：
    (1)、称取处方量1/4-1/2羟丙甲纤维素和十二烷基硫酸钠溶解到内加物质总重量的30-50％水中，形成澄清制粒液，备用；
    (2)、称取处方量的利伐沙班、一水乳糖和剩余的羟丙甲纤维素混合；
    (3)、将步骤(2)得到的混合物经comil过筛；
    (4)、将步骤(3)得到的混合物与70-95％处方量的微晶纤维素和全部交联聚维酮混合制粒；
    (5)、将步骤(1)中制粒液喷在上述混合物，湿整粒，干燥，干整粒，加入润滑剂、剩余微晶纤维素、胶态二氧化硅总混，测定中间体含量，压片，即得所述药物组合物。
  9. 根据权利要求8所述的药物组合物，其特征在于，步骤(1)中羟丙甲基纤维素为处方量的1/4。
  10. 根据权利要求1所述的药物组合物，其特征在于，其中交联聚维酮的粒径为Cl-F级。
  11. 权利要求1所述的药物组合物在制备治疗静脉血栓疾病的药物中的应用。
PCT/CN2021/108796 2021-06-24 2021-07-28 一种含有利伐沙班的药物组合物及其应用 WO2022267169A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110704987.5A CN113425729B (zh) 2021-06-24 2021-06-24 一种含有利伐沙班的药物组合物及其应用
CN202110704987.5 2021-06-24

Publications (1)

Publication Number Publication Date
WO2022267169A1 true WO2022267169A1 (zh) 2022-12-29

Family

ID=77754232

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/108796 WO2022267169A1 (zh) 2021-06-24 2021-07-28 一种含有利伐沙班的药物组合物及其应用

Country Status (3)

Country Link
US (1) US20220409626A1 (zh)
CN (1) CN113425729B (zh)
WO (1) WO2022267169A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114081866A (zh) * 2021-11-08 2022-02-25 则正(上海)生物科技有限公司 一种评价格列吡嗪片体内外相关性方法
CN114767645B (zh) * 2022-04-27 2024-04-05 北京斯利安药业有限公司 叶酸片及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105078997A (zh) * 2014-05-19 2015-11-25 广东东阳光药业有限公司 一种利伐沙班药用组合物及其制备方法
CN106265547A (zh) * 2015-05-12 2017-01-04 北京济美堂医药研究有限公司 一种改进了生产工艺的利伐沙班药物组合物的制备方法
CN107773548A (zh) * 2016-08-30 2018-03-09 重庆植恩药业有限公司 含有利伐沙班的固体组合物及其制备方法
JP2019108324A (ja) * 2017-12-15 2019-07-04 エルメッド株式会社 リバーロキサバン含有医薬組成物
WO2021071444A1 (en) * 2019-10-10 2021-04-15 Santa Farma İlaç Sanayi̇ A.Ş. A unique granulation process for rivaroxaban containing granules

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10355461A1 (de) * 2003-11-27 2005-06-23 Bayer Healthcare Ag Verfahren zur Herstellung einer festen, oral applizierbaren pharmazeutischen Zusammensetzung
CN103550165B (zh) * 2013-10-19 2019-07-16 浙江华海药业股份有限公司 一种含有利伐沙班的药物组合物及其制备方法
WO2015124995A1 (en) * 2014-02-19 2015-08-27 Aurobindo Pharma Ltd Solid dosage forms of rivaroxaban
CN104055743B (zh) * 2014-06-10 2016-01-06 吉林省博大制药有限责任公司 一种含利伐沙班口服制剂的制备方法
CN104042580B (zh) * 2014-06-17 2016-08-24 珠海润都制药股份有限公司 一种缬沙坦分散片及其制备方法
CN105287414A (zh) * 2015-10-21 2016-02-03 南京百迪尔生物医药有限公司 一种含有利伐沙班的固体药物组合物及其制备方法
CN110652499A (zh) * 2018-06-28 2020-01-07 北京万全德众医药生物技术有限公司 缬沙坦口崩片
CN110946835A (zh) * 2018-09-27 2020-04-03 海南先声药业有限公司 一种利伐沙班固体分散片及其制备方法
ES2945809T3 (es) * 2019-10-02 2023-07-07 Intas Pharmaceuticals Ltd Composiciones farmacéuticas sólidas efervescentes prácticamente sin sodio
CN111297822A (zh) * 2019-12-20 2020-06-19 青岛黄海制药有限责任公司 一种利伐沙班微丸胶囊及其制备方法
CN110898021B (zh) * 2019-12-27 2020-11-10 瀚晖制药有限公司 一种厄贝沙坦氢氯噻嗪的复合制剂及其制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105078997A (zh) * 2014-05-19 2015-11-25 广东东阳光药业有限公司 一种利伐沙班药用组合物及其制备方法
CN106265547A (zh) * 2015-05-12 2017-01-04 北京济美堂医药研究有限公司 一种改进了生产工艺的利伐沙班药物组合物的制备方法
CN107773548A (zh) * 2016-08-30 2018-03-09 重庆植恩药业有限公司 含有利伐沙班的固体组合物及其制备方法
JP2019108324A (ja) * 2017-12-15 2019-07-04 エルメッド株式会社 リバーロキサバン含有医薬組成物
WO2021071444A1 (en) * 2019-10-10 2021-04-15 Santa Farma İlaç Sanayi̇ A.Ş. A unique granulation process for rivaroxaban containing granules

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHONG YI-WEI;HU XIANG;LU YANG: "Preparation and Formulation Optimization of Rivaroxaban Tablets", ANHUI MEDICAL AND PHARMACEUTICAL JOURNAL, vol. 19, no. 2, 3 March 2015 (2015-03-03), pages 225 - 229, XP093016009, ISSN: 1009-6469, DOI: 10.3969/j.issn.1009-6469.2015.02.006 *

Also Published As

Publication number Publication date
CN113425729A (zh) 2021-09-24
CN113425729B (zh) 2022-11-15
US20220409626A1 (en) 2022-12-29

Similar Documents

Publication Publication Date Title
JP6041919B2 (ja) ８−［｛１−（３，５−ビス−（トリフルオロメチル）フェニル）−エトキシ｝−メチル］−８−フェニル−１，７−ジアザ−スピロ［４．５］デカン−２−オンの塩を含む錠剤処方物およびそれから作製される錠剤
JP5401327B2 (ja) 溶出性の改善された錠剤
CN108938585A (zh) 柠檬酸铁剂型
JP2011126916A (ja) プラミペキソール又はその医薬品として許容される塩を含む放出が延長された錠剤調合物、その製造方法及びその使用
WO2022267169A1 (zh) 一种含有利伐沙班的药物组合物及其应用
CN109528675B (zh) 一种他达拉非肠溶片剂及其制备方法
CN113413388A (zh) 含有枸橼酸西地那非的药物组合物、制备方法及其应用
CN110354086B (zh) 一种坎地沙坦酯片剂的制备方法
CN113209042A (zh) 一种氢溴酸右美沙芬硫酸奎尼丁胶囊及其制备方法
EP3829546A1 (en) Immediate release formulation of a triple combination of active pharmaceutical ingredients useful in the treatment of polycystic ovary syndrome
CN112516101B (zh) 一种含有富马酸喹硫平的片剂及其制备方法
CN105106149B (zh) 左炔诺孕酮片及其制法
CN114129524A (zh) 对乙酰氨基酚片剂及其制备方法
CN109700773B (zh) 一种替格瑞洛制剂组合物及其制备方法
CN107582528B (zh) 用于湿法制粒的方法及其产品
AU2013347264B2 (en) Dispersible tablet
CN105853367B (zh) 地拉罗司固体分散体的制备方法及其药物制剂
AU2004324858B2 (en) Compressed solid dosage form manufacturing process well-suited for use with drugs of low aqueous solubility and compressed solid dosage forms made thereby
CN117045610B (zh) 一种溶出高稳定性的盐酸拉贝洛尔组合物及其制备方法
CN116889555B (zh) 一种阿戈美拉汀片剂及其制备方法
CN112933060B (zh) 一种吡拉西坦片及其制备方法
WO2022042646A1 (zh) 盐酸鲁拉西酮组合物及其制备方法
CN106727375A (zh) 阿戈美拉汀片剂及其制备方法
CN115590823A (zh) 一种利伐沙班颗粒制剂及其制备方法
CN111053753A (zh) 一种利伐沙班药物组合物及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21946656

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE