WO2022012172A1 - 一种难溶性药物口服缓释组合物及其制备方法 - Google Patents

一种难溶性药物口服缓释组合物及其制备方法 Download PDF

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WO2022012172A1
WO2022012172A1 PCT/CN2021/095791 CN2021095791W WO2022012172A1 WO 2022012172 A1 WO2022012172 A1 WO 2022012172A1 CN 2021095791 W CN2021095791 W CN 2021095791W WO 2022012172 A1 WO2022012172 A1 WO 2022012172A1
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Prior art keywords
release
sustained
oral sustained
release composition
enteric
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French (fr)
Inventor
刘锋
谭晓峰
梁文伟
周伟杰
黄俊龙
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Diqi Pharmaceuticlas Co Ltd
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Diqi Pharmaceuticlas Co Ltd
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Priority to JP2023503122A priority Critical patent/JP7551182B2/ja
Priority to US18/005,179 priority patent/US12533320B2/en
Priority to EP21841654.3A priority patent/EP4159203B1/en
Publication of WO2022012172A1 publication Critical patent/WO2022012172A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
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    • 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
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/20—Pills, tablets, discs, rods
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    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide

Definitions

  • the invention belongs to the field of medicine, in particular to an oral sustained-release composition, in particular to a low-dose insoluble drug oral sustained-release composition and a preparation method thereof.
  • CN107405311 discloses a poorly soluble drug sustained-release preparation formed by combining a matrix type sustained-release tablet I and a coated positioning-release tablet II. The combination requires the preparation of two separate tablets, which are combined by filling capsules.
  • the formulation industry There is a high complexity in the transformation.
  • CN103442698 provides a controlled-release gastric retention system, which achieves a greater degree of retention in the stomach to form a sustained-release effect through different combinations, and provides more solutions for the sustained-release development of poorly soluble drugs.
  • Common colon positioning technologies include enteric material coating and enteric material skeleton, wherein the use of solvent evaporation and hot melt extrusion to prepare enteric material and drug into microspheres or granules is a common preparation method for enteric material skeleton.
  • enteric-coated materials and APIs or further adding other release-adjusted materials to prepare slow-release or localized-release is a better formulation process, but the process of preparing matrix microspheres by solvent evaporation method is cumbersome, the preparation conditions are harsh, and the quality is acceptable. Poor controllability; hot melt extrusion granulation method requires special equipment for hot melt extrusion, and the production efficiency of this process is low, which is not conducive to large-scale industrialization.
  • CN1204895 discloses a pharmaceutical composition containing etoposide, which comprises using an enteric material as a solid dispersion carrier, using an organic solvent to dissolve and disperse the main drug in the carrier and then drying and pulverizing, and the solid dispersion is combined with a skeleton-type buffer.
  • the (controlled) release material is mixed, granulated, tableted, and enteric-coated to obtain a sustained and controlled release preparation.
  • the content of the method described in this patent is suitable for compounds with high solubility like etoposide.
  • a large part of poorly soluble drugs need to be dissolved in a large amount of organic solvents, and subsequent drying will also bring about the problem of excessive preparation time.
  • the industrialization of the solid dispersion preparation method is difficult and the efficiency is low.
  • Some patients with chronic diseases and tumors such as low-dose immunomodulators Apremilast, lenalidomide, tofacitinib, anticoagulant apixaban, etc., take long-term medication and may take multiple times a day , the sustained-release preparation will be beneficial to control blood drug concentration, reduce side effects, and reduce the number of times of medication, therefore, the development of an oral sustained-release composition suitable for low-dose insoluble drugs and its preparation method is in great clinical demand.
  • the present invention provides an oral sustained-release composition of low-dose insoluble drugs and a preparation method thereof.
  • the sustained-release granules containing enteric-coated materials are rapidly prepared by spraying the drug-containing suspension onto a liquid strong adsorption carrier.
  • the uniformity of drug content is improved, the preparation process uses less solvent, and the production efficiency is high; combined with the hydrophilic gel skeleton material, multiple slow-release and controlled-release effects are formed to achieve the effect of continuous slow-release.
  • the oral sustained-release composition provided by the present invention is composed of two parts: sustained-release granules and gel skeleton.
  • the gel skeleton wraps the sustained-release granules to form a dual sustained-release system, wherein the sustained-release granules contain insoluble drugs, Enteric material, liquid strong adsorption carrier, and the gel skeleton part contains hydrophilic gel skeleton material.
  • the sustained and controlled release particles are obtained by preparing a drug-containing suspension with a poorly soluble drug and a liquid substance containing an enteric material, and then spraying it onto a liquid strong adsorption carrier.
  • the insoluble drug accounts for 2% to 15% of the weight of the sustained and controlled release particles
  • the weight ratio of the insoluble drug to the enteric material is 1:2 to 1:4
  • the liquid strong adsorption carrier accounts for 35% to 75% of the weight of the sustained-release granules, 40% to 70% of the weight of the oral sustained-release composition
  • the dosage of the hydrophilic gel matrix material accounts for 20% to 50% of the weight of the oral sustained-release composition. %.
  • the insoluble drug of the present invention accounts for less than 10% by weight in the oral sustained-release composition.
  • the low-dose insoluble drugs of the present invention include apremilast, lenalidomide, tofacitinib, and apixaban.
  • the particle size of the insoluble drug is controlled so that d90 is less than 20 microns; preferably d90 is less than 10 microns; most preferably d90 is less than 5 microns.
  • the smaller the particle size of the insoluble drug the easier it is to be encapsulated by the enteric material to form a slow and controlled release, which is also more conducive to the later dissolution.
  • the enteric-coated material in the present invention refers to a series of polymer materials that are soluble in the pH range of 6-8, which can ensure that the drug wrapped by the enteric-coated material can be completely released in the colon.
  • the enteric material includes methacrylic acid and methyl methacrylate copolymer (the molar ratio of methacrylic acid to methyl methacrylate ranges from 1:0.5 to 1:2), methacrylic acid and methyl acrylate and methyl methacrylate.
  • methyl acrylate (1:1:1) copolymers commonly used include methacrylic acid and methyl methacrylate (1:2) copolymers, methacrylic acid and methyl methacrylate (1:2) 1) Copolymers, methacrylic acid and methyl acrylate and methyl methacrylate (1:1:1) copolymers, preferably methacrylic acid and methyl methacrylate (1:1) copolymers, methacrylic acid and Methyl acrylate and methyl methacrylate (1:1:1) copolymer.
  • methacrylic acid and methyl methacrylate (1:2) copolymers are acrylic resin No.
  • the enteric-coated material in the slow-release granules of the present invention is added in liquid form.
  • the liquid substance containing the enteric material is in the form of an aqueous dispersion or a solution in an organic solvent.
  • the enteric material aqueous dispersion can be prepared by itself, and there are also commercial products. In some embodiments, the commercial products include Eudragit FS 30D and the like.
  • the organic solvent solution of the enteric material is obtained by dissolving the enteric material with an organic solvent.
  • Alkaline substances include ammonia, sodium hydroxide, and potassium hydroxide.
  • the organic solvent solution of the enteric material can be obtained by dissolving the enteric material with acetone, ethanol, carbon tetrachloride and isopropanol.
  • an anti-sticking agent Before the liquid substance of the enteric coating material is used, an anti-sticking agent, a plasticizer, a surfactant and the like can also be added.
  • Anti-sticking agents include micronized silica gel, talc, glycerol monostearate (GMS); plasticizers include glycerol monostearate (GMS), triethyl citrate (TEC), polyethylene glycol; surface active Agents include fatty acid sorbitan (Span), polysorbate (Tween), sodium lauryl sulfate.
  • the insoluble drug can be dispersed into the liquid substance containing enteric material by various methods such as stirring, high-speed shear homogenization, high-speed vortex, ultrasonic dispersion, etc. to obtain a drug-containing suspension, or the insoluble drug can be mixed with The solvent is mixed and dispersed, and then added to the liquid substance containing the enteric material to be uniformly mixed to obtain a drug-containing suspension.
  • the solid content of the drug-containing suspension is 10-35%, preferably 15-25%.
  • the liquid strong adsorption carrier in the present invention is a class of substances that are insoluble in water but have a large liquid adsorption capacity, which can meet the requirements of timely adsorption of excess solvent in the rapid spraying process of the drug-containing suspension, and reduce the excessive growth of particles caused by excessive humidity. Large and uneven granulation, so as to quickly and smoothly realize the process of enteric-coated material liquid granulation into slow-release granules.
  • the liquid strong adsorption carrier includes microcrystalline cellulose, croscarmellose sodium, croscarmellose, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, starch, Pregelatinized starch, preferably microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose.
  • the slow and controlled release granules of the present invention can also be added with a binder in a proportion of 0 to 5% by weight of the slow and controlled release granules, so as to obtain slow and controlled release granules with better granulation effect.
  • the binder includes polyvinylpyrrolidone, hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose, carrageenan, alginic acid, acacia, pectin, xanthan gum, and tragacanth. any one or more.
  • the anti-sticking agent is selected from micropowder silica gel, talc, glyceryl monostearate;
  • the plasticizer is selected from glycerol monostearate, triethyl citrate , polyethylene glycol;
  • the surfactant is selected from fatty acid sorbitan, polysorbate, sodium lauryl sulfate.
  • the slow and controlled release granules of the present invention can be added to the components of the gel skeleton part for co-granulation, or the gel skeleton part can be granulated separately and then mixed with the prepared slow and controlled release granules, or the slow and controlled release granules can be mixed together. It can be directly mixed with the gel backbone part components.
  • the gel skeleton part contains a hydrophilic gel skeleton material, and may also contain other pharmaceutical excipients, including fillers, adhesives, glidants, and lubricants.
  • the hydrophilic gel matrix material includes gum arabic, gum tragacanth, polyvinyl pyrrolidone (PVP or povidone), hydroxypropyl methylcellulose (HPMC), shellac, hydroxypropyl cellulose (HPC). ), hydroxyethyl cellulose (HEC), alginate, methyl cellulose (MC), carrageenan, carboxymethyl cellulose and sodium salt, carbomer, polyvinyl alcohol (PVA), etc.
  • the hydrophilic gel material in the present invention can realize rapid hydration to form a gel layer, so as to achieve the purpose of controlling the dissolution rate in the early stage.
  • the tablet can be eroded within a certain period of time, and the controlled-release particle part will leave the tablet during the erosion process to form an independent sustained-controlled release unit.
  • the dosage of the hydrophilic gel skeleton material accounts for 20% to 50% of the weight of the preparation, preferably 20% to 40%.
  • the amount of hydrophilic gel skeleton material exceeds about 50%, the variation range of its sustained-release effect is significantly reduced, and the material cost is increased instead.
  • Fillers, binders, lubricants and glidants are optionally added to the gel matrix portion.
  • the fillers in the gel backbone part of the present invention include, but are not limited to, any one or both of cellulose derivatives and starch derivatives, such as lactose, mannitol, xylitol, fructose, sucrose, dextrin, Microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, methylcellulose, hydroxypropyl starch, etc.; more preferably one of lactose, mannitol, dextrin, microcrystalline cellulose, pregelatinized starch species or several.
  • the dosage of the hydrophilic gel skeleton material accounts for 0% to 35% of the weight of the preparation.
  • the main function of the filler is to improve the compressibility, fluidity, particle formability and other effects.
  • the amount of the filler can be adjusted according to the needs of the target product to play a certain auxiliary role.
  • the binders include but are not limited to polyvinylpyrrolidone, starch syrup, hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose, dextrin, carrageenan, alginic acid, acacia, pectin, yellow Original Gum, Gum Tragacanth.
  • the main function of the binder is to rapidly granulate and improve compressibility.
  • the amount of the binder accounts for 0% to 10% of the total weight of the oral sustained-release composition.
  • Such lubricants include, but are not limited to, magnesium stearate, calcium stearate, sodium stearate, stearic acid, sodium stearyl fumarate, talc, glyceryl behenate, hydrogenated vegetable oils, and stearyl alcohol.
  • the amount of lubricant accounts for 0% to 5% of the total weight of the oral sustained-release composition.
  • the glidants include, but are not limited to, talc, micronized silica gel, silicon dioxide, sodium lauryl sulfate, and stearic acid and metal salts thereof.
  • the amount of the glidant accounts for 0% to 5% of the total weight of the oral sustained-release composition.
  • the oral sustained-release composition comprises two parts: sustained and controlled release particles and a gel matrix, wherein the sustained and controlled release particle part comprises apremilast, an enteric material, a liquid strong adsorption carrier, and a gel
  • the skeleton part comprises a hydrophilic gel skeleton material; wherein the enteric material is Eudragit S100, Eudragit FS 30D; the liquid strong adsorption carrier comprises microcrystalline cellulose, croscarmellose sodium, Cross-linked carboxymethyl cellulose, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose;
  • the hydrophilic gel backbone materials include gum arabic, gum tragacanth, polyvinyl pyrrolidone (PVP or povidone), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), alginate, methyl cellulose (MC), carrageenan, carboxymethyl cellulose and sodium salt, Carbomer, polyvinyl
  • the oral sustained-release composition provided by the present invention is a suspension obtained by dispersing a poorly soluble drug in a liquid substance containing an enteric material, sprayed onto a liquid strong adsorption carrier to form a sustained-release particle part, and then combined with the gel skeleton part of the material After processing, the mixed granules are obtained and then compressed into tablets.
  • the sustained-release granules in the oral sustained-release composition provided by the present invention can be obtained by wet granulation, such as high shear granulation, fluidized bed granulation, and side spray granulation; the gel skeleton part can be directly mixed with powder, Wet granulation process, dry granulation process to obtain.
  • wet granulation such as high shear granulation, fluidized bed granulation, and side spray granulation
  • the gel skeleton part can be directly mixed with powder, Wet granulation process, dry granulation process to obtain.
  • the prepared sustained-release granules can be added to the components of the gel skeleton part for co-granulation, or the gel skeleton part can be granulated separately and then mixed with the prepared slow-release granules.
  • the controlled-release granules are mixed together, and then the subsequent tableting process is performed.
  • the sustained-release particles are partially encapsulated by a gel matrix to form a multiple sustained and controlled-release system.
  • the sustained and controlled release granules in the present invention can form three kinds of dissolution and release effects of immediate release, sustained release, and localized controlled release, wherein the uncoated part of the raw drug by the enteric material exhibits an immediate release effect, and the rapid granulation and drying process will form some holes , so that the enteric-coated material skeleton has a sustained-release effect in an acidic medium, while a part of the fully encapsulated API exhibits an enteric-coated localized release effect.
  • the gel sustained-release layer can effectively resist the high pH environment in the duodenum, jejunum, ileum, etc., to ensure that a part of the active ingredients that are completely encapsulated by the enteric material reach the cecum and colon for release, and the release is complete, Form a stable and effective positioning release effect.
  • the dissolution rate of the sustained and controlled release granules of the present invention in an acidic medium can be evaluated and detected by the degree of encapsulation of the bulk drug by the enteric material and the degree of control over the drug release.
  • the rotation speed is 75rpm
  • the hydrochloric acid solution of sodium chloride (pH1.2) is used as the release medium with a volume of 900ml
  • the temperature is 37°C ⁇ 0.5°C. .
  • the target control range of the acid solubility of the slow-release granules in the present invention is 33% to 80%; preferably, the control range is 50% to 80%.
  • the oral sustained-release composition of the present invention can be released continuously for 24 hours, wherein the dissolution is not more than 30% in 2 hours, 50%-80% in 12 hours and more than 80% in 20 hours.
  • the oral sustained-release composition of the present invention refers to the second method of the Four General Principles ⁇ 0931> of the 2020 edition of the Chinese Pharmacopoeia. Take 6 unit doses of samples for parallel testing, use sodium chloride hydrochloric acid solution (pH1.2), volume 750ml as the release medium, take samples to detect the dissolution after 120min, add 0.3mol of the above acid solution with a temperature of 37°C ⁇ 0.5°C /L sodium phosphate solution 150mL, continue to run for 10h, and then add 100mL of 0.5mol/L sodium phosphate solution at a temperature of 37°C ⁇ 0.5°C to the above acid solution (if necessary, use 2mol/L hydrochloric acid solution or 2mol/L sodium hydroxide The pH value of the solution is adjusted to 7.8), or according to the time specified under each variety, absorb an appropriate amount of the dissolution solution at the specified sampling point, filter, and complete the filtration from sampling to filtration within 30 seconds. Measure according to the method specified under each item, and calculate the dissolved
  • the present invention discloses the technology of forming a dual slow-release and controlled-release system by partially encapsulating the slow-release granules by a gel skeleton, and the prepared low-dose insoluble drug oral slow-release composition has the following advantages:
  • the preparation process is simple, the use of solvent is small, and the efficiency is high: the raw material drug and the enteric material are dispersed together into a suspended liquid substance, the drug loading capacity is increased, the solvent consumption is reduced, and the material with a large liquid adsorption capacity is used as a carrier to achieve rapid spraying Granulate and dry to obtain slow-release granules;
  • the sustained and controlled release granules in the present invention can form three kinds of dissolution and release effects of immediate release, sustained release, and localized controlled release, and the sustained and controlled release granules have multi-level release coordination
  • the sustained-release effect of the gel matrix can effectively prolong the release time, and it is completely dissolved in the intestinal tract.
  • step 2) The suspension in step 1) is sprayed on the microcrystalline cellulose by the WBF-2G fluidized bed top spray granulation method, and the atomization pressure is controlled at 0.5 ⁇ 2.0 bar (every 10min is increased by 0.5 bar, to the maximum value) up to) and spray speed of 5 ⁇ 15g/min (up to 5g/min every 10min, until the maximum value), air volume of 90m 3 /h, inlet air temperature of 45°C, after spraying, drying at 50 ⁇ 60°C for 20min , remove the residual solvent and obtain dry particles;
  • step 2) The dry granules obtained in step 2) are dried and granulated using a 40-mesh sieve to obtain slow-release granules.
  • Example 5-8 The formulations and dosage ratios used in Examples 5-8 are shown in Table 2 below, wherein the particle size distribution d90 of the bulk drug used in Apremilast is 7.4 microns, and the total amount of materials in each batch is 500 g (excluding solvent weight).
  • the amount of purified water includes the amount of water in the Eudragit water dispersion and the amount of additional water, and the purified water will be dried and removed during processing.
  • the other components except the liquid strong adsorption carrier and the adhesive are prepared into a suspension with the solvent, and the amount of the solvent used is about 20% to 25% of the solid content in the suspension.
  • step 2) The suspension in step 1) is sprayed on the microcrystalline cellulose by the WBF-2G fluidized bed top spray granulation method, and the atomization pressure is controlled at 0.5 ⁇ 2.0 bar (every 10min is increased by 0.5 bar, to the maximum value) up to) and spray speed of 5 ⁇ 15g/min (up to 5g/min every 10min, until the maximum value), air volume of 90m 3 /h, inlet air temperature of 45°C, after spraying, drying at 50 ⁇ 60°C for 20min , remove the residual solvent and obtain dry particles;
  • step 2) The dry granules obtained in step 2) are dried and granulated using a 30-mesh sieve to obtain slow-release granules.
  • Example 9 The composition and dosage ratio used in Example 9 are shown in Table 3 below, wherein the particle size distribution d90 of the bulk drug used in Apremilast is 15 microns, and the total amount of materials in each batch is 500 g (excluding solvent weight).
  • step 2) The suspension in step 1) is sprayed on the microcrystalline cellulose by the WBF-2G fluidized bed top spray granulation method, and the atomization pressure is controlled at 0.5 ⁇ 2.0 bar (every 10min is increased by 0.5 bar, to the maximum value) up to) and spray speed of 5 ⁇ 15g/min (up to 5g/min every 10min, until the maximum value), air volume of 90m 3 /h, inlet air temperature of 45°C, after spraying, drying at 50 ⁇ 60°C for 20min , remove the residual solvent and obtain dry particles;
  • step 2) The dry granules obtained in step 2) are dried and granulated using a 20-mesh sieve to obtain slow-release granules.
  • Example 18 The formulation and dosage ratio used in Example 18 are shown in Table 8 below, wherein the particle size distribution of apixaban is d90 of 4.3 microns, and the total weight of the mixed particles is 500 g.
  • the amount of purified water includes the amount of water in the Eudragit water dispersion and the amount of additional water, and the purified water will be dried and removed during processing.
  • the other components except the liquid strong adsorption carrier and the adhesive are formulated into a suspension with the solvent, and the amount of the solvent used is about 30% of the solid content in the suspension.
  • step 2) Slowly pour the suspension in step 1) into the enteric material Eudragit FS 30D, stir with a common mixer at a medium speed, and filter the suspension with a 40-mesh sieve for subsequent use;
  • step 3 Add the binder and the liquid strong adsorption carrier into the EMG2-6 high-shear granulator for pre-mixing for 5 minutes and mix evenly, and then spray the suspension obtained in step 2) into the material in the granulator within 1-3 minutes , continue to stir for 2min to obtain a soft material with a suitable degree of wetting;
  • step 4) the soft material of step 3) is wet granulated by using a 40-mesh swing granulator;
  • step 4) The material obtained in step 4) is dried, and the obtained dried granules are dried and granulated by using a 15-mesh sieve to obtain slow-release granules.
  • the gel skeleton part is prepared by high shear granulation process. After adding the hydrophilic gel material and filler into the high shear granulator and mixing evenly, the solvent purified water is sprayed into the material in the granulator, and the stirring is continued to obtain a soft material with suitable wetting degree;
  • step 2) the soft material of step 2) is wet granulated by adopting a rotary Comil pulverizer under a 8*8mm square-hole sieve;
  • step 3 drying the material obtained in step 3), and the obtained dried particles adopt a 20-mesh sieve to dry and granulate to obtain gel skeleton particles;
  • Example 18 the acid dissolution rate of a certain amount of slow-release granules (containing about 10 mg of apixaban) was 60%.
  • Example 19 The formulation and dosage ratio used in Example 19 are shown in Table 9 below, wherein the particle size distribution of lenalidomide is d90 of 7.5 microns, and the total weight of the mixed particles is 500 g.
  • the gel skeleton part is prepared by fluidized bed granulation process. After adding the hydrophilic gel material and filler into the granulation fluidized bed and mixing for 10 minutes, the solvent purified water was sprayed into the material in the granulator, the temperature of the material was controlled at about 40 °C, and the air volume was controlled at 110 3 m/h. Granulate, and dry for 30 minutes after spraying to obtain dry granules;
  • step 2) the dry particles obtained in step 2) are dried and granulated using a 20-mesh sieve to obtain gel skeleton particles;
  • Example 19 The acid dissolution rate of the sustained and controlled release granules in Example 19 is 68%, the dissolution conditions of the prepared tablets are shown in Table 11, and the dissolution curve can be seen in Figure 3.
  • Example 20 The formulation and dosage ratio used in Example 20 are shown in Table 10 below, wherein the particle size distribution of tofacitinib is d90 of 10 microns, and the total weight of the mixed particles is 500 g.
  • the amount of purified water includes the amount of water in the Eudragit water dispersion and the amount of additional water.
  • the purified water will be dried and removed during processing.
  • the other components except the liquid strong adsorption carrier and the adhesive are prepared into a suspension with the solvent, and the amount of the solvent used is about 20% to 25% of the solid content in the suspension.
  • the gel skeleton part is prepared by high shear granulation process. After the slow-release granules, hydrophilic gel material and filler are added to the high shear granulator and mixed evenly, the solvent purified water is sprayed into the material in the granulator for granulation, and the solvent purified water is sprayed into the granulator. In the material in the granulator, continue to stir to obtain a soft material with a suitable degree of wetting;
  • step 2) the soft material of step 2) is wet granulated by adopting a rotary Comil pulverizer under a 8*8mm square-hole sieve;
  • step 3 drying the material obtained in step 3), and the obtained dried granules adopt a 20-mesh sieve to dry and granulate to obtain granulated granules;
  • step 5) mixing the granulated particles and lubricants obtained in step 4) in a mixing tank for 20 min to obtain total mixed particles;
  • Example 20 a certain amount of slow-release granules (containing about 22 mg of tofacitinib) had an acid dissolution rate of 66%, and the dissolution profiles of the prepared tablets were shown in Table 11 below, and the dissolution curves were shown in Figure 3.
  • CN1204895 discloses the preparation process of solid dispersion, and use the formula similar to the slow-release particles in Example 1 of the present invention to prepare samples for comparison.
  • Example 1 adopts a common fluidized bed granulator to quickly spray the suspension onto the liquid strong adsorption carrier by spraying to complete the granulation operation, and the time can be controlled within 60min. , good drying effect.
  • the present invention can significantly reduce the amount of organic solvent, shorten the drying time, save energy and protect the environment, and has high efficiency.
  • Comparative example 2 prepares a sample with reference to the similar prescription of slow and controlled release granules in Example 5 of the present invention, the difference is that the liquid strong adsorption carrier microcrystalline cellulose is replaced with lactose with poor liquid adsorption, and the obtained slow and controlled release granules adopt Example 14 Formulation process to obtain tablets.
  • Comparative Example 3 and Comparative Example 4 were prepared by referring to the formulation of the sustained and controlled release granules in Example 6 of the present invention and the formulation of Example 15, wherein the formulation of the sustained and controlled release granules of Comparative Example 3 was not granulated separately but mixed by powder mixing.
  • Example 15 of the present invention effectively ensures that the content uniformity of the tablet is within the qualified range, and the tablet dissolves slowly and lastingly, and the final dissolution is complete (more than 80% in 20 hours).
  • a low-dose insoluble drug sustained-release oral composition disclosed in the present invention is prepared by using a high pH-sensitive enteric material to prepare a suspension of the raw material drug and spraying to prepare the composition with immediate-release, sustained-release,
  • the controlled-release and comprehensive controlled-release granules are further sustained-released through the hydrophilic gel material to form multiple sustained and controlled-release of the drug; at the same time, the dispersion and controlled-release of the enteric material can effectively ensure the full dissolution of the insoluble drugs, Avoid the incomplete dissolution phenomenon that occurs in poorly soluble drugs.
  • the sample prepared by the invention has good content uniformity, long dissolution and release time, simple process and strong practicability.

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Abstract

一种难溶性药物口服缓释组合物，包含缓控释颗粒和凝胶骨架两部分，其中缓控释颗粒部分包含难溶性药物、肠溶材料、液体强吸附载体，凝胶骨架部分包含亲水性凝胶骨架材料；缓控释颗粒是通过将难溶性药物与肠溶材料制备成混悬液后喷洒到液体强吸附载体上获得。其中缓释颗粒部分被凝胶骨架包裹形成多重缓控释体系，延长释放时间。

Description

一种难溶性药物口服缓释组合物及其制备方法 技术领域
本发明属于医药领域，具体涉及一种口服缓释组合物，特别是一种低剂量难溶性药物口服缓释组合物及其制备方法。
背景技术
在制药领域，目前已经有不少药品被开发为持续缓释、多级释放的控释制剂以便达到稳定血药浓度、减少用药次数，达到增加患者服药的依从性，提高用药安全、疗效及降低副反应等目的。高活性药物在临床中使用剂量低，表现出良好的治疗效果，但有时也因血药浓度高低水平以及波动带来毒副作用。故低剂量的高活性药物很大比例存在开发成缓释、控释制剂的需要。目前最成熟的口服缓控释技术包括骨架缓释、膜控缓释、渗透泵控释等，而这些技术仍很难满足一些难溶性药物的缓释制剂开发，其问题主要表现为工艺制备复杂，成本高，还包括释放速度和程度控制不佳、释放不充分等方面。
在《Oral Controlled Release Formulation Design and Drug Delivery》(Hong Wen)中提到食物由口到盲肠大概3～7h，其中胃部pH值在1～5左右，十二指肠pH值在5-7，而在结肠阶段转运将持续10～24h，而结肠的平均pH值为6.8左右。结肠pH值相对较高，而且停留时间长，给药物吸收提供了一个重要的窗口。
缓慢释放和定位释放技术结合可以做到药物的持续释放。CN107405311中公布一种基质型缓释片剂I与包衣定位释放片剂II组合形成的难溶性药物缓释制剂，该组合需要单独制备两种片剂，并通过灌装胶囊实现合并，制剂产业化上存在较高复杂度。CN103442698提供了一种控释胃滞留系统，通过不同组合搭配实现在胃部较大程度的滞留形成缓释效果，为难溶性药物的缓释开发提供更多方案。
常见结肠定位技术包括肠溶材料包衣、肠溶材料骨架，其中采用溶剂蒸发法和热熔挤出将肠溶材料与药物制备成微球或颗粒是常用的肠溶材料骨架制备手段。
Fahima M.Hashem等在《In Vitro and In Vivo Evaluation of Combined Time and pH-Dependent Oral Colonic Targeted Prednisolone Microspheres》报道使用
Figure PCTCN2021095791-appb-000001
S 100、乙基纤维素和药物配制成甲醇溶液后分散在石蜡中，利用乳化剂
Figure PCTCN2021095791-appb-000002
80形成细小的微球，再洗脱、干燥，获得强的松龙微球制剂，可定位 结肠给药强的松龙。
Kiran Prakash Sawant等在《Extended release delivery system of metoprolol succinate using hot-melt extrusion:effect of release modifier on methacrylic acid copolymer》中公开使用
Figure PCTCN2021095791-appb-000003
S100和
Figure PCTCN2021095791-appb-000004
L100与一定量脱模改性剂Polyox TM WSR 303和
Figure PCTCN2021095791-appb-000005
L100-55结合，采用热熔挤出(HME)技术制造琥珀酸美托洛尔的缓释剂型。
采用肠溶材料与原料药，或进一步加入其它调整释放的材料制备成缓释或者定位释放是一种较好的处方工艺，但采用溶剂蒸发法制备骨架微球工艺繁琐，制备条件苛刻，质量可控性差；采用热熔挤出制粒的方式需要有热熔挤出的专用设备，且该工艺生产效率较低，不利于大规模的产业化。
CN1204895公开一种含依托泊甙的药物组合物，其中包括采用肠溶材料作为固体分散载体，采用有机溶剂将主药溶解分散与载体中再进行干燥、粉碎，该固体分散物再和骨架型缓(控)释材料进行混合制粒压片、肠溶包衣获得缓控释制剂。但该专利所述方法内容适合于类似依托泊甙的高溶解度的化合物，很大一部分难溶性药物需要使用大量的有机溶剂来溶解，后续干燥也会带来制备时间过长的问题，而且所述固体分散体制备方法的工业化难度大，效率低。
一些慢性疾病、肿瘤等用药患者，如低剂量的免疫调节剂阿普斯特、来那度胺、托法替布，抗凝药阿哌沙班等，长期服药而且每日可能服用多次药物，缓释制剂将有利于控制血药浓度，降低副作用，减少服药次数，因此，开发出一种适用于低剂量难溶性药物的口服缓控释组合物及其制备方法临床需求大。
发明人在研究过程中发现采用难溶性药物与缓控释材料物理混合，或进一步制粒，再压片，易出现溶出过快或最终溶出不完全的问题，无法获得满意的缓控释制剂开发处方工艺。发明人后续发现采用肠溶材料与小粒径的难溶性化合物配制成混悬液可以有效分散原料药，不仅可以有效控制药物在低pH值溶液下的溶出速度，也可以确保在高pH值溶液下药物能够充分溶出，这一性质可很好的用于难溶性药物的缓控释制剂开发中。
发明内容
发明目的：本发明提供一种低剂量难溶性药物的口服缓释组合物及其制备方法，通过将含药混悬液喷洒到液体强吸附载体上快速制备含肠溶材料的缓控释颗粒，提高药物含量均匀度，制备工艺使用溶剂量少，生产效率高；与亲水凝胶骨 架材料组合，形成多重缓控释效果，达到持续缓释的效果。
技术方案：本发明提供的口服缓释组合物由缓控释颗粒和凝胶骨架两部分构成，凝胶骨架包裹缓控释颗粒形成双重缓控释体系，其中缓控释颗粒包含难溶性药物、肠溶材料、液体强吸附载体，凝胶骨架部分包含亲水性凝胶骨架材料。所述缓控释颗粒通过将难溶性药物与含有肠溶材料的液体物质制备成含药混悬液后喷洒到液体强吸附载体上获得。
本发明所述口服缓释组合物中难溶性药物占缓控释颗粒重量的2％～15％，难溶性药物与肠溶材料的重量比例为1:2～1:4，液体强吸附载体占缓控释颗粒重量的35％～75％，缓控释颗粒占口服缓释组合物重量的40％～70％，亲水性凝胶骨架材料用量占口服缓释组合物重量的20％～50％。
本发明所述难溶性药物在口服缓释组合物中重量占比小于10％。
本发明所述低剂量难溶性药物包括阿普斯特、来那度胺、托法替布、阿哌沙班。
所述难溶性药物粒径控制在d90小于20微米；优选d90小于10微米；最优选d90小于5微米。难溶性药物粒径越小，越容易被肠溶材料包裹形成缓控释，也更利于后期的溶出。
本发明所述肠溶材料是指在pH值6～8范围内可溶解的系列高分子材料，可以确保被肠溶材料包裹的药物在结肠部位能完全释放出来。所述肠溶材料包括甲基丙烯酸和甲基丙烯酸甲酯共聚物(甲基丙烯酸与甲基丙烯酸甲酯摩尔比范围为1:0.5～1:2)、甲基丙烯酸和丙烯酸甲酯和甲基丙烯酸甲酯(1:1:1)共聚物中的任意一种；常用的包括甲基丙烯酸和甲基丙烯酸甲酯(1:2)共聚物、甲基丙烯酸和甲基丙烯酸甲酯(1:1)共聚物、甲基丙烯酸和丙烯酸甲酯和甲基丙烯酸甲酯(1:1:1)共聚物，优选甲基丙烯酸和甲基丙烯酸甲酯(1:1)共聚物、甲基丙烯酸和丙烯酸甲酯和甲基丙烯酸甲酯(1:1:1)共聚物。商业化的肠溶材料产品中，甲基丙烯酸和甲基丙烯酸甲酯(1:2)共聚物为丙烯酸树脂2号、尤特奇L100等；甲基丙烯酸和甲基丙烯酸甲酯(1:1)共聚物为丙烯酸树脂3号、尤特奇S100等；甲基丙烯酸和丙烯酸甲酯和甲基丙烯酸甲酯(1:1:1)共聚物为尤特奇FS 30D等。本发明所述缓控释颗粒中肠溶材料以液体形式加入。含有肠溶材料的液体物质为水分散体形式或有机溶剂溶液形式。肠溶材料水分散体可以自行制备，也有商业化产品，一些实施例中包括商业化产品有尤特奇FS 30D等。所述肠溶材料的有 机溶剂溶液通过采用有机溶剂溶解肠溶材料获得。
肠溶材料水分散体制备过程中除肠溶材料、水外，还需加入碱性物质。碱性物质包括氨水、氢氧化钠、氢氧化钾。肠溶材料有机溶剂溶液可以采用丙酮、乙醇、四氯化碳、异丙醇溶解肠溶材料获得。
所述肠溶材料的液体物质在使用前，还可加入抗粘剂、增塑剂、表面活性剂等。抗粘剂包括微粉硅胶、滑石粉、单硬脂酸甘油酯(GMS)；增塑剂包括单硬脂酸甘油酯(GMS)、柠檬酸三乙酯(TEC)、聚乙二醇；表面活性剂包括脂肪酸山梨坦(司盘)、聚山梨酯(吐温)、十二烷基硫酸钠。
本发明中难溶性药物可采用搅拌、高速剪切匀浆、高速涡旋、超声分散等多种方式分散到含有肠溶材料的液体物质得到含药混悬液，也可以将难溶性药物提前与溶剂混合分散后再加入含有肠溶材料的液体物质中进行混合均匀得到含药混悬液。
所述含药混悬液中固含量为10-35％，优选为15-25％。
本发明中所述液体强吸附载体为水不溶性但液体吸附量大的一类物质，可以满足含药混悬液快速喷洒过程中及时吸附多余的溶剂，减少过湿而出现的颗粒增长过快过大、制粒不均匀现象，从而快速、顺利实现肠溶材料液体制粒成缓控释颗粒的过程。
所述液体强吸附载体包括微晶纤维素、交联羧甲基纤维素钠、交联羧甲基纤维素、交联聚维酮、羧甲基淀粉钠、低取代羟丙纤维素、淀粉、预胶化淀粉，优选微晶纤维素、交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、低取代羟丙纤维素。
本发明所述缓控释颗粒中还可加入缓控释颗粒重量0～5％比例的粘合剂，以便于获得成粒效果较好的缓控释颗粒。所述粘合剂包括聚乙烯吡咯烷酮、羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素、卡拉胶、海藻酸、阿拉伯胶、果胶、黄原胶、西黄蓍胶中的任意一种或几种。
所述含有肠溶材料的液体物质在使用前，可选地加入缓控释颗粒重量0～8％的抗粘剂、0～8％的增塑剂、0～3％的表面活性剂中的任意一种或几种的组合，其中，所述抗粘剂选自微粉硅胶、滑石粉、单硬脂酸甘油酯；所述增塑剂选自单硬脂酸甘油酯、柠檬酸三乙酯、聚乙二醇；所述表面活性剂选自脂肪酸山梨坦、聚山梨酯、十二烷基硫酸钠。
本发明所述缓控释颗粒可加入到凝胶骨架部分的组分中共同制粒，也可以将凝胶骨架部分单独制粒后再与制备的缓控释颗粒共同混合，或者缓控释颗粒可直接与凝胶骨架部分组分混合。
本发明所述的口服缓释组合物，其中凝胶骨架部分含有亲水性凝胶骨架材料，还可含有其它药用辅料，包括填充剂、粘合剂、助流剂、润滑剂。
所述亲水性凝胶骨架材料包括阿拉伯胶、黄蓍胶、聚乙烯基吡咯烷酮(PVP或聚维酮)、羟丙基甲基纤维素(HPMC)、虫胶、羟丙基纤维素(HPC)、羟乙基纤维素(HEC)、海藻酸盐、甲基纤维素(MC)、卡拉胶、羧甲基纤维素及钠盐、卡波姆、聚乙烯醇(PVA)等。
本发明中所述亲水凝胶材料可实现快速水化形成凝胶层，达到控制前期溶出速率的目的。通过调整亲水性凝胶骨架种类和用量，可实现片剂在一定时间内完成溶蚀，缓控释颗粒部分在溶蚀过程将离开片剂，形成独立的缓控释单元。
本发明中亲水性凝胶骨架材料用量占制剂重量的20％～50％，优选的20％～40％。随着亲水性凝胶骨架材料用量超过50％左右时，其缓释作用变化幅度显著降低，反而增加物料成本。
所述凝胶骨架部分中可选地加入填充剂、粘合剂、润滑剂和助流剂。
本发明所述凝胶骨架部分中填充剂包括但不限于纤维素衍生物和淀粉衍生物中的任意一种或两种，如包括乳糖、甘露醇、木糖醇、果糖、蔗糖、糊精、微晶纤维素、预胶化淀粉、羧甲基淀粉钠、甲基纤维素、羟丙基淀粉等；更优选为乳糖、甘露醇、糊精、微晶纤维素、预胶化淀粉中的一种或几种。本发明中亲水性凝胶骨架材料用量占制剂重量的0％～35％。
填充剂主要作用为提高可压性、流动性、颗粒形成性等效果，填充剂的用量可根据目标产品的需要作出调整，起到一定的辅助作用。
所述粘合剂包括但不限于聚乙烯吡咯烷酮、淀粉浆、羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素、糊精、卡拉胶、海藻酸、阿拉伯胶、果胶、黄原胶、西黄蓍胶。粘合剂主要作用是快速成粒以及提高可压性。本发明中粘合剂用量占口服缓释组合物总重的0％～10％。
所述润滑剂包括但不限于硬脂酸镁、硬脂酸钙、硬脂酸钠、硬脂酸、硬脂富马酸钠、滑石粉、山嵛酸甘油酯、氢化植物油和硬脂醇。本发明中润滑剂用量占口服缓释组合物总重的0％～5％。
所述助流剂包括但不限于滑石粉、微粉硅胶、二氧化硅、月桂基硫酸钠和硬脂酸及其金属盐。本发明中助流剂用量占口服缓释组合物总重的0％～5％。
在一个优选的实施方式中，所述口服缓释组合物包含缓控释颗粒和凝胶骨架两部分，其中缓控释颗粒部分包含阿普斯特、肠溶材料、液体强吸附载体，凝胶骨架部分包含亲水性凝胶骨架材料；其中所述肠溶材料为尤特奇S100、尤特奇FS 30D；所述液体强吸附载体包括微晶纤维素、交联羧甲基纤维素钠、交联羧甲基纤维素、交联聚维酮、羧甲基淀粉钠、低取代羟丙纤维素；所述亲水性凝胶骨架材料包括阿拉伯胶、黄蓍胶、聚乙烯基吡咯烷酮(PVP或聚维酮)、羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、海藻酸盐、甲基纤维素(MC)、卡拉胶、羧甲基纤维素及钠盐、卡波姆、聚乙烯醇(PVA)；其中阿普斯特与肠溶材料重量比为1:2～1:4；所述缓控释颗粒是通过将难溶性药物与肠溶材料的制备成混悬液后喷洒到液体强吸附载体上获得。
本发明提供的口服缓释组合物是将难溶性药物分散在含有肠溶材料的液体物质得到的混悬液喷洒到液体强吸附载体上形成缓控释颗粒部分，再与凝胶骨架部分物料组合加工，获得总混颗粒再进行压片获得。
本发明提供的口服缓释组合物中缓控释颗粒可采用湿法制粒工艺获得，如高剪切制粒、流化床制粒、侧喷制粒；凝胶骨架部分可采用粉末直接混合、湿法制粒工艺、干法制粒工艺获得。
本发明提供的口服缓释组合物制备过程可以将制备好的缓控释颗粒加入到凝胶骨架部分的组分中共同制粒，也可以将凝胶骨架部分单独制粒后再与制备的缓控释颗粒共同混合，再进行后续压片工艺。
本发明供的口服缓释组合物中缓释颗粒部分被凝胶骨架包裹形成多重缓控释体系。本发明中缓控释颗粒可形成速释、缓释、定位控释的三种溶出释放效果，其中原料药被肠溶材料未包裹部分呈现速释效果，而快速制粒干燥过程会形成一部分孔洞，从而在酸性介质中出现肠溶材料骨架缓释效果，而完全被包裹的一部分原料药则表现出肠溶定位释放效果，缓控释颗粒中速释部分因外层被凝胶骨架包裹后可有效形成缓释，而且凝胶缓释层可以有效抵抗在十二指肠、空肠、回肠等部位的高pH环境，确保一部分被肠溶材料完全包裹有效成分到达盲肠、结肠再释放，释放完全，形成稳定有效的定位释放效果。
本发明所述缓控释颗粒的在酸性介质中的溶出度可评估检测原料药被肠溶 材料的包裹程度以及对药物释放的控制程度。参考中国药典2015年版四部通则〈0931〉第二法，转速75rpm，以氯化钠的盐酸溶液(pH1.2)，体积900ml为释放介质，温度37℃±0.5℃进行缓控释颗粒溶出度检测。取120min溶出度称之为酸溶出度。
本发明中所述缓控释颗粒酸溶解度目标控制范围为33％～80％；较优的，控制范围为50％～80％。
本发明的口服缓释组合物参考中国药典2020年版四部通则〈0941〉含量均匀度检查法。取缓释片10个，测定每一个单剂以标示量为100的相对含量x i，求其均值和标准差S以及标示量与均值之差的绝对值A，计算A+2.2S，当A+2.2S小于15时，可认为含量均匀度合格。
本发明的口服缓释组合物可持续释放24小时，其中2小时溶出不大于30％，12小时溶出50％～80％并且20小时释放80％以上。
本发明的口服缓释组合物参考中国药典2020年版四部通则〈0931〉第二法，转速75rpm，温度37℃±0.5℃进行溶出度检测。取样品6个单位剂量平行检测，以氯化钠的盐酸溶液(pH1.2)，体积750ml为释放介质，120min后取样检测溶出度，上述酸液中加入温度为37℃±0.5℃的0.3mol/L磷酸钠溶液150mL，继续运转10h，然后在上述酸液中加入温度为37℃±0.5℃的0.5mol/L磷酸钠溶液100mL(必要时用2mol/L盐酸溶液或2mol/L氢氧化钠溶液调节pH值至7.8)，或按各品种项下规定的时间，在规定取样点吸取溶出液适量，滤过，自取样至滤过应在30秒钟内完成。按各品种项下规定的方法测定，计算每片(粒)的缓冲液中溶出量。
有益效果：与现有技术相比，本发明公开了缓释颗粒部分被凝胶骨架包裹形成双重缓控释体系技术，所制备的低剂量难溶性药物口服缓释组合物具有如下优点：
(1)制备工艺简单、使用溶剂少，效率高：原料药与肠溶材料共同分散成混悬液体物质，提高载药量，减少溶剂用量，利用液体吸附量大的材料作为载体，实现快速喷洒制粒、干燥，获得缓控释颗粒；
(2)原料药以混悬液进行喷雾形式加入到其它物料中，分散均匀，减少混合均匀度风险，保证药物的含量均匀度；
(3)多重缓控释体系，延长释放时间，溶出完全：本发明中缓控释颗粒可 形成速释、缓释、定位控释的三种溶出释放效果，缓控释颗粒多层次的释放配合凝胶骨架缓释作用可有效延长释放时间，而且在肠道溶出完全。
附图说明
图1实施例10～13溶出曲线；
图2实施例14～17溶出曲线；
图3实施例18～20溶出曲线。
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。
实施例1～4
实施例1～4所用的组方和用量比例如下表1所示，每批次的物料总量为500g(不计溶剂重量)：
表1
Figure PCTCN2021095791-appb-000006
*溶剂在加工过程将被干燥去除。
实施例1～4制备工艺步骤：
1)将尤特奇S 100溶于适量乙醇(95％)中；阿普斯特、滑石粉和柠檬酸三乙酯加入适量乙醇(95％)中，用匀浆机匀化约10分钟，然后倒入尤特奇S 100溶液中，在制粒过程中用搅拌器不断搅拌混悬液；
2)将步骤1)混悬液通过WBF-2G流化床顶喷制粒方式喷洒在微晶纤维素中，过程中控制雾化压力在0.5～2.0bar(每10min上调0.5bar，到最大值为止)和喷速5～15g/min(每10min上调5g/min，到最大值为止)、风量90m 3/h，进风温度45℃，完成喷液后，在采用50～60℃进行干燥20min，去除残留溶剂，获得干燥颗粒；
3)将步骤2)所得干燥颗粒采用孔径40目筛网进行干整粒，获得缓控释颗粒。
取样检测缓控释颗粒酸溶出度，每份样品中含有阿普斯特约60mg。
实施例5～8
实施例5～8所用的组方和用量比例如下表2所示，其中阿普斯特所用原料药粒径分布d90为7.4微米，每批次的物料总量为500g(不计溶剂重量)。
表2
Figure PCTCN2021095791-appb-000007
Figure PCTCN2021095791-appb-000008
*以尤特奇水分散体中固体物质重量计。
**纯化水用量包括尤特奇水分散体中水量和外加水量，纯化水在加工过程会被干燥去除。处方中除液体强吸附载体、粘合剂外其它组分与所述溶剂配制成混悬液，所用溶剂用量为所述混悬液中固含量为20％～25％左右。
实施例5～8制备工艺步骤：
1)将抗粘剂、增塑剂、表面活性剂、主药加到一定量溶剂热水(70℃～80℃)中，用高剪切匀化机匀化10分钟，获得混悬液，持续搅拌备用；
2)将步骤1)混悬液通过WBF-2G流化床顶喷制粒方式喷洒在微晶纤维素中，过程中控制雾化压力在0.5～2.0bar(每10min上调0.5bar，到最大值为止)和喷速5～15g/min(每10min上调5g/min，到最大值为止)、风量90m 3/h，进风温度45℃，完成喷液后，在采用50～60℃进行干燥20min，去除残留溶剂，获得干燥颗粒；
3)将步骤2)所得干燥颗粒采用孔径30目筛网进行干整粒，获得缓控释颗粒。
取样检测缓控释颗粒酸溶出度，每份样品中含有阿普斯特约60mg。
实施例9
实施例9所用的组方和用量比例如下表3所示，其中阿普斯特所用原料药粒径分布d90为15微米，每批次的物料总量为500g(不计溶剂重量)。
表3
Figure PCTCN2021095791-appb-000009
*处方中除液体强吸附载体、粘合剂外其它组分与所述溶剂配制成混悬液，所用溶剂用量为所述混悬液中固含量为25.4％，纯化水在加工过程会被干燥去除。
实施例9制备工艺步骤：
1)将肠溶材料尤特奇L100缓慢倒入水中，搅拌5-10分钟。待肠溶材料完全润湿，后缓慢加入氢氧化钠粉末或溶液并不停搅拌，最后再继续搅拌30分钟。然后加入原料药、增塑剂和抗粘剂，持续搅拌均匀后用40目筛过滤，获得混悬液，保持搅拌备用；
2)将步骤1)混悬液通过WBF-2G流化床顶喷制粒方式喷洒在微晶纤维素中，过程中控制雾化压力在0.5～2.0bar(每10min上调0.5bar，到最大值为止)和喷速5～15g/min(每10min上调5g/min，到最大值为止)、风量90m 3/h，进风温度45℃，完成喷液后，在采用50～60℃进行干燥20min，去除残留溶剂，获得干燥颗粒；
3)将步骤2)所得干燥颗粒采用孔径20目筛网进行干整粒，获得缓控释颗粒。
取样检测缓控释颗粒酸溶出度，每份样品中含有阿普斯特约60mg。
实施例10～13
实施例10～13所用的组方和用量比例如下表4所示，每批次的总混颗粒重量为400g。
表4
Figure PCTCN2021095791-appb-000010
实施例10～13制备工艺步骤：
1)将缓控释颗粒与亲水凝胶材料、润滑剂混合10min，获得总混颗粒；
2)将总混颗粒倒入压片机中，选择Φ11mm的圆形冲模进行，按照目标片重进行压片，获得缓控释片剂。
实施例10～13制备所得片剂溶出情况如下表5，溶出曲线可见图1。
表5 溶出度(％)
时间/小时 0 1 2 3 6 9 12 16 20 24
实施例10 0 14 30 45 69 75 80 89 95 99
实施例11 0 12 24 35 62 68 70 85 92 97
实施例12 0 10 19 30 45 51 56 72 90 99
实施例13 0 7 14 23 34 42 51 71 85 95
实施例14～17
实施例14～17所用的组方和用量比例如下表6所示，每批次的总混颗粒重量为400g：
表6
Figure PCTCN2021095791-appb-000011
实施例14～17制备工艺步骤：
1)将缓控释颗粒与亲水凝胶材料、润滑剂混合10min，获得总混颗粒；
2)将总混颗粒倒入压片机中，选择胶囊型冲模按照目标片重进行压片，获得缓控释片剂。
实施例14～17制备所得片剂溶出情况如下表7，溶出曲线可见图2。
表7 溶出度(％)
时间/小时 0 1 2 3 6 9 12 16 20 24
实施例14 0 15 29 45 65 73 78 89 95 99
实施例15 0 13 27 38 55 68 70 84 94 99
实施例16 0 10 23 32 49 55 59 79 91 98
实施例17 0 8 21 29 43 47 51 73 85 95
实施例18
实施例18所用的组方和用量比例如下表8所示，其中阿哌沙班的粒径分布为d90为4.3微米，总混颗粒重量为500g。
表8
Figure PCTCN2021095791-appb-000012
*以尤特奇水分散体中固体物质重量计。
**纯化水用量包括尤特奇水分散体中水量和外加水量，纯化水在加工过程会被干燥去除。处方中除液体强吸附载体、粘合剂外其它组分与所述溶剂配制成混悬液，所用溶剂用量为所述混悬液中固含量为30％左右。
实施例18制备工艺步骤：
1)将抗粘剂、增塑剂、表面活性剂、主药加到一定量溶剂热水(70℃～80℃) 中，用高剪切匀化机匀化10分钟，获得混悬液的固体含量约30％，持续搅拌备用；
2)将步骤1)混悬液慢慢地倒入肠溶材料尤特奇FS 30D中，同时用普通搅拌机中速搅拌，再将混悬液用40目筛过滤，备用；
3)将粘合剂、液体强吸附载体加入EMG2-6高剪切制粒机中预混合5min混合均匀后，再将步骤2)所得混悬液在1～3min内喷洒到制粒机中物料中，继续搅拌2min，得到润湿程度适宜软材；
4)将步骤3)的软材采用摇摆制粒机40目进行湿整粒；
5)将步骤4)得到物料进行干燥，所得干燥颗粒采用孔径15目筛网进行干整粒，获得缓控释颗粒。
6)凝胶骨架部分采用高剪切制粒工艺制备。将亲水凝胶材料、填充剂加入高剪切制粒机中混合均匀后，将溶剂纯化水喷洒到制粒机中物料中，继续搅拌，得到润湿程度适宜软材；
7)将步骤2)的软材采用旋转式Comil粉碎机在8*8mm方孔筛下进行湿整粒；
8)将步骤3)得到物料进行干燥，所得干燥颗粒采用孔径20目筛网进行干整粒，获得凝胶骨架颗粒；
9)将缓控释颗粒、凝胶骨架颗粒、润滑剂在混合桶中混合20min，获得总混颗粒；
10)将总混颗粒采用高速旋转压片机进行压片，选择Φ10mm圆形冲模，每片含有阿哌沙班10mg，获得阿哌沙班缓释片。
实施例18中取一定量缓控释颗粒(含阿哌沙班约10mg)的酸溶出度为60％，制备所得片剂溶出情况如下表11，溶出曲线可见图3。
实施例19
实施例19所用的组方和用量比例如下表9所示，其中来那度胺的粒径分布为d90为7.5微米，总混颗粒重量为500g。
表9
Figure PCTCN2021095791-appb-000013
*溶剂在加工过程会被干燥去除。
实施例19制备工艺步骤：
1)缓控释颗粒部分的制备工艺参考实施例1；
2)凝胶骨架部分采用流化床制粒工艺制备。将亲水凝胶材料、填充剂加入制粒流化床中混合10min后，将溶剂纯化水喷洒到制粒机中物料中，控制物料温度在40℃左右，风量控制在110 3m/h进行制粒，喷液完成后干燥30min，得到干燥颗粒；
3)将步骤2)所得干燥颗粒采用孔径20目筛网进行干整粒，获得凝胶骨架颗粒；
4)将缓控释颗粒、凝胶骨架颗粒、润滑剂在混合桶中混合20min，获得总混颗粒；
5)将总混颗粒采用高速旋转压片机进行压片，选择Φ12mm圆形冲模，按照目标片重进行压片，获得来那度胺缓释片素片；
6)将胃溶包衣层物料分散在纯化水中得到10％固含量的混悬液，将素片放于高效多孔包衣机中喷入混悬液进行包衣，按照片芯重量的3％增重进行包衣，获得来那度胺缓释片。
实施例19中缓控释颗粒的酸溶出度为68％，制备所得片剂溶出情况如下表11，溶出曲线可见图3。
实施例20
实施例20所用的组方和用量比例如下表10所示，其中托法替布的粒径分布为d90为10微米，总混颗粒重量为500g。
表10
Figure PCTCN2021095791-appb-000014
*以尤特奇水分散体中固体物质重量计。
**该纯化水用量包括尤特奇水分散体中水量和外加水量，纯化水在加工过程会被干燥去除。处方中除液体强吸附载体、粘合剂外其它组分与所述溶剂配制成混悬液，所用溶剂用量为所述混悬液中固含量为20％～25％左右。
实施例20制备工艺步骤：
1)缓控释颗粒部分的制备工艺参考实施例1；
2)凝胶骨架部分采用高剪切制粒工艺制备。将缓控释颗粒、亲水凝胶材料、填充剂加入高剪切制粒机中混合均匀后，将溶剂纯化水喷洒到制粒机中物料中，进行制粒，将溶剂纯化水喷洒到制粒机中物料中，继续搅拌，得到润湿程度适宜软材；
3)将步骤2)的软材采用旋转式Comil粉碎机在8*8mm方孔筛下进行湿整 粒；
4)将步骤3)得到物料进行干燥，所得干燥颗粒采用孔径20目筛网进行干整粒，获得整粒颗粒；
5)将步骤4)所得整粒颗粒、润滑剂在混合桶中混合20min，获得总混颗粒；
6)将总混颗粒采用高速旋转压片机进行压片，选择Φ11mm圆形冲模，按照目标片重进行压片获得托法替布缓释片。
实施例20中取一定量缓控释颗粒(含托法替布约22mg)的酸溶出度为66％，制备所得片剂溶出情况如下表11，溶出曲线可见图3。
表11 溶出度(％)
时间/小时 0 1 2 3 6 9 12 16 20 24
实施例18 0 7 12 21 40 55 72 89 95 99
实施例19 0 8 16 32 55 65 70 82 91 99
实施例20 0 10 21 29 46 52 59 82 93 98
对比例1
为了区分本发明与公开技术的差别，发明人参考CN1204895公开固体分散体制备工艺，采用本发明实施例1中缓控释颗粒相似的处方来制备样品进行对比。
(1)参考CN1204895方法制备阿普斯特固体分散体，首先将阿普斯特10g与尤特奇S100粉末20g溶解于乙醇中需要乙醇大于15L；而本发明中实施例1处方来计算，制备同样10g阿普斯特样品使用乙醇小于1L，显著减少有机溶剂用量。
(2)由于CN1204895骨架型片剂中固体分散体制备方法未充分公开，故采用常用的烘干法将上述装有溶液A 200mL的烧杯采用60℃下烘箱蒸发溶剂48h发现固体物质未完全干燥，继续干燥将耗费大量的时间；而本发明中实施例1采用常见的流化床制粒机通过喷雾方式将混悬液快速喷到液体强吸附载体上完成制粒操作，时间可控制在60min以内，干燥效果好。
故与CN1204895记录方法相比，本发明可显著减少有机溶剂用量，缩短干燥时间，节能环保，效率高。
对比例2
对比例2参考本发明实施例5中缓控释颗粒相似的处方来制备样品，不同之处在于采用液体吸附力差的乳糖更换其中的液体强吸附载体微晶纤维素，所得缓控释颗粒采用实施例14处方工艺获得片剂。
试验过程中，发现缓控释颗粒制粒过程颗粒大小不一，容易出现分层现象。对样品进行检测，对比例2的缓控释颗粒的酸溶出度为91％，超过控制目标上限80％；片剂的含量均匀度A+2.2S为16.2，超过合格限度15；片剂溶出也明显过快，具体情况如下表12。
表12 溶出度(％)
时间/小时 0 1 2 3 6 9 12 16 20 24
对比例2 0 21 35 49 67 82 92 95 97 97
对比例3～4
对比例3、对比例4参考本发明实施例6中缓控释颗粒处方和实施例15处方进行片剂制备，其中对比例3的缓控释颗粒处方不单独制粒而采用粉末混合方式混合后再与羟丙甲纤维素K15M PH DC、乳糖、硬脂酸镁混合后再进行压片，获得对比例3片剂；对比例4的缓控释颗粒处方制粒时，将原料药先与聚维酮K30、羧甲基淀粉钠混合，肠溶材料、抗粘剂、增塑剂、表面活性剂单独制备成混悬液，后续的喷雾制粒、压片工艺参考实施例15进行，得到对比例4片剂。
对样品进行检测，对比例3、对比例4的片剂的含量均匀度A+2.2S分别为17.2、18.3，超过合格限度15；对比例3片剂溶出也明显过快，对比例4出现终溶出不完全的情况，溶出度具体情况如下表13。
表13 溶出度(％)
时间/小时 0 1 2 3 6 9 12 16 20 24
对比例3 0 22 35 45 64 76 85 91 92 95
对比例4 0 19 32 41 55 64 68 74 76 79
相比较对比例3、对比例4，采用本发明内容的实施例15有效保证片剂的含量均匀度在合格范围内，而且片剂溶出缓慢持久，最终溶出完全(20小时溶出大于80％)。
综上所述，本发明公开的一种低剂量难溶性药物缓释口服组合物通过采用高 pH敏感的肠溶材料对原料药制备成混悬液采用喷洒方式制备成具有速释、缓释、控释综合的缓控释颗粒，再通过亲水凝胶材料进一步缓释，对药物形成多重缓控释；同时通过肠溶材料的分散和控释作用，可有效保证难溶性药物的充分溶出，避免难溶性药物中出现的溶出不完全现象。本发明所制备的样品含量均匀度好，溶出释放时间长，工艺简单，实用性强。

Claims (13)

  1. 一种难溶性药物口服缓释组合物，其特征在于，所述口服缓释组合物包含缓控释颗粒和凝胶骨架两部分，其中缓控释颗粒部分包含难溶性药物、肠溶材料和液体强吸附载体；所述凝胶骨架部分包含亲水性凝胶骨架材料；所述缓控释颗粒通过将难溶性药物与含有肠溶材料的液体物质制备成含药混悬液后喷洒到液体强吸附载体上获得，其中缓控释颗粒中难溶性药物占缓控释颗粒重量的2％～15％，难溶性药物与肠溶材料的重量比例为1:2～1:4，液体强吸附载体占缓控释颗粒重量的35％～75％；缓控释颗粒占口服缓释组合物重量的40％～70％；亲水性凝胶骨架材料用量占口服缓释组合物重量的20％～50％。
  2. 根据权利要求1所述的口服缓释组合物，其特征在于，所述难溶性药物在口服缓释组合物中重量占比小于10％。
  3. 根据权利要求1所述的口服缓释组合物，其特征在于，所述难溶性药物粒径控制在d90小于20微米。
  4. 根据权利要求1所述的口服缓释组合物，其特征在于，所述肠溶材料为在pH值6～8范围内可溶解高分子材料，被肠溶材料包裹的药物在结肠部位能完全释放出来。
  5. 根据权利要求1所述的口服缓释组合物，其特征在于，所述含有肠溶材料的液体物质为肠溶材料的水分散体形式或有机溶剂溶液形式，其中，所述肠溶材料的水分散体形式通过向肠溶材料中加入水和/或含碱性物质的水中得到，所述肠溶材料的有机溶剂溶液通过采用有机溶剂溶解肠溶材料获得。
  6. 根据权利要求4或5所述的口服缓释组合物，其特征在于，所述肠溶材料为甲基丙烯酸和甲基丙烯酸甲酯共聚物的混合物、甲基丙烯酸和丙烯酸甲酯和甲基丙烯酸甲酯共聚物中的任意一种。
  7. 根据权利要求1所述的口服缓释组合物，其特征在于，所述含药混悬液的固含量为10-35％。
  8. 根据权利要求1所述的口服缓释组合物，其特征在于，所述液体强吸附载体为微晶纤维素、交联羧甲基纤维素钠、交联羧甲基纤维素、交联聚维酮、羧甲基淀粉钠、低取代羟丙纤维素、淀粉、预胶化淀粉中的任意一种。
  9. 根据权利要求1所述的口服缓释组合物，其特征在于，所述缓控释颗粒中可加入粘合剂，所述粘合剂包括聚乙烯吡咯烷酮、羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素、卡拉胶、海藻酸、阿拉伯胶、果胶、黄原胶、西黄蓍胶中的 任意一种或几种，所述粘合剂的用量为缓控释颗粒重量的0～5％。
  10. 根据权利要求1所述的口服缓释组合物，其特征在于，所述含有肠溶材料的液体物质在使用前，可选地加入缓控释颗粒重量0～8％的抗粘剂、0～8％的增塑剂、0～3％的表面活性剂中的任意一种或几种的组合，其中，所述抗粘剂选自微粉硅胶、滑石粉、单硬脂酸甘油酯；所述增塑剂选自单硬脂酸甘油酯、柠檬酸三乙酯、聚乙二醇；所述表面活性剂选自脂肪酸山梨坦、聚山梨酯、十二烷基硫酸钠。
  11. 根据权利要求1所述的口服缓释组合物，其特征在于，所述亲水性凝胶骨架材料为阿拉伯胶、黄蓍胶、聚乙烯基吡咯烷酮、羟丙基甲基纤维素、虫胶、羟丙基纤维素、羟乙基纤维素、海藻酸盐、甲基纤维素、卡拉胶、羧甲基纤维素及羧甲基纤维素钠、卡波姆、聚乙烯醇中的任意一种。
  12. 根据权利要求1所述的口服缓释组合物，其特征在于，所述凝胶骨架部分中可选地加入填充剂、粘合剂、润滑剂和助流剂。
  13. 权利要求1所述的口服缓释组合物的制备方法，其特征在于，包括如下步骤：
    (1)将难溶性药物分散到包含肠溶材料的液体溶液中得到混悬液，然后将所得的混悬液喷洒到液体强吸附载体上制粒形成缓控释颗粒；
    (2)将步骤(1)得到的缓控释颗粒与包含亲水凝胶骨架材料的物料混合、压片获得，其中，将缓控释颗粒加入到凝胶骨架部分的组分中共同制粒，或将凝胶骨架部分单独制粒后再与制备的缓控释颗粒共同混合、压片制得。
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