CN114983961A - Paliperidone sustained-release tablet and preparation method thereof - Google Patents
Paliperidone sustained-release tablet and preparation method thereof Download PDFInfo
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- CN114983961A CN114983961A CN202210776404.4A CN202210776404A CN114983961A CN 114983961 A CN114983961 A CN 114983961A CN 202210776404 A CN202210776404 A CN 202210776404A CN 114983961 A CN114983961 A CN 114983961A
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- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 title claims abstract description 83
- 229960001057 paliperidone Drugs 0.000 title claims abstract description 80
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title abstract description 5
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- 239000003814 drug Substances 0.000 claims abstract description 180
- 239000011247 coating layer Substances 0.000 claims abstract description 61
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- 238000000576 coating method Methods 0.000 claims description 46
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- 238000002955 isolation Methods 0.000 claims description 29
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 12
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical group CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 9
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 8
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- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 claims description 3
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- 239000001103 potassium chloride Substances 0.000 claims description 3
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 3
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- 229960002622 triacetin Drugs 0.000 claims description 3
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- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 3
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- 230000000694 effects Effects 0.000 abstract description 6
- 238000013268 sustained release Methods 0.000 abstract description 5
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- 239000003153 chemical reaction reagent Substances 0.000 description 2
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- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
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- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940013946 invega Drugs 0.000 description 1
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- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of pharmaceutical preparations, in particular to a paliperidone sustained-release tablet and a preparation method thereof. The paliperidone sustained-release tablet comprises a tablet core and a semi-permeable coating layer coated outside the tablet core, wherein the tablet core comprises a first medicine-containing layer and a second medicine-containing layer which are positioned at two ends, and a pushing layer positioned between the first medicine-containing layer and the second medicine-containing layer, and the semi-permeable coating layer close to the first medicine-containing layer and the second medicine-containing layer is provided with medicine release holes; the water absorbent and the extrusion lubricant are added into the first medicine-containing layer, the first retarder is added into the pushing layer, and the second retarder is added into the second medicine-containing layer. The paliperidone sustained-release tablet can release part of paliperidone at the initial stage of administration (for example, within 2 hours after administration), can remarkably improve the timeliness of paliperidone release under the condition of ensuring the sustained-release effect, and is beneficial to timely and rapidly exerting the drug effect.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a paliperidone sustained-release tablet and a preparation method thereof.
Background
Paliperidone, the active metabolite of the atypical antipsychotic drug risperidone, 9-hydroxyrisperidone, is a derivative of benzisoxazole with the structural formula shown below, which exerts antipsychotic action mainly by blocking the 5-hydroxytryptamine 2A (5-HT2A) receptor and the dopamine D2(DA2) receptor.
Paliperidone sustained-release tablet developed by qiangsheng corporation, trade name: invega, approved by the FDA in 2006, and specifications include 1.5mg, 3mg, 6mg, and 9 mg. The paliperidone sustained release tablet developed by Qiangsheng company adopts OROS technology (oral osmotic pump drug delivery controlled release system) and consists of a tablet core, an isolation coating layer, a semi-permeable coating layer and a coloring coating layer, wherein the tablet core consists of a boosting layer positioned at the bottom, a first drug layer positioned at the top and a second drug layer positioned in the middle, and 2 laser-punched drug release holes are formed in the isolation coating layer and the semi-permeable coating layer on one side of the first drug layer. Under the environment of gastrointestinal tract, the coloring coating layer can be quickly corroded, water enters the tablet core through the semi-permeable membrane coating layer, the hydrophilic material in the tablet core and the paliperidone form a jelly to push the medicine to be discharged from a medicine-releasing small hole at the top end of the tablet, and insoluble ingredients are discharged along with feces. The semipermeable membrane coating layer can control the speed of water entering the tablet core, thereby controlling the release speed of the drug.
In the process of implementing the present invention, the inventors found that the drug release amount of the paliperidone sustained-release tablet is small at the initial stage of administration, and specifically, the paliperidone sustained-release tablet releases substantially no drug within the first 2 hours after administration and releases only a small amount of drug within 4 hours after administration.
Disclosure of Invention
Therefore, the invention aims to overcome the defect that the drug release amount at the initial stage of medication is less in the existing paliperidone sustained-release tablet, thereby providing the paliperidone sustained-release tablet and the preparation method thereof.
Therefore, the invention provides a paliperidone sustained-release tablet, which comprises a tablet core and a semi-permeable coating layer coated outside the tablet core, wherein the tablet core comprises a first medicine-containing layer and a second medicine-containing layer which are positioned at two ends, and a pushing layer positioned between the first medicine-containing layer and the second medicine-containing layer, and the semi-permeable coating layer close to the first medicine-containing layer and the second medicine-containing layer is provided with medicine release holes;
the water absorbent and the extrusion lubricant are added into the first medicine-containing layer, the first retarder is added into the push layer, and the second retarder is added into the second medicine-containing layer.
Optionally, the total weight of the first drug-containing layer is taken as a reference, the content of the water absorbent is 10-20 wt%, and the content of the extrusion lubricant is 1-2 wt%;
based on the total weight of the push layer, the content of the first retarder is 15-20 wt%;
the content of the second retarder is 5-10 wt% based on the total weight of the second drug-containing layer.
Optionally, the weight ratio of the first medicine-containing layer to the pushing layer to the second medicine-containing layer is (1-3): (2-3): (1-3).
Optionally, the water absorbent is sodium alginate; the extrusion lubricant is selected from at least one of glyceryl behenate, dimethicone, glycerin and hydrogenated vegetable oil, preferably glyceryl behenate; the first retarder is low-substituted hydroxypropyl cellulose; the second retarder is low-substituted hydroxypropylcellulose.
Optionally, the particle size D90 of the low-substituted hydroxypropyl cellulose is 50-100 μm;
optionally, the weight ratio of the first retarder to the second retarder is (2-4): 1.
optionally, the first drug-containing layer further contains paliperidone, a carrier material and a tabletting lubricant, wherein the content of the paliperidone is 2-4 wt%, the content of the carrier material is 72-86 wt% and the content of the tabletting lubricant is 1-2 wt% based on the total weight of the first drug-containing layer;
the push layer also contains a push material, a penetrating agent and a tabletting lubricant, and based on the total weight of the push layer, the content of the push material is 56.5-63.5 wt%, the content of the penetrating agent is 10-30 wt%, and the content of the tabletting lubricant is 1-2 wt%;
the second medicine-containing layer also contains paliperidone, a carrier material and a tabletting lubricant, and the content of the paliperidone, the carrier material and the tabletting lubricant are respectively 2-4 wt%, 83-91.5 wt% and 1-2 wt% based on the total weight of the second medicine-containing layer;
optionally, for a single paliperidone sustained-release tablet, the total weight of paliperidone in the first drug-containing layer and the second drug-containing layer is 1.5-12 mg;
optionally, the carrier material is selected from at least one of polyoxyethylene with a molecular weight of 100000-400000, hydroxypropyl methylcellulose, hydroxypropyl cellulose and poloxamer; the tabletting lubricant is selected from at least one of stearic acid, magnesium stearate and sodium stearyl fumarate; the pushing material is selected from at least one of polyoxyethylene with molecular weight of 4000000-7000000, hydroxypropyl methylcellulose, hydroxypropyl cellulose and poloxamer; the osmotic agent is selected from at least one of sodium chloride, potassium chloride, glucose and sodium citrate;
optionally, the push layer further comprises 0.5-1.5 wt% of a first colorant, the second drug-containing layer further comprises 0.5-1.0 wt% of a second colorant, the first colorant is different from the second colorant, and the first colorant and the second colorant are independently selected from any one of iron oxide red, iron oxide yellow, brilliant blue, indigo, carmine and curcumin.
Optionally, the weight of the semi-permeable coating layer is 18-22% of that of the tablet core, the semi-permeable coating layer contains a semi-permeable material and a pore-forming agent, the total weight of the semi-permeable coating layer is taken as a reference, the content of the semi-permeable material is 98-99 wt%, and the content of the pore-forming agent is 1-2 wt%;
optionally, the semi-permeable material is selected from at least one of cellulose acetate, ethyl cellulose and acrylic resin; the pore-forming agent is selected from at least one of polyethylene glycol, triethyl citrate and triacetin;
optionally, the paliperidone sustained-release tablet further comprises an isolation coating layer, the isolation coating layer is positioned between the tablet core and the semi-permeation coating layer, and the drug release holes penetrate through the isolation coating layer; the weight of the isolation coating layer is 8-12% of that of the tablet core, the isolation coating layer contains hydroxypropyl cellulose and povidone, and based on the total weight of the isolation coating layer, the content of the hydroxypropyl cellulose is 50-90 wt%, and the content of the povidone is 10-50 wt%;
optionally, the paliperidone sustained-release tablet further comprises a protective coating layer, and the protective coating layer is coated on the outer surface of the semi-permeable coating layer; the weight of the protective coating layer is 5-10% of that of the tablet core, the protective coating layer contains hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, iron oxide red and talcum powder, and based on the total weight of the protective coating layer, the content of the hydroxypropyl methylcellulose is 52-79 wt%, the content of the polyethylene glycol is 10-20 wt%, the content of the titanium dioxide is 5-15 wt%, the content of the iron oxide red is 1-3 wt%, and the content of the talcum powder is 5-10 wt%.
Optionally, the number of the drug releasing holes close to one end of the first drug-containing layer is 1-3, the number of the drug releasing holes close to one end of the second drug-containing layer is 1-3, and the aperture of the drug releasing holes is 0.5-0.7 mm.
The invention also provides a method for preparing the paliperidone sustained-release tablet, which comprises the following steps:
carrying out layered tabletting on the first medicine-containing layer premixed powder, the pushing layer premixed powder and the second medicine-containing layer premixed powder to respectively form a first medicine-containing layer, a pushing layer and a second medicine-containing layer, enabling the first medicine-containing layer and the second medicine-containing layer to be located at two ends, and enabling the pushing layer to be located between the first medicine-containing layer and the second medicine-containing layer to obtain a tablet core; the water absorbent and the extrusion lubricant are added into the first medicine-containing layer premixed powder, the first retarder is added into the pushing layer premixed powder, and the second retarder is added into the second medicine-containing layer premixed powder;
coating the tablet core by using a semi-permeable coating solution to form a semi-permeable coating layer outside the tablet core;
laser drilling of the semipermeable coating adjacent to the first drug-containing layer and the second drug-containing layer.
Optionally, the total weight of the first medicine-containing layer premixed powder is taken as a reference, the content of the water absorbent is 10-20 wt%, and the content of the extrusion lubricant is 1-2 wt%; based on the total weight of the pre-mixed powder of the push layer, the content of the first retarder is 15-20 wt%; and taking the total weight of the second medicine-containing layer premixed powder as a reference, wherein the content of the second retarder is 5-10 wt%.
Optionally, the weight ratio of the first medicine-containing layer premixed powder, the pushing layer premixed powder and the second medicine-containing layer premixed powder is (1-3): (2-3): (1-3).
Optionally, the water absorbent is sodium alginate; the extrusion lubricant is selected from at least one of glyceryl behenate, dimethicone, glycerin and hydrogenated vegetable oil, preferably glyceryl behenate; the first retarder is low-substituted hydroxypropyl cellulose; the second retarder is a low-substituted hydroxypropylcellulose.
Optionally, the particle size D90 of the low-substituted hydroxypropyl cellulose is 50-100 μm.
Optionally, the weight ratio of the first retarder to the second retarder is (2-4): 1.
optionally, the first drug-containing layer premixed powder further comprises paliperidone, a carrier material and a tabletting lubricant, and based on the total weight of the first drug-containing layer premixed powder, the content of the paliperidone is 2-4 wt%, the content of the carrier material is 72-86 wt%, and the content of the tabletting lubricant is 1-2 wt%.
Optionally, the push layer premixed powder further comprises a push material, a penetrating agent and a tabletting lubricant, and based on the total weight of the push layer premixed powder, the content of the push material is 56.5-63.5 wt%, the content of the penetrating agent is 10-30 wt%, and the content of the tabletting lubricant is 1-2 wt%.
Optionally, the second drug-containing layer premixed powder further comprises paliperidone, a carrier material and a tabletting lubricant, and based on the total weight of the second drug-containing layer premixed powder, the content of the paliperidone is 2-4 wt%, the content of the carrier material is 83-91.5 wt%, and the content of the tabletting lubricant is 1-2 wt%.
Optionally, the carrier material is selected from at least one of polyoxyethylene with a molecular weight of 100000-400000, hydroxypropyl methylcellulose, hydroxypropyl cellulose and poloxamer; the tabletting lubricant is at least one selected from stearic acid, magnesium stearate and sodium stearyl fumarate; the pushing material is selected from at least one of polyoxyethylene with molecular weight of 4000000-7000000, hydroxypropyl methylcellulose, hydroxypropyl cellulose and poloxamer; the osmotic agent is at least one selected from sodium chloride, potassium chloride, glucose and sodium citrate.
Optionally, the push layer premixed powder further comprises 0.5-1.5 wt% of a first colorant, the second medicine layer premixed powder further comprises 0.5-1.0 wt% of a second colorant, the first colorant is different from the second colorant, and the first colorant and the second colorant are independently selected from any one of iron oxide red, iron oxide yellow, brilliant blue, indigo, carmine and curcumin.
Optionally, before coating the tablet core with the semipermeable coating solution, the method further comprises an operation of coating the tablet core with an isolation coating solution to form an isolation coating layer on the surface of the tablet core, and then coating the surface of the isolation coating layer with the semipermeable coating solution to form a semipermeable coating layer;
when laser drilling is carried out, laser drilling is carried out on the isolation coating layer and the semi-permeable coating layer which are close to the first medicine-containing layer and the second medicine-containing layer;
optionally, the method further comprises an operation of coating the surface of the laser-drilled semipermeable coating layer with a protective coating solution to form a protective coating layer;
optionally, the semi-permeable coating liquid contains a semi-permeable material and a pore-forming agent;
optionally, the isolating coating solution contains hydroxypropyl cellulose and povidone;
optionally, the protective coating solution contains hypromellose, polyethylene glycol, titanium dioxide, iron oxide red and talcum powder.
Optionally, the isolation coating solution contains hydroxypropyl cellulose and povidone, and based on the dry weight of the isolation coating solution, the content of hydroxypropyl cellulose is 50-90 wt%, and the content of povidone is 10-50 wt%. The dry weight of the isolation coating liquid is 8-12% of the total weight of the first medicine-containing layer premixed powder, the push layer premixed powder and the second medicine-containing layer premixed powder.
Optionally, the semi-permeable coating liquid contains a semi-permeable material and a pore-forming agent, and the content of the semi-permeable material is 98-99 wt% and the content of the pore-forming agent is 1-2 wt% based on the dry weight of the semi-permeable coating liquid; the semi-permeable material is selected from at least one of cellulose acetate, ethyl cellulose and acrylic resin; the pore-forming agent is selected from at least one of polyethylene glycol, triethyl citrate and triacetin. The dry weight of the semi-permeable coating liquid is 18-22% of the total weight of the first medicine-containing layer premixed powder, the push layer premixed powder and the second medicine-containing layer premixed powder.
Optionally, the protective coating solution contains hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, iron oxide red and talcum powder, and based on the dry weight of the protective coating solution, the content of hydroxypropyl methylcellulose is 52-79 wt%, the content of polyethylene glycol is 10-20 wt%, the content of titanium dioxide is 5-15 wt%, the content of iron oxide red is 1-3 wt%, and the content of talcum powder is 5-10 wt%. The dry weight of the protective coating solution is 5-10% of the total weight of the first drug-containing layer premixed powder, the push layer premixed powder and the second drug-containing layer premixed powder.
Optionally, the solvent of the barrier coating solution may be selected within a certain range, for example, the solvent of the barrier coating solution may be selected from at least one of ethanol, acetone and water, preferably ethanol.
Optionally, the solvent of the semipermeable coating solution may be selected within a certain range, for example, the solvent of the semipermeable coating solution may be selected from at least one of acetone, water, ethanol and dichloromethane, and is preferably a mixed solvent of acetone and water.
Optionally, the solvent of the protective coating solution may be selected within a certain range, for example, the solvent of the protective coating solution may be selected from water and/or ethanol, preferably water.
The technical scheme of the invention has the following advantages:
1. the paliperidone sustained-release tablet provided by the invention can release part of paliperidone at the initial stage of administration (for example, within 2 hours after administration), can remarkably improve the timeliness of paliperidone release under the condition of ensuring the sustained and controlled release effect, and is beneficial to timely and rapidly exerting the drug effect.
Specifically, the tablet core of the paliperidone sustained-release tablet comprises a first drug-containing layer and a second drug-containing layer which are positioned at two ends, and a push layer which is positioned between the first drug-containing layer and the second drug-containing layer, wherein a water absorbent and an extrusion lubricant are added into the first drug-containing layer, a first retardant is added into the push layer, and a second retardant is added into the second drug-containing layer; the water absorbent and the extrusion lubricant contained in the first medicine-containing layer can soften the first medicine-containing layer after water absorption and reduce the friction force between the first medicine-containing layer and the medicine release hole, so that the release speed of the first medicine-containing layer is accelerated, and the paliperidone sustained release tablet can start to release medicines at the initial stage of medication; the first retardant contained in the pushing layer can delay the extrusion of the pushing layer from the drug releasing hole after the first drug-containing layer is completely extruded from the drug releasing hole, so that the pushing layer can still generate enough pushing force to push the second drug-containing layer to be extruded; the second retardant contained in the second drug-containing layer can delay the extrusion of the second drug-containing layer from the drug release hole, so that the second drug-containing layer is not released in the early stage after the drug is applied and begins to be released in the middle and later stages after the drug is applied.
2. The paliperidone sustained-release tablet provided by the invention further optimizes the extrusion effect of the push layer on the second medicine-containing layer and the sustained-release effect of the second medicine-containing layer by optimizing the relative dosage of the first retardant and the second retardant.
3. The paliperidone sustained-release tablet provided by the invention selects low-substituted hydroxypropyl cellulose as the first retarder and the second retarder, and optimizes the particle size of the low-substituted hydroxypropyl cellulose, thereby further optimizing the sustained-release effect of the paliperidone sustained-release tablet.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a graph showing the release rate profiles of several sustained-release tablets of paliperidone in the experimental example of the present invention.
Detailed Description
The following examples are provided to better understand the present invention, not to limit the best mode, and not to limit the content and protection scope of the present invention, and any product that is the same or similar to the present invention and is obtained by combining the present invention with other features of the prior art and the present invention falls within the protection scope of the present invention.
The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or instruments used are not indicated by manufacturers, and are all conventional reagent products which can be obtained commercially.
Example 1
4000 tablets of paliperidone sustained release tablets were prepared as follows:
(1) according to the prescription shown in table 1, paliperidone, polyoxyethylene (carrier material, molecular weight is 200000), sodium alginate (water absorbent), glyceryl behenate (extrusion lubricant) and magnesium stearate (tabletting lubricant) are taken, sieved by a 20-mesh sieve and mixed to obtain a first medicine-containing layer premixed powder;
(2) taking polyoxyethylene (propellant with molecular weight of 7000000), sodium chloride (penetrant), low-substituted hydroxypropylcellulose (first retardant with particle size D90 of 83.2 μm), iron oxide red (first colorant) and magnesium stearate (tabletting lubricant) according to a formula shown in Table 1, sieving with a 20-mesh sieve, and mixing to obtain push layer premixed powder;
(3) according to the formula shown in table 1, paliperidone, polyoxyethylene (carrier material, molecular weight is 200000), low-substituted hydroxypropylcellulose (second retarder, particle size D90 is 83.2 μm), iron oxide yellow (second colorant) and magnesium stearate (tabletting lubricant) are taken, sieved by a 20-mesh sieve and mixed to obtain a second drug-containing layer premixed powder;
(4) tabletting the first medicine-containing layer premixed powder, the pushing layer premixed powder and the second medicine-containing layer premixed powder obtained in the steps (1) - (3) by using a three-layer tabletting machine to enable the first medicine-containing layer and the second medicine-containing layer to be positioned at two ends, and enabling the pushing layer to be positioned between the first medicine-containing layer and the second medicine-containing layer to obtain a tablet core;
(5) preparing an isolation coating solution according to a formula shown in table 1, coating the tablet core obtained in the step (4) at 40-50 ℃ by using the isolation coating solution to form an isolation coating layer on the surface of the tablet core, and drying at 60 ℃ after coating until the water content is less than 3%;
(6) preparing a semi-permeable coating solution according to a formula shown in table 1, coating the dried coating product obtained in the step (5) at 25-35 ℃ by using the semi-permeable coating solution to form a semi-permeable coating layer on the surface of the isolation coating layer, and drying at 60 ℃ after coating until the water content is less than 3%;
(7) performing laser drilling on the isolation coating layer and the semi-permeation coating layer which are close to the first medicine-containing layer and the second medicine-containing layer in the dried coating product obtained in the step (6), and drilling a medicine release hole with the aperture of 0.6mm at each end;
(8) preparing a protective coating solution according to a formula shown in table 1, coating the punched product in the step (7) at 40-50 ℃ by using the protective coating solution to form a protective coating layer on the surface of the semi-permeable coating layer, and drying at 60 ℃ after coating until the moisture content is less than 3% to obtain the paliperidone sustained-release tablet.
TABLE 1 EXAMPLE 1 paliperidone extended release tablet formulation
The paliperidone sustained-release tablet prepared by the embodiment comprises a tablet core, and an isolation coating layer, a semi-permeation coating layer and a protection coating layer which are sequentially coated outside the tablet core; the tablet core comprises a first medicine-containing layer and a second medicine-containing layer which are positioned at two ends, and a push layer which is positioned between the first medicine-containing layer and the second medicine-containing layer, wherein a water absorbent (sodium alginate) and an extrusion lubricant (glyceryl behenate) are added into the first medicine-containing layer, a first retardant (low-substituted hydroxypropyl cellulose) is added into the push layer, and a second retardant (low-substituted hydroxypropyl cellulose) is added into the second medicine-containing layer; the isolation coating layer and the semi-permeable coating layer close to the first medicine-containing layer and the second medicine-containing layer are provided with medicine releasing holes.
Wherein, the weight ratio of the first medicine-containing layer, the pushing layer and the second medicine-containing layer is 50: 100: 50; based on the total weight of the first medicine-containing layer, the content of the water absorbent (sodium alginate) is 10 wt%, and the content of the extrusion lubricant (glyceryl behenate) is 1 wt%; the content of the first retarder (low substituted hydroxypropylcellulose) was 15 wt% based on the total weight of the push layer; the content of the second retarder (low-substituted hydroxypropyl cellulose) is 5 wt% based on the total weight of the second drug-containing layer; the weight of the first retarder is 6 times that of the second retarder.
Example 2
4000 tablets of paliperidone extended release tablet were prepared according to the method of example 1, except that: the formulation of paliperidone sustained release tablet of this example is shown in table 2.
Table 2 example 2 paliperidone sustained release tablet formulation
In the paliperidone sustained-release tablet prepared in this embodiment, the weight ratio of the first drug-containing layer, the push layer, and the second drug-containing layer is 50: 100: 50; based on the total weight of the first medicine-containing layer, the content of the water absorbent (sodium alginate) is 20 wt%, and the content of the extrusion lubricant (glyceryl behenate) is 2 wt%; the content of the first retarder (low substituted hydroxypropylcellulose) was 20 wt%, based on the total weight of the push layer; the content of the second retarding agent (low substituted hydroxypropyl cellulose) is 10 wt% based on the total weight of the second medicine-containing layer; the weight of the first retarder is 4 times that of the second retarder.
Example 3
4000 tablets of paliperidone sustained release tablets were prepared according to the method of example 1, except that: the formulation of paliperidone sustained release tablet of this example is shown in table 3.
Table 3 example 3 paliperidone sustained release tablet formulation
In the paliperidone sustained-release tablet prepared in this embodiment, the weight ratio of the first drug-containing layer, the push layer, and the second drug-containing layer is 50: 100: 75; based on the total weight of the first medicine-containing layer, the content of the water absorbent (sodium alginate) is 20 wt%, and the content of the extrusion lubricant (glyceryl behenate) is 2 wt%; the content of the first retarder (low substituted hydroxypropylcellulose) was 15 wt% based on the total weight of the push layer; the content of the second retarder (low-substituted hydroxypropyl cellulose) is 10 wt% based on the total weight of the second drug-containing layer; the weight of the first retarder is 2 times that of the second retarder.
Example 4
4000 tablets of paliperidone sustained release tablets were prepared according to the method of example 1, except that: the formulation of paliperidone sustained release tablet of this example is shown in table 4.
TABLE 4 example 4 paliperidone extended release tablet formulation
In the paliperidone sustained-release tablet prepared in this embodiment, the weight ratio of the first drug-containing layer, the push layer, and the second drug-containing layer is 50: 100: 50; based on the total weight of the first medicine-containing layer, the content of the water absorbent (sodium alginate) is 20 wt%, and the content of the extrusion lubricant (glyceryl behenate) is 2 wt%; the content of the first retarder (low substituted hydroxypropylcellulose) was 15 wt% based on the total weight of the push layer; the content of the second retarder (low-substituted hydroxypropyl cellulose) is 10 wt% based on the total weight of the second drug-containing layer; the weight of the first retarder was 3 times that of the second retarder.
Examples of the experiments
The paliperidone sustained release tablets prepared in examples 1 to 4 and the commercially available paliperidone sustained release tablets (name: Ruida; manufacturer: Janssen Cilag Manufacturing L.L.C.; lot: 19AD4321) were taken, the release rate was measured by the paddle method, the rotation speed was 50rpm, the release medium was hydrochloric acid aqueous solution with pH 1.0, the volume of the release medium was 500ml, 10ml of the solution was taken at 1 st, 2 nd, 4 th, 6 th, 8 th, 12 th, 14 th, 18 th and 24 th hours after the start of the test, the initial filtrate was filtered by a 0.45 μm filter membrane and 3ml of the initial filtrate was discarded, the subsequent filtrate was used as a test solution, and then the chromatographic conditions were measured by high performance chromatography: c18 chromatographic column (ACE C184.6X 150mm chromatographic column), the mobile phase is ammonium formate buffer solution (4.2 g ammonium formate, adding water for dissolving, adding 5ml formic acid, adding water for diluting to 4000ml) acetonitrile, the volume ratio is 70:30, the flow rate is 1.0ml/min, the temperature of the chromatographic column is 35 ℃, the detection wavelength is 275nm, the sample injection amount is 10 mul, and the test results are shown in Table 5 and figure 1.
TABLE 5 Release Rate of several paliperidone sustained release tablets
| Sampling time, h | Example 1 | Example 2 | Example 3 | Example 4 | Commercially available product |
| 1 | 5.0％ | 6.0％ | 6.0％ | 5.0％ | 0.7％ |
| 2 | 10.0％ | 15.0％ | 13.0％ | 11.0％ | 1.5％ |
| 4 | 20.0％ | 27.0％ | 28.0％ | 22.0％ | 6.4％ |
| 6 | 30.0％ | 38.0％ | 41.0％ | 32.0％ | 14.4％ |
| 8 | 41.0％ | 49.0％ | 54.0％ | 43.0％ | 25.2％ |
| 12 | 65.0％ | 73.0％ | 76.0％ | 62.0％ | 52.1％ |
| 14 | 77.0％ | 84.0％ | 82.0％ | 72.0％ | 65.0％ |
| 18 | 90.0％ | 93.0％ | 88.0％ | 83.0％ | 88.0％ |
| 24 | 100.0％ | 101.0％ | 93.0％ | 91.0％ | 100.0％ |
As can be seen from table 1 and fig. 1, compared with the products on the market, the paliperidone sustained release tablet of the present invention releases a part of paliperidone within 2 hours after administration, which significantly improves the timeliness of paliperidone release under the condition of ensuring the sustained and controlled release effect, and is beneficial to the timely and rapid exertion of the drug effect.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (10)
1. The paliperidone sustained-release tablet is characterized by comprising a tablet core and a semi-permeable coating layer coated outside the tablet core, wherein the tablet core comprises a first medicine-containing layer and a second medicine-containing layer which are positioned at two ends, and a pushing layer positioned between the first medicine-containing layer and the second medicine-containing layer, and the semi-permeable coating layer close to the first medicine-containing layer and the second medicine-containing layer is provided with medicine release holes;
the water absorbent and the extrusion lubricant are added into the first medicine-containing layer, the first retarder is added into the push layer, and the second retarder is added into the second medicine-containing layer.
2. The paliperidone sustained-release tablet of claim 1,
based on the total weight of the first medicine-containing layer, the content of the water absorbent is 10-20 wt%, and the content of the extrusion lubricant is 1-2 wt%;
based on the total weight of the push layer, the content of the first retarder is 15-20 wt%;
the content of the second retarder is 5-10 wt% based on the total weight of the second medicine-containing layer;
optionally, the weight ratio of the first medicine-containing layer to the pushing layer to the second medicine-containing layer is (1-3): (2-3): (1-3).
3. The paliperidone sustained-release tablet of claim 1 or 2,
the water absorbent is sodium alginate;
the extrusion lubricant is selected from at least one of glyceryl behenate, dimethicone, glycerin and hydrogenated vegetable oil, preferably glyceryl behenate;
the first retarder is low-substituted hydroxypropyl cellulose;
the second retarder is low-substituted hydroxypropylcellulose.
4. The paliperidone sustained-release tablet of claim 3, wherein the particle size D90 of the low-substituted hydroxypropylcellulose is 50-100 μm;
optionally, the weight ratio of the first retarder to the second retarder is (2-4): 1.
5. the paliperidone sustained-release tablet of claim 1,
the first medicine-containing layer also contains paliperidone, a carrier material and a tabletting lubricant, and the content of the paliperidone, the carrier material and the tabletting lubricant is 2-4 wt%, 72-86 wt% and 1-2 wt%, respectively, based on the total weight of the first medicine-containing layer;
the push layer also contains a push material, a penetrating agent and a tabletting lubricant, and based on the total weight of the push layer, the content of the push material is 56.5-63.5 wt%, the content of the penetrating agent is 10-30 wt%, and the content of the tabletting lubricant is 1-2 wt%;
the second medicine-containing layer also contains paliperidone, a carrier material and a tabletting lubricant, and the content of the paliperidone, the carrier material and the tabletting lubricant are respectively 2-4 wt%, 83-91.5 wt% and 1-2 wt% based on the total weight of the second medicine-containing layer;
optionally, for a single paliperidone sustained-release tablet, the total weight of paliperidone in the first drug-containing layer and the second drug-containing layer is 1.5-12 mg;
optionally, the carrier material is selected from at least one of polyoxyethylene with a molecular weight of 100000-400000, hydroxypropyl methylcellulose, hydroxypropyl cellulose and poloxamer; the tabletting lubricant is at least one selected from stearic acid, magnesium stearate and sodium stearyl fumarate; the pushing material is selected from at least one of polyoxyethylene with molecular weight of 4000000-7000000, hydroxypropyl methylcellulose, hydroxypropyl cellulose and poloxamer; the osmotic agent is selected from at least one of sodium chloride, potassium chloride, glucose and sodium citrate;
optionally, the push layer further comprises 0.5-1.5 wt% of a first colorant, the second drug-containing layer further comprises 0.5-1.0 wt% of a second colorant, the first colorant is different from the second colorant, and the first colorant and the second colorant are independently selected from any one of iron oxide red, iron oxide yellow, brilliant blue, indigo, carmine and curcumin.
6. The paliperidone sustained-release tablet of claim 1, wherein the weight of the semi-permeable coating layer is 18-22% of the weight of the tablet core, the semi-permeable coating layer contains a semi-permeable material and a pore-forming agent, and based on the total weight of the semi-permeable coating layer, the content of the semi-permeable material is 98-99 wt%, and the content of the pore-forming agent is 1-2 wt%;
optionally, the semi-permeable material is selected from at least one of cellulose acetate, ethyl cellulose, and acrylic resin; the pore-forming agent is selected from at least one of polyethylene glycol, triethyl citrate and triacetin;
optionally, the paliperidone sustained-release tablet further comprises an isolation coating layer, the isolation coating layer is positioned between the tablet core and the semi-permeation coating layer, and the drug release holes penetrate through the isolation coating layer; the weight of the isolation coating layer is 8-12% of that of the tablet core, the isolation coating layer contains hydroxypropyl cellulose and povidone, and based on the total weight of the isolation coating layer, the content of the hydroxypropyl cellulose is 50-90 wt%, and the content of the povidone is 10-50 wt%;
optionally, the paliperidone sustained-release tablet further comprises a protective coating layer, and the protective coating layer is coated on the outer surface of the semi-permeable coating layer; the weight of the protective coating layer is 5-10% of that of the tablet core, the protective coating layer contains hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, iron oxide red and talcum powder, and based on the total weight of the protective coating layer, the content of the hydroxypropyl methylcellulose is 52-79 wt%, the content of the polyethylene glycol is 10-20 wt%, the content of the titanium dioxide is 5-15 wt%, the content of the iron oxide red is 1-3 wt%, and the content of the talcum powder is 5-10 wt%.
7. The paliperidone sustained-release tablet of claim 1, wherein the number of the drug release holes near one end of the first drug-containing layer is 1-3, the number of the drug release holes near one end of the second drug-containing layer is 1-3, and the aperture of the drug release holes is 0.5-0.7 mm.
8. A method for preparing the paliperidone sustained-release tablet of any one of claims 1-7, comprising the following operations:
carrying out layered tabletting on the first medicine-containing layer premixed powder, the pushing layer premixed powder and the second medicine-containing layer premixed powder to respectively form a first medicine-containing layer, a pushing layer and a second medicine-containing layer, enabling the first medicine-containing layer and the second medicine-containing layer to be located at two ends, and enabling the pushing layer to be located between the first medicine-containing layer and the second medicine-containing layer to obtain a tablet core; the water absorbent and the extrusion lubricant are added into the first medicine-containing layer premixed powder, the first retarder is added into the pushing layer premixed powder, and the second retarder is added into the second medicine-containing layer premixed powder;
coating the tablet core by using a semi-permeable coating solution to form a semi-permeable coating layer outside the tablet core;
laser drilling of the semipermeable coating adjacent to the first drug-containing layer and the second drug-containing layer.
9. The method of claim 8, wherein the first drug-containing layer premix powder further comprises paliperidone, a carrier material, and a tableting lubricant;
the pushing layer premixed powder also contains a pushing material, a penetrating agent and a tabletting lubricant;
the second medicine-containing layer premixed powder also contains paliperidone, a carrier material and a tabletting lubricant;
optionally, the push layer premixed powder further contains a first colorant, and the second drug-containing layer premixed powder further contains a second colorant.
10. The method according to claim 8 or 9, wherein prior to coating the core with the semipermeable coating solution, the method further comprises the operation of coating the core with an isolating coating solution to form an isolating coating layer on the surface of the core, and then coating the surface of the isolating coating layer with the semipermeable coating solution to form a semipermeable coating layer;
when laser drilling is carried out, carrying out laser drilling on the isolation coating layer and the semi-permeation coating layer which are close to the first medicine-containing layer and the second medicine-containing layer;
optionally, the method further comprises an operation of coating the surface of the laser-drilled semipermeable coating layer with a protective coating solution to form a protective coating layer;
optionally, the semi-permeable coating liquid contains a semi-permeable material and a pore-forming agent;
optionally, the isolating coating solution contains hydroxypropyl cellulose and povidone;
optionally, the protective coating solution contains hypromellose, polyethylene glycol, titanium dioxide, iron oxide red and talcum powder.
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| CN202210776404.4A CN114983961B (en) | 2022-06-30 | 2022-06-30 | Paliperidone sustained release tablet and preparation method thereof |
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Citations (4)
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|---|---|---|---|---|
| WO2015001488A1 (en) * | 2013-07-01 | 2015-01-08 | Ranbaxy Laboratories Limited | Extended-release tablets of paliperidone and processes of preparation thereof |
| CN104857515A (en) * | 2014-02-25 | 2015-08-26 | 中国科学院上海药物研究所 | Controlled release dosing medicine core composition and osmotic pump preparation comprising medicine core composition |
| CN107281151A (en) * | 2016-04-01 | 2017-10-24 | 天津市汉康医药生物技术有限公司 | Paliperidone osmotic pump type controlled release tablets |
| CN114601813A (en) * | 2022-03-30 | 2022-06-10 | 深圳市泛谷药业股份有限公司 | Paliperidone double-layer osmotic pump sustained-release preparation and preparation method thereof |
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2022
- 2022-06-30 CN CN202210776404.4A patent/CN114983961B/en active Active
Patent Citations (4)
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|---|---|---|---|---|
| WO2015001488A1 (en) * | 2013-07-01 | 2015-01-08 | Ranbaxy Laboratories Limited | Extended-release tablets of paliperidone and processes of preparation thereof |
| CN104857515A (en) * | 2014-02-25 | 2015-08-26 | 中国科学院上海药物研究所 | Controlled release dosing medicine core composition and osmotic pump preparation comprising medicine core composition |
| CN107281151A (en) * | 2016-04-01 | 2017-10-24 | 天津市汉康医药生物技术有限公司 | Paliperidone osmotic pump type controlled release tablets |
| CN114601813A (en) * | 2022-03-30 | 2022-06-10 | 深圳市泛谷药业股份有限公司 | Paliperidone double-layer osmotic pump sustained-release preparation and preparation method thereof |
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| CN114983961B (en) | 2024-05-10 |
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