CN114601813A - Paliperidone double-layer osmotic pump sustained-release preparation and preparation method thereof - Google Patents
Paliperidone double-layer osmotic pump sustained-release preparation and preparation method thereof Download PDFInfo
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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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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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
- A61K9/2004—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
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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
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
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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
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2893—Tablet coating processes
-
- 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
Abstract
The invention discloses a paliperidone double-layer osmotic pump sustained-release preparation and a preparation method thereof, and the paliperidone double-layer osmotic pump sustained-release preparation comprises a double-layer tablet core and a semipermeable membrane coating coated on the surface of the double-layer tablet core, wherein the double-layer tablet core comprises a medicine layer and a push layer, the surface of one side of the semipermeable membrane coating, which is close to the medicine layer, is provided with at least one medicine release hole, the medicine layer comprises a medicine active ingredient, an osmotic polymer and a penetrating agent, the medicine active ingredient comprises paliperidone and pharmaceutically acceptable salts or esters thereof, the push layer comprises the osmotic polymer and the penetrating agent, and the aperture of the medicine release hole is 0.3-1.2 mm. The paliperidone double-layer osmotic pump sustained-release preparation adopting the structure and the preparation method thereof not only simplifies the production and preparation process and reduces the production cost and the equipment requirement, but also can effectively control the drug release rate, so that the blood concentration curve is stable, the fluctuation of the drug concentration is reduced, and the safety of taking the drug by a patient is improved.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a paliperidone double-layer osmotic pump sustained-release preparation and a preparation method thereof.
Background
Currently, paliperidone sustained release tablets (trade name: Ruida; England name: Invega) are three-layer osmotic pump formulations manufactured by Janssen Inc., mainly used for the treatment of schizophrenia. However, the existing paliperidone sustained-release tablets have the following disadvantages: (1) the preparation process is complex, the production time is long, and the workload and the cost are high. The existing three-layer paliperidone osmotic pump sustained-release tablet comprises two drug layers with different drug concentrations and a boosting layer. Therefore, in the preparation process, two medicine layer granules with different medicine contents need to be prepared, the granule contents are respectively measured, and then tabletting is carried out, so that the production time is long, and the workload and the cost are high. In addition, the tabletting requires special three-layer tabletting machine equipment, the equipment requirement is high, and the difficulty of accurately controlling the weight and the drug content of each layer is high. (2) The three-layer osmotic pump sustained release tablet releases paliperidone at an increasing release rate, and the fluctuation of blood concentration is relatively large, thereby reducing the safety of taking medicine by patients.
Disclosure of Invention
The invention aims to provide a paliperidone double-layer osmotic pump sustained-release preparation and a preparation method thereof, and aims to solve the problems that the preparation process of the paliperidone osmotic pump sustained-release preparation is complex, the production time is long, and the blood concentration fluctuation is large due to the increment of the paliperidone release rate.
In order to achieve the purpose, the invention provides a paliperidone double-layer osmotic pump sustained-release preparation and a preparation method thereof, the paliperidone double-layer osmotic pump sustained-release preparation comprises a double-layer tablet core and a semipermeable membrane coating wrapped on the surface of the double-layer tablet core, the double-layer tablet core comprises a drug layer and a push layer, the surface of one side of the semipermeable membrane coating, which is close to the drug layer, is provided with at least one drug release hole, the drug layer comprises a drug active ingredient, an osmotic polymer and an osmotic agent, the drug active ingredient comprises paliperidone and pharmaceutically acceptable salts or esters thereof, the push layer comprises the osmotic polymer and the osmotic agent, and the aperture of the drug release hole is 0.3-1.2 mm.
Preferably, the osmopolymer comprises polyoxyethylene, the average molecular weight of the polyoxyethylene in the drug layer is 10000-300000, which accounts for more than 70% of the mass of the drug layer, and the average molecular weight of the polyoxyethylene in the push layer is 4000000-7000000, which accounts for more than 65% of the mass of the push layer.
Preferably, the mass percentage of the active pharmaceutical ingredients in the drug layer is 1-10%.
Preferably, the osmotic agent comprises a salt, a saccharide, or a mixture thereof. More preferably, the osmotic agent may be sodium chloride, magnesium chloride, potassium chloride, lactose, glucose, fructose, or a mixture thereof.
Preferably, the medicine layer and the pushing layer both further comprise a lubricant, a solvent and a medicine auxiliary material, and the medicine layer further comprises a colorant. More preferably, the lubricant can be magnesium stearate, stearic acid, talcum powder, sodium stearyl fumarate and the like, the solvent can be water, ethanol, propanol, isopropanol, methanol and the like, the pharmaceutical auxiliary material can be povidone K-29, povidone K-32 and the like, and the colorant can be one or more of red ferric oxide, yellow ferric oxide, brown ferric oxide, purple ferric oxide or black ferric oxide.
Preferably, the ratio of osmotic agent to osmopolymer in the drug layer is from 1:4.5 to 1:17 and the ratio of osmotic agent to osmopolymer in the push layer is from 1:2.5 to 1: 6.
A preparation method of a paliperidone double-layer osmotic pump sustained-release preparation comprises the following steps:
(1) sieving and mixing the active components, osmopolymer, penetrant, colorant, medicinal adjuvants, lubricant and solvent by wet method to obtain medicinal layer granule;
(2) preparing the osmotic polymer, the osmotic agent, the pharmaceutical excipients, the lubricant and the solvent into push layer particles by a sieving and mixing wet method;
(3) pressing the medicine layer particles and the push layer particles into a double-layer tablet core consisting of a medicine layer and a push layer by adopting a twice tabletting technology;
(4) preparing polyethylene glycol into a clear aqueous solution, adding propanol, uniformly mixing, adding cellulose acetate, and stirring to obtain a clear solution to obtain a semipermeable membrane coating;
(5) coating the prepared double-layer tablet core with a semipermeable membrane coating to obtain a coated tablet, and drilling a drug release hole on one side of the semipermeable membrane coating close to the drug layer by using laser or mechanical equipment to obtain the paliperidone double-layer osmotic pump sustained release preparation.
Preferably, in the step (5), the semipermeable membrane coating accounts for 10-20% of the mass of the double-layer tablet core.
Therefore, the paliperidone double-layer osmotic pump sustained-release preparation and the preparation method thereof adopting the structure not only simplify the production and preparation process and reduce the production cost and equipment requirements, but also can effectively control the drug release rate, so that the blood concentration curve is stable, the fluctuation of the drug concentration is reduced, and the safety of taking the drug by a patient is improved.
The technical solution of the present invention is further described in detail by the accompanying drawings and embodiments.
Drawings
FIG. 1 is a cumulative drug release profile for the formulation of example 1;
FIG. 2 is a cumulative release profile of the drug from the formulation of example 2;
FIG. 3 is a cumulative drug release profile for the formulation of example 3;
FIG. 4 is a cumulative release profile of the drug from the formulation of example 4;
FIG. 5 is a cumulative release profile of the drug from the formulation of example 5;
figure 6 is a cumulative drug release profile for the formulation of example 6.
Detailed Description
The present invention will be further described below, and it should be noted that the present embodiment is based on the technical solution, and a detailed implementation manner and a specific operation process are provided, but the present invention is not limited to the present embodiment.
Examples 1 to 5
Tables 1 and 2 show the formulation composition of the bilayer tablet core and the semipermeable membrane coating of examples 1-5, respectively.
TABLE 1 tablet core formulation composition
TABLE 2 formulation composition of semipermeable membrane coating
Note: the solid content of the coating liquid is 5% (w/w)
A preparation method of a paliperidone double-layer osmotic pump sustained-release preparation comprises the following steps:
(1) sieving and mixing the active components, osmopolymer, penetrant, colorant, medicinal adjuvants, lubricant and solvent by wet method to obtain medicinal layer granule;
(2) preparing the osmotic polymer, the osmotic agent, the pharmaceutical excipients, the lubricant and the solvent into push layer particles by a sieving and mixing wet method;
(3) pressing the medicine layer particles and the push layer particles into a double-layer tablet core consisting of a medicine layer and a push layer by adopting a twice tabletting technology;
(4) preparing polyethylene glycol into a clear aqueous solution, adding propanol, uniformly mixing, adding cellulose acetate, and stirring to obtain a clear solution to obtain a semipermeable membrane coating;
(5) and coating the prepared double-layer tablet core with a semipermeable membrane coating to obtain a coated tablet, wherein the semipermeable membrane coating accounts for 16% of the mass of the double-layer tablet core, and drilling drug release holes on one side of the semipermeable membrane coating close to the drug layer by using laser or mechanical equipment to obtain the paliperidone double-layer osmotic pump sustained release preparation.
Examples 1-5 paliperidone bilayer osmotic pump sustained release formulations were prepared as described above.
Example 6
Example 6 is different from example 1 in that the semipermeable membrane coating accounts for 17% of the mass of the bilayer tablet core, and the pore diameter of the drug release pore is 0.3 mm.
Example 7
Example 7 is different from example 6 in that the pore diameter of the drug release pore is 0.65 mm.
Example 8
Example 8 is different from example 6 in that the pore diameter of the drug release pore is 1.2 mm.
The degrees of release of examples 1 to 8 were measured according to the standard method for measuring the degrees of release, and samples were taken and measured by high performance liquid chromatography using usp slurry method with hydrochloric acid solution (pH 1, 500mL) containing 0.2% sodium chloride as a release medium at 4, 8, 12, 14, 18, 20, and 24 hours. FIGS. 1-5 are the cumulative release profiles of the drugs of examples 1-5, FIG. 6 is the cumulative release profiles of the drugs of examples 6-8, and Table 3 is the mean release rates of the drugs of the formulations of examples 1-8 from hour 4 to hour 20, respectively.
TABLE 3 mean release rates of drugs from the 4 th hour to the 20 th hour of the formulations of examples 1-8
It can be seen from fig. 1-6 and table 3 that the paliperidone bilayer osmotic pump sustained release formulations prepared in examples 1-8 can effectively control the release rate of the drug, even though the drug release curves and average release rates are almost identical under different pore diameters of the drug release pores, which indicates that the formulations prepared by the present invention can maintain the same amount of drug released per hour, thereby reducing the fluctuation of blood drug concentration after the patient takes the drug and increasing the safety of the patient taking the drug.
Therefore, the paliperidone double-layer osmotic pump sustained-release preparation and the preparation method thereof adopting the structure not only simplify the production and preparation process and reduce the production cost and equipment requirements, but also can effectively control the drug release rate, so that the blood concentration curve is stable, the fluctuation of the drug concentration is reduced, and the safety of taking the drug by a patient is improved.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting the same, and although the present invention is described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that: modifications and equivalents may be made to the invention without departing from the spirit and scope of the invention.
Claims (8)
1. A paliperidone double-layer osmotic pump sustained-release preparation is characterized in that: the double-layer tablet core comprises a medicine layer and a pushing layer, wherein the surface of one side, close to the medicine layer, of the semipermeable membrane coating is provided with at least one medicine release hole, the medicine layer comprises a medicine active ingredient, an osmotic polymer and a penetrating agent, the medicine active ingredient comprises paliperidone and pharmaceutically acceptable salts or esters thereof, the pushing layer comprises the osmotic polymer and the penetrating agent, and the hole diameter of the medicine release hole is 0.3-1.2 mm.
2. The bi-layer osmotic pump sustained release formulation of paliperidone according to claim 1, characterized in that: the osmotic polymer comprises polyoxyethylene, the average molecular weight of the polyoxyethylene in the drug layer is 10000-300000 and accounts for more than 70 percent of the mass of the drug layer, and the average molecular weight of the polyoxyethylene in the push layer is 4000000-7000000 and accounts for more than 65 percent of the mass of the push layer.
3. The bi-layer osmotic pump sustained release formulation of paliperidone according to claim 1, characterized in that: the active components account for 1-10% of the medicine layer.
4. The bi-layer osmotic pump sustained release formulation of paliperidone according to claim 1, characterized in that: the osmotic agent includes salts, saccharides, or mixtures thereof.
5. The bi-layer osmotic pump sustained release formulation of paliperidone according to claim 1, characterized in that: the medicine layer and the pushing layer both comprise a lubricant, a solvent and a medicine auxiliary material, and the medicine layer also comprises a colorant.
6. The bi-layer osmotic pump sustained release formulation of paliperidone according to claim 1, characterized in that: the ratio of osmotic agent to osmopolymer in the drug layer is 1:4.5-1:17, and the ratio of osmotic agent to osmopolymer in the push layer is 1:2.5-1: 6.
7. The process for preparing a paliperidone bi-layer osmotic pump sustained release formulation of claims 1-6, wherein: the method comprises the following steps:
(1) sieving and mixing the active components, osmopolymer, penetrant, colorant, medicinal adjuvants, lubricant and solvent by wet method to obtain medicinal layer granule;
(2) preparing the osmotic polymer, the osmotic agent, the pharmaceutical excipients, the lubricant and the solvent into push layer particles by a sieving and mixing wet method;
(3) pressing the medicine layer particles and the push layer particles into a double-layer tablet core consisting of the medicine layer and the push layer by adopting a twice tabletting technology;
(4) preparing polyethylene glycol into a clear aqueous solution, adding propanol, uniformly mixing, adding cellulose acetate, and stirring to obtain a clear solution to obtain a semipermeable membrane coating;
(5) coating the prepared double-layer tablet core with a semipermeable membrane coating to obtain a coated tablet, and drilling a drug release hole on one side of the semipermeable membrane coating close to the drug layer by using laser or mechanical equipment to obtain the paliperidone double-layer osmotic pump sustained release preparation.
8. The method for preparing a paliperidone bi-layer osmotic pump sustained release formulation according to claim 7, characterized in that: in the step (5), the semipermeable membrane coating accounts for 10-20% of the mass of the double-layer tablet core.
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| CN202210330380.XA CN114601813A (en) | 2022-03-30 | 2022-03-30 | Paliperidone double-layer osmotic pump sustained-release preparation and preparation method thereof |
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| CN202210330380.XA CN114601813A (en) | 2022-03-30 | 2022-03-30 | Paliperidone double-layer osmotic pump sustained-release preparation and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114983961A (en) * | 2022-06-30 | 2022-09-02 | 苏州中化药品工业有限公司 | Paliperidone sustained-release tablet and preparation method thereof |
| WO2024083087A1 (en) * | 2022-10-20 | 2024-04-25 | Anxo Pharmaceutical Co., Ltd. | Sustained release osmotic-controlled pharmaceutical composition and preparation method thereof |
| CN114983961B (en) * | 2022-06-30 | 2024-05-10 | 苏州中化药品工业有限公司 | Paliperidone sustained release tablet and preparation method thereof |
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2022
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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 |
| US20200253861A1 (en) * | 2018-03-05 | 2020-08-13 | Kashiv Biosciences, Llc | Programmable pharmaceutical compositions for chrono drug release |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114983961A (en) * | 2022-06-30 | 2022-09-02 | 苏州中化药品工业有限公司 | Paliperidone sustained-release tablet and preparation method thereof |
| CN114983961B (en) * | 2022-06-30 | 2024-05-10 | 苏州中化药品工业有限公司 | Paliperidone sustained release tablet and preparation method thereof |
| WO2024083087A1 (en) * | 2022-10-20 | 2024-04-25 | Anxo Pharmaceutical Co., Ltd. | Sustained release osmotic-controlled pharmaceutical composition and preparation method thereof |
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