CN110974797A - Paricalcitol tablet and preparation method thereof - Google Patents
Paricalcitol tablet and preparation method thereof Download PDFInfo
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- CN110974797A CN110974797A CN201911265331.7A CN201911265331A CN110974797A CN 110974797 A CN110974797 A CN 110974797A CN 201911265331 A CN201911265331 A CN 201911265331A CN 110974797 A CN110974797 A CN 110974797A
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- Prior art keywords
- paricalcitol
- controlled release
- controlled
- agent
- tablet
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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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
- A61P5/20—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of PTH
Abstract
The invention discloses a paricalcitol controlled-release tablet and a preparation method thereof, the paricalcitol controlled-release tablet consists of a paricalcitol tablet core and a controlled-release coating layer coated outside the tablet core, the tablet core consists of paricalcitol, a filling agent and an antioxidant, the controlled-release coating layer consists of a controlled-release material, a plasticizer, a pore-forming agent and an anti-sticking agent, and the preparation method is characterized in that the paricalcitol tablet core is coated with the controlled-release coating layer. The invention solves the problems of single dosage form, poor stability of oral preparations and the like of the paricalcitol on the market, achieves the aims of long acting and increased curative effect, can also reduce the dosage and reduce the side effect when maintaining the same drug effect, has simple preparation process, and ensures that the obtained product has stable quality and is suitable for large-scale production.
Description
Technical Field
The invention relates to a western medicine preparation technology, in particular to a paricalcitol controlled release tablet, and a preparation method thereof, belonging to the technical field of medicines.
Background
Secondary Hyperparathyroidism (SHPT) is caused by the presence of factors that stimulate the parathyroid glands, especially hypocalcemia, magnesium hypofunction and hyperphosphatemia, and the glands proliferate and hypertrophy after stimulation, secrete excessive parathyroid hormone, and compensate and maintain the normocalcium and phosphorus. The disease is mostly seen in vitamin D deficiency, severe renal insufficiency, osteomalacia, pregnancy or lactating women.
The bioactive form of vitamin D, calcitriol, plays a key role in a series of physiological functions such as calcium balance in vivo, hormone secretion and cell proliferation and differentiation. The supplement of calcitriol becomes an important way for clinically treating secondary hyperparathyroidism. However, in clinical application, calcitriol has toxic and side effects of significantly increased blood calcium. In view of the limitations of calcitriol in clinical therapy, a number of vitamin D analogs with low side effects and high selectivity have been developed in succession.
Paricalcitol is a vitamin D analogue developed by yapei corporation, and exerts its corresponding physiological effects by binding to Vitamin D Receptor (VDR) as calcitriol. The medicine can inhibit parathyroid hormone more quickly and durably, has small influence on calcium, phosphorus and calcium-phosphorus deposition, so continuous hypercalcemia is less generated, the curative effect of the medicine in reducing aortic calcification and improving bone is also better than that of calcitriol, and the medicine can reduce the fatality rate, the hospitalization frequency and the hospitalization time of a patient, so that the medicine is an excellent medicine for treating osteoporosis. In 1998, injection preparations of paricalcitol (Zemplar) were marketed in the U.S. for the prevention and treatment of SHPT, which was effective in the prevention and treatment of SHPT in patients with Chronic Kidney Disease (CKD) in stages iii and iv before dialysis and transplantation surgery.
Paricalcitol is a synthetic bioactive vitamin D analog, and has modifications of calcitriol side chain (D2) and A ring (19-nor) of formula C27H44O3The structure is as follows:
the paricalcitol is insoluble in water, soluble in organic solvents, very unstable in chemical properties and sensitive to oxygen. At present, the paricalcitol in the market only has two dosage forms, namely a soft capsule and an injection, the dosage forms are single, and patients have no choice. The injection is inconvenient to administer and limited in use; the soft capsule has poor stability, and is easy to absorb moisture to influence disintegration and content in long-term storage, thereby influencing bioavailability and curative effect.
Disclosure of Invention
In order to solve the problems of single dosage form, poor stability and the like of the existing paricalcitol, the invention develops an oral solid preparation with high stability, convenient taking and simple preparation process.
In order to achieve the purpose, the invention adopts the technical scheme that:
the controlled release paricalcitol tablet consists of a paricalcitol tablet core and a controlled release coating layer coated outside the tablet core, wherein the tablet core consists of paricalcitol, a filling agent and an antioxidant, and the controlled release coating layer consists of a controlled release material, a plasticizer, a pore-forming agent and an anti-sticking agent, and is characterized in that the controlled release coating layer consists of the following components in percentage by weight:
paricalcitol 0.00002%
55 to 65 percent of filling agent
0.02 to 0.04 percent of antioxidant
20 to 30 percent of controlled release material
3 to 10 percent of plasticizer
3 to 10 percent of pore-foaming agent
3-10% of an anti-sticking agent.
Wherein the filler is lactose; the antioxidant is tert-butyl hydroquinone; the controlled release material is chitosan or ethylene acrylic acid copolymer; the plasticizer is dimethyl phthalate; the pore-foaming agent is polyethylene glycol or polyvidone; the antisticking agent is magnesium stearate.
Wherein, the controlled release material is preferably chitosan; the pore-forming agent is preferably polyethylene glycol.
Wherein, the weight ratio of the chitosan to the polyethylene glycol is preferably 3-5: 1-2; most preferably, the weight ratio of chitosan to polyethylene glycol is 5: 1.
the paricalcitol controlled-release tablet can be prepared by the following method:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) uniformly mixing paricalcitol, a filling agent and an antioxidant, sieving with a 20-24 mesh sieve by using absolute ethyl alcohol as an adhesive, granulating, drying and tabletting to obtain a paricalcitol tablet core for later use;
(3) dissolving the controlled release material, the plasticizer, the pore-forming agent and the anti-sticking agent by 80 percent ethanol to prepare controlled release coating liquid;
(4) uniformly spraying the prepared controlled-release coating solution on the surface of the tablet core prepared in the step (2), and drying to obtain the paricalcitol controlled-release tablet;
(5) and (6) inspecting, packaging, and warehousing qualified products.
The paricalcitol controlled-release tablet provided by the invention has the following beneficial effects:
(1) the product has high quality stability and improves the bioavailability;
(2) the selected auxiliary materials are common, the preparation process is simple, the obtained product has stable quality, and the method is suitable for large-scale production.
Detailed Description
The following further describes the embodiments of the present invention with reference to examples, but these examples are only illustrative and do not limit the scope of the present invention. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
Examples 1-5 preparation of Parricalciferol controlled-release tablets
A preparation method of paricalcitol controlled-release tablets comprises the following steps:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) uniformly mixing paricalcitol, a filling agent and an antioxidant, sieving with a 20-24 mesh sieve by using absolute ethyl alcohol as an adhesive, granulating, drying and tabletting to obtain a paricalcitol tablet core for later use;
(3) dissolving the controlled release material, the plasticizer, the pore-forming agent and the anti-sticking agent by 80 percent ethanol to prepare controlled release coating liquid;
(4) uniformly spraying the prepared controlled-release coating solution on the surface of the tablet core prepared in the step (2), and drying to obtain the paricalcitol controlled-release tablet;
(5) and (6) inspecting, packaging, and warehousing qualified products.
The paricalcitol controlled-release tablet is prepared according to the preparation method and the raw and auxiliary materials in the formula (1000 tablets) in the following table 1. Where "/" indicates unused.
Test example 1 accelerated stability test
Accelerated stability tests were performed according to the guidelines of stability of crude drugs and preparations 9001, the general guidelines of the four ministry of the pharmacopoeia of China 2015 edition. The controlled release tablets of paricalcitol obtained in examples 1 to 5 and the reference preparation, paricalcitol soft capsules (trade name: Zemplar), were used as test samples and packaged commercially and left for 6 months at a temperature of 40 ℃. + -. 2 ℃ and a relative humidity of 75%. + -. 5%. Samples were taken at the end of 1 month, 2 months, 3 months and 6 months during the test period, and the content of the paricalcitol preparation was determined according to the paricalcitol content detection method.
The method for detecting the content of paricalcitol comprises the following steps:
testing the spectrum condition and the system applicability: octadecylsilane chemically bonded silica is used as a filling agent; chromatographic conditions are as follows: mobile phase: acetonitrile-water (75: 25); detection wavelength: 265 nm; column temperature: 20 ℃; flow rate: 1.0 ml/min; sample introduction amount: 20 mu l of the mixture; the number of theoretical plates should not be less than 5000 in terms of paricalcitol peak.
The determination method comprises the following steps: and (4) avoiding light. Precisely weighing a proper amount of a test sample (about 5 mu g of paricalcitol), placing the test sample into a 10ml centrifuge tube, precisely adding 5ml of methanol, shaking for 2 min, freezing in a refrigerator at the temperature of-18 ℃ for 30 min, taking out, centrifuging (4000 r/min) for 5 min, taking the supernatant methanol clear liquid as a test sample solution, precisely measuring 50 mu l, injecting into a liquid chromatograph, and recording a chromatogram. An appropriate amount of paricalcitol control was precisely weighed, dissolved in methanol and diluted to a solution containing about 1.0. mu.g of paricalcitol per 1ml, and the content was measured by the same method. Calculating according to the peak area by an external standard method to obtain the product. The results of the content determination of the accelerated stability test of paricalcitol are shown in table 2.
Test example 2 Long-term stability test
A long-term stability test is carried out according to 9001 guiding principle of stability of raw material medicines and preparations in accordance with the general guidelines of the four ministry of the chapter of the book of Chinese pharmacopoeia 2015. The controlled release tablets of paricalcitol obtained in examples 1 to 5 and the reference preparation, paricalcitol soft capsules (trade name: Zemplar), were used as test samples and packaged commercially for 24 months at a temperature of 25 ℃. + -. 2 ℃ and a relative humidity of 60% + -10%. Samples were taken at the end of 0 month, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months of the test period, and the content of the paricalcitol preparation was determined according to the paricalcitol content detection method.
The method for detecting the content of paricalcitol comprises the following steps:
testing the spectrum condition and the system applicability: octadecylsilane chemically bonded silica is used as a filling agent; chromatographic conditions are as follows: mobile phase: acetonitrile-water (75: 25); detection wavelength: 265 nm; column temperature: 20 ℃; flow rate: 1.0 ml/min; sample introduction amount: 20 mu l of the mixture; the number of theoretical plates should not be less than 5000 in terms of paricalcitol peak.
The determination method comprises the following steps: and (4) avoiding light. Precisely weighing a proper amount of a test sample (about 5 mu g of paricalcitol), placing the test sample into a 10ml centrifuge tube, precisely adding 5ml of methanol, shaking for 2 min, freezing in a refrigerator at the temperature of-18 ℃ for 30 min, taking out, centrifuging (4000 r/min) for 5 min, taking the supernatant methanol clear liquid as a test sample solution, precisely measuring 50 mu l, injecting into a liquid chromatograph, and recording a chromatogram. An appropriate amount of paricalcitol control was precisely weighed, dissolved in methanol and diluted to a solution containing about 1.0. mu.g of paricalcitol per 1ml, and the content was measured by the same method. Calculating according to the peak area by an external standard method to obtain the product. The results of the content determination of the paricalcitol long-term stability test are shown in table 3.
As can be seen from table 2 and table 3, the content measurement results of the accelerated and long-term stability tests of paricalcitol in example 1 are significantly better than those of the control preparation paricalcitol soft capsule and examples 2-5, when accelerated for 6 months and long-term for 24 months, which indicates that when chitosan is used as the controlled release material and polyethylene glycol is used as the pore-forming agent, the weight ratio of the controlled release material to the pore-forming agent is 5: 1, the prepared paricalcitol controlled-release tablet has the best stability effect and is superior to the paricalcitol soft capsules on the market.
Claims (5)
1. The controlled release paricalcitol tablet consists of a paricalcitol tablet core and a controlled release coating layer coated outside the tablet core, wherein the tablet core consists of paricalcitol, a filling agent and an antioxidant, and the controlled release coating layer consists of a controlled release material, a plasticizer, a pore-forming agent and an anti-sticking agent, and is characterized in that the controlled release coating layer consists of the following components in percentage by weight:
paricalcitol 0.00002%
55 to 65 percent of filling agent
0.02 to 0.04 percent of antioxidant
20 to 30 percent of controlled release material
3 to 10 percent of plasticizer
3 to 10 percent of pore-foaming agent
3-10% of an anti-sticking agent.
2. The paricalcitol controlled release tablet according to claim 1, characterized in that the filler is lactose; the antioxidant is tert-butyl hydroquinone; the controlled release material is chitosan or ethylene acrylic acid copolymer; the plasticizer is dimethyl phthalate; the pore-foaming agent is polyethylene glycol or polyvidone; the antisticking agent is magnesium stearate.
3. Controlled release tablets according to claim 2, characterized in that the controlled release material is preferably chitosan; the pore-forming agent is preferably polyethylene glycol.
4. The paricalcitol controlled release tablet according to claim 3, characterized in that the weight ratio of chitosan to polyethylene glycol is preferably 3-5: 1-2; most preferably, the weight ratio of chitosan to polyethylene glycol is 5: 1.
5. the controlled release tablets of paricalcitol according to claim 1, which can be prepared by the following method:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) uniformly mixing paricalcitol, a filling agent and an antioxidant, sieving with a 20-24 mesh sieve by using absolute ethyl alcohol as an adhesive, granulating, drying and tabletting to obtain a paricalcitol tablet core for later use;
(3) dissolving the controlled release material, the plasticizer, the pore-forming agent and the anti-sticking agent by 80 percent ethanol to prepare controlled release coating liquid;
(4) uniformly spraying the prepared controlled-release coating solution on the surface of the tablet core prepared in the step (2), and drying to obtain the paricalcitol controlled-release tablet;
(5) and (6) inspecting, packaging, and warehousing qualified products.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911265331.7A CN110974797A (en) | 2019-12-11 | 2019-12-11 | Paricalcitol tablet and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911265331.7A CN110974797A (en) | 2019-12-11 | 2019-12-11 | Paricalcitol tablet and preparation method thereof |
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| Publication Number | Publication Date |
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| CN110974797A true CN110974797A (en) | 2020-04-10 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201911265331.7A Withdrawn CN110974797A (en) | 2019-12-11 | 2019-12-11 | Paricalcitol tablet and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117398397A (en) * | 2023-11-30 | 2024-01-16 | 正大制药（青岛）有限公司 | Parcalcitol-containing composition and preparation method thereof |
| CN117398397B (en) * | 2023-11-30 | 2024-05-14 | 正大制药（青岛）有限公司 | Parcalcitol-containing composition and preparation method thereof |
-
2019
- 2019-12-11 CN CN201911265331.7A patent/CN110974797A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117398397A (en) * | 2023-11-30 | 2024-01-16 | 正大制药（青岛）有限公司 | Parcalcitol-containing composition and preparation method thereof |
| CN117398397B (en) * | 2023-11-30 | 2024-05-14 | 正大制药（青岛）有限公司 | Parcalcitol-containing composition and preparation method thereof |
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Application publication date: 20200410 |