CN110917169A - Parlcidol capsule and preparation method thereof - Google Patents
Parlcidol capsule and preparation method thereof Download PDFInfo
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- CN110917169A CN110917169A CN201911265332.1A CN201911265332A CN110917169A CN 110917169 A CN110917169 A CN 110917169A CN 201911265332 A CN201911265332 A CN 201911265332A CN 110917169 A CN110917169 A CN 110917169A
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- Prior art keywords
- paricalcitol
- enteric
- pellets
- capsule
- plasticizer
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- 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 enteric capsule and a preparation method thereof, the paricalcitol enteric capsule is prepared by putting paricalcitol enteric pellets into a capsule shell, the paricalcitol enteric pellets comprise paricalcitol pellets and an enteric coating layer coated outside the paricalcitol pellets, the paricalcitol pellets comprise paricalcitol, a filling agent and an antioxidant, the enteric coating layer comprises an enteric material, a plasticizer, a pore-forming agent and a lubricant, and the paricalcitol pellets are coated with the enteric coating layer and then encapsulated during preparation. The medicine is convenient to take, has an ideal enteric effect, can improve the stability and bioavailability of the paricalcitol, has a simple preparation process, and is suitable for large-scale production, and the obtained product has stable quality.
Description
Technical Field
The invention relates to a western medicine preparation technology, in particular to a paricalcitol enteric capsule, and also relates to a preparation method of the enteric capsule, 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:
a paricalcitol enteric capsule comprises paricalcitol, a filler, an antioxidant, an enteric material, a plasticizer and a lubricant, and is characterized in that the content of each component is as follows according to the weight percentage:
paricalcitol 0.00002%
45 to 55 percent of filling agent
0.01 to 0.05 percent of antioxidant
30 to 40 percent of enteric-coated material
3 to 10 percent of plasticizer
3 to 10 percent of pore-foaming agent
3-10% of lubricant.
Preferably, the content of each component is as follows according to weight percentage:
paricalcitol 0.00002%
50 percent of filler
0.03 percent of antioxidant
Enteric material 35%
6 percent of plasticizer
Pore-foaming agent 5%
4% of lubricant.
Wherein the filler is lactose; the antioxidant is tert-butyl hydroquinone; the enteric material is one or more of hydroxypropyl methyl cellulose phthalate, polyvinyl alcohol acetate phthalate or algin; the plasticizer is dibutyl phthalate; the pore-foaming agent is povidone; the lubricant is magnesium stearate.
Wherein, the enteric material is preferably hydroxypropyl methyl cellulose phthalate, polyvinyl alcohol acetate phthalate; preferably, the weight ratio of the hydroxypropyl methyl cellulose phthalate to the polyvinyl alcohol acetate phthalate is 1: 1.
the paricalcitol enteric capsule can be prepared by the following method:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) mixing paricalcitol with filler, and making into 20-30 mesh paricalcitol pellet with anhydrous ethanol as binder;
(3) dissolving the enteric material, the plasticizer, the pore-forming agent and the lubricant by 80 percent ethanol to prepare enteric coating liquid;
(4) uniformly spraying the prepared enteric coating solution in the step (3) on the surface of the paricalcitol pellet prepared in the step (2), and drying to obtain the paricalcitol enteric pellet;
(5) filling the paricalcitol enteric-coated pellets into a capsule shell to obtain paricalcitol enteric-coated capsules;
(6) and (6) inspecting, packaging, and warehousing qualified products.
The paricalcitol enteric capsule provided by the invention has the following beneficial effects:
(1) the product has stable quality, can reduce the stimulation of the medicine to gastric mucosa, has ideal enteric effect, and improves the stability and bioavailability of the paricalcitol;
(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 1-6 preparation of Parricalcitol enteric capsules
A preparation method of a paricalcitol enteric capsule comprises the following steps:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) mixing paricalcitol with filler, and making into 20-30 mesh paricalcitol pellet with anhydrous ethanol as binder;
(3) dissolving the enteric material, the plasticizer, the pore-forming agent and the lubricant by 80 percent ethanol to prepare enteric coating liquid;
(4) uniformly spraying the prepared enteric coating solution in the step (3) on the surface of the paricalcitol pellet prepared in the step (2), and drying to obtain the paricalcitol enteric pellet;
(5) filling the paricalcitol enteric-coated pellets into a capsule shell to obtain paricalcitol enteric-coated capsules;
(6) and (6) inspecting, packaging, and warehousing qualified products.
The paricalcitol enteric-coated capsule is prepared according to the preparation method by using the raw and auxiliary materials in the prescription (1000 granules) 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 paricalcitol enteric-coated tablets obtained in examples 1 to 6 and the comparative preparation paricalcitol soft capsules (trade name: Zemplar) were used as test articles, packaged on the market, 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 paricalcitol enteric-coated tablets obtained in examples 1 to 6 and the comparative preparation paricalcitol soft capsules (trade name: Zemplar) were used as test articles, packaged on the market, and left 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 the results of the content measurement of the accelerated and long-term stability tests of paricalcitol in tables 2 and 3, the content measurement results of the paricalcitol enteric-coated tablet in example 4 at the accelerated time of 6 months and the long time of 24 months are significantly better than those of the paricalcitol soft capsule in the control formulation and other examples, which indicates that when hydroxypropyl methylcellulose phthalate and polyvinyl alcohol acetate phthalate are used as enteric-coated materials, the weight ratio of the hydroxypropyl methylcellulose phthalate to the polyvinyl alcohol acetate phthalate is 1: 1, the prepared paricalcitol enteric-coated tablet has the best stability effect and is superior to the paricalcitol soft capsules on the market.
Claims (3)
1. The paricalcitol enteric capsule is prepared by putting paricalcitol enteric pellets into a capsule shell, wherein the paricalcitol enteric pellets comprise paricalcitol pellets and an enteric coating layer coated outside the paricalcitol pellets, the paricalcitol pellets comprise paricalcitol, a filling agent and an antioxidant, and the enteric coating layer comprises an enteric material, a plasticizer, a pore-forming agent and a lubricant, and is characterized in that the paricalcitol enteric capsule comprises the following components in percentage by weight:
paricalcitol 0.00002%
50 percent of filler
0.03 percent of antioxidant
Enteric material 35%
6 percent of plasticizer
Pore-foaming agent 5%
4% of lubricant.
2. Parcalcitol enteric capsule according to claim 1, characterized in that the filler is lactose; the antioxidant is tert-butyl hydroquinone; the enteric-coated material is hydroxypropyl methyl cellulose phthalate and polyvinyl alcohol acetate phthalate, and the weight ratio of the hydroxypropyl methyl cellulose phthalate to the polyvinyl alcohol acetate phthalate is 1: 1; the plasticizer is dibutyl phthalate; the pore-foaming agent is povidone; the lubricant is magnesium stearate.
3. A method of preparing the paricalcitol enteric capsule according to claim 1, comprising the steps of:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) mixing paricalcitol with filler, and making into 20-30 mesh paricalcitol pellet with anhydrous ethanol as binder;
(3) dissolving the enteric material, the plasticizer, the pore-forming agent and the lubricant by 80 percent ethanol to prepare enteric coating liquid;
(4) uniformly spraying the prepared enteric coating solution in the step (3) on the surface of the paricalcitol pellet prepared in the step (2), and drying to obtain the paricalcitol enteric pellet;
(5) filling the paricalcitol enteric-coated pellets into a capsule shell to obtain paricalcitol enteric-coated capsules;
(6) and (6) inspecting, packaging, and warehousing qualified products.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201911265332.1A CN110917169A (en) | 2019-12-11 | 2019-12-11 | Parlcidol capsule and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201911265332.1A CN110917169A (en) | 2019-12-11 | 2019-12-11 | Parlcidol capsule and preparation method thereof |
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| CN110917169A true CN110917169A (en) | 2020-03-27 |
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| CN201911265332.1A Withdrawn CN110917169A (en) | 2019-12-11 | 2019-12-11 | Parlcidol capsule and preparation method thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1251527A (en) * | 1996-12-30 | 2000-04-26 | 骨疗国际公司 | Method of treating prostatic disease using delayed and/or sustained release vitamin D formulations |
| CN104800166A (en) * | 2015-04-22 | 2015-07-29 | 青岛正大海尔制药有限公司 | Alfacalcidol powder and preparation method thereof |
| CN107362151A (en) * | 2017-08-01 | 2017-11-21 | 国药集团川抗制药有限公司 | A kind of calcitriol liquid hard capsule and preparation method thereof, application |
| CN107875134A (en) * | 2017-11-02 | 2018-04-06 | 国药集团川抗制药有限公司 | paricalcitol liquid hard capsule and preparation method thereof |
| US20180271884A1 (en) * | 2013-03-15 | 2018-09-27 | Opko Ireland Global Holdings, Ltd. | Stabilized Modified Release Vitamin D Formulation and Method of Administering Same |
-
2019
- 2019-12-11 CN CN201911265332.1A patent/CN110917169A/en not_active Withdrawn
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1251527A (en) * | 1996-12-30 | 2000-04-26 | 骨疗国际公司 | Method of treating prostatic disease using delayed and/or sustained release vitamin D formulations |
| US20180271884A1 (en) * | 2013-03-15 | 2018-09-27 | Opko Ireland Global Holdings, Ltd. | Stabilized Modified Release Vitamin D Formulation and Method of Administering Same |
| CN104800166A (en) * | 2015-04-22 | 2015-07-29 | 青岛正大海尔制药有限公司 | Alfacalcidol powder and preparation method thereof |
| CN107362151A (en) * | 2017-08-01 | 2017-11-21 | 国药集团川抗制药有限公司 | A kind of calcitriol liquid hard capsule and preparation method thereof, application |
| CN107875134A (en) * | 2017-11-02 | 2018-04-06 | 国药集团川抗制药有限公司 | paricalcitol liquid hard capsule and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 黄峻主编: "《临床药物手册》", 31 January 2015, 上海科学技术出版社 * |
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Application publication date: 20200327 |