CN111544418A - Parlcidol capsule - Google Patents
Parlcidol capsule Download PDFInfo
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- CN111544418A CN111544418A CN202010428480.7A CN202010428480A CN111544418A CN 111544418 A CN111544418 A CN 111544418A CN 202010428480 A CN202010428480 A CN 202010428480A CN 111544418 A CN111544418 A CN 111544418A
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- paricalcitol
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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
- A61K9/5015—Organic compounds, e.g. fats, sugars
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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
- A61K9/48—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
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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
- A61K9/5036—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
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- Bioinformatics & Cheminformatics (AREA)
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- Diabetes (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
Abstract
The invention discloses a paricalcitol sustained-release capsule which is prepared by filling paricalcitol sustained-release pellets into a capsule shell, wrapping a drug-containing layer and a coating layer outside a blank pellet core to obtain the paricalcitol sustained-release pellets, and filling the paricalcitol sustained-release pellets into the capsule shell. The invention has uniform drug release, can achieve the purposes of long acting and improving curative effect, and can also reduce the dosage while maintaining the same drug effect, thereby reducing the side effect of patients caused by taking the drug.
Description
Technical Field
The invention relates to a western medicine preparation technology, in particular to a paricalcitol sustained-release 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 can be used for treating ossificationTriol side chain (D2) and ring A (19-nor) are modified to have the 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 develop a sustained-release capsule with stable quality, uniform drug release and simple preparation process, the invention provides a paricalcitol sustained-release capsule by screening auxiliary materials and optimizing the process through a large number of tests. The sustained-release capsule has stable quality, uniform drug release, and simple preparation process.
In order to achieve the purpose, the invention adopts the technical scheme that:
a paricalcitol sustained-release capsule is formed by filling paricalcitol sustained-release pellets in a capsule shell, wherein the paricalcitol sustained-release pellets comprise a blank pellet core, a drug-containing layer coated outside the blank pellet core and a coating layer coated outside the drug-containing layer, and is characterized in that the blank pellet core is 40-50%, the drug-containing layer is 20-40% and the coating layer is 20-30% in percentage by weight.
Wherein, the medicine-containing layer comprises 0.000025 percent of paricalcitol, 20 to 30 percent of filling agent, 0.01 to 0.05 percent of antioxidant and 3 to 10 percent of adhesive according to the total weight percentage of the sustained-release pellet.
Wherein, the coating layer comprises a slow release material, a plasticizer, a pore-forming agent and an anti-sticking agent, and the coating layer comprises 3 to 10 percent of the plasticizer, 1 to 5 percent of the anti-sticking agent and the balance of the rest components according to the total weight percentage of the slow release pellet; wherein the weight ratio of the slow release material to the pore-foaming agent is 4-6: 1; preferably, the weight ratio of the slow-release material to the pore-forming agent is 5: 1.
wherein the blank pellet core is made of sucrose; the filler is microcrystalline cellulose or dextrin; the antioxidant is tert-butyl p-hydroxyanisole; the binder is povidone; the slow release material is polyvinyl acetate or carnauba wax; the plasticizer is triacetin; the pore-foaming agent is sodium dodecyl sulfate or hydroxymethyl cellulose; the antisticking agent is magnesium stearate.
Wherein the filler is preferably microcrystalline cellulose; the slow release material is preferably carnauba wax; the pore-forming agent is preferably hydroxymethyl cellulose.
The paricalcitol sustained-release capsule can be prepared by the following method:
(1) putting a certain amount of sucrose in a centrifugal granulator, and preparing blank pill cores with the particle size of 40-60 meshes by using water as a binder;
(2) weighing paricalcitol, a filling agent, an antioxidant and an adhesive according to the weight percentage, preparing the adhesive into a 4-8% aqueous solution, placing the paricalcitol, the filling agent and the antioxidant in a powder supply chamber of a centrifugal granulator, taking a proper amount of blank pellet cores prepared in the step (1) in a granulation pot, preparing drug-containing pellets by taking the aqueous solution of the adhesive as the adhesive, drying the pellets at 50-60 ℃ after the pellets are taken out of the granulation pot, and screening the pellets by 15-25 meshes for next coating;
(3) dissolving the slow release material, the plasticizer, the pore-forming agent and the anti-sticking agent by using 80% ethanol solution to prepare slow release coating liquid;
(4) uniformly spraying the prepared sustained-release coating solution on the surfaces of the drug-containing pellets prepared in the step (2), and drying to obtain paricalcitol sustained-release pellets;
(5) and (5) filling the paricalcitol sustained-release pellets prepared in the step (4) into a capsule shell to obtain the paricalcitol sustained-release capsule.
The paricalcitol sustained-release capsule provided by the invention has the following beneficial effects:
(1) the drug is released uniformly, the purposes of long acting and improving curative effect can be achieved, and the dosage can be reduced while the same drug effect is maintained, so that the side effect of patients caused by taking the drug is reduced;
(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.
A preparation method of a paricalcitol sustained-release capsule comprises the following steps:
(1) putting a certain amount of sucrose in a centrifugal granulator, and preparing blank pill cores with the particle size of 40-60 meshes by using water as a binder;
(2) weighing paricalcitol, a filling agent, an antioxidant and an adhesive according to the weight percentage, preparing the adhesive into a 4-8% aqueous solution, placing the paricalcitol, the filling agent and the antioxidant in a powder supply chamber of a centrifugal granulator, taking a proper amount of blank pellet cores prepared in the step (1) in a granulation pot, preparing drug-containing pellets by taking the aqueous solution of the adhesive as the adhesive, drying the pellets at 50-60 ℃ after the pellets are taken out of the granulation pot, and screening the pellets by 15-25 meshes for next coating;
(3) dissolving the slow release material, the plasticizer, the pore-forming agent and the anti-sticking agent by using 80% ethanol solution to prepare slow release coating liquid;
(4) uniformly spraying the prepared sustained-release coating solution on the surfaces of the drug-containing pellets prepared in the step (2), and drying to obtain paricalcitol sustained-release pellets;
(5) and (5) filling the paricalcitol sustained-release pellets prepared in the step (4) into a capsule shell to obtain the paricalcitol sustained-release capsule.
Examples 1-8 preparation of Parricalcitol extended release capsules
The paricalcitol sustained-release capsule is prepared according to the preparation method and the raw and auxiliary materials in the formula shown in the table. Where "\\" represents unused.
Test example 1 measurement of Release degree of Parricalciferol sustained Release capsules obtained in examples 1 to 8
According to the guidance principle of slow release, controlled release and delayed release preparations of 9013 in the rules of four divisions of the 2015 edition of the Chinese pharmacopoeia, 0.25% of sodium dodecyl sulfate is used as a release medium, a proper amount (about 100 mg) of the paricalcitol slow release pellets prepared in the examples 1-8 is precisely weighed respectively, the peak area is measured by an HPLC method according to the first method of 0931 in the rules of four divisions of the 2015 edition of the Chinese pharmacopoeia, and the drug concentration and the cumulative release percentage are calculated. The results are shown in Table 1.
TABLE 1 examination of the release rates of the Parlcidol sustained release capsules obtained in examples 1 to 8
As can be seen from Table 1, the sustained-release capsules prepared in examples 1-8 have appropriate release rate, smooth drug release, and can maintain the effective blood concentration of the drug for a long time and reduce the times of drug administration; the sustained-release capsule of example 4 slowly releases within 20 hours, which shows that the sustained-release capsule of paricalcitol prepared by using microcrystalline cellulose as a filler, carnauba wax as a sustained-release material and hydroxymethyl cellulose as a pore-forming agent has the best effect.
Examples 9-11 preparation of Parricalcitol extended release capsules
The paricalcitol sustained-release capsule is prepared according to the preparation method and the raw and auxiliary materials in the formula shown in the table.
Test example 2 determination of Release degree of Parlcidol sustained Release capsules obtained in examples 9 to 11
The measurement method was the same as in test example 1, and the measurement results are shown in Table 2.
TABLE 2 examination of the release rates of the Parlcidol sustained-release capsules obtained in examples 9 to 11
As can be seen from table 2, the sustained-release paricalcitol capsule of example 10 slowly released over 24 hours, which shows that when carnauba wax is used as the sustained-release material and hydroxymethyl cellulose is used as the pore-forming agent, the weight ratio of the sustained-release material to the pore-forming agent is 5: 1, the prepared paricalcitol sustained-release capsule has the best sustained-release effect.
Test example 3 accelerated stability test
Accelerated stability tests were carried out according to 9001 "guidelines on stability of crude drugs and preparations" in the four ministry of the pharmacopoeia of China 2015 edition. The sustained-release paricalcitol capsules obtained in examples 7 to 11 and the reference preparation paricalcitol soft capsules (trade name: Zemplar) were used as test samples, and were packaged on the market and allowed to stand at a temperature of 40 ℃. + -. 2 ℃ and a relative humidity of 75% + -5% for 6 months. 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 3.
TABLE 3 measurement results of accelerated stability test content of paricalcitol
Test example 4 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' of the general rules of the four departments of the version 2015 in the Chinese pharmacopoeia. The sustained-release paricalcitol capsules obtained in examples 1 to 6 and the reference preparation paricalcitol soft capsules (trade name: Zemplar) were used as test samples, packaged on the market, and left at 25 ℃. + -. 2 ℃ and 60%. + -. 10% relative humidity for 24 months. 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 4.
TABLE 4 Long-term stability test for paricalcitol content determination
As can be seen from the results of content measurement of accelerated and long-term stability tests of paricalcitol in tables 3 and 4, the content measurement results of the paricalcitol sustained-release capsule in example 10 at accelerated time of 6 months and long time of 24 months are significantly better than those of the paricalcitol soft capsule as a control preparation and other examples, which shows that when carnauba wax is used as the sustained-release material and hydroxymethyl cellulose is used as the pore-forming agent, the weight ratio of the sustained-release material to the pore-forming agent is 5: 1, the prepared paricalcitol sustained-release capsule has the best effect and is superior to the paricalcitol soft capsules on the market.
In summary, when carnauba wax is used as the slow release material and hydroxymethyl cellulose is used as the pore-forming agent, the weight ratio of the slow release material to the pore-forming agent is 5: 1 hour, the prepared paricalcitol slow-release capsule can be slowly released at a constant speed, has good stability and is superior to the paricalcitol soft capsules on the market.
Claims (4)
1. A paricalcitol sustained-release capsule is formed by filling paricalcitol sustained-release pellets in a capsule shell, wherein the paricalcitol sustained-release pellets comprise a blank pellet core, a drug-containing layer coated outside the blank pellet core and a coating layer coated outside the drug-containing layer, and is characterized in that the blank pellet core is 30-50%, the drug-containing layer is 30-50% and the coating layer is 15-25% in percentage by weight.
2. The paricalcitol sustained-release capsule according to claim 1, characterized in that the drug-containing layer comprises paricalcitol, filler, antioxidant and adhesive, wherein the total weight percentage of the sustained-release pellet is 0.000025%, the filler is 20-30%, the antioxidant is 0.01-0.05%, and the adhesive is 3-10%; the coating layer comprises a slow release material, a plasticizer, a pore-forming agent and an anti-sticking agent, wherein the plasticizer accounts for 3-10 percent of the total weight of the slow release pellet, the anti-sticking agent accounts for 1-5 percent of the total weight of the slow release pellet, and the balance is the rest components; wherein the weight ratio of the slow release material to the pore-foaming agent is 4-6: 1.
3. the paricalcitol sustained-release capsule according to claim 2, characterized in that the weight ratio of the sustained-release material to the pore-forming agent is 5: 1.
4. the paricalcitol sustained release capsule according to claim 2, characterized in that: the blank pellet core is made of sucrose; the filler is microcrystalline cellulose; the antioxidant is tert-butyl p-hydroxyanisole; the binder is povidone; the slow release material is carnauba wax; the plasticizer is triacetin; the pore-foaming agent is hydroxymethyl cellulose; the antisticking agent is magnesium stearate.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010428480.7A CN111544418A (en) | 2020-05-20 | 2020-05-20 | Parlcidol capsule |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010428480.7A CN111544418A (en) | 2020-05-20 | 2020-05-20 | Parlcidol capsule |
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| CN111544418A true CN111544418A (en) | 2020-08-18 |
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| CN202010428480.7A Withdrawn CN111544418A (en) | 2020-05-20 | 2020-05-20 | Parlcidol capsule |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114557980A (en) * | 2022-03-22 | 2022-05-31 | 郑州市中医院（郑州市红十字医院） | Calcitriol sustained-release pellet and preparation method thereof |
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2020
- 2020-05-20 CN CN202010428480.7A patent/CN111544418A/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114557980A (en) * | 2022-03-22 | 2022-05-31 | 郑州市中医院（郑州市红十字医院） | Calcitriol sustained-release pellet and preparation method thereof |
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Application publication date: 20200818 |