CN112546023A - Calcitriol enteric-coated granule - Google Patents
Calcitriol enteric-coated granule Download PDFInfo
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- CN112546023A CN112546023A CN202011446938.8A CN202011446938A CN112546023A CN 112546023 A CN112546023 A CN 112546023A CN 202011446938 A CN202011446938 A CN 202011446938A CN 112546023 A CN112546023 A CN 112546023A
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- Prior art keywords
- calcitriol
- enteric
- coated
- percent
- quick
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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
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
-
- 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
- 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
- A61K9/5089—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Abstract
The invention discloses a calcitriol enteric-coated granule and a preparation method thereof, the calcitriol enteric-coated granule consists of a calcitriol quick-release granule core and an enteric-coated layer coated outside the calcitriol quick-release granule core, the quick-release granule core comprises calcitriol, a filler, an antioxidant and a disintegrant, the enteric-coated layer comprises an enteric material, a plasticizer and a lubricant, and the calcitriol quick-release granule core is coated with the enteric-coated layer during preparation. The invention can improve the stability and bioavailability of calcitriol, reduce the stimulation of the medicine to gastric mucosa, has simple preparation process, stable quality of the obtained product and is suitable for large-scale production.
Description
Technical Field
The invention relates to a western medicine preparation technology, in particular to calcitriol enteric-coated particles, and belongs to the technical field of medicines.
Background
Calcitriol is mainly used for treating postmenopausal and senile osteoporosis; chronic renal failure, particularly renal osteodystrophy in patients receiving hemodialysis; postoperative hypoparathyroidism; idiopathic hypoparathyroidism; pseudohypoparathyroidism; vitamin D dependent rickets; rickets with low blood phosphorus and vitamin D resistance.
The existing calcitriol oral preparation has the defects of poor disintegration and dissolution effects and low bioavailability, influences the clinical treatment effect of the calcitriol oral preparation and needs to be improved. And when a patient takes calcitriol in a large dose for a long time, symptoms such as stomach irritation may occur. Calcitriol enteric particles have not been reported in the prior art, which can avoid gastric irritation while improving bioavailability.
Enteric formulations are those which release no or little drug in a defined acidic medium, but release most or all of the drug in a phosphate buffered solution at ph6.8 for the required period of time. The enteric granule is one of enteric preparations, can prevent the drug from being damaged by enzymes in the stomach or gastric acid, prevent the drug from stimulating the gastric mucosa, provide delayed release effect, transmit the drug mainly absorbed by the small intestine to the part with the highest concentration as possible, and is helpful for improving bioavailability.
Disclosure of Invention
In order to solve the problems of single dosage form, poor stability and the like of the existing calcitriol and research and develop 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 calcitriol enteric-coated granule comprises calcitriol, a filler, an antioxidant, a disintegrating agent, an enteric-coated material, a plasticizer and a lubricant, and is characterized in that the calcitriol enteric-coated granule comprises the following components in percentage by weight:
calcitriol 0.000025%
50 to 60 percent of filler
0.01 percent of antioxidant
1 to 10 percent of disintegrating agent
30 to 40 percent of enteric-coated material
1 to 10 percent of plasticizer
1-10% of lubricant.
Preferably, the content of each component is as follows according to weight percentage:
calcitriol 0.000025%
55 percent of filler
0.01 percent of antioxidant
8 percent of disintegrating agent
Enteric material 32%
Plasticizer 3%
2% of lubricant.
Wherein the filler is microcrystalline cellulose; the antioxidant is butyl hydroxy anisole; the disintegrating agent is sodium dodecyl sulfate; the enteric material is one or more of acrylic resin EuS100, polyvinyl alcohol phthalate or polyvinyl alcohol titanate; the plasticizer is propylene glycol; the lubricant is magnesium stearate.
Wherein, the enteric material is preferably acrylic resin EuS100, polyvinyl alcohol phthalate; preferably, the weight ratio of the acrylic resin EuS100 to the polyvinyl alcohol phthalate is 1: 1.
the calcitriol enteric granule can be prepared by the following method:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) uniformly mixing calcitriol, a filler, an antioxidant and a disintegrating agent, and granulating with 20-24 mesh sieve by using absolute ethyl alcohol as an adhesive to obtain a calcitriol quick-release granule core;
(3) dissolving the enteric material, the plasticizer 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 calcitriol quick-release granule core prepared in the step (2), and drying to obtain calcitriol enteric granules;
(5) and (6) inspecting, packaging, and warehousing qualified products.
The calcitriol enteric granule 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 calcitriol;
(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 enteric particles of calcitriol
A preparation method of calcitriol enteric particles comprises the following steps:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) uniformly mixing calcitriol, a filler, an antioxidant and a disintegrating agent, and granulating with 20-24 mesh sieve by using absolute ethyl alcohol as an adhesive to obtain a calcitriol quick-release granule core;
(3) dissolving the enteric material, the plasticizer 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 calcitriol quick-release granule core prepared in the step (2), and drying to obtain calcitriol enteric granules;
(5) and (6) inspecting, packaging, and warehousing qualified products.
The calcitriol enteric-coated granules are prepared according to the preparation method by using the raw and auxiliary materials in the formula shown in the table 1. Where "/" indicates unused.
Test example 1 dissolution rate measurement of calcitriol enteric granules obtained in examples 1 to 6
According to the guidance principle of slow release, controlled release and delayed release preparation of 9013 in 2015 th four-part general rule of Chinese pharmacopoeia, a proper amount of calcitriol enteric-coated particles prepared in examples 1-6 are respectively and precisely weighed by using artificial gastric juice with pH1.2 and artificial intestinal juice medium with pH6.8, and the dissolution rate is determined according to 0931 in 2015 th four-part general rule of Chinese pharmacopoeia. The results are shown in tables 2 and 3.
As can be seen from Table 2, the calcitriol enteric particles prepared in examples 1-6 are slowly dissolved in artificial gastric juice with pH of 1.2, the dissolution time is only 10.9% at most after 4h, and the calcitriol enteric particles have better acid resistance; wherein the calcitriol enteric granule of example 5 dissolves the least in 4h, which indicates that acrylic resin EuS100 and polyvinyl alcohol phthalate are used as enteric coating materials for coating, and the weight ratio is 1: 1, the prepared calcitriol enteric-coated particles have the best acid resistance.
As can be seen from Table 3, the calcitriol enteric particles prepared in examples 1-6 are rapidly released in the artificial intestinal juice with pH of 6.8, so as to achieve the purpose of quick release; the dissolution rate of the calcitriol enteric-coated particles in example 5 is the highest in 60min, which indicates that acrylic resin EuS100 and polyvinyl alcohol phthalate are used as enteric-coated materials, and the weight ratio of the enteric-coated particles is 1: 1 hour, the prepared calcitriol enteric-coated particles have the best quick release effect in intestinal tracts.
Test example 2 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 calcitriol enteric granules obtained in examples 1 to 6 and a calcitriol soft capsule (trade name: Luo Gao quan) as a comparative preparation were packaged on the market and allowed to stand at 40 ℃. + -. 2 ℃ and a relative humidity of 75% + -5% for 6 months. Sampling once at the end of 1 month, 2 months, 3 months and 6 months respectively during the test period, and determining the content of the calcitriol preparation according to a calcitriol content detection method.
The calcitriol content detection method comprises the following steps:
chromatographic conditions and system applicability test: 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 calcitriol 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 calcitriol), placing the test sample into a 10ml centrifuge tube, precisely adding 5ml of methanol, shaking for 2 minutes, placing the test sample into a refrigerator at the temperature of 18 ℃ below zero for freezing for 30 minutes, taking out the test sample, centrifuging (4000 r/min) for 5 minutes, taking the supernatant methanol clear liquid as a test sample solution, precisely measuring 50 mu l of the supernatant methanol clear liquid, injecting the solution into a liquid chromatograph, and recording a chromatogram. An appropriate amount of calcitriol control is precisely weighed, dissolved in methanol and diluted to a solution containing about 1.0 μ g of calcitriol per 1ml, and the determination is carried out by the same method. Calculating according to the peak area by an external standard method to obtain the product. The results of the calcitriol accelerated stability test are shown in table 4.
Test example 3 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 calcitriol enteric granules obtained in examples 1 to 6 and a calcitriol soft capsule (trade name: Luo Gao quan) as a comparative preparation were packaged on the market and left for 24 months at a temperature of 25 ℃. + -. 2 ℃ and a relative humidity of 60% + -10%. Sampling once at the end of 0 month, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months during the test period, and determining the content of the calcitriol preparation according to a calcitriol content detection method.
The calcitriol content detection method comprises the following steps:
chromatographic conditions and system applicability test: 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 calcitriol 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 calcitriol), placing the test sample into a 10ml centrifuge tube, precisely adding 5ml of methanol, shaking for 2 minutes, placing the test sample into a refrigerator at the temperature of 18 ℃ below zero for freezing for 30 minutes, taking out the test sample, centrifuging (4000 r/min) for 5 minutes, taking the supernatant methanol clear liquid as a test sample solution, precisely measuring 50 mu l of the supernatant methanol clear liquid, injecting the solution into a liquid chromatograph, and recording a chromatogram. An appropriate amount of calcitriol control is precisely weighed, dissolved in methanol and diluted to a solution containing about 1.0 μ g of calcitriol per 1ml, and the determination is carried out by the same method. Calculating according to the peak area by an external standard method to obtain the product. The results of the assay of calcitriol long-term stability are shown in table 5.
As can be seen from the results of the assay of calcitriol accelerated and long-term stability tests in tables 4 and 5, the assay of the calcitriol enteric granule of example 5 at 6 months accelerated and 24 months long time is significantly better than the assay of the calcitriol soft capsule of the control formulation and other examples, which indicates that when the acrylic resin EuS100 and the polyvinyl phthalate are used as enteric materials, and the weight ratio is 1: 1, the prepared calcitriol enteric-coated granule has the best stability effect and is superior to the calcitriol soft capsules on the market.
Claims (3)
1. The calcitriol enteric-coated granule consists of a calcitriol quick-release granule core and an enteric-coated layer coated outside the calcitriol quick-release granule core, wherein the quick-release granule core comprises calcitriol, a filler, an antioxidant and a disintegrant, and the enteric-coated layer comprises an enteric material, a plasticizer and a lubricant, and is characterized in that the calcitriol enteric-coated granule comprises the following components in percentage by weight:
calcitriol 0.000025%
50 to 60 percent of filler
0.01 percent of antioxidant
1 to 10 percent of disintegrating agent
30 to 40 percent of enteric-coated material
1 to 10 percent of plasticizer
1-10% of lubricant.
2. Calcitriol enteric particle according to claim 1, characterized in that preferably the contents of the components are, in weight percent:
calcitriol 0.000025%
55 percent of filler
0.01 percent of antioxidant
8 percent of disintegrating agent
Enteric material 32%
Plasticizer 3%
2% of lubricant.
3. Calcitriol enteric granule according to claim 1, characterized in that the filler is microcrystalline cellulose; the disintegrating agent is sodium dodecyl sulfate; the antioxidant is butyl hydroxy anisole; the enteric-coated material is acrylic resin EuS100 and polyvinyl alcohol phthalate, and the weight ratio is 1: 1; the plasticizer is propylene glycol; the lubricant is magnesium stearate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011446938.8A CN112546023A (en) | 2020-12-11 | 2020-12-11 | Calcitriol enteric-coated granule |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011446938.8A CN112546023A (en) | 2020-12-11 | 2020-12-11 | Calcitriol enteric-coated granule |
Publications (1)
| Publication Number | Publication Date |
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| CN112546023A true CN112546023A (en) | 2021-03-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011446938.8A Withdrawn CN112546023A (en) | 2020-12-11 | 2020-12-11 | Calcitriol enteric-coated granule |
Country Status (1)
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| CN (1) | CN112546023A (en) |
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2020
- 2020-12-11 CN CN202011446938.8A patent/CN112546023A/en not_active Withdrawn
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Application publication date: 20210326 |
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