CN112546028A - Novel alfacalcidol solid oral preparation - Google Patents
Novel alfacalcidol solid oral preparation Download PDFInfo
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- CN112546028A CN112546028A CN202011463506.8A CN202011463506A CN112546028A CN 112546028 A CN112546028 A CN 112546028A CN 202011463506 A CN202011463506 A CN 202011463506A CN 112546028 A CN112546028 A CN 112546028A
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- alfacalcidol
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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
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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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
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Abstract
The invention discloses alfacalcidol enteric-coated particles and a preparation method thereof. The invention can improve the stability and bioavailability of alfacalcidol, reduce the stimulation of the drug 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 alfacalcidol enteric-coated particles, and belongs to the technical field of medicines.
Background
Alfacalcidol has the functions of regulating the balance of calcium and phosphorus in human body, increasing the absorption of calcium and phosphorus in intestinal tract, reducing the parathyroid hormone level in blood plasma, and improving menopause and osteoporosis caused by using hormone medicines in women. It is suitable for treating osteoporosis, rickets and osteomalacia caused by various reasons.
The existing alfacalcidol oral preparation has the defects of poor disintegration and dissolution effects and low bioavailability, influences the clinical treatment effect of the alfacalcidol oral preparation and needs to be improved. And patients taking alfacalcidol in large doses for a long period of time may develop symptoms such as gastric irritation. Alfacalcidol 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 alfacalcidol 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:
an alfacalcidol enteric-coated granule comprises alfacalcidol, a filler, an antioxidant, a disintegrating agent, an enteric material, a plasticizer and a lubricant, and is characterized in that the alfacalcidol enteric-coated granule comprises the following components in percentage by weight:
alfacalcidol 0.000025%
40 to 60 percent of filling agent
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:
alfacalcidol 0.000025%
50 percent of filler
0.01 percent of antioxidant
8 percent of disintegrating agent
Enteric material 35%
4 percent of plasticizer
3% of lubricant.
Wherein the filler is dextrin; the antioxidant is tert-butyl hydroquinone; the disintegrating agent is sodium dodecyl sulfate; the enteric material is one or more of acrylic resin I, acrylic resin II or polyvinyl alcohol titanate; the plasticizer is propylene glycol; the lubricant is magnesium stearate.
Wherein, the enteric material is preferably acrylic resin I and acrylic resin II; preferably, the weight ratio of the acrylic resin I to the acrylic resin II is 1: 1.
the alfacalcidol enteric-coated particles of the invention can be prepared by the following method:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) uniformly mixing alfacalcidol, a filler, an antioxidant and a disintegrating agent, and granulating with a 20-24-mesh sieve by using absolute ethyl alcohol as an adhesive to obtain an alfacalcidol 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 alfacalcidol quick-release particle core prepared in the step (2), and drying to obtain alfacalcidol enteric particles;
(5) and (6) inspecting, packaging, and warehousing qualified products.
The alfacalcidol enteric-coated particles provided by the invention have the following beneficial effects:
(1) the product has stable quality, can reduce the stimulation of the medicament to gastric mucosa, has ideal enteric effect, and improves the stability and bioavailability of alfacalcidol;
(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 alfacalcidol enteric particles
A preparation method of alfacalcidol enteric particles comprises the following steps:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) uniformly mixing alfacalcidol, a filler, an antioxidant and a disintegrating agent, and granulating with a 20-24-mesh sieve by using absolute ethyl alcohol as an adhesive to obtain an alfacalcidol 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 alfacalcidol quick-release particle core prepared in the step (2), and drying to obtain alfacalcidol enteric particles;
(5) and (6) inspecting, packaging, and warehousing qualified products.
The alfacalcidol 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 test of alfacalcidol enteric-coated 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, a proper amount of alfacalcidol 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 measured according to 0931 in 2015 th four-part general rule in china pharmacopoeia. The results are shown in tables 2 and 3.
As can be seen from Table 2, the alfacalcidol enteric particles prepared in examples 1-6 are slowly dissolved in artificial gastric juice with pH of 1.2, the dissolution time is only 10.4% at most after 4h, and the alfacalcidol enteric particles have better acid resistance; wherein alfacalcidol enteric particles of example 5 dissolve the least in 4h, indicating that acrylic resin No. i and acrylic resin No. ii are used as enteric materials for the coating, and the weight ratio is 1: 1, the prepared alfacalcidol enteric-coated particles have the best acid resistance.
As can be seen from Table 3, the alfacalcidol enteric particles prepared in examples 1-6 are rapidly released in the artificial intestinal juice with pH of 6.8, and the purpose of quick release can be achieved; the alfacalcidol enteric particles in example 5 have the highest dissolution rate in 60min, which indicates that acrylic resin I and acrylic resin II are used as enteric coating materials for coating, and the weight ratio of the alfacalcidol enteric particles to the acrylic resin II is 1: 1, the prepared alfacalcidol enteric-coated particles have the best quick release effect in the intestinal tract.
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 alfacalcidol enteric-coated granules obtained in examples 1 to 6 and comparative preparation alfacalcidol tablets (trade name: celebrate) 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 alfacalcidol preparation content was determined according to the alfacalcidol content detection method.
The alfacalcidol 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 alfacalcidol 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 alfacalcidol), placing the test sample into a 10ml centrifuge tube, precisely adding 5ml of methanol, shaking for 2 minutes, freezing for 30 minutes in a refrigerator at the temperature of-18 ℃, taking out, centrifuging (4000 r/min) for 5 minutes, 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 alfacalcidol control was precisely weighed, dissolved in methanol and diluted to a solution containing about 1.0. mu.g of alfacalcidol per 1ml, and the measurement was performed in the same manner. Calculating according to the peak area by an external standard method to obtain the product. The results of the alfacalcidol 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 alfacalcidol enteric-coated particles obtained in examples 1 to 6 and comparative preparation alfacalcidol tablets were used as test samples, packaged on the market, and placed under the conditions of a temperature of 25 ℃. + -. 2 ℃ and a relative humidity of 60% + -10% 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 alfacalcidol preparation was determined by the alfacalcidol content detection method.
The alfacalcidol 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 alfacalcidol 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 alfacalcidol), placing the test sample into a 10ml centrifuge tube, precisely adding 5ml of methanol, shaking for 2 minutes, freezing for 30 minutes in a refrigerator at the temperature of-18 ℃, taking out, centrifuging (4000 r/min) for 5 minutes, 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 alfacalcidol control was precisely weighed, dissolved in methanol and diluted to a solution containing about 1.0. mu.g of alfacalcidol per 1ml, and the measurement was performed in the same manner. Calculating according to the peak area by an external standard method to obtain the product. The results of the alfacalcidol long-term stability test are shown in table 5.
As can be seen from the results of content measurement of alfacalcidol accelerated and long-term stability tests in tables 4 and 5, the content measurement results of the alfacalcidol enteric-coated particles of example 5 at accelerated time of 6 months and long time of 24 months are significantly better than those of the alfacalcidol tablet of the control preparation and other examples, which indicates that when acrylic resin No. i and acrylic resin No. ii are used as enteric materials, and the weight ratio is 1: 1, the prepared alfacalcidol enteric-coated particles have the best stability effect and are superior to the marketed alfacalcidol tablets.
Claims (3)
1. The alfacalcidol enteric-coated granule consists of a fast-release alfacalcidol granule core and an enteric-coated layer coated outside the fast-release alfacalcidol granule core, wherein the fast-release granule core comprises alfacalcidol, 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 contents of the components are as follows by weight percent:
alfacalcidol 0.000025%
40 to 60 percent of filling agent
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. Alfacalcidol enteric particle according to claim 1, characterized in that it preferably comprises, in weight percent:
alfacalcidol 0.000025%
50 percent of filler
0.01 percent of antioxidant
8 percent of disintegrating agent
Enteric material 35%
4 percent of plasticizer
3% of lubricant.
3. Alfacalcidol enteric particles according to claim 1, characterized in that said filler is dextrin; the disintegrating agent is sodium dodecyl sulfate; the antioxidant is tert-butyl hydroquinone; the enteric material is acrylic resin I and acrylic resin II, 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 |
|---|---|---|---|
| CN202011463506.8A CN112546028A (en) | 2020-12-14 | 2020-12-14 | Novel alfacalcidol solid oral preparation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011463506.8A CN112546028A (en) | 2020-12-14 | 2020-12-14 | Novel alfacalcidol solid oral preparation |
Publications (1)
| Publication Number | Publication Date |
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| CN112546028A true CN112546028A (en) | 2021-03-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011463506.8A Withdrawn CN112546028A (en) | 2020-12-14 | 2020-12-14 | Novel alfacalcidol solid oral preparation |
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| CN (1) | CN112546028A (en) |
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2020
- 2020-12-14 CN CN202011463506.8A patent/CN112546028A/en not_active Withdrawn
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Application publication date: 20210326 |
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