CN112546011A - Novel alfacalcidol enteric-coated preparation and preparation method thereof - Google Patents
Novel alfacalcidol enteric-coated preparation and preparation method thereof Download PDFInfo
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- CN112546011A CN112546011A CN202011462985.1A CN202011462985A CN112546011A CN 112546011 A CN112546011 A CN 112546011A CN 202011462985 A CN202011462985 A CN 202011462985A CN 112546011 A CN112546011 A CN 112546011A
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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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 an alfacalcidol enteric-coated tablet 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 tablets, and also relates to a preparation method of the enteric-coated tablets, belonging 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-coated tablets have not been reported in the prior art, and can avoid stomach irritation and improve bioavailability simultaneously.
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-coated tablet is one of enteric-coated 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 the effect of delaying release, transfer the drug mainly absorbed by the small intestine to the part as much as possible at the highest concentration, and is favorable for improving the 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 tablet 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 tablet comprises the following components in percentage by weight:
alfacalcidol 0.000025%
50 to 70 percent of filling agent
0.01 percent of antioxidant
1 to 10 percent of disintegrating agent
Enteric material 20-30%
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%
60 percent of filler
0.01 percent of antioxidant
7 percent of disintegrating agent
Enteric material 24%
Plasticizer 5%
4% of lubricant.
Wherein the filler is microcrystalline cellulose; the antioxidant is tert-butyl hydroquinone; the disintegrating agent is sodium carboxymethyl starch; the enteric material is one or more of hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate or acrylic resin I; the plasticizer is dimethyl phthalate; the lubricant is magnesium stearate.
Wherein, the enteric material is preferably hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate; preferably, the weight ratio of the hydroxypropyl methyl cellulose phthalate to the cellulose acetate trimellitate is 2: 1.
the alfacalcidol enteric-coated tablet 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, granulating with 20-24 mesh sieve by using absolute ethyl alcohol as an adhesive, drying, and tabletting to obtain an alfacalcidol tablet 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 tablet core prepared in the step (2), and drying to obtain an alfacalcidol enteric tablet;
(5) and (6) inspecting, packaging, and warehousing qualified products.
The alfacalcidol enteric-coated tablet provided by the invention has 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-coated tablets
A preparation method of alfacalcidol enteric-coated tablets 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, granulating with 20-24 mesh sieve by using absolute ethyl alcohol as an adhesive, drying, and tabletting to obtain an alfacalcidol tablet 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 tablet core prepared in the step (2), and drying to obtain an alfacalcidol enteric tablet;
(5) and (6) inspecting, packaging, and warehousing qualified products.
The alfacalcidol enteric-coated tablets are prepared according to the preparation method by using the raw and auxiliary materials in the prescription (1000 tablets) in the following table 1. Where "/" indicates unused.
Test example 1 dissolution test of alfacalcidol enteric-coated tablets obtained in examples 1 to 6
According to the guiding 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 tablets 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 chinese pharmacopoeia. The results are shown in tables 2 and 3.
As shown in Table 2, the alfacalcidol enteric-coated tablets prepared in examples 1 to 6 are slowly dissolved in artificial gastric juice with pH of 1.2, the dissolution time is only 10.2% at most after 4 hours, and the alfacalcidol enteric-coated tablets have better acid resistance; wherein the alfacalcidol enteric-coated tablet of example 5 dissolves the least in 4h, indicating that hydroxypropyl methylcellulose phthalate and cellulose acetate trimellitate are used as enteric-coated materials and the weight ratio is 2: 1, the prepared alfacalcidol enteric-coated tablet has the best acid resistance.
As can be seen from Table 3, the alfacalcidol enteric-coated tablets 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 dissolution rate of the alfacalcidol enteric-coated tablet in example 5 is the highest in 60min, which indicates that hydroxypropyl methylcellulose phthalate and cellulose acetate trimellitate are used as enteric-coated materials, and the weight ratio of the enteric-coated tablet to the enteric-coated tablet is 2: 1, the prepared alfacalcidol enteric-coated tablet has the best quick release effect in the intestinal tract.
Test example 2 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 alfacalcidol enteric-coated tablets 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 in accordance with the general guidelines of the four ministry of the chapter of the book of Chinese pharmacopoeia 2015. The alfacalcidol enteric-coated tablets and the comparative preparation alfacalcidol tablets obtained in examples 1 to 6 are taken as test products, packaged according to the market and placed for 24 months under the conditions of the temperature of 25 +/-2 ℃ and the 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 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 table 4 and table 5, the content measurement results of the alfacalcidol accelerated and long-term stability tests show that the content measurement results of the alfacalcidol enteric-coated tablet of example 5 are significantly better than those of the alfacalcidol tablet of the control preparation and other examples when hydroxypropyl methylcellulose phthalate and cellulose acetate trimellitate are used as enteric materials, and the weight ratio is 2: 1, the prepared alfacalcidol enteric-coated tablet has the best stability effect and is superior to the marketed alfacalcidol tablets.
Claims (4)
1. An alfacalcidol enteric-coated tablet comprises an alfacalcidol tablet core and an enteric coating layer coated outside the alfacalcidol tablet core, wherein the tablet core comprises alfacalcidol, a filling agent, an antioxidant and a disintegrating agent, and the enteric coating layer comprises an enteric material, a plasticizer and a lubricant, and is characterized in that the alfacalcidol enteric-coated tablet comprises the following components in percentage by weight:
alfacalcidol 0.000025%
50 to 70 percent of filling agent
0.01 percent of antioxidant
1 to 10 percent of disintegrating agent
Enteric material 20-30%
1 to 10 percent of plasticizer
1-10% of lubricant.
2. Alfacalcidol enteric-coated tablet according to claim 1, characterized in that, preferably, the contents of the components are, in weight percent:
alfacalcidol 0.000025%
60 percent of filler
0.01 percent of antioxidant
7 percent of disintegrating agent
Enteric material 24%
Plasticizer 5%
4% of lubricant.
3. Alfacalcidol enteric tablet according to claim 1, characterized in that said filler is microcrystalline cellulose; the disintegrating agent is sodium carboxymethyl starch; the antioxidant is tert-butyl hydroquinone; the enteric material is hydroxypropyl methyl cellulose phthalate and cellulose acetate trimellitate, and the weight ratio is 2: 1; the plasticizer is dimethyl phthalate; the lubricant is magnesium stearate.
4. A process for preparing an alfacalcidol enteric tablet as claimed in claim 1, comprising the steps of:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) uniformly mixing alfacalcidol, a filler, an antioxidant and a disintegrating agent, granulating with 20-24 mesh sieve by using absolute ethyl alcohol as an adhesive, drying, and tabletting to obtain an alfacalcidol tablet 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 tablet core prepared in the step (2), and drying to obtain an alfacalcidol enteric tablet;
(5) and (6) inspecting, packaging, and warehousing qualified products.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011462985.1A CN112546011A (en) | 2020-12-14 | 2020-12-14 | Novel alfacalcidol enteric-coated preparation and preparation method thereof |
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| CN202011462985.1A CN112546011A (en) | 2020-12-14 | 2020-12-14 | Novel alfacalcidol enteric-coated preparation and preparation method thereof |
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| CN112546011A true CN112546011A (en) | 2021-03-26 |
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| CN202011462985.1A Withdrawn CN112546011A (en) | 2020-12-14 | 2020-12-14 | Novel alfacalcidol enteric-coated preparation and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115350149A (en) * | 2022-08-30 | 2022-11-18 | 南通华山药业有限公司 | Stable alfacalcidol water-based solution preparation and preparation method thereof |
-
2020
- 2020-12-14 CN CN202011462985.1A patent/CN112546011A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115350149A (en) * | 2022-08-30 | 2022-11-18 | 南通华山药业有限公司 | Stable alfacalcidol water-based solution preparation and preparation method thereof |
| CN115350149B (en) * | 2022-08-30 | 2023-12-15 | 南通华山药业有限公司 | Stable alfacalcidol water-based solution preparation and preparation method thereof |
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Application publication date: 20210326 |
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