CN112516102A - Novel alfacalcidol sustained-release preparation and preparation method thereof - Google Patents

Abstract

The invention discloses an alfacalcidol sustained-release tablet and a preparation method thereof. The medicine solves the problems of single formulation, poor stability of oral preparations and the like of alfacalcidol on the market, achieves the aims of long acting and increased curative effect, can also reduce the dosage and reduce the side effect while maintaining the same drug effect, has simple preparation process, and is suitable for large-scale production, and the obtained product has stable quality.

Description

Novel alfacalcidol sustained-release preparation and preparation method thereof

Technical Field

The invention relates to a western medicine preparation technology, in particular to alfacalcidol sustained-release tablets, and also relates to a preparation method of the sustained-release 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.

The sustained release preparation is a preparation form which purposefully controls the release of the drug to achieve reasonable treatment effect, and the drug is slowly and uniformly released from the preparation form after being taken, so that a human body obtains stable treatment blood concentration, thereby avoiding the 'peak valley' phenomenon caused by frequent administration of common preparations and improving the safety, effectiveness and adaptability of the drug. The sustained release tablet is one of sustained release preparations, can reduce the medicine taking times of a patient, is convenient for the patient to take medicine for a long time, improves the compliance of the patient for taking medicine, ensures that the medicine is slowly absorbed at a proper speed by controlling the medicine release speed, stabilizes the blood concentration, avoids or reduces the peak valley phenomenon, is beneficial to reducing the toxic and side effect of the medicine, improves the curative effect, reduces the local concentration of the medicine in the gastrointestinal tract and reduces the irritation.

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 sustained-release tablet comprises an alfacalcidol tablet core and a sustained-release coating layer coated outside the tablet core, wherein the tablet core consists of alfacalcidol, a filling agent and an antioxidant, and the sustained-release coating layer consists of a sustained-release material, a plasticizer, a pore-forming agent and an anti-sticking agent, and is characterized in that the alfacalcidol sustained-release tablet comprises the following components in percentage by weight:

alfacalcidol 0.000025%

55 to 65 percent of filling agent

0.01 percent of antioxidant

20 to 40 percent of slow release material

1 to 10 percent of plasticizer

1 to 10 percent of pore-foaming agent

1-10% of an anti-sticking agent.

Wherein the filler is microcrystalline cellulose; the antioxidant is tert-butyl hydroquinone; the slow release material is polymethacrylate or ethylene acrylic acid copolymer; the plasticizer is dimethyl phthalate; the pore-foaming agent is povidone or hydroxypropyl cellulose; the antisticking agent is magnesium stearate.

Wherein, the slow release material is preferably polymethacrylate; the pore-forming agent is preferably povidone.

Wherein, the weight ratio of the polymethacrylate to the povidone is preferably 4-17: 1; most preferably, the weight ratio of polymethacrylate to povidone is 8: 1.

the alfacalcidol sustained-release tablet can be prepared by the following method:

(1) weighing raw and auxiliary materials according to the prescription amount;

(2) uniformly mixing alfacalcidol with a filler and an antioxidant, sieving with a 20-24 mesh sieve by using absolute ethyl alcohol as an adhesive, granulating, drying, and tabletting to obtain an alfacalcidol tablet core for later use;

(3) dissolving the slow release material, the plasticizer, the pore-forming agent and the anti-sticking agent by 80 percent ethanol to prepare slow release coating liquid;

(4) uniformly spraying the prepared sustained-release coating solution on the surface of the tablet core prepared in the step (2), and drying to obtain alfacalcidol sustained-release tablets;

(5) and (6) inspecting, packaging, and warehousing qualified products.

The alfacalcidol sustained-release tablet provided by the invention has the following beneficial effects:

(1) the product has high quality stability and improves the bioavailability;

(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 1-5 preparation of alfacalcidol sustained Release tablets

A preparation method of alfacalcidol sustained-release tablets comprises the following steps:

(1) weighing raw and auxiliary materials according to the prescription amount;

(2) uniformly mixing alfacalcidol with a filler and an antioxidant, sieving with a 20-24 mesh sieve by using absolute ethyl alcohol as an adhesive, granulating, drying, and tabletting to obtain an alfacalcidol tablet core for later use;

(3) dissolving the slow release material, the plasticizer, the pore-forming agent and the anti-sticking agent by 80 percent ethanol to prepare slow release coating liquid;

(4) uniformly spraying the prepared sustained-release coating solution on the surface of the tablet core prepared in the step (2), and drying to obtain alfacalcidol sustained-release tablets;

(5) and (6) inspecting, packaging, and warehousing qualified products.

The alfacalcidol sustained-release 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 measurement of Release degree of alfacalcidol sustained Release tablets obtained in examples 1 to 5

According to the 'guidance principle of sustained release, controlled release and delayed release preparations' of 9013 in the four-part general rule of 2015 edition, 0.25% of sodium dodecyl sulfate is used as a release medium, a proper amount of alfacalcidol sustained release tablets prepared in examples 1-5 is respectively and precisely weighed, the first method of 0931 in the four-part general rule of 2015 edition in the Chinese pharmacopoeia is adopted to determine the peak area, and the drug concentration and the cumulative release percentage are calculated. The results are shown in Table 2.

As can be seen from Table 2, the alfacalcidol sustained-release tablets prepared in examples 1 to 5 can be slowly released at a constant rate, which indicates that the effective blood concentration of the drug can be maintained for a long time and the frequency of taking the drug can be reduced; the alfacalcidol sustained-release tablet in example 1 is slowly released within 24 hours, which shows that the alfacalcidol sustained-release tablet prepared by using polymethacrylate as a sustained-release material and povidone as a pore-forming agent has a good effect.

EXAMPLE 6-8 preparation of alfacalcidol sustained Release tablets

According to the raw and auxiliary materials in the following formula, the alfacalcidol sustained-release tablet is prepared according to the preparation method.

Test example 2 measurement of Release degree of alfacalcidol sustained Release tablets obtained in examples 6 to 8

The measurement method was the same as in test example 1, and the measurement results are shown in Table 4.

As can be seen from table 4, the alfacalcidol sustained release tablet of example 6 slowly releases within 24 hours, which indicates that when polymethacrylate is used as the sustained release material and povidone is used as the pore-forming agent, the weight ratio of the sustained release material to the pore-forming agent is 8: 1, the slow release effect of the alfacalcidol slow release tablet is best.

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 alfacalcidol sustained-release tablets and comparative preparation alfacalcidol tablets (trade name: liqing) obtained in examples 1 to 5 were used as test samples, 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 5.

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 alfacalcidol sustained-release tablets and the comparative preparation alfacalcidol tablets obtained in examples 1 to 5 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 6.

As can be seen from table 5 and table 6, the content measurement results of alfacalcidol accelerated and long-term stability tests show that the content measurement results of the alfacalcidol sustained-release tablet of example 6 are significantly better than those of the alfacalcidol tablet of the control preparation and examples 1, 7-8 when the alfacalcidol sustained-release tablet is accelerated for 6 months and is prolonged for 24 months, which indicates that when polymethacrylate is used as the sustained-release material and povidone is used as a pore-forming agent, the weight ratio of the sustained-release material to the pore-forming agent is 8: 1, the prepared alfacalcidol sustained-release tablet has the best stability effect and is superior to the marketed alfacalcidol tablets.

Claims (5)

1. An alfacalcidol sustained-release tablet comprises an alfacalcidol tablet core and a sustained-release coating layer coated outside the tablet core, wherein the tablet core consists of alfacalcidol, a filling agent and an antioxidant, and the sustained-release coating layer consists of a sustained-release material, a plasticizer, a pore-forming agent and an anti-sticking agent, and is characterized in that the alfacalcidol sustained-release tablet comprises the following components in percentage by weight:

alfacalcidol 0.000025%

55 to 65 percent of filling agent

0.01 percent of antioxidant

20 to 40 percent of slow release material

1 to 10 percent of plasticizer

1 to 10 percent of pore-foaming agent

1-10% of an anti-sticking agent.

2. Alfacalcidol sustained-release tablet according to claim 1, characterized in that the filler is microcrystalline cellulose; the antioxidant is tert-butyl hydroquinone; the slow release material is polymethacrylate or ethylene acrylic acid copolymer; the plasticizer is dimethyl phthalate; the pore-foaming agent is povidone or hydroxypropyl cellulose; the antisticking agent is magnesium stearate.

3. Alfacalcidol sustained-release tablet according to claim 2, characterized in that the sustained-release material is preferably polymethacrylate; the pore-forming agent is preferably povidone.

4. Alfacalcidol sustained release tablets according to claim 3, characterized in that the weight ratio of polymethacrylate to povidone is 8: 1.

5. alfacalcidol sustained release tablets according to claim 1, which can be prepared by the following method:

(1) weighing raw and auxiliary materials according to the prescription amount;

(2) uniformly mixing alfacalcidol with a filler and an antioxidant, sieving with a 20-24 mesh sieve by using absolute ethyl alcohol as an adhesive, granulating, drying, and tabletting to obtain an alfacalcidol tablet core for later use;

(3) dissolving the slow release material, the plasticizer, the pore-forming agent and the anti-sticking agent by 80 percent ethanol to prepare slow release coating liquid;

(4) uniformly spraying the prepared sustained-release coating solution on the surface of the tablet core prepared in the step (2), and drying to obtain alfacalcidol sustained-release tablets;

(5) and (6) inspecting, packaging, and warehousing qualified products.