CN112494446A - Calcitriol enteric-coated tablet and preparation method thereof - Google Patents

Abstract

The invention discloses a calcitriol enteric-coated tablet and a preparation method thereof, the calcitriol enteric-coated tablet consists of a calcitriol tablet core and an enteric-coated layer coated outside the calcitriol tablet core, the tablet core comprises calcitriol, a filling agent, an antioxidant and a disintegrating agent, the enteric-coated layer comprises an enteric material, a plasticizer and a lubricant, and the calcitriol tablet 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

Calcitriol enteric-coated tablet and preparation method thereof

Technical Field

The invention relates to a western medicine preparation technology, in particular to a calcitriol enteric-coated tablet, and also relates to a preparation method of the enteric-coated tablet, belonging 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-coated tablets are not 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 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 tablet 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 tablet 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

Enteric material 20-40%

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 carboxymethyl starch; the enteric material is one or more of acrylic resin EuS100, acrylic resin II or acrylic resin I; the plasticizer is propylene glycol; the lubricant is magnesium stearate.

Wherein, the enteric material is preferably acrylic resin EuS100, acrylic resin II; preferably, the weight ratio of the acrylic resin EuS100 to the acrylic resin II is 1: 1.

the calcitriol enteric-coated tablet 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, granulating with 20-24 mesh sieve by using absolute ethyl alcohol as an adhesive, drying, and tabletting to obtain a calcitriol 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 calcitriol tablet core prepared in the step (2), and drying to obtain a calcitriol enteric tablet;

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

The calcitriol enteric-coated tablet 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 calcitriol enteric-coated tablets

A preparation method of calcitriol enteric-coated tablets 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, granulating with 20-24 mesh sieve by using absolute ethyl alcohol as an adhesive, drying, and tabletting to obtain a calcitriol 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 calcitriol tablet core prepared in the step (2), and drying to obtain a calcitriol enteric tablet;

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

Preparing calcitriol enteric-coated tablets according to the preparation method by using the raw and auxiliary materials in the formula (1000 tablets) shown in the following table 1. Where "/" indicates unused.

Test example 1 dissolution rate measurement of calcitriol enteric-coated tablets obtained in examples 1 to 6

According to the guidance principle of slow release, controlled release and delayed release preparations of 9013 in 2015 th four-part general rules, a proper amount of calcitriol 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 rules in the Chinese pharmacopoeia. The results are shown in tables 2 and 3.

As can be seen from Table 2, the calcitriol enteric-coated tablets prepared in examples 1-6 are slowly dissolved in artificial gastric juice with a pH of 1.2, are only 10.6% at most after 4 hours of dissolution, and have better acid resistance; the calcitriol enteric-coated tablet in example 5 is dissolved in 4 hours to the minimum, and the coating enteric-coated materials of acrylic resin EuS100 and acrylic resin II are used, wherein the weight ratio of the coating enteric-coated tablets to the acrylic resin II is 1: 1, the prepared calcitriol enteric-coated tablet has the best acid resistance.

As can be seen from Table 3, the calcitriol enteric-coated tablets prepared in examples 1 to 6 are rapidly released in the artificial intestinal juice with pH of 6.8, so that the purpose of quick release can be achieved; the dissolution rate of the calcitriol enteric-coated tablet in example 5 is the highest at 60min, which indicates that acrylic resin EuS100 and acrylic resin II are used as enteric-coated materials, and the weight ratio is 1: 1 hour, the prepared calcitriol 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 calcitriol enteric-coated tablets obtained in examples 1 to 6 and the calcitriol soft capsules (trade name: Rogaiquan) 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 in accordance with the general guidelines of the four ministry of the chapter of the book of Chinese pharmacopoeia 2015. The calcitriol enteric-coated tablets obtained in examples 1 to 6 and the calcitriol soft capsules (trade name: Rogaiquan) 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 results of the calcitriol enteric-coated tablet of example 5 at 6 months accelerated and 24 months long are significantly better than those of the calcitriol soft capsule of the control preparation and other examples, which indicates that when the enteric-coated tablet is prepared by using the acrylic resin EuS100 and the acrylic resin ii as enteric-coated materials, the weight ratio is 1: 1, the prepared calcitriol enteric-coated tablet has the best stability effect and is superior to the calcitriol soft capsules on the market.

Claims (4)

1. The calcitriol enteric-coated tablet consists of a calcitriol tablet core and an enteric-coated layer coated outside the calcitriol tablet core, wherein the tablet core comprises calcitriol, a filler, an antioxidant and a disintegrating agent, and the enteric-coated layer comprises an enteric material, a plasticizer and a lubricant, and is characterized in that the calcitriol enteric-coated tablet 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

Enteric material 20-40%

1 to 10 percent of plasticizer

1-10% of lubricant.

2. Calcitriol enteric tablet 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 tablet according to claim 1, characterized in that the filler is microcrystalline cellulose; the disintegrating agent is sodium carboxymethyl starch; the antioxidant is butyl hydroxy anisole; the enteric-coated material is acrylic resin EuS100 and acrylic resin II, and the weight ratio is 1: 1; the plasticizer is propylene glycol; the lubricant is magnesium stearate.

4. A method of preparing calcitriol enteric tablets according to claim 1, comprising the steps of:

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

(2) uniformly mixing calcitriol, 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 a calcitriol 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 calcitriol tablet core prepared in the step (2), and drying to obtain a calcitriol enteric tablet;

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