CN111821275A

CN111821275A - Fluorocalcitriol controlled release tablet

Info

Publication number: CN111821275A
Application number: CN202010629639.1A
Authority: CN
Inventors: 孙桂玉; 刘晓霞; 陈阳生; 臧云龙; 王明刚; 杜昌余; 牛建兴; 薛文静; 王婷婷
Original assignee: CP Pharmaceutical Qingdao Co Ltd
Current assignee: CP Pharmaceutical Qingdao Co Ltd
Priority date: 2020-07-03
Filing date: 2020-07-03
Publication date: 2020-10-27

Abstract

The invention provides a preparation method of a controlled release tablet of fluocalcitriol, belonging to the technical field of medicines. The controlled release preparation of the fluocalcitriol is composed of a medicine-containing tablet core and a coating film layer coated outside the medicine-containing tablet core, wherein the medicine-containing tablet core comprises the fluocalcitriol, a filling agent and sodium chloride, the coating film layer comprises a controlled release material, a plasticizer and a pore-forming agent, and the preparation method is characterized in that the coating film layer is coated outside the medicine-containing tablet core. The main ingredient of the preparation is fluocalcitriol vitamin D3 analog, and the preparation has effects in regulating calcium metabolism and resisting rickets, and can be used for treating hypoparathyroidism. The medicine can be slowly and uniformly released to achieve the purposes of long acting and improving curative effect, and the dosage can be reduced while the same medicine effect is maintained, so that the side effect of patients caused by taking the medicine is reduced, the preparation process is simple, the quality of the obtained product is stable, and the medicine is suitable for large-scale production and application.

Description

Fluorocalcitriol controlled release tablet

Technical Field

The invention belongs to the technical field of medicines, and relates to a preparation method of a controlled release tablet of fluorcalcitriol.

Background

Fluorocalcitriol, a vitamin D3 analog, is a derivative of active form of small intestine, acts by binding to receptors distributed in target tissues, can regulate calcium metabolism, resist rickets, and is used for treating hypoparathyroidism. The existing fluorocalcitriol preparation is mainly a tablet, and the fluorocalcitriol tablet is researched and developed by Nippon Sumitomo and Nippon Dazheng medicine together for sale in 4 months in the first 2001; is not marketed in other countries.

Parathyroid glands are endocrine glands located behind the thyroid side lobes in the front of the human neck, and about 80% of people have 4 parathyroid glands, and the hormone secreted by parathyroid glands is mainly parathyroid hormone, which mainly regulates calcium and phosphorus metabolism and skeletal metabolism in the human body. Hypoparathyroidism, also called as parathyroid disease, is characterized by that due to several reasons, the parathyroid hormone production is reduced or its action is deficient, so that the hypocalcemia and hyperphosphatemia are the main test abnormalities, and the patient can take the calcium preparation and vitamin D preparation for a long time to control his disease condition.

The existing preparation of the fluorocalcitriol is mainly a tablet, is a common tabletting method, and at present, no controlled release preparation of the fluorocalcitriol exists.

Disclosure of Invention

The medicine can be slowly and uniformly released to achieve the purposes of long acting and improving curative effect, and the dosage can be reduced while the same medicine effect is maintained, so that the side effect of patients caused by taking the medicine is reduced, the preparation process is simple, the quality of the obtained product is stable, and the medicine is suitable for large-scale production and application. The invention provides a controlled release preparation which is safe and effective, has stable quality, low cost, less administration frequency and enhanced patient compliance.

In order to solve the defects of inconvenient administration and low bioavailability of the existing fluorocalcitriol preparation, the invention provides a fluorocalcitriol controlled release tablet, which reduces the administration times, slows down the absorption rate, prolongs the biological half-life period, and controls the blood concentration within the effective blood concentration range, thereby reducing the side effect and improving the compliance of patients.

The applicant finds that the flucalcitriol is combined with specific auxiliary materials to prepare the controlled release tablet, and the controlled release tablet has the advantages of high stability, good controlled release effect and high bioavailability.

The application provides a controlled release tablet of fluorcalcitriol, which is marked by weight parts and comprises the following components in parts by weight: 1-3 parts of fluorocalcitriol, 20-30 parts of a filling agent, 5-8 parts of an osmotic pressure active substance, 15-35 parts of a controlled release material, 4-8 parts of a plasticizer, 3-6 parts of a pore-forming agent and a proper amount of ethanol.

Preferably, the formulation of the controlled release tablet is (by weight): 1.5 parts of fluorocalcitriol, 28 parts of filler, 7.5 parts of osmotic pressure active substance, 28 parts of controlled release material, 6 parts of plasticizer, 4.5 parts of pore-forming agent and a proper amount of ethanol.

In the application, the specific auxiliary materials are selected to prepare the controlled-release tablet of the fluorcalcitriol. The filler is at least one of lactose or dextrin; the osmotic pressure active substance is one or two of potassium chloride or sodium chloride; the controlled-release material is cellulose acetate and sodium alginate; the plasticizer is triethyl citrate; the pore-foaming agent is polyethylene glycol 4000.

Further preferably, the controlled release material is cellulose acetate and sodium alginate, and the weight ratio of the cellulose acetate to the sodium alginate is 1: 3.

The preparation method of the controlled release tablet of the fluocalcitriol comprises the following steps:

(1) uniformly mixing the flucalcitriol, the filling agent and the osmotic pressure active substance according to the weight part ratio, preparing a soft material by taking 85% ethanol as an adhesive, granulating through a sieve of 18-24 meshes, drying and tabletting to obtain a medicine-containing tablet core;

(2) dissolving the controlled release material, the plasticizer and the pore-forming agent by 80 percent ethanol to prepare controlled release coating liquid;

(3) and (3) uniformly spraying the prepared controlled-release coating solution on the surface of the medicine-containing tablet core prepared in the step (1), and drying to obtain the fluocalcitriol controlled-release tablet.

The invention relates to a fluocalcitriol controlled release tablet which has the following beneficial effects:

(1) the drug is released uniformly, the purposes of long acting and improving curative effect can be achieved, and the dosage can be reduced while the same drug effect is maintained, so that the side effect of patients caused by taking the drug is reduced;

(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 and application.

Detailed Description

The inventors screened the prescription using the above method to obtain examples 1-6.

Examples 1-6 preparation of Fluorocalcitriol controlled-release tablets

According to the raw materials and auxiliary materials in the following table, the preparation method is adopted to prepare the controlled release tablet of the flucalcitriol of six examples, wherein "/" represents that the controlled release tablet is not used.

Table 1 examples 1-6

Test example 1 measurement of in vitro Release degree of Fluorocalcitriol controlled-Release tablets obtained in examples 1 to 6

The release rate was measured by a dissolution rate and release rate measuring method (refer to 0931, the four general rules of characteristics inspection in chinese pharmacopoeia 2015), distilled water was used as a dissolution medium, samples were taken at 1, 2, 4, 6, 8, 12, 16, and 24 hours, absorbance was measured, and the cumulative release rate was calculated from a standard curve. The dissolution rate of the controlled-release tablets of flucalcitriol prepared in examples 1 to 6 was measured within 24 hours. The test results are shown in Table 2.

TABLE 2 EXAMPLES 1-6 in vitro Release test Table (dissolution Medium: distilled Water)

As can be seen from Table 1, the controlled release tablets prepared in examples 1 to 6 can be uniformly released at a constant speed, which indicates that the effective blood concentration of the drug can be maintained for a long time and the number of times of taking the drug can be reduced; the controlled release tablets of examples 1, 2 and 6 have the highest release degree in 12 hours, which indicates that the bioavailability is higher, and the controlled release effect of the prepared controlled release tablet of the fluocalcitriol is the best when the weight ratio of the cellulose acetate to the sodium alginate is 1: 3.

Test example 2 stability test

The contents of the tablets of examples 1 to 6 were subjected to the influence factor examination.

(1) High-temperature test: a suitable amount of the samples of examples 1 to 12 were spread on a petri dish and placed in an incubator at 60 ℃ for 10 days, during which time the samples were taken for the measurement on days 0, 5 and 10, respectively, and the measurement results are shown in Table 3.

(2) High humidity test: a suitable amount of the samples of examples 1 to 12 were plated on a petri dish and left to stand at 25 ℃ and a relative humidity RH of 70% + -5% for 10 days, during which time samples were taken for the measurement on days 0, 5 and 10, respectively, and the measurement results are shown in Table 3.

(3) In the intense light irradiation test, a proper amount of the samples of examples 1 to 12 were spread on a petri dish and placed in a light cabinet to be irradiated with light at 4500 Lx. + -. 500Lx for 10 days, during which time, samples were taken on days 0, 5 and 10, respectively, and the measurement results are shown in Table 5.

TABLE 3 stability of tablets of the examples at high temperature, high humidity and under high light

As can be seen from the stability test results, examples 1 to 6 were acceptable in content and stable in quality.

Claims

1. A controlled release tablet, wherein the active ingredient is fluorcalcitriol, characterized by comprising a drug-containing core and a coating film layer coated outside the drug-containing core, the drug-containing core comprises fluorcalcitriol, a filler and an osmotic pressure active substance, the coating film layer comprises a controlled release material, a plasticizer and a pore-forming agent, and is characterized in that the controlled release tablet comprises the following components in parts by weight: 1-3 parts of fluorocalcitriol, 20-30 parts of a filling agent, 5-8 parts of an osmotic pressure active substance, 15-35 parts of a controlled release material, 4-8 parts of a plasticizer, 3-6 parts of a pore-forming agent and a proper amount of ethanol.

2. The controlled-release tablet of tromethamine according to claim 1, characterized in that: the weight portions of the components are as follows:

1.5 parts of fluorocalcitriol, 28 parts of filler, 7.5 parts of osmotic pressure active substance, 28 parts of controlled release material, 6 parts of plasticizer, 4.5 parts of pore-forming agent and a proper amount of ethanol.

3. The controlled-release tablet of tromethamine according to claim 2, characterized in that: the filler is at least one of lactose or dextrin; the osmotic pressure active substance is one or two of potassium chloride or sodium chloride; the controlled-release material is cellulose acetate and sodium alginate; the plasticizer is triethyl citrate; the pore-foaming agent is polyethylene glycol 4000.

4. The controlled-release tablet of tromethamine according to claim 3, characterized in that: the controlled-release material is cellulose acetate and sodium alginate, and the weight ratio of the cellulose acetate to the sodium alginate is 1: 3.

5. A method for preparing the controlled-release tablet of tromethamine according to any one of claims 1 to 5, comprising the steps of:

(1) uniformly mixing the flucalcitriol, the filling agent and the osmotic pressure active substance according to the weight part ratio, preparing a soft material by taking 75% ethanol as an adhesive, granulating through a sieve of 18-24 meshes, drying and tabletting to obtain a medicine-containing tablet core;

(2) dissolving the controlled release material, the plasticizer and the pore-forming agent by using 75% of ethanol to prepare controlled release coating liquid;