CN106309387B

CN106309387B - Everolimus tablet

Info

Publication number: CN106309387B
Application number: CN201510404952.4A
Authority: CN
Inventors: 张贵民; 孟凡波
Original assignee: Shandong New Time Pharmaceutical Co Ltd
Current assignee: Shandong New Time Pharmaceutical Co Ltd
Priority date: 2015-07-11
Filing date: 2015-07-11
Publication date: 2020-04-24
Anticipated expiration: 2035-07-11
Also published as: CN106309387A

Abstract

The invention belongs to the technical field of medicines, and particularly relates to an everolimus tablet. The everolimus tablet contains everolimus, polyethylene glycol and hydroxypropyl cellulose, and is prepared by the following method: heating and melting everolimus and polyethylene glycol, adding the molten liquid into an ethanol solution of hydroxypropyl fiber, uniformly stirring, and finally granulating, drying and tabletting the suspension on pharmaceutically acceptable auxiliary materials. Compared with the prior art, the invention has rapid dissolution.

Description

Everolimus tablet

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an everolimus tablet.

Background

Everolimus (everolimus), molecular formula: c₅₃H₈₃NO₁₄Molecular weight: 958.22, the structural formula is as follows:

everolimus is an inhibitor of mTOR (the mammalian target of rapamycin), a serine threonine kinase downstream of the PI3K/AKT pathway. Everolimus was first developed by NovartiS, switzerland, under the tradename certian, first marketed in sweden in 2003 and has fully dominated the european market in 2006.

According to the study of novartis, everolimus can slow down the growth of renal cancer cells, reducing the mortality rate by 67%. Directly acts on the tumor cells by inhibiting the growth and proliferation of the tumor cells; by inhibiting angiogenesis, an indirect effect is exerted (by effectively inhibiting the production of VEGF by tumor cells and VEGF-induced proliferation of endothelial cells) resulting in a decrease in tumor vascularity.

In 2010, everolimus was approved for the prevention of organ rejection in heart and kidney transplant patients. In addition to renal cell carcinoma and rejection after organ transplantation, everolimus is also being studied for neuroendocrine tumors, lymphomas, other cancers, and tuberous sclerosis, either as a single agent or in combination with existing cancer treatment methods.

Everolimus is white to yellowish powder, is lipophilic, and has solubility in water of less than 0.01% (g/ml) at 25 ℃, so that the improvement of the dissolution rate is particularly important.

The Chinese invention patent CN102138903A discloses an everolimus solid oral pharmaceutical composition, which comprises a composition consisting of everolimus or derivatives thereof and an excipient, wherein the pH value of an aqueous solution of the composition is 4-7, the everolimus or derivatives thereof accounts for 0.05-5% of the composition by weight, and main drugs are uniformly dispersed by a fluidized bed coating technology. The disadvantages of complex preparation process, high difficulty of production and operation and high cost; in the preparation process, water or other solvents are used and heating is needed, so that the prepared medicine has large impurities and poor stability.

Chinese patent CN 103610646A discloses a method for preparing everolimus-containing solid dispersion, which is prepared by dissolving everolimus and a high polymer carrier HPMC in an organic solvent and then carrying out centrifugal spray drying. The method has the disadvantages that the use of the organic solvent can not influence everolimus and excipient, the residual problem of the organic solvent, the equipment problem, the personnel operation safety problem, the detection problem of the residual solvent and the like, the complexity of the operation process can be increased, the potential safety hazard also exists, and the cost is increased.

Currently, tablets and dispersible tablets of everolimus are marketed by Nowa, but contain di-t-butyl-p-cresol. Di-tert-butyl-p-cresol is an oil-soluble organic compound that is mainly used as an antioxidant in food additives because it chemically reacts with free radicals and slows down the redox reaction in foods, thereby maintaining the color, smell and taste of foods. Since di-t-butyl-p-cresol has low toxicity and deteriorates when exposed to moisture or light, it is prohibited to add it to food in Japan, Romania, Sweden, Australia, USA, etc. Antioxidant di-tert-butyl-p-cresol is added into the marketed preparation of Nowa, so that the property of the product is influenced, and potential safety hazards are brought to patients.

Disclosure of Invention

Aiming at the defects of the prior art, the inventor intends to provide an everolimus tablet capable of quickly dissolving out.

Specifically, the invention is realized by the following technologies:

the everolimus tablet contains everolimus, polyethylene glycol and hydroxypropyl cellulose, and is prepared by the following method: heating and melting everolimus and polyethylene glycol, adding the molten liquid into an ethanol solution of hydroxypropyl fiber, uniformly stirring, and finally granulating, drying and tabletting the suspension on pharmaceutically acceptable auxiliary materials.

The weight ratio of everolimus to polyethylene glycol of the everolimus tablet is 1: 0.5-1.5; preferably, the weight ratio is 1: 1.

The weight ratio of everolimus to hydroxypropyl cellulose of the everolimus tablet is 1: 3-5; preferably, the weight ratio is 1: 4.

The pharmaceutically acceptable auxiliary materials of the everolimus tablet are mannitol, sodium carboxymethyl starch and magnesium stearate.

The pharmaceutically acceptable auxiliary materials of the everolimus tablet are microcrystalline cellulose, sodium carboxymethyl starch and magnesium stearate.

Compared with the prior art, the medicine of the invention is dissolved out rapidly.

Detailed Description

The following examples further illustrate the benefits of the present invention, and the examples are for illustrative purposes only and do not limit the scope of the present invention, and variations and modifications apparent to those of ordinary skill in the art in light of the present disclosure are intended to be included within the scope of the present invention.

Example 1

The preparation process comprises the following steps:

heating everolimus and polyethylene glycol 4000 at 80 ℃ for melting, adding the molten liquid into an ethanol solution of hydroxypropyl cellulose in a formula amount, uniformly stirring, and finally granulating, drying and tabletting the suspension on pharmaceutically acceptable auxiliary materials.

Example 2

The preparation process comprises the following steps:

heating everolimus and polyethylene glycol 4000 at 70 ℃ for melting, adding the molten liquid into an ethanol solution of hydroxypropyl cellulose in a formula amount, uniformly stirring, and finally granulating, drying and tabletting the suspension on pharmaceutically acceptable auxiliary materials.

Example 3

The preparation process comprises the following steps:

Comparative example 1

The preparation process comprises the following steps:

according to the formula, 200-mesh everolimus and polyethylene glycol 4000 are weighed and are added into the ethanol solution of hydroxypropyl cellulose, the mixture is uniformly stirred, and finally the suspension is granulated, dried and tabletted on pharmaceutically acceptable auxiliary materials.

Verification examples

And (4) determining the dissolution rate. Taking the product, according to a dissolution determination method (XC third method which is an appendix of the second part of the 2010 edition of Chinese pharmacopoeia), taking 500ml of 0.1% sodium dodecyl sulfate aqueous solution as a dissolution medium, rotating at 50 revolutions per minute, operating according to the method, taking a proper amount of solution after 3, 5 and 15 minutes, filtering, and taking a subsequent filtrate as a test solution. And precisely weighing about 12.5mg of everolimus reference substance, placing the everolimus reference substance into a 50ml measuring flask, firstly adding 5ml of acetonitrile to dissolve the everolimus reference substance, then adding a dissolution medium to dilute to a scale, shaking up, precisely weighing lml, placing the lml into the 50ml measuring flask, adding the dissolution medium to dilute to the scale, and shaking up to obtain the reference substance solution. Precisely measuring 100 microliters of the two solutions according to chromatographic conditions under content determination terms, injecting the two solutions into a liquid chromatograph, recording a chromatogram, and calculating the dissolution amount of each tablet according to an external standard method by using the sum of the peak areas of a main peak and an isomer.

TABLE 1 measurement results of examples

Examples	3min dissolution (%)	Dissolution rate at 5min (%)	15min dissolution (%)
				Example 1	99.8	99.9	99.9
Example 2	99.8	99.9	100.1
				Example 3	100.1	100.1	100.1
Comparative example 1	43.5	60.4	77.2

As can be seen from the table, the dissolution of the inventive examples is rapid; comparative example 1, with the addition of polyethylene glycol, but without melt granulation, dissolution was slower than the present invention.

Claims

1. An everolimus tablet is characterized by comprising everolimus, polyethylene glycol and hydroxypropyl cellulose, wherein the weight ratio of the everolimus to the polyethylene glycol is 1:0.5-1.5, and the weight ratio of the everolimus to the hydroxypropyl cellulose is 1: 3-5.

2. The everolimus tablet of claim 1, wherein the weight ratio of everolimus to polyethylene glycol is 1: 1.

3. The everolimus tablet of claim 1, wherein the weight ratio of everolimus to hydroxypropylcellulose is 1: 4.

4. The everolimus tablet of claim 1, wherein the pharmaceutically acceptable excipients are mannitol, sodium carboxymethyl starch, magnesium stearate.

5. The everolimus tablet of claim 1, wherein the pharmaceutically acceptable excipients are microcrystalline cellulose, sodium carboxymethyl starch, magnesium stearate.