Patent Application
20180280392
The present invention relates to the field of pharmaceutical preparation, and specifically relates to a pharmaceutical preparation for use as a cyclin inhibitor and a preparation method thereof.
Cyclin-dependent kinase (CDK) has 13 members in total, which all belong to the serine/threonine protein kinase family, and has key functions such as promoting the phase transition of cell cycle, initiating DNA synthesis and regulating cell transcription and the like, depending on the combination with a cyclin.
CDKs play a key role in the proliferation and death of all cells, including healthy cells and tumor cells. Broad-spectrum CDK inhibitors can hardly exhibit high therapeutic window on patients, especially on patients who have not undergone a gene screening. The toxicity will be severe when the dosage is too high, while the efficacy will be negligible when the dosage is too low. Therefore, it is very important to selectively inhibit some CDKs. Of course, since most of the CDK subtypes have relatively similar chemical structures, how to improve the selectivity of CDK inhibitors is another challenge.
The advantages of using CDK4/6 as an anti-tumor target are as follows: (1) the inhibitors of CDK4/6 do not exhibit cytotoxicities of “pan-CDK inhibitors,” such as myelosuppression and intestinal responses; and (2) the increase of cell cyclin D level or the inactivation of P161NK4a can improve the sensitivity of cells to drugs. The aforementioned phenomena are presented in tumor cells relative to normal cells, therefore the targeted property of drugs will be increased to a certain extent. The compound of formula I is a targeted CDK4/6 inhibitor, which can selectively inhibit cyclin-dependent kinase 4 and 6 (CDK4/6), restore cell cycle control, and block the proliferation of tumor cells. It acts on MDA-MB-435 breast cancer cells, and can effectively reduce the phosphorylation of retinoblastoma tumor suppressor (RB) on Ser780 and Ser795 sites, and the IC50 are 66 nM and 63 nM, respectively.
Breast cancer is one of the most common malignant tumors of women, with high incidence rates and invasiveness, but the course of progress is slow. The data published by the International Cancer Research Center showed that about 1.67 million cases were newly diagnosed around the world in 2012, which accounted for 25% of all cancers. According to the Survey of Epidemiology and End Results (SEER) of the U.S. National Cancer Institute, the estimated incidence rate of breast cancer was 123.8 per one hundred thousand people in the U.S. in 2013, and the incidence rate of breast cancer of Asian females was 94.5 per one hundred thousand people in 2005-2009. There is no official data in China, but it is estimated that the estrogen or progesterone receptor is positive among 60%-70% of breast cancer patients in China. The incidence rate of estrogen receptor positive breast cancer was thus calculated to be 56.7-66.15 per one hundred thousand people in China in 2005-2009. According to Thomson's prediction, the sales of this product will increase significantly after it comes onto the market, and the sales are expected to reach 2.027 billion U.S. dollars in 2019.
The objective of the present invention is to provide a pharmaceutical preparation comprising 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-yl-amino)-8H-pyrido[2,3-d]pyrimidin-7-one and a salt thereof, and a preparation method thereof. The technical solution of the present invention is achieved as follows:
A pharmaceutical composition, comprising the compound of formula I or the salt thereof, and a pharmaceutically acceptable excipient as a vehicle, wherein the salt comprises hydrochloride or isethionate.
Preferably, the compound of formula I is present in an amount of 10%-80%, preferably 15%-60%, further preferably 20%-40% by weight, relative to the weight of the composition.
Preferably, the composition comprises the compound of formula I or the salt thereof and the excipient, wherein the excipient is one or more selected from the group consisting of a disintegrant, diluent, binder, surfactant, and lubricant, preferably, the weight percentage of each component is as follows:
0-20%.
Optionally, the composition can also comprise a flavoring agent, a colorant or a coating material, most preferably, the sum of the weight percentages of the aforementioned components is 100%.
Further preferably, in the pharmaceutical composition, the weight percentage of each component is as follows:
Optionally, the composition can also comprise a flavoring agent, a colorant or a coating material, most preferably, the sum of the weight percentages of the aforementioned components is 100%.
More preferably, in the pharmaceutical composition, the weight percentage of each component is as follows:
Preferably, the diluent is at least one selected from the group consisting of starch, powdered sugar, dextrin, lactose, pregelatinized starch, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, mannitol, sorbitol and microcrystalline cellulose. More preferably, the diluent is at least one selected from the group consisting of lactose, microcrystalline cellulose, starch and mannitol, most preferably, the diluent is selected from the group consisting of lactose and microcrystalline cellulose.
Preferably, the weight ratio of lactose to microcrystalline cellulose is 1:2-2:1, preferably 1:1.
Preferably, the binder is at least one selected from the group consisting of starch slurry, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, methyl cellulose, sodium carboxymethyl cellulose, and polyethylene glycol. More preferably, the diluent is at least one selected from the group consisting of hydroxypropyl cellulose and povidone.
Preferably, the disintegrant is at least one selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, crospovidone, dry starch, and low-substituted hydroxypropyl cellulose. More preferably, the disintegrant is at least one selected from the group consisting of crospovidone, sodium carboxymethyl starch, and croscarmellose sodium.
Preferably, the lubricant is at least one selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, colloidal silica, talc, and silica. More preferably, the lubricant is at least one selected from the group consisting of stearic acid, glyceryl behenate, and colloidal silica.
Preferably, the surfactant is sodium dodecyl sulfate, Tween 80 and poloxamer. More preferably, the surfactant is sodium dodecyl sulfate.
In another aspect, the present invention provides a preparation method of the compound of formula I or the salt thereof. The preparation process comprises wet granulation, dry granulation, direct mixing and the like, and the dosage form comprises a tablet or capsule.
Preferably, the composition is obtained by wet granulation, and the method comprises the following steps of:
(1) pre-mixing the compound of formula I or the salt thereof with a portion of a lubricant in a wet mixing granulator to obtain a pre-mixture;
(2) adding a granulation liquid to granulate the pre-mixture obtained in step (1), preferably, the granulation liquid being water;
(3) drying the granule obtained in step (2) in a fluidized bed dryer or a drying oven;
(4) optionally, dry screening the dry granule obtained in step (3);
(5) mixing the dry granule obtained in step (4) with the rest of excipient(s) to obtain a final mixture;
(6) optionally, filling the mixture obtained in the aforementioned step (5) by a suitable capsule filling machine to prepare a capsule;
(7) optionally, pressing the mixture obtained in the aforementioned step (5) by a suitable tabletting machine to obtain a tablet core; and
(8) optionally, film coating the tablet core obtained in step (7) with a film coating.
Preferably, the composition is obtained by dry granulation, and the method comprises the following steps of:
(1) mixing the compound of formula I or the salt thereof with the majority of excipients including a binder in a hopper mixer to obtain a pre-mixture;
(2) pressing the mixture obtained in step (1) in a suitable roller press machine;
(3) crushing the ribbon obtained during step (2) into a granule by a suitable grinding or screening step;
(4) optionally, mixing the granule obtained in step (3) with the rest of the excipient in a mixer to obtain a final mixture;
(5) optionally, filling the mixture obtained in the aforementioned step (4) by a suitable capsule filling machine to prepare a capsule;
(6) optionally, pressing the mixture obtained in the aforementioned step (4) by a suitable tabletting machine to obtain a tablet core; and
(7) optionally, film coating the tablet core obtained in step (6) with film a coating. The present invention provides a pharmaceutical preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-yl-amino)-8H-pyrido[2,3-d]pyrimidin-7-one and a salt thereof, which is stable and suitable for medical applications. The pharmaceutical preparation has excellent dissolution behavior and good stability, which meets the requirements for clinical use, and enables the active ingredient to achieve a good in vivo bioavailability.
The embodiments of the present invention will be described in detail with reference to specific examples. The following examples are only intended to illustrate the present invention, and should not be considered as limiting the scope of the present invention.
1.1 Composition of Unit Formula
1.2 Preparation
The compound of formula I and the excipients in the aforementioned formulation, except magnesium stearate, in an amount for 1000 tablets were mixed in a hopper mixer, and a wetting agent was added to carry out wet granulation. The granule was dried in a fluidized bed at 45° C. for 10 minutes, and sieved through a 1.0 mm sieve. Magnesium stearate was added, and the mixture was blended for 10 minutes. The content was monitored on line. The mixture was filled in capsules, or pressed into tablets.
1.3 Dissolution Data
The dissolution rate of each formula in 0.1 mol/L HCl is shown in the table below.
2.1 Composition of Unit Formula
2.2 Preparation
The compound of formula I and the excipients in the aforementioned formulation, except magnesium stearate, in an amount for 1000 tablets were mixed in a hopper mixer. The mixture was pressed into a ribbon by using a roller press machine, then the ribbon was crushed into a granule. Magnesium stearate was added, and the mixture was blended for 10 minutes. The content was monitored on line. The mixture was filled in capsules, or pressed into tablets.
2.3 Dissolution Data
3.1 Composition of Unit Formula
3.2 Preparation
The compound of formula I and the excipients in the aforementioned formulation in an amount for 1000 tablets were mixed in a hopper mixer. The content was monitored on line. The mixture was filled in capsules, or pressed into tablets.
3.3 Dissolution Data
4.1 Composition of Unit Formula
4.2 Preparation
The API and excipients in the aforementioned formulation, except magnesium stearate, in an amount for 1000 tablets were mixed in a hopper mixer, and a wetting agent was added to carry out wet granulation. The granule was dried in a fluidized bed at 45° C. for 10 minutes, and sieved through a 1.0 mm sieve. Magnesium stearate was added, and the mixture was blended for 10 minutes. The content was monitored on line. The mixture was filled in capsules, or pressed into tablets.
4.3 Dissolution Data
5.1 Composition of Unit Formula
5.2 Preparation
The API and excipients in the aforementioned formulation, except magnesium stearate, in amount for 1000 tablets were mixed in a hopper mixer. The mixture was pressed into a ribbon by using a roller press machine, and the ribbon was then crushed into granules. Magnesium stearate was added, and the mixture was blended for 10 minutes. The content was monitored on line. The mixture was filled in capsules, or pressed into tablets.
5.3 Dissolution Data
6.1 Composition of Unit Formula
6.2 Preparation
The API and excipients in the aforementioned formulation in an amount for 1000 tablets were mixed in a hopper mixer. The content was monitored on line. The mixture was filled in capsules, or pressed into raw tablets, which were then coated. The weight increase of coating was controlled by 3%.
6.3 Dissolution Data
7.1 Unit Dosage Formula
7.2 Preparation
For formulas 26-28, the API and excipients in the formulation in an amount for 1000 tablets were mixed in a hopper mixer. The content was monitored on line. The mixture was filled in capsules. For formulas 29-30, after mixing, the mixture was directly pressed into raw tablets, which were then coated. The weight increase of coating was controlled by 3%.
7.3 Dissolution Data
8.1 Unit Dosage Formula
8.2 Preparation
For formulas 31-32, the API and excipients in the formulation in an amount for 1000 tablets were mixed in a hopper mixer. The content was monitored on line. The mixture was filled in capsules. For formulas 33-34, after mixing, the mixture was directly pressed into raw tablets, which were then coated. The weight increase of coating was controlled by 3%. For formula 35, the compound of formula I and other excipients, except magnesium stearate, were mixed in a hopper mixer. The mixture was pressed into a ribbon by using a roller press machine, and the ribbon was then crushed into granules. Magnesium stearate was added, and the mixture was blended for 10 minutes. The content was monitored. The mixture was pressed into tablets, which were then coated. The weight increase of coating was controlled by 3%.
8.3 Dissolution data
8.4 Stability Data
The capsules prepared in Example 8 were packaged in a commercially available package, and then placed under a relative humidity of 75%±5% at 40° C.±2° C. for 6 months. The results are shown in Table 1.
1the conversion coefficient of the compound of formula I to a hydrochloride salt is 447.53/484.03 = 92.4%, i.e., 75 mg of the compound of formula I corresponds to 81 mg of the hydrochloride salt of the compound of formula I; the conversion coefficient of the compound of formula I to an isethionate salt is 447.53/573.53 = 78.0%, i.e., 75 mg of the compound of formula I corresponds to 96 mg of the isethionate salt of the compound of formula I; other specifications are converted correspondingly.
Wet granulation was carried out with the salt of the compound of formula I and excipients except lubricant, the granule was sieved after drying, a lubricant was added, and the mixture was blended for 10 minutes. The content was monitored on line. For formulas 36-38, the mixture was filled in capsules; for formulas 39-41, the mixture was pressed into tablets, which were then coated, and the weight increase of coating was controlled by 3%.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201410623810.2 | Nov 2014 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2015/093953 | 11/6/2015 | WO | 00 |
