CN113274363B

CN113274363B - Indapamide preparation

Info

Publication number: CN113274363B
Application number: CN202110469904.9A
Authority: CN
Inventors: 关东; 林创生; 符联昌; 谢斌; 兰柳琴
Original assignee: Zhuhai Rundu Pharmaceutical Co Ltd
Current assignee: Zhuhai Rundu Pharmaceutical Co Ltd
Priority date: 2021-04-29
Filing date: 2021-04-29
Publication date: 2023-02-10
Anticipated expiration: 2041-04-29
Also published as: CN113274363A

Abstract

The invention provides an indapamide preparation, which consists of indapamide, a filling agent, an adhesive, a retardant and a flow aid, wherein the filling agent is selected from one or more of powdered sugar, dextrin, corn starch, microcrystalline cellulose, pregelatinized starch, mannitol, calcium sulfate dihydrate, lactose and sucrose, the adhesive is selected from hydroxypropyl methylcellulose E3, the retardant is selected from hydroxypropyl methylcellulose E5, and the flow aid is selected from one or more of talcum powder, micropowder silica gel and silicon dioxide. The formula of the invention uses hypromellose E3 as an adhesive, and the influence of auxiliary materials on genotoxic impurities of the indapamide preparation is reduced to the minimum, so that the indapamide preparation is safer to use.

Description

Indapamide preparation

Technical Field

The invention belongs to the field of medicinal preparations, and particularly relates to an indapamide preparation for improving gene impurity control of the indapamide preparation.

Background

Genotoxic impurities can cause damage to human cellular DNA at very low concentrations, resulting in genetic mutation or in vivo mutagenesis, with a carcinogenic risk. The common genotoxic impurities include aflatoxins, methyl sulfonate, nitrosamine compounds and other compounds and some chemotherapeutic drugs.

The intake of acceptable risk, namely the toxic substance limit TTC, is 1.5 mug/day, which is equivalent to the daily intake of 1.5 mug of genotoxic impurities, is introduced in the guiding principle of genetic toxic impurity limit of EMA (European drug evaluation organization).

Indapamide is a non-thiazide sulfonamide diuretic, is a drug with the effects of reducing blood pressure, promoting urination and calcium antagonism, and has the structural formula:

. The maximum API daily dose (MDD) of the indapamide preparation is 10 mg/day, and the acceptability of genotoxic impurities of the indapamide in bulk drugs is 150ppm calculated by TTC (ug/day)/MDD (g/day) according to TTC1.5 mu g/day. The risk is considered negligible at 1.5 mug daily intake, since the theoretical cancer risk for life-long exposure is less than one hundred thousand as a control criterion for acceptable limits.

The genotoxic impurities are required to be controlled in the process when the genotoxic impurities have high toxicity. Methods are given for process control in ICH M7. Adding impurities into the quality standards of the raw material medicines, the starting materials or the intermediates for detection and establishing the quality standards, according to ICH Q6A, if the subsequent production process can control the impurity residual level of the raw material medicines to be lower than the acceptable limit, the subsequent process is not required to detect, or the mutagenic impurities in the raw material medicines are detected to be lower than 30% of the acceptable limit in at least 6 continuous pilot batches or 3 continuous production batches, and the regular detection can be carried out. If the condition is not met, the raw material medicines need to be subjected to conventional detection.

Indapamide degradation may produce 1-amino-2-methylindoline (impurity C), the structural formula of which is:

1-nitroso-2-methylindoline (impurity D) of the formula:

the impurities C and D belong to nitrosamine compounds, belong to common genotoxic impurities and are strictly controlled, and in published patents and literatures, no report on the control of the genotoxic impurities C and D is found in indapamide preparations.

Disclosure of Invention

The invention provides an indapamide preparation, which comprises indapamide, a filler, an adhesive, a retardant and a glidant, wherein the filler is selected from one or more of powdered sugar, dextrin, corn starch, microcrystalline cellulose, pregelatinized starch, mannitol, calcium sulfate dihydrate, lactose and sucrose, the adhesive is selected from hydroxypropyl methylcellulose E3, the retardant is selected from hydroxypropyl methylcellulose E5, the glidant is selected from one or more of talcum powder, micro-powder silica gel and silicon dioxide, and the preparation can improve the control of gene impurities of the indapamide preparation.

Further, the formula of the indapamide preparation is as follows:

name of material	Dosage unit (mg/tablet or mg/granule)
		Indapamide	2.5
Lactose	6.0-7.3
		Corn starch	60.0-73.3
Hydroxypropyl methylcellulose E3	1.2-4.8
		Hydroxypropyl methylcellulose E5	2.8-3.4
Silicon dioxide	1.5-1.8

A method for preparing indapamide preparation comprises putting indapamide, filler, adhesive, retarder and glidant into a mixer, setting the rotation speed of a stirring paddle to be 13-17Hz and the rotation speed of a granulating cutter to be 13-17Hz, and mixing for 10-15min.

Further, the indapamide preparation is prepared into capsules or tablets.

According to the invention, through the comparative research on the forming mechanism of the indapamide gene impurities and the types and proportions of different auxiliary materials, the formula of the indapamide preparation is re-optimized in order to reduce the indapamide preparation gene impurities, so that the genotoxic impurities in the optimized formula are controlled and improved.

The method for preparing the indapamide preparation adopts a new formula, uses hydroxypropyl methylcellulose E3 as an adhesive, and reduces the influence of auxiliary materials on genotoxic impurities of the indapamide preparation to the minimum, so that the indapamide preparation is safer to use.

The indapamide preparation prepared by the method can improve genotoxicity impurities of the indapamide preparation.

Drawings

FIG. 1 is a graph of the dissolution profiles of reference formulation, formula 3 and formula 4 in hydrochloric acid solution at pH1.2

FIG. 2 is a graph of the dissolution profiles of the reference formulation, formula 4, formula 5 and formula 6 in hydrochloric acid solution at pH 1.2.

Detailed Description

The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.

Example 1 Effect of Povidone on Gene impurities in the formulation

In the prior art, povidone is commonly used as a binder in the preparation of indapamide formulations.

The mechanism of the degradation of indapamide to generate impurity D is as follows:

indapamide is firstly hydrolyzed under the acid-base condition to generate impurity C and 4-chlorine-3-sulfonamide benzoic acid, and the impurity C is further oxidized to generate impurity D under the action of peroxide. Since the formation of impurity D is not isolated from peroxide, but is not used directly or introduced into the process, a potential source of risk is peroxide that povidone may introduce. To assess whether peroxide limits in povidone are applicable, the following comparative test was conducted on a scale of 9000 grains per batch.

Indicating that the higher the povidone K value, the lower the genotoxic impurities.

Example 2 recipe optimization

As for the research on genotoxic impurities of the bulk drugs, 3 impurities with warning structures or nitrosamines possibly involved or introduced in the production process of API exist, and the control measures are detailed as follows:

in addition, in combination with the API degradation pathway analysis and the possibility of reaction of impurity C with peroxide in the adjuvant, it can be estimated that:

from the above evaluations, 6 potential degradation impurities were found, as shown in the following table.

As can be seen from the above table, impurities C and D contain guard structures and are controlled in the finished product, with limits of 600ppm or less and 150ppm or less, respectively. The impurities A and B are common impurities and are respectively less than or equal to 0.2 percent and less than or equal to 0.5 percent under the control limit of a finished product. The 2-methylindoline and the 4-chloro-3-sulfonamide benzamide are common impurities, the introduction risk is low, and the limit is less than or equal to 0.1 percent as any single impurity control.

Considering that genotoxic impurity D is generated by over-oxidation after the indapamide is hydrolyzed, two formulas are designed, wherein the first formula removes purified water in the original formula of the product, the corn starch is dried, the second formula replaces povidone K90 with hydroxypropyl methylcellulose E3 on the basis of the first formula, the formula is designed as the following table, and the batch size is 9000 granules per batch.

The process is described as follows: sequentially putting silicon dioxide, lactose, polyvidone K90 or hydroxypropyl methylcellulose E3, hydroxypropyl methylcellulose E5, indapamide and corn starch into an HLSG10 wet mixing granulator, and starting mixing after setting the rotating speed of a stirring paddle to be 15Hz and the rotating speed of a granulating cutter to be 15Hz, wherein the mixing time is 10min.

The dissolution curves of the self-made samples (batch number: prescription 3 and prescription 4) and the reference preparation (batch number: 968861) in the key dissolution medium pH1.2 hydrochloric acid solution are calculated to obtain the similarity factor f2.

The experimental results are as follows: the results of the measurement of the release rates of the sample and the reference preparation after the prescription optimization show that f2 similarity factors of the release rates of the self-made sample (batch number: prescription 3 and prescription 4) and the reference preparation (batch number: 968861) in a key dissolution medium pH1.2 hydrochloric acid solution are more than 50, and the in-vitro release behaviors of the self-made sample and the reference preparation are proved to have better similarity. The preparation method of the invention can ensure that the medicine and the auxiliary materials are mixed uniformly and can achieve the similar release characteristics with the reference preparation.

The influence factors after the aluminum-plastic packaging are examined for 30 days, and the results are as follows.

The samples and the reference preparation after the prescription 3 and the prescription 4 are filled with capsules and packaged by aluminum plastic (PVC/PVDC) are respectively placed under the conditions of high humidity of 92.5 percent, high temperature of 60 ℃ and illumination, the content and the genotoxic impurity condition of the samples after 30 days and 0 day are inspected, and the storage condition and the packaging mode of the samples are determined.

The results show that genotoxic impurities are detected in the indapamide capsule formulation under high humidity conditions for 30 days and in the presence of povidone K90 with peroxide (formulation 3), while genotoxic impurities are not detected in formulation 4 without povidone K90, so that the exchange of povidone K90 for hypromellose E3 can improve and control the increase of the genotoxic impurities in the indapamide formulation.

Example 3 screening of the amount ratio of hydroxypropyl methylcellulose E3 as a binder

The dissolution behavior of the selected binder, i.e., hypromellose E3, in hydrochloric acid solution at pH1.2 was compared with that of the reference preparation (lot number 968861), as shown in Table 10-11 and FIG. 2.

The experimental results are as follows: the results of the measurement of the release rates of the self-made sample and the reference preparation show that f2 similarity factors of the release rates of the self-made sample (batch number: formula 4, formula 5 and formula 6) and the reference preparation (batch number: 968861) in a key dissolution medium pH1.2 hydrochloric acid solution are all more than 50, and the results show that the in vitro release behaviors of the self-made sample and the reference preparation have better similarity. This requires a binder dosage ratio of 1.2% to 4.8%.

In summary, the binder is finally identified as hypromellose E3, and the optimal formulation ratio is 2.4%.

Claims

1. The indapamide preparation is characterized by comprising indapamide, a filler, a binder, a retarder and a glidant, wherein the filler is selected from corn starch and lactose, the binder is selected from hypromellose E3, the retarder is selected from hypromellose E5, the glidant is selected from silicon dioxide, and the indapamide preparation comprises the following components:

the indapamide preparation is prepared by the following method: and (2) putting the indapamide, the filling agent, the adhesive, the retarder and the glidant into a mixing machine, setting the rotating speed of a stirring paddle to be 13-17Hz and the rotating speed of a granulating cutter to be 13-17Hz, and then starting mixing for 10-15min to obtain the indapamide capsule or tablet.