In vitro release studies of vaginal tablets

1. Vaginal tablets in brief：

Vaginal tablets are tablets that are placed in the vagina for use. It is characterized by easy dissolution, or melting, disintegration and release of drugs in the vagina. They are absorbed through the vaginal mucosa into the local or systemic blood circulation and are often used in the treatment of vaginitis and other clinical diseases. They can be divided into ordinary vaginal tablets, double-layer vaginal tablets, vaginal effervescent tablets, vaginal slow-release tablets, and bio-adhesive vaginal tablets (the latter three of which are new vaginal dosage forms, with the main research focusing on how to improve the adhesion of the preparations or give the preparations a slow and controlled release performance).

2. In vitro release assay of vaginal tablets:

In order to ensure the safety and effectiveness of patients' medication, and to promote the improvement of the R&D and production level of generic drugs, CFDA pointed out in the Technical Requirements for the Evaluation of Generic Drugs of Topically Acting Vaginal Preparations (Vaginal Tablets, Vaginal Suppositories) (Draft for Public Comments) released in 2018 that: for the test of the in vitro release of vaginal preparation, it is recommended to combine with the physiological environment of the vagina and to use a dissolution device that simulates the in vivo release of vaginal preparations.

The normal vaginal pH value of women of childbearing age ranges from 3.8 to 4.4, which is a weakly acidic environment with a balanced flora in the vagina. While in the inflammatory state, the vaginal pH will increase to varying degrees depending on the type of inflammation (literature studies have indicated that the vaginal microbial status changes when the vaginal pH is in the range of 5.0-5.5 or 6.0-7.5, supporting the idea that the vaginal pH increases during vaginal infections). In contrast, the amount and state of vaginal fluid production varies depending on the body's health, diet, and menstrual cycle.

3. A case for in vitro release of vaginal tablets:

In this case sharing, Raytor brings you the in vitro release study of clotrimazole vaginal tablets. Based on the above, we made the following considerations when choosing the experimental parameters:

1） Considering that when vaginal tablets are used, the preparation is fixed by the muscle contraction of the vaginal wall (i.e., there are differences in the peristaltic environment of the gastrointestinal tract faced with oral preparations), we did not use the traditional dissolution device (paddle, basket method of mechanical mixing), but instead used a flow cell dissolution device with the most moderate fluid dynamics conditions to .to carry out the in vitro release of this vaginal tablets test (and with a v-shape bracket to fix the position of tablets placed).

2） Vaginal tablets are usually used when the area is inflamed, so we used a dissolution medium with a pH slightly higher than 4.5 (acetate buffer pH 5.2).

3） Clotrimazole vaginal tablets themselves have a large tablet weight (1.5g/tablet), and the proportion of the main drug in the prescription is also large (500mg/tablet), and contain more diluents, binders, disintegrants, lubricants and other excipients. Therefore, during the experimental process, how to choose the appropriate filtration components to effectively avoid clogging in the  cell (and ensure complete drug dissolution) is a very critical issue.

1

Experimental Methods and Test Parameters

Main analyzing instrument

Rator RT7 Flow-Through Cell Dissolution System

Analytical balance

High performance liquid chromatography

Dissolution test parameters

Dissolution device: flow-through cell  (Standard cell, 22.6mm inner diameter)

Temperature:37℃±0.5°C

Flow rate: 16mL/min

Pulsation mode: pulsation-free mode

2

Experimental results and dissolution phenomena

In this test, we simultaneously conducted in vitro release tests on three batches of clotrimazole vaginal tablets, and the final test results showed that the experimental parameters of the cell method successfully differentiated the in vitro release behavior of clotrimazole tablets with three different prescription processes. It provides a valuable reference for the subsequent adjustment of the prescription process. And there was no blockage in the cell during the whole experimental process (at 120 min, the dissolution amount of the samples from the three batches was >85%).

4. Summary:

Vaginal drug delivery system has unique use and therapeutic advantages, and has a good development prospect. Clotrimazole vaginal tablets are widely used in clinical practice and are in great demand.CFDA listed it as one of the varieties of the National Drug Quality Evaluative Sampling and Testing Program as early as 2016, and required testing organizations to evaluate its current quality standards and the quality of the product.

Therefore, in order to ensure that its quality is controllable and its efficacy is reliable, and to ensure the safety of the clinical use of this drug. In the process of carrying out the research and development of generic drugs of this variety, researchers should choose the correct equipment and experimental parameters according to the development of various new in vitro drug dissolution test devices and biological dissolution methods in recent years.