RU2149399C1 - Method for estimation of in vitro intravaginal medicinal forms - Google Patents

Abstract

FIELD: medicine, in particular, process engineering of medicinal forms. SUBSTANCE: method consists in the fact that in the conditions of thermostating at 37 C a mixture of specimen under investigation with an aqueous solution of cellulose derivatives is applied onto the supporting structure of film of 18-22% polyacrylamidic gel, and the run-off rate at an inclination of 10 and 70 deg is determined; then, the second supporting structure with an evenly applied aqueous solution of cellulose derivatives is prepared, the specimen under investigation is placed on it, and the area of distribution is determined, and at its value from 13.8 sq.mm and higher and run-off rate from 1.12 mm/s at an inclination of 10 deg, and from 14.68 mm/s and lower at an inclination of 70 deg, respectively, the medicinal form is estimated as an effective one. EFFECT: enhanced correctness of selection of compositions and process engineerings of vaginal medicinal forms. 1 cl, 1 ex, 3 dwg, 2 tbl

Description

 The invention relates to medicine, namely to the technology of dosage forms.

 The development of drug technology is inextricably linked with the development of ideas about the behavior of the drug in the body. So, for example, the use of gastro- and fluoroscopy, tomography, physical and physico-chemical methods of analysis in studying the behavior of oral drugs made it possible to determine the main stages of the drug’s stay from the moment of its administration - ingestion into the stomach until the absorption of drugs (the so-called "pharmaceutical phase") and to identify the effect of qualitative and quantitative indicators of gastric and intestinal juices, the state of the gastrointestinal mucosa on the behavior of the drug for each om of these steps. This, in turn, made it possible to improve the technology of oral dosage forms in terms of the directional action of drugs (prolonged forms, gastrointestinal or enteric-soluble tablets and capsules, osmotic systems).

 The impossibility of the routine use of such research methods in everyday practice in the development of drugs and the desire to standardize the conditions for studying their behavior in the "pharmaceutical phase" have led to the creation of formalized models (model systems) that mimic certain properties of the body. Such model systems include devices for determining the disintegration of tablets and capsules ("Swinging basket"), studying the release of drugs ("Rotating basket"), which are included in almost all pharmacopoeias of the world [1,2,3]. A similar picture is observed when studying the behavior of soft dosage forms, where the Kruvchinsky dialysis unit, the Sartorius apparatus [4], can be considered as model systems that can evaluate the processes of percutaneous absorption.

 Currently, to assess the quality of vaginal dosage forms, there is a test described in the Pharmacopoeia of Great Britain in 1993, which consists in determining the decomposition (disintegration) time of vaginal dosage forms (tablets and suppositories) placed on a perforated metal plate of the device in an aqueous medium [2] . The device consists of a transparent glass or plastic cylinder, in the wall of which a metal insert is fixed using three holders. The insert consists of two round, 30 mm spaced, perforated stainless steel plates, each of which has 39 holes with a diameter of 4 mm.

The device is lowered into a vessel containing 4 liters of water (37 ^o C), equipped with a slowly working stirrer and holder, which allows you to fix the device in a vertical position at a depth of 1 to 90 mm below the water level and turn it 180 ^o without removing it from the water .

 A suppository or tablet is considered disintegrated if, within a certain time (up to 60 minutes), the constituent components are separated (fatty on the surface, insoluble at the bottom, soluble dissolved) or the suppository softened to such an extent that the resulting mass did not resist the pressure of the glass sticks.

 However, this test does not reflect the real processes that occur with the drug on the vaginal mucosa (destruction of the dosage form in a small volume of fluid, mixing with it and distribution on the surface of the mucosa, adhesion to the surface). In addition, the test is based on the mechanical destruction of tablets and suppositories and is not universal for evaluating vaginal dosage forms in general, as it cannot be used to assess the behavior of other dosage forms (ointments, capsules, etc.).

 The lack of a method for evaluating dosage forms that takes into account the real processes that occur when a drug enters the vaginal environment makes it difficult to select formulations and develop technologies for intravaginal drugs.

 In this regard, the development of an in vitro test method based on the assessment of the behavior of drugs in the vagina, which allows more correct selection of compositions and technologies of vaginal dosage forms, is relevant.

 The objective of the invention is to develop a method for evaluating in vitro intravaginal dosage forms.

 The problem is solved in that they prepare a model fluid that simulates vaginal discharge, in the amount necessary for the study. As a liquid, aqueous solutions of cellulose derivatives are used: hydroxyethyl cellulose (OEC) 5.3-6.0%; methyl cellulose (MC) 2.5, -2.9%; polycarboxymethyl cellulose ether sodium salt (NaKMC) 3.5-3.8%; the sodium salt of the hydrogenated form of polycarboxymethyl cellulose ether (NaNSCM) 3.3-3.6%.

Two model substrates (A and B) are prepared that mimic the vaginal mucosa. A: the substrate is obtained in a vessel with a lid, the area of which is about 50 cm ² . The free air space between the surface of the substrate and the lid of the vessel is calculated so that its volume is ≈ 100 cm ³ . Knowing the total volume of the cup, an amount of polymer solution is poured so that the remaining free volume is ≈ 100 cm ³ . B: the substrate is obtained on a glass plate with a width of 15 cm and a length of 30 cm, thermostatically controlled at 37 ^o C. On the reverse surface of the glass, a start line and a finish line are pre-applied across the width at opposite edges.

 As the substrate, a polymer film is used - polyacrylamide (acrylamide 18-22%, N, N '- methylenebisacrylamide (abbreviated bis-acrylamide) 0.2-0.3%, water 81.8-77.7%).

On the surface of the substrate A, 2.0 ml of model fluid is applied, uniformly distributed over the entire surface of the film, covered with a lid on top and thermostatted at 37 ^o C. The test drug (vaginal tablet, suppository, sample of ointment, etc.) is placed on the surface of the substrate at 37 ^o C. Observe at different intervals, noting the distribution area for each drug. The homogeneity of the drug mass formed on the surface of the mucosa is also noted.

On the surface of the substrate B at the level of the "start" line, the studied medicinal product is spotted, pre-mixed at 37 ^° C with 2.0 ml of model fluid. The plate is placed in space so that the plane of the surface of the plate forms an angle of 10 and 70 ^o with the plane of the horizontal surface (table). In this case, the "start" line should be at the top of the corner. The travel time of the front of the droplet from the start line to the finish line is measured at given tilt angles.

 A comparative assessment is carried out for various samples of this dosage form. For each sample, the number of tests necessary to obtain statistically reliable data is carried out. After each test, the surface of the substrate is cleaned with purified water, the excess of which is removed with filter paper.

 A sample of the drug, which showed the maximum area and speed of distribution, is characterized by the ability to be distributed as much as possible on the surface of the mucosa.

 A sample of a medicinal product that has shown a minimum flow time is characterized by the ability to stay at the injection site for as long as possible.

 Based on the studies, dosage forms of such a composition are selected that, taking into account the physicochemical properties of the drug substance, the etiology and pathogenesis of the disease, most fully meet the stated requirements.

 The proposed method allows a comparative assessment of the behavior of vaginal dosage forms according to the parameters of speed and time of distribution over the surface of the mucosa and the ability to hold on this surface, located at an angle (adhesive properties) and is based on the following prerequisites.

 The behavior of the drug in the vagina is characterized by the processes of: disintegration (also dissolution or melting); distribution of the resulting mixture on the surface of the mucosa and the release of drugs from it; retention of the mixture on the surface of the mucosa, located at an angle. The course of these processes depends mainly on the physicochemical characteristics of the vaginal mucosa and vaginal discharge: the volume of the separated vagina; pH of the medium; affinities of the vaginal discharge for hydrophilic and lipophilic substances; viscosity of discharge; wetting detachable vaginal wall; adhesive properties of the discharge in relation to the mucosa.

From the point of view of a functional system suitable for assessing the behavior of drugs, the vagina can be represented as a certain biological structure, representing a hollow tube with a diameter of 1.5-2 cm, a length of 8-9 cm, coated from the inside with a layer of viscous fluid with a volume of ≈ 1.5-5, 0 ml and located in space vertically at an angle from 10 ^o to 70 ^o , which corresponds to the position of the body lying and standing (Fig 1).

 In a longitudinal section, this system will represent a plate having a size of ≈ 6 cm x 9 cm, the upper surface of which (mucous membrane) is covered with a layer of viscous fluid (detachable vagina) with a thickness of ≈ 0.2-0.9 mm (Fig. 2).

 Assessing the behavior of vaginal drugs in a living human organism, due to social, psychological and technical reasons, is extremely difficult. Studying the behavior of drugs in the vaginal environment using biological material is not very possible due to a number of reasons related to its features (inaccessibility, non-standard, the need for canning). In this regard, a model system was developed that reflects the most important processes that occur with the dosage form when the vagina enters the environment.

 Implementation example.

A polyacrylamide film (acrylamide 20%, bis-acrylamide 0.25%, water 79.75%) is obtained in a Petri dish, the area of which is 50 cm ² , which corresponds to the average surface area of the vaginal mucosa. On the surface of the film, 2.0 ml of a 3.8% NaKMC aqueous solution is applied, evenly distributing over the entire surface of the film, cover with a lid and thermostat at 37 ^o C. Prepare one cup for each series of preparations.

The vaginal suppository from the study series (1.1., 1.2., 1.3., 2.1., 2.2., 2.3., 3.1., 3.2., 3.3., Flagil suppositories, Betadine suppositories) are placed on the surface of the mucosa at 37 ^o C (Fig. 3) Observed at various time intervals, noting the distribution area for each drug (table. 1).

 The homogeneity of the drug mass formed on the surface of the mucosa is also noted.

A polyacrylamide film (acrylamide 20%, bis-acrylamide 0.25%, water 79.75%) is obtained on a glass plate with a width of 15 cm and a length of 30 cm and thermostatically controlled at 37 ^o C. On the reverse surface of the glass is pre-applied in width at the opposite the edges of the "start" line and the "finish" line. A sample of the drug is mixed at 37 ^° C. with 2.0 ml of a 3.8% NaCMC aqueous solution and applied to the start line. The plate is positioned in space so that the plane of the surface of the plate forms an angle of 10 ^o and 70 ^o with the plane of the horizontal surface of the table. In this case, the "start" line should be at the top of the corner. The swelling time is measured for each series of test drugs at given tilt angles (Table 2).

 After each test, the surface of the substrate is cleaned with purified water, the excess of which is removed with filter paper.

 Suppositories from the series 2.1, 2.2, 2.3, Betadine suppositories showed the maximum area and speed of distribution and are characterized by the ability to be distributed as much as possible on the surface of the mucosa.

 Suppositories from the series 1.1., 1.2., 1.3., 2.1., 2.2., 2.3., Flagil candles showed the minimum swelling time and are characterized by the ability to stay at the injection site for as long as possible.

 Thus, from the studied samples of vaginal suppositories, suppositories of the series 2.1., 2.2., 2.3. showed, on the one hand, the ability to be distributed as much as possible on the surface of the mucosa, and, on the other hand, to stay on it for a long time.

 When using the various abovementioned cellulose derivatives as the model fluid in the indicated concentration ranges, comparable results are obtained.

 Technical and economic significance.

 The proposed method allows to conduct, on the basis of a comparative assessment of in vitro, the selection of dosage forms of such a composition that, when exposed to the environment of the vagina, are characterized by certain indicators of time and area of distribution over the surface of the mucosa, as well as the ability to stay on it for a certain time and, taking into account physico-chemical properties of the drug substance, etiology and pathogenesis of the disease, have the most complete total effect.

 This allows you to use a more advanced approach in the creation of vaginal dosage forms, aimed at optimizing their compositions and technology.

LITERATURE
1. The State Pharmacopoeia of the USSR of the XIth edition: in 2 volumes. - M.: Medicine. 1990.

 2. British Pharmacopea, 1993.

 3. USP 23.1995.

 4. The technology of dosage forms. M .: Medicine, - 1986, in 2 t, t 2.

Claims (1)

A method for evaluating in vitro intravaginal dosage forms, characterized in that under thermostating conditions at 37 ^° C, a mixture of the test drug with an aqueous solution of cellulose derivatives is applied to a substrate of 18–22% polyacrylamide gel film and the flow rate is determined at a slope of 10 and 70 ^° , then prepare a second substrate with a uniformly applied aqueous solution of cellulose derivatives, place the test preparation on it and determine the distribution area and its value from 13.8 mm ² and above and the runoff speed from 1.12 mm / s when tilted e 10 ^o and from 14.68 mm / s and below with a slope of 70 ^o respectively evaluate the dosage form as effective.

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