RU2315599C2 - Method for preparing medicinal membrane - Google Patents

Abstract

FIELD: pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to preparing medicinal formulations as film membranes in aims for providing hemostatic, wound-healing, anti-inflammatory effect in medicinal practice. Membrane comprises furacillin as a medicinal component, chitosan as a film-forming agent and dimethylsulfoxide, aerosil, 98% acetic acid for preparing its 2% solution and water as accessory substances. The novel medicinal membrane possesses the prolonged curative effect. Invention expands region for using the membrane.

EFFECT: valuable medicinal properties of membrane.

7 tbl, 3 dwg, 1 ex

Description

The invention relates to the field of the pharmaceutical industry, in particular to the production of combined dosage forms in the form of film membranes for the provision of hemostatic, wound healing, anti-inflammatory effects in medical practice.

In pharmaceutical technology, a method is known for producing dosage forms in the form of drug film membranes [3-5]. However, their manufacture is carried out using gelatin, agar-agar, methyl cellulose, Na-carboxymethyl cellulose, collagen, sodium alginate as the base film former. These film former do not have a wide range of therapeutic effects, which reduces the scope of their application.

For the prototype of the invention, we took the method of porous plates "algipore", including the use of sodium alginate, calcium gluconate, furatsilina [2] and involving the use of sophisticated equipment.

A disadvantage of the known method for producing a medicinal membrane is the low effectiveness of the therapeutic effect and the limited scope of medicinal membranes.

The aim of the invention is to expand the scope of the obtained medicinal membranes and increase the effectiveness of their therapeutic effects.

This goal is achieved by the fact that in the process of production, chitosan is used as a film former and auxiliary substances are added dimethyl sulfoxide, aerosil, acetic acid 98% for the manufacture of its 2% solution and purified water, in the following ratio of components wt.%:

furatsilin 0.6-0.8 dimethyl sulfoxide 12.0-16.0 acetic acid 98% 1.6-1.64 aerosil 4.0-5.5 chitosan 2.3-2.46 purified water up to 100.0

Comparison of the proposed method with other known methods [1, 6-8] showed its compliance with the criteria of the invention.

The claimed method is implemented by the following example.

Example 1

a) the manufacture of a solution of acetic acid 2% from acetic acid 98% glacial (GOST 61-75): 79.28 ml of purified water and 1.62 ml of acetic acid 98% are measured in a 50 ml sterile container, mixed. Obtain 80.9 ml of 2% acetic acid. Used to prepare a 3% solution of chitosan.

b) the preparation of a 3% solution of chitosan: 2.43 g of chitosan (TU 9289-003-49857769-2003 - “Chitosan crab”) is placed in a sterile container per 100 ml and poured with a 2% solution of acetic acid at room temperature in an amount of 80.9 ml . It is kept under aseptic conditions for 2-3 hours until the dissolution of chitosan and the formation of a clear solution. The resulting solution is filtered.

c) the manufacture of a medicinal membrane:

0.6 g of furatsilin is weighed into a sterile mortar (lower limit of the ratio specified in the application formula) (FS 42-2522-88), dissolved in 12.0 g (lower limit of the ratio specified in the application formula) dimethyl sulfoxide (DMSO) - ( VFS 42-1166-81). Aerosil (GOST 14922-77) is added to the resulting solution of furatsilin (GOST 14922-77) in an amount of 4.0 g (the lower limit of the ratio indicated in the application formula) and mixed until a uniform lemon-yellow powder is obtained. A 3% chitosan solution prepared in parts is added to it, homogenized, kept for 30 minutes to remove air and poured into sterile glass molds with an area of 553 cm ² with a film thickness of 5 mm.

Dry under aseptic conditions at room temperature to a residual moisture content of 2%.

After drying, the resulting plates with a thickness of 1 mm are dispensed onto membranes of various sizes: 1 × 2 cm, 0.5 × 2 cm, 2 × 3 cm and other sizes, depending on the required area as prescribed by the doctor. Packed in plastic film (GOST 10354-82 N (food grade)) or glass bottles (TU 9461-006-05766126-2002) with a rubber stopper and aluminum caps for “running in” and sterilized by radiation sterilization (Co ⁶⁰ ) for 2 hours at a dose rate of 10 kGy / hour.

Examples of other optimal ratios are given in table 1 (compositions 1-4). The manufacturing technology of medicinal membranes was carried out analogously to example 1.

Table 1
Optimal drug membrane formulations Name of components The concentration of components,% Formulation Examples one 2 3 four Furatsilin 0.65 0.7 0.75 0.8 Dimethyl sulfoxide 13.0 14.0 15.0 16,0 Aerosil 4.33 4.66 5,0 5.3 Chitosan 2.46 2.42 2,38 2,3 Acetic acid 98% 1,64 1,61 1,59 1,6 Purified water 77.92 76.61 75.28 74.0 Total 100.0 100.0 100.0 100.0

A change in the quantities (exorbitant parameters) of drugs and excipients with respect to those indicated in the table does not lead to a positive effect.

To confirm the claimed optimal compositions, the quality assessment of all samples of medicinal membranes obtained during the experiment was applied using a comparative analysis of the organoleptic properties of the obtained membranes using the generalized Harrington desirability function.

The method of the generalized desirability function [5] includes the calculation of the values of the partial most significant indicators of desirability of individual properties (d) and the generalized desirability function (D) of these indicators.

A value of D = 0 corresponds to an absolutely unacceptable level of this property (very poor quality), and D = 1 to the best value of the property (very good quality). The base marks of the desirability function are presented in table 2.

table 2
Desire Scale Base Marks Desirability Scale Desirability of response value 0.8-1.00 Very well 0.63-0.80 Good 0.37-0.63 Satisfactorily 0.20-0.37 poorly 0.00-0.20 Very bad

Having several responses converted to the d scale, we can calculate the generalized desirability function as the geometric mean of the particular desirability functions of individual properties by the formula

where q is the number of particular desirability functions.

The following membrane criteria were evaluated: color, uniformity, elasticity, ability to lag behind the form, which served as responses when calculating function D. Its value was calculated by the formula

Desirability for individual properties is indicated by:

d ₁ - uniformity; d ₂ - elasticity; d ₃ - the ability to lag behind the form; d ₄ - antimicrobial activity.

The distribution of desirability for individual properties by membrane composition is presented in table 3.

Table 3
Desirability Distribution for Experimental Medicinal Membrane Composition number Desirability for individual properties d ₁ d ₂ d ₃ d ₄ D one. 0.8 0.4 0.4 0.2 0.40 2. 1,0 0.4 0.4 0.2 0.42 3. 0.8 0.4 0.6 0.2 0.44 four. 1,0 1,0 1,0 1,0 1.00 5. 1,0 1,0 1,0 1,0 1.00 6. 1,0 1,0 1,0 1,0 1.00 7. 1,0 1,0 1,0 1,0 1.00 8. 1,0 1,0 1,0 1,0 1.00 9. 0.6 0.2 0.4 0.8 0.44 10. 0.4 0.2 0.2 0.8 0.34 eleven. 0.6 0.2 0.4 1,0 0.47 12. 0.4 0.2 0.2 1,0 0.36

As can be seen from the data in table 3, the compositions No. 4, 5, 6, 7, 8 are optimal according to the selected quality assessment criteria.

Samples No. 1, 2, 3, 9, 10, 11 and 12, containing exorbitant amounts of components, do not have optimal qualities. Extreme amounts in the direction of increase (compositions 9, 10, 11, 12) lead to fragile samples requiring the addition of additional plasticizers and, in connection with this, a change in composition. And the transcendental compositions in the direction of reducing the quantities of the starting components have low antimicrobial activity (compositions 1-3).

The dosage form obtained by the claimed method has a pronounced prolonged cleansing and antimicrobial effect, which is confirmed by the experimental data presented in figures 1, 2, 3 and in tables 4-6.

As you know, when creating therapeutic systems with any medicinal substance, information is needed on the features of diffusion transfer in polymeric materials. One of the main parameters of a system having diffusion capabilities is its moisture absorption.

Therefore, the process of membrane swelling will affect the release of furatsilin contained in it. In addition, the membrane will absorb the contents of the wound, helping to cleanse it.

The results of determining the amount of water absorbed by a membrane weighing 0.0695 are presented in figure 1.

The graph curve characterizes only the swelling process. A decrease in the membrane mass at the 10th hour of the experiment indicates the beginning of its dissolution. Thus, the developed membrane swells for a long time, while absorbing water, on average, by 375% more than the mass of the initial film, which indicates its osmotic activity and the cleansing effect.

To study the nature of the release of furatsilin from the developed dosage form, the well-known equilibrium dialysis method was used.

In the experiment, dialysis tubes with an inner diameter of 25 ± 0.1 mm and a height of 100 mm were used. A semipermeable membrane was fixed at one end of the tube, which was cellophane. To remove the lacquer coating from its surface, the cellophane was presoaked in water purified for 30 minutes.

Five discs with a diameter of 20 ± 0.1 mm were cut from the test samples and placed inside the tube on cellophane, avoiding the ingress of air between it and the test membrane. The tubes were thermostatically controlled at a temperature of 37 ± 1 ° С together with beakers, into which 30 ml of purified water was previously poured. The end of the cellophane tube was lowered to the surface of the water. Within 10 hours at certain intervals, samples were taken in an amount of 5 ml, while the volume of dialysis fluid was replenished with the same volume of purified water. The furatsilin concentration was determined spectrophotometrically. The method is based on the well-known reaction of interaction of furatsilina with an alkali solution with the formation of a yellow-orange acinitrosol. The reaction product of furatsilin and sodium hydroxide has a maximum absorption at a wavelength of 380 nm.

Based on the results obtained, graphs of the dependence of the concentration of furatsilin on time were constructed. In this case, purified water served as a comparison solution. In parallel, the optical density of the dialysis fluid was measured from a dosage form not containing furatsilina (placebo) (figure 2).

The results presented in figure 2, show that at the 1st hour of the experiment in the dialysis fluid creates a bactericidal concentration of furatsilina (1 × 10 ^-6 g / ml), which remains for 10 hours of observation. The bactericidal concentration was previously determined according to the well-known GF XI method [4].

To confirm the antimicrobial activity of the membrane, it was studied in an in vitro experiment [4]. The data obtained, presented in table 4, indicate a high sensitivity of microorganisms E. coli and St. aureus to the action of the dosage form.

Table 4
Antimicrobial activity of the drug membrane with furacilin Name LF Zone of growth inhibition of test strains on a solid nutrient medium, mm St. aureus E. coli Drug membrane 31.5 ± 0.1 29.0 ± 0.1

To identify the correlation of the in vitro experiment, we studied the antimicrobial action of the membranes in an in vivo model of a purulent wound. The results indicate a pronounced antimicrobial effect of the drug (table 5) and its ability to have an effective healing effect on purulent wounds (figure 3, table 6).

The total percentage of wound healing using medicinal membranes with furatsilinom (group No. 1) amounted to 99.01% by the 25th day; placebo membranes (group No. 2) - 90.43%; official 0.2% ointment of furatsilin (group No. 3) - 88.76%. While in the control group (group No. 4) for the same period, healing amounted to 78.68%. The results are statistically significant (P <0.05).

Table 5
Bacteriological study of wound contents in experimental animals of various groups Group No. 1 Membrane treatment with furacilin Group 2 Placebo Membrane Treatment Group No. 3 Treatment with officinal furacilin ointment on petroleum jelly Group No. 4 Control The presence of purulent exudate The presence of microbial growth The presence of purulent exudate The presence of microbial growth The presence of purulent exudate The presence of microbial growth The presence of purulent exudate The presence of microbial growth Source + abundant growth + abundant growth + abundant growth + abundant growth four + moderate growth + abundant growth + abundant growth + abundant growth 8 - moderate growth + moderate growth + abundant growth + abundant growth 12 - meager growth - moderate growth + abundant growth + abundant growth fourteen - absent - moderate growth + moderate growth + moderate growth 19 - absent - meager growth - moderate growth - moderate growth 25 - absent - absent - meager growth - meager growth

Table 6
Duration of purulent wound healing in experimental animals of different groups Day from the start of treatment Group No. 1 Membrane treatment with furacilin Group 2 Placebo Membrane Treatment Group No. 3 Treatment with officinal furacilin ointment Group No. 4 Control The area of wounds, mm ² The dynamics of contraction of the wound,% of the original area The area of wounds, mm ² The dynamics of contraction of the wound,% of the original area The area of wounds, mm ² The dynamics of contraction of the wound,% of the original area The area of wounds, mm ² The dynamics of contraction of the wound,% of the original area Source 394.50 ± 4.74 - 397.00 ± 5.50 - 397.49 ± 2.76 - 396.99 ± 1.84 - four 308.41 ± 4.72 5.46% 325.74 ± 4.71 4.51% 344.31 ± 5.07 3.34% 376.84 ± 1.72 1.27% 8 220.87 ± 3.51 7.10% 274.99 ± 6.32 3.89% 299.24 ± 2.55 3.27% 337.12 ± 2.81 2.64% 12 116.12 ± 1.77 11.86% 168.94 ± 6.08 9.64% 196.50 ± 3.81 8.58% 299.24 ± 4.55 2.81% fourteen 46.57 ± 5.14 29.95% 103.13 ± 4.06 19.48% 126.86 ± 4.61 17.72% 187.10 ± 6.96 18.74% 19 23.84 ± 1.41 9.76% 65.27 ± 4.98 7.34% 88.81 ± 1.38 6.00% 122.90 ± 2.47 6.86% 25 3.88 ± 0.42 16.74% 38.01 ± 1.67 6.96% 44.69 ± 1.37 8.27% 84.65 ± 2.23 5.19% Total total healing% - 99.01% - 90.43% - 88.76% - 78.68%

Thus, the obtained experimental data form the basis for expanding the assortment of antimicrobial, osmotic, wound healing drugs used in surgery, gynecology, traumatology, dermatology, otorhinolaryngology, ophthalmology, since the analysis of dosage forms with furacilin registered in the State Register of the Russian Federation [2 ] did not allow to find a similar dosage form (table 7).

INFORMATION SOURCES

1. Alekseeva I.V. Development of dosage forms for the treatment of wounds // Pharmacy. - 2003. - No. 2. - S. 43-45.

2. The state register of medicines. - M., 2004 - V.1. - 1404 s.

3. State Pharmacopoeia X ed. - M.: Medicine, 1968 .-- 1037 p.

4. State Pharmacopoeia XI ed. - M .: Medicine, 1989.4.2 - S.187-225.

5. Groshovy T.A. Mathematical design of an experiment in pharmaceutical technology. / T.A. Groshovy, E.V. Markova, V.A. Golovkin. - Kiev: Vishcha school, 1992. - 185 p.

6. RF patent No. 2155071, issue. 08/27/2000

7. RF patent No. 2179456, issue. 02/20/2002

8. Reference Vidal. - M.: AstraPharmService, 2002 - 2005 .-- 1404 p.

Table 7
Dosage forms with furacilin registered in the State Register of the Russian Federation p / p Drug name Structure Application Title of normative document MONO DRUGS one. Furaplast (with perchlorovinyl) Furatsilin outwardly FS 42-2134-92 2. Furatsilin tablets Furacilina 0.02 g outwardly FSP 42-0054-2447-02
FSP 42-0260-4472-03 3. Furatsilin tablets Furacilina 0.1 g outwardly FS 42-2609-99 four. Furatsilina solution 0.2% aqueous solution of furacilin outwardly Reg. No. 71/566/23 5. Furatsilina alcohol solution 0.067% alcohol solution outwardly FS 42-2087-83 6. Furacilin ointment 0.02% outwardly FS 42-94-72 7. Furacilin paste outwardly FS 42-2302-93 COMPLEX MEDICINES one. Algipor M - porous sheets Calcium gluconate 20.72 g; sodium alginate 63.51 g; furatsilina 3.04 g outwardly FSP 42-0264-1102-01 2. Algipor Sodium alginate 0.7262 g; calcium gluconate 0.2372 g furatsilina 0.035 g outwardly FSP 42-0372-2739-02 3. Lifusol outwardly FS 42-2589-88 four. Statisol Furatsilina 0.014; Sea buckthorn oil 3.6 g. outwardly FS 42-2840-92 5. Camofomen Camphor oil 0.61 g; menthol 0.06 g; furatsilin 0.002 g; eucalyptus oil 0.61 g outwardly FS 42-1991-91 6. Klefurin Furacilin 0.002 g; adhesive base BF-8 99.8 g outwardly VFS 42-1855-88 7. Fastin Benzocaine 3.0 g; furatsilina 2.0 g; chloramphenicol 1.6 g; basics up to 100 g outwardly FS 42-1582-93 8. Fulevid Furatsilin, chloramphenicol, retinol outwardly VFS 42-1541-85

Claims (1)

A method of producing a medicinal membrane containing furatsilin as a medicinal component, characterized in that in the manufacturing process, chitosan was used as a film former and auxiliary substances dimethyl sulfoxide, aerosil, acetic acid 98% for the manufacture of its 2% solution and purified water were added in the following ratio of components, wt.%: furatsilin 0.6-0.8 dimethyl sulfoxide 12.0-16.0 acetic acid 98% 1.6-1.64 aerosil 4.0-5.5 chitosan 2.3-2.46 purified water up to 100.0

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