RU2697834C1 - Method for preparing a wound healing composition based on colloidal zinc oxide, modified with colloidal silver - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry. In order to intensify the mixing process, preparing the wound healing composition based on colloidal zinc oxide modified with colloidal silver involves additional treatment of the reaction mixture by exposure to ultrasonic radiation at the following values of parameters: frequency of working solution sounding 20–30 kHz, ultrasonic modulation frequency 5–50 Hz, working solution sounding time 5–30 min, relative power of ultrasonic radiation 50–75 W/l.

EFFECT: what is presented is a method for preparing a wound healing composition based on colloidal zinc oxide modified with colloidal silver.

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Description

A method of obtaining a wound healing composition based on colloidal zinc oxide modified with colloidal silver

FIELD OF THE INVENTION

The invention relates to the field of chemistry, chemical synthesis, methods for producing external medicines with wound healing effect, made in the form of a hydrophilic ointment, gel, emulsion, liniment. A feature of the invention is the use as active components of colloidal forms of zinc oxide and silver, as well as the intensification of the mixing process using exposure to ultrasonic radiation

State of the art

A known method of preparing ointments for wound healing, anti-burn and anti-inflammatory effects for animals (See US Pat. RU No. 2162700 C1, publ. 02/10/2001, Bull. No. 4). The method involves preheating vaseline and lanolin, a fractional supply of all components of the mixture with thorough mixing of each portion, while the components are taken in the following ratio, wt.%:

Fir oil 5-10 Lanolin 0.2 - 5 Petroleum jelly rest.

Vaseline is preheated to a temperature of 65 - 75 ºC, maintained at this temperature for 50 minutes; lanolin is preheated to a temperature of 60 - 65 ºC and maintained for 40 minutes, then 2/3 of the petroleum jelly are separated, mixed for 10 minutes, after which lanolin is fractionally fed and the resulting mixture is stirred for 10 - 15 minutes. Then the remaining 1/3 of the petroleum jelly is fed, the resulting mass is kept at a temperature of 65 - 70 ºC for 1 hour, after which a ten-fold fractional feed of fir oil is carried out with ten-minute stirring of each portion. The resulting mixture is maintained at a temperature of 55-60 ºC for 1 hour, after which it is cooled to a temperature of 45-40 ºC. Packing is carried out at a temperature of 35 - 40 ºC. The preparation is a homogeneous pasty mass of light yellow color with a soft consistency.

The disadvantage of this method is the complexity of the production process, which consists in the fractional supply of components, since it is difficult to separate with high accuracy 2/3 parts, then 1/3 part and so on. In addition, there is evidence that fir oil and lanolin have an allergenic effect.

Known hydrophilic gel, its production method (options), wound dressing and dressing based on it (See US Pat. RU No. 2422133 C1, publ. 06/27/2011, Bull. No. 18). The invention provides several options for producing a hydrophilic gel for wound dressing, for example, a method for producing a hydrophilic gel comprising mixing chitosan with a polyanionic hydrocolloid, a hydrocolloid, which is sucralfate or polyalginic acid, into which a high molecular weight polyalcohol and excipients are previously introduced, characterized in that that before mixing with chitosan, the hydrocolloid, when alkalized to a pH of 5.5 to 6.5, is subjected to physico-chemical activation by freezing Ivanov-thawing, autoclaving, microwave or ultrasound treatment. In a further embodiment, a hydrophilic wound-coating gel is prepared by mixing chitosan with a polyanionic hydrocolloid, a hydrocolloid, which is sucralfate or polyalginic acid, into which silver nitrate and auxiliary substances are preliminarily introduced, and then the resulting product is exposed to light until silver monoclusters are formed.

The disadvantage is that the invention does not indicate the modes of physical effects, which can lead to destabilization of the entire system when processing a hydrophilic gel using non-optimal modes.

A special place among external medicines is plant-based. So, there is a wound-healing ointment “pink malamo” (See Pat. RU No. 2571487 C1, publ. March 11, 2015, Bull. No. 35), obtained by mixing plant materials, namely, the aerial part of St. John's wort perforated, plantain leaves, motherwort seeds, aerial parts of celandine, dry petals of a food rose, with cow's ghee, lamb internal fat, which were previously brought to a boil, with the addition of badger fat, while the components are taken in the following ratio:

Aerial part of Hypericum perforatum 500 g Plantain Leaves (Autumn harvest) 500 g Motherwort seeds 150 g The aboveground part of the celandine 500 g Dry rose petals 150 g Cow Ghee 1 kg Lamb fat 1 kg Badger Fat 1 kg

The ointment is prepared as follows: the plant material necessary for the preparation of the ointment is collected and mechanically mixed in the above amounts. Then cow ghee and mutton internal fat in the same amount (1 kg) are brought to a boil and all of the listed herbs are added, the mixture is boiled for 10 to 15 minutes. Then it is removed from the heat and allowed to cool for 20 to 30 minutes, after which 1 kg of badger fat, which does not need to be boiled, is added, stirred with a wooden spatula two to three times until cooling is 30 - 35 ° C, filtered and cooled to 20 ° C , then the resulting product is poured into glass jars, after cooling the dishes with the finished ointment put in the refrigerator for storage. The resulting product is poured into glass jars, which are placed in a refrigerator for storage.

The disadvantage of the above ointment is its excessive multicomponentness and the need to use multi-stage synthesis with pre-treatment of some components, the complexity of this method of production. The invention indicates that when using quantitative ratios of components other than those proposed, the pharmacological wound healing activity of the ointment is reduced, the uniformity of the composition is violated.

Known wound healing agent and method for its production (See US Pat. RU No. 2383349 C1, publ. 03/10/2010, Bull. No. 7). A method of obtaining a wound healing agent, comprising mixing the components and treating the suspension with ultrasound, characterized in that the ultrasound treatment is carried out for 60 to 120 minutes. The result is a wound healing agent in the form of a stable gel, including the active active ingredient - nanoparticles containing 98 - 99% iron oxide-hydroxide (OHL) and oxides of silicon, aluminum, calcium and other metals isolated from groundwater at deferrization stations; polymer; polyvinyl alcohol and water in the following ratio of components, g:

OHL nanoparticles 40 - 90 Polyvinyl alcohol 15 Distilled water up to 100

The disadvantages of this method of obtaining a wound healing agent is the minimum of the specified parameters of ultrasonic treatment, (only the time of sounding of the suspension is indicated) and the composition of iron oxide-hydroxide (OHL) is not specified.

The closest in technical essence to the claimed invention is a pharmaceutical composition for the treatment of wounds and burns (see US Pat. RU No. 2636530 C2, publ. 11/23/2017, Bull. No. 33) and the method for its preparation presented in this patent. The essence of obtaining a pharmaceutical hydrophilic ointment composition for the treatment of burns is as follows. The required amount of methylcellulose grade MC-100 is mixed with distilled water and left to swell for 30 to 60 minutes. Then, the necessary amount of colloidal zinc oxide (ZnO), glycerol and colloidal silver is added to the formed gel of methyl cellulose with constant stirring, followed by physicochemical action to prevent the processes of destabilization and aggregation of ZnO and Ag colloidal particles in the following ratio of components in wt. %:

Colloidal silver 0,000 - 0,1 Colloidal zinc oxide 5 - 15 Glycerol 0.05 - 5 Cellulose 0.05 - 5 Distilled water rest

The developed ointment composition is an odorless white or yellow ointment, uniform in consistency (it does not have mechanical impurities) and has a neutral reaction of the medium (pH ≈ 7).

The claimed method for producing a wound healing composition based on colloidal zinc oxide modified with colloidal silver, and its prototype combines a similar component composition of the resulting wound healing compositions.

The fundamental difference between the claimed invention and the prototype lies in the use of ultrasonic radiation as an additional processing of the reaction mixture, indicating the following parameters: sound frequency of the working solution, modulation frequency of ultrasonic radiation, sound time of the working solution, relative power of ultrasonic radiation.

Brief description of drawings and other materials

In FIG. 1 shows a histogram of the distribution of particles of a wound healing composition based on colloidal zinc oxide modified with colloidal silver, obtained according to photon correlation spectroscopy, performed according to Example 1.

In FIG. 2 presents a histogram of the distribution of particles of a wound healing composition based on colloidal zinc oxide modified with colloidal silver, obtained according to photon correlation spectroscopy, performed according to Example 2.

In FIG. 3 shows a histogram of the distribution of particles of a wound healing composition based on colloidal zinc oxide modified with colloidal silver, obtained according to photon correlation spectroscopy, performed according to Example 3.

In FIG. 4 presents a histogram of the distribution of particles of a wound healing composition based on colloidal zinc oxide modified with colloidal silver, obtained according to photon correlation spectroscopy, performed according to Example 4.

In FIG. 5 shows absorption spectra in the visible and UV spectral regions obtained by spectrophotometry, a wound healing composition based on colloidal silver oxide modified with colloidal silver, which was obtained in accordance with Example 1.

In FIG. 6 shows absorption spectra in the visible and UV spectral regions obtained using spectrophotometry, a wound healing composition based on colloidal silver oxide modified with colloidal silver, which was obtained in accordance with Example 2.

In FIG. 7 shows absorption spectra in the visible and UV spectral regions obtained by spectrophotometry, a wound healing composition based on colloidal silver oxide modified with colloidal silver, which was obtained in accordance with Example 3.

In FIG. Figure 8 shows the absorption spectra in the visible and UV spectral regions obtained by spectrophotometry, a wound healing composition based on colloidal silver oxide modified with colloidal silver, which was obtained in accordance with Example 4.

In FIG. 9 shows rheograms of the flow of samples of a wound healing composition based on colloidal zinc oxide modified with colloidal silver, made in accordance with Examples 1 to 4.

Disclosure of invention

The problem to which the invention is directed, is to develop a new method for producing a wound healing composition based on silver modified colloidal zinc oxide, using additional processing of the reaction mixture by the action of ultrasonic radiation at the homogenization stage.

The technical result that can be achieved using the present invention is to intensify the process of obtaining a wound healing composition based on colloidal zinc oxide modified with silver, which consists in mixing the reaction mixture using ultrasonic radiation.

The technical result is achieved using ultrasonic radiation with the following parameter values:

Sound frequency of working solution 20 - 30 kHz Ultrasound modulation frequency 5 - 50 Hz Sound time for working solution 5 to 30 minutes Relative power of ultrasonic radiation 50 - 75 W / l

The obtained wound healing composition based on colloidal zinc oxide modified with silver is an ointment of white or yellow color, odorless, uniform in structure, without foreign inclusions, whose active acidity is pH ≈ 7, which has aggregative stability during storage.

The implementation of the invention

Example 1

Obtaining a wound healing ointment composition based on colloidal zinc oxide modified with colloidal silver is carried out in stages.

At the first stage, a preparation of colloidal silver stabilized by didecyldimethylammonium bromide is obtained by chemical reduction in an aqueous solution. For this, working solutions of didecyldimethiammonium bromide and sodium borohydride are prepared. Then in a glass reactor, protected from light and equipped with a magnetic stirrer, make 100 ml of a 7.8% solution of didecyldimethylammonium bromide. With constant stirring, sodium borohydride is added to the didecyldimethylammonium bromide solution. The resulting mixture was stirred for 15 minutes. To prepare a working solution of silver nitrate on an analytical balance, 0.385 g of silver nitrate is weighed in a separate bottle and quantitatively transferred to a 20 ml volumetric flask, the volume is adjusted to the mark with bidistilled water. To the resulting reaction mass containing a stabilizer and a reducing agent, 20 ml of an aqueous solution of silver nitrate are added dropwise with vigorous stirring. After adding the entire amount of silver nitrate, the homogenization of the reaction mass is continued for another 1 hour until a uniform dark brown solution is formed.

In the second stage, colloidal zinc oxide is obtained by the sol-gel method. At the beginning, a zinc acetate solution is prepared. To do this, on an analytical balance weighed 8.76 grams of zinc acetate 2-aqueous. Quantitatively, it is transferred to a chemical reactor, 200 ml of distilled water are added, and the resulting mixture is stirred for 15 minutes until complete dissolution. Under intense stirring, a 25% ammonia solution with constant pH control is added dropwise to the prepared zinc acetate solution. The process ends at pH ≈ 8. Freshly prepared sols are aged for the purpose of gelation. The resulting gel was centrifuged at 2500 rpm for 5 minutes and washed with distilled water. The washed gels are dried at a temperature of 100 ⁰ C. The obtained colloidal zinc oxide is calcined at a temperature of from 125 to 750 ⁰ C.

In the third stage, a directly healing composition based on colloidal zinc oxide modified with colloidal silver is obtained. For this, the required amount of MT-100 grade cellulose is mixed with distilled water and left to swell for 30-60 minutes. Then, the necessary amount of colloidal zinc oxide, glycerol and colloidal silver is added to the formed methyl cellulose gel with constant stirring. The obtained ointment composition has the following ratio of components in mass%: colloidal silver - 0.0001-0.1; colloidal zinc oxide - 5-15; glycerin - 5-15; methyl cellulose - 0.05-5; distilled water - the rest.

At the last stage of the synthesis of a wound healing composition based on colloidal zinc oxide modified with colloidal silver, an additional treatment of the reaction mixture is carried out by the action of ultrasonic radiation in order to intensify the mixing process. Ultrasonic radiation has the following parameter values:

Sound frequency of working solution 10 - 20 kHz Ultrasound modulation frequency 1 - 5 Hz Sound time for working solution 15 minutes Relative power of ultrasonic radiation 10 - 50 W / l

Example 2

Carried out analogously to example 1, but with the following parameters of the ultrasonic radiation:

Sound frequency of working solution 20 - 30 kHz Ultrasound modulation frequency 5 - 50 Hz Sound time for working solution 5 to 30 minutes Relative power of ultrasonic radiation 50 - 75 W / l

Example 3

Carried out analogously to example 1, but with the following parameters of the ultrasonic radiation:

Sound frequency of working solution 30 - 48 kHz Ultrasound modulation frequency 50 - 100 Hz Sound time for working solution 30 - 60 minutes Relative power of ultrasonic radiation 75 - 100 W / l

Example 4

Carried out analogously to example 1, but with the following parameters of the ultrasonic radiation:

Sound frequency of working solution 48 - 60 kHz Ultrasound modulation frequency 100 - 150 Hz Sound time for working solution 60 - 120 minutes Relative power of ultrasonic radiation 100 - 150 W / L

In order to determine the effect of ultrasonic radiation, a wound healing composition based on colloidal zinc oxide modified with silver was studied by photon correlation spectroscopy, spectrophotometry, and viscometry.

According to the results of the study using photon correlation spectroscopy were obtained histograms of the distribution of the hydrodynamic radii of the particles (Figs. 1-4) in a wound healing composition based on colloidal zinc oxide modified with silver, performed according to Examples 1-4.

It was found that in the sample wound healing composition based on colloidal zinc oxide modified with silver, made according to Example 1, there are two fractions of particles. The hydrodynamic radius of the particles of the first fraction is 10 - 30 nm, the second is of the order of 100 - 2000 nm (Fig. 1).

In a sample of a silver-modified colloidal zinc oxide-based wound healing composition made according to Example 2, two fractions of particles prevail with an average hydrodynamic radius of the first — of the order of 3–7 nm and the second — of the order of 9–30 nm (Fig. 2).

In the sample of the wound healing composition based on colloidal zinc oxide, modified with silver, made according to Example 3, there are two fractions of particles with an average hydrodynamic radius of the first - more than 1 μm and a minor nanoscale fraction of 3 - 110 nm. (figure 3).

In a sample of a silver-modified colloidal zinc oxide-based wound healing composition made according to Example 4, the main fraction of particles has a hydrodynamic radius of 30 to 10,000 nm. The minor fraction of particles has an average hydrodynamic radius of the order of 5 - 13 nm and makes an insignificant mass contribution to the total number of particles (Fig. 4).

Spectrophotometric studies of a silver-modified colloidal zinc oxide-based wound healing composition performed in accordance with Examples 1 to 4 showed the presence of an absorption band at 405 nm in all samples, which corresponds to the unique optical characteristic of colloidal silver - the plasmon resonance band.

It was found that in the sample of a silver-modified colloidal zinc oxide-based wound healing composition made in accordance with Example 2, the absorption band has the maximum intensity, which indicates that the colloidal silver particles retain their unique optical properties under these exposure conditions of ultrasonic radiation in the process of obtaining a wound healing composition based on colloidal zinc oxide modified with silver.

The structural and mechanical parameters of the wound healing composition based on colloidal zinc oxide modified with silver were measured on a Fungilab Expert rotational viscometer (Fungilab SA, Spain), the action of which is based on the use of viscous friction arising in a fluid layer flowing in an annular gap between rotating and fixed cylinders. Studied were samples of a wound healing composition based on colloidal zinc oxide modified with colloidal silver, made according to Examples 1 to 4.

Each of the analyzed samples (about 20 g) was placed in a measuring tank. The cylinder rotation speed was initially sequentially increased from the minimum at which measurements could be taken to the maximum. After reaching the maximum value for this device, the shear stress was also successively reduced. The obtained dependences are presented in FIG. 9.

To study the rheological properties, the flow curves of the samples were constructed in the coordinates “shear rate - shear stress”. During the period of destruction of structured systems (ascending curve) with the help of an increasing speed of rotation of the inner cylinder, the system is diluted (their viscosity decreases), which never reaches the end, since a certain fraction of the bonds is reversibly restored even at high speeds. The downward curve reflects the ability of the system to recover with a gradual decrease in shear rate. The area enclosed between the upward and downward curve is called the hysteresis loop. By the area of the hysteresis loop, one can judge the mechanical stability of structured systems: the smaller it is, the more mechanically stable the system.

The obtained curves of samples of a wound healing composition based on colloidal zinc oxide modified with colloidal silver, made according to Examples 1, 3, 4, show insignificant hysteresis loops close to a straight line starting from the origin. The curve obtained in the study of a sample of a wound healing composition based on colloidal zinc oxide modified with colloidal silver, made according to Example 2, is represented by a significant hysteresis loop. Moreover, the “upward” curve characterizing the destruction of the system differs from the “downward” curve characterizing the restoration of the system and is explained by the preservation of permanent deformation after a strong weakening of the structure under the influence of the previously applied stress. The presence of upward and downward curves of the hysteresis loop indicates that the sample under study has rheopexic properties. At low shear rates, the structure of the system is destroyed and completely restored (in this case, the system has the highest viscosity). With an increase in the shear rate, the destruction of the structure of the substance begins to prevail over the reduction, and the viscosity decreases. At high shear rates, the structure is completely destroyed.

Claims (2)

A method of obtaining a wound healing composition based on colloidal zinc oxide modified with colloidal silver, characterized in that during the homogenization process, the reaction mixture is further treated with ultrasonic radiation, and the ultrasonic radiation has the following parameter values: Sound frequency of working solution 20 - 30 kHz Ultrasound modulation frequency 5 - 50 Hz Sound time for working solution 5 - 30 min Relative power of ultrasonic radiation 50 - 75 W / l

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