RU2235536C1 - Metronidasol-containing preparation for treating eye diseases - Google Patents

Abstract

FIELD: medicine, pharmaceutics, ophthalmology.

SUBSTANCE: the present innovation deals with treating keratitis and conjunctivitis. The suggested gel contains metronidasol as an active substance, buffer solution consisting of sodium tetraborate, and gel foundation that consists of styrene copolymer with maleic anhydride and purified water at the following ratio of components, weight%: metronidasol 0.5; sodium tetraborate 0.018; styrene copolymer with maleic anhydride 1.0; purified water up to 100.0. The suggested gel is of prolonged antiviral, antiphlogistic and antibacterial actions, it is hygienic and comfortable in application.

EFFECT: higher efficiency of therapy.

3 dwg, 6 ex, 1 tbl

Description

The present invention relates to medicine, namely to pharmacy, and relates to the development of a medicament containing metronidazole, and can be used to treat eye diseases, including keratitis (acanthomebic and herpetic) and conjunctivitis.

Known drug with antiviral action, - "Means for the treatment of herpetic keratitis", which contains a copolymer of styrene with maleic anhydride (CCMA) and purified water / 1 /.

The described drug having an antiviral effect is the closest analogue to the invention according to the technical essence and the achieved result.

However, a known drug containing 1% aqueous solution of SSMA has the following disadvantages. The therapeutic effect of SSMA has an antiviral effect in the tissues of the eye, but does not have an effect on protozoa and obligate anaerobic bacteria and does not have an anti-inflammatory effect.

The objective of the invention is the creation of a new domestic drug in the form of a gel containing metronidazole, a buffer solution and a gel base, which has anti-inflammatory, antibacterial and effective against protozoa with good fixation and uniform distribution on the eye tissue due to the gel base, ease of use, expressed in prolonged action of the drug.

The technical result is a reduction in the treatment time of patients in the treatment of eye diseases, including keratitis (acanthomebic and herpetic) and conjunctivitis due to the possibility of good fixation on the tissues of the eye, prolonged action, as well as the convenience and hygiene of use.

This object is achieved in that the claimed gel for the treatment of eye diseases, including keratitis (acanthomebic, herpetic) and conjunctivitis, contains the active substance metronidazole, which has a wide spectrum of action against protozoa, antimicrobial and anti-inflammatory action; a buffer solution containing sodium tetraborate acid and purified water, providing the necessary pH value from 6.2 to 7.0, suitable for ophthalmic dosage forms; a gel base, which includes a copolymer of styrene with maleic anhydride and purified water, which has an antiviral effect and provides a prolonged effect of the drug complex due to surface-active properties in the following ratio of components, wt.%:

Metronidazole 0.5

Sodium tetraborate 0.018

Styrene copolymer

with maleic anhydride 1

Purified water Up to 100

All components that make up the gel are approved for medical use. Metronidazole (FS 42-2283-93). A copolymer of styrene with maleic anhydride (CCMA) or modified Plastigel styromal a rare cross-linked water-swelling polymer (Patent for the treatment of herpetic keratitis, patent No. 2135187, 1999, IPC A 61 K 31/765), (TU 6-01-02274010913 -01) - the product of the copolymerization of styrene with maleic anhydride, modified with ammonia, is a white powder. The appearance of a 1% solution of styrene copolymer in water is a clear or slightly turbid gel liquid. Soluble in water - swells, soluble in glycerin, alcohol.

As a result of experimental studies, it was found that a 1% gel base provides reliable fixation of the drug on the tissues of the eye, promotes better dissolution of metronidazole in the base, a thin, even and continuous smear, the gel base has a prolonged effect and increases the bioavailability of metronidazole due to surface-active properties, and a buffer solution helps maintain the necessary pH. Giving the drug a gel form provides convenience and hygiene of use, the drug forms a fixed thin non-slip film, storage stability.

In addition to the manifestation of known properties, each component of the claimed composition in the aggregate enhances its effect, which is explained, obviously, by their synergism.

Example 1. The composition of 100.0 ophthalmic gel: metronidazole 0.5; sodium tetraboric acid 0.018; SSMA 1.0; purified water to 100.0. Receive an eye gel as follows. In a beaker in a water bath in purified water (FS 42-2619-97) at a temperature of 100 ° C, tetraboric acid sodium (GOST 8429-77), metronidazole (FS 42-2283-93) are dissolved and mixed until completely dissolved, then a styrene-maleic anhydride copolymer is added, stirred with a stirrer and allowed to swell for 60 minutes without heating until completely cooled at room temperature. The finished eye gel is a uniform transparent gel, density 1.0 g / cm ³ , gel pH 6.2, refractive index n = 1.3348, which ensures the absence of a decrease in visual acuity at the time of gel administration due to refraction. The resulting gel has a normal consistency, is easily smeared on the conjunctiva of the eye with the formation of a thin, even continuous smear, the gel due to the consistency and physico-chemical properties of the gel base is firmly held on the mucous surface (conjunctiva) of the eye and has a prolonged effect of metronidazole due to incoming surfactants , as well as convenient and hygienic to use, which is explained by the proposed composition of the ingredients.

Example 2. The composition of 100.0 ophthalmic gel: metronidazole 1.0; sodium tetraboric acid 0.018; SSMA 1.0; purified water to 100.0. A gel is made in a similar manner. The resulting gel has a normal consistency, but after storage after 5 days the gel becomes cloudy and white flakes form in it, microscopy of which confirms the presence of hexagonal crystals of metronidazole, which is unacceptable in an ophthalmic dosage form.

Example 3. The composition of 100.0 ophthalmic gel: metronidazole 0.5; sodium tetraboric acid 0.018; SSMA 2.5; purified water to 100.0. A gel is made in a similar manner. The resulting gel has a thick and viscous consistency, there are inconveniences when applying and applying to the conjunctival surface, the smear is uneven, discomfort, a decrease in visual acuity due to refraction.

Example 4. The composition of 100.0 ophthalmic gel: metronidazole 0.5; sodium tetraborate acid 0.05; SSMA 1.0; purified water to 100.0. A gel is made in a similar manner. The resulting gel has a normal consistency, but there are discomfort phenomena - burning, lacrimation, which is explained by a high pH of 8.5-9.0.

Example 5. The composition of 100.0 ophthalmic gel: metronidazole 0.5; sodium tetraboric acid 0.018; SSMA 1.0; purified water to 100.0. A gel is prepared without heating in a water bath at room temperature in a similar manner. The resulting gel is cloudy, white. Particles of undissolved drug are visible. Discomfort, a decrease in visual acuity due to refraction were noted.

Example 6. Composition 100.0 ophthalmic gel: metronidazole 0.5; sodium tetraboric acid 0.018; SSMA 1.0; purified water to 100.0. A gel is made in a similar manner. The resulting gel has a liquid consistency, which is explained by the low content of the base-forming SSMA, and also has a reduced antiviral activity.

From the above examples it is seen that the composition described in example 1 is optimal from the point of view of consistency, ease of use, treatment effectiveness.

The possibility of using a gel with metronidazole for the healing of cut wounds of the cornea in rats was studied. Studies of the wound healing activity of the gel with metronidazole were carried out on white sexually mature rats without regard to sex weighing 180-220 g, divided into three groups. In the first group of 6 animals, and in the remaining groups of 4 experimental animals in each. Under ether anesthesia (with an exposure of 2-3 minutes), the surface layers of the cornea of the left eye of rats were excised with a microsurgical blade (under microscopic control), to a depth of 1/2 the thickness of the cornea, in its central part, with an area of up to 1/3 of the cornea. In two cases, perforation of the cornea occurred. These animals were not included in the general statistics. In the postoperative period, eye ointments were applied daily 2 times a day with 1% gel (first group), 0.5% metronidazole gel (second group), and petrolatum base (third group). The animals were removed from the experiment on the 3rd, 7th and 14th day. When performing experimental-morphological studies for the first term of removing animals from the experiment (3 days) in all three groups, complete corneal defect epithelization was observed. In this regard, the analysis of morphological data was carried out to normalize the structure of the epithelium. The thickness of the epithelium was estimated by the average values of the variation series in microns; the presence of pathological growths of the epithelium in qualitative parameters; presence of “+”, absence of “-”; differentiation of the layers of the epithelium according to a three-point system: one point - absence, two points - weak, three points - complete (table). When performing experimental-morphological studies for the third period of animal elimination from the experiment (14 days) in the first group (1% gel), reduction of blood capillaries was observed, the epithelium was uniform, a typical basement membrane was not formed under the epithelium. In the stroma, keratoblasts are evenly distributed, which corresponds to the norm, and the stroma thickness is 100 μm (Fig. 1). Then, when removing from the experiment (14 days) in the second group (gel with metronidazole), the structure of all layers of the cornea was restored, with a stroma thickness of 90 μm. The thickness of the epithelium is 20-25 microns, consists of 5 layers of cells that are clearly differentiated, keratoblasts are evenly distributed, and the basement membrane is restored. The cells of the basal layer of the epithelium have rounded nuclei, which gradually flatten to the surface layers. The structural integrity of endothelial cells, i.e. there is a full restoration of the epithelium (figure 2). In the third group (the petrolatum base), a slowdown in regeneration, a thinned stroma and a non-healing structure of the cornea are evident. The cornea exfoliated, visible epithelium and stroma. When stained according to Van Gieson, the epithelium is not uniform throughout the defect, the stroma thickness is 60 μm (Fig. 3).

In the early stages of healing on the 3rd day, the formation of a full epithelial cover is determined, in the control series the formed epithelial cover is also determined, but there are no signs of its structural organization. Thus, on the basis of morphological studies, the inventive gel with metronidazole for the treatment of eye diseases provides an acceleration of the processes of regeneration and its differentiation.

Observation on patients showed a positive effect of the eye gel, and the amount of drug applied at this ratio of components is the same. This enables the doctor in practical medicine, depending on the form and severity of the disease, to recommend to patients the application of the eye gel on the conjunctiva on their own, which makes the inventive gel a promising dosage form in ophthalmic practice. After conducting full-scale clinical trials for the treatment of eye diseases - keratitis (acanthomebic, herpetic), conjunctivitis and the development of quality control methods, a pharmacopeia article is planned.

Sources of information

1. An agent for the treatment of herpetic keratitis (patent No. 2135187, 1999, IPC A 61 K 31/765.

Claims (1)

An agent for treating eye diseases, including keratitis, acantomebic, herpetic and conjunctivitis, containing a copolymer of styrene with maleic anhydride and purified water as a gel base, characterized in that it additionally contains metronidazole and sodium tetraborate in the following ratio of components, wt.% : Metronidazole 0.5 Sodium tetraborate 0.018 Styrene copolymer with maleic anhydride 1.0 Purified water Up to 100.0

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