RU2561046C1 - Gel-like eye drops for treatment of inflammatory allergic, bacterial, viral, traumatic and dystrophic eye diseases - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: eye drops contain recombinant interferon, selected from the group: alpha-, beta-, gamma-recombinant interferon, antioxidant, preservative, antihistamine medication, gel-forming preparation and water.

EFFECT: creation of gel-like eye drops, which simultaneously provide anti-inflammatory and immunomodulating action, which do not contain toxic preservatives and render moistening and lubricating effect without manifestation of side effects and irritating action on eye cornea and well-tolerated by patients.

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Description

The invention relates to pharmacology, specifically to the preparation of interferon-containing gel-like eye compositions intended for the treatment of inflammatory, allergic, bacterial, viral, traumatic and degenerative eye diseases.

Inflammatory, allergic, bacterial, viral and degenerative eye diseases are known to be highly common eye lesions. Moreover, the number of patients is growing steadily, as the general circulation of eye patients to medical institutions is increasing (Neroev V.V. The main ways of development of the ophthalmological service of the Russian Federation // IX Congress of Russian ophthalmologists, - M. - 2010, p. 52-55), the number of patients with inflammatory eye pathology reaches up to 18 million patients per year in the country (Y. Maychuk. Modern possibilities of conjunctivitis therapy. // Transactions of the XYII Russian National Congress “Man and Medicine.” - M. - 2011. - T. 2 - p. 215-225), diseases are difficult, often with relapses, often lead to loss of vision and blindness.

There are a large number of drugs that are used in the treatment of these diseases (Egorov EA, Astakhov Yu.S., Stavitskaya TV Ophthalmopharmacology. A guide for doctors. M. - 2005. - S. 464). However, the treatment of these eye diseases is very difficult. This is due to various reasons: an increase in the resistance of infectious agents to anti-infective drugs, toxic and allergic side effects of drugs containing obsolete irritating preservatives, the absence of antioxidant agents in complex therapy, and the need for the simultaneous use of drugs with different effects.

That is why the demands of practical ophthalmology raise the urgent need to create complex drugs that simultaneously provide anti-inflammatory effects (antioxidant, reparative, regenerative), anti-infectious (antibacterial, antiviral) that do not contain toxic preservatives that have a prolonged effect of drugs.

In ophthalmology, infectious pathology occupies one of the leading places. The arsenal of antimicrobials is quite extensive. However, to date, there are significant difficulties in the pharmacotherapy of viral eye diseases. This is due to the fact that for the treatment of many viral infections of the eyes, as well as viral infections in general, there are practically no specific drugs.

In the practice of the treatment of diseases such as conjunctivitis, adenovirus, epidemic, hemorrhagic (enterovirus), herpetic, adenoviral keratitis, herpetic (vesicular, punctate, treelike, tree-like), herpetic stromal keratitis with manifestation and without manifestation, etiology, , herpetic keratouveitis (with and without manifestation), a rather high efficacy of natural interferon preparations is indicated for topical application.

In our country, for these purposes, “Lockeron” is used, which contains interferon synthesized by leukocytes of donated blood under the influence of an inducer virus (parainfluenza virus 1 Seydai GKB N "2339, the drug is concentrated and purified by microfiltration and ultrafiltration.

(RU, patent 2108804, A61K 38/21, 1998)

However, as drugs for which human blood is used, interferons of natural origin are unsafe from the point of view of the absence of contaminant viruses (hepatitis viruses, AIDS, cytomegalovirus, herpes virus infections, etc.).

This leads to an increasingly widespread introduction into the practice of healthcare of interferon preparations of genetically engineered origin, as the most purified (purification degree up to 98%) and guaranteed to be safe from the point of view of viral contamination.

Also known is a pharmaceutical composition of antiviral action for the preparation of eye drops, containing human interferon, a biocompatible polymer - polyglucin 6% solution and a buffer mixture with the following components in 1 ml of solution:

Interferon, ME - (1-6.6) · 10

Biologically compatible polymer (polyglucin) - 5-30

Buffer mixture - up to pH 7.0-7.6

(RU, patent 2095081, class А61К 38/21, 1997)

Known drug "Beaufort" company BOEHRTNGER INGELHEIM "(Austria), intended for eye drops. The drug is prepared by recombinant DNA technology using bacterial strains of E. coli.

(F. I. Ershov. The interferon system is normal and in pathology. M: Medicine, 1996, p. 216.)

The known drug "Reaferon", which is a recombinant alpha-interferon produced by a bacterial strain of pseudomonad, in the genetic apparatus of which is integrated the human leukocyte alpha-interferon gene. The drug has antiviral immunomodulating and antitumor activity. Reaferon is used in isotonic sodium chloride solution with viral conjunctivitis, keratoconjunctivitis, keratitis in the form of eye drops, 2 drops 6-8 times a day, then 3-4 times for 2 weeks. 1 ampoule is diluted in 10 ml of saline. A diluted preparation is suitable for use only a day.

(Μ.D. Mashkovsky. Medicines. M: Medicine, 1993, part 2, pp. 390-391.)

A known antiviral agent is Ophthalmoferon eye drops containing recombinant interferon, a stabilizer of biological, physicochemical properties selected from the group of polyvinylpyrrolidone, polyvinyl alcohol, a derivative of methylcellulose (Na CMC), a stabilizer of resistance to microbial contamination, selected from the group of four nipag ammonium compounds, chlorhexidine, antioxidant: Trilon B and / or butyloxytoluene, diphenhydramine and a buffer mixture, in which they contain acetate-borate or phosphate buffer.

(RU, 2140286, A61K 38/21, 1999)

The closest analogue of this invention to the proposed essence and the achieved result are eye drops containing recombinant interferon selected from the group: alpha, beta, gamma interferon, water-soluble polymers, preservatives, antioxidants, antihistamines, in addition, containing sodium chloride and / or sodium acetate and a buffer mixture in a certain ratio of components.

(RU, 2473363 C1, A61K 38/21, 2013)

However, the experience gained in recent years of the clinical use of eye drops with interferons indicates the possibility of increasing their effectiveness by using complex dosage forms (taking into account the pathogenetic features of specific diseases) to ensure anti-infectious and anti-inflammatory effects, while not showing any cytostatic or other side effects. This makes it expedient to develop various dosage forms of eye drops.

The objective of the invention is to develop gel-like eye drops that simultaneously provide anti-inflammatory (antioxidant, reparative, regenerative), anti-infectious (antibacterial, antiviral) and immunomodulating effects that do not contain toxic preservatives and have a moisturizing and lubricating effect without manifesting side effects and irritating effects on the cornea of the eye and well tolerated by patients.

The technical result of the invention is to increase the duration of the therapeutic effect of using the claimed gel-like eye drops in the treatment of inflammatory, allergic, bacterial, viral, traumatic and dystrophic diseases of the eyes due to their prolonged action by increasing the contact time of the drug with the cornea of the eye, which reduces the course of therapy, reduces irritating effects on the cornea, reduction of complications and increased tolerance by patients compared with prototype.

To achieve the technical result, gel-like eye drops for the treatment of inflammatory, allergic, bacterial, viral, traumatic and degenerative eye diseases containing recombinant interferon selected from the group: alpha, beta, gamma recombinant interferon, antioxidant, preservative, antihistamine, the gel-forming preparation and water according to the invention contain synthetic carnosine, or Mexidol, or Taurine, as an antihistamine, containing antioxidant containing diphenhydramine, contain as a preservative selected from the group of boric acid, polyhexanide, chlorhexidine, cetylpyridinium chloride as the gelling formulation contain selected from the group: hyaluronic ksilota, carbomer, povidone, with the following component ratio, wt. %:

An analysis of the prior art by the applicants, including a search by patent and scientific and technical sources of information, and identification of sources containing information about analogues of the declared gel-like eye drops, made it possible to establish that the applicants did not find an analogue characterized by features identical (identical) to all the essential features of the claimed gel-like eye drops.

The definition from the list of identified analogues of the prototype allowed us to identify a set of essential in relation to the perceived technical result of the distinguishing features in the claimed pharmaceutical composition set forth in the claims.

Therefore, the claimed gel-like eye drops meet the criterion of "novelty."

To verify the conformity of the claimed gel-like eye drops, the applicants conducted an additional search for known solutions to identify signs that match the distinctive features of the claimed invention from the prototype.

The search results showed that the claimed invention does not follow explicitly from the prior art as determined by the applicants for the specialist, the effect of the transformations provided for by the essential features of the claimed gel-like eye drops on the achievement of the technical result is not revealed.

Therefore, the claimed invention meets the criterion of "inventive step".

The criteria of the invention "industrial applicability" is confirmed by the fact that the claimed gel-like eye drops that simultaneously provide anti-inflammatory effects (antioxidant, reparative, regenerative), immunomodulatory, anti-infective (antibacterial, antiviral) that do not contain toxic preservatives, which have a prolonged effect of drugs without side effects can be successfully used in ophthalmology.

The present invention is illustrated by specific examples of execution, which, however, are not the only possible, but clearly demonstrate the ability to achieve the desired technical result.

Example 1. The preparation of the claimed gel-like eye drops is carried out in a standard way for the preparation of eye drops, by mixing all of their components to obtain a gel-like homogeneous mass. The resulting eye drops meet the requirements for a pharmaceutical agent.

These components of the claimed gel-like eye drops are taken in the following ratio, mass. %:

Example 2. Carry out analogously to example 1 with the exception of the composition of the components, which are taken in the following ratio, mass. %:

Example 3. Carry out analogously to example 1 with the exception of the composition of the components, which are taken in the following ratio, mass. %:

The obtained compositions were controlled by a number of characteristics that reflect the quality and effectiveness. These are pH values, transparency, optical refraction, moisturizing effect, surface tension, dynamic viscosity, the absence of irritating effects on the cornea of the eye, as well as the duration of retention on the cornea.

The pH values of the developed eye drop formulations underwent a slight change and ranged from 6.8-7.6.

Measurement by known surface tension methods of eye drop formulations showed that all formulations have surface activity and, therefore, spread well over the cornea.

The refractive index of the developed formulations of eye drops is small, does not cause blurring of the eye and is close to tear fluid (1,334).

The retention time of the claimed eye drops on the cornea was determined on a group of rabbits. The results of the study showed a 2-3 times greater prolonging ability of the claimed formulations of eye drops due to increased penetration into the tissues of the eye, their increased enveloping effect, increased viscosity and increased selectivity relative to the surface of the eye compared to the prototype.

The irritating and toxic effects of the formulations of the claimed gel-like eye drops were studied in rabbits when they were introduced into the conjunctival sac 5-8 times a day, 1-2 drops for 2 weeks. As a result of the study, no hyperemia, edema, or other conjunctival changes were found. No animal deaths or acute poisoning have been reported.

On a model of mild non-infectious inflammation of the conjunctiva of the eye, the treatment time for lesions of the conjunctiva of the eye was reduced when applying the claimed eye drops.

The effectiveness of the claimed gel-like eye drops made according to the presented examples was investigated in patients.

Example 4. Patient C, 45 years old. Diagnosis: herpetic keratitis with ulceration of the left eye, corneal defect, third relapse. Eye irritated, photophobia, lacrimation. The conjunctiva is hyperemic, edematous, the corneal reaction is weakly expressed. In the paracentral region outside the cornea, stromal infiltration, irregular surface ulceration of 3 × 5 mm.

Conducted conventional therapy using ophthalmopheron (prototype).

Assigned to the treatment of the claimed gel-like eye drops made according to example 1, 2 drops 6 times a day. The duration of treatment is 3 weeks. As the condition of the eye improved, the number of installations was reduced to 4, and then to 3 times a day. Condition after 3 weeks: the ulcer surface healed, does not stain with fluorescein, edema and stromal infiltration decreased, the eye is calm. Visual acuity increased from 0.3 to 0.7. Remains cloud-like clouding of the cornea.

Rehabilitation therapy: artificial tear.

Example 5. Patient R. 35 years. Diagnosis: recurrent corneal erosion with a secondary staphylococcal and allergic reaction (drug). The right eye is irritated, the discharge is mild, mucous. The mucous membrane is hyperemic, loosened, swollen. The eroded surface of the cornea. It is stained with fluorescein. The treatment was prescribed by the declared gel-like eye drops made according to examples 2 and 3, 2-4 drops 6 times a day for the first 3 days, then 4 times a day for 2 weeks. The condition began to improve already in the first 2 days, significantly improved by the end of the first week. Erosion zones have ceased to grow. Over the next 6 months, erosion did not recur.

Experimental studies have shown that the choice of the components of eye drops and their quantitative values made it possible to obtain a new technical result: an increase in the duration of the therapeutic effect of using the claimed gel-like eye drops in the treatment of inflammatory, allergic, bacterial, viral, traumatic and degenerative eye diseases due to their prolonged action by increasing the contact time of the drug with the cornea of the eye, which reduces the irritating effect effects on the cornea of the eye, reduced complications and increased tolerance by patients compared to the prototype. A decrease in the course of therapy in the treatment of trophic keratitis by 24% compared with the prototype, when used in the treatment of herpetic keratitis and bacterial ulcers by 20%, with dry keratoconjunctivitis by 32%.

Thus, the claimed gel-like eye drops simultaneously provide anti-inflammatory effects (antioxidant, reparative, regenerative), anti-infectious (antibacterial, antiviral), do not contain toxic preservatives and, compared with the prototype, have an increased duration of therapeutic effect in the treatment of inflammatory, allergic, bacterial, viral, traumatic and degenerative eye diseases.

Claims (1)

Gel-like eye drops for the treatment of inflammatory, allergic, bacterial, viral, traumatic and dystrophic eye diseases containing recombinant interferon selected from the group: alpha, beta, gamma recombinant interferon, antioxidant, preservative, antihistamine, gelling drug and water, characterized in that as an antioxidant they contain synthetic carnosine, or Mexidol, or Taurine, they contain diphenhydramine as an antihistamine, they contain selected from the group: boric acid, polyhexanide, chlorhexidine, cetylpyridinium chloride, as a gelling agent, they contain selected from the group: hyaluronic acid, carbomer, povidone, in the following ratio of components, mass. %:
recombinant interferon, ME 500-10000000 antioxidant 0.001-5.0 diphenhydramine 0.001-5.0 preservative 0.001-5.0 gelling agent 0.001-5.0 water rest