RU2581025C1 - Eye medicinal film with moxifloxacin - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to ophthalmology, and can be used in preoperative and postoperative prevention and treatment of infectious inflammatory complications following abdominal operations on eyeball. Eye film comprises polyvinyl alcohol, dihydroquercetin as an active substance of vegetable origin, moxifloxacin as an antibiotic. Invention increases range of therapeutic action of film by giving it strong antioxidant, anti-inflammatory, immunomodulatory properties, provides long-term effect eye film.

EFFECT: eye medicinal films with moxifloxacin are easy to use, have prolonged antimicrobial, antioxidant, immunomodulatory, anti-inflammatory properties.

1 cl, 1 dwg

Description

The invention relates to medicine, in particular to ophthalmology, and can be used in preoperative and postoperative prevention and treatment of infectious inflammatory complications arising after abdominal operations on the eyeball.

At the heart of many infectious diseases is inflammation, which is accompanied by a complex of systemic changes, known as acute phase response. One of these answers is the activation of lipid peroxidation processes. The products of lipid peroxidation damage cellular structures, tissues and organs [Bubinets OV Features of the immune status and immunobiological reactions with the use of antioxidants // Abstract. dis. competition. scientist step. Cand. farm. Sciences (03/14/60) / Bubinets Olga Vladimirovna; - Vladivostok, 2011. - 3 p .; Saxena R., Garq P., Jain D.K. In Vitro Anti-oxidant Effect of Vitamin E on Oxidative Stress Induced Due to Pesticides in Rat Erythrocytes // Toxicol. Int. 2010. - No. 18 (1). - P. 73-76]. With excessive activation of endogenous mechanisms of formation of reactive oxygen species, the intensity of oxidative reactions in the body increases [Gromov MI, Kaplina E.N. The use of immunomodulators in surgical practice // Modern problems of science and education. 2006. - No. 5 - S. 52-54; Wanq Q., Lianq B., Shitwany N.A., Zou M.N. 2-Deoxy-D-Glucose Treatment of Endothelial Cells Induces Autophagy by Reactive Oxygen Species-Mediated Activation of the AMP Activated Protein Kinase // PloS One. - 2011. No. 2. - R. 28]. Under these conditions, the use of antioxidants is necessary.

With the development of bacterial infections and intoxications, specific pathogenic factors of infection are affected and non-specific functional and metabolic disorders occur that determine the severity of the course and outcome of the disease. Under conditions of circulatory hypoxia, free radical lipid oxidation is activated, destabilizing biomembranes. In this regard, the possibility of inhibiting the cytopathogenic effects of toxic and enzymatic pathogenicity factors due to the activation of lipid peroxidation [Kosinets V.A. Antioxidant activity of the drug cytoflavin in experimental widespread purulent peritonitis // Experimental and Clinical Pharmacology. - 2010. No. 1. - S. 30-33; Nagoyev B.S., Ivanova Z.O. Lipid peroxidation in pneumonia of bacterial and viral etiology // Clinical laboratory diagnostics. 2009. - No. 11. - S. 30-32; Bubinets O.V. Features of the immune status and immunobiological reactions with the use of antioxidants // Abstract. dis. competition. scientist step. Cand. farm. Sciences (03/14/60) / Bubinets Olga Vladimirovna; - Vladivostok, 2011. - 3 p.]. Dihydroquercetin, which has pronounced antioxidant, immunomodulatory and anti-inflammatory properties, can be used in the practical work of ophthalmologists to increase the immunological reactivity of eye tissues and, accordingly, increase the effectiveness of treatment of inflammatory diseases.

For the prevention and treatment of inflammatory eye diseases, various methods of introducing drugs into the tissues of the eye are used. The most widely used were eye drops, ointments, gels, subconjunctival, intracameral injections. The instillation technique has several disadvantages. When using eye drops, an intensive regimen of the drug is needed (every 4 hours, and for severe infections every hour) for a certain period of time. In addition, studies of Russian and foreign colleagues showed that the instillation of antibiotics is not accompanied by the achievement in the moisture of the anterior chamber of the eye of the necessary concentration to inhibit the growth of microorganisms [Mashkovsky M.D. Medicines Ed. 15th, Moscow: New Wave, 2005, p. 803-804, 807-808, 847-848; Barry P., ESCRS Guidelines for the Prevention and Treatment of Endophthalmitis after Cataract Surgery: Evidence, Dilemmas and Conclusions 2013 / P. Barry, Cordoves L., Gardner S .; per. with eng. B.E. Malyugina - published by the European Society of Specialists in Surgical Treatment of Cataracts and Refractive Disorders of Cataract and Refractive Surgeons, Temple house, Ireland 2013. - 30 p.]. Currently, in the US and some European countries, intra-chamber injection of an antibiotic is widely used at the final stage of surgical intervention. However, this method of prevention is dangerous by the development of toxic syndrome of the anterior segment of the eye and cystic macular edema. There is also no information about the optimal concentration, dose and method of preparation of the drug for intracameral administration. For effective treatment, the choice of not only a medicinal product, but also the optimal dosage form that provides long-term action is of great importance [Aznabaev MT, Azamatova GA, Avkhadeeva SR, Batyrshin RA, Zagidullina A.Sh . Modern methods of antibiotic prophylaxis of intraocular infection in cataract surgery // Practical medicine. - 2011. - No. 2. - S. 218-220; Maychuk Yu.F. Optimization of antibiotic therapy for eye infections / Yu.F. Maychuk, A.M. Yuzhakov // Refractive surgery and ophthalmology. - 2002. - T.2, No. 2 - S. 44-52; Pozdnyakov V.I., Matz A.N. // VI Ros. Nat Congress "Man and Medicine". M., 1999; S. 325-326.]. The above circumstances naturally stimulate the search for new methods of prophylaxis in eye surgery. The use of a soluble ophthalmic drug film with an antibiotic would be one of the possible solutions to this problem. When using an ophthalmic drug film, there is no loss of the drug substance, a long release of the drug is provided, which allows maintaining the necessary concentration of the antibiotic in the treatment zone for a long time. Thanks to the ophthalmic drug film, the number of instillations is reduced, which makes it possible to reduce the dose of the drug, and therefore, reduce its toxicity and the risk of side effects while maintaining efficacy [Maychuk Yu.F. Ophthalmic medicinal films / Yu.F Maychuk, V.I. Pozdnyakov, G.L. Khromov, E.B. Koneva, L.N. Starukova // Bulletin of Ophthalmology. - 1974. - No. 6. - p. 419-423]. It is also important that in the area of film adhesion, the cornea and sclera become a kind of secondary depot, from which the drug continues to flow into the eye after complete dissolution of the polymer mass [V. Nuritdinov. Polyacrylamide as the basis of ophthalmic medicinal films / V.A. Nuritdinov // Bulletin of Ophthalmology. - 1981. - No. 2. - p. 59-60].

Known ophthalmic drug films with various drugs, such as gentamicin, pyobacteriophage, kanamycin, pilocarpine, fibrinolysin, streptodecase, emoxipin, gamma globulin, sulfapyridazine [Malanova NL, Murzin A.A. et al. Medicinal films with fibrinolysin in ophthalmology // Bulletin of Ophthalmology. - 1979. - No. 3. - from. 58-59; Maychuk Yu.F., Yerichev V.P. Pharmaceutical and clinical evaluation of soluble eye films with pilocarpine // Bulletin of Ophthalmology. - 1981. - No. 2. - from. 48-49; Maychuk Yu.F., Yerichev VP, Salminen L. Influence of various medicinal bases on the miotic effect of pilocarpine // Bulletin of Ophthalmology. - 1982. - No. 4. - from. 16-17; Romashchenko A.D. Patent RU 2056819 dated 03/27/1996; Aznabaev M.T. et al. Patent No. 2160074, 1998, patent No. 2173178, 2001].

The closest analogue of the invention is an ophthalmic drug film containing the following ratio of components, wt. %: polyvinyl alcohol 82.5, arabinogalactan 16.5 and levofloxacin 1.0 [patent RU 2404779, 2010].

The main disadvantage of the ophthalmic drug film with levofloxacin is that this antibiotic does not cover the entire spectrum of pathogens of postoperative infectious complications - it is inactive against clinically significant anaerobes. Over the past few years, there has been an increase in the minimum inhibitory concentration of levofloxacin, which indicates the formation of resistance to it. In the foreign literature there are reports of the development of resistance to this fluoroquinolone. [E. Donnenfeld, Optimization of Outcomes and Postoperative Wound Healing, Eyeworld 2005]. Also, the ophthalmic drug film with levofloxacin does not affect the active forms of oxygen, the products of lipid peroxidation, formed during inflammation and aggravating the course of infectious inflammatory complications.

The basis of the invention is the creation of ophthalmic medicinal films having not only the effect of an effective bactericidal antibiotic, but also pronounced antioxidant, anti-inflammatory and immunomodulating properties.

The technical result is an increase in the breadth and duration of the therapeutic effect of the film due to giving it antioxidant, anti-inflammatory and immunomodulating properties.

The specified technical result is achieved in that the ophthalmic drug film containing polyvinyl alcohol, an active substance of plant origin and an antibiotic in an amount of 1 wt. %, according to the invention, as the active substance of plant origin and antibiotic contains respectively dihydroquercetin and moxifloxacin in the following ratio of components, wt. % .:

Polyvinyl alcohol 80.0 Dihydroquercetin 19.0 Moxifloxacin 1,0

The invention is illustrated by the figure, which shows the pharmacodynamics of the concentration of moxifloxacin (M) in the moisture of the anterior chamber of the eyes of rabbits, where: 1 - instillation of a 0.5% aqueous solution of M (eye drops), 2 - application of an eye film based on polyvinyl alcohol (PVA), 3 - application of an eye film based on PVA with dihydroquercetin.

An eye film is prepared as follows. Polyvinyl alcohol, which has good solubility in water, was used for the production of eye films. When heated to 60-80 ° C, an aqueous solution of polyvinyl alcohol (PVA) was prepared in a glass flask, stirring occasionally until a homogeneous solution was obtained. Dihydroquercetin was added to the PVA solution to ensure a longer therapeutic effect and give new properties of HFL. A predetermined amount of moxifloxacin was added to the prepared base. The resulting mixture was stirred for 60 minutes at a temperature of 25 ° C. Then the polymer solution with moxifloxacin was poured on the surface of the sterile glass in an even layer and the solvent was evaporated in vacuo over phosphorus pentoxide. The film mass was dried at a temperature of 25 ° C in vacuum to a residual moisture content of 5-7%. The plate thickness was 0.5 mm. Ophthalmic medical films of the required size were cut from the obtained plates, which were packaged and sterilized.

The amount of PVA was 0.04 g per 1 cm ^{2 of} eye film. 0.25 mg of moxifloxacin was contained in one finished dosage form. With a decrease in the amount of drug substance less than 0.25 mg, the therapeutic effect is not enough manifested. Increasing the dose of more than 0.25 mg is impractical.

Moxifloxacin (8-methoxyquinolone) is a representative of the fourth generation of fluoroquinolones with a wide spectrum of activity, significant activity against gram-positive, gram-negative aerobic and microflora anaerobes, intracellular pathogens [Strachunsky L. S., Krechikov V. A. Moxifloxacin is a new generation of fluoroquinolone with a wide spectrum of activity (Literature Review), Clinical Microbiology and Antimicrobial Chemotherapy No. 3, Volume 3, 2007, pp. 243-246, 248, 253, 255]. The most important in the molecule of this fluoroquinolone are the groups occupying positions 1, 7 and 8. The cyclopropyl group in position 1 provides activity against gram-negative microorganisms. Attaching an additional ring at position 7 gives high activity in relation to gram-positive microflora, including pneumococci. The addition of a methoxy group at position 8 to the structure of the molecule led to an increase in activity against anaerobes without increasing the risk of potential phototoxicity [Appelbaum P., Hunter P., The fluoroquinolone antibacterials: past, present and future perspectives. Int J Antimicrob Agents 2005; 16: 5-15]. The main target of moxifloxacin in gram-positive microorganisms is mainly topoisomerase IV, and in gram-negative, DNA gyrase [Ricci V., Piddock L. Characterization of the QRDR of gyrA of Bacteroides fragilis and role in fluoroquinolone resistance. Proceedings of the 38th ICAAC Sep 24-27 2009; San Diego, USA. p. 121].

When using moxifloxacin, the likelihood of resistance development in gram-positive microorganisms is lower than when using other fluoroquinolones, due to its high affinity for both topoisomerase IV and DNA gyrase [Hooper D. Mechanisms of fluoroquinolone resistance. Drug Resistance Updates 2004; 2: 38-55; Schedletzky H., Wiedemann B., Heisig P. The effect of moxifloxacin on its target topoisomerases from Escherichia coli and Staphylococcus aureus. J Antimicrob Chemother 2003; 43 (Suppl B): 31-7]. All this allows moxifloxacin to avoid the formation of step-like mutations in bacteria and to provide an almost constant effect on sensitive strains.

Moxifloxacin has a high activity against gram-positive aerobes - Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, gram-negative aerobes - Haemophilus influenza, Moraxella catarrhalis, Escherichia coli, Klebsiella cerefloin aeroferinofermosa aeromas, pneumonia, Mycoplasma pneumonia. Moxifloxacin has a high bactericidal index against anaerobes, comparable with the "reference" antianerobic agent - metronidazole [Applebaum PC. Quinolone activity against anaerobes. Drugs 1999; 58 (suppl. 2): 60-64]. This fluoroquinolone is also active against microorganisms that have developed resistance to other classes of antibacterial drugs, including macrolido- and penicillin-resistant pneumococci and b-lactamase-producing strains of Haemophilus influenza.

Moxifloxacin is 8 times more active than ciprofloxacin and 2-4 times more active than levofloxacin against Staphylococcus aureus [Souli M., Weneersten C., Eliopoulos G. In vitro activity of BAY 12-8039, a novel 8-methoxyquinolone, against species representative of respiratory tract infections. Proceedings of the 37th ICAAC ⁶ , 2007. Poster F126]. According to M. Jones et al., Moxifloxacin is one of the most active fluoroquinolones against staphylococci. Many researchers note that the susceptibility of pneumococci to moxifloxacin is higher than to other fluoroquinolones: it is 2 times more active than sparfloxacin [Jones M., Staple A., Critchley I., et al. Benchmarking the in vitro activities of moxifloxacin and comparator agents against resent respiratory isolates from 377 medical centers throughout the United States. Antimicrob Agents Chemother 2005; 44: 2645-52] and gatifloxacin, 4-8 times - levofloxacin [Buxbaum A., Straschil U., Moser C., Graninger W., Georgopoulos A. Comparative susceptibility to penicillin and quinolones of 1385 Streptococcus pneumoniae isolates. J Antimicrob Chemother 2006; 43 (Suppl B): 13-8.], 8 times - ciprofloxacin and ofloxacin. In relation to Streptococcus pyogenes, moxifloxacin is 2-4 times more active than ofloxacin, ciprofloxacin and levofloxacin, has the same activity with gatifloxacin. Unlike fluoroquinolones of the II-III generations (ciprofloxacin, ofloxacin, levofloxacin), moxifloxacin has a high activity against anaerobes. The post-antibiotic effect of moxifloxacin for various microorganisms increases with increasing concentration of the drug [Strachunsky L.S., Krechikov V.A. Moxifloxacin - a new generation of fluoroquinolone with a wide spectrum of activity (Literature Review), Clinical Microbiology and Antimicrobial Chemotherapy, No. 3, Volume 3, 2009, p. 253, 255].

Due to the high effectiveness of moxifloxacin against most pathogens of eye infections, significant bioavailability, good pharmacokinetics, a favorable tolerance profile, and minimally tolerable side effects, it can be used to prevent and treat postoperative inflammatory infectious complications.

Dihydroquercetin (DHA) is one of the representatives of polyphenolic flavonoids isolated from Daurian, Siberian larch and Douglas spruce. This compound is a powerful antioxidant, exhibits P-vitamin activity, and therefore, it was proposed to use it as medicines and food additives. Dihydroquercetin has anti-inflammatory, radioprotective, antihistamine, antitumor, antidiabetic, capillary-strengthening actions [I. Pegova The development of mineral-biotic complexes "Dihydroquercetin-metal asparaginates" // Abstract. dis. competition. scientist step. Cand. farm. Sciences (15.00.02) / Pegova Irina Alekseevna; - Samara, 2007. - 5 p.]. Also, this flavonoid affects enzyme systems, antioxidant activity and exhibits an affinity for the phospholipid membrane components.

In experimental studies, the use of dihydroquercetin together with antibacterial drugs in the acute infectious process led to the restoration of the lymphocyte reaction, reduction of CD 4+ lymphocyte deficiency, stimulation of B cells and their activity in providing the body with immunoglobulins of the main classes, and increased efficiency of phagocytic reactions [A. A.V. ., Ovcharova E.A. The immune status of people exposed to chronic radiation exposure in the long term // Medical radiology and radiation safety. 2007. - No. 3. - S. 5-9; Bubinets O.V. Features of the immune status and immunobiological reactions with the use of antioxidants // Abstract. dis. competition. scientist step. Cand. farm. Sciences (03/14/60) / Bubinets Olga Vladimirovna; - Vladivostok, 2011. - 3 p.]. In model experiments, Pegovoi I.A. revealed that dihydroquercetin significantly enhances permeability in biological membranes [I. Pegova Development of mineral-biotic complexes "Dihydroquercetin-metal asparaginates" // atoref. dis. competition. scientist step. Cand. farm. Sciences (15.00.02) / Pegova Irina Alekseevna; - Samara, 2007. - 5 p.]. The multifaceted activity of dihydroquercetin allows one to obtain ophthalmic medicinal films that have not only the specific action of an antibiotic, but also antioxidant, immunomodulatory and anti-inflammatory properties.

1. The antimicrobial activity of eye films with moxifloxacin was determined by the disco-diffuse method in accordance with the methodological recommendations. Used cultures of Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, Escherichia coli. Standard discs with levofloxacin, moxifloxacin, and ocular drug films with moxifloxacin were placed on the surface of seeded agar. Next, Petri dishes were placed in a thermostat at a temperature of 37 ° C for 24 hours. The degree of antimicrobial activity was determined by the zone of absence of growth of microorganisms around standard discs and an ophthalmic drug film. Bacteriological studies have shown various antimicrobial activity. The largest zone of lysis of microorganisms in all cups was observed with the use of an eye film with moxifloxacin.

2. The tolerability of ocular drug films with moxifloxacin was studied in 6 chinchilla rabbits. The obtained eye films were laid for the lower eyelid 1 time per day for 4 weeks. Daily biomicroscopy of animal eyes was performed. Also during the study period, tonometry and a test for the integrity of the anterior corneal epithelium of laboratory animals were repeatedly performed. At the end of the experiment, rabbit eyes underwent morphological examination. Studies in the eyes of rabbits showed a good tolerance profile and absolute harmlessness of the films with moxifloxacin. A histological study of the structures of the eyeball revealed no negative changes.

3. In an experimental study, chamber moisture was studied in 24 rabbit eyes for the content of moxifloxacin. The concentration of the drug in the moisture of the anterior chamber was determined spectrophotometrically at 1, 4, 8, and 24 hours after a single injection of the ophthalmic drug film. In comparative studies, after a single administration of an eye film with PVA-based moxifloxacin, PVA-based moxifloxacin-based film and DHA instillation of a 0.5% aqueous solution of moxifloxacin, the antibiotic concentration in the moisture of the anterior chamber of the rabbit eye was respectively (μg / ml): after 1 hour 5.8 ± 0.2, 3.7 ± 0.3 and 6.1 ± 0.15,

after 4 hours 4.02 ± 0.03, 5.1 ± 0.3 and 0.85 ± 0.02,

after 8 hours 3.11 ± 0.02, 5.62 ± 0.2 and 0.12 ± 0.2,

after 24 hours, 1.21 ± 0.03, 6.23 ± 0.15 and 0.01 ± 0.1.

The figure shows that the films based on PVA and DHA have longer effects. This is due to the transformation in the supramolecular structure of solutions. When two polymers interact, the particle sizes decrease and their packing density increases, which contributes to a longer retention of moxifloxacin in SOD. It should be noted that a high concentration of the antibiotic in the moisture of the anterior chamber is created and retained for 24 hours by a PVA-based film with DHA as compared with the control, which indicates the effectiveness of dihydroquercetin used as a depot agent to increase the duration of the antibiotic's action.

The positive effect of the use of the proposed eye films for the prevention and treatment of infectious inflammatory diseases of the eye is to achieve a high constant concentration of the drug in the moisture of the anterior chamber.

The use of ophthalmic medicinal films does not adversely affect the organ of vision and has a good tolerance profile. The proposed eye films are completely biodegradable and non-toxic. The technique for using these ophthalmic medicinal films does not require high qualifications or special training for ophthalmologists. Ophthalmic drug films with an antibiotic can be used as an effective method for the prevention of infectious inflammatory complications in ophthalmic surgery.

Claims (1)

An ophthalmic drug film containing polyvinyl alcohol, an active substance of plant origin and an antibiotic in an amount of 1.0 wt. %, characterized in that it as an active substance of plant origin and antibiotic contains, respectively, dihydroquercetin and moxifloxacin in the following ratio of components, wt. %:
Polyvinyl alcohol 80.0 Dihydroquercetin 19.0 Moxifloxacin 1,0

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