Drops for the treatment of inflammatory eye diseases (options)

 

(57) Abstract:

The invention relates to medicine, in particular to the pharmaceutical industry. Part of the eye drops in addition to the main active substance ortofena(diclofenac sodium) is added to the co-solvent(propylene glycol), antioxidant(sodium thiosulfate), preservatives(nipagin,nipazol), the prolongator(poliglyukin). As a package for the use of glass bottles and plastic tubes-droppers. Eye drops can be used without preservatives in surgical interventions on the eye tissue, as well as in pediatric practice. The invention enables use in pediatric practice due to the absence of allergic reactions to drops. 2 S. and 1 C.p. f-crystals, 3 tab., 1 Il.

The invention relates to the pharmaceutical industry and for the composition of eye drops, diclofenac sodium (o-((2,6-dichlorophenyl)amino)phenyl acetate sodium), produced by the domestic industry under the name ortofen.

Known ophthalmic solution WO 95/31179 Ophthalmic solution based on diclofenak and tobramicin and its application. The solution contains the equivalent of tobramycin 0.001 - 0.45%, obtained from the tobramycin or its isomer; the equivalent of diclofenac 0.1%, planirovanie; a viscosity modifier; helatoobrazovatel; preservative. Application: treatment of eye and ear inflammations. therapeutic effect of the data eye drops based on the presence in the composition of the antibiotic of the aminoglycoside tobramycin. Diclofenac sodium is a substance related therapy. Aminoglycoside antibiotics are quite highly effective in the treatment of inflammatory processes of various etiologies, but also have their fairly significant drawbacks.

The disadvantages is that the local use of this composition (i.e. as eye drops) is very high possibility of allergic reactions in the form of a petechial rash (microchromosome), pruritus and angioedema may also result in severe irritation and ulceration of the mucous membrane of the eye. With long-term use of eye drops for chronic inflammatory processes may develop General resorptive actions, especially in patients with acute renal failure. This phenomenon is manifested by ototoxicity from its weak form (hearing loss) before its severe forms (irreversible hearing loss), nephrotoxicity, tobramycin also has an effect on the fetus while taking salmoni chloride), along with its high antimicrobial activity and good solubility in water is not stable during thermal sterilization, as its aqueous solutions are unstable at elevated temperatures. Not very well matched the pH of the eye drops, because the greatest therapeutic effect of NSAIDs including ortofena is achieved at a pH in the range of from 6.5 to 7.5

Also known eye drops called "Naclof 0.1% French company CIBA Vision (Naclof, eye drops. // New in ophthalmology: Ref. Zhur. - 1995. - N 1. - S. 32-33.). According to ophthalmologists, they have some significant drawbacks. Drops cannot be used for surgical interventions, as they have a preservative (mercury, etildiocolmain) and, in addition, mercury, etildiocolmain can have toxic effects on the damaged tissue of the eye; eye drops "Naclof 0.1%" is not recommended for use in pediatric practice, because the preservative has a negative impact on the growing child's body. The method of application and dosage prescribed by the developers (1-2 drops every 3-4 hours), indicate short-term effects of diclofenac sodium, which is not only uncomfortable for the patient, but also can have negative vastaarel non-steroidal anti-inflammatory drugs ortofena, stable during long-term storage and with specific anti-inflammatory activity and do not cause allergic reactions using only domestic raw materials.

The problem is solved by using as a prolongator poliglyukina - 6% solution of medium molecular fraction (60000 10000) partially hydrolyzed dextran in isotonic sodium chloride solution with wound healing and regenerating effect and antioxidant sodium thiosulfate and co-solvent of propylene glycol.

We studied the possibility of making eye drops ortofena 0.1 and 0.2 % concentrations of prolonged action using poliglyukina and their effectiveness, and stability during long-term storage.

When developing eye drops ortofena in the first place it was necessary to create aqueous solutions of sparingly soluble substances that are stable during storage. Considering the chemical structure ortofena, namely, that it is the sodium salt of organic acid (sodium salt of o-((2,6-dichlorophenyl)-amino)-phenylacetic acid), little is soluble in water (light), can be either hydrolyzed and oxidized with obrazovanie and preservatives. Of all the used antioxidants are the most effective was the sodium thiosulfate.

The hallmark of the part of the eye drops is the proportion of the components, namely the content of the antioxidant (sodium thiosulfate) in an amount equal to the number ortofena. This combination of components allows not only to obtain stable solutions in the process of long-term storage, but also to identify additional positive properties of this combination, i.e., eye drops ortofena do not cause allergic reactions that are installed in experiments on animals, although sodium thiosulfate in such concentrations as antihistaminic agent is not used

The prolongator for data eye drops, poliglyukin (partially hydrolyzed dextran) is a microbial polysaccharide and, therefore, a good breeding ground for microorganisms that are not valid during production and further use of eye drops. In this regard, optimal and effective concentration of preservatives for prolonged eye drops ortofena 0.1 and 0.2%, and also carried out a determination of the minimum sterilizing time is selected preservatives put the s preservatives for prolonged eye drops ortofena 0.1 and 0.2% corresponds to 0.02% nipazola and 0.06 % nipagina.

Was determined the specific activity of the eye drops ortofena in anti-inflammatory and regenerating action. Anti-inflammatory eye drops ortofena was studied on a model of acute inflammatory response in rabbits, which was characterized by tenderness, injection of the vessels of the sclera, hyperemia of the iris, constriction of the pupil, blepharospasm and lacrimation. Action eye drops ortofena was evaluated visually marked by signs.

As a counterpart in the development of eye drops - used eye drops "Naclof 0.1%," the company CIBA Vision, France 2 drops every 4 hours (1st group), the 2nd group of animals in the cavity of the conjunctiva of the right eye was injected eye drops ortofena 0.1% on polyglycine 2 drops 3 times a day, the fifth group - eye-drops ortofena of 0.2% on polyglycine 2 drops 3 times a day. As the intact control used a group of untreated animals, which were injected with isotonic solution of sodium chloride and 2 drops 4 times a day (4).

To quantify the activity of eye drops and verify the adequacy of the selected model and the treatment regimen was used alternative cumulative index: time, neoblog relatively intact control. The specific activity of the eye drops ortofena 0.1 and 0.2%, and prolonged was evaluated in comparison with the similar.

When you use a similar recovery was 1.5 times more effective than no treatment. Active eye drops ortofena 0.1% on polyglycine exceeded activity similar to 1.30 times, while eye drops ortofena 0.2% polyglycine were more similar to 1.6 times. The results obtained on the basis of statistical processing method of variance analysis.

Developed eye drops ortofena 0.1 and 0.2% concentrations contain substances with the following ratios:

ortofena - 1.0 - 2.0 g/l

propylene glycol - 200 g/l

sodium thiosulfate - 1.0-2.0 g/l

nipagina - 0.6 g/l

nipazola - 0.2 g/l

solution poliglyukina up to 1 litre

Eye drops ortofena made in compliance with all requirements of the minor. Part of the solution poliglyukina dissolved propylene glycol, then successively added preservatives, antioxidant and ortofen in quantities specified in the recipe, mix until dissolved, filtered and bring the prepared solution by polyglycine to 1 liter Bottled in glass bottles with a capacity of 10 and 5 ml, sealed, S 42-1594-86) - 200.0 g/l

sodium thiosulfate (....) - 1.0 g/l

nipagin (FS 42-14-60-89) - 0.6 g/l

nipazol (TU 6-09-4727-79) - 0.2 g/l

solution poliglyukina (FS 42-2023-83) - up to 1 liter

Eye drops were prepared under the conditions of asepsis. 50 ml poliglyukina mixed with 200.0 g of propylene glycol was then dissolved preservative (nipagin and nipazol), antioxidant sodium thiosulfate was then added ortofen and stirred until complete dissolution. The solution was filtered into a volumetric flask with a capacity of 100 ml in sterile combination filter and brought the solution polyglycine to the mark. Eye drops are Packed in sterile vials from data for drugs with a capacity of 10 or 5 ml, which corked sterile rubber stoppers and were checked with metal caps. Eye drops sterilized.

Example 2.

Part 2

ortofen (FS 42-2824-92) - 2.0 g/l

propylene glycol (VFS 42-1594-86) - 200.0 g/l

sodium thiosulfate (....) - 2.0 g/l

nipagin (FS 42-14-60-89) - - 0.6 g/l

nipazol (TU 6-09-4727-79) - 0.2 g/l

solution poliglyukina (FS 42-2023-83) - up to 1 liter

Eye drops can also be produced as in example 1

Before and after sterilization has examined the appearance of the solution, the quantitative content of the ortofena and preservatives, pH, storysupplement indicators. The results of the analysis are presented in table No. 1.

During the whole observation period, they remained clear, colorless, sterile, there is no mechanical switching, the pH during the entire observation period was almost unchanged. Quantitative content ortofena in a given period of time ranged from 3.15%, which is placed in an error experience and allowable deviations. The viscosity of the eye drops ortofena not changed.

A study was conducted to establish deadlines for the safe use of eye drops ortofena after opening the package. (As preservatives used nipazol nipagin in the ratio 1:3)

It was found that eye drops ortofena remain sterile for 30 days after opening the sterile package. In eye drops without preservatives was observed the growth of microorganisms already in 3 days.

The range of dosage forms for the eyes, nowadays produced in the factory in dropper tubes, small and needs further expansion. Of all domestic droplets produced in this package, you can select eye drops sulfatsila sodium, taufona.

Critical annum above requirements. At least three main reasons to consider the bottles for medicines are unsuitable for dispensing eye drops. A greater number of solution approximately 12 days daily installations 3-4 times a day, usually brownish in 3-4 days due to microbial contamination and destructive processes of drugs. Thus, about 40% of the initial solution, as a rule, disappears. Glass bottles can recognize, of course, suitable chemical composition for aqueous solutions, and they are basically designed for the storage of lyophilised preparations. And, finally, the need to use together with such bottles conventional eye dropper often leads the instillation to colonization, as the contents of the vial, and the eyes of the patient by various microorganisms, which can lead to serious complications.

As packaging for eye drops ortofena along with glass bottles investigated the possibility of using polyethylene tubes droppers. Small volume, and a special dosing device dropper provide the convenience of applying the eye drops, enable you to preserve the sterility of the solution during the whole time of Isla infants and children up to 1 year, in connection with the special requirements for this group of dosage forms and in various surgical interventions. Given the small volume (1 ml) and a special way of dispensing eye drops, excluded and preservatives. The latter is important because if their introduction sometimes there may be a heightened sensitivity to them.

Example 3.

Part 3

ortofen (FS 42-2824-92) - 0.001 g/ml

propylene glycol(VFS 42-1594-86) - 0.2 g/ml

sodium thiosulfate (FS.....) - 0.001 g/ml

solution poliglyukina (FS 42-2023-83.) to 1 ml

Under aseptic conditions with 50 ml poliglyukina - mix 200.0 g of propylene glycol, then add an antioxidant, and may also fuse, mix until dissolved. Filter into a measuring flask of 100 ml capacity through a combination filter and bring the solution polyglycine to the mark. Eye drops filtered under pressure through a membrane filter "Vladipor" with a pore diameter of 0.22 μm, poured into 1 ml plastic tube-droppers (TU 64-3-95-75) syringe method, and thermally sealed, check the tightness. The marking, clearance tube-droppers carried out in accordance with current regulatory documents.

Example 4.

Part 3

ortofen (FS 42-2824-92 glycine (FS 42-2023-83.) - to 1 ml

Eye drops are made by analogy with example 3.

Before and after sterilization has examined the appearance of the solution, the quantitative content of the ortofena and preservatives, pH, sterility, viscosity. During long-term storage is also performed quality control on above indicators. The results of the analysis of examples 3 and 4 are presented in tables 2 and 3.

The mass of the tube-droppers containing eye drops ortofena in the course of storage under natural conditions is reduced by an average of 2.45%, and at 303 K at an average rate of 4.29%. This is because part of the eye drops poliglyukin gives a certain viscosity and prevents intensive release of solvent (water) through the shell of polyethylene tubes droppers.

When storing tubes droppers in natural conditions and under conditions of high temperature, a decrease of mass dropper tubes together with a simultaneous increase in the concentration ortofena. This is due to the phenomenon of permeability of the solvent through the walls of plastic packaging. It should be noted that with increasing experimental temperature, the permeability of the solvent increases and there is a more significant increase in the concentration of the conditions for 25 months, an average of 4.49%, the same figure for eye drops stored at 303 K, equal to 9.8%, which is well within the acceptable limits of deviations that in both cases does not exceed the permissible limits of deviation for these solutions.

For the rest of the investigated indices eye drops remained stable. Eye drops dropper tubes during long-term storage meet the requirements of normative documents, that are transparent, colorless, there is no mechanical inclusions. Quantitative content ortofena fluctuated within the limits of error of the methods. Eye drops remained sterile, established microbiological studies on GFH.

A study was conducted to establish deadlines for the safe use of eye drops ortofena after opening the package. (Eye drops without preservatives) found that eye drops ortofena remain sterile for 3 days after opening the sterile package. When the store of eye drops in the refrigerator this time was 7 days.

Were conducted to investigate the kinetics of release ortofena of eye drops in experiments in vitro. As a result, provident prolonging effect, due to the increase in their viscosity. The maximum concentration ortofena is achieved in 5 to 6 hours from the beginning of the experiment and up to 8 h is maintained at a high level.

The biological tests of eye drops ortofena on animals. Found that eye drops ortofena have specific anti-inflammatory activity. Not have allergenic, local irritation and toxic actions.

Thus, the proposed formulations eye drops ortofena 0.1 and 0.2% concentration in different types of packaging have a prolonged action, consistent for all the studied parameters (quantitative content ortofena, pH and appearance of the solution, sterility, viscosity, absence of mechanical inclusions in glass vials within 27 months of storage under natural conditions and at elevated temperature "method of accelerated aging"; in plastic dropper tubes within 25 months of storage under natural conditions and at elevated temperature "method of accelerated aging". Have a specific anti-inflammatory activity, do not have allerleirauh, irritant and toxic effects.

1. Drops for the treatment of waspa the ant, characterized in that they additionally contain sodium thiosulfate, propylene glycol, nipagin, nipazol, the solution poliglyukina when the following ratio of components, g/l:

Ortofen - 1,0 - 2,0

Propylene glycol - 200,0

Sodium thiosulfate - 1,0 - 2,0

Nipagin - 0,6

Nipazol - 0,2

Solution poliglyukina Up to 1 litre

2. Drops for the treatment of inflammatory eye diseases on the basis of diclofenac-sodium (ortofen), characterized in that they additionally contain sodium thiosulfate, propylene glycol, the solution poliglyukina in the following ratio of components (per 1 ml), g/l:

Ortofen - 0,001 - 0,002

Propylene glycol - 0,2

Sodium thiosulfate - 0,001 - 0,002

Solution poliglyukina To 1 ml

3. Drops for the treatment of inflammatory eye diseases on the basis of diclofenac sodium under item 2, characterized in that they can be produced in plastic tubes dropper.

 

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