RU2149611C1 - Drops for treatment of eye inflammatory diseases (variants) - Google Patents

Abstract

FIELD: medicine, ophthalmology, pharmacy. SUBSTANCE: eye drops containing the main active component ortophen (diclofenac-sodium) has additionally cosolvent (propylene glycol), antioxidant (sodium thiosulfate), preserving agents (nipagin, nipazol), prolonging agent (polyglucin). Glass flasks and polyethylene dropping tubes are used as package. Eye drops can be used in surgery operations in eye tissue and in pediatry being without preserving agents. EFFECT: absence of allergic responses. 3 cl, 3 tbl, 1 dwg, 4 ex

Description

 The invention relates to the pharmaceutical industry and relates to the composition of eye drops of diclofenac sodium (o - ((2,6-dichlorophenyl) amino) phenylacetate sodium), a domestic industry produced under the name orthophene.

 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 tobramycin itself or its isomer; the equivalent of diclofenac 0.1%, obtained from diclofenac itself or its isomer; optionally solubilizing agent; a substance for isotonation; viscosity modifier; chelating agent; preservative. Application: treatment of eye and ear inflammations. The therapeutic effect of these eye drops is based on the presence of the tobramycin aminoglycoside group in the antibiotic. Diclofenac sodium is a concomitant therapy substance. Aminoglycoside antibiotics are quite highly effective in the treatment of inflammatory processes of various etiologies, but they also have their rather significant drawbacks.

 The disadvantages are that with the local use of this composition (that is, as eye drops), the possibility of developing allergic reactions in the form of a petechial rash (microbleeding), itching and angioedema is very great, and severe irritation and ulceration of the mucous membrane of the eye is also possible. With prolonged use of eye drops in chronic inflammatory processes, the development of a general resorptive action is possible, especially in patients with acute renal failure. This phenomenon is manifested by ototoxicity from its weak forms (hearing loss) to its severe forms (irreversible hearing loss), nephrotoxicity, tobramycin also has an effect on the fetus during pregnancy, even with topical application.

The preservative that is part of this dosage form (benzalkonium 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. The pH of the solution of eye drops is not very well selected, since the greatest therapeutic effect of NSAIDs, including orthophene, is achieved at a pH in the range from 6.5 to 7.5
Eye drops are also known under the name "0.1% Naklof" by the French company CIBA Vision (Naklof, eye drops. // New in ophthalmology: ref. Journal. - 1995. - N 1. - P.32-33.). According to ophthalmologists, they have a number of significant drawbacks. Drops cannot be used in surgical interventions, since they contain a preservative (mercury ethylthiosalicylate) and, in addition, mercury ethylthiosalicylate can have a toxic effect on damaged eye tissue; eye drops "Naklof 0.1%" is not recommended for use in children's practice, since the preservative has a negative effect on the growing children's body. The method of administration and dosage prescribed by the developers (1-2 drops every 3-4 hours) indicate a short-term effect of diclofenac sodium, which is not only inconvenient for the patient, but can also have a negative effect on eye tissue.

 The objective of the invention was to develop a composition of prolonged eye drops of a non-steroidal anti-inflammatory drug orthophene, stable during long-term storage and possessing specific anti-inflammatory activity and not causing allergic reactions using only domestic raw materials.

 The problem is solved by using as a prolongator polyglucin - a 6% solution of the average molecular fraction (60,000 ± 10,000) of partially hydrolyzed dextran on an isotonic sodium chloride solution that has a wound healing and regenerating effect, as well as sodium antioxidant thiosulfate and a co-solvent of propylene glycol.

 The possibility of making orthophene eye drops of 0.1 and 0.2% concentrations of prolonged action using polyglucin and their effectiveness and stability during long-term storage was studied.

 When developing eye drops of orthophene, it was first necessary to create aqueous solutions of a sparingly soluble substance that were stable during storage. Given the chemical structure of orthophene, namely, that it is a sodium salt of an organic acid (sodium salt of o - ((2,6-dichlorophenyl) amino) phenylacetic acid), it is slightly soluble in water (with opalescence), and can hydrolyze oxidize to form colored products, turning pink or yellow, solvents and antioxidants and preservatives were selected. Of all the antioxidants used, sodium thiosulfate proved to be the most effective.

A distinctive feature of the composition of eye drops is the quantitative ratio of the components, namely the content of the antioxidant (sodium thiosulfate) in an amount equal to the amount of orthophene. This ratio of components allows not only to obtain stable solutions during long-term storage, but also to identify additional positive properties of such a combination, i.e. orthophene eye drops do not cause the development of allergic reactions, which is established in animal experiments, although sodium thiosulfate in concentrations such as an antihistamine is not used
The prolongator for these eye drops, polyglucin, (partially hydrolyzed dextran) is a microbial polysaccharide and, therefore, a good medium for the propagation of microorganisms, which is not permissible in the manufacture and further use of eye drops. In this regard, the optimal and effective concentration of preservatives for prolonged orthophene eye drops of 0.1 and 0.2% was determined, and the minimum sterilizing time of the selected preservatives was determined by seeding samples of solutions with test cultures on nutrient media. The effective and optimal concentration of the amount of preservatives for prolonged orthophene eye drops of 0.1 and 0.2% corresponds to 0.02% nipazole and 0.06% nipagin.

 The specific activity of orthophene eye drops was determined by its anti-inflammatory and regenerative effect. The anti-inflammatory effect of orthophene eye drops was studied on the model of an acute inflammatory reaction in rabbits, which was characterized by pain on palpation, injection of scleral vessels, hyperemia of the iris, narrowing of the pupil, brepharospasm and lacrimation. The actions of orthophene eye drops were evaluated visually by the noted signs.

 As an analogue in the development of eye drops - used eye drops "Naklof 0.1%", CIBA Vision, France, 2 cap. every 4 hours (1st group), the 2nd group of animals in the cavity of the conjunctiva of the right eye was injected with 0.1% orthophene eye drops on polyglucin in 2 drops. 3 times a day, the fifth group - eye drops of orthophene 0.2% on polyglucin 2 cap. 3 times a day. As an intact control, a group of untreated animals was used, which were injected with an isotonic sodium chloride solution of 2 cap. 4 times a day (4th group).

 To quantify the activity of eye drops and verify the adequacy of the selected model and treatment regimen, a cumulative alternative indicator was used: the time required for the symptoms of the inflammatory process of the eye to completely disappear, with a preliminary assessment of the analogue relative to intact control. The specific activity of orthophene eye drops of 0.1 and 0.2%, also prolonged, was evaluated in comparison with the analogue.

 When using an analogue, recovery was 1.5 times more effective than without treatment. The activity of 0.1% orthophene eye drops on polyglucin exceeded the analogue activity by 1.30 times, while 0.2% orthophene eye drops on polyglucin were 1.6 times more active than the analogue. The results are obtained on the basis of statistical processing using the analysis of variance.

The developed eye drops of orthophene 0.1 and 0.2% concentration contain substances in the following ratios:
orthophene - 1.0 - 2.0 g / l
propylene glycol - 200 g / l
sodium thiosulfate - 1.0-2.0 g / l
nipagina - 0.6 g / l
nipazole - 0.2 g / l
polyglucin solution - up to 1 l
Orthophene eye drops are made subject to all aseptic requirements. Propylene glycol is dissolved in part of the polyglucin solution, then preservatives, an antioxidant and orthophene are added sequentially in the amounts indicated in the recipe, mixed until complete dissolution, filtered and the prepared solution is adjusted with polyglucin to 1 liter. Poured into glass bottles with a capacity of 10 and 5 ml, sealed, sterilized.

 Example 1

Composition 1
ortofen (FS 42-2824-92) - 1.0 g / l
propylene glycol (VFS 42-1594-86) - 200.0 g / l
sodium thiosulfate (....) - 1.0 g / l
nipagin (FS 42-14-60-89) - 0.6 g / l
nipazole (TU 6-09-4727-79) - 0.2 g / l
polyglucin solution (FS 42-2023-83) - up to 1 l
Eye drops were prepared under aseptic conditions. 50 ml of polyglucin was mixed with 200.0 g of propylene glycol, then the preservative (nipagin and nipazole), sodium antioxidant thiosulfate were dissolved, then orthophene was added and mixed until completely dissolved. The solution was filtered into a 100 ml volumetric flask through a sterile combination filter and the solution was adjusted to the mark with polyglucin. Eye drops were packaged in sterile vials from a drug drip with a capacity of 10 or 5 ml, which were sealed with sterile rubber stoppers and wrapped in metal caps. Eye drops were sterilized.

 Example 2

Composition 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
nipazole (TU 6-09-4727-79) - 0.2 g / l
polyglucin solution (FS 42-2023-83) - up to 1 l
Eye drops are made as in example 1
Before and after sterilization, the appearance of the solution, the quantitative content of orthophene and preservatives, pH, sterility, viscosity (for examples 1 and 2) were checked. During long-term storage, quality control was also performed according to the above indicators. The results of the analysis are presented in table No. 1.

 During the entire observation period, they remained transparent, colorless, sterile, there were no mechanical inclusions, and the pH value practically did not change during the entire observation period. The quantitative content of orthophene for a given period of time ranged within 3.15%, which fits into the experimental error and permissible deviation norms. The viscosity of orthophene eye drops did not change.

A study was conducted to establish the timing of safe use of orthophene eye drops after opening the package. (As preservatives used nipazole nipagin in a ratio of 1: 3)
It was found that orthophene eye drops remain sterile for 30 days after opening the sterile package. In eye drops without preservatives, growth of microorganisms was observed already for 3 days.

 The assortment of eye dosage forms currently available in the factory in tube droppers is small and needs further expansion. Of all the domestic drops produced in this package, eye drops of sodium sulfacyl and taufon can be distinguished.

 A critical analysis of the packaging materials allows us to conclude that none of them fully meets the requirements listed above. At least three main reasons make us consider vials for medicines unsuitable for dispensing eye drops. A larger amount of solution for approximately 12 days of daily installations 3-4 times a day, usually already cloudy for 3-4 days due to microbial contamination and the destructive processes of drugs. Thus, about 40% of the initial amount of solution, as a rule, disappears. Glass vials cannot be recognized, of course, suitable in chemical composition for aqueous solutions, and they are mainly intended for the storage of lyophilized preparations. And finally, the need to use ordinary eye droppers together with such vials often results in instillation of contamination of both the contents of the vial and the patient’s eye with various microorganisms, which can lead to serious complications.

 As a package for orthophene eye drops, along with glass bottles, the possibility of using polyethylene dropper tubes has been investigated. A small volume and a special dropper dispensing device provide ease of use for eye drops, keep the solution sterile for the entire time of use without adding a preservative, and make it possible to use eye drops in pediatrics and, especially for newborns and children up to 1 year old, due to increased requirements for this group of dosage forms and with various surgical interventions. Given the small volume (1 ml) and a special way of dispensing eye drops, preservatives are also excluded. The latter is also important because with their introduction, sometimes there may be an increased sensitivity to them.

 Example 3

Composition 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
polyglucin solution (FS 42-2023-83.) - up to 1 ml
Under aseptic conditions, 200.0 g of propylene glycol is mixed with 50 ml of polyglucin - then an antioxidant is added, and orthophene is mixed until completely dissolved. Filter into a 100 ml volumetric flask through a combination filter and adjust the solution with polyglucin to the mark. Eye drops are filtered under pressure through a Vladipor membrane filter with a pore diameter of 0.22 μm, poured 1 ml each into polyethylene tube droppers (TU 64-3-95-75) using a syringe method, and are sealed thermally, checked for leaks. Labeling, design of tube droppers is carried out in accordance with current regulatory documentation.

 Example 4

Composition 3
ortofen (FS 42-2824-92) - 0.002 g / ml
propylene glycol (VFS 42-1594-86) - 0.2 g / ml
sodium thiosulfate (FS .....) - 0.002 g / ml
polyglucin solution (FS 42-2023-83.) - up to 1 ml
Eye drops are made by analogy with example 3.

 Before and after sterilization, the appearance of the solution, the quantitative content of orthophene and preservatives, pH, sterility, and viscosity were checked. During long-term storage, quality control was also performed according to the above indicators. The results of the analysis of examples 3 and 4 are presented in tables 2 and 3.

 The mass of tube droppers containing orthophene eye drops during storage under natural conditions decreases by an average of 2.45%, and at 303 K - by an average of 4.29%. This is due to the fact that polyglucin, which is part of the eye drops, gives a certain viscosity and prevents the intensive exit of the solvent (water) through the shell of the polyethylene tube droppers.

 When storing a tube dropper in vivo and at elevated temperatures, a decrease in the mass of the tube dropper is observed with a simultaneous increase in the concentration of orthophene. This is explained by the phenomenon of solvent permeability through the walls of the polymer 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 drug substance. So the increase in the concentration of orthophene in eye drops stored under natural conditions for 25 months is on average 4.49%, the same indicator for eye drops stored at 303 K is 9.8%, which fits into the acceptable deviation standards, which in both cases does not exceed the permissible deviation limits for these solutions.

 According to the rest of the studied parameters, eye drops remained stable. Eye drops in a dropper tube during long-term storage corresponded to the requirements of regulatory documentation, that is, they were transparent, colorless, they did not contain mechanical impurities. The quantitative content of orthophene varied within the limits of the error of the methods. Eye drops remained sterile, as established by microbiological studies conducted on GFH1.

 A study was conducted to establish the timing of safe use of orthophene eye drops after opening the package. (Eye drops without preservatives) It was found that orthophene eye drops remain sterile for 3 days after opening the sterile package. When storing eye drops in the refrigerator, these periods were 7 days.

 Studies were conducted kinetics of the release of orthophene from eye drops in experiments in vitro. As a result of the studies, it was found that orthophene eye drops made on polyglucin have a significant prolonging effect, due to their increase in the viscosity of the solution. The maximum concentration of orthophene is achieved at 5-6 hours from the start of the experiment and is maintained at a high level up to 8 hours.

 Biological tests of orthophene eye drops in animals have been conducted. Orthophene eye drops have been found to have specific anti-inflammatory activity. They do not have allergic, local irritant and toxic effects.

 Thus, the proposed compositions of orthophene eye drops of 0.1 and 0.2% concentration in various types of packaging have a prolonged effect, are stable according to all studied parameters (quantitative content of orthophene, pH and appearance of the solution, sterility, viscosity, absence of mechanical inclusions in glass vials for 27 month of storage in vivo and at elevated temperature by the method of accelerated aging "; in polyethylene tube droppers for 25 months of storage in vivo and at elevated t temperature “accelerated aging method.” They have specific anti-inflammatory activity, do not have allergenic, locally irritating and toxic effects.

Claims (1)

1. Drops for the treatment of inflammatory eye diseases based on diclofenac-sodium (orthophene), containing the active substance and preservative, characterized in that they additionally contain sodium thiosulfate, propylene glycol, nipagin, nipazole, polyglucin solution in the following ratios of components, g / l:
Ortofen - 1.0 - 2.0
Propylene glycol - 200.0
Sodium thiosulfate - 1.0 - 2.0
Nipagin - 0.6
Nipazole - 0.2
Polyglucin solution - Up to 1 L
2. Drops for the treatment of inflammatory eye diseases based on diclofenac sodium (orthophene), characterized in that they additionally contain sodium thiosulfate, propylene glycol, polyglucin solution 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
Polyglucin Solution - Up to 1 ml
3. Drops for the treatment of inflammatory eye diseases based on diclofenac sodium according to claim 2, characterized in that they can be produced in polyethylene dropper tubes.

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