FI107700B - Process for the preparation of ophthalmic compositions - Google Patents

Abstract

Novel pharmaceutical compositions for ophthalmic use, particularly instillable ophthalmic compositions having average viscosity and characterized in that they contain, as the active principle, an anti-flammatory agent which is optionally combined with an antibacterial agent, a gellable acrylic acid polymer and a basic agent to form a fluid aqueous solute with a pH of 7.0-8.0. The compositions are useful for treating inflammatory diseases of the eyeball.

Description

107700

Process for the preparation of ophthalmic mixtures - Förfarande för framställning av oftalmiska sammansättningar

The present invention relates to a process for the preparation of ophthalmic compositions having a medium viscosity which may be dripped and which contains an anti-inflammatory agent from the group of oxicams.

It is known that, when ophthalmic formulations are applied to the eye, a significant amount of this preparation spontaneously discharges from the eye, either because it is dripped incorrectly or because the palpebral reflex causes the product to disappear. The second portion of the sil-10 drip preparation drains into the tear duct and thereby flows into the nasal passages. Therefore, administration of eye drops or any other eye preparation is believed to result in a very significant loss of the active ingredient. This phenomenon is all the more pronounced when more or less reluctant young children or elderly people whose movements are clumsy have to be administered.

To counteract such a situation, more concentrated solutions may be resorted to, given that the small volume of volume that remains in contact with the eyeball or tear pouch reaches the target organ and is more effective. However, these ophthalmic solutions have even greater drawbacks than dilute solutions. Hypertonic solutions 20 cause pain. Concentrated solutions leave an accumulation on the surface of the eyeball and impair vision. A further disadvantage of concentrated solutions is that they are more likely to have undesirable side effects associated with systemic activity.

• ·· • · ♦ .Hyperviscous solutions that have been applied to the eyelid or eyelid have also been used in the past. Such preparations are described in French Patent No. 2 407 714 or European Patent 0 166 061 and are gels with viscosities in the range of 1000 to 100 000 centipoises at 20 ° C. In fact, they are eye creams with water as a filler. It is not certain that such preparations will remain. are easily spread on the surface of the eye, primarily in the presence of electrolytes designed to slow the breakdown of the gel. For this reason, they may, ·; · * 30 should only be used to treat infections of the eyelids or the periphery of the eye.

• · · • · · · · [···. It is an object of the present invention to overcome the above deficiencies by providing a sterile drip preparation, i.e., a preparation which can be administered in the form of eye drops, but which already has a significant viscosity due to the poly- ·· 2,107,700 meers, the quality of which guarantees better adhesion and longer residence time of the active ingredient.

The present invention thus relates to a process for the preparation of ophthalmic compositions having medium viscosity which are known to contain, as an active ingredient, an anti-inflammatory agent selected from the group of oxicams as disclosed in the appended claims. The objective, which is particularly sought with antiinflammatory agents, is to ensure the highest bioavailability possible by the fact that the resulting aqueous solution is finally sufficiently fluid while having a pH of 6.5 to 8 where maximum gelling occurs.

In the case of oxicam-type anti-inflammatory agents, Carbopol's function is to ensure the retention and adhesion of the active ingredient, thereby ensuring better contact with the target organ.

Namely, it has been found that the use of an acrylic acid polymer can achieve a pH of 15 which is compatible with the ophthalmic medium while maintaining the active ingredient in dissolved form.

The invention is also characterized in that the gelling polymer is an acrylic acid polymer or carbomer, in particular one sold under the trade names Carbobopol 934, 934 P, 940 and 941 (Goodrich).

20 The acrylic acid polymer is added to the medium in amounts of from 0.05 to 0.5% by weight, preferably from 0.1 to 1% by weight, so that, after neutralization with, or almost neutralization with, a basic substance, the viscosity of the medium remains within predetermined ranges. . Namely, acrylic acid polymers are known to provide ****: flowable solutions of acidic pH which become viscous from pH 5 ··· 25 until they form solid gels and then re-issue flowable solutions at pH above 10. The viscosity of acrylic acid polymer solutions so adjusting is a difficult problem. This is done either by changing the polymer concentrations or by adjusting the pH to high viscosity regions or vice versa to low viscosity regions, which however are compatible with the physiological conditions * and the stability of the active ingredient.

• · · • · · ·. ···. In the formulations of the present invention, the viscosity problem is solved by using highly dilute acrylic acid polymer blends. In this way, it is possible to adjust the pH of the preparation to near neutral, which is the best ··· tolerated area of the eye, and / or to a pH range suitable for the stability of the active ingredient.

3 107700

The basic substance which serves to regulate the pH and thereby create the viscosity of the stock solution is an inorganic base such as an alkali metal carbonate or an alkali metal bicarbonate or another alkali metal hydroxide. The basic substance may also be an organic base such as a dialkylamine, for example diethylamine, a trialkylamine, for example triethylamine or a hydroxyalkylamine such as ethanolamine, triethanolamine, N-methylglucamine or trimethanol.

Most preferably, the basic substance is sodium hydroxide or lithium hydroxide, which is added in such calculated doses that the final pH of the solution is within the desired range of about 10 for thalamic use.

The ophthalmic formulations of the invention further contain a preservative such as phenolic acid or an ester thereof such as parabens or gallate and the preservative may also be a quaternary ammonium salt such as cetrimide bromide, benzalkonium chloride or benzododecmium.

It may be advantageous to add a complexing agent to the preparation to provide better stability of the molecule when the active ingredient is sensitive to the presence of metal residues that may promote its degradation. For this purpose, nitrilotriacetic acid, ethylenediaminetetraacetic acid or ethylenediamino-NN'-20 diethyl-NN'-dipropionic acid are used.

The function of the chelating agent is also to promote the complexation of divalent ions (calcium, mag * · V *: magnesium) which adversely affect the development of the dosage form during storage.

• · · • · · ·

The ophthalmic formulations of the invention also contain an isotonic agent, preferably an organic molecule, suitable for controlling the concentration of molar · · · *** * in the vicinity of the isotone.

: ·· · Most suitable isotonizing agents are polyols such as mannitol, sorbitol. li, xylitol, dulsitol, lactitol or carmitol, which, by virtue of their high molecular weight, allow very precise control of the required amount of isotonizing agent.

*: · • · •: ***: The active ingredient is an anti-inflammatory agent of the oxicam type which is capable of reducing the synthesis of prostaglandins by inhibiting prostaglandin synthetases and / or syldooxygenases. Namely, intravascular perfusion of prostaglandins (PG A2 or PG A2 107700 PG No) significantly increases intraocular pressure. Thus, eye drops containing anti-inflammatory agents are used to prevent an increase in intraocular pressure. They also actively inhibit the synthesis of leukotrienes and lipoxins.

Suitable anti-inflammatory agents for this purpose include, in particular, meloxicam, isoxicam, droxicam, piroxicam, oxicam, tenoxicam or sudoxicam. These compounds can conveniently be defined by the general formula

OH

X ^^ A ^^ CONH. Do | N-CH3

v'A

wherein X and Y together form a monocyclic aromatic ring which is optionally substituted and Ar is a heterocyclic, optionally substituted phenyl radical such as pyridyl, 5-methyl-3-isoxazolyl.

These compounds behave like weak acids as a result of ionization of the phenolic functional group and can therefore be converted into a solution in an alkaline medium.

They are used in acid form or more conveniently in the filtration of an inorganic base. ***. 15 (sodium salt) or organic base salts (trimethanol salt, lysine salt; N-methylglucamine salt or monoethanolamine salt). The concentration of the anti-inflammatory agent is 0.01-0.5%, and preferably 0.05-0.2%, depending on their activity: level.

• · · ··· ♦

The formulations of the invention may also contain an antibacterial agent and in particular an antibiotic or quinolone antibacterial agent. agent. Particularly preferred antimicrobial agents include chloramate, phenicol, thiamphenicol, polymyxin, tyrosidine, gramicidine, colistinime sodium, • tansulfonate, tetracycline, penicillin, neomycin, gentamicin, dihydrost, kanamycin, dibecacin, micronomycin, fosfomycin, Rifa-25 mycine or sulbactam; the antibacterial agent may also be a quinolone-type synthetic agent such as norfloxacin, pefloxacin, ofloxacin, amifloxacin or ciprofloxacin.

• · • · 5 107700

The invention also relates to a process for the preparation of drip ophthalmic preparations according to the invention, wherein the acrylic acid polymer is dissolved or dispersed in an aqueous medium, to which is added a preservative, an isotonic agent and a chelating agent, until a homogeneous viscous mixture is obtained.

The active ingredient may also be added directly to one of the aqueous solutions. Each solution or dispersion or active ingredient itself is sterilized by appropriate physical means. Mixing of the solutions is then performed.

The pharmaceutical compositions of the invention may additionally contain other active ingredients, such as an antibacterial agent.

The drip ophthalmic compositions of the invention may be used in the treatment of ocular disorders, in particular in the treatment of ocular flushing or microbial or viral infections, allergic symptoms, inflammation, keratitis, with or without associated ocular inflammation, particularly in the preparation of a patient. The dosage is 1-5 drops to each eye per day, divided into several administrations.

The presence of an acrylic acid polymer in the formulation results in a reduction in the number of drips and a decrease in the active ingredient concentration.

The following examples illustrate the invention without limiting it.

··· • · · ·> *. : Example 1 • Piroxicam-based drip preparation • Acrylic Acid Polymer, available from y.V. ' under the tradename Carbopol 940 (Goodrich) 7.50 g * '25 Sodium ethylene diaminotetraacetate 0.50 g

Cetrimidibromide 0.50 g * * Sorbitol 200.00 g * · ·

Piroxicam 5.00 g

Sodium hydroxide 4.00 g ···. 30 Water 4783,00 g * · * for a total volume of about 5,000 g.

«· · • · · • • • ♦ ♦ * i • · · ♦ · 6 107700

Procedure (a) Preparation of the acrylic acid polymer solution Place 750 ml of water in a 5 liter flask and, with stirring at about 500 rpm, gradually add 7.50 g of the acrylic acid polymer and continue stirring until a homogeneous solution is obtained.

b) Sodium tetrasemate solution To 1000 ml of water, add successively and with stirring sodium tetrasemate (0.50 g), then cetrimide bromide (0.50 g) and finally sorbitol (200 g).

Transfer this solution to a 5-liter flask, rinse the vessel with 250 ml of water, and generate homo-10.

Transfer the entire solution into a container. Rinse the flask again with 250 ml of water and heat sterilize the mixture.

Preparation of the neutralization solution Dissolve 4 g of sodium hydroxide in 40 ml of water with stirring. 33 ml of the solution thus prepared are placed in a pressure chamber for subsequent filtration.

Place the remaining 7 ml of the previously prepared sodium solution in a beaker containing 1993 ml of water with stirring. Homogenize a solution of pH ·: · (pH = 12,2) which is gradually introduced into a beaker containing accurately weighed 5,00 g of piroxicam. Stirring is continued until almost the end of the addition 20. Piroxicam is soluble and the pH of the solution thus prepared is 10.0.

In a dish, stirring is continued by sterile filtration of 33 ml of sodium solution with a sterilization filter and sterile nitrogen pressure for neutralization.

··· ♦ ♦ * • · ·

Rinse the beaker and the filter with 250 ml of water.

Under the same conditions, sterilize the filter under sterile conditions · ♦ · 25 piroxicam solution and rinse the vessel. The solution is introduced into a vessel already containing an acrylic acid polymer, homogenized for one hour and then taken into sterile] ···. a sample to check the pH (7.4-7.8). Allow to rest for 24 hours, then genotype the homo · · * * * for a further 10 minutes and then take a new sample whose pH and viscosity: .v is checked. The viscous solution is ready to be packaged in 0.2 ml single dose vials.

7 107700

By the same procedure, an ophthalmic solution based on 2% sudoxicam or an ophthalmic solution based on 1% tenoxicam can be prepared.

Example 2 A drip preparation based on piroxicam and polymyxin

Acrylic Acid Polymer sold under the tradename Carbopol 940 (Goodrich) 7.50 g

Sodium ethylenediaminetetraacetate 0.50 g

Benzalkonium chloride 0.125 g Piroxicam 5.00 g

Polymyxin in sulphate form 750,000,000 single bonds

Sodium hydroxide 4.00 g

Sodium chloride 40.00 g

Water q.s. ad about 5,000 g.

Polymyxin may be replaced by an equivalent amount of ciprofloxacin (15 g active ingredient).

• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •••••••••••••••••••••••••••••••••••••••• I IM • · · ♦ 1 2 3 • · · · · · · · · · · · · · · · · · · · · · · · · · ··· ·

Claims (8)

A process for the preparation of ophthalmic compositions which have medium viscosity and are readily drip-containing, and which contain an anti-inflammatory agent in the group of oxycams, characterized in that a water dispersion of a gel-forming acrylic acid polymer can react with a basic aqueous substance already containing a previously dissolved oxycam, a homogeneous viscous mixture, the final mixture having a pH between 6.5-8. Process according to claim 1, characterized in that the final composition has a pH of 7-8. Process according to claim 1, characterized in that the final composition has a pH of 7.4-7.8. Process according to claim 1, characterized in that the active agent has a concentration in the aqueous solution between 0.01 and 0.5% by weight. Process according to claim 1, characterized in that the basic substance is an inorganic or organic base. 6. A process according to claim 1, characterized in that the anti-inflammatory agent is selected from the group consisting of droxicam, proxicam, sudoxicam, oxicam, tenoxicam, ice oxicam and flour oxicam. Method according to any of the preceding claims, characterized in that the ophthalmic compositions contain an additional antibacterial substance selected in the group of antibiotics and among quinolones. A process according to any of the preceding claims, characterized in that the acrylic acid polymer has a concentration between 0.05 and 5% by weight, preferably about 0.1% by weight. '· £ ·· * ·· «» ·> ·' ·