MXPA00009715A - The process for manufacturing topical ophthalmic preparations without systemic effects - Google Patents

Abstract

For treating eye diseases, various kinds of medications are used. They are used in form of topical preparations or in form of systemic preparations to be taken orally or parenterally. Of topical preparations some are for topical use only e.g. framycetin, neomycin, loteprednol ebanoate, etc. However, large majority of topical ophthalmic drugs are for systemic use also, e.g.. Ciprofloxacin, Gentamicin, Timolol, Clonidine, Dexamethasone, Betamethasone, Carbachol, etc. Some of these drugs when used topically are also found to have systemic effects and if they are of serious nature limits the use of that drug, e.g. cardiopulmonary effects of B-blockers like timolol. Dryness of mouth, flush, fever, tachy cardia, urinary retention, convulsion irritability with atropine. Hypertension with phenylephine. Increased salivation, nausea, vomiting, diarrhea, stomach cramps, bronchial secretions, bronchial constriction, asthma, bradycardia, paresthesia with miotics, Hypotension with clonidine. Dry mouth, fatigue and drowsiness with apraclonidine and brimonidine.

Description

PROCEDURE FOR THE MANUFACTURE OF TOPICAL OPHTHALMIC PREPARATIONS WITHOUT SYSTEMATIC EFFECTS DESCRIPTIVE MEMORY The present invention relates to the process for preparing topical ophthalmic preparations without systemic effects. Many topical ophthalmic preparations have systemic effects. These systemic effects are responsible for the contraindications, the side effects, the toxicity of some topical ophthalmic preparations. Likewise, due to the systemic effects some topical ophthalmic preparations have not been commercialized. The present invention is directed to the preparation of topical ophthalmic preparations so that the systemic effects of said topical ophthalmic preparation do not manifest themselves. Topical ophthalmic preparations can be divided into two groups. One group includes preparations wherein the active ingredients are for topical use only and have no systemic effects. This group of drugs includes antibiotics such as framycetin, neomycin, fucidine, steroids such as loteprednol ebanate, triamcinolone, alpha agonists such as aparaclonidine, brimonidine, etc. The other group of topical ophthalmic preparations has active ingredients that are generally used for their effects. This group of preparations includes antibiotics such as ciprofloxacin, norfloxacin, ofloxacin, gentamicin, tobramycin, steroids such as dexamethasone, betamethasone, beta-blockers such as timolol, betaxolol, etc. It has also been discovered that some of these drugs when used topically frequently have systemic effects. When the nature of the systemic effects is severe, the result is to limit the use of a drug_ as a contraindication or amount of drug to be used. Examples of known systemic effects of topical ophthalmic preparations include cardiopulmonary effects of β-blockers such as timolol, levobunolol, metipranolol, carteolol, etc. It has been found that atropine ophthalmic drops cause dry mouth, redness, fever, tachycardia, urinary retention, irritability, seizures. Systemic hypertension is associated with topical mydriatic phenylephrine. Symptoms are observed as increased salivation, nausea, vomiting, diarrhea, stomach cramps, bronchial secretions, bronchial constriction, asthma, bradycardia, parasitism with miotic agents. Systemic hypotension is the main limiting factor for the use of clonidine in the management of glaucoma. Dry mouth, fatigue and malaise observed with brimonidine and apraclonifine are some of the systemic effects they present. The systemic side effects, which are manifested by the use of topical ophthalmic preparations, result in the interruption of the therapy or not starting a therapy or reducing the amount of drug or opting for a drug that does not have a great acceptance. Due to the above, attempts have been made to reduce the systemic effects of topically applied drugs.

The systemic effects are due to the plasma concentration of a drug. It depends on the absorption of the drug from the conjunctival or nasal mucosa in the systemic circulation (serum levels of the drug). The mechanisms to reduce the plasma concentration of a drug include the reduction in the size of the drop, thus reducing the amount of drug available in the conjunctiva as well as in the nasal mucosa. Blockage of the nasolacrimal duct also temporarily or permanently reduces the drug reaching the nasal mucosa through the nasolacrimal passages, and in this way the amount of drug available systemically is reduced. Increasing the viscosity of a formulation also reduces the plasma concentration of a drug. The slow release of a drug through a mechanism / sustained release device is known to reduce the plasma concentration of topical ophthalmic preparations. The inclusion of vasoconstrictive agents in a topical ophthalmic preparation also reduces the plasma level of topically applied drugs. The other mechanism used to reduce systemic effects includes the use of a prodrug as a topical ophthalmic preparation that becomes active compound only at the site of action, for example dipivethrin for epinephrine and phenylephrine, oxazoline for phenylephrine. The other known mechanism includes the formulation of a preparation as an ointment. The film that is formed with the use of the ointment is thick, with a low transmission of light and an irregular anterior surface. This results in blurred vision and is therefore not very accepted. It also causes the eyelashes and eyelid boundaries to become sticky. This limits its use to a large extent and when used, it is restricted to an application before sleep. None of the methods described above alone or in combination with each other has been successful in eliminating the systemic effects of topical ophthalmic preparations. Most of the efforts are centered around the topical β-blockers to reduce their systemic effects, for example the reduction of the pulse rate. All the known methods have been able to reduce the reduction of the pulse rate, but none of them has managed to eliminate it completely. The aim of the present invention is to provide topical ophthalmic preparations without systemic effects without reducing the concentration of the active ingredient. A further objective of the present invention is to provide topical ophthalmic preparations that do not cause significant visual problems that limit their use during waking hours. A further objective of the present invention is to provide topical ophthalmic preparations that are equally effective after a long period of storage. A further object of the present invention is to provide topical ophthalmic preparations that do not require special storage conditions.

Thus, a method for making topical ophthalmic preparations without systemic side effects comprising the following steps is provided: 1. The liquid formulation of a selected drug is prepared so as to contain excipients, pH regulators and preservatives in distilled water. The pH of this solution is adjusted to provide a stable formulation for topical ophthalmic use. 2. In a separate vessel dissolve a polymer in a solvent, preferably water and stir well to form a gel. 3. The solution containing the drug selected as formulated in step 1 is gradually added to the gel as formed in step 2. 4. Volume is added by adding distilled water / solvent as necessary. 5. The pH is checked and adjusted as necessary to provide a stable formulation for instillation in the eye. The drug described can be any of the existing ophthalmic preparations or any other drug that can not be used as a topical preparation at a desired concentration for instillation in the eye. The drugs that are used most frequently and are known to have systemic effects include ß-blockers such as Timolol, Levobunolol, Metipranalol, etc.

Similarly, mydriatics such as phenylephrine, atropine, cyclopentolate, tropicamide have systemic effects and their use is restricted by them. Clonidine is an example of a drug that significantly decreases intraocular pressure but can not be used as a 0.1% or 0.2% concentration due to its systemic hypotensive effect. The polymer that will be used to prepare the topical formulation according to the present invention should form a gel when it is solubilized. For the purpose of the present invention, it is desirable to select a polymer with mucoadhesive properties. To avoid the discomfort and visual problems associated with the use of viscous solutions, it is desirable that the selected polymer demonstrate a pseudoplastic behavior in a formulation. The polymers which are used for the purposes of the present invention having the aforementioned properties are known and include polyacrylic acid, polyacrylic esters, polycarboxyl, polyvinyl acetate, acryptol, xanthan gum, guar gum, hydroxyethylcellulose, polyvinyl alcohol, PVP, carbomers , hydrogels prepared by combining various polymers, etc. The names of the above polymers exemplify the process and not the invention is not restricted thereto. For the purposes of avoiding the systemic defects of a formulation prepared in accordance with the present invention, it is necessary that it have a viscosity above 100,000 cps (one hundred thousand cps), preferably about 400,000 (four hundred thousand cps).

The final volume adjustment and amount of polymer that will be used should be designed considering these requirements. The amount of polymer in a final formulation to obtain the desired viscosity is variable, but it is already known. It varies with the polymer and also with the molecular weight of some polymers. Pharmaceutical preparations made in this way can be sterilized by known methods of sterilization, including the autoclave. If it is likely that the sterilization procedure will As a result of the destabilization of the drug, it can be prepared as a sterile product through the procedure.

EXAMPLES OF FORMULATIONS I.- Timolol A. Timolol 0.5% Timolol Maleate 0.72 gm. equivalent to 0.5 gm of timolol Benzylconium chloride 0.0107 gm Polyacrylic acid 1.5 gm to 2.5 gm (Carbopol 940) Sodium hydroxide to adjust pH 6.5 to 7.5 Water for CS injection to make 100 ml.

B. Timolol 0.25% Maleate of Timolol 0.36 gm. equivalent to 0.5 gm of timolol Benzyl Chloride 0.0107 gm Polyacrylic Acid 1.5 gm to 2.5 gm (Carbopol 940) Sodium hydroxide to adjust pH 6.5 to 7.5 Water for CS injection to make 100 ml.

II.- Timolol A. Timolol 0.5% Maleate of Timolol 0.72 gm. equivalent to 0.5 gm of timolol Benzylconium chloride 0.0107 gm Carbopol ETD 2001 1.5 gm at 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5 Water for CS injection to make 100 ml.

B. Timolol 0.25% Maleate of Timolol 0.36 gm. equivalent to 0.5 gm of Timolol Benzylconium chloride 0.0107 gm Carbopol ETD 2001 1.5 gm at 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5 Water for CS injection to make 100 ml.

III.- Timolol A. Timolol 0.5% Timolol Maleate 0.72 gm. equivalent to 0.5 gm of Timolol Benzylconium chloride 0.0107 gm Carbopol 981 1.5 gm at 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5 Water for CS injection to make 100 ml.

B. Timolol 0.25% Timolol Maleate 0.36 gm. equivalent to 0.5 gm of Timolol Benzylconium chloride 0.0107 gm Carbopol 981 1.5 gm at 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5 Water for CS injection to make 100 ml.

IV.- Timolol A. Timolol 0.5% Timolol Maleate 0.72 gm. equivalent to 0.5 gm of Timolol Benzyl Chloride 0.0107 gm Polycarbophil 1.5 gm to 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5 Water for CS injection to make 100 ml.

B. Timolol 0.25% Maleate of Timolol 0.36 gm. equivalent to 0.5 gm of Timolol Benzyl Chloride 0.0107 gm Polycarbophil 1.5 gm to 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5 Water for CS injection to make 100 ml.

V.- Clonidine A. Clonidine 0.1% Clonidine hydrochloride 0.1 gm Benzylconium chloride 0.0107 gm Polyacrylic acid 1.5 gm at 2.5 gm (carbopol 940) Sodium hydroxide to adjust pH 6.5 to 7.5 Water for CS injection to make 100 ml.

B. Clonidine 0.2% Clonidine hydrochloride 0.2 gm Benzylconium chloride 0.0107 gm Polyacrylic acid 1.5 gm at 2.5 gm (carbopol 940) Sodium hydroxide to adjust pH 6.5 to 7.5 Water for CS injection to make 100 ml.

VI.- Clonidine A. Clonidine 0.1% Clonidine hydrochloride 0.1 gm Benzylconium chloride 0.0107 gm Carbopol ETD 2001 1.5 gm to 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5 Water for CS injection to make 100 ml.

B. Clonidine 0.2% Clonidine hydrochloride 0.2 gm Benzylconium chloride 0.0107 gm Carbopol ETD 2001 1.5 gm at 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5 Water for CS injection to make 100 ml.

Vil.- Clonidine A. Clonidine 0.1% Clonidine hydrochloride 0.1 gm Benzylconium chloride 0.0107 gm Carbopol 981 1.5 gm to 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5 Water for CS injection to make 100 ml.

B. Clonidine 0.2% Clonidine hydrochloride 0.2 gm Benzylconium chloride 0.0107 gm Carbopol 981 1.5 gm at 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5 Water for CS injection to make 100 ml.

VIII.- Clonidine A. Clonidine 0.1% Clonidine hydrochloride 0.1 gm Benzylconium chloride 0.0107 gm Polycarbophil 1.5 gm at 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5 Water for CS injection to make 100 ml.

B. Clonidine 0.2% Clonidine hydrochloride 0.2 gm Benzylconium chloride 0.0107 gm Polycarbophil 1.5 gm at 2.5 gm Sodium hydroxide to adjust pH 6.5 to 7.5 Water for CS injection to make 100 ml.

IX.- Betaxolol Betaxolol 0.5% Betaxolol hydrochloride 0.56 gm equivalent to 0.5 gm betaxolol Benzyl Chloride 0.01 gm Dibasic sodium phosphate 0.05 gm Monobasic sodium phosphate 0.025 gm EDTA disodium 0.05 gm Sodium chloride 0.3 gm Propylene glycol 2.5 gm Carbopol ETD 2001 2.0 gm Water for CS injection to make 100 ml X.- Betaxolol Betaxolol 0.5% Betaxolol hydrochloride 0.56 gm equivalent to 0.5 gm betaxolol Benzylconium chloride 0.01 gm Dibasic sodium phosphate 0.05 gm Monobasic sodium phosphate 0.025 gm Disodium EDTA 0.05 gm Sodium chloride 0.3 gm Propylene glycol 2.5 gm Polyacrylic acid 2.0 gm (Carbopol 940) Water for CS injection to make 100 ml.

XI.- Betaxolol Betaxolol 0.5% Betaxolol hydrochloride 0.56 gm equivalent to 0.5 gm betaxolol Benzyl Chloride 0.01 gm Dibasic sodium phosphate 0.05 gm Monobasic sodium phosphate 0.025 gm Disodium EDTA 0.05 gm Sodium chloride 0.3 gm Propylene glycol 2.5 gm Carbopol 981 2.0 gm Water for CS injection to make 100 ml XII.- Betaxolol Betaxolol 0.5% Betaxolol hydrochloride 0.56 gm equivalent to 0.5 gm of betaxolol Benzyl Chloride 0.01 gm Dibasic sodium phosphate 0.05 gm Monobasic sodium phosphate 0.025 gm EDTA disodium 0.05 gm Sodium chloride 0.3 gm Propylene glycol 2.5 gm Polycarbophil 2.0 gm Water for CS injection to make 100 ml The stability and effectiveness of the pharmaceutical composition was evaluated elaborated in this way. The pharmaceutical composition prepared in this way was evaluated under different conditions of temperature and humidity test (under the ICH guidelines, 40 ° C / 75% relative humidity, 25 ° C / 60% relative humidity) for a period of time which extends up to 12 months. Samples of formulations prepared in such a way were used to study them. The topical ophthalmic preparation of 0.1% and 0.2% clonidine prepared in this way was evaluated in in vivo studies. Normal healthy volunteers (10) received instillation of the drug in the eyes. Subsequently, the intraocular pressure and blood pressure were taken every 2 hours. The control group (10) received a placebo .. Only decrease in intraocular pressure was observed in eyes receiving clonidine. It was found that they were in a range of 30% of initial intraocular pressure. It was found that the effect on intraocular pressure lasts from 8 to 10 hours. The effect on blood pressure in both groups, ie clonidine and placebo, was identical for systolic as well as diastolic blood pressure, and was not important. The peak reduction in systolic blood pressure was 4.4 mm Hg for placebo, 4.11 mm Hg for clonidine 0. 1% and 3.93 mm Hg for 0.2% clonidine. The peak reduction in diastolic blood reduction was 4.23 mm Hg for placebo, 4.49 mm Hg for 0.1% clonidine and 2.89 mm for Hg for 0.2% clonidine. Clonidine eye drops, even when used in concentrations of 0.05% to 0.06%, are associated with a reduction in systemic blood pressure. The topical ophthalmic preparation of 0.5% timolol maleate was made in accordance with the present invention and the systemic effects were evaluated and compared with Timolol and Timoptic XE eye drops. In normal healthy volunteers (10 in each group), various Timolol and placebo drug formulations were instilled in both eyes. The intraocular pressure and the pulse rate at rest were measured every two hours. The peak reduction in mean intraocular pressure was 25% with timolol drops, 27% with Timoptic XE and 40% with timolol made according to the present invention. The change in rest pulse rate was identical in placebo and timolol according to the present invention. It was 13.2% with timolol drops and 13.33% with Timoptic XE. In this manner, both preparations of clonidine as well as timolol were made in accordance with the present invention and were found to have no systemic effects. Efforts were made to discover the plasma concentration of the drug but none of the drugs showed plasma concentrations that could be detected. In this way, the present provides a procedure for making topical ophthalmic preparations without systemic effect.

The above examples of formulations are provided as a proof of processing this invention and should not be restricted to these alone. Any useful drug after instillation in the eye can be formulated in accordance with the present invention without systemic effects.

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Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A method for preparing a formulation of topical ophthalmic preparations without systemic effects comprising the following steps: i) making a gel using polymers with or without pH regulators, excipients and physiologically acceptable preservatives; ii) adding a liquid formulation of a drug in a gel prepared according to step (i) while stirring slowly; iii) adjust the pH and volume before final packing.

2. The process according to claim 1, wherein the polymer can be any polymer having a pseudoplastic behavior.

3. The process according to claims 1 and 2 wherein the polymer must have a mucoadhesive property.

4. The process according to claims 1 to 3, wherein the polymer can be, but is not restricted to Carbopol 940 (polyacrylic acid), Carbopol ETD 2001, Carbopol 981, Polycarbophil, polyvinyl alcohol, hydroxyethyl cellulose, polyacrylic esters, acripol, xanthan gum, guar gum, polyvinyl ester, carbomer, etc.

5. The polymer as claimed in claims 1 to 4 can be used alone or in combination with other polymers.

6. - The process according to claims 1 to 5, wherein the viscosity of the final formulation is more than 100,000 cps (one hundred thousand cps).

7. The process according to claims 1 to 6, wherein physiologically acceptable excipients, pH regulators and preservatives are used.

8. The process according to claims 1 to 7, wherein the liquid formulation of a drug can be in the form of an aqueous solution, suspension or emulsion.

9. The process according to claims 1 to 8, wherein the volume of the formulation is adjusted to obtain the desired concentration of a drug in a final formulation.

10. The method according to claims 1 to 9, and how it was substantially described in the example in the attached detailed description.