WO2003051351A1 - Ophthalmic rofecoxib suspension for the treatment of ocular pain and inflammation - Google Patents

Abstract

The invention relates to the ophthalmologic applications of a formulation of a Rofecoxib suspension (specific inhibitor of cyclooxygenase isoform 2 (COX-2)) which is used for the following: treatment of cystoid macular oedema in the retina (phakic and pseudophakic); prevention of transoperative miosis; definitive or adjuvant treatment of the following conditions, which are accompanied by intraocular inflammation: anterior uveitis, iritis, cyclitis, iridocyclitis, trabeculitis, intermediate uveitis, posterior uveitis (choroiditis, retinitis, chorioretinitis, retinochoroiditis), optic neuritis; definitive or adjuvant treatment of all known variants of glaucoma, both open angle and closed angle, primary and secondary; definitive or adjuvant treatment of allergic conjunctival disease, including stable allergic conjunctivitis, vernal conjunctivitis, atopic blepharoconjunctivitis, giant papillary conjunctivitis and contact conjunctivitis; treatment of chronic and acute non-specific, non-infectious conjunctiva, and symptomatic management of infectious viral, bacterial and mycotic conjunctiva using both protozoa and helminths; definitive or adjuvant treatment of external inflammatory diseases, including keratitis, scleritis (necrotising and non-necrotizing, anterior and/or posterior), episcleritis (nodular and diffuse), and symptomatic management of pingueculitis and pterygium; and post-operative treatment following any surgical procedure involving the eyeball and/or its appendages.

Description

ROFECOX1B OPHTHALMIC SUSPENSION FOR THE TREATMENT OF INFLAMMATION AND EYE PAIN

TECHNICAL FIELD OF THE INVENTION Rofecoxib, which is chemically described as 4- [4-

(Methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone, has been characterized as a potent and effective inhibitor of cyclooxygenase-2 (COX-2). The inhibition of this enzyme results in the cessation of the synthesis of prostaglandins mediating the inflammatory response in damaged tissue. In addition to regulating physiological processes, prostaglandins are important mediators of the inflammatory response in all body tissues.

The present invention relates to a suspension of Rofecoxib for topical ophthalmic use, useful in the treatment of pain and any ocular inflammatory disorder, including inflammation and post-surgical pain.

Thus, the clinical scope of the Rofecoxib suspension, object of the present invention, should include the treatment of pain and / or inflammation of the eye and its annexes, whether due to infectious or non-infectious processes, as well as subsequent to surgical procedures of the anterior segment, posterior segment or both, as well as the surgery of some of the ocular annexes (conjunctiva and extraocular muscles) and as a treatment or adjunct treatment of glaucoma. The dose is 1 drop every 4 to 24 hours depending on the severity of the case and during the time indicated by the doctor, with minimal restrictions for prolonged use given the low incidence of local or systemic reactions considered toxic or unsafe, as well as effects adverse effects attributable to the use of Rofecoxib.

The present invention relates to ophthalmological applications of a suspension formula of Rofecoxib (specific inhibitor of cyclooxygenase isoform 2 (COX-2)) useful in the treatment of cystic macular edema in the retina (aphaco and pseudophaco); prevention of intraoperative myosis; definitive or adjuvant treatment of the following conditions with infraocular inflammation: anterior uveitis, iritis, cyclitis, iridocyclitis, trabeculitis, intermediate uveitis, posterior uveitis (choroiditis, retinitis, chorioretinitis, retinocoroiditis), optic neuritis; as a definitive or adjuvant treatment of all known glaucoma variants, both open-angle and closed-angle, primary or secondary; definitive or adjuvant treatment of allergic conjunctival disease that includes stationary allergic conjunctivitis, spring conjunctivitis, atopic blepharoconjunctivitis, giant papillary conjunctivitis as well as contact conjunctivitis; symptomatic treatment of nonspecific acute and chronic non-infectious conjunctivitis, as well as symptomatic management of both viral, bacterial, fungal and conjunctivitis as well as protozoan and helminth infections, definitive or adjuvant treatment of external inflammatory diseases including keratitis, scleritis (necrotizing and non-infectious necrotizing, anterior and / or posterior), episcleritis (nodular and diffuse) and symptomatic management of pingueculitis and of the pterygium; as well as treatment of post-operative pain after any surgical procedure of the eyeball and / or its annexes.

BACKGROUND OF THE INVENTION Inflammation is an extremely complex process that generally occurs in response to different types of aggressions suffered by tissues. Several cell lines and a large number of substances that are called inflammation mediators participate in this process.

Pharmacological manipulation of the inflammatory phenomenon is based on the suppression of the release of proinflammatory mediators by the participating cells, or by inhibiting one or more of the key steps in their biosynthesis.

The most potent anti-inflammatory drugs known at the moment are spheroids, these compounds are capable of suppressing an inflammatory reaction by acting at both cellular and humoral levels. However, the use of synthetic spheroids also leads to the inhibition of substances that in many cases it would be desirable not to do, which is why research in clinical pharmacology has tried to be increasingly selective in the inhibition only of steps considered keys in the development of inflammation, trying to keep the physiological pathways intact so that the incidence of undesirable adverse effects is as low as possible. One of the most important mediator groups in the inflammatory response is prostaglandins. These are derived from the metabolism of arachidonic acid by the enzyme cyclooxygenase (COX). There are two isoforms of this enzyme, COX-1, which works in physiological situations in all tissues of the body, most obviously in kidney and stomach and COX-2, which participates in the production of prostaglandins in the framework of a response inflammatory in any tissue of the body. In most body tissues including the eye the most active metabolic pathway during the inflammatory response is that of cyclooxygenases.

Anti-inflammatory drugs are classified into two types, steroids and non-steroids (NSAIDs). Rofecoxib, reason for this patent belongs to the group of non-steroidal anti-inflammatory drugs (NSAIDs), which are specific inhibitors of COX-2 already synthesized.

US Patent 5,474,995, of Ducharme et al, refers to the use of phenyl heterocycles as COX-2 inhibitors, in said patent compositions as well as methods for the treatment of cyclooxygenase-2-mediated diseases are claimed, by oral administration of said heterocyclic phenyl compounds including Rofecoxib.

In WO 48583, formulations of 5-HT antagonists with COX-2 inhibitors are described, and particularly the use of Rofecoxib in the treatment of migraines is described, by the simultaneous administration of a therapeutically effective amount of a 5-agonist. -HT coordinated with a therapeutically effective amount of a non-spheroidal anti-inflammatory agent (NSAID), particularly a long-acting NSAID in the class of NSAIDs called oxygenase cycle inhibitors, such as Celecoxib, Rofecoxib, Meloxicam, Piroxicam, JTE-522, L -745,337 and NS398. However, both its use and its form of administration, differ totally from what is considered as the objective of the present invention, which is to provide an ophthalmic composition for topical use, in the treatment of pain and ocular inflammations, which contains Rofecoxib as active ingredient.

As is already known, Dexamethasone is the most used and effective steroidal anti-inflammatory, it acts among many other known mechanisms inhibiting the synthesis of COX-2 but its application produces many undesirable side effects, due to the diversity of biological effects that it has as a spheroid.

On the other hand, it has been observed that the use of NSAIDs that non-selectively inhibit the two COX isoforms, produces many undesirable effects (especially in the stomach, kidney and central nervous system) that appear after use, especially systemic of said NSAIDs.

As mentioned earlier, COX-2 is the soforma responsible for the production of prostaglandins in the framework of the inflammatory response, in addition to being one of those involved in the genesis of pain at the sites of inflammation. Traditional NSAIDs such as Acetyl Salicylic Acid, Indomethacin, Ibuprofen, Naproxen, Diclofenac, etc. they share the same mechanism of action with each other and this is because their effectiveness is based on the inhibition of the action of COX, both in its isoform 1 and in 2.

The ocular inflammation is similar to that which can occur in other body tissue and is characterized by its four cardinal signs: hyperemia, protein exudation, pain and cellular response. In the trials of inhibition of inflammation with Dexamethasone it has been shown that COX-2 is the COX isoform that actively participates in producing inflammation-mediating prostaglandins at the ocular level.

In addition to functioning as mediators of inflammation, prostaglandins perform physiological functions in the eye and this has been proven by identifying receptors for prostaglandins in virtually all eye tissues, such as: retina, ciliary body, pupillary sphincter, mesh trabecular, ciliary muscle, non pigmented epithelium of the ciliary body, corneal epithelium, ciliary processes, etc. The synthesis of prostaglandins in baseline physiological conditions seems to depend mostly, if not entirely on the activity of COX-1.

In the eye, after trauma, cataract surgery or laser iridotomy, it has been possible to identify elevated levels of prostaglandins in the aqueous humor. These prostaglandins at concentrations higher than baseline have effects on the ocular level, decrease in infraocular pressure, increased permeability of blood-brain barriers in addition to conjunctival hyperemia. It is worth mentioning that the inflammatory response, regardless of the stimulus that triggers it, can be harmful.

At present, the rule in the use of anti-inflammatory drugs at the ocular level is restricted to steroidal anti-inflammatories because of their ability to inhibit many crucial steps of the inflammatory response, including the synthesis of COX-2, unfortunately spheroid anti-inflammatories produce some undesirable effects. which can be serious, such as ocular hypertension, cataract, immunosuppression, susceptibility to infections, delayed healing time, etc.

The use of topical NSAIDs in Ophthalmology is increasingly common and a sample of this is the presence in this field of salts such as diclofenac, ketorolac, indomethacin and flurbiprofen. Its advantages and disadvantages in the field of ophthalmology are gradually becoming known. Unfortunately, the use of medications such as diclofenac has been associated with disorders of the corneal architecture which are believed to be due to the inhibition of the physiological action of COX-1 at this level.

Thus, having a non-steroidal anti-inflammatory agent that specifically inhibits the action of COX-2 represents an important advantage since the beneficial effect of the blockade of proinflammatory prostaglandin synthesis would be achieved, without altering homeostasis at the ocular level and without the adverse effects that are inherent in spheroid anti-inflammatory agents.

Rofecoxib is a non-steroidal anti-inflammatory agent with activity, analgesic, anti-inflammatory and antipyretic. It is highly specific to inhibit COX-2 activity and its effectiveness has been proven in the treatment of dysmenorrhea, osteoarthritis, rheumatoid arthritis and pain after dental surgery. Rofecoxib represents an advantage over other COX-2 inhibitors such as celecoxib since it lacks sulfamide groups that make its administration safe in people allergic to sulfa drugs. In addition to the absence of allergic reactions, Rofecoxib has other additional advantages, such as the time of the analgesic effect (24 hours against 5 hours of celecoxib) and the time of onset of action (30 minutes. Rofecoxib against 1 hour celecoxib).

It is therefore an object of the present invention to provide a topical composition for use in the treatment of inflammatory eye conditions and cyclooxygenase-2-mediated eye diseases without the concomitant inhibition of COX-1.

Another object of the invention is to provide a composition in the form of an aqueous suspension of Rofecoxib for use in the treatment of inflammatory ocular conditions and ocular conditions mediated by cyclooxygenase-2 without the concomitant inhibition of COX-1. A further object of the present invention is to provide a method for the manufacture of an aqueous suspension of Rofecoxib for topical use.

DETAILED DESCRIPTION OF THE INVENTION.

After analyzing the pH, osmolarity and conductivity characteristics that an ophthalmic application product must have, the test of different vehicles and buffer solutions to solubilize Rofecoxib and make its application tolerable began.

After several attempts it was decided to prepare Rofecoxib in suspension since it is not feasible to solubilize in water or other solvents commonly used in the area of ophthalmic pharmacology. For this, it was thought to use a suspension that in addition to the active ingredient, contained some other agents necessary for the formulation of a suspension for ophthalmic use, such as an isotonic agent to maintain the osmolarity of the suspension; at least one buffer or pH regulator; an antioxidant agent; a sequestering agent, a conservative agent, at least one suspension forming agent; a surfactant and water.

Preferred agents for the preparation of the composition are: Sodium chloride as an isotonizing agent to maintain the osmolarity of the suspension; Dibasic sodium phosphate anhydrous and sodium monobasic phosphate monohydrate as buffering or pH regulating agents;

Sodium Bisulfite as an antioxidant agent;

Disodium edetate dihydrate, as sequestering agent; - Benzalkonium chloride as a preservative agent;

Hydroxypropyl methylcellulose and / or polyvinyl alcohol as suspending agents; Y

Polysorbate 80 as a surfactant

The preparation of two suspensions of

Rofecoxib, both of topical ocular application (corneal and conjunctival surface).

PREPARATION EXAMPLE 1 Solution A

In 40 ml of purified water, at room temperature and with constant stirring it is dissolved in the following order: 0.50 g of sodium chloride, 0.058 g of anhydrous sodium dibasic phosphate, 0.013 g of monobasic sodium monobasic phosphate, 0.10 g of bisulfite of sodium, 0.010 g of disodium edetate dihydrate and 0.022 g of 50% benzalkonium chloride

Solution B.

In 15 ml of purified water and at a temperature between 80 and 90 ° C, 0.35 g of hydroxypropyl methylcellulose are dissolved with constant stirring. Once dissolved it is allowed to cool in an ice bath. Solution C.

In 35 ml of purified water and at room temperature 0.50 g of polysorbate 80 are integrated and then 0.10 g of Rofecoxib previously micronized in mortar are added.

With constant stirring, solution B is integrated with solution A and then solution C. The pH is adjusted to 7.2 with 2.5 N NaOH. Stirring is continued for an additional 30 minutes to ensure that it has been perfectly homogenized. It is added to 100 ml with purified USP grade water.

A composition according to formula 1 is obtained:

Formula 1

Ingredient Amount Concentration

Rofecoxib 0.10 g 0.1%

Sodium Chloride 0.50 g 0.5%

Anhydrous sodium dibasic phosphate 0.058 g 0.058%

Monobasic Sodium Phosphate Monohydrate 0.013 g 0.013%

Sodium Bisulfite 0.10 g 0.1%

Edetate disodium dihydrate 0.010 g 0.01%

50% Benzalkonium Chloride 0.022 g 0.011%

Hydroxypropyl methylcellulose 0.35 g 0.35%

Polysorbate 80 0.50 g 0.5%

Purified water c.b.p. 100 mi

With the above formula a homogeneous white suspension is obtained, free of foreign particles with an osmolarity of 213 mOsm / Kg. The pH is adjusted to 7.2 with 1.77 ml of 2.5 N NaOH. PREPARATION EXAMPLE 2 Solution A.

In 25 ml of purified water at a temperature between 70 and 80 ° C, 1.40 g of polyvinyl alcohol are dissolved with constant stirring. Once dissolved, it is allowed to cool to room temperature.

Solution B.

In 50 ml of purified water at room temperature and with constant stirring, they are dissolved in the following order: 0.60 g of sodium chloride, 0.10 g of disodium edetate dihydrate, 0.034 g of anhydrous sodium dibasic phosphate, 0.514 g of monobasic sodium phosphate monohydrate and 0.022 of 50% benzalkonium chloride.

Solution C. In 20 ml of purified water and at room temperature 0.50 g of polysorbate 80 are integrated and then 0.10 g of Rofecoxib previously micronized in mortar are added.

With constant stirring, solution A is integrated with solution B and then solution C. The pH is adjusted to 7.2 with 2.5 N NaOH. Stirring is continued for an additional 30 minutes to ensure that it has been perfectly homogenized. Formula 2

Ingredient Amount Concentration

Rofecoxib 0.10 g 0.1%

Sodium Chloride 0.60 g 0.6%

Anhydrous Sodium Dibasic Phosphate 0.034 g 0.034%

Monobasic Sodium Phosphate Monohydrate 0.514 g 0.514%

Disodium edetate dihydrate 0.10 g 0.1%

50% Benzalkonium Chloride 0.022 g 0.011%

Polyvinyl alcohol 1.40 g 1.4%

Polysorbate 80 0.50 g 0.5%

Purified water c.b.p. 100 mi

With the above formula a homogeneous white suspension is obtained, free of foreign particles with an osmolarity of 320 mOsm / Kg. The pH is adjusted to 7.2 with 6.4 ml of 2.5 N NaOH.

The applicant states that, in relation to the date, the best method to implement the claimed invention is that described in the description and examples above, however, it should be clear that the possible modifications in terms of ingredients or Form of preparation of the aqueous suspension motive of the present invention, fall within the spirit of the invention

Having described the invention as above, the contents of the following claims are claimed as property:

Claims

1. Ophthalmic anti-inflammatory suspension based on rofecoxib formulated as an aqueous suspension containing approximately 0.1% by weight of the active ingredient; from about 0.5 to about 0.6% by weight of an isotonizing agent; from about 0.071 to about 0.548% by weight of a pH regulating buffering agent; from 0 to about 0.10% by weight of an antioxidant agent; from 0.01 to 0.1% by weight of a sequestering agent; about 0.11% by weight of a preservative agent; from 0.35 to 1.4% by weight of a suspending agent; and about 0.5% by weight of a surfactant and sufficient amount of purified water to complete 100% of the suspension. 2. The suspension according to claim 1, characterized in that the active ingredient is Rofecoxib; the isotonizing agent is sodium chloride; the pH buffering agent is selected from anhydrous sodium dibasic phosphate and monobasic sodium monobasic phosphate and mixtures thereof; the antioxidant agent is sodium bisulfite; the sequestering agent is disodium edetate dihydrate; the preservative agent is benzalkonium chloride; The suspending agent is selected from hydroxypropyl methylcellulose, polyvinyl alcohol and mixtures thereof; and the surfactant is polysorbate 80. 3. The suspension according to claims 1 and 2, characterized in that it consists of 0.1% by weight of Rofecoxib; 0.5% in weight of sodium chloride; 0.058% by weight of sodium dibasic phosphate anhydrous; 0.013% by weight sodium monobasic phosphate monohydrate; 0.10% by weight of sodium bisulfite; 0.010% by weight of disodium edetate dihydrate; 0.01 1% by weight of benzalkonium chloride; 0.35%) by weight of hydroxypropyl methylcellulose; 0.5% by weight of polysorbate 80 and water purified in an amount sufficient to complete 100% by weight of the suspension. 4. The suspension according to claims 1 and 2, characterized in that it consists of 0.1% by weight of Rofecoxib; 0.6% in weight of sodium chloride; 0.034% by weight of anhydrous sodium dibasic phosphate; 0.514% by weight sodium monobasic phosphate monohydrate; 0.10%) by weight of disodium edetate dihydrate; 0.01 1% by weight of benzalkonium chloride; 1.4% by weight of polyvinyl alcohol; 0.5% in weight of polysorbate 80 and purified water in an amount sufficient to complete 100% by weight of the suspension. 5. A method for preparing a suspension of in accordance with claim 3, characterized in that it comprises the steps of: a) prepare a solution A, dissolving In 40 ml of purified water, to room temperature and with constant stirring, in the following order: 0.50 g of sodium chloride, 0.058 g of anhydrous sodium dibasic phosphate, 0.013 g of monobasic sodium phosphate monohydrate, 0.10 g of sodium bisulfite, 0.010 g of disodium edetate dihydrate and 0.022 g of benzalkonium chloride; b) prepare a solution B, dissolving 0.35 g of hydroxypropyl methylcellulose in 15 ml of purified water with constant stirring and at a temperature between 80 and 90 ° C, and once dissolved, allow to cool in an ice bath; c) prepare a solution C by mixing 0.050 g of polysorbate 80 in 35 ml of purified water, at room temperature and then add 0.10 g of Rofecoxib previously micronized in mortar; d) with constant stirring, solution B is integrated with solution A and then solution C; e) The pH is adjusted to 7.2 with 2.5 N NaOH; f) Stirring is continued for 30 more minutes until a complete homogenization; g) is added to 100 ml with purified USP grade water. 6. A method for preparing a suspension of in accordance with claim 4, characterized in that it comprises the steps of: a) prepare a solution A, dissolving 1.40 g of polyvinyl alcohol in 25 ml of purified water, at a temperature between 70 and 80 ° C and with constant stirring; b) allow solution A to cool to room temperature; c) prepare a solution B, dissolving in 50 ml of purified water, at room temperature, in the following order: 0.60 g of sodium chloride, 0.10 g of disodium edetate dihydrate; 0.034 g of anhydrous sodium dibasic phosphate, 0.514 g of monobasic sodium monobasic phosphate, and 0.022 g of benzalkonium chloride; d) Prepare a solution C by mixing 0.50 g of polysorbate 80 in 20 ml of purified water, at room temperature and then add 0.10 g of Rofecoxib previously micronized in mortar; e) with constant stirring, solution A is integrated with solution B and then solution C; f) The pH is adjusted to 7.2 with 2.5 N NaOH; g) Stirring is continued for an additional 30 minutes to ensure complete homogenization; h) it is added to 100 ml with purified USP grade water. 7. The use of the compound 4- [4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone, in the elaboration of an ophthalmic suspension of topical application, for the treatment of cystic macular edema in the retina ( aphacus and pseudophak); prevention of intraoperative myosis; definitive or adjuvant treatment of the following conditions that present with intraocular inflammation: anterior uveitis, iritis, cyclitis, iridocyclitis, trabeculitis, intermediate uveitis, posterior uveitis (choroiditis, retinitis, chorioretinitis, retinocoroiditis), optic neuritis; as a definitive or adjuvant treatment of all known glaucoma variants, both open-angle and primary or secondary closed-angle; definitive or adjuvant treatment of allergic conjunctival disease that includes stationary allergic conjunctivitis, spring conjunctivitis, atopic blepharoconjunctivitis, giant papillary conjunctivitis as well as contact conjunctivitis; treatment of nonspecific acute and chronic non-infectious conjunctivitis, as well as symptomatic management of both viral, bacterial, fungal and conjunctivitis as well as protozoan and helminth infections, definitive or adjuvant treatment of external inflammatory diseases including keratitis, scleritis (necrotizing and non-necrotizing , anterior and / or posterior), episcleritis (nodular and diffuse) and symptomatic management of pingueculitis and pterygium; as well as post-operative treatment after any surgical procedure of the eyeball and / or its annexes.