SUSPENSION FORMULATIONS OF NEPAFENACAND OTHER OPHTHALMIC DRUGS FORTOPICALTREATMENT OF OPHTHALMIC

DISORDERS

BACKGROUND OF THE INVENTION

This invention relates to pharmaceutical compositions for treating ophthalmic disorders. In particular, the present invention relates to topically administrable suspension formulations of nepafenac and other ophthalmic drugs.

Nepafenac is also known as 2-amino-3-benzoylphenylacetamide. The topical use of nepafenac and other amide and ester derivatives of 3- benzoylphenylacetic acid to treat ophthalmic inflammation and pain is disclosed in U.S. Patent No. 5,475,034. According to the '034 patent, compositions containing the 3-benzoylphenylacetic acid derivatives can be formulated into a variety of topically administrable ophthalmic compositions, such as solutions, suspensions, gels, or ointments. The compositions optionally contain preservatives, such as benzalkonium chloride, and thickening agents, such as carbomers, hydroxyethylcellulose or polyvinyl alcohol. The '034 patent, however, does not disclose any formulations of nepafenac or other ophthalmic drugs containing a combination of a poloxamer or meroxapol surfactant and propylene glycol.

Attempts have been made to increase the corneal flux of topically administrable drugs for some time. Many glycols, including propylene glycol are known "penetration enhancers." See, for example, U.S. Patent No. 6,765,001. This patent discloses formulations of corticosteroids for topical application to the skin. The reference formulations contain propylene glycol as a skin penetration enhancer.

Corneal penetration enhancers for topically administrable ophthalmic drugs have also been sought. See, for example, U.S. Patent No. 5,369,095, which discloses the use of dodecyl maltoside as a corneal penetration enhancer. See also, U.S Patent Nos. 6,630,135 and 6,835,392, which in addition to dodecyl maltoside disclose other penetration enhancers for mucosal tissues. These penetration enhancers are intended to increase the corneal penetration of the topically administered drug.

Poloxamer, meroxapol, and poloxamine surfactants are known. They are used in contact lens care solutions and therapeutic ophthalmic compositions including anti-inflammatory compositions. See, for example, U.S. Patent Nos. 6,037,328; 6,544,953; 6,486,215; and 5,631 ,005.

While poloxamer and meroxapol surfactants (including those commercially available as Pluronic ^® and Pluronic ^® R surfactants) and propylene glycol are separately known to be useful in topically administrable ophthalmic compositions, they have not been used in combination with nepafenac and their combined effect on the corneal penetration of sparingly water-soluble ophthalmic drugs has not been disclosed.

SUMMARY OF THE INVENTION

The compositions of the present invention are aqueous suspension compositions of nepafenac or other ophthalmic drugs that are sparingly soluble in water. The compositions of the present invention comprise a combination of a poloxamer or meroxapol surfactant and a glycol tonicity-adjusting agent. Unlike conventional suspension compositions, the compositions of the present invention do not contain a water-soluble polymeric suspending or viscosifying agent such as a carbopol.

Suspension compositions of sparingly-soluble ophthalmic drugs containing a combination of a poloxamer or meroxapol surfactant and

propylene glycol show significantly greater corneal penetration of such drugs than similar compositions that do not contain such a combination of excipients.

DETAILED DESCRIPTION OF THE INVENTION

Unless indicated otherwise, all ingredient concentrations are presented in units of % weight/volume (% w/v).

As used herein, "sparingly soluble in water" or "sparingly-soluble ophthalmic drug" means a drug that has a solubility limit in water at 25 ⁰ C in the range of 0.001 - 0.05 %.

The aqueous compositions of the present invention contain a pharmaceutically effective amount of nepafenac or other sparingly soluble ophthalmic drug. Nepafenac is a known nonsteroidal anti-inflammatory compound. It can be made by known methods. See, for example, U.S. Patent Nos. 5,475,034 and 4,313,949, the entire contents of which are incorporated by reference. The nepafenac compositions of the present invention will generally contain 0.01 - 0.3 % (w/v) nepafenac, preferably 0.03 - 0.1 % (w/v) nepafenac.

Particularly with the enhanced corneal penetration of the compositions of the present invention, nepafenac can be used to treat ophthalmic disorders not only of the ocular surface but also of the back of the eye. For example, the topically administrable nepafenac compositions of the present invention may be used to treat ocular surface pain, uveitis, scleritis, episcleritis, keratitis, surgically-induced inflammation, endophthalmitis, iritis, atrophic macular degeneration, retinitis pigmentosa, iatrogenic retinopathy, retinal tears and holes, cystoid macular edema, diabetic macular edema, diabetic retinopathy, sickle cell retinopathy, retinal vein and artery occlusion, optic neuropathy, exudative macular degeneration, neovascular glaucoma, corneal neovascularization, cyclitis, sickle cell retinopathy, and pterygium.

The compositions may contain a sparingly soluble drug compound other than nepafenac. For example, the compositions of the present invention may comprise a sparingly soluble carbonic anhydrase inhibitor, such as brinzolamide; an antifungal agent, such as natamycin; a phosphodiesterase IV inhibitor (PDE-IV or PDE-4) inhibitor, such as roflumilast; a receptor tyrosine kinase inhibitor; a steroid, such as fluorometholone, hydrocortisone, dexamethasone, prednisolone, loteprednol, or medrysone; or a nonsteroidal anti-inflammatory agent that is sparingly soluble in water. All of the foregoing are known compounds and can be made by known methods.

In addition to at least one sparingly soluble ophthalmic drug, the compositions of the present invention comprise a poloxamer nonionic surfactant of formula I or a meroxapol nonionic surfactant of formula II:

CH3

I HO-(CH ₂ CH ₂ O) _X -(CH ₂ CHOV(CH ₂ CH ₂ O) _X -H (I)

wherein x is 2 - 125 and y is 5 - 235, provided that 2x is 10 - 80% of 2x + y, and further provided that the number average molecular weight of the poloxamer nonionic surfactant is 1 ,100 - 14,600;

CH ₃ CH ₃ I I

HO-(CH ₂ CHO) _a -(CH ₂ CH ₂ O) _b -(CH ₂ CHO) _a -H (II)

wherein a is 4 - 60 and b is 4 - 120, provided that b is 10 - 80% of 2a + b, and further provided that the number average molecular weight of the meroxapol nonionic surfactant is 1 ,900 - 7,000.

Poloxamer and meroxapol nonionic surfactants of formulas I and Il above are poly(oxyethylene) and poly(oxypropylene) block copolymers. They are known and are commercially available as Pluronic ^® and Pluronic ^® R

surfactants from BASF Corporation, Performance Products, Florham Park, New Jersey. Poloxamer and meroxapol are the names adopted for such surfactants by The CTFA International Cosmetic Ingredient Dictionary.

The most preferred poloxamer surfactant is a poloxamer surfactant where x is about 23, y is about 67, and the number average molecular weight of the poloxamer surfactant is about 5,900. This poloxamer surfactant is commercially available as Pluronic ^® P104.

The compositions of the present invention comprise a total of 0.001 -

0.15 % of a poloxamer surfactant of formula I or a meroxapol surfactant of formula II. Included within the scope of this invention are mixtures of poloxamer surfactants, mixtures of meroxapol surfactants, and mixtures of both poloxamer and meroxapol surfactants. Higher total concentrations of the poloxamer or meroxapol surfactants can reduce the availability of the ophthalmic drug. Preferably, the compositions of the present invention comprise a total of 0.005 - 0.12 % poloxamer or meroxapol surfactant. Most preferably, the compositions of the present invention comprise a total of 0.1 % poloxamer or meroxapol surfactant.

In addition to the ophthalmic drug and the poloxamer or meroxapol surfactant, the compositions of the present invention comprise a glycol tonicity- adjusting agent in a total amount of at least 1 % but less than 4.0 %. The glycol tonicity-adjusting agent is selected from the group consisting of: propylene glycol; glycerol; dipropylene glycol; diethylene glycol; triethylene glycol; 1 ,3- butylene glycol; 2,3-butylene glycol; 3-methyl-1 ,3-butylene glycol; diglycerol; erythritol; pentaerythritol; and neopentyl glycol. Included within the scope of this invention are mixtures of glycol tonicity-adjusting agents. Too much glycol tonicity-adjusting agent results in compositions that are uncomfortable when administered because their osmolalities are too high. The compositions of the present invention have osmolalities from 150 - 500 mOsm/Kg. Preferably, the total amount of glycol tonicity-adjusting agent is 2.0 - 3.5 %. Most preferably, the total amount of glycol tonicity-adjusting agent in the compositions of the

present invention is 3.0 %. Tonicty-adjusting agents of this type are known and many are commercially available. Preferred glycol tonicity-adjusting agents are propylene glycol, glycerol, and mixtures thereof.

The compositions of the present invention optionally contain metal chloride salts (such as sodium chloride) or non-ionic tonicity adjusting agents (such as mannitol) as additional tonicity-adjusting agents.

The aqueous compositions of the present invention optionally comprise one or more excipients selected from the group consisting of buffering agents, pH-adjusting agents, chelating agents, and preservatives. Buffering agents include phosphate buffers, such as disodium phosphate and monosodium phosphate; borate buffers, such as boric acid and sodium borate; and citrate buffers. The buffering agent is chosen based upon the target pH for the composition, which generally ranges from pH 6.5 - 8.5. The target pH for the composition depends upon the chosen ophthalmic drug. In the case of nepafenac, the desired pH is 7.0 - 8.5, preferably 7.5 - 8.0, and most preferably 7.8. Ophthalmically acceptable pH adjusting agents are known and include, but are not limited to, hydrochloric acid (HCI) and sodium hydroxide (NaOH).

Suitable chelating agents include edetate disodium; edetate trisodium; edetate tetrasodium; and diethyleneamine pentaacetate. Most preferred is edetate disodium. If included, the chelating agent will typically be present in an amount from 0.001 - 0.1 %. In the case of edetate disodium, the chelating agent is preferably present at a concentration of 0.01 %.

Many ophthalmically acceptable preservatives are known and include, but are not limited to, benzalkonium halides and polyquaternium-1. Most preferred preservatives are benzalkonium chloride ("BAC") and polyquaternium-

1. In the case of benzalkonium chloride, the preservative is preferably present in an amount from 0.001 - 0.01 %, and most preferably 0.005 %.

The compositions of the present invention optionally comprise a sulfite salt. Examples of sulfite salts include sodium sulfite; potassium sulfite; magnesium sulfite; calcium sulfite; sodium bisulfite; potassium bisulfite; magnesium bisulfite; calcium bisulfite; sodium metabisulfite; potassium metabisulfite; and calcium metabisulfite. If included, the sulfite salt will typically be present in an amount from 0.01 - 1 %.

The compositions of the present invention may be prepared by conventional methods of preparing aqueous pharmaceutical suspension compositions, including sizing the drug using known sizing techniques, such as ball-milling. For example, a slurry containing the sparingly soluble drug, a surfactant and sizing beads is tumbled for a time sufficient to obtain drug of desired particle sizes. The sizing beads are then separated from the slurry and the slurry is added to the remaining aqueous ingredients. Preferably, however, the compositions of the present invention are made in a specific manner. According to the preferred method, the drug is first added to a mixture of the poloxamer or meroxapol surfactant and propylene glycol. Preferably, the mixture is warmed (for example, to 50 ⁰ C) while the drug is stirred with the mixture to speed up and enhance the dissolution of the drug. After maximizing the dissolution of the drug, the remaining aqueous ingredients (e.g., water, buffering agent, pH-adjusting agent, chelating agent, preservative) are added with vigorous stirring to the dissolved drug. The order of addition to form a mixture of the remaining aqueous ingredients is not critical. This preferred method of preparing the suspension compositions produces a fine suspension of the drug without the need of ball milling to size the drug. In general, target particle sizes for the suspension compositions of the present invention range from 0.1 - 100 μm, and preferably range from 0.5 - 50 μm.

The following examples are intended to illustrate, but not limit, the present invention.

Example 1

The formulation shown below is representative of the compositions of the present invention.

Example 2

The formulation shown below is representative of the compositions of the present invention.

Example 3

The formulations shown in Table 1 were prepared and evaluated in an ex vivo corneal permeation model. The corneal penetration results are also shown in Table 1. Formulations A - C were prepared by ball-milling nepafenac in a slurry containing tyloxapol and/or polysorbate 80 for approximately 18 hours. Formulation AA was prepared by dissolving the nepafenac in a mixture of Pluronic ^® P-104 and propylene glycol, then adding the remaining ingredients. The ex vivo corneal penetration rabbit model is briefly described below:

Rabbits were sacrificed by first anaesthetizing with ketamine (30mg/Kg) and xylazine (6mg/Kg) followed by an injection of an overdose of SLEEPAWAY® (sodium pentobarbital, 1 ml of a 26% solution) into the marginal ear vein. The intact eyes, along with the lids and conjunctival sacs were then enucleated and immediately stored in about 70 ml of fresh BSS PLUS® irrigation solution saturated with O ₂ ICO ₂ (95:5). Within one hour, the enucleated rabbit eyes were mounted in the modified perfusion chambers as described by Schoenwald, et al., "Corneal Penetration Behavior of ^-Blocking Agents I: Physiochemical Factors," Journal of Pharmaceutical Sciences, 72(11) ( November 1983). After mounting in the chambers, 7.5 mis of BSS PLUS® was placed in the receiving side of the chamber with stirring and bubbling and immediately capped to prevent contamination. Then, 7 mis of each test formulation was dosed on the donor side of the chamber for 5 minutes with stirring and bubbling. Afterwards, the donor chamber was emptied with suction and filled with 7mls of BSS PLUS® for approximately 15 seconds. This suction and rinsing with BSS PLUS® was repeated 7 times, and on the 8th fill, the BSS PLUS® was left in the donor chamber. Samples were withdrawn from the receiving chamber every 30 minutes over a five hour period, and the levels of test drug were determined using HPLC. The rate of drug accumulation in the receiver compartment and 5 hour accumulations were then calculated from graphs of the data.

The solubility of the test drug was determined using HPLC analysis after filtering the test formulation through a 0.25 micron screen.

TABLE 1

Formulation B is the same as Formulation A with the known penetration enhancer dodecyl maltoside ("DDM") added. The results show that the penetration of B is slightly inferior to A, showing that DDM is not an effective penetration enhancer in the tested formulation.

Formulation C is a viscous formulation containing polyethylene glycol (5%). The solubility of nepafenac is almost doubled compared to Formulation A, but the penetration results are inferior to A.

Formulation AA is a formulation according to the present invention. It contains a combination of a poloxamer surfactant and propylene glycol. The penetration results are superior to A.

Example 4

The formulations shown in Table 2 were prepared and evaluated in the ex vivo corneal penetration model described above. The corneal penetration results are also shown in Table 2. All Formulations were prepared in the same manner as Formulation AA.

TABLE 2

Each of the formulations shown in Table 2 contains 3 % propylene glycol. The amount of poloxamer surfactant (Pluronic ^® P-104) is varied from 0 % (Formulation D) to 3 % (Formulation II). The results show that over this range, the solubility of nepafenac increases from 15 ppm to 70 ppm. The drug penetration data, however, show that corneal drug penetration increases with increasing poloxamer concentration up to a poloxamer concentration of 0.1 %, then corneal penetration decreases with increasing poloxamer concentration.

Example 5

The formulations shown in Table 3 were prepared and evaluated in the ex vivo corneal penetration model described above. The corneal penetration results are also shown in Table 3. Formulation E was prepared in the same manner as Formulation A. Formulation JJ was prepared in the same manner as Formulation AA.

TABLE 3

The penetration results shown in Table 3 demonstrate that the compositions of the present invention possess superior corneal penetration when the drug is not nepafenac but is another sparingly soluble ophthalmic drug. In this case, the sparingly soluble ophthalmic drug is the carbonic anhydrase inhibitor known as brinzolamide.

Example 6

The formulations shown in Table 4 were prepared and evaluated in the ex vivo corneal penetration model described above. The corneal penetration results are also shown in Table 4. Formulation F was prepared in the same

manner as Formulation A. Formulation KK was prepared in the same manner as Formulation AA.

TABLE 4

The penetration results shown in Table 4 demonstrate that the compositions of the present invention possess superior corneal penetration when the drug is not nepafenac but is another sparingly soluble ophthalmic drug. In this case, the sparingly soluble ophthalmic drug is dexamethasone.

The invention has been described by reference to certain preferred embodiments; however, it should be understood that it may be embodied in other specific forms or variations thereof without departing from its spirit or essential characteristics. The embodiments described above are therefore considered to be illustrative in all respects and not restrictive, the scope of the

invention being indicated by the appended claims rather than by the foregoing description.