Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-01-09
2003-10-21
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06635654
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition for relieving ocular allergies. More particularly, the present invention relates to ophthalmic compositions comprising ethyl 4-(8-chloro-5,6-dihydro-11-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate, otherwise known as loratadine.
BACKGROUND OF THE INVENTION
Allergic conjunctivitis is an ocular allergy characterized by redness, itching and swelling of the eyes. Allergic conjunctivitis is a similar reaction to allergies of the sinuses, nose, or lungs, in that it is characterized by the release of histamines from contact with allergens such as pollen, pet hair or dander, or dust. H
1
histamine receptor antagonists are used widely in the systemic treatment of allergies, and have recently been shown to be effective when used topically on the eye. (Doughty, The Pharmaceutical Journal, 268, 367-370, Mar. 16, 2002). Two H
1
histamine receptors, emedastine and levocabastine, are currently available in eye drop formulations for treatment of allergic conjunctivitis and related conditions. Another H
1
histamine receptor, Loratadine, sold by Schering-Plough under the brand name Claritin®, is used widely in the oral dosages forms of tablets and syrup for the systemic treatment of allergies. However, no topical ophthalmic product containing loratadine is currently available due to its insolubility and instability in aqueous solutions. The low water solubility of loratadine results in poor delivery of the drug topically, resulting in limited ocular activity. For water insoluble active agents such as loratadine, ophthalmic formulations typically comprise a suspension or a solution containing solubilizers such as surfactants, cosolvents and complexing agents to enhance the solubility of the compound.
The manufacturer of Claritin®, Schering-Plough, has experimentally prepared an ophthalmic formulation of loratadine using Tween-80®, a surfactant, as a solubilizer. (WO9715307) This formulation required at least 2.3% Tween-80® to solubilize 0.05% loratadine in solution. However, the relatively high concentration of surfactant increases eye irritation, which is counterproductive in a product intended to reduce ocular discomfort and irritation. Claritin® syrup is formulated at pH 2.5-3.1, at which pH loratadine is more soluble. However, this acidic pH is not suitable for ophthalmic liquids. In addition to being less soluble at the desirable ophthalmic pH range of 6-8, loratadine is also chemically unstable at this pH range. The cleavage of the ester linkage leads to the formation of the corresponding acid and ethyl alcohol much more readily in neutral or basic aqueous solutions.
Schering-Plough also formulated eye drops containing loratadine metabolites or derivatives that had some improved properties (WO 9848803). However, despite these efforts, no topical ophthalmic product containing loratadine as the active ingredient is currently available, although the patent for loratadine (U.S. Pat. No. 4,282,233) issued in 1981. Given the importance of loratadine in treating systemic allergies, one skilled in the art would expect that a topical ophthalmic product containing loratadine would also make a significant contribution to the treatment of ocular allergies. The lack of an available topical ophthalmic product containing loratadine therefore shows that difficulties in formulating loratadine have not been overcome, and that a need still exists to formulate the compound into effective topical ophthalmic product.
SUMMARY OF THE INVENTION
DETAILED DESCRIPTION OF THE INVENTION
Unexpectedly, we have found that the difficulties experienced by others in formulating loratadine are overcome by the present invention, which delivers loratadine in an aqueous ophthalmic emulsion composition. In the present invention, the loratadine is dissolved in the oil phase of an oil-in-water emulsion system. This confers three main advantages to this invention over previous topical ophthalmic loratadine products. These advantages are higher drug absorption, minimal decomposition of loratadine by hydrolysis, and lubrication and improved comfort to the eye.
We have found that the solubility of loratadine in vegetable oils is great enough to formulate an effective amount of the agent into an ophthalmic emulsion formulation (see Table 1) to be used for allergic conjunctivitis and
TABLE 1
Solubility of Loratadine in Vegetable Oils
Oil
Solubility (mg/mL)
Castor Oil
85
Corn Oil
25
Miglyol 810N
15
Peanut Oil
15
Sesame Oil
15
Soybean Oil
15
Polysorbate 80 (Nonionic surfactant)
25
related conditions. The solubility of loratadine in vegetable oils is comparable to or better than its solubility in a surfactant. In particular, castor oil dissolves more than three times as much loratadine as Polysorbate 80, a commonly used surfactant in ophthalmic solutions. By contrast to the irritation to the eye caused by the surfactant alone, it has been shown in commonly assigned U.S. Pat. No. 5,668,133, incorporated herein by reference, that an emulsion actually provides lubrication and improved comfort to the eye. It has also been shown, in European Patent No. 1044678, that an emulsion of vegetable oil and water delivers a higher concentration of the drug cyclosporin A to the conjunctiva of a rabbit eye than the individual oil. Additionally, dissolving the hydrophobic loratadine in the oil phase of an emulsion significantly reduces the contact of the hydrophobic loratadine with water, enabling a formulation to be prepared in the ophthalmically useful pH range of 6-8. This is in contrast with aqueous solutions where the loratadine is readily hydrolyzed in the desired ophthalmic pH range, greatly reducing the activity and the shelf life of the product.
The present invention is directed to an ophthalmic formulation which comprises a therapeutically effective amount of loratadine, a fatty acid ester, and a surfactant. In the preferred embodiment of this invention, the fatty acid ester is a vegetable oil. A fatty acid ester has the meaning commonly understood in the art, being an ester formed between an alcohol and a fatty acid. While not intending to limit the scope of this invention, some examples of readily available fatty acid esters are triglyceride esters commonly known as vegetable oils, mono and diglyceride esters of fatty acids, and fatty acid methyl esters. The fatty acid ester may be a mixture of several chemical compounds or an essentially pure compound. Preferably, the fatty acid ester is a vegetable oil. Examples of vegetable oils include castor oil, sesame oil, soybean oil, cottonseed oil, olive oil, peanut oil, safflower oil, sunflower oil, palm oil, palm kernel oil, canola oil, and Miglyol oil. Most preferably, the fatty acid ester is castor oil.
The determination of a therapeutically effective amount of loratadine used in this formulation can be readily determined by one skilled in the art. Preferably, the concentration of loratadine is between about 0.01% and about 1.5%. More preferably, the concentration of loratadine is about 0.0125% or about 0.0625%.
The term surfactant used in this invention has the meaning commonly understood in the art. Surfactants are used to both help facilitate the formation of the emulsion and improve its stability. Anionic, cationic, amphoteric, zwitterionic, and nonionic surfactants may all be used in this invention. Preferably, a nonionic surfactant is used in this invention. While not intending to limit the scope of the invention, some examples of useful nonionic surfactants are polysorbates, poloxamers, alcohol ethoxylates, ethylene glycol-propylene glycol block copolymers, fatty acid amides, alkylphenol ethoxylates, and phospholipids. Most preferably, Polysorbate 80 is used as the surfactant. Polysorbate 80 is a mixture of oleate esters of sorbitol and sorbitol anhydrides, consisting predominantly of the monoester, condensed with approximately 20 moles of ethylene oxide. It conforms generally to the formula:
where w+x+y+z has an average value of 20. Polysorba
Chang Chin-Ming
Chang James N.
Farnes Eldon Q.
Olejnik Orest
Allergan Inc.
Baran Robert J.
Henley III Raymond
Johnson Brent A.
Voet Martin A.
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