Title:  Pheniramine-containing compositions and method for treating allergic responses

United States Patent:  6,274,626

Assignee:  Bausch & Lomb Incorporated (Rochester, NY)

Filed:  December 22, 1998

This invention relates to compositions comprising pheniramine. In particular, it has been found that pheniramine in combination with n effective amount of a povidone provides improved comfort and reduces the symptoms of dryness compared to compositions with pheniramine alone.

DETAILED DESCRIPTION OF THE INVENTION

Pheniramine is a well-established anti-histaminic compound. Pheniramine, the free base and its ophthalmically acceptable salts, is a compound of the alkylamine type that is commonly used as an antihistamine for local and generalized allergic reactions.

In the preferred form of the maleate salt, it is soluble in water and its chemical name is N, N-dimethyl-gamma-phenyl-2-pyridine-propanamine, butenedoic acid or 1-phenyl-1-(2-pyridyl)-3-dimethylaminopropane maleate. Pheniramine may be prepared in the manner described by Sperber et al. in U.S. Pat. No. 2,567,245 and 2,676,964. Alternately, pheniramine is also commercially available from Loftus Bryan Chemicals Ltd., Rathdrum Co. (Wicklow, Ireland) or Kongo Chemical Co. (Toyama, Japan). Derivatives of pheniramine include, for example, the halogenated derivatives chloropheniramine and bromopheniramine.

According to the present invention, pheniramine (or derivatives thereof), in the amount of 0.10 to 0.50 weight percent, preferably about 0.40 to 0.45 weight percent, in combination with an effective amount of povidone effectively treats the symptoms of both allergy and dryness. The present invention may remove redness, for example, over a period of 5 to 10 minutes. Such compositions have been found to alleviate dryness in combination with the so-called stinging and burning associated with the allergic response.

In addition to pheniramine maleate, other substantially non-toxic or non-irritating pheniramine salts that may be topically administered according to this invention include those derived from organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric. methanesulfonic, acetic, citric, succinic, citric, lactic, tartaric, benzoic acids and the like.

Povidone is a Category I demulcent in the OTC Ophthahnic Drug Products Monograph of the USFDA. Polyvinylpyrrolidone (PVP) is a linear homopolymer or copolymer comprising at least about 80%, preferably at least about 90% of repeat units derived from 1-vinyl-2-pyrrolidone monomers, the polymer more preferably comprising at least about 95% or essentially all of such repeat units, the remainder selected from polymerization-compatible monomers, preferably neutral monomers, such as alkenes or acrylates. Other synonyms for PVP include povidone, polyvidone, 1-vinyl-2-pyrolidinone, and 1-ethenyl-2-pyrolionone (CAS registry number 9003-39-8). PVP has a weight average molecular weight of about 10,000 to 250,000, preferably 30,000 to 100,000. Such materials are sold by various companies, including ISP Technologies, Inc. under the trademark PLASDONE.TM. K-29/32, BASF under the trademark KOLLIDON.TM. for USP grade PVP, for example KOLLIDON.TM. K-30 or K-90 (BASF Corporation, NV Division, 3000 Continental, Mount Olive, N.J. 07628-1234, USA). It is to be understood, however, that the invention is not limited to any specific PVP and that any equivalent PVP of acceptable purity for ophthalmic use, preferably pharmaceutical grade, may be used.

PVP also acts as a water-soluble viscosity builder. Optionally, additional viscosity builders or demulcents may be employed in the present composition, for example, cellulose derivatives, glycerin, and the like. Such viscosity builders or demulcents may be employed in a total amount ranging from about 0.01 to about 5.0 weight percent or less. Suitably, the viscosity of the final formulation is 10 cps to 50 cps.

In the present compositions, povidone is suitably present in a total amount of 0.1 to 5.0% by weight, preferably 0.5 to 2.0 percent by weight of the composition.

The solutions of this invention will also contain water and one or more other components that are commonly present in ophthalmic solutions. In addition to the active ingredients described above, solutions according to the present invention may contain buffers, various surfactants, stabilizers, isotonic agents and the like which aid in making ophthalmic compositions more comfortable to the user. The aqueous solutions of the present invention are typically adjusted with tonicity agents to approximate the osmotic pressure of normal lachrymal fluids which is equivalent to a 0.9% solution of sodium chloride or a 2.5% solution of glycerol. The solutions are made substantially isotonic with physiological saline used alone or in combination, otherwise if simply blended with sterile water and made hypotonic or made hypertonic the lenses will lose their desirable optical parameters. Correspondingly, excess salt or other tonicity agent may result in the formation of a hypertonic solution that will cause stinging and eye irritation. An osmolality of about 225 to 400 mOsm/kg is preferred, more preferably 280 to 320 mOsm/kg.

The pH of the present solutions should be maintained within the range of 5.0 to 8.0, more preferably about 6.0 to 8.0, most preferably about 6.5 to 7.8. Suitable buffers may be added, such as boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na₂ HPO₄, NaH₂ PO₄ and KH₂ PO₄) and mixtures thereof. Borate buffers are preferred. Generally, buffers will be used in amounts ranging from about 0.05 to 2.5 percent by weight, and preferably, from 0.1 to 1.5 percent.

In addition to buffering agents, in some instances it may be desirable to include sequestering agents in the present solutions in order to bind metal ions that might otherwise react with the lens and/or protein deposits and collect on the lens. Ethylene-diaminetetraacetic acid (EDTA) and its salts (disodium) are preferred examples. They are usually added in amounts ranging from about 0.01 to about 0.2 weight percent.

As indicated above, the present invention is useful for relieving the symptoms of allergies, including eye irritation, itching and burning, redness, etc. In addition, the compositions are useful for simultaneously treating dryness. Thus, as mentioned above, compositions of the present invention can function as artificial tears and can be used, as needed, for the temporary relief of eye irritation of discomfort. For example, many people suffer from eye conditions in which the eye's tear system fails to provide adequate tear volume or tear film stability necessary to remove irritating environmental contaminants such as dust, pollen, or the like. In persons suffering from the symptoms of dryness, the film on the eye tends to become discontinuous. Because of their emollient and lubricating effect, artificial tears can be used to soothe the eye.

Typically, compositions for treating the symptoms of allergy that have been on the market are not recommended for use with lenses in place. An advantage of one embodiment of the present invention is that the compositions can be used with or without the lenses in place, so that contact lenses do not have to be removed.

The solutions of this invention can be prepared by a variety of techniques, the best mode being illustrated in the Examples below. In general, aqueous ophthalmic solutions used in accordance with this invention may be formulated, for example, in accord with the procedures set forth in Chapter 83 of Remington's Pharmaceutical Sciences, 14th Edition, Mack Publishing Company. Such ophthalmic solutions are sterile and may contain a bacteriological preservative to maintain sterility during use. The quaternary ammonium bacteriostats such as benzalkonium chloride are satisfactory for this purpose. An antioxidant may also be employed if desired. By way of example, suitable antioxidants include sodium bisulfite, N-acetylcysteine salts, sodium ascorbate and other water-soluble ophthalmologically acceptable antioxidants known to the pharmaceutical art.

The quantity of a solution according to the present invention to be administered daily, which may vary from 1 to 3 drops, will depend mainly on the severity of the allergy reaction. Compositions according to the present invention can be applied by instilling about 1 or 2 drops in the affected eye(s) as needed, for the temporary relief of symptoms due to allergic reaction.

Claim 1 of 8 Claims

We claim:

1. A method of treating allergic symptoms and dryness which comprises administering a therapeutically effective amount of an ophthalmic solution comprising

(a) from about 0.10 to 0.55 weight percent of pheniramine maleate, a molar equivalent of another salt, or a derivative thereof, and

(b) an effective amount of povidone.

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