Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-10-24
2004-08-17
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S400000, C514S424000, C514S952000, C514S970000, C514S973000, C514S975000
Reexamination Certificate
active
06777401
ABSTRACT:
FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable.
BACKGROUND OF THE INVENTION
The invention disclosed herein generally relates to the field of solvents capable of dissolving medicaments. More particularly, it relates to the field of water-containing solvents capable of dissolving medicaments not regularly soluble in aqueous solutions, such as steroids (especially corticosteroids) and antimicrobial phenols (especially chloroxylenol). The present invention is especially suited for dissolving hydrocortisone into a clear solution for topical application.
One application of the present invention is in the field of treatment of ear aches and similar maladies of the ear. One problem to which the present invention is directed is the relative inability of water to dissolve medicaments commonly used to treat such ear maladies, and the relative inability or undesirability of organic solvent solutions for delivery of medicaments for topical applications using certain methods.
The auricle of the ear is covered with a layer of skin that extends part way into the external ear canal. The inner part of the ear canal, including the external surface of the ear drum, is covered with a thin layer of epithelial cells. The outer part of the external ear canal has ceruminous glands which produces a waxy material composed of free fatty acids, other organic compounds, salts and water. This area also contains hair which prevents debris in the immediate environment from entering the ear canal. The epithelial cells of the canal slough off and combine with the waxy organic materials, water, cells, debris and hair to form cerumin, commonly known as ear wax. No bland organic agent or water will dissolve all of the ear wax particles. However, water and organic solvents (and combinations) will loosen and swell the wax.
Excessive water in the ear canal will swell the ear wax, leading to a plugging of the canal, which may thereby become infected. This condition is sometimes called swimmer's ear, or otitis externa. Ear drops containing antimicrobial agents are commonly applied to the external ear canal to abate the infection; other medicaments within the ear drops, such as hydrocortisone, may reduce inflammation, while local anesthetics (such as, for example, pramoxine) reduce pain. Substances such as glycerol, for example, also aid in the removal of excess ear wax.
Ear plugs or wicks made of cloth, plastic or cellulose (collectively “wicks”) may be inserted into the ear canal after the ear drop medicaments are applied to the ear canal. These wicks expand and retain the ear drops within the ear canal. For ear drops to expand the wick within several minutes, the ear drops must contain 33% or more water.
Hydrocortisone is approved as 1±0.2% concentration for ear drop pharmaceutical products. Hydrocortisone is nearly insoluble in water (0.028% on a weight volume basis) and glycerol. However, it is soluble to at least 1% in several organic solvents such as propylene glycol, polypropylene glycol diacetate, hexenyl glycol, 2-propanol, ethanol and in pure (glacial) acetic acid. It is also solubalized in non-ionic surfactants (micells and colloids).
Many solutions of hydrocortisone have a relatively short “shelf life,” losing efficacy if not used fairly promptly after mixing. The stability of hydrocortisone in solution is relative, since there is a gradual loss of this chemical over time; in many such solutions, hydrocortisone becomes oxidized or otherwise rendered less active (or completely inactive) after a period of days or months in storage at room temperature.
Monder,
Endocrinology
82(2),318 (1968), reported that aqueous solutions of hydrocortisone were rapidly oxidized and lost. Short, et al.,
J. Pharm. Pharmacology
61(11), 17825 (1972) studied the cause of the loss of hydrocortisone in solution and Bansal, et al.,
J. Pharm. Sci.
72(9) 1079 (1983) slowed this loss by adding 0.1% fructose. Barry, et al.,
J. Pharm. Pharmacology
28(3), 210 (1976) and Hajratwala, et al.,
J. Pharm. Pharmacology
28(3),934 (1976) reported on surfactants to produce micells of hydrocortisone in water. Lovgren, et al.,
J. Pharm. Sci.
67(10), 1419 (1978), Hagen, et al.,
J. Pharm. Sci.
72(4),409 (1983), Gupta,
Drug Development and Industrial Pharmacy
11(12),2083097 (1985) reported on the use of surfactants and the loss of hydrocortisone in these solutions.
Due to the low solubility of hydrocortisone in many solvents, such as glycerol and water, the preparation of clear solutions of 1%-2% concentrations of the drug solution is difficult. Co-solvents such as lower molecular weight alcohols, i.e., ethanol, 2-propanol and glycols (propylene glycol, hexenyl glycol) may be added to increase the water content of the solutions. Also, surfactants may be added to form micells in water.
Jacobson, U.S. Pat. No. 2,779,707 disclosed the use of 20% water and 80% hexenyl glycol to prepare 0.8% hydrocortisone acetate to be used for intravenous administration.
U.S. Pat. No. 2,880,130 issued to Johnson in 1959 described the possible use of polyoxyethylene sorbitan monooleate (Tween 80) in amounts of 2-25% for the vehicle to obtain micells in water of 0.2% hydrocortisone. This was to be applied to the eye, ear, nose and throat.
Two Italian patents Rom RO 65,112 and 84,025 reported on the formulation of hydrocortisone and antibiotics in oil for the treatment of otitis externa.
U.S. Pat. No. 3,422,186 issued to Sasmor in 1969 discloses aqueous, viscous solutions of 0.05-0.5% hydrocortisone using (10%) water, propylene glycol, glycerol or polyoxyethylene glycol. These were to be used to dissolve ear wax and to treat ear disease in the human and animal.
A stable, sprayable 0.5% hydrocortisone preparation is disclosed in U.S. Pat. No. 4,213,979 issued to Levine in 1980. Said compound employs polyoxypropylene-(12)-polyoxyethylene-(50)-lanolin, 15% ethanol, 25% propylene glycol to form a film. Moreover, it contains a relatively high ethanol content, limiting its usefulness for topical application (especially to the ear, near the eye).
U.S. Pat. No. 4,289,764 issued to Yarrow et al. in 1981 describes formulations containing 0.025 to 0.4% hydrocortisone in an aqueous propylene glycol (15-50%) solution with citric acid; it discloses dissolving more than 0.1% hydrocortisone in 50:50 v/v water: propylene glycol solution exceed known physical solubility values of hydrocortisone.
U.S. Pat. No. 4,305,936 issued to Klein in 1981 provides for a 0.005 to 2.5% hydrocortisone clear cream formulation containing 1 to 4% by weight of a glycerol ester of fatty acids having 6-22 carbon atoms, 1-3% by weight of the hydrocortisone of a betaine surfactant, and 10-50% of an alkanol co-solvent, preferably ethanol; solutions having such surfactants generally have stability problems, and are not recommended for topical application to the ear. Furthermore, it contains a relatively high ethanol content, limiting its usefulness for topical application (especially to the ear, near the eye).
U.S. Pat. No. 5,728,690 issued to Chen in 1998 discloses a clear non-alcoholic 1-2% hydrocortisone preparation using 15-30% polyethylene glycol, 15-30% propylene glycol, 5-20% glycerol, 3-12.4% sodium diactyl sulfosuccinate, and as much as 20% water to make a liquid or gel product for application to the skin.
U.S. Pat. No. 5,744,166 describes a hydrocortisone composition with aminopolysaccharides; such as, chitosan and chitosan derivatives and polycationic polymers that forms a film when applied dermally.
Purwar, et al., WO 9,639,146 describes an aqueous solution of the antimicrobial ciprofloxacin for the treatment of otitis externa and media. Hydrocortisone is mentioned as a possible ingredient in the ciprofloxacin preparation.
One primary object of the present invention is to provide a clear aqueous solution capable of delivering the optimal allowable amount of medicament(s) for topical application, especially to the ear canal of humans or animals.
Another object of the present invention is to provide a clear aqueous solution containing the optimal amount of hydrocortison
Blansett Pharmacal Co., Inc.
King & Spalding LLP
Qazi Sabiha
Sullivan Clark G.
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