Drug – bio-affecting and body treating compositions – Topical body preparation containing solid synthetic organic... – Ophthalmic preparation
Reexamination Certificate
2001-09-20
2003-06-03
Tate, Christopher R. (Department: 1651)
Drug, bio-affecting and body treating compositions
Topical body preparation containing solid synthetic organic...
Ophthalmic preparation
C424S078020, C514S912000
Reexamination Certificate
active
06572849
ABSTRACT:
FIELD OF THE INVENTION
The current invention concerns buffered, low pH, self-preserved nasal, inhalable and topical ophthalmic preparations and medications which destroy, inhibit or sufficiently limit microbial growth within said preparations or medications. In particular, the current invention involves nasal, inhalable and topical ophthalmic preparations and medications having low pH of about 3.5 or lower, to inhibit microbial growth, wherein immediately upon application to the eye surface or a mucosal surface, the pH rises to physiologic levels.
BACKGROUND OF THE INVENTION
To prevent infection with use, currently available multidose preparations and medications are sterilized during manufacture and have a variety of preservatives added to destroy or inhibit the growth of microorganisms inadvertently introduced into the product after opening.
It is well recognized that the preservatives used in topical ophthalmic medications and preparations can be toxic to the eye surface and respiratory mucosa. The most widely used ophthalmic preservative, benzalkonium chloride (BAK), can cause damage to the conjunctival and corneal epithelium (
Cornea,
1:221-225 (1992);
Arch Opthalmol,
110:528-532 (1992) and
CLAO J,
18:260-266 (1992)). BAK is now thought to be also a significant cause of rhinitis medicamentosa, as described in
Allergy,
52:627-632 (1997), and has been also shown to damage respiratory mucosa (
Am Rev Respir Dis,
141:1405-1408 (1990) and
Acta Otolaryngol,
116:868-875 (1996)). Reducing the concentration of BAK reduces its toxic effect, but at too low a concentration, BAK is no longer effective as a preservative. Although alternatives to BAK are available, all preservatives have some potential for toxicity.
Pressurized aerosol containers used for inhalation or as a spray are an exception, needing no preservative since no air or contamination enters the container as doses are extracted. However, such packaging is relatively bulky and expensive, often contains CFC propellants which can harm the atmosphere, and precludes drop administration.
In recent years, preparations and medications have been packaged in unit-dose containers, thus avoiding the need for potentially toxic preservatives. In this arrangement, a single dose of medicine is provided by a given container. With sterile packaging, microbial contamination is theoretically not a concern, since the consumer/patient is instructed to discard the container after each single use. However, there are several problems with unit dose containers. First, the packaging is bulky and inconvenient. Second, cost per dose is significantly higher than with multidose containers. Third, patients often retain the opened container for many hours or even more than one day, contradicting the package instructions. This pattern of use increases the probability of microbial contamination of the medication or preparation.
Thus, it would be desirable to have available preservative-free preparations and medications suitable for topical, mucosal and inhalation use that could be stored in multi-dose containers without risk of microbial contamination.
All patents, patent applications and publications are hereby incorporated by reference.
SUMMARY OF THE INVENTION
One aspect of the current invention is a topical ophthalmic, nasal, or inhalable preparation or medication which is self-preserved, that is, which destroys, inhibits or sufficiently limits growth and multiplication of various microorganisms without the addition of preservative agents.
Another aspect of the current invention is a mildly buffered, topical ophthalmic, nasal, or inhalable preparation which is self-preserved by having a pH of from about 1.5 to about 3.5 with preferred pH at about 2.5 or lower.
Another aspect of the current invention is a self-preserved topical ophthalmic, nasal, or inhalable preparation or medication comprising a pharmaceutically acceptable excipient or additive selected from the group consisting of dextrose, polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), sodium chloride, potassium chloride, calcium chloride, magnesium chloride, phosphoric acid, disodium edetate, bicarbonate, phosphate, povidone, carboxymethylcellulose, hydroxyethylcellulose, methylcellulose, microcrystalline cellulose, glycerin, polyvinyl alcohol, dextran 40, dextran 70, mannitol, gelatin, polyol, polysorbate 80, propylene glycol, zinc sulfate, poloxamer 188, 282, 407, ephedrine hydrochloride, naphazoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, lecithin, oleic acid, sorbitan, pheniramine maleate, pyrilamine maleate, antazoline phosphate, glycine, camphor, eucalyptol, menthol, benzyl alcohol, lavender oil, tyloxapol, bornyl acetate, and phenylethyl alcohol, and a buffering agent, said preparation or medication adjusted to a low pH between about 1.5 to about pH 3.5, with most preferred pH at about pH 2.5 or lower, said medication optionally containing analgesics, anti-inflammatories, mast cell stabilizers, diagnostic aids, antibiotics, antiglaucoma drugs, decongestants, bronchodilators, vasoconstricting or hypertonicity agents, astringents and topical anesthetics.
Still another aspect of the current invention is a physiologically compatible self-preserved lightly buffered topical ophthalmic, nasal, or inhalable preparation or medication containing no preservation agents, formulated and maintained at about pH 2.5 or lower, wherein immediately upon application to the eye or a mucosal surface, such preparation permits the pH to rise to physiologic levels to maintain patient comfort, prevent tissue damage, and enhance drug delivery.
Still yet another aspect of the current invention is a multidose topical ophthalmic, nasal, or inhalable preparation or medication lightly buffered to maintain a stable pH in the multidose container, thereby maintaining its self-preserving characteristic.
Still another aspect of the current invention is a method for preparation of a topical ophthalmic, nasal or inhalable self-preserved solution comprising steps of:
a) preparing a formulation comprising
a pharmaceutically acceptable excipient or additive selected from the group consisting of dextrose, polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), sodium chloride, potassium chloride, calcium chloride, magnesium chloride, phosphoric acid, disodium edetate, bicarbonate, phosphate, povidone, carboxymethylcellulose, hydroxyethylcellulose, methylcellulose, microcrystalline cellulose, other cellulose derivatives, glycerin, polyvinyl alcohol, dextran 40, dextran 70, mannitol, gelatin, polyols, polysorbate 80, propylene glycol, zinc sulfate, poloxamer 188, 282, 407, ephedrine hydrochloride, naphazoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, lecithin, oleic acid and sorbitan, pheniramine maleate, pyrilamine maleate, antazoline phosphate, glycine, camphor, eucalyptol, menthol, benzyl alcohol, lavender oil, tyloxapol, bornyl acetate, phenylethyl alcohol, alone or in admixture; and
a buffering agent; and
b) adjusting pH of said formulation to from about pH 1.5 to pH about 3.5.
DEFINITIONS
As used herein:
“Preparation” means a topical ophthalmic, nasal, or inhalable preparations, including topical eye preparations such as artificial tears, contact lens solutions and eye irrigating solutions; nasal preparations such as saline; and inhalable preparations.
“Medication” means topical ophthalmic, nasal, or inhalable preparations comprising a pharmaceutical agent suitable for topical ophthalmic, nasal or inhalable administration wherein the pharmaceutical agent for ophthalmic use is an astringent, analgesic, hypertonicity agent, antihistamine, anti-inflammatory drug, mast cell stabilizer, diagnostic aid, anesthetic, antibiotic, antiglaucoma drug and vasoconstricting agent, the agent for nasal use is a decongestant and the agent for inhalable use is a bronchodilator
“Physiologically compatible” means a preparation
Verny Hana
Winston Randall
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