Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-03-15
2002-11-26
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S652000, C514S912000
Reexamination Certificate
active
06486208
ABSTRACT:
TECHNICAL FIELD
The present invention relates to improved nonstinging, sustained release ophthalmic formulations for ocular therapy and methods of treatment comprising administering such formulations topically to the eye when indicated.
BACKGROUND ART
Numerous drugs are not readily accepted by many patients because they cause ocular discomfort, i.e., “stinging,” upon instillation to the eyes. This side effect is problematic because it results in poor patient compliance and because it restricts the amount of drug which can be included in topical formulations. Further, to meet USP and global microbiological standards, one or more preservatives must be included in ocular formulations. These preservatives, particularly those required to meet more stringent global requirements, have the tendency to increase the level of “stinging”, thereby augmenting patient discomfort. Thus, the combined requirements of comfort and satisfactory patient compliance together with provision of a composition which meets stringent global preservative requirements pose a challenge which, to date, has not been satisfactorily achieved.
One method for addressing the problems associated with the topical administration is described in U.S. Pat. No. 4,911,920. Glaucoma is a disease characterized by an elevated intraocular pressure (IOP) associated with optic nerve head damage and loss of visual field. Statistically, when IOP is lowered, the prognosis for preserving visual field in an eye with elevated IOP is improved. Thus, a goal of glaucoma therapy is to reduce the IOP to a level within a range tolerated by the eye to slow the progressive loss of visual field. Current medical therapy of glaucoma involves the reduction of IOP by various drugs, predominantly ophthalmic beta adrenergic blocking drugs. Betaxolol is among the ophthalmic beta blockers approved for use to treat glaucoma in the United States. In the '920 patent, actives such as betaxolol are administered to treat glaucoma in a composition which includes, inter alia, an ion exchange resin and a polyanionic polymer. These compositions have an excellent comfort profile but “stinging” is still experienced by some patients.
Thus, there exists a need to provide an ophthalmic composition which achieves the combined requirements of comfort and satisfactory patient compliance, while, at the same time, meets stringent global preservative requirements.
DISCLOSURE OF THE INVENTION
An advantage of the present invention is that it achieves the combined requirements of comfort and satisfactory patient compliance, while, at the same time, meets stringent global preservative requirements, thereby permitting the topical administration of ophthalmic drugs and in higher concentrations.
Additional advantages and other features of the present invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from the practice of the invention. The objects and advantages of the invention may be realized and obtained as particularly pointed out in the appended claims.
According to the present invention, the foregoing and other advantages are achieved in part by an ophthalmic composition, comprising: a) at least one basic active; b) a polyanionic polymer; c) an ion exchange resin; and d) a pH adjusting agent, wherein said agent is present in an amount sufficient to adjust the pH of the composition to between about 3.5 and 9.5.
Another aspect of the present invention is a method of treatment which comprises administering topically to an affected eye, an ophthalmic composition comprising: a) at least one basic active; b) a polyanionic polymer; c) an ion exchange resin; and d) a pH adjusting agent, wherein said agent is present in an amount sufficient to adjust the pH of the composition to between about 3.5 and about 9.5.
Additional objects and advantages of the present invention will become readily apparent to those skilled in this art from the following detailed description, wherein only the preferred embodiment of the invention is, shown and described, simply by way of illustration of the best mode contemplated for carrying out the invention. As will be realized, the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the invention. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.
DESCRIPTION OF THE INVENTION
The present invention is based, in part, on the surprising and unexpected discovery that the use of certain pH adjusting agents, result in ophthalmic compositions which achieve the combined requirements of comfort and satisfactory patient compliance, while, at the same time, meets stringent global preservative requirements.
The pH adjusting agents useful in the present invention may be any “basic amine”, i.e., any amine which shows basicity and does not substantially disrupt interaction between a basic active and an ion exchange resin. Preferred pH adjusting agents include ammonia, tromethamine (TRIS or Tris(hydroxymethyl) aminomethane), triethanolamine (TEA), N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES), and mixtures thereof
Disruptions between a basic active and an ion exchange resin normally occur when smaller ions such as sodium ions are used to adjust the pH of the compositions of concern because they sterically fit better into the resin binding site thereby displacing the basic active from the resin and increasing the concentration of “free” basic active in solution. Since ocular discomfort with many basic actives is proportional to the amount of this “free”, or unassociated basic active present in the composition, the level of discomfort experienced by patients increases as the concentration of unassociated basic active increases. While not wishing to be bound by any particular theory, it is believed that the pH adjusting agents of the present invention minimize disruption of the basic active/resin interaction as the pH is adjusted which normally occurs with smaller ions such as sodium ions. It is believed that the larger ions provided by the present invention do not fit as well into the resin binding site and therefore, do not displace as many basic active molecules.
The term “basic active” as used throughout the specification means the active ingredient or ingredients in the inventive formulations which may cause ocular discomfort upon instillation to the eye and have the desired effect and which bear, or are capable of bearing a positive charge during formulation of the final product or as formulated in the final product form. Thus, the term basic, or cationic, active is descriptive for purposes of the disclosure and claims.
Such basic actives include all ophthalmic agents which can be topically applied. Such ophthalmic agents include, but are not limited to, glaucoma agents, such as beta-blockers, muscarinics, and carbonic anhydrase inhibitors; dopaminergic agonists and antagonists; &agr;-2 agonists; anti-infectives; non-steroidal and steroidal anti-inflammatories; prostaglandins; proteins; growth factors and anti-allergics. Compositions of the present invention may also include combinations of ophthalmic agents.
A preferred basic active is beta blockers which, typically, are represented by the following generic structure, which structure also represents the beta blocker basic actives of the present invention:
R
1
—O—CH
2
—CH(OH)—CH
2
—NR
2
R
3
(I)
wherein: R
1
is a substituted or unsubstituted cyclic or aliphatic moiety; cyclic moieties include mono- and polycyclic structures which may contain one or more heteroatoms selected from C, N, and O; R
2
and R
3
are independently selected from H and substituted and unsubstituted alkyl. With regard to Structure (I), above, the following references are incorporated herein by reference:
Annual Reports in Medicinal Chemistry
14, 81-87 (1979);
J. Med. Chem
. 1983, 26,1570-15
Castillo Ernesto J.
Sarkar Ruma
Singh Onkar N.
Weiner Alan L.
Yarborough Cody
Alcon Laboratories Inc.
Fay Zohreh
McDermott & Will & Emery
LandOfFree
Sustained release, and comfortable opthalmic composition and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Sustained release, and comfortable opthalmic composition and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Sustained release, and comfortable opthalmic composition and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2981605