Drug – bio-affecting and body treating compositions – Topical body preparation containing solid synthetic organic... – Ophthalmic preparation
Reexamination Certificate
1999-12-08
2001-07-10
Kulkosky, Peter F. (Department: 1615)
Drug, bio-affecting and body treating compositions
Topical body preparation containing solid synthetic organic...
Ophthalmic preparation
Reexamination Certificate
active
06258350
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to ophthalmic formulations of cationic, pharmaceutically active agents. The formulations of the present invention are characterized by sustained release of the active agent, and are initially and continually comfortable to the eye. Specifically, the invention relates to formulations of the above characteristics which comprise, inter alia, a basic active and certain cationic exchange resins (finely divided) dispersed in an aqueous solution or gel of an acidic mucomimetic polymer. Such formulations are characterized by controlled cationic-anionic interactions, which appear to be responsible for the resulting comfort and sustained release properties. This invention also relates to methods of treatment which comprise administering the described compositions to the eye.
U.S. Pat. No. 4,911,920, the entire contents of which are incorporated by reference, discloses sustained release formulations for glaucoma therapy, wherein the formulations comprise a basic active and a cationic exchange resin dispersed in an aqueous solution or gel of an acidic, mucomimetic polymer. The cationic-exchange resin in the '920 formulations can be “any pharmaceutical grade cationic exchange resin” (Col. 3, lines 65-66 of the '920 patent) and include the “Amberlite” (Rohm & Haas) and “Dowex” (Dow Chemical Co.) lines of commercially available resins. Examples 2 and 3 of the '920 patent disclose Amberlite IRP-69 resin, a sodium poly(styrenedivinyl benzene) sulfonate having an approximately 8% degree of cross-linking according to its product brochure.
SUMMARY OF THE INVENTION
The ophthalmic formulations of the present invention are in the form of pourable, aqueous dispersions and aqueous gels. The formulations comprise a polyanionic polymer, a poly(styrenedivinyl) benzene cation exchange resin having a degree of cross-linking from about 4 to about 4.5%, and a basic active.
The formulations of the present invention demonstrate sustained release of the basic active and are comfortable on topical administration to the eye. When basic actives are topically administered, a stinging sensation generally results. Achieving both comfort and sustained release permits administration of a class of compounds that otherwise might not be considered. The cationic exchange resins contained in the formulations of the present invention are an essential ingredient for both comfort and sustained release. These cationic exchange resins provide unexpectedly superior sustained release profiles compared to analogous, but more highly cross-linked, resins.
DETAILED DESCRIPTION OF THE INVENTION
The formulations of the present invention comprise, in addition to conventional ingredients which provide, for example, bacteriostatic and formulatory balance functions, a basic active, a polyanionic polymer and a poly(styrenedivinyl) benzene cation exchange resin having a degree of cross-linking from about 4 to about 4.5%.
Basic Active Component
As used herein, “basic active” means a positively-charged, ophthalmically acceptable active agent. Suitable basic actives include all presently known beta blockers which demonstrate the requisite cationic charge and act to reduce intraocular pressure. Typically, such beta blockers are represented by the following generic structure:
R
1
—O—CH
2
—CH
2
—NR
2
R
3
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, 1570-1576; ibid., 1984, 27, 503-509, ibid., 1983, 26, 7-11; ibid, 1983, 26, 1561-1569; ibid., 1983, 1109-1112; ibid., 1983, 26, 352-357. Representative of such basic actives are betaxolol, timolol, befunolol, labetalol, propanolol, bupranolol, metaprolol, bunalol, esmalol, pindolol, carteolol, hepunolol, metipranolol, celiprolol, azotimolol, diacetolol, acebutolol, salbutamol, atenulol, isoxaprolol, and the like.
Basic actives also include the following classes of drugs which are used in treatment of ocular hypertension and glaucoma: pilocarpine, epinephrine; proepinephrine, norepinephrine; pronorepinephrine, clonidine; and clonidine derivatives, for example, p-aminoclonidine, pacetoamidoclonidine and brimonidine.
Thus, in summary, the basic active component of the present invention is defined as an ophthalmically acceptable pharmaceutical active having a cationic nature in an aqueous medium in the pH range of from 3.0 to 8.5. The most preferred basic actives are betaxolol and timolol. The basic active is present at a level of from about 0.01 to 4.0 wt. %; the most preferred range is from 0.10 to 1.0 wt. %.
Polyanionic Polymer Component
The high molecular weight, polyanionic polymers useful in the present invention are ophthalmically acceptable and have a molecular weight of from about 50,000 to about 6 million. The polymers are characterized as having carboxylic acid functional groups, and preferably contain from 2 to 7 carbon atoms per functional group. Depending upon the identity and concentration of the polyanionic polymer, the compositions of the present invention may be in the form of a liquid or a gel.
Suitable anionic polymers useful in the present invention include carboxyl vinyl polymers. Preferred polymers include the so called carbomers, available under the trade name Carbopol from the B.F. Goodrich Company; and ethylene maleic anhydride polymeric material, available under the trade name EMA from the Monsanto Company. The known and readily available polymers Carbopol 934P, 940 and 974P are most preferred. The polymers are used in the aqueous gel compositions at a level up to about 8% by weight; pourable liquid compositions generally comprise about 0.05% to about 2.0% weight polymer.
Ion Exchange Resin
The cationic exchange resin component of the formulations of the present invention provides an additional means of sustained release of the basic active, and appears to be necessary for initial and prolonged comfort. Such resins are characterized as either strongly acidic such as those having sulfonic acid functionality, or weakly acidic cation exchangers such as those having carboxylic acid functionality. The average particle size of the commercially available forms of the resins is about 40 to 150 microns. The particle size of the resin is critical for topically administrable ophthalmic compositions. Accordingly, for topically administrable ophthalmic compositions, commercially available resin particles are reduced by known techniques, including grinding, ball milling and microfluidization, to a particle size of about 20 &mgr;m or less, such that the average particle size is ≦10 &mgr;m. Preferably, the resin particles are reduced to a particle size of about 10 &mgr;m or less. Ion exchange resins are typically used in an amount from about 0.05 to about 10% (w/w), preferably a 1:1 ratio with the basic active.
Without being bound to any theory, it is believed that the release of the basic active held by the cation exchange resin and the anionic polymer is achieved when ions naturally present in the tear fluid, principally sodium and potassium, compete with the bound basic active for sites on the polymer vehicle and the ion exchange resin. Thus released, the basic active is presented to the eye surface for transport to the receptor sites.
Any pharmaceutical grade poly(styrenedivinyl benzene) cationic ion exchange resin having a degree of cross-linking, from about 4 to about 4.5% is suitable for the formulation, and can be used either in the hydrogen form or sodium form. Such resins are available, for example, from Rohm & Haas as Amberlite IR-118H (4.5% cross-linking) or Amberlyst 131 (4% cross-linking).
The compositions of the present invention can also include other components, for example, pharmaceuticall
Alcon Manufacturing Ltd.
Kulkosky Peter F.
Ryan Patrick M.
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