Medication indicated for ocular hypertension
First Claim
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1. An ocular insert comprising depots of from 0.01 weight percent to 50 weight percent of a beta-adrenergic receptor blocker drug solute comprising a solute of the formula selected from the group consisting of (1) R1 -O-CH2--CH--(OR2)--CH2 --NH--R3 and (2) R5 --CH(OR2)--CH(R4)--NH--R3 wherein:
- R1 is a member selected from the group consisting essentially of unsubstituted and substituted phenyl, indanyl and indenyl, with the substituent bonded thereto a member selected from the group consisting essentially of lower alkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower alkenyloxy, lower alkynyloxy, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy, lower alkylthio, lower alkenylthio, lower alkylthio-lower alkyl, lower alkoxy-lower alkylthio, halogen, halogen-lower alkyl, hydroxyl, hydroxyl-lower alkyl, carboxyl, carboamoyl, N-lower alkyl carbamoyl, N,N-dilower alkyl carbamoyl, N-lower alkyl carbamoyl-lower alkyl, N,N-di-lower alkyl carbamoyl-lower alkyl, lower alkanoylamino-lower alkenyl, lower alkanoylamino-lower alkenyl, lower alkyanoylamino-lower alkenyl, lower alkoxy, N-lower alkylamino, N,N-di-lower alkylamino, lower alkoxycarbonyl, lower alkoxy-carbonylamino, lower alkoxycarbonylamino-lower alkyl, lower alkoxycarbonylamino-lower alkenyl, lower alkoxycarbonylamino-lower alkoxy, lower akylcarbonylamino-lower alkyl, N'"'"'-lower alkyl-ureido, N,N'"'"'-di-lower alkyl-ureido, lower alkylsulphonylamino, cyano, nitro, and, cycloaliphatic;
R2 is a member selected from the group consisting of hydrogen and acyl;
R3 is a member selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloaliphatic, aryl, araliphatic, lower alkyl-aryl, lower alkoxy-aryl, lower alkyl aryl-lower alkoxy, lower alkyl aryl-lower alkyl, lower alkyl aryl-lower alkenyl, lower alkyl aryl-lower alkynyl, lower alkoxy aryl-lower alkyl, lower alkoxy aryl-lower alkenyl, lower alkoxy aryl-lower alkynyl, lower alkoxy aryl-lower alkoxy, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl,aryl-lower alkoxy, aryloxy-lower alkyl, aryloxy-lower alkoxy, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, lower alkoxycarbamoyl-lower alkyl, cyano-lower alkyl, arylcarbamoyl, and lower alkoxyphenyl-carbamoyl;
R4 is a member selected from the group consisting of hydrogen and lower alkyl;
R5 is the same as R1 with the provisions when R5 is substituent with hydroxyl, the ring has an additional substituent other than hydroxyl bonded thereto selected from R1 ; and
the remaining weight percent up to 100 weight percent of a pharmaceutically acceptable, non-toxic polymer, that surrounds substantially individually the depots of the beta-adrenergic drug solute, and binds them into the ocular insert, said polymer a member selected from the group consisting of poly(olefin), poly(vinylolefin), poly(halo-olefin), poly(styrene), poly(vinyl), poly(acrylate), poly(methacrylate), poly(oxide), poly(ester), poly(amide), and poly(carbonate), which insert is sized, shaped and adapted for easy insertion and prolonged retention in the eye for administering a therapeutically effective amount of the drug thereto to occupy and interact with the beta-receptors for managing intraocular pressure over a prolonged period of time.
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Abstract
An ocular therapeutic system is disclosed for dispensing a medicament to an ocular environment. The system comprises a beta-blocking drug in a polymer with the drug surrounded by the polymer. A method is disclosed for the management of ocular hypertension using the system. Also disclosed, is a composition comprising the drug and the polymer.
102 Citations
24 Claims
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1. An ocular insert comprising depots of from 0.01 weight percent to 50 weight percent of a beta-adrenergic receptor blocker drug solute comprising a solute of the formula selected from the group consisting of (1) R1 -O-CH2--CH--(OR2)--CH2 --NH--R3 and (2) R5 --CH(OR2)--CH(R4)--NH--R3 wherein:
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R1 is a member selected from the group consisting essentially of unsubstituted and substituted phenyl, indanyl and indenyl, with the substituent bonded thereto a member selected from the group consisting essentially of lower alkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower alkenyloxy, lower alkynyloxy, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy, lower alkylthio, lower alkenylthio, lower alkylthio-lower alkyl, lower alkoxy-lower alkylthio, halogen, halogen-lower alkyl, hydroxyl, hydroxyl-lower alkyl, carboxyl, carboamoyl, N-lower alkyl carbamoyl, N,N-dilower alkyl carbamoyl, N-lower alkyl carbamoyl-lower alkyl, N,N-di-lower alkyl carbamoyl-lower alkyl, lower alkanoylamino-lower alkenyl, lower alkanoylamino-lower alkenyl, lower alkyanoylamino-lower alkenyl, lower alkoxy, N-lower alkylamino, N,N-di-lower alkylamino, lower alkoxycarbonyl, lower alkoxy-carbonylamino, lower alkoxycarbonylamino-lower alkyl, lower alkoxycarbonylamino-lower alkenyl, lower alkoxycarbonylamino-lower alkoxy, lower akylcarbonylamino-lower alkyl, N'"'"'-lower alkyl-ureido, N,N'"'"'-di-lower alkyl-ureido, lower alkylsulphonylamino, cyano, nitro, and, cycloaliphatic; R2 is a member selected from the group consisting of hydrogen and acyl; R3 is a member selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloaliphatic, aryl, araliphatic, lower alkyl-aryl, lower alkoxy-aryl, lower alkyl aryl-lower alkoxy, lower alkyl aryl-lower alkyl, lower alkyl aryl-lower alkenyl, lower alkyl aryl-lower alkynyl, lower alkoxy aryl-lower alkyl, lower alkoxy aryl-lower alkenyl, lower alkoxy aryl-lower alkynyl, lower alkoxy aryl-lower alkoxy, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl,aryl-lower alkoxy, aryloxy-lower alkyl, aryloxy-lower alkoxy, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, lower alkoxycarbamoyl-lower alkyl, cyano-lower alkyl, arylcarbamoyl, and lower alkoxyphenyl-carbamoyl; R4 is a member selected from the group consisting of hydrogen and lower alkyl; R5 is the same as R1 with the provisions when R5 is substituent with hydroxyl, the ring has an additional substituent other than hydroxyl bonded thereto selected from R1 ; and
the remaining weight percent up to 100 weight percent of a pharmaceutically acceptable, non-toxic polymer, that surrounds substantially individually the depots of the beta-adrenergic drug solute, and binds them into the ocular insert, said polymer a member selected from the group consisting of poly(olefin), poly(vinylolefin), poly(halo-olefin), poly(styrene), poly(vinyl), poly(acrylate), poly(methacrylate), poly(oxide), poly(ester), poly(amide), and poly(carbonate), which insert is sized, shaped and adapted for easy insertion and prolonged retention in the eye for administering a therapeutically effective amount of the drug thereto to occupy and interact with the beta-receptors for managing intraocular pressure over a prolonged period of time. - View Dependent Claims (2, 3, 4, 5, 24)
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- 6. The composition of matter consisting essentially of from 0.01 weight percent of 50 weight percent of a beta-adrenergic receptor blocker drug solute selected from the group consisting of acebutolol, alprenolol, atenolol, bevantol, bupranolol, bunitrolol, exaprolol, indenolol, indanolol, labetalol, metoprolol, moprolol, nifenalol, nitrolol, oxprenolol, pamatolol, penbutolol, pargolol, procinolol, practolol, sotalol, triprenolol, tolamolol, and toliprolol, said drug solute present as the therapeutically acceptable salt in the composition with up to 100 weight percent of a polymer that is non-toxic, non-biodegradable and non-dissolvable when in contact with aqueous and biological fluids, said polymer a member selected from the group consisting of poly(olefin), poly(vinyl-olefin), poly(halo-olefin), poly(styrene), poly(vinyl), poly(acrylate), poly(methacrylate), poly(oxide), poly(ester), poly(amide), and poly(carbonate), and which composition forms a film sized, shaped and adapted for easy insertion and prolonged retention in a biological environment of use for releasing a therapeutically effective amount of the beta-adrenergic receptor blocker drug to the biological environment over a prolonged period of time.
- 11. An ocular therapeutic insert for the dispensing of a beta-adrenergic receptor blocker drug to an eye, said system sized, shaped and structured for easy insertion and adapted for comfortable retention in the eye, and comprising depots of from 0.01 weight percent to 50 weight percent of the drug solute selected from the group consisting of acebutolol, alprenolol, atenolol, bevantol, bupranolol, bunitrolol, exaprolol, indenolol, indanolol, labetalol, metoprolol, moprolol, nifenalol, nitrolol, oxprenolol, pamatolol, penbutolol, pargolol, procinolol, practolol, sotalol, triprenolol, tolamolol and toliprolol, said drug solute present as the therapeutically acceptable salt of 0.1 to 400 micron size, said depots dispersed in and surrounded substantially individually by up to 100 weight percent of polymer that is non-toxic, non-biodegradable, substantially impermeable to the passage of drug solute, is permeable to the passage of eye fluid, and which polymer is a member selected from the group consisting of poly(olefins), poly(vinyl-olefins), poly(acrylates), poly(methacrylates), poly(oxides), poly(esters), poly(amides) and poly(carbonates).
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14. An ocular insert consisting essentially of (a) discrete depots of a medication osmotically effective solute selected from the group consisting of acebutolol, alprenolol, atenolol, bevantol, bupranolol, bunitrolol, exaprolol, indenolol, labetalol, metoprolol, moprolol, nifenalol, nitrolol, oxprenolol, pamatolol, penbutolol, pargolol, procinolol, practolol, sotalol, triprenolol, tolamolol and toliprolol, which solutes have a size of 0.1 to 100 microns and exhibit an osmotic pressure gradient across the wall of the depot against an external fluid present in the environment of use;
- (b) a film of a member selected from the group consisting of poly(olefin), poly(vinyl-olefin), poly (halo-olefins), poly(styrene), poly(vinyls), poly(acrylates), poly(methacrylate), poly(oxide), poly(esters), poly(amide), and poly(carbonate), forming the insert, imparting size and shape to the insert for easy insertion and prolonged retention in the environment of use, said film substantially impermeable to the passage of solute, permeable to the passage of the external fluid, nondissolvable in the fluid, and substantially surrounds individually and serves as the wall of the depots; and
(c) wherein when the insert is positioned in the environment of use, fluid from the environment is imbibed through the wall into the depots to continuously dissolve the solutes and generate a hydrostatic pressure in the depots, which pressure is applied against the wall of the depots thereby forming apertures and releasing the medication from the depots at the surface and from within the insert by the inward progressive aperature formulation in depots at a controlled rate over a prolonged period of time.
- (b) a film of a member selected from the group consisting of poly(olefin), poly(vinyl-olefin), poly (halo-olefins), poly(styrene), poly(vinyls), poly(acrylates), poly(methacrylate), poly(oxide), poly(esters), poly(amide), and poly(carbonate), forming the insert, imparting size and shape to the insert for easy insertion and prolonged retention in the environment of use, said film substantially impermeable to the passage of solute, permeable to the passage of the external fluid, nondissolvable in the fluid, and substantially surrounds individually and serves as the wall of the depots; and
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15. In a method for treating glaucoma in a warm-blooded animal, which method consists essentially in lowering the intraocular pressure associated with glaucoma by administering to the eye of the animal a medication, for glaucoma, the method consisting essentially in the steps of:
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(a) positioning in the eye an ocular insert containing said medication, the improvement wherein said insert comprises; (1) discrete depots of ocular administrable medication of the formula R1 --O--CH2 --CH(OR2)--CH2 --NH--R3 wherein;
R1 is a member selected from the group consisting essentially of unsubstituted and substituted phenyl, indanyl and indenyl, with the substitutent bonded thereto a member selected from the group consisting essentially of lower alkyl, lower alkenyl, lower alkynyl, lower alkyloxy, lower alkenyloxy, lower alkynyloxy, lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy, lower alkylthio, lower alkenylthio, lower alkylthio-lower alkyl, lower alkoxy-lower alkylthio, halogen, halogen-lower alkyl, carboxyl, carbamoyl, N-lower alkyl carbamoyl, N,N-di-lower alkyl carbamoyl, N-lower alkyl carbamoyl-lower alkyl, N,N-di-lower alkyl carbamoyl-lower alkyl, acyl, acyloxy, acylamino, lower alkanoylamino-lower alkenyl, lower alkanoylamino-lower alkynyl, lower alkanoylamino-lower alkoxy, N-lower alkylamino, N,N-di-lower alkylamino, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkoxycarbonylamino-lower alkyl, lower alkoxycarbonylamino -lower alkenyl, lower alkoxcarbonylamino-lower alkoxy, lower alkylcarbonylamino-lower alkyl, N'"'"'-lower alkyl-ureido, N'"'"',N'"'"'-di-lower alkyl-ureido, lower alkylsulphonylamino, cyano, nitro and cycloaliphatic;
R2 is a member selected from the group consisting of hydrogen and acyl; and
R3 is a member selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloaliphatic, aryl, araliphatic, lower alkylaryl-lower alkenyl, lower alkyl aryl-lower alkynyl, lower alkoxy aryl-lower alkyl, lower alkoxy aryl-lower alkynyl, lower alkoxy aryl-lower alkoxy, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkyl, aryl-lower alkenyl, aryl-lower alkynyl, aryl-lower alkoxy, aryloxy-lower alkyl, aryloxy-lower alkoxy, N-lower alkyl, aryloxy-lower alkoxy, N-lower alkylcarbamoyl, N,N-di-lowere alkylcarbamoyl, lower alkoxycarbamoyl-lower alkyl, cyano-lower alkyl, aryl-carbamoyl and lower alkoxyphenylcarbamoyl;
which solutes exhibit osmotic pressure gradients across the wall of the depot against an external fluid, said depots dispersed in;(2) a film sized and shaped as an insert for easy positioning and comfortable retention in the eye of the animal, said film an ocular acceptable polymeric material that surrounds individually and forms the wall of the discret depots, is nonerodible, impermeable to the passage of the solutes, and permeable to the passage of fluid; (b) imbibing fluid from the eye into the depots to dissolve the solutes and fill the depots with solution, thereby exerting pressure against the wall of the depot and forming apertures that release formulation from the depots at the surface and from the interior of the insert through beta-adrenergic receptor blocking medication paths by the inward progressive aperture formation in closely related depots;
thereby(c) dispensing the medication embraced by the formula at a controlled rate for treating glaucoma over a prolonged period of time. - View Dependent Claims (16, 17, 18, 19, 20)
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Specification
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Current AssigneeALZA Corporation (Johnson & Johnson)
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Original AssigneeALZA Corporation (Johnson & Johnson)
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InventorsShell, John W., Gale, Robert M.
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Primary Examiner(s)Rose, Shep K.
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Application NumberUS06/137,456Time in Patent Office606 DaysField of Search128/260, 424/14, 424/19-22, 424/28US Class Current424/427CPC Class CodesA61K 9/0051 Ocular inserts, ocular impl...
