Ophthalmic drug delivery with thermoreversible polyoxyalkylene gels adjustable for pH

Claim 2

A hyperosmotic, iso-osmotic, or hypo-osmotic aqueous composition for use as a vehicle for drug delivery, a drug delivery composition, or a medical device for treating an eye condition, where said composition is a liquid at room temperature or below and a gel with a desired osmolality at mammalian body temperature, said aqueous composition containing: (A) about 10 to about 50% by weight of a polyoxyalkylene block copolymer of formula Y[(A).sub.n --E--H].sub.x (I) wherein A is a polyoxyalkylene moiety having an oxygen/carbon atom ratio of less than 0.5, x is at least 1, Y is derived from water or an organic compound containing x reactive hydrogen atoms, E is a polyoxyethylene moiety, n has a value such that the average molecular weight of A is at least about 500, as determined by the hydroxyl number of an intermediate of formula Y[(A).sub.n --H].sub.x (II) and the total average molecular weight of the polyoxyalkylene block copolymer is at least about 5000 and (B) about 80% to about 20% by weight of water; wherein the osmolality of the aqueous composition in the liquid state is adjusted to achieve the desired value of the osmolality of the gel by assuming that the polyoxyalkylene block copolymer does not contribute to the osmolality in the gel.

Claim 3

The composition of claim 1 wherein said Y in said polyoxyalkylene block copolymer is derived from a water soluble organic compound having 1 to about 6 carbon atoms and wherein said composition further contains a pharmacologically effective amount of a drug selected from the group consisting of antibacterials, decongestants, anti-inflammatories, miotics, mydriatics, antiglaucoma drugs, carbonic anhydrase inhibitors, ophthalmic diagnostic agents, ophthalmic agents used as adjuvants in surgery, chelating agents, local anesthetics, analgesics, immunosuppressive agents and antimetabolites.

Claim 4

The composition of claim 1 wherein said Y in said polyoxyalkylene block copolymer is derived from a water soluble organic compound having 1 to about 6 carbon atoms and wherein said composition further contains a pharmacologically effective amount of a drug, wherein said drug is an antihistamine, an anticholinergic, or an antiparasitic, wherein said antiparasitic is selected from the group consisting of antivirals, antifungals, amoebicidals, and trichomonocidals.

Claim 5

The composition of claim 1 wherein said polyoxyalkylene moiety is derived from an alkylene oxide selected from the group consisting of butylene oxide, propylene oxide, and mixtures thereof and Y is derived from an organic compound selected from the group consisting of propylene glycol, glycerin, pentaerythritol, trimethylolpropane, ethylenediamine and mixtures thereof.

Claim 6

The composition of claim 4 wherein said copolymer is a polyoxyethylene-polyoxypropylene block copolymer wherein said polyoxyethylene moiety constitutes at least about 70% by weight of the copolymer, the average molecular weight of A is at least about 1200, and the total molecular weight of the copolymer is at least about 5,000.

Claim 7

The composition of claim 5 wherein the intermediate of Formula II is prepared by initiation with propylene glycol and has a molecular weight of at least about 1500.

Claim 8

The composition of claim 6 wherein said polyoxyalkylene block copolymer has the formula HO(C.sub.2 H.sub.4 O).sub.b (C.sub.4 H.sub.8 O).sub.a (C.sub.2 H.sub.4 O).sub.b H (III) wherein a and b are integers such that the hydrophobe base represented by (C 4 H 8 O) a has an average molecular weight of at least about 500 as determined by hydroxyl number, the polyoxyethylene chain constituting at least about 70% by weight of the polyoxyalkylene block copolymer, and the polyoxyalkylene block copolymer having a total average molecular weight of at least 15,000; or has the formula HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.a (C.sub.2 H.sub.4 O).sub.b H (IV) wherein a and b are integers such that the hydrophobe base represented by (C 3 H 6 O) a has an average molecular weight of at least about 900, as determined by hydroxyl number, the polyoxyethylene chain constituting at least about 70% by weight of the polyoxyalkylene block copolymer, and the polyoxyalkylene block copolymer having a total average molecular weight of at least 15,000; or has the formula ##STR4## wherein a and b are integers such that the polyoxyalkylene block copolymer has an average hydrophobe molecular weight of at least about 1500, a hydrophile content of at least about 70% by weight, and a total average molecular weight of at least about 15,000.

Claim 9

The composition of claim 7 wherein said polyoxyalkylene block copolymer is ##STR5## present in the amount of about 10 to about 40% by weight of the total weight of said composition.

Claim 10

The composition of claim 7 wherein said polyoxyalkylene block copolymer is present in the amount of about 15 to about 30% by weight in said aqueous composition and wherein the pH is maintained at about 7.4±0.2 and the osmolality in the gel is maintained at about 290 mOsm/kg.

Claim 11

A hyperosmotic, iso-osmotic, or hypo-osmotic aqueous composition for use as a vehicle for drug delivery, a drug delivery composition, or a medical device for treating an eye condition, where said aqueous composition is a gel with a desired osmolality at mammalian body temperature, said aqueous composition containing: a surfactant and a polyoxyalkylene polyether, said surfactant and said polyoxyalkylene polyether being present in a combined total amount not exceeding about 10% by weight having a molecular weight of about 10,000 to about 100,000 which is selected from the group consisting of (A) polyoxyalkylene polyethers prepared by reacting ethylene oxide and at least one lower alkylene oxide having 3 to 4 carbon atoms with at least one active hydrogen-containing compound having from 3 to 10 carbon atoms and from 3 to 6 active hydrogens to prepare a heteric or block copolymer intermediate and further reacting said copolymer intermediate with at least one alpha-olefin oxide having an average carbon chain length of about 20 to 45 aliphatic carbon atoms and wherein said alpha-olefin oxide is present in the amount of about 0.3 to 10 percent by weight based upon the total weight of said polyether and (B) polyoxyalkylene polyethers prepared by reacting ethylene oxide with at least one active hydrogen-containing compound having from 2 to 10 carbon atoms and from 2 to 6 active hydrogens to prepare a homopolymer intermediate and further reacting said homopolymer intermediate with at least one alpha-olefin oxide having an average carbon chain length of about 20 to 45 aliphatic carbon atoms and wherein said alpha-olefin oxide is present in the amount of about 0.3 to 10 percent by weight based on the total weight of said polyether; wherein the osmolality of the aqueous composition is adjusted to achieve the desired value of the osmolality of the gel by assuming that the polyoxyalkylene polyether does not contribute to the osmolality in the gel.

Claim 12

A hyperosmotic, iso-osmotic, or hypo-osmotic aqueous composition for use as a vehicle for drug delivery, a drug delivery composition, or a medical device for treating an eye condition, where said aqueous composition is a gel with a desired osmolality at mammalian body temperature, said aqueous composition containing: a surfactant and a polyoxyalkylene polyether, said surfactant and said polyoxyalkylene polyether being present in a combined total amount not exceeding about 10% by weight having a molecular weight of about 10,000 to about 100,000 which is selected from the group consisting of (A) polyoxyalkylene polyethers prepared by reacting ethylene oxide and at least one lower alkylene oxide having 3 to 4 carbon atoms with at least one active hydrogen-containing compound having from 3 to 10 carbon atoms and from 3 to 6 active hydrogens to prepare a heteric or block copolymer intermediate and further reacting said copolymer intermediate with at least one alpha-olefin oxide having an average carbon chain length of about 20 to 45 aliphatic carbon atoms and wherein said alpha-olefin oxide is present in the amount of about 0.3 to 10 percent by weight based upon the total weight of said polyether and (B) polyoxyalkylene polyethers prepared by reacting ethylene oxide with at least one active hydrogen-containing compound having from 2 to 10 carbon atoms and from 2 to 6 active hydrogens to prepare a homopolymer intermediate and further reacting said homopolymer intermediate with at least one alpha-olefin oxide having an average carbon chain length of about 20 to 45 aliphatic carbon atoms and wherein said alpha-olefin oxide is present in the amount of about 0.3 to 10 percent by weight based on the total weight of said polyether; wherein the osmolality of the aqueous composition is adjusted to achieve the desired value of the osmolality of the gel by assuming that the polyoxyalkylene polyether does not contribute to the osmolality in the gel.

Claim 13

The composition of claim 10 wherein said polyether is prepared using a heteric copolymer intermediate and wherein said aqueous composition further contains a pharmacologically effective amount of a drug selected from the group consisting of antibacterials, decongestants, anti-inflammatories, miotics, mydriatics, antiglaucoma drugs, carbonic anhydrase inhibitors, ophthalmic diagnostic agents, ophthalmic agents used as adjuvants in surgery, chelating agents, local anesthetics, analgesics, immunosuppressive agents and antimetabolites, wherein the drug is present at about 0.01% to 60% by weight based on the total weight of the aqueous composition.

Claim 14

The composition of claim 10 wherein said aqueous composition further contains a pharmacologically effective amount of a drug, wherein said drug is an antihistamine, an anticholinergic, or an antiparasitic, wherein said antiparasitic is selected from the group consisting of antivirals, antifungals, amoebicidals, and trichomonocidals, wherein the drug is present at about 0.01% to 60% by weight based on the total weight of the aqueous composition.

Claim 15

The composition of claim 10 wherein said polyether is prepared using an alpha-olefin oxide having an average carbon chain length of about 20 to 30 carbon atoms, present in the amount of about 0.3 to 10 percent of the total weight of said polyether.

Claim 16

The composition of claim 13 wherein the polyether is prepared using a proportion of ethylene oxide residue to the residue of said lower alkylene oxide of about 70 to about 90 percent by weight of ethylene oxide residue to about 30 to about 10 percent by weight of said lower alkylene oxide residue.

Claim 17

The composition of claim 14 wherein said polyether is prepared using propylene oxide as the lower alkylene oxide.

Claim 18

The composition of claim 15 wherein said polyether is prepared using a block copolymer intermediate.

Claim 19

The composition of claim 16 wherein said polyether is prepared using an alpha-olefin oxide having an average carbon chain length of about 20 to 30 carbon atoms, present in the amount of about 0.3 to 10 percent of the total weight of said polyether.

Claim 20

The composition of claim 17 wherein the polyether is prepared using a proportion of ethylene oxide residue to the residue of said lower alkylene oxide of about 70 to about 90 percent by weight of ethylene oxide residue to about 30 to about 10 percent by weight of said lower alkylene oxide residue.

Claim 21

The composition of claim 18 wherein said polyether is prepared using propylene oxide as the lower alkylene oxide.

Claim 22

The composition of claim 19 wherein said polyether is polyether (B).

Claim 23

The composition of claim 10 wherein said polyether is prepared using an alpha-olefin oxide having an average carbon chain length of about 20 to 30 carbon atoms, present in the amount of about 0.3 to 10 percent of the total weight of said polyether and wherein the pH is maintained at about 7.4±0.2 and the osmolality of the gel is maintained at about 290 mOsm/kg.

Claim 24

A process for treating an eye condition requiring the use of a medical device or pharmacological treatment which comprises administering to the eye of a mammal a hyperosmotic, iso-osmotic, or hypo-osmotic aqueous composition, where said aqueous composition is a liquid at room temperature or below and a gel with a desired osmolality at mammalian body temperature, said aqueous composition containing: (A) about 10 to about 50% by weight of a polyoxyalkylene block copolymer of formula Y[(A).sub.n --E--H].sub.x (I) wherein A is a polyoxyalkylene moiety having an oxygen/carbon atom ratio of less than 0.5, x is at least 1, Y is derived from water or an organic compound containing x reactive hydrogen atoms, E is a polyoxyethylene moiety, n has a value such that the average molecular weight of A is at least about 500, as determined by the hydroxyl number of an intermediate of formula Y[(A).sub.n --H].sub.x (II) and the total average molecular weight of the polyoxyalkylene block copolymer is at least about 5000 and (B) about 80% to about 20% by weight of water; wherein the osmolality of the aqueous composition in the liquid state is adjusted to achieve the desired value of the osmolality of the gel by assuming that the polyoxyalkylene block copolymer does not contribute to the osmolality in the gel.

Claim 25

A process for treating an eye condition requiring the use of a medical device or pharmacological treatment which comprises administering to the eye of a mammal a hyperosmotic, iso-osmotic, or hypo-osmotic aqueous composition, where said aqueous composition is a liquid at room temperature or below and a gel with a desired osmolality at mammalian body temperature, said aqueous composition containing: (A) about 10 to about 50% by weight of a polyoxyalkylene block copolymer of formula Y[(A).sub.n --E--H].sub.x (I) wherein A is a polyoxyalkylene moiety having an oxygen/carbon atom ratio of less than 0.5, x is at least 1, Y is derived from water or an organic compound containing x reactive hydrogen atoms, E is a polyoxyethylene moiety, n has a value such that the average molecular weight of A is at least about 500, as determined by the hydroxyl number of an intermediate of formula Y[(A).sub.n --H].sub.x (II) and the total average molecular weight of the polyoxyalkylene block copolymer is at least about 5000 and (B) about 80% to about 20% by weight of water; wherein the osmolality of the aqueous composition in the liquid state is adjusted to achieve the desired value of the osmolality of the gel by assuming that the polyoxyalkylene block copolymer does not contribute to the osmolality in the gel.

Claim 26

A process for treating an eye condition requiring the use of a medical device or pharmacological treatment which comprises administering to the eye of a mammal a hyperosmotic, iso-osmotic, or hypo-osmotic aqueous composition, where said aqueous composition is a gel with a desired osmolality at mammalian body temperature, said aqueous composition containing: a surfactant and a polyoxyalkylene polyether, said surfactant and said polyoxyalkylene polyether being present in a combined total amount not exceeding about 10% by weight having a molecular weight of about 10,000 to about 100,000 which is selected from the group consisting of (A) polyoxyalkylene polyethers prepared by reacting ethylene oxide and at least one lower alkylene oxide having 3 to 4 carbon atoms with at least one active hydrogen-containing compound having from 3 to 10 carbon atoms and from 3 to 6 active hydrogens to prepare a heteric or block copolymer intermediate and further reacting said copolymer intermediate with at least one alpha-olefin oxide having an average carbon chain length of about 20 to about 45 aliphatic carbon atoms and wherein said alpha-olefin oxide is present in the amount of about 0.3 to 10 percent by weight based upon the total weight of said polyether and (B) polyoxyalkylene polyethers prepared by reacting ethylene oxide with at least one active hydrogen-containing compound having from 2 to 10 carbon atoms and from 2 to 6 active hydrogens to prepare a homopolymer intermediate and further reacting said homopolymer intermediate with at least one alpha-olefin oxide having an average carbon chain length of about 20 to about 45 aliphatic carbon atoms and wherein said alpha-olefin oxide is present in the amount of about 0.3 to 10 percent by weight based on the total weight of said polyether; wherein the osmolality of the aqueous composition is adjusted to achieve the desired value of the osmolality of the gel by assuming that the polyoxyalkylene polyether does not contribute to the osmolality in the gel.

Claim 27

A process for treating an eye condition requiring the use of a medical device or pharmacological treatment which comprises administering to the eye of a mammal a hyperosmotic, iso-osmotic, or hypo-osmotic aqueous composition, where said aqueous composition is a gel with a desired osmolality at mammalian body temperature, said aqueous composition containing: a surfactant and a polyoxyalkylene polyether, said surfactant and said polyoxyalkylene polyether being present in a combined total amount not exceeding about 10% by weight having a molecular weight of about 10,000 to about 100,000 which is selected from the group consisting of (A) polyoxyalkylene polyethers prepared by reacting ethylene oxide and at least one lower alkylene oxide having 3 to 4 carbon atoms with at least one active hydrogen-containing compound having from 3 to 10 carbon atoms and from 3 to 6 active hydrogens to prepare a heteric or block copolymer intermediate and further reacting said copolymer intermediate with at least one alpha-olefin oxide having an average carbon chain length of about 20 to about 45 aliphatic carbon atoms and wherein said alpha-olefin oxide is present in the amount of about 0.3 to 10 percent by weight based upon the total weight of said polyether and (B) polyoxyalkylene polyethers prepared by reacting ethylene oxide with at least one active hydrogen-containing compound having from 2 to 10 carbon atoms and from 2 to 6 active hydrogens to prepare a homopolymer intermediate and further reacting said homopolymer intermediate with at least one alpha-olefin oxide having an average carbon chain length of about 20 to about 45 aliphatic carbon atoms and wherein said alpha-olefin oxide is present in the amount of about 0.3 to 10 percent by weight based on the total weight of said polyether; wherein the osmolality of the aqueous composition is adjusted to achieve the desired value of the osmolality of the gel by assuming that the polyoxyalkylene polyether does not contribute to the osmolality in the gel.