US4959217A — Delayed/sustained release of macromolecules

Claim 1

Independent Claim 78 words

A drug delivery device for the controlled administration of a macromolecular drug, said device comprising: (a) a pharmaceutically acceptable carrier; (b) a macromolecular drug having a molecular weight greater than about 1,000 mixed with said carrier; and (c) an initially partially-hydrated, non-biodegradable, hydrogel rate-limiting membrane, wherein said membrane: (i) comprises a homopolymer or a copolymer material surrounding said carrier and drug, and (ii) has an initial water content such that it is substantially non-permeable to said macromolecular drug.

Claim 2

Dependent Claim 78 words

A drug delivery device for the controlled administration of a macromolecular drug, said device comprising: (a) a pharmaceutically acceptable carrier; (b) a macromolecular drug having a molecular weight greater than about 1,000 mixed with said carrier; and (c) an initially partially-hydrated, non-biodegradable, hydrogel rate-limiting membrane, wherein said membrane: (i) comprises a homopolymer or a copolymer material surrounding said carrier and drug, and (ii) has an initial water content such that it is substantially non-permeable to said macromolecular drug.

Claim 3

Dependent Claim 34 words

The drug delivery device of claim 1 wherein said carrier is saturated with said drug and wherein an excess of said drug in a solid state is disposed in contact with said drug-saturated carrier.

Claim 4

Dependent Claim 22 words

The drug delivery device of claim 1 wherein said membrane is initially hydrated to such an extent that it is structurally manipulable.

Claim 5

Dependent Claim 15 words

The drug delivery device of claim 1 wherein said membrane comprises a crosslinked HEMA homopolymer.

Claim 6

Dependent Claim 12 words

The drug delivery device of claim 1, which is a monolithic reservoir.

Claim 7

Dependent Claim 13 words

The drug delivery device of claim 1 wherein said carrier is silicone oil.

Claim 8

Independent Claim 90 words

A device for the delayed/sustained release of a compound, said device comprising: (a) a macromolecular compound having a molecular weight greater than about 1,000; (b) a carrier having said macromolecular compound mixed therewith; and (c) an initially partially-hydrated, non-biodegradable, hydrogel rate-limiting membrane, wherein said membrane: (i) comprises a homopolymer or a copolymer material surrounding said carrier and macromolecular compound, (ii) is substantially non-permeable to said macromolecular compound when in said initially partially-hydrated state, and (iii) is hydratable, when placed in a delivery environment, to become permeable to said macromolecular compound.

Claim 9

Independent Claim 90 words

A device for the delayed/sustained release of a compound, said device comprising: (a) a macromolecular compound having a molecular weight greater than about 1,000; (b) a carrier having said macromolecular compound mixed therewith; and (c) an initially partially-hydrated, non-biodegradable, hydrogel rate-limiting membrane, wherein said membrane: (i) comprises a homopolymer or a copolymer material surrounding said carrier and macromolecular compound, (ii) is substantially non-permeable to said macromolecular compound when in said initially partially-hydrated state, and (iii) is hydratable, when placed in a delivery environment, to become permeable to said macromolecular compound.

Claim 10

Dependent Claim 12 words

The drug delivery device of claim 1 useful as an ocular insert.

Claim 11

Dependent Claim 31 words

The drug delivery device of claim 1 wherein said membrane is selected from the group of crosslinked and non-crosslinked homopolymers or copolymers consisting of: HEMA, GMA, HEMA/GMA, HEMA/MMA, GMA/MMA, and HEMA/GMA/MMA.

Claim 12

Dependent Claim 17 words

The drug delivery device of claim 9, which is a reservoir, wherein said carrier is silicone oil.

Claim 13

Dependent Claim 12 words

The drug delivery device of claim 9 useful as an ocular insert.

Claim 14

Dependent Claim 15 words

The drug delivery device of claim 1 wherein said macromolecular drug comprises a hydrophilic polypeptide.

Claim 15

Dependent Claim 23 words

The drug delivery device of claim 1 wherein said macromolecular drug comprises a luteinizing hormone-releasing hormone analog or a pharmaceutically acceptable salt thereof.

Claim 16

Dependent Claim 34 words

The drug delivery device of claim 13 wherein said carrier is saturated with said drug and wherein an excess of said drug in a solid state is disposed in contact with said drug-saturated carrier.

Claim 17

Dependent Claim 22 words

The drug delivery device of claim 13 wherein said analog is a luteinizing hormone-releasing hormone agonist or a pharmaceutically acceptable salt thereof.

Claim 18

Dependent Claim 22 words

The drug delivery device of claim 13 wherein said analog is a luteinizing hormone-releasing hormone antagonist or a pharmaceutically acceptable salt thereof.

Claim 19

Dependent Claim 13 words

The drug delivery device of claim 13 wherein said analog is nafarelin acetate.

Claim 20

Dependent Claim 22 words

The drug delivery device of claim 17 wherein said membrane is initially hydrated to a water content of less than about 30%.

Claim 21

Dependent Claim 20 words

The drug delivery device of claim 17 wherein said membrane is hydratable to an equilibrium water content of about 35%-45%.

Claim 22

Dependent Claim 20 words

The drug delivery device of claim 17 wherein said membrane is hydratable to an equilibrium water content of about 39%.

Claim 23

Dependent Claim 15 words

The drug delivery device of claim 13 wherein said analog is aza-Gly 10 nafarelin acetate.

Claim 24

Dependent Claim 34 words

The drug delivery device of claim 1 wherein said membrane is hydratable to an equilibrium water content such that it limits the diffusion of said macromolecular drug from said carrier to a delivery environment.

Claim 25

Dependent Claim 33 words

The drug delivery device of claim 1 wherein said macromolecular drug is selected from the group consisting of: hormonally active polypeptides, mammalian growth hormones, mammalian growth hormone-releasing hormones, and polypeptides having thymosin activity.

Claim 26

Dependent Claim 103 words

A pharmaceutical formulation for controlled release of a luteinizing hormone-releasing hormone analog, said formulation comprising: (a) a pharmaceutically acceptable carrier; (b) an effective amount of at least one luteinizing hormone-releasing hormone analog or a pharmaceutically acceptable salt thereof disposed in contact with said carrier; and (c) an initially partially-hydrated, non-biodegradable, hydrogel rate-limiting membrane surrounding said carrier, said membrane being: (i) initially hydrated to a water content of about 5% to less than about 30% by weight before placement in a delivery environment, and (ii) hydratable to an equilibrium water content of about 30% to about 80% by weight when in a delivery environment.

Claim 27

Dependent Claim 103 words

A pharmaceutical formulation for controlled release of a luteinizing hormone-releasing hormone analog, said formulation comprising: (a) a pharmaceutically acceptable carrier; (b) an effective amount of at least one luteinizing hormone-releasing hormone analog or a pharmaceutically acceptable salt thereof disposed in contact with said carrier; and (c) an initially partially-hydrated, non-biodegradable, hydrogel rate-limiting membrane surrounding said carrier, said membrane being: (i) initially hydrated to a water content of about 5% to less than about 30% by weight before placement in a delivery environment, and (ii) hydratable to an equilibrium water content of about 30% to about 80% by weight when in a delivery environment.

Claim 28

Dependent Claim 14 words

The formulation of claim 24 wherein said analog is a luteinizing hormone-releasing hormone agonist.

Claim 29

Dependent Claim 14 words

The formulation of claim 24 wherein said analog is a luteinizing hormone-releasing hormone antagonist.

Claim 30

Dependent Claim 11 words

The formulation of claim 24 wherein said analog is nafarelin acetate.

Claim 31

Dependent Claim 145 words

The formulation of claim 25 wherein said analog is a nonapeptide or a decapeptide having the formula: (pyro)Glu-His-V-Ser-W-X-Y-Arg-Pro-Z or a pharmaceutically acceptable salt thereof, wherein: V is tryptophyl, phenylalanyl or 3-(1-naphthyl)-L-alanyl; W is tyrosyl, phenylalanyl or 3-(1-pentafluorophenyl)-L-alanyl; X is a D-amino acid residue having the formula: ##STR5## wherein R is: (a) a carbocyclic aryl-containing radical selected from the group consisting of naphthyl, anthryl, fluorenyl, phenylanthryl, biphenylyl, benzhydryl and phenyl substituted with three or more straight chain lower alkyl groups; or (b) a saturated carbocyclic radical selected from the group consisting of cyclohexyl substituted with three or more straight chain lower alkyl groups, perhydronaphthyl, perhydrobiphenylyl, perhydro-2,2-diphenylmethyl and adamantyl; Y is leucyl, isoluecyl, nor-leucyl or N-methyl-leucyl; and Z is glycinamide or --NH--R 1 , wherein R 1 is lower alkyl, cycloalkyl, fluoro lower alkyl or has the formula: ##STR6## wherein R 2 is hydrogen or lower alkyl.

Claim 32

Dependent Claim 34 words

The formulation of claim 28 wherein: V is tryptophyl or phenylalanyl; W is tyrosyl; X is 3-(2-naphthyl)-D-alanyl or 3-(2,3,6-trimethylphenyl)-D-alanyl; I is leucyl or N-methyl-leucyl; and Z is glycinamide, NHEt or has the formula: ##STR7##

Claim 33

Dependent Claim 20 words

The formulation of claim 24 wherein said luteinizing hormone-releasing hormone analog is (pyro)Glu-His-Trp-Ser-Tyr-3-(naphthyl)-D-alanyl-Leu-Arg-Pro-Gly-NH 2 or a pharmaceutically acceptable salt thereof.

Claim 34

Dependent Claim 47 words

The formulation of claim 30 comprising an ocular insert containing 2.0 mg of said luteinizing hormone-releasing hormone analog suspended in 0.2 ml of a silicone oil carrier, wherein said membrane is a 0.5% EGDMA-crosslinked HEMA homopolymer having an initial water content less than or equal to 29%.

Claim 35

Dependent Claim 19 words

The formulation of claim 24 wherein said luteinizing hormone-releasing hormone analog is (pyro)Glu-His-Trp-Ser-Tyr-3-(naphthyl)-D-alanyl-Leu-Arg-Pro-aza-Gly-NH.sub.2 or a pharmaceutically acceptable salt thereof.

Claim 36

Dependent Claim 47 words

The formulation of claim 32 comprising a reservoir device containing 30.0 mg of said luteinizing hormone-releasing hormone analog suspended in 0.3 ml of a silicone oil carrier, wherein said membrane is a 0.5% EGDMA-crosslinked HEMA homopolymer having an initial water content less than or equal to 29%.

Claim 37

Dependent Claim 31 words

The formulation of claim 24, wherein the luteinizing hormone-releasing hormone is an analog of natural luteinizing hormone-releasing hormone, in which the 6-position residue is changed from Gly to a D-amino acid.

Claim 38

Dependent Claim 16 words

A formulation according to claim 34, wherein the D-amino acid is D-Ala, D-Lue, D-Phe or D-Trp.

Claim 39

Dependent Claim 13 words

A formulation according to claim 34, wherein the D amino acid is D-Leu.

Claim 40

Dependent Claim 13 words

A formulation according to claim 34, wherein the D amino acid is D-Trp.

Claim 41

Dependent Claim 38 words

The formulation according to claim 24, wherein said carrier is selected from the group: (a) aqueous systems; (b) solvents; (c) solid substrates; (d) unpolymerized monomers or comonomers; (e) xerogels; (f) partially hydrated hydrogels; and (g) fully hydrated hydrogels.

Claim 42

Dependent Claim 12 words

The formulation according to claim 38, wherein said carrier is silicone oil.

Claim 43

Dependent Claim 74 words

A drug delivery device for the controlled administration of a macromolecular drug, said device comprising: (a) a pharmaceutically acceptable carrier; (b) a macromolecular drug having a molecular weight greater than about 1,000 disposed in contact with said carrier; and (c) an initially partially-hydrated, non-biodegradable, hydrogel rate-limiting membrane, wherein said membrane: (i) comprises a homopolymer or a copolymer material surrounding said carrier, and (ii) has an initial water content such that it is structurally manipulable.

Claim 44

Dependent Claim 74 words

A drug delivery device for the controlled administration of a macromolecular drug, said device comprising: (a) a pharmaceutically acceptable carrier; (b) a macromolecular drug having a molecular weight greater than about 1,000 disposed in contact with said carrier; and (c) an initially partially-hydrated, non-biodegradable, hydrogel rate-limiting membrane, wherein said membrane: (i) comprises a homopolymer or a copolymer material surrounding said carrier, and (ii) has an initial water content such that it is structurally manipulable.

Claim 45

Dependent Claim 33 words

The drug delivery device of claim 40 wherein said macromolecular drug is selected from the group consisting of: hormonally active polypeptides, mammalian growth hormones, mammalian growth hormone-releasing hormones, and polypeptides having thymosin activity.

Claim 46

Dependent Claim 35 words

The formulation of claim 24 wherein said hydrogel comprises a copolymer of: (a) 50-100 mole % HEMA; (b) 0-50 mole % MMA; (c) 0-10 mole % crosslinking agent; and (d) 0.01-5 mole % polymerization initiator.

Claim 47

Dependent Claim 35 words

The formulation of claim 24 wherein said hydrogel comprises a copolymer of: (a) 75-100 mole % HEMA; (b) 0-25 mole % MMA; (c) 0-5 mole % crosslinking agent; and (d) 0.01-2 mole % polymerization initiator.

Claim 48

Dependent Claim 29 words

The formulation of claim 24 wherein said membrane is selected from the group of crosslinked and non-crosslinked homopolymers or copolymers consisting of: HEMA, GMA, HEMA/GMA, HEMA/MMA, GMA/MMA, and HEMA/GMA/MMA.

Claim 49

Dependent Claim 16 words

The formulation according to claim 24, wherein said membrane comprises a 0.32% EGDMA-crosslinked homopolymer of HEMA.

Claim 50

Dependent Claim 11 words

The formulation according to claim 24, which is a reservoir device.

Claim 51

Dependent Claim 11 words

The formulation according to claim 24 useful as an ocular insert.

Claim 52

Dependent Claim 32 words

The device of claim 7 wherein said membrane is hydratable to an equilibrium water content at which it limits the diffusion of said macromolecular compound from said carrier to a delivery environment.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1993-09-24	1994-03-26	1994-09-25	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	1997-09-24	1998-03-26	1998-09-25	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2001-09-24	2002-03-26	2002-09-25	$7700.00	Window Closed / Lapsed

Delayed/sustained release of macromolecules

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