US5122384A — Oral once-per-day organic nitrate formulation whi…

Claim 1

Independent Claim 146 words

A controlled-release organic nitrate formulation for once-per-day oral administration, comprising spheres having a core including sugar spheres coated with at least one organic nitrate; a seal coat formed over said core; and a diffusion control membrane surrounding said seal coat comprising a pharmaceutically acceptable, film forming polymer, said film forming polymer being present in an amount effective to permit release of said at least one organic nitrate from said spheres, over a 24 hour dosing period, at a rate of release that achieves a therapeutically effective level of the at least one organic nitrate for at least 16 hours after administration of the nitrate formulation, while providing less than therapeutically effective levels of the at least one organic nitrate for the remainder of the 24 hour dosing period so as not to induce nitrate tolerance in a patient administered the nitrate formulation once every 24 hours.

Claim 2

Dependent Claim 146 words

A controlled-release organic nitrate formulation for once-per-day oral administration, comprising spheres having a core including sugar spheres coated with at least one organic nitrate; a seal coat formed over said core; and a diffusion control membrane surrounding said seal coat comprising a pharmaceutically acceptable, film forming polymer, said film forming polymer being present in an amount effective to permit release of said at least one organic nitrate from said spheres, over a 24 hour dosing period, at a rate of release that achieves a therapeutically effective level of the at least one organic nitrate for at least 16 hours after administration of the nitrate formulation, while providing less than therapeutically effective levels of the at least one organic nitrate for the remainder of the 24 hour dosing period so as not to induce nitrate tolerance in a patient administered the nitrate formulation once every 24 hours.

Claim 3

Dependent Claim 26 words

The controlled-release organic nitrate formulation according to claim 1, wherein said core further comprises a glidant selected from the group consisting of talc and silicon dioxide.

Claim 4

Dependent Claim 26 words

The controlled-release organic nitrate formulation according to claim 1, wherein said seal coat is formed by coating said core with a solution comprising povidone in alcohol.

Claim 5

Dependent Claim 21 words

The controlled-release organic nitrate formulation according to claim 1, wherein the formulation is in the form of a capsule or tablet.

Claim 6

Dependent Claim 83 words

The controlled-release organic nitrate formulation of claim 1, wherein the film forming polymer is present in an amount effective to permit release of said at least one organic nitrate from said spheres at a rate of release that achieves a therapeutically effective level of the at least one organic nitrate for about 18 hours after administration of the nitrate formulation, while providing less than therapeutically effective levels of the at least one organic nitrate for the remainder of the 24 hour dosing period.

Claim 7

Dependent Claim 33 words

The controlled-release organic nitrate formulation according to claim 1, wherein said at least one organic nitrate is a member selected from the group consisting of nitroglycerin, isosorbide 5-mononitrate, isosorbide dinitrate, and mixtures thereof.

Claim 8

Dependent Claim 19 words

The controlled-release organic nitrate formulation according to claim 6, wherein said at least one organic nitrate is isosorbide 5-mononitrate.

Claim 9

Dependent Claim 19 words

The controlled-release organic nitrate formulation according to claim 6, wherein said at least one organic nitrate is isosorbide dinitrate.

Claim 10

Dependent Claim 22 words

The controlled-release organic nitrate formulation according to claim 6, wherein said membrane comprises ethylcellulose, a methacrylic acid co-polymer, or a pharmaceutical glaze.

Claim 11

Dependent Claim 18 words

The controlled-release organic nitrate formulation according to claim 6, wherein said at least one organic nitrate is nitroglycerin.

Claim 12

Dependent Claim 16 words

The controlled-release organic nitrate formulation according to claim 10, wherein said nitroglycerin comprises a nitroglycerin triturate.

Claim 13

Dependent Claim 27 words

The controlled-release organic nitrate formulation according to claim 11, wherein said nitroglycerin triturate includes a member selected from the group consisting of lactose, mannitol, and mixtures thereof.

Claim 14

Dependent Claim 19 words

The controlled-release organic nitrate formulation according to claim 11, wherein said nitroglycerin triturate includes 1-20 percent by weight nitroglycerin.

Claim 15

Dependent Claim 73 words

The controlled-release organic nitrate formulation according to claim 11, wherein said rate of release of the nitroglycerin triturate is approximately equivalent to a rate of release of the nitroglycerin triturate as measured in vitro in a basket assembly according to U.S. Pharmacopoeia XXI, wherein less than 30% of the nitroglycerin triturate is released after 1 hour of measurement, and less than 90% of the nitroglycerin triturate is released after 24 hours of measurement.

Claim 16

Dependent Claim 18 words

The controlled-release organic nitrate formulation according to claim 7, wherein said isosorbide 5-mononitrate comprises an isosorbide 5-mononitrate triturate.

Claim 17

Dependent Claim 28 words

The controlled-release organic nitrate formulation according to claim 15, wherein said isosorbide 5-mononitrate triturate includes a member selected from the group consisting of lactose, mannitol, and mixtures thereof.

Claim 18

Dependent Claim 22 words

The controlled-release organic nitrate formulation according to claim 15, wherein said isosorbide 5-mononitrate triturate includes about 5-100 percent by weight isosorbide 5-mononitrate.

Claim 19

Dependent Claim 96 words

The controlled-release organic nitrate formulation according to claim 15, wherein said rate of release of the isosorbide 5-mononitrate triturate is approximately equivalent to a rate of release of the isosorbide 5-mononitrate triturate as measured in vitro in a basket assembly according to U.S. Pharmacopoeia XXI Apparatus II, paddle method, wherein less than 30% of the isosorbide 5-mononitrate triturate is released after 1 hour of measurement, less than 65% of the isosorbide 5-mononitrate triturate is released after 4 hours of measurement, and less than 90% of the isosorbide 5-mononitrate triturate is released after 12 hours of measurement.

Claim 20

Dependent Claim 18 words

The controlled-release organic nitrate formulation according to claim 8, wherein said isosorbide dinitrate comprises a isosorbide dinitrate triturate.

Claim 21

Dependent Claim 24 words

The controlled-release organic nitrate formulation according to claim 19, wherein said isosorbide dinitrate triturate comprises about 1 to 90% percent by weight isosorbide dinitrate.

Claim 22

Dependent Claim 102 words

The controlled-release organic nitrate formulation according to claim 19, wherein said rate of release of the isosorbide dinitrate triturate is approximately equivalent to a rate of release of the isosorbide dinitrate triturate as measured in vitro in a basket assembly according to U.S. Pharmacopoeia XXI Apparatus II, paddle method, in a 7.5 pH phosphate buffer, wherein less than 30% of the isosorbide dinitrate triturate is released after 1 hour of measurement, less than 75% of the isosorbide dinitrate triturate is released after 8 hours of measurement, and less than 100% of the isosorbide dinitrate triturate is released after 16 hours of measurement.

Claim 23

Dependent Claim 14 words

The controlled-release organic nitrate formulation according to claim 9, wherein said membrane includes plasticizer.

Claim 24

Dependent Claim 35 words

The controlled-release organic nitrate formulation according to claim 22, wherein said plasticizer is selected from the group consisting of diethyl sebacate, crotonic acid, diethyl phthalate, polyethylene glycol, citric acid esters, castor oil, and mixtures thereof.

Claim 25

Dependent Claim 15 words

The controlled-release organic nitrate formulation according to 22, wherein said membrane includes a porosity modifier.

Claim 26

Dependent Claim 15 words

The controlled-release organic nitrate formulation according to 22, wherein said membrane includes a porosity modifier.

Claim 27

Dependent Claim 26 words

The controlled-release organic nitrate formulation according to claim 24, wherein said porosity modifier is selected from the group consisting of talc and salts of fatty acids.

Claim 28

Dependent Claim 28 words

The controlled-release organic nitrate formulation according to claim 24, wherein said membrane is applied as a suspension comprising ethylcellulose, 1,2,3 propanetriol triacetate and sorbitol powder in a co-solvent.

Claim 29

Dependent Claim 46 words

The controlled-release organic nitrate formulation according to claim 26, wherein said suspension comprises, by weight per volume, 5% ethylcellulose, 0.1% 1,2,3 propanetriol triacetate, and 1.7% sorbitol powder in a co-solvent system of about one part by volume methylene chloride and about two parts by volume isopropanol.

Claim 30

Dependent Claim 47 words

The controlled-release organic nitrate formulation according to claim 26, wherein said membrane is applied as a solution comprising ethylcellulose and diethyl phthalate in a co-solvent system of about one part by volume methylene chloride to about two parts by volume isopropanol, along with talc and calcium stearate.

Claim 31

Independent Claim 166 words

A method of treating a mammal by the once-per-day oral administration of organic nitrate comprising: orally administering once during each 24 hour time period a controlled-release organic nitrate formulation comprising spheres having a core including sugar spheres coated with at least one organic nitrate; a seal coat formed over said core; and a diffusion control membrane surrounding said seal coat comprising a pharmaceutically acceptable, film forming polymer, said film forming polymer being present in an amount effective to permit release of said at least one organic nitrate from said spheres, over a 24 hour dosing period, at a rate of release that achieves a therapeutically effective level of the at least one organic nitrate for at least 16 hours after administration of the nitrate formulation, while providing less than therapeutically effective levels of the at least one organic nitrate for the remainder of the 24 hour dosing period so as not to induce nitrate tolerance in a patient administered the nitrate formulation once every 24 hours.

Claim 32

Independent Claim 166 words

A method of treating a mammal by the once-per-day oral administration of organic nitrate comprising: orally administering once during each 24 hour time period a controlled-release organic nitrate formulation comprising spheres having a core including sugar spheres coated with at least one organic nitrate; a seal coat formed over said core; and a diffusion control membrane surrounding said seal coat comprising a pharmaceutically acceptable, film forming polymer, said film forming polymer being present in an amount effective to permit release of said at least one organic nitrate from said spheres, over a 24 hour dosing period, at a rate of release that achieves a therapeutically effective level of the at least one organic nitrate for at least 16 hours after administration of the nitrate formulation, while providing less than therapeutically effective levels of the at least one organic nitrate for the remainder of the 24 hour dosing period so as not to induce nitrate tolerance in a patient administered the nitrate formulation once every 24 hours.

Claim 33

Dependent Claim 80 words

The method of claim 29, wherein the film forming polymer is present in an amount effective to permit release of said at least one organic nitrate from said spheres at a rate of release that achieves a therapeutically effective level of the at least one organic nitrate for about 18 hours after administration of the nitrate formulation, while providing less than therapeutically effective levels of the at least one organic nitrate for the remainder of the 24 hour dosing period.

Claim 34

Dependent Claim 39 words

The method of treating a mammal according to claim 29, wherein the treating comprises treating the human mammal for congestive heart failure, systemic hypertension, pulmonary hypertension, cardiomyopathic heart, valvular heart disease, vasospastic disease, congenital heart disease, or esophageal spasms.

Claim 35

Dependent Claim 32 words

The method of treating a mammal according to claim 29, wherein said at least one organic nitrate is a member selected from the group consisting of nitroglycerin, isosorbide 5-mononitrate, and isosorbide dinitrate.

Claim 36

Dependent Claim 19 words

The method of treating a mammal according to claim 32, wherein said at least one organic nitrate is nitroglycerin.

Claim 37

Dependent Claim 20 words

The method of treating a mammal according to claim 32, wherein said at least one organic nitrate is isosorbide 5-mononitrate.

Claim 38

Dependent Claim 20 words

The method of treating a mammal according to claim 32, wherein said at least one organic nitrate is isosorbide dinitrate.

Claim 39

Dependent Claim 70 words

The method of treating a mammal according to claim 33, wherein said rate of release of the nitroglycerin is approximately equivalent to a rate of release of said nitroglycerin as measured in vitro in a basket assembly according to U.S. Pharmacopoeia XXI, wherein less than 30% of the nitroglycerin is released after 1 hour of measurement, and less than 90% of said nitroglycerin is released after 24 hours of measurement.

Claim 40

Dependent Claim 93 words

The method of treating a mammal according to claim 34, wherein said rate of release of the isosorbide 5-mononitrate is approximately equivalent to a rate of release of said isosorbide 5-mononitrate as measured in vitro according to dissolution testing in accordance with U.S. Pharmacopoeia XXI Apparatus II, paddle method, wherein less than 30% of said isosorbide 5-mononitrate is released after 1 hour of measurement, less than 65% of said isosorbide 5-mononitrate is released after 4 hours of measurement, and less than 90% of said isosorbide 5-mononitrate is released after 12 hours of measurement.

Claim 41

Dependent Claim 99 words

The method of treating a mammal according to claim 35, wherein said rate of release of said isosorbide dinitrate is approximately equivalent to a rate of release of said isosorbide dinitrate as measured in vitro according to dissolution testing in accordance with U.S. Pharmacopoeia XXI Apparatus II, paddle method, in a 7.5 pH phosphate buffer, wherein less than 30% of said isosorbide dinitrate is released after 1 hour of measurement, less than 75% of said isosorbide dinitrate is released after 8 hours of measurement, and less than 100% of said isosorbide dinitrate is released after 16 hours of measurement.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1995-06-16	1995-12-16	1996-06-16	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	1999-06-16	1999-12-16	2000-06-16	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2003-06-16	2003-12-16	2004-06-16	$7700.00	Window Closed / Lapsed

Oral once-per-day organic nitrate formulation which does not induce tolerance

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