Michael E Heffernan

US Patent:

7038085, May 2, 2006

Filed:

Oct 22, 2003

Appl. No.:

10/691465

Inventors:

Roman V. Rariy - Allston MA, US
Michael Heffernan - Hingham MA, US
Stephen L. Buchwald - Newton MA, US
Timothy M. Swager - Newton MA, US

Assignee:

Collegium Pharmaceutical, Inc. - Cumberland RI

International Classification:

C07C 233/05
A61K 31/165

US Classification:

564165, 564164, 564171, 564190, 514620, 514624

Abstract:

The present invention relates generally to the enantiomers of para-hydroxy-milnacipran or congeners thereof. Biological assays revealed that racemic para-hydroxy-milnacipran is approximately equipotent in inhibiting serotonin and norepinephrine uptake (IC=28. 6 nM for norepinephrine, IC=21. 7 nM for serotonin). Interestingly, (+)-para-hydroxy-milnacipran is a more potent inhibitor of norepinephrine uptake than serotonin uptake (IC=10. 3 nM for norepinephrine, IC=22 nM for serotonin). In contrast, (−)-para-hydroxy-milnacipran is a more potent inhibitor of serotonin uptake compared to norepinephrin uptake (IC=88. 5 nM for norepinephrine, IC=40. 3 nM for serotonin). The invention also relates to salts and prodrug forms of the aforementioned compounds. In certain embodiments, the compounds of the present invention and a pharmaceutically acceptable excipient are combined to prepare a formulation for administration to a patient. Finally, the present invention relates to methods of treating mammals suffering from various afflictions, e. g.

US Patent:

7704527, Apr 27, 2010

Filed:

Sep 16, 2008

Appl. No.:

12/211780

Inventors:

Jane C. Hirsh - Wellesley MA, US
Roman V. Rariy - Allston MA, US
Shubha Chungi - Chestnut Hill MA, US
Srinivas G. Rao - Encinitas CA, US
Michael T. Heffernan - Hingham MA, US

Assignee:

Collegium Pharmaceutical, Inc. - Cumberland RI

International Classification:

A61K 9/22
A61K 9/20
A61K 9/28

US Classification:

424468, 424464, 424465, 424474

Abstract:

A milnacipran formulation that provides delayed and extended release of milnacipran has been developed. The formulation comprises milnacipran or a salt thereof; an extended release excipient, and a delayed release excipient. The formulation provides, upon administration to a human subject, a Tof 4-10 hours.

US Patent:

8021687, Sep 20, 2011

Filed:

Apr 7, 2010

Appl. No.:

12/755847

Inventors:

Jane C. Hirsh - Wellesley MA, US
Roman V. Rariy - Allston MA, US
Shubha Chungi - Chestnut Hill MA, US
Srinivas G. Rao - Encinitas CA, US
Michael T. Heffernan - Hingham MA, US

Assignee:

Collegium Pharmaceutical, Inc. - Cumberland RI

International Classification:

A61K 9/14
A61K 31/56
A61K 9/28
A61P 29/00
A61P 25/24
A61P 25/06
A61P 25/08
A61P 25/22
A61P 25/18
A61P 11/08
A61P 11/06
A61P 9/00
A61P 1/00
A61P 21/02

US Classification:

424465, 424490, 424497, 424498, 424494, 424495, 424496, 514619, 514171

Abstract:

A milnacipran formulation that provides delayed and extended release of milnacipran has been developed. The formulation comprises milnacipran or a salt thereof; an extended release excipient, and a delayed release excipient. The formulation provides, upon administration to a human subject, a Tof 4-10 hours.

US Patent:

8512751, Aug 20, 2013

Filed:

Dec 20, 2005

Appl. No.:

11/793392

Inventors:

Roman V. Rariy - Allston MA, US
Michael Heffernan - Hingham MA, US

Assignee:

Collegium Pharmaceutical, Inc. - Cumberland RI

International Classification:

A61K 31/4164

US Classification:

424488, 514385

Abstract:

Pharmaceutical compositions are provided for the pharmacological treatment of breathing disorders and, more specifically, to compositions containing agents having serotonin receptor modulating activity for the alleviation of sleep apnea (central and obstructive) and other sleep-related breathing disorders wherein the active ingredients are released such as to extend effective blood plasma concentrations across the period of sleep.

US Patent:

20040121010, Jun 24, 2004

Filed:

Oct 22, 2003

Appl. No.:

10/690872

Inventors:

Jane Hirsh - Wellesley MA, US
Roman Rariy - Allston MA, US
Michael Heffernan - Hingham MA, US

Assignee:

Collegium Pharmaceutical, Inc.

International Classification:

A61K009/22
A61K031/165

US Classification:

424/468000, 514/620000

Abstract:

A once-a-day oral milnacipran pulsatile release composition has been developed that releases the drug in spaced apart “pulses”. The dosage forms are comprised of first, second and optional third dosage units, with each dosage unit having a different drug release profile. This dosage form provides in vivo drug plasma levels characterized by Cbelow 3000 ng/ml, preferably below 2000 ng/ml, and most preferably below 1000 ng/ml. These levels help to avoid stimulation of the cholinergic effects on the CNS. The composition allows milnacipran to be delivered over approximately 24 hours, when administered to a patient in need, resulting in diminished incidence or decreased intensity of common milnacipran side effects such as sleep disturbance, nausea, vomiting, headache, tremulousness, anxiety, panic attacks, palpitations, urinary retention, orthostatic hypotension, diaphoresis, chest pain, rash, weight gain, back pain, constipation, vertigo, increased sweating, agitation, hot flushes, tremors, fatigue, somnolence, dyspepsia, dysoria, nervousness, dry mouth, abdominal pain, irritability, and insomnia.

US Patent:

20040122104, Jun 24, 2004

Filed:

Oct 23, 2003

Appl. No.:

10/691936

Inventors:

Jane Hirsh - Wellesley MA, US
Roman Rariy - Allston MA, US
Shubha Chungi - Sharon MA, US
Michael Heffernan - Hingham MA, US

Assignee:

Collegium Pharmaceutical, Inc.

International Classification:

A61K009/22
A61K031/165

US Classification:

514/620000, 424/468000

Abstract:

A once-a-day oral milnacipran modified release formulation has been developed. The formulation comprises an extended release dosage unit (optionally containing the immediate release portion) coated with delayed release coating. The milnacipran composition, when administered orally, first passes through the stomach releasing from zero to less than 10% of the total milnacipran dose and then enters the intestines where drug is released slowly over an extended period of time. The release profile is characterized by a 0.05-4 hours lag time period during which less than 10% of the total milnacipran dose is released followed by a slow or extended release of the remaining drug over a defined period of time. The composition provides in vivo drug plasma levels characterized by Tat 4-10 hours and an approximately linear drop-off thereafter and Cbelow 3000 ng/ml, preferably below 2000 ng/ml, and most preferably below 1000 ng/ml. The composition allows milnacipran to be delivered over approximately 24 hours, when administered to a patient in need, resulting in diminished incidence or decreased intensity of common milnacipran side effects such as sleep disturbance, nausea, vomiting, headache, tremulousness, anxiety, panic attacks, palpitations, urinary retention, orthostatic hypotension, diaphoresis, chest pain, rash, weight gain, back pain, constipation, vertigo, increased sweating, agitation, hot flushes, tremors, fatigue, somnolence, dyspepsia, dysoria, nervousness, dry mouth, abdominal pain, irritability, and insomnia.

US Patent:

20040132826, Jul 8, 2004

Filed:

Oct 22, 2003

Appl. No.:

10/690947

Inventors:

Jane Hirsh - Wellesley MA, US
Roman Rariy - Allston MA, US
Shubha Chungi - Sharon MA, US
Michael Heffernan - Hingham MA, US
Srinivas Rao - San Diego CA, US

International Classification:

A61K009/22
A61K031/165

US Classification:

514/620000, 424/468000

Abstract:

A once-a-day oral milnacipran modified release formulation has been developed. The formulation comprises an extended release dosage unit (optionally containing the immediate release portion) coated with delayed release coating. The milnacipran composition, when administered orally, first passes through the stomach releasing from zero to less than 10% of the total milnacipran dose and then enters the intestines where drug is released slowly over an extended period of time. The release profile is characterized by a 0.05-4 hours lag time period during which less than 10% of the total milnacipran dose is released followed by a slow or extended release of the remaining drug over a defined period of time. The composition provides in vivo drug plasma levels characterized by Tat 4-10 hours and an approximately linear drop-off thereafter and Cbelow 3000 ng/ml, preferably below 2000 ng/ml, and most preferably below 1000 ng/ml. The composition allows milnacipran to be delivered over approximately 24 hours, when administered to a patient in need, resulting in diminished incidence or decreased intensity of common milnacipran side effects such as sleep disturbance, nausea, vomiting, headache, tremulousness, anxiety, panic attacks, palpitations, urinary retention, orthostatic hypotension, diaphoresis, chest pain, rash, weight gain, back pain, constipation, vertigo, increased sweating, agitation, hot flushes, tremors, fatigue, somnolence, dyspepsia, dysoria, nervousness, dry mouth, abdominal pain, irritability, and insomnia.

US Patent:

20060003004, Jan 5, 2006

Filed:

Jul 29, 2005

Appl. No.:

11/192697

Inventors:

Jane Hirsh - Wellesley MA, US
Roman Rariy - Allston MA, US
Michael Heffernan - Hingham MA, US

International Classification:

A61K 9/22

US Classification:

424468000

Abstract:

A once-a-day oral milnacipran pulsatile release composition has been developed that releases the drug in spaced apart “pulses”. The dosage forms are comprised of first, second and optional third dosage units, with each dosage unit having a different drug release profile. This dosage form provides in vivo drug plasma levels characterized by Cbelow 3000 ng/ml, preferably below 2000 ng/ml, and most preferably below 1000 ng/ml. The composition provides pulsatile release of milnacipran to produce a therapeutic effect over approximately 24 hours, when administered to a patient in need, resulting in diminished incidence or decreased intensity of common milnacipran side effects such as sleep disturbance, nausea, vomiting, headache, tremulousness, anxiety, panic attacks, palpitations, urinary retention, orthostatic hypotension, diaphoresis, chest pain, rash, weight gain, back pain, constipation, vertigo, increased sweating, agitation, hot flushes, tremors, fatigue, somnolence, dyspepsia, dysoria, nervousness, dry mouth, abdominal pain, irritability, and insomnia.