Michael P Heffernan, 6637 Armbruster Rd, Rochester, NY 14623

7038085, May 2, 2006

Oct 22, 2003

10/691465

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

Collegium Pharmaceutical, Inc. - Cumberland RI

C07C 233/05
A61K 31/165

564165, 564164, 564171, 564190, 514620, 514624

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.

7704527, Apr 27, 2010

Sep 16, 2008

12/211780

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

Collegium Pharmaceutical, Inc. - Cumberland RI

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

424468, 424464, 424465, 424474

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.

8021687, Sep 20, 2011

Apr 7, 2010

12/755847

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

Collegium Pharmaceutical, Inc. - Cumberland RI

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

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

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.

8512751, Aug 20, 2013

Dec 20, 2005

11/793392

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

Collegium Pharmaceutical, Inc. - Cumberland RI

A61K 31/4164

424488, 514385

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.

2004012, Jun 24, 2004

Oct 22, 2003

10/690872

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

Collegium Pharmaceutical, Inc.

A61K009/22
A61K031/165

424/468000, 514/620000

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.

2004012, Jun 24, 2004

Oct 23, 2003

10/691936

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

Collegium Pharmaceutical, Inc.

A61K009/22
A61K031/165

514/620000, 424/468000

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.

2004013, Jul 8, 2004

Oct 22, 2003

10/690947

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

A61K009/22
A61K031/165

514/620000, 424/468000

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.

2006000, Jan 5, 2006

Jul 29, 2005

11/192697

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

A61K 9/22

424468000

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.