US 7,070,803 B2 · Controlled release pharmaceutical composition for oral use containing midodrine and/or active metabolite, desglymidodrine

Abstract

Novel controlled release pharmaceutical compositions for oral use containing midodrine and/or its active metabolite desglymidodrine. The novel compositions are designed to release midodrine and/or desglymidodrine after oral intake in a manner which enables absorption to take place in the gastrointestinal tract so that a relatively fast peak plasma concentration of the active metabolite desglymidodrine is obtained followed by a prolonged and relatively constant plasma concentration of desglymidodrine. The novel compositions may be designed for administration once or twice daily, i.e. a therapeutically effective concentration of desglymidodrine is maintained for a period of at least 10-16 hours followed by a wash out period of about 8-12 hours in order to avoid the well-known midodrine related side effect with respect to supine hypertension. The therapeutically effective concentration of desglymidodrine is regarded as a plasma concentration of desglymidodrine of at least about 3 ng/ml. A composition is designed to release midodrine and/or desglymidodrine in at least the following consecutive steps: i) an initial relatively fast release of midodrine and/or desglymidodrine (in order to obtain a relatively fast onset of action), ii) a steady release or a slower release than in step 1 of midodrine and/or desglymidodrine (in order to maintain a plasma concentration of desglymidodrine which is prolonged and relatively constant), iii) a second rise in release of midodrine and/or desglymidodrine (in order to take advantage of absorption from the colon, i.e. such a second rise release is designed to take place when the composition (or the disintegrated parts of the composition) reaches the colon; normally this is regarded to take about 8 hours after oral intake, and iv) a decline in release rate corresponding to that essentially all midodrine and/or desglymidodrine have been released from the composition. Also disclosed is a method for treating orthostatic hypotension and/or urinary incontinence, the method comprising administration to a patient in need thereof of an effective amount of midodrine and/or desglymidodrine in a composition according to the invention.

Claims27

Dependent claims

A controlled release pharmaceutical composition for oral use comprising midodrine (ST 1085) or a pharmaceutically acceptable salt thereof and/or its active metabolite desglymidodrine (ST 1059) or a pharmaceutically acceptable salt thereof,

wherein the in vitro release rate of midodrine and/or desglymidodrine has the following course of events
i) a relatively fast first initial release followed by
ii) a steady release or a slower release than in step i) above, which is followed by
iii) a second rise in release rate that takes place 5-10 hours after start of an in vitro dissolution test and, finally,
iv) a decline in release rate
wherein the composition upon administration provides a relatively fast peak plasma concentration of desglymidodrine, and a therapeutically effective plasma concentration of desglymidodrine is maintained for at least about 9 hours.

3 more elements

wherein the in vitro release rate of midodrine and/or desglymidodrine has the following course of events
i) a relatively fast first initial release followed by
ii) a steady release or a slower release than in step i) above, which is followed by
iii) a second rise in release rate that takes place 5-10 hours after start of an in vitro test and, finally,
iv) a decline in release rate
and wherein the release pattern of midodrine and/or desglymidodrine from the composition—when tested in vitro employing an in vitro dissolution method as described herein—is as follows (±30% w/w of the values stated below):
about 28% w/w is released about 30 min after start of the test,
about 35% w/w is released about 1 hour after start of the test,
about 41% w/w is released about 2 hours after start of the test,
about 45% w/w is released about 3 hours after start of the test,
about 55% w/w is released about 4 hours after start of the test,
about 70 w/w is released about 6 hours after start of the test,
about 78% w/w is released about 7 hours after start of the test,
about 90% w/w is released about 8 hours after start of the test,
about 95% w/w is released about 10 hours after start of the test, and
about 100% w/w is released about 12 hours after start of the test.

13 more elements

Dependencies are inferred from the claim text.

Controlled release pharmaceutical composition for oral use containing midodrine and/or active metabolite, desglymidodrine

Life of this patent

Controlled release pharmaceutical composition for oral use containing midodrine and/or active metabolite, desglymidodrine

Life of this patent

Abstract

Claims27