Pharmaceutical kit comprising midodrine as active drug...

Details Pharmaceutical kit comprising midodrine as active drug... Pharmaceutical kit comprising midodrine as active drug...

2001-03-29

2004-07-13

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S465000, C424S468000

Reexamination Certificate

active

06761904

ABSTRACT:

The present Invention relates to a method for treating mammals (such as, e.g., humans) in need thereof with a novel controlled release pharmaceutical composition for oral use containing midodrine and/or its active metabolite desglymidodrine together with a relatively fast onset composition of midodrine and/or its active metabolite desglymidodrine. The present invention also relates to a kit comprising a controlled release composition, e.g. intended for administration once or twice daily, together with one or more relatively fast onset compositions for supplemental and individual administration.
The invention also relates to a pharmaceutical composition comprising comprising midodrine (ST 1085) or a pharmaceutically acceptable salt thereof and/or its active metabolite desglymidodrine (ST 1059) or a pharmaceutically acceptable salt thereof, the composition being adapted to provide midodrine and/or desglymidodrine in such a manner that a relatively fast therapeutically effective concentration of desglymidodrine is obtained after administration of the composition.
The novel controlled release 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. However, the patient may due to individual needs or because of activities during the day experience situations where an increase in the plasma concentration is needed for an optimal treatment regimen. Therefore, the patient may on an individual basis supply the controlled release composition with one or more administrations of a quick release composition or another composition providing a relatively fast onset.
The indications of midodrine include symptomatic orthostatic hypotension, orthostatic intolerance, symptomatic hypotension (e.g. hypotension associated with infections, the convalescent period, surgical operations, delivery, changes in the weather as well as what is called “difficulties in getting started in the mornings”), as well as in the control of hypotensive side effects of hypnotics and psychotropics. Futhermore, midodrine is expected to be effective in the treatment of urinary incontinence. Many of these indications call for a very individual treatment regimen where a basic “all day” treatment supplied with one or more fast onset formulations are very beneficial.
In another aspect, the invention relates to a method for treating 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 controlled release composition according to the invention together with one or more fast onset compositions comprising an effective amount of midodrine and/or desglymidodrine.
One of the advantages of the invention is that the controlled release composition provides a base line plasma concentration, which during most of the day is therapeutically effective. When a higher concentration is needed, only a minor supply of active drug substance is necessary to obtain a very fast relief from symptoms. If the constant base line plasma concentration was absent, it would be necessary to use a relative higher fast onset dose to reach the high therapeutically effective level. The high therapeutically effective level may be due to individual circumstances in the patient or may be a consequence of physical routines and/or the nature of the underlying disease. The situations and symptoms are often well recognized and experienced by the patient himself. The kit according to the present invention is a superior tool for obtaining an optimal treatment with a minimum of active drug substance.
The novel compositions are also designed for administration once or twice daily, preferably once 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. In the present context a therapeutically effective concentration of desglymidodrine is defined as a plasma concentration of desglymidodrine of at least about 3 ng/ml such as, e.g. at least about 3.2 ng/ml, at least about 3.5 ng/ml, at least about 3.7 ng/ml, at least about 4.0 ng/ml, at least about 4.2 ng/ml, at least about 4.5 ng/ml, at least about 4.7 ng/ml or at least about 5 ng/ml.
BACKGROUND OF THE INVENTION
Controlled release midodrine compositions are known from the prior art, e.g. U.S. Pat. No. 5,128,144 (Korsatko-Waabnegg et al.), EP-B-0 164 571 (CL Pharma Aktiengesellschaft) and AT-8-B-383 270 (Chemie Linz Aktiengesellschaft). However, in none of these documents are any compositions intended for less frequent administration such as, e.g., once or twice daily and furthermore, there is no indication of absorption of midodrine (or its active metabolite) from the colon.
DISCLOSURE OF THE INVENTION
Midodrine is a prodrug, which is activated within the human body by an enzymatic hydrolysis to release the therapeutically active metabolite desglymidodrine. Desglymidodrine acts by a stimulation of &agr;
1
receptors. Midodrine is used in the treatment of symptomatic orthostatic hypotension. Disorders causing orthostatic hypotension are
Generalized Primary Autonomic Failure
Pure autonomic failure or idiopathic orthostatic hypotension (Bradbury-Eggleston syndrome)
Pure autonomic failure with multiple-system atrophy or Shy-Drager syndrome
Acute pandysautonomia (panautonomic neuropathy)
Familial dysautonomia (Riley-Day syndrome)
Partial Primary Autonomic Failure
Dopamine E-hydroxylase deficiency
Postural orthostatic tachycardia syndrome (length-dependent autonomic neuropathy)
Monoamine oxidase deficiency
Pure vasomotor failure
Disorders of Idiopathic Orthostatic Intolerance
Postural orthostatic tachycardia syndrome
Mitral valve prolapse
Due to prolonged bed rest or space flight
Due to asthenic habitus
Disorders of the Central Nervous System
Tumors (hypothalamic, parasellar, posterior fossa)
Multiple cerebral infarcts
Wernicke's encephalopathy
Tabes dorsalis
Traumatic and inflammatory myelopathies
Parkinson's disease
Hereditary system degenerations
Syringomyelia
Dysautonomia of advanced age
Multiple sclerosis
Systemic Diseases with Autonomic Neuropathy
Botulism
Diabetic neuropathy
Primary systemic amyloidosis
Guillain-Barrésyndrome
Porphyria
Lambert-Eaton myasthenic syndrome
Paraneoplastic autonomic neuropathy
Uremic neuropathy
Connective tissue disease
Tangier and Fabry's diseases
Vincristine and heavy metal neuropathies
Leprosy
B
12
deficiency
4 Chronic Chagas' disease
Propafenone neuropathy (16)
Endorcine-metabolic Disorders
Primary and secondary adrenocortical insufficiency
Pheochromocytoma
Marked potassium depletion
Severe hypoaldosteronism
Latrogenic Causes
Antihypertensive drugs (&Dgr;-methyldopa, guanethidine, prazosin, E blockers)
Psychotropic drugs (phenothiazines, butyrophenones)
Antiparkinsonian drugs (Sinemet, Parlodel)
Vasodilator drugs (nitrates)
Certain illicit drugs (marijuana)
Thoracolumbar sympathectomy
Disorders with Diminished Cardiac Output
Reduced intravascular volume
Acute and chronic blood loss
Fluid loss due to vomiting, diarrhea, diuretics
Gastrectomy with the dumping syndrome
Salt-losing nephropathy
Altered capillary permeability
Impaired venous return
Severe varicose veins
Venous obstruction (late pregnancy)
Reflex and pharmacologic vasodilatation
Muscle wasting and prolonged recumbency
Intrinsic cardiac disease
Myocardial infarct
Arrhythmias
Restrictive pericardial/myocardial diseases
Miscellaneous Causes
Hyperbradykinnism
Chronic renal hemodialysis
Anorexia nervosa
Reduced aortic compliance
Mastocytosis
Baroreflex failure.
Furthermore, midodrine may be used in disorders retrograde ejaculation; disorder of semen ejaculation, or to attenuate symptoms o

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