Compositions and methods for inducing urinary voiding and defecation
Inventors
Thor, Karl B. • Kullmann, Florenta Aura
Assignees
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Publication Number
US-10086034-B2
Publication Date
2018-10-02
Expiration Date
Abstract
Methods, pharmaceutical formulations, and kits are provided for using neurokinin 2 receptor agonists to effectuate voluntary “on-demand” voiding of urine and feces in mammals who cannot void without external invasion of the bladder and bowel or those who void involuntarily (i.e., those having urinary and/or fecal incontinence). The pharmaceutical formulations and kits can also be useful for inducing voiding of urine and defecation in mammals that do not have a voiding dysfunction such as, for example, in a person who is comatose and may void unconsciously or in a pet at a convenient location at a specific time. The methods and compositions provide patients with voiding dysfunction control over when and where they void.
Core Innovation
The invention provides a method for inducing one or both of urinary voiding and defecation in a mammal by administering, on an as-needed basis, a therapeutically effective amount of a neurokinin 2 receptor (NK2R) agonist with selectivity over neurokinin 1 (NK1R) and neurokinin 3 (NK3R) receptors. The NK2R agonist is an NKA analogue, or a pharmaceutically acceptable salt thereof, and is formulated as an immediate release dosage form. The administering is by a mode selected from transmucosal, intramuscular, and subcutaneous routes.
The NK2R agonist or pharmaceutically acceptable salt has a rapid onset and a short duration of action to induce as-needed urinary voiding and/or defecation. Dependent refinements describe that the as-needed administering occurs up to about 5 minutes before the desired voiding and/or defecation. Additional refinements define pharmacokinetic timing characteristics for the short duration of action, including T1/2 ranges and rapid-onset thresholds such as Tmax.
The disclosed approach further includes an optional counter-regimen in which an NK2R antagonist, or pharmaceutically acceptable salt, is administered to terminate at least a majority of the effects of the NK2R agonist. The NK2R antagonist is constrained by a duration of action less than about 4 hours. The document also identifies representative NK2R agonist embodiments by listing specific NKA analogues, including [Lys5,MeLeu9,Nle10]-NKA(4-10) (SEQ ID NO:1), and other NKA analogue candidates by name and sequence identifiers.
Claims Coverage
The patent contains three independent claims. Across these, the coverage centers on as-needed induction of urinary voiding and/or defecation using an NK2R-selective NKA analogue agonist in an immediate release dosage form, treatment of urinary voiding/defecation dysfunction using the same class of agonist with rapid-onset and short-duration characteristics, and a claim specifically directed to [Lys5,MeLeu9,Nle10]-NKA(4-10) (SEQ ID NO:1).
As-needed NK2R-selective NKA-analogue induction via immediate release and selected administration routes
Administering on an as-needed basis a therapeutically effective amount of an NK2R agonist that has selectivity over NK1R and NK3R, wherein the NK2R agonist is a NKA analogue, or a pharmaceutically acceptable salt, formulated as an immediate release dosage form, and wherein administration is by transmucosal, intramuscular, or subcutaneous routes; the NK2R agonist has a rapid onset and a short duration of action to induce the as-needed one or both of urinary voiding and defecation.
Immediate release [Lys5,MeLeu9,Nle10]-NKA(4-10) as-needed voiding/defecation induction via selected administration routes
Administering on an as-needed basis a therapeutically effective amount of [Lys5,MeLeu9,Nle10]-NKA(4-10) (SEQ ID NO:1), or a pharmaceutically acceptable salt, formulated as an immediate release dosage form, with administration by transmucosal, intramuscular, or subcutaneous routes, to induce the as-needed one or both of urinary voiding and defecation.
As-needed NK2R-selective NKA-analogue treatment of urinary voiding/defecation dysfunction with rapid onset and short duration
Administering on an as-needed basis to a mammal in need of treatment a therapeutically effective amount of an NK2R agonist with selectivity over NK1R and NK3R, wherein the NK2R agonist is a NKA analogue, or a pharmaceutically acceptable salt, formulated as an immediate release dosage form, with administration by transmucosal, intramuscular, and subcutaneous routes, and wherein the NK2R agonist has a rapid onset and a short duration of action to induce the as-needed one or both of urinary voiding and defecation.
Overall claim coverage is directed to inducing and treating urinary voiding and/or defecation using an NK2R agonist that is selective over NK1R and NK3R, implemented as an NKA analogue, or salt, in an immediate release dosage form and administered via transmucosal, intramuscular, or subcutaneous routes, with rapid-onset and short-duration characteristics.
Stated Advantages
Rapid onset induction of as-needed urinary voiding and/or defecation.
Short duration of action to support on-demand induction.
Optional termination of NK2R agonist effects by administering an NK2R antagonist with a duration of action less than about 4 hours.
Documented Applications
Inducing one or both of urinary voiding and defecation in a mammal on an as-needed basis, including in mammals in need of such induction.
Treating one of urinary voiding and defecation dysfunction in a mammal in need of treatment by as-needed administration of an NK2R-selective NKA-analogue agonist.
Voidance and defecation dysfunction arising from conditions including spinal cord injury, traumatic brain injury, multiple sclerosis, spina bifida, degenerative brain disease, Alzheimer’s, Parkinson’s, dementia, diabetes, advanced age, or postoperative status.
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