Compositions for inducing urinary voiding and defecation
Inventors
RICCA, Daniel Joseph • Burgard, Edward C.
Assignees
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Publication Number
US-11352391-B2
Publication Date
2022-06-07
Expiration Date
Abstract
Eleven synthetic neurokinin A peptide analogs are provided as therapeutic compounds for inducing 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). This control over when and where individuals void offers a drastic improvement in quality of life.
Core Innovation
The invention relates to synthetic neurokinin A (NKA) heptapeptide analogs that target NK2 receptor (NK2R/hNK2R). The peptide analogs are identified by amino acid sequences corresponding to SEQ ID NOs: 1-11, including compounds A–K, and are described as tachykinin NK2R agonists for inducing urinary voiding and defecation in mammals.
The disclosed peptides are intended for on-demand induction of voiding/defecation in mammals having voiding/defecation dysfunction, with a therapeutic rationale focused on rapid-onset and short-duration prokinetic activity. The document contrasts the peptide-based approach with other approaches such as catheter/enema and cholinergic agonists, and further discusses minimizing NK1-mediated adverse effects that could be associated with NK1 receptor (NK1R/hNK1R) activity.
The patent also describes formulation and dosing concepts aimed at achieving rapid, on-demand effects, including immediate release dosage form concepts and multiple administration routes. It further discusses handling peptide solubility through hydrophilic versus hydrophobic peptide formulation concepts, and it includes the possibility of using an NK2R antagonist to terminate peptide effects.
Preclinical support described in the document includes receptor binding/affinity and selectivity for hNK2R over hNK1R using radioligand competition binding assays, and functional receptor activation assessed by intracellular calcium mobilization in CHO cells expressing recombinant hNK1R/hNK2R. The document further reports rapid pharmacokinetics in rat plasma and pharmacodynamic efficacy in acute spinal cord injury (aSCI) rat bladder/bowel pressure models and in anesthetized dogs via colorectal pressure manometry.
Claims Coverage
The document provides three independent claims: one covering a selected group of specific synthetic peptide sequences, one covering an as-needed method for inducing urinary voiding and/or defecation using those peptide compositions, and one covering a preparation method for those peptides. Across these independent claims, the inventive coverage centers on the defined peptide sequence set and sequence-restricted peptide-based NK2R agonist use for on-demand voiding/defecation induction, plus chemical synthesis followed by purification.
Selected synthetic peptide sequences
A synthetic peptide selected from the group consisting of the amino acid sequence Asp-Arg-Phe-Val-Gly-(NMe-Leu)-Nle-NH2 (SEQ ID NO: 2); the amino acid sequence Asp-Lys-Phe-Val-(β-Ala)-Leu-Nle-NH2 (SEQ ID NO: 7); the amino acid sequence Asp-Lys-Phe-Val-(β-Ala)-Leu-Met-NH2 (SEQ ID NO: 5); the amino acid sequence Asp-Arg-Phe-Val-(β-Ala)-Leu-Nle-NH2 (SEQ ID NO: 11); the amino acid sequence Asp-Arg-Phe-Val-Gly-(NMe-Leu)-Met-NH2 (SEQ ID NO: 3); and the amino acid sequence Asp-Arg-Phe-Val-(β-Ala)-Leu-Met-NH2 (SEQ ID NO: 9).
As-needed induction of urinary voiding and defecation using a sequence-selected peptide composition
A method for inducing one or both of urinary voiding and defecation in a mammal, which comprises administering on an as-needed basis to the mammal a therapeutically effective amount of a composition comprising a peptide selected from the group consisting of SEQ ID NOs: 2, 3, 5, 7, 9, and 11, or a pharmaceutically acceptable salt thereof, to induce the as-needed one or both of urinary voiding and defecation.
Preparing sequence-selected peptides by chemical synthesis and purification
A method for preparing a peptide selected from the group consisting of SEQ ID NOs: 2, 3, 5, 7, 9, and 11, the method comprising: chemically synthesizing a peptide comprising the amino acid sequence of a peptide selected from the group consisting of SEQ ID NOs: 2, 3, 5, 7, 9, and 11; and purifying the peptide.
Overall, the claim set is anchored by a defined subset of synthetic NKA heptapeptide analog sequences (SEQ ID NOs 2, 3, 5, 7, 9, and 11, within the independent peptide selection) and uses these sequence-selected peptide compositions for as-needed induction of urinary voiding and/or defecation. In parallel, the claims also cover preparing those same sequence-selected peptides by chemically synthesizing and purifying the peptides.
Stated Advantages
Rapid-onset and short-duration prokinetic activity for inducing urinary voiding and defecation.
Improved selectivity for hNK2R over hNK1R, intended to minimize NK1-mediated adverse effects.
On-demand/as-needed induction of urinary voiding and defecation in mammals with dysfunction.
Ability to terminate peptide effects using an NK2R antagonist.
Documented Applications
Inducing one or both of urinary voiding and defecation in a mammal on an as-needed basis in connection with voiding/defecation dysfunction.
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