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Dosage regimes for the administration of glucagon-like-peptide-2 (glp-2) analogues

Pending Publication Date: 2020-01-02
ZEALAND PHARM AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes a method for optimizing the use of a GLP-2 analogue called glepaglutide in the treatment of small intestinal damage caused by chemotherapy or radiation therapy. The method involves administering a specific amount of glepaglutide to the patient and monitoring the changes in their urine volume. By adjusting the amount of glepaglutide, the treatment can be optimized to reduce fluid overload and improve efficacy while avoiding side effects. The method can be carried out early in the treatment and can be repeated at regular intervals to adjust the dosage as the patient's condition progresses. The invention also provides a method for prophylaxis and treatment of small intestinal damage caused by chemotherapy or radiation therapy.

Problems solved by technology

However, the native hGLP-2, a 33 amino acid gastrointestinal peptide, is not a useful in a clinical setting due to its very short half-life in humans of around 7 minutes for full length GLP-2 [1-33] and 27 minutes for truncated GLP-2 [3-33].
However, a major difficulty with the delivery of such therapeutic peptides is their short plasma half-life, mainly due to rapid serum clearance and proteolytic degradation via the action of plasma proteases, necessitating frequent, often daily, injections.
Patients dislike injections, which leads to reduced compliance and reduced drug efficacy.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

of ZP1848 Metabolites

[0127]Solid phase peptide synthesis was performed on a CEM Liberty Peptide Synthesizer using standard Fmoc chemistry. TentaGel S Ram S resin (1.33 g; 0.25 mmol / g) was swelled in DMF (10 ml) prior to use and transferred between tube and reaction vessel using DCM and DMF.

Coupling

[0128]An Fmoc-amino acid in DMF / DCM (2:1; 0.2 M; 5 ml) was added to the resin in a CEM Discover microwave unit together with COMU / DMF (0.5 M; 2 ml) and DIPEA&DMF (2.0 M; 1 ml). The coupling mixture was heated to 75° C. for 5 min while nitrogen was bubbled through the mixture. The resin was then washed with DMF (4×10 ml). Fmoc-Phe-Ser(Psi Me,Me,Pro)-OH pseudoproline was used for amino acid number six and seven.

Deprotection

[0129]Piperidine / DMF (20%; 10 ml) was added to the resin for initial deprotection and the mixture was heated by microwaves (30 sec; 40° C.). The reaction vessel was drained and a second portion of piperidine / DMF (20%; 10 ml) was added and heated (75° C.; 3 min.) again. The...

example 2

50 Measurements

Generation of Cell Line Expressing Human GLP-2 Receptors

[0132]The hGLP2-R was purchased from MRC-geneservice, Babraham, Cambridge as an Image clone: 5363415 (11924-I17). For subcloning into a mammalian expression vector, primers for subcloning were obtained from DNA-Technology, Risskov, Denmark. The 5′ and 3′ primers used for the PCR reaction include terminal restriction sites for cloning and the context of the 5′ primer is modified to a Kozak consensus without changing the sequence of the product encoded by the ORF. A standard PCR reaction was run using Image clone 5363415 (11924-I17) as a template with the above mentioned primers and Polymerase Herculase II Fusion in a total vol. of 50 μl. The generated PCR product was purified using GFX PCR and Gel band purification kit, digested with restriction enzymes and cloned into the mammalian expression vector using Rapid DNA Ligation Kit. Ligation reaction was transformed to XL10 Gold Ultracompetent cells and colonies were...

example 3

inetic and Pharmacodynamic Profiling of GLP-2 Analogues

[0135]A phase 2 clinical trial was conducted to i.a. determine the PK profile of ZP1848 and metabolites in human SBS patients.

Method

[0136]The study was designed as a randomized, cross-over and double-blinded with three different doses of ZP1848 (10 mg, 1 mg, 0.1 mg) in 16 SBS patients.

[0137]The study protocol was approved by the Danish Medical Agency and The Danish Committee on Health Research Ethics.

[0138]The 18 SBS patients (16 patients completed the study) were randomized evenly and in a double-blinded fashion to each of the six cross-over dose level combinations: 10 mg / 1 mg, 10 mg / 0.1 mg, 1 mg / 10 mg, 1 mg / 0.1 mg, 0.1 mg / 10 mg, 0.1 mg / 1 mg of ZP1848. The patients were injected once daily (QD) subcutaneously with the above doses of ZP1848.

[0139]Blood samples for PK analysis were collected on several study visits throughout the study period: the study comprised a 1st baseline balance study (4 days), a 1st treatment period (21 d...

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PUM

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Abstract

Dosage regimes for the administration of glucagon-like-peptide-2 (GLP-2) analogues and their medical use are disclosed, for example in the treatment and / or prevention of stomach and bowel-related disorders and for ameliorating side effects of chemotherapy and radiation therapy. Dosage regimes for the administration of glucagon-like-peptide-2 (GLP-2) analogues for inducing longitudinal growth of the intestines are described, for example for the treatment of patients with short bowel syndrome (SBS). Medical uses for adjusting the volume of parenteral support (PS) provided to subjects receiving treatment with GLP-2 analogues in response to the treatment and to algorithms for determining PS volume changes are also described.

Description

SEQUENCE LISTING[0001]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jul. 12, 2019 is named ‘50412-113001—Sequence Listing’ and is 4,592 bytes in size.FIELD OF THE INVENTION[0002]The present invention relates to dosage regimes for the administration of glucagon-like-peptide-2 (GLP-2) analogues and their medical use, for example in the treatment and / or prevention of stomach and bowel-related disorders and for ameliorating side effects of chemotherapy and radiation therapy. The present invention further relates to dosage regimes for the administration of glucagon-like-peptide-2 (GLP-2) analogues for inducing longitudinal growth of the intestines, for example for the treatment of patients with short bowel syndrome (SBS). The present invention further relates to medical uses for adjusting the volume of parenteral support (PS) provided to subje...

Claims

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Application Information

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IPC IPC(8): A61K38/26A61K9/00A61P1/00
CPCA61K38/26A61P1/00A61K9/0019C07K14/605
Inventor SONNE, KIMMOURITZEN, ULRIKGLERUP, PETERJEPPESEN, PALLE BEKKER
Owner ZEALAND PHARM AS
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