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Gastrin compositions and formulations, and methods of use and preparation

a technology of compositions and formulations, applied in the field of gastrin compositions and formulations, and methods of use and preparation, can solve the problems of short plasma half-life, lower drug concentration than is required to be effective, and insufficient clearance of a therapeutic agent, so as to achieve the effect of high therapeutic efficacy and short plasma half-li

Inactive Publication Date: 2004-12-30
WARATAH PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These agents are often eliminated by the kidneys within a short period of time or are destroyed by proteases therefore limiting their bioavailability, resulting in short plasma half-life and lower drug concentrations than are required to be efficacious.
A high clearance of a therapeutic agent is not optimal in cases where it is desired to maintain a high serum level over an extended period of time to obtain maximal efficacy.
Increased doses or increased frequency of administration often result in a higher therapeutic efficacy but a higher risk of side effects as well, limiting the dose or frequency that can be administered.
Many peptide hormones have extremely short half-lives in the bloodstream, resulting in the loss of biological activity not long after administration.
However, when gastrin is administered alone, there is only limited efficacy.
In addition, it has been found that gastrin has a relatively short half life.

Method used

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  • Gastrin compositions and formulations, and methods of use and preparation
  • Gastrin compositions and formulations, and methods of use and preparation

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0100] Pharmacokinetic Example of Unmodified Gastrin Following Administration by Intravenous Injection to Male Cynomolgus Monkeys

[0101] This example was conducted to assess the pharmacokinetic (PK) profile of unmodified gastrin (referred to herein as compound B; see Table 3) following administration by a single intravenous injection to male cynomolgus monkeys. The 17 amino acid gastrin analog used has a single amino acid change at position 15, where methionine has been substituted by leucine. While compound B thus is not identical to naturally occurring gastrin, all available evidence indicates that it is functionally equivalent to gastrin.

[0102] Terms associated with PK analysis terms are defined as follows:

[0103] C.sub.max--The maximum observed plasma concentration

[0104] t.sub.max.--The time to maximum concentration

[0105] AUC--Area under the curve, a measure of total exposure to a drug over a period of time

[0106] Plasmat.sub.1 / 2--A measure of how long a drug stays in the blood. th...

example 2

[0117] Effect of Unmodified Gastrin on Fasting Blood Glucose Levels and Pancreatic Insulin Content in NOD Mice with Recent Onset Diabetes

[0118] Non-obese diabetic (NOD) female mice were monitored for diabetes development as determined by a fasting blood glucose (FBG) level of >6.6 mmol / l. After diabetes onset, mice were treated with (i) vehicle (n=4); or, (ii) gastrin (compound B as listed in Table 3) in the amount of 3 .mu.g / kg / day, given i.p. once daily (n=5) for 14 days. Mice did not receive insulin-replacement treatment. Fasting blood glucose levels and pancreatic insulin content were assessed for the two treatment groups at both day 0 and day 35 (21 days after cessation of treatment).

[0119] FIG. 1 shows that in the vehicle-treated control animals, fasting blood glucose levels (FBG) were doubled after 35 days. In contrast, treatment with gastrin prevented some of the increase in glucose levels from rising in the diabetic NOD mice, however, the FBG levels remained significantly h...

example 3

[0121] Peptide Synthesis of Gastrin Peptides

[0122] Gastrin peptides may be readily synthesized by anyone with ordinary skills in the art, using standard techniques for solid phase peptide synthesis, for example as described by Steward, J. M. and Young, J. D. (1984) in "Solid Phase Peptide Synthesis", 2.sup.nd ed., Pierce Chemical Company. Purification of gastrin peptides may be performed using standard techniques, for example using reverse phase HPLC with a volatile binary gradient system consisting of 0.1% TFA in H.sub.2O and 0.1% TFA in acetonitrile. Monitoring elution by UV absorbance allows for collection of purified peptide, which is then lyophilized to dryness and subsequently dissolved for administration and testing, or for further conjugation reactions where required.

[0123] Gastrin synthetic peptides may be synthesized containing any consecutive portion of residues 1-28 in addition to residues 29-34 of SEQ ID NO: 1 or 2 or containing any consecutive portion of residues 1-11 ...

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Abstract

An embodiment of the invention provided herein is a pharmaceutical composition comprising a gastrin compound having an extended activity upon administration to a subject in comparison with native gastrin. Methods are provided of conjugating portions of the amino acid sequence of gastrin having functional ability to bind to the gastrin / CCK receptor, to various carrier moieties, including the use of amino acid spacer regions, and use of bifunctional cross-linking reagents. Methods of treating a diabetes patient with the compositions are provided.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 60 / 428,100, filed Nov. 21, 2002, and U.S. Provisional Application No. 60 / 428,562, filed Nov. 22, 2002, and U.S. Provisional Application No. 60 / 430,590, filed Dec. 3, 2002, U.S. Provisional Application No. 60 / ______, filed Nov. 14, 2003, and is a continuation in part of U.S. application Ser. No. 10 / 691,123, filed Oct. 22, 2003, which claims the benefit of U.S. Provisional Application No. 60 / 420,187, filed Oct. 22, 2002, and U.S. Provisional Application No. 60 / 420,399, filed Oct. 22, 2002.[0002] The invention in various embodiments provides gastrin compositions having longer active function in vivo than gastrin peptides, and methods of making and using the gastrin compositions for treatment of diabetes.BACKGROUND OF INVENTION[0003] Therapeutic agents such as peptides and low molecular weight proteins used in the treatment of diseases suffer from significant limitations. These agents are often eliminated by ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K45/06A61KA61K31/133A61K31/135A61K31/136A61K31/14A61K31/343A61K31/436A61K31/519A61K31/52A61K31/573A61K31/675A61K38/00A61K38/08A61K38/10A61K38/16A61K38/18A61K38/21A61K38/22A61K38/28A61K39/385A61K39/395A61K48/00A61P3/10A61P37/06A61P43/00C07K14/595
CPCA61K31/436A61K38/1808A61K38/2207A61K47/48046A61K47/48215A61K2300/00A61K38/26A61K47/60A61K47/543A61P3/10A61P37/06A61P43/00A61K38/16A61K38/10
Inventor CRUZ, ANTONIO
Owner WARATAH PHARMA INC
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