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Veldoreotide with poor solubitliy in physiological conditions for use in the treatment of acromegaly, acromegaly cancer, sst-r5 expressing tumors, type 2 diabetes, hyperglycemia, and hormone-related tumors

A technology of vedoretide and dextrose, applying vedoretide with poor solubility under physiological conditions for the treatment of acromegaly, acromegaly cancer, SST-R5 expressing tumor, type II In the field of diabetes, hyperglycemia and hormone-related tumors, it can solve the problems of poor solubility, increased dosage, low solubility, etc.

Pending Publication Date: 2019-03-12
STRONGBRIDGE IRELAND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Once vedoreotide was tested in humans, it was found that although vedoreotide acetate has the same GH inhibitory receptor affinity as octreotide, when the two are injected in lactate buffer, in order to achieve the same pharmacology Effect requires increased dose
After investigating what caused this problem, it was found that vedoretide acetate is poorly soluble under physiological conditions, resulting in "flip-flop" pharmacokinetics
Previous studies with vedoretide acetate have found that injectable solutions of vedoretide acetate lead to adverse injection site reactions and limited bioavailability due to its relatively low solubility in isotonic solutions

Method used

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  • Veldoreotide with poor solubitliy in physiological conditions for use in the treatment of acromegaly, acromegaly cancer, sst-r5 expressing tumors, type 2 diabetes, hyperglycemia, and hormone-related tumors
  • Veldoreotide with poor solubitliy in physiological conditions for use in the treatment of acromegaly, acromegaly cancer, sst-r5 expressing tumors, type 2 diabetes, hyperglycemia, and hormone-related tumors
  • Veldoreotide with poor solubitliy in physiological conditions for use in the treatment of acromegaly, acromegaly cancer, sst-r5 expressing tumors, type 2 diabetes, hyperglycemia, and hormone-related tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0161] The solubility of vedoretide acetate in aqueous media was screened by the following method. A fixed amount of 10 mg of peptide was weighed and dissolved by increasing volume (incremental) of the test medium at ambient temperature until complete solubility was observed, i.e. a clear / transparent solution and no precipitation occurred (solubility was determined according to USP guidelines endpoint value). Following the results of the screening studies, various media were selected for validation studies based on quantitative assessment of peptide concentration (maximum solubility) by HPLC. The results of the screening study are described in Table 1, while the results of the validation study are included in Table 2. From the data it can be concluded that vedoretide acetate exhibits high solubility in water and other aqueous media, while being limited by limited solubility in isotonic media.

[0162] Table 1: Solubility Screening of Vedoretide Acetate

[0163]

[0164] ...

Embodiment 2

[0187] The effect of vedoreotide acetate on the density, pH and surface tension of water is shown in Table 4. It has been found that vedoreotide acetate behaves as a peptide amphiphile and lowers the surface tension of water. However, the reduction in water surface tension was not in a dose-dependent manner, suggesting that vedoretide acetate acts as a hydrotrope rather than a surfactant.

[0188] Tween 80 was used as a control surfactant for comparison. Density was measured with a fixed volume of 1 mL of sample. All tests were repeated three times at 25°C. The effect of vetoreotide acetate on the pH of double distilled water (DDW) was the same at all vetoreotide acetate concentrations. The pH 5.0 of DDW was lowered to pH 4.5. The effect of vedoretide acetate on DDW density (the initial density of DDW is 1.003g / ml) is concentration-dependent from 1.4mg / ml to 21.5mg / ml, and the density is in the range of 0.986 to 0.998g / ml respectively . However, at vedoretide acetate con...

Embodiment 3

[0222] Preparation of Vedoretide Acetate Immediate Release Formulations (Groups 1M-6M) for Injection into HSD: SPRAGUE In rats, as shown in Table 8 below. The lactic acid vehicle for the formulations shown in Table 7 below was prepared as follows:

[0223] Table 7

[0224]

[0225] The formulations prepared for rat injection are summarized in Table 8.

[0226] Each treatment was injected into test rats in groups of 5 rats (average weight of each subject was about 370 g) according to the above-mentioned dosing regimen. Baseline tail blood samples from rats were collected 2 days prior to dosing. For group 1M, blood samples were taken at 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours after dosing. For groups 2M-6M, tail blood samples were collected at 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 8 hours, 12 hours and 24 hours after dosing. Blood samples were approximately 300 uL whole blood collected in commercially available...

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Abstract

The present invention provides compositions comprising water soluble peptides with poor solubility in isotonic solutions which exhibit enhanced bioavailability with reduced adverse effects including injection site reactions. Methods are also disclosed for using such compositions for the treatment of diseases including, but not limited to, cancer, type 2 diabetes, acromegaly, metabolic disorders, endocrine disorders, exocrine tumors, and hormone-related tumors. Methods to reduce adverse injection site reactions and improve bioavailability are also disclosed.

Description

field of invention [0001] The present disclosure relates to pharmaceutical compositions comprising a peptide or a pharmaceutically acceptable salt thereof, wherein the peptide is soluble in water but has low solubility under physiological conditions and methods for using such pharmaceutical compositions . Background technique [0002] A major problem hindering the use of linear peptides as pharmaceuticals is related to the fact that such peptides exist in rapid equilibrium between multiple conformations, only a very small number of which are biologically active. Such mobility results in poor selectivity, rapid proteolytic digestion, and low bioavailability. One of the best ways to overcome this problem is through cyclization, which introduces conformational constraints into the peptide. [0003] In naturally occurring cyclic peptides, cyclization links together specific side chains and / or terminal groups in the peptide. These cyclization patterns, referred to as classical...

Claims

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Application Information

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IPC IPC(8): A61K38/00A61K9/00A61K31/00A61P5/00A61P35/00A61P3/00
CPCA61K38/00A61K9/0019A61P3/00A61P35/00A61P5/00A61P3/10A61K38/27
Inventor M·阿法甘
Owner STRONGBRIDGE IRELAND LTD
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