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Bendamustine solid dispersions and continuous infusion

A technology of solid dispersion and bendamustine, which is applied in the direction of liquid delivery, drug delivery, powder delivery, etc., and can solve the problems of time-consuming, cumbersome, increasing potency, loss of impurities, etc.

Inactive Publication Date: 2016-11-09
V·沃道里斯
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition to being tedious and time-consuming for the health care professional responsible for reconstituting the product, prolonged exposure of bendamustine to water during the reconstitution process increases due to loss of potency through product hydrolysis with water and formation of impurities. possibility

Method used

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  • Bendamustine solid dispersions and continuous infusion
  • Bendamustine solid dispersions and continuous infusion
  • Bendamustine solid dispersions and continuous infusion

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0179] Example 1: HPLC procedure

[0180] Bendamustine and bendamustine degradation products are measured by high performance liquid chromatography according to Method 1 or Method 2 below.

[0181] method 1

[0182]

[0183] method 1

[0184] parameter value

[0185] Running time: 36 minutes

[0186] result:

[0187] The retention times for some bendamustine impurities using Method 1 described above are shown in Table 1.

[0188]

[0189] HP2 is a compound seen in formula V resulting from further hydrolysis of HP1.

[0190]

example 2

[0191] Example 2: Bendamustine / mannitol-based composition without hydrolysis degradation products.

[0192] Two batches (Batch 1 and Batch 2) each having a different pharmaceutical composition were produced, the pharmaceutical composition comprising a solid dispersion in dry powder form and substantially free of hydrolytic degradation products. For each batch, two pre-dried intermediate compositions are formulated in separate containers. For batch 1, an aqueous pre-dried composition consisting of 2380 mg of mannitol dissolved in 70 ml of water was formulated. The non-aqueous pre-dried composition was prepared by dissolving 1400 mg of bendamustine in 70 ml of n-propanol. For batch 2, the aqueous pre-dried composition consisted of 1190 mg of mannitol dissolved in 70 ml of water. A non-aqueous pre-dried composition was prepared by dissolving 700 mg of bendamustine hydrochloride in 70 ml of ethanol. The ethanol / bendamustine solution can be cooled to minimize the degree of possible...

example 3

[0206] Example 3. Amorphous solid dispersion.

[0207] Two batches (Batch 3 and Batch 4) each having a different pharmaceutical composition were produced, the pharmaceutical composition comprising a solid dispersion in dry powder form and substantially free of hydrolytic degradation products. For each batch, a pre-dried intermediate composition is formulated in an acceptable container. This pre-dried intermediate composition consists of an organic solvent, bendamustine hydrochloride and excipients soluble in the organic solvent. Use a non-aqueous pre-dried solution. For batch 3, it was obtained by dissolving 600 mg of bendamustine HCL and 3000 mg of Plasdone K-17 (polyvinylpyrrolidone, PVP) in 120 ml of pure ethanol. The ratio of PVP to bendamustine is 5:1. Therefore, the total solids ratio of this batch is 3.0%. Batch 4 was obtained by dissolving 300 mg of bendamustine HCL and 900 mg of HPMC-AS in 40 ml of pure methanol. The ratio of HPMC-AS to bendamustine is 3:1. The tot...

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Abstract

Provided herein are pharmaceutical compositions comprising nitrogen mustard, for example bendamustine hydrochloride, solid dispersions substantially free of degradants. Also provided are methods of producing and administering nitrogen mustards and in particular bendamustine hydrochloride solid dispersions substantially free of degradants. The pharmaceutical compositions can be used for any disease that is sensitive to treatment with bendamustine hydrochloride, such as neoplastic diseases.

Description

[0001] Cross reference [0002] This patent application claims the benefit of U.S. Provisional Application No. 61 / 952,624 filed on March 13, 2014, the contents of which are hereby incorporated by reference in their entirety. Technical field [0003] Provided herein are pharmaceutical compositions for the treatment of various disease states such as tumor diseases and autoimmune diseases, methods of use thereof, and methods of preparation thereof. Useful pharmaceutical compositions include nitrogen mustards, such as nitrogen mustards bendamustine such as bendamustine hydrochloride. Background technique [0004] The following description includes information that may be useful in understanding the embodiments herein. It is not an admission that any such information is prior art to the embodiments claimed herein, or is related to the embodiments claimed herein, or that any publications mentioned explicitly or implicitly are prior art. [0005] Due to their high reactivity in aqueous sol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/14A61K9/16A61K9/19A61K31/4184
CPCA61K9/0019A61K9/145A61K9/1623A61K9/19A61K31/4184A61P35/00A61P35/02A61K9/10A61K9/08A61K9/146A61K47/26
Inventor V·沃道里斯
Owner V·沃道里斯