Methods and formulations for the delivery of pharmacologically active agents

a technology formulations, applied in the field of formulations of pharmacologically active agents, can solve the problems of limiting the full potential of the very effective paclitaxel molecule, the association of significant side effects of the cremophor formulation, and the inability to deliver intravenously

Inactive Publication Date: 2011-03-03
ABRAXIS BIOSCI LLC
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the quest for next generation therapies to treat cancer, scientist often discover promising compounds only to find that the molecule is highly insoluble in water, and hence impossible to deliver intravenously.
Such was the problem with paclitaxel, an extremely effective anti-tumor agent discovered over a quarter century ago by the Nation Cancer Institute.
The cremophor formulation of paclitaxel is associated with significant side-effects including life-threatening allergic reactions requiring the need for steroid pre-treatment for every patient receiving the drug, and severe infections as a result of lowering of white blood cells requiring the need for expensive blood cell growth factors.
Ultimately these toxicities result in dose-limitation of cremophor-based paclitaxel formulations...

Method used

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  • Methods and formulations for the delivery of pharmacologically active agents
  • Methods and formulations for the delivery of pharmacologically active agents
  • Methods and formulations for the delivery of pharmacologically active agents

Examples

Experimental program
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example 1

Preclinical Studies Confirm the Modulation of Paclitaxel Release by the Protein Nanosphere and Increased Efficacy of Equi-dose of ABI-007 vs Taxol

[0051]Using radio labeled paclitaxel, the enahanced intra-cellular availability of paclitaxel has been confirmed following injection of ABI-007. In addition, the entrapment of Cremophor-bound paclitaxel has also been confirmed. This difference in findings correlates with in-vivo studies in mice bearing human breast cancer, with the finding that ABI-007 at equi-dose to Taxol, resulted in improved outcomes that these 130 nanometer size particles distributed throughout the body.

[0052]Thus, human MX-1 mammary tumor fragments were implanted subcutaneously in female athymic mice. Radiolabelled drug was administered when tumors reached about 500 mm3. Tritium-labelled ABI-007 or tritium-labelled Taxol were administered at a dose of 20 mg / kg. Both groups received about 7-10 μCi / mouse of tritium-labelled paclitaxel. Saline was used as the diluent fo...

example 2

Toxicity Studies

[0056]Toxicity was assessed for Taxol, cremophor and ABI-007. ABI-007 was found to be 50-fold less toxic than Taxol, and 30-fold less toxic than the cremophor vehicle alone, as illustrated in the following table:

AgentLD50, mg / kgTaxol9.4Cremophor13.7ABI-007448.5

example 3

In vivo Tumor Xenografts

[0057]Human tumor fragments were implanted subcutaneously in female athymic mice. Treatment was initiated when tumors reached about 150 mm3. The mice received either CONTROL (saline), ABI-007 (4 dose levels: 13.4, 20, 30 and 45 mg / kg) or TAXOL (3 dose levels: 13.4, 20, and 30 mg / kg) administered I.V. daily for 5 days. Saline was used as the diluent for both drugs.

[0058]Determination of Equitoxic dose or MTD: The Equitoxic dose or MTD for each drug was determined by satisfying one of the following criteria:[0059]a) Dose for each drug that resulted in similar body weight loss (≦20%) if no deaths were seen;[0060]b) If body weight loss could not be matched, the highest dose at which no deaths were seen;[0061]If neither a) nor b) could be satisfied, the lowest dose that resulted in similar death rate.

[0062]Tumor response to the drugs was compared at the Equitoxic dose or MTD established as above. Results for several different tumor types are presented in FIGS. 4-8...

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Abstract

In accordance with the present invention, novel formulations have been developed which are much more effective for the delivery of hydrophobic drugs to patients in need thereof than are prior art formulations. Invention formulations are capable of delivering more drug in shorter periods of time, with reduced side effects caused by the pharmaceutical carrier employed for delivery.

Description

RELATED APPLICATIONS[0001]The present application is a continuation of U.S. Ser. No. 11 / 240,940, filed Sep. 29, 2005, now pending, which is a continuation of U.S. Ser. No. 10 / 146,706, filed May 14, 2002, now abandoned, which is a continuation-in-part of U.S. Ser. No. 09 / 628,388, filed Aug. 1, 2000, now issued U.S. Pat. No. 6,506,405, which is a divisional of U.S. Ser. No. 08 / 926,155, filed Sep. 9, 1997, now issued as U.S. Pat. No. 6,096,331, which is a continuation-in-part of U.S. Ser. No. 08 / 720,756, filed Oct. 1, 1996, now issued as U.S. Pat. No. 5,916,596, and U.S. Ser. No. 08 / 485,448, filed Jun. 7, 1995, now U.S. Pat. No. 5,665,382, which is, in turn, a continuation-in-part of U.S. Ser. No. 08 / 200,235, filed Feb. 22, 1994, now issued as U.S. Pat. No. 5,498,421, which is, in turn, a continuation-in-part of U.S. Ser. No. 08 / 023,698, filed Feb. 22, 1993, now issued as U.S. Pat. No. 5,439,686 and U.S. Ser. No. 08 / 035,150, filed Mar. 26, 1993, now issued as U.S. Pat. No. 5,362,478, t...

Claims

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Application Information

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IPC IPC(8): A61K9/14A61K31/337A61P35/00A23L33/00A61K9/00A61K9/50A61K9/51A61K47/48A61K49/18A61K49/22
CPCA23L1/296A61K9/0026A61K9/5052A61K9/5138A61K9/5146A61K9/5161B82Y5/00A61K47/48869A61K47/48876A61K49/0002A61K49/222A61K49/223A61K49/226A61K9/5169A23L33/40A61K47/6925A61K47/6927A61P35/00
Inventor SOON-SHIONG, PATRICKDESAI, NEIL P.
Owner ABRAXIS BIOSCI LLC
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