Particulate Constructs For Release of Active Agents

a technology of active agents and constructs, applied in the field of compositions, can solve the problems of increasing the solubility of hydrophobic drugs, unable to meet the requirements of small particles, and ineffective approaches in small particles, and achieves the effect of reducing toxicity and high loading capacity

Inactive Publication Date: 2008-12-04
CELATOR PHARMA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0024]The present invention provides particulate constructs that can be adapted to the release of active agents of various types useful in both pharmaceutical and non-pharmaceutical applications. These delivery systems provide high loading capacity for active compounds as well as provide a means for controlled release of the active, reduction in toxicity where relevant, and, if desired, selective delivery to a target site. The active agents may include various therapeutic agents such as platinum agents, taxanes and antibiotics, actives important in other applications such as pigments, dyes, fragrances and flavors, and may be applied in in vivo therapeutic and diagnostic contexts, in agricultural applications and in industrial uses.

Problems solved by technology

This approach is not effective in smaller particles, such as nanoparticles.
While the art provides many descriptions for preparation of nanoparticles containing active agents, none is completely satisfactory.
Conjugation of drugs to PEG has been shown to provide long circulation times in vivo, and increases the solubility of hydrophobic drug.
According to this disclosure, other phospholipids such as phosphatidyl inositol and phosphatidyl glycerol are unworkable in this system.
Despite the substantial number of preparations of microparticle, matrix chelator and nanoparticle formulations designed for drug delivery and other applications, an ideal composition has not been achieved.
Due to this complexity, achieving cures with a single agent has been met with limited success.
Administration of free drug cocktails often results in rapid clearance of one or all of the drugs before reaching the tumor site.

Method used

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  • Particulate Constructs For Release of Active Agents
  • Particulate Constructs For Release of Active Agents
  • Particulate Constructs For Release of Active Agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

Conjugation of Paclitaxel to Vitamin E Succinate (VitES)

[0137]280 mg of VitES were dissolved in 20 ml of dichloromethane and brought to 0° C. Then, 27 μL of diisopropylcarbodiimide were added, followed by 150 mg of paclitaxel and 33 mg of dimethylaminopyridine. The reaction vessel was warmed to room temperature, and left to react for 16 hours. The reaction solution was washed with 0.1 N hydrochloric acid, dried with magnesium sulfate, filtered, and dried in vacuo. The product was characterized and verified to be paclitaxel-VitES by High Performance Liquid Chromatography (HPLC) and Nuclear Magnetic Resonance (NMR) analysis.

example 2

Conjugation of Paclitaxel to Polycaprolactone with Terminal Carboxylic Acids

[0138]A. 79 mg of PCL (MW 2.2 kg / mole, PCL2.2) end-terminated with carboxylic acid groups were dissolved in 20 ml of dichloromethane and brought to 0° C. 26 μL of diisopropylcarbodiimide were added, followed by 146 mg of paclitaxel and 32 mg of dimethylaminopyridine. The reaction vessel was warmed to room temperature, left to react for 16 hours, and washed with 0.1 N hydrochloric acid, dried with magnesium sulfate, filtered, and dried in vacuo. The amount of excess paclitaxel in the reaction product was reduced by recrystallization from amyl acetate. The product was characterized and verified as PCL-paclitaxel by HPLC and NMR analysis.

[0139]B. The procedure of paragraph A was also carried out using PCL1.45 and PCL3.5.

example 3

Nanoparticles with Methoxy Polyethylene Glycol-Polycaprolactone (mPEG-PCL) and Paclitaxel-VitE

[0140]As a control, 15 mg of methoxy polyethylene glycol-(MW 5 kg / mole)-polycaprolactone (methoxy polyethylene glycol molecular weight of 5 kg / mole, PCL molecular weight of 7 kg / mole) (mPEG5-PCL7) in THF to make a 1 wt % solution (w:w) of mPEG5-PCL7. Then, 8 mg of paclitaxel and 10 mg of VitES were added to the solution and mixed using the vortex mixer at a flow rate of 12 ml / min against water at 120 ml / min. Crystals were visible about 20 minutes after mixing, and no particles were detected by Dynamic Light Scattering (DLS).

[0141]20 mg of mPEG5-PCL7 were dissolved in THF to make a 0.5 wt % solution. Then, 23 mg of paclitaxel-VitES along with 17.4 mg VitES prepared as described in Example 1 was added to make a 0.58 wt % paclitaxel-VitES solution, and mixed using the vortex mixer at a flow rate of 12 ml / min against water at 120 ml / min. Nanoparticles with an average diameter of 126 nm, as dete...

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Abstract

Particulate constructs stabilized by amphiphilic copolymers and comprising at least one active coupled to a hydrophobic moiety provide sustained release of the active in both in vitro and in vivo environments.

Description

RELATED APPLICATION[0001]This application claims benefit of U.S. application Ser. No. 60 / 589,164 filed 19 Jul. 2004, which is incorporated herein by reference in its entirety.TECHNICAL FIELD[0002]The description relates to compositions and methods for improved delivery and performance of active agents. More particularly, the invention concerns particulate constructs stabilized by an amphiphilic compound and comprising at least one active agent coupled through a linker to a hydrophobic moiety, which agent can be released from the construct by cleavage of the linker.BACKGROUND ART[0003]Sustained release is desirable in many applications to provide optimal use and effectiveness of active agents, including pharmaceuticals, cosmetics, food, and fragrances. Attempts have been made to solubilize, target, stabilize, and control the release of substances, including use of microparticles, nanoparticles, and polymer conjugation.[0004]Approaches based on using polymer encapsulation to formulate...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/14A61K47/14A61K8/30A61K47/30A61K47/42
CPCA61K8/85A61K9/5153A61K45/06A61K47/48107A61K47/48115A61K47/48176A61K47/48192A61K47/48215A61K47/48907A61K2800/57A61Q17/04B82Y5/00A61K47/22A61K47/482A61K47/60A61K47/552A61K47/58A61K47/593A61K47/6935A61K47/551A61K47/59A61K47/543A61K47/545A61K47/55A61K47/6931A61K47/54
Inventor MAYER, LAWRENCE D.PRUD'HOMME, ROBERT K.ALLEN, CHRISTINE J.SAAD, WALID S.
Owner CELATOR PHARMA INC
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