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Nanoparticulate formulations and methods for the making and use therof

Inactive Publication Date: 2009-01-01
MARINUS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0021]In yet another embodiment, the present invention is directed to a method for preparing stabilized drug particles, comprising: a) reducing the size of drug particles capable of forming a cyclodextrin inclusion complex and having an aqueous solubility of less than 1 mg / ml in a pH of about 7.4 into a size range of about 50 nm to about 200 nm; b) adding an effective amount of a surface stabilizer to the drug particles before, during or after reducing the size of the drug particles to form particles comprising the drug and the surface stabilizer; and c) further stabilizing the particles of step b) by adding an effective amount of a complexing agent capable of forming a cyclodextrin inclusion complex to provide particles that attain a stabilized size such that the volume weighted median diameter (D50) of the particles is from about 50 nm to about 500 nm.
[0079]“Treat” or “treatment” refers to any treatment of a disorder or disease, such as preventing the disorder or disease from occurring in a subject which may be predisposed to the disorder or disease, but has not yet been diagnosed as having the disorder or disease; inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or reducing the symptoms of the disease or disorder.

Problems solved by technology

The drugs that would benefit from this approach are limited to those that can form a cyclodextrin complex.

Method used

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  • Nanoparticulate formulations and methods for the making and use therof
  • Nanoparticulate formulations and methods for the making and use therof
  • Nanoparticulate formulations and methods for the making and use therof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of USP Simulated Gastric and Intestinal Fluid

Simulated Intestinal Fluid (SIF)

[0352]Monobasic potassium phosphate (6.8 g) and sodium hydroxide (0.616 g) are added into 250 ml of distilled water in a 1000 ml volumetric flask and swirled until dissolved. 700 ml distilled water is added and the pH checked. The pH is adjusted to pH 6.8+ / −0.1 by adding either 0.2N sodium hydroxide or 0.2N hydrochloric acid and the volume is brought to 1000 ml.

Simulated Gastric Fluid (SGF)

[0353]Sodium chloride (2 g), 750 ml distilled water, and 7.0 ml of concentrated hydrochloric acid are added into a 1000 ml volumetric flask. The flask is swirled to mix and the volume brought to 1000 ml with distilled water. The pH should be approx. 1.2.

example 2

Particle Size Measurement Method

[0354]The following methods and settings for particle size measurement were used for all D50 values for ganaxolone and phenyloin.

Particle Size Method Using Horiba Laser Scattering Particle Size Distribution Analyzer LA-910

[0355]Particle size measurement using Horiba laser scattering particle size distribution analyzer is generally well known for those skilled in the art. It is important that the parameters be kept constant when measuring different samples if they are used for comparison purposes. For ganaxolone and phenyloin nanoparticulate compositions, instrument settings and sample preparation method are described below:

Instrument Settings and Parameters:

[0356]Measure Conditions: Circulation=4; ultrasonic time=1; agitation=1; sampling times: red laser=10, blue lamp=2; preferred % transmittance: blue lamp=75-80%; blank: red laser=10, blue lamp=2. For D50 values after sonication, the sonication power is set to low and the sonication time is 1 minute....

example 2a

Sample Preparation and Particle Size (D50) Determination

[0359]For concentrated nanoparticle drug suspensions, dilute the nanoparticulate composition with deionized water to approximately 5 mg / mL API concentration. Shake well for 15-30 seconds. Add 120 mL of deionized water to the chamber, turn agitation and recirculation settings on. Transfer the nanoparticulate suspension via a pipette to the sample chamber in sufficient quantity to reach the transmittance range of 75-80% blue lamp. If a suspension or stability indicating dispersion is at a concentration of approximately 0.5 mg / ml do not further dilute if not necessary and use directly for particle size measurement. Transfer the sample to be measured via a pipette to up to the desired transmittance range (75-80% blue lamp). Take a measurement and collect the D50 value. This will be the unsonicated particles size. Sonicate for 1 min and take a measurement again to collect D50 value. This will be the particle size after 1 minute soni...

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Abstract

The present invention is directed to size-stabilized drug nanoparticulate compositions and methods of preparation thereof.

Description

[0001]This application claims the benefit of U.S. Provisional Patent Application No. 60 / 861,616, filed on Nov. 28, 2006, the disclosure of which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]Described herein are nanoparticulate formulations of drugs having an aqueous solubility of less than 1 mg / ml in a pH of about 7.4 which provide enhanced stability, physical and chemical properties and can provide enhanced pharmacokinetic properties to achieve an optimal balance between pharmacodynamic and side effect profiles in mammals, and dosage forms containing the same, as well as methods of making nanoparticulate drug formulations and their use in the treatment of various disorders.BACKGROUND OF THE INVENTION[0003]It has been very difficult to formulate therapeutically effective dosage forms specific for drugs having an aqueous solubility of less than 1 mg / ml in a pH of about 7.4, across a broad range of therapeutic agents (e.g. medroxyprogesterone acetate...

Claims

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Application Information

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IPC IPC(8): A61K9/48A61K9/14A61K9/20
CPCA61K9/1623A61K9/0075A61K9/2886A61K9/5078A61K47/48961B82Y5/00A61K31/58A61K8/63A61K9/145A61K47/14C07J71/00Y10S977/906Y10S977/773A61K9/007A61K9/0073A61K9/008A61K9/0078A61K9/1652A61K47/6949A61P11/00A61P17/04A61P27/02A61K47/50A61K9/10A61K9/16
Inventor SHAW, KENNETHZHANG, MINGBAO
Owner MARINUS PHARMA
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