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Preparation of submicron sized particles with polymorph control and new polymorph of itraconazole

A polymorphic, particle technology, applied to water-insoluble drugs, 6,596 discloses an organic phase in which a pharmacological activator is dispersed and a nanoparticle field of 20 nanometers, which can solve problems such as drug overtime growth

Inactive Publication Date: 2005-10-26
BAXTER INT INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A disadvantage of these formulations is that certain drugs in suspension tend to grow over time due to a dissolution and reprecipitation phenomenon known as "Oswald maturation"

Method used

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  • Preparation of submicron sized particles with polymorph control and new polymorph of itraconazole
  • Preparation of submicron sized particles with polymorph control and new polymorph of itraconazole
  • Preparation of submicron sized particles with polymorph control and new polymorph of itraconazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Example 1: Preparation of itraconazole suspension by homogenization

[0109] Add 1680mL of water to a 3-liter flask, heat the liquid to 60°C-65°C, slowly add 44g of Pluronic F-68 (poloxamer 188), and 12g of sodium deoxycholate, each time Stir after adding the solids. After complete addition of solids, stir at 60°C-65°C for 15 minutes to ensure complete dissolution. A 50 mM Tris (trimethylolaminomethane) buffer was prepared for addition by dissolving 6.06 grams of tris in 800 mL of water. The solution was titrated to pH 8.0 with 0.1M hydrochloric acid. Additional water was added to dilute the obtained solution to 1 liter. Add 200 mL of Tris buffer to the poloxamer / deoxycholic acid solution. Stir thoroughly to combine the solution.

[0110] Add 20 g of itraconazole and 120 mL of N-methyl-2-pyrrolidone to a 150 mL beaker. Heat the mixture to 50°C-60°C, stirring to dissolve the solids. After complete dissolution was visible, stir for an additional 15 minutes to ens...

Embodiment 2

[0117] Example 2: Preparation of itraconazole suspension using ultrasonication.

[0118] Add 252mL of water for injection into a 500mL stainless steel container. The liquid was heated to 60-65°C, then 6.6 grams of Pluronic F-68 (poloxamer 188), and 0.9 grams of sodium deoxycholate were added slowly, stirring after each addition to dissolve the solids. After complete addition of the solid phase, stir at 60-65°C for 15 minutes to ensure complete dissolution. A 50 mM tris (trishydroxymethylaminomethane) buffer was prepared by dissolving 6.06 g of tris in 800 mL of water for injection. The solution was titrated to pH 8.0 with 0.1M hydrochloric acid. Dilute the obtained solution to 1 liter with additional water for injection. Add 30 mL of tris buffer to the poloxamer / deoxycholate solution. Stir well to combine the solution.

[0119] Add 3 g of itraconazole and 18 mL of N-methyl-2-pyrrolidone to a 30 mL container. Heat the mixture to 50°C-60°C, stirring to dissolve the solid...

Embodiment 3

[0122] Example 3: Preparation of itraconazole suspension by homogenization.

[0123] A 50 mM tris (trishydroxymethylaminomethane) buffer was prepared by dissolving 6.06 g of tris in 800 mL of water for injection. The solution was titrated to pH 8.0 with 0.1M hydrochloric acid. The obtained solution was diluted to 1 liter with additional water for injection. Add 1680 mL of water for injection to a 3 L flask. Add 200 mL of tris buffer to 1680 mL of water. Stir well to combine the solution.

[0124] Add 44 g of Pluronic F-68 (poloxamer 188) to a 150 mL beaker, and add 12 g of sodium deoxycholate to 120 mL of N-methyl-2-pyrrolidone. Heat the mixture to 50°C-60°C, stirring to dissolve the solids. After complete dissolution was visible to the naked eye, it was stirred for an additional 15 minutes to ensure complete dissolution. 20 g of itraconazole were added to the solution and stirred until completely dissolved. The itraconazole-NMP solution was cooled to room temperature...

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Abstract

The present invention provides a method of preparing particles with polymorph and size control of a pharmaceutical compound, the method including the steps of: (1) providing pharmaceutical compound in a first phase; (2) seeding the compound; (3) causing a phase change in the pharmaceutical compound to a second phase of a desired polymorphic form; and (4) wherein the mean particle size of the particles is less than 7 mum. The present invention further provides a polymorphic form of itraconazole.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of co-pending U.S. Patent Applications 10 / 246,802, filed September 17, 2002, and 10 / 213,352, filed August 5, 2002, both of which were filed October 19, 2001. 10 / 035,821, which is a continuation in part of Serial No. 09 / 953,979, filed September 17, 2001, which is a continuation of Serial No. 09 / 874,637, filed June 5, 2001 , the latter claiming priority from provisional application 60 / 258,160 filed December 22, 2000, each of which is hereby incorporated by reference and made a part of this application. Background of the invention [0003] Drugs that are poorly soluble or insoluble in aqueous solutions are increasingly formulated into formulations. These drugs pose problems associated with administering drugs by injectable forms such as parenteral administration. For water-insoluble drugs, there can be significant benefit in formulating them as stable suspensions of particles smaller th...

Claims

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Application Information

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IPC IPC(8): A61K9/00
Inventor 简·韦林詹姆斯·E·基普拉亚拉姆·西里拉姆马克·J·多蒂克里斯蒂娜·L·里贝克王重德
Owner BAXTER INT INC
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