Stable shaped particles of crystalline organic compounds

• US 6,528,094 B1
• Filed: 05/23/2001
• Issued: 03/04/2003
• Est. Priority Date: 02/25/1998
• Status: Expired due to Term

• Current Assignee: Skendi Finance, Ltd.
• Original Assignee: Abraham Gomez, Aurelio D.E. Gyves, John-Claude Savoir, Juan Angeles
• Inventors: Gomez, Abraham, Savoir, John-Claude, Angeles, Juan, De Gyves, Aurelio
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Pulliam, Amy E
• Application Number:
  US09/862,723
• Time in Patent Office: 650 Days
• Field of Search: 424/489, 424/408, 424/439, 424/451, 424/457, 424/458, 424/465, 424/469
• US Class Current: 424/489
• CPC Class Codes: A61K 9/1688 resulting in pure drug agglomerate optionally containing up to 5% of excipient
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 5/30 Oestrogens
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]
• CPC Class Codes: Y10T 428/2989 Microcapsule with solid core [includes liposome]

Abstract

The present invention provides storage stable, shaped particles of allotropic organic compounds. The particles of the present invention can be shaped according to the desired application. Preferred shapes of such particles are microspheres, particularly those having diameters of about 1 to about 1,000 microns. The stable shaped particles of the present invention are particularly well-suited to the fabrication of pharmaceutical formulations, particularly where sustained release and uniform bioavailability are desired. The storage stable particles are formed by a solid state crystallization of allotropic organic compounds. The solid state crystallization process of the present invention affords a means for achieving a storage stable crystalline form of said allotropic compound without loss or deterioration of the original particle dimensions.

Claims

1. A method for forming a plurality of storage stable particles of uniform shape consisting essentially of a plurality of allotropic organic compounds, each of which is of a uniform crystalline character, said method comprising:

(1) forming a mixture consisting essentially of a plurality of allotropic organic compounds that are in a mixed crystalline, amorphous, or crystalline and amorphous form;

(2) melt congealing said mixture into particles of uniform shape;

(3) effecting a solid state crystallization of said particles by exposing said particles to vapors of a solvent of each of said allotropic organic compounds for sufficient time to permit the solid state crystallization of said particles; and

(4) recovering said particles

wherein said particles have retained said uniform shape and consist of a plurality of crystalline domains of uniform crystalline character of each of the allotropic organic compounds.

2. The method of claim 1, wherein the uniform shape is a microsphere of about 10 to about 300 microns.

3. The method of claim 1, wherein one of the allotropic organic compounds is cholesterol.

4. The method of claim 1, wherein one of the allotropic organic compounds is selected from the group consisting of 17-β

-estradiol, estrogen, testosterone, progesterone, and cholesterol.

5. The method of claim 1, wherein the particles are of uniform shape but vary in diameter from about 1 to about 1,000 microns.

6. A method for forming a plurality of particles of uniform shape comprising:

(1) forming a mixture of allotropic organic compounds consisting essentially of a combination of cholesterol and one or more pharmacotherapeutic agents selected from the group consisting of 17-β

-estradiol, estrogen, testosterone, progesterone, cholesterol, and mixtures thereof;

(2) melt congealing said mixture into spherical particles of diameter of about 10 to about 300 microns;

(3) effecting a solid state crystallization of said microspheres by exposing said particles to vapors of a solvent of each of said allotropic organic compounds for sufficient time to permit the solid state crystallization of said particles; and

(4) recovering said particles

wherein said recovered particles have retained the size and shape of the melt congealed spherical particles formed in step (2), and each allotropic organic compound within the spherical particle is of uniform crystalline character.

7. A method for effecting a solid state crystallization of a plurality of particles consisting essentially of a plurality of allotropic molecular organic compounds, said method comprising:

(1) creating a formulation consisting essentially of a plurality of allotropic molecular organic compounds of mixed crystalline, amorphous, or both crystalline and amorphous forms;

(2) melt congealing said formulation into microspheres of uniform size, wherein said size is a diameter ranging from about one to 1,000 microns;

(3) exposing said microspheres to an atmosphere that is below the melting temperature and pressure of each of said allotropic molecular organic compounds and which is saturated with a solvent for each of said allotropic molecular organic compounds for a time sufficient to effect solid state crystallization of said microspheres; and

(4) recovering said microspheres,

wherein each of said allotropic organic compounds in said recovered microspheres is of a uniform crystalline structure, said microspheres have retained the dimensions of the microspheres fabricated in step (2), and said microspheres retain said dimensions on storage in aqueous media for at least about one month.

8. A method for effecting a solid state crystallization of a plurality of particles consisting essentially of a plurality of allotropic molecular organic compounds, said method comprising:

(1) creating a formulation consisting essentially of a plurality of allotropic molecular organic compounds of mixed crystalline, amorphous, or both crystalline and amorphous forms;

(2) melt congealing said formulation into microspheres of various diameters ranging from about one to about 1,000 microns;

(3) exposing said microspheres to an atmosphere that is below the melting temperature and pressure of each of said allotropic molecular organic compounds and which is saturated with a solvent for each of said allotropic molecular organic compounds for a time sufficient to effect solid state crystallization of said microspheres; and

(4) recovering said microspheres,

wherein each of said allotropic organic compounds in said recovered microspheres is of a uniform crystalline structure, said microspheres have retained the dimensions of the microspheres fabricated in step (2), and said microspheres retain said dimensions on storage in aqueous media for at least about one month.