Amorphous Medicinal Fine Particles Produced By Pulsed Laser Ablation In Liquid And The Production Method Thereof

• US 20130209523A1
• Filed: 02/13/2013
• Published: 08/15/2013
• Est. Priority Date: 02/13/2012
• Status: Active Grant

• Current Assignee: IMRA America Incorporated (Aisin Corp.)
• Original Assignee: IMRA America Incorporated (Aisin Corp.)
• Inventors: Ichikawa, Yuki, Marcinkevicus, Andrius
• Granted Patent: US 9,463,243 B2
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A61J 3/02 into the form of powders pulverising in general B02C
• CPC Class Codes: A61K 41/00 Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
• CPC Class Codes: A61K 9/50 Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167
• CPC Class Codes: A61K 9/51 Nanocapsules; Nanoparticles; nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]

Abstract

The present disclosure is directed to an in-liquid laser-based method for fabricating a solution of fine particles of amorphous solid medicinal compounds, a solution of fine particles of amorphous medicinal agents made with the method, and fine particles made with the method. By using a target solidified via a phase transition process to covert an initial crystalline structure into an amorphous solid, technical difficulties with handling a hydraulically-pressed target are overcome. The laser-based ablation process produces amorphous solid medicinal compound fine particles, which improves the bioavailability and solubility of the medicinal compound. The improvement results from a combination of: disordered crystalline structure and enlarged relative surface area by particle size reduction. The laser based method may be carried out with ultrashort pulsed laser systems, or with UV nanosecond lasers. Results obtained with an ultrashort near IR laser and a UV nanosecond laser show formation of amorphous solid curcumin fine particles.

Claims

1. A solution of fine particles of a poorly water soluble medicinal compound comprising:

a liquid; and

a plurality of fine particles of a medicinal compound dispersed in said liquid, said fine particles comprising an amorphous solid and said fine particles having an average particle diameter of from 1 to 5000 nanometers, wherein said fine particles are derived from a poorly water soluble bulk material of said medicinal compound by pulsed-laser-ablation processing of said bulk material and wherein said fine particles retain the chemical composition of said bulk material.

2. The solution of claim 1, wherein said bulk material comprises an amorphous solid of said medicinal compound.

3. The solution of claim 1, wherein said plurality of fine particles of said medicinal compound have a degree of amorphicity of at least 50%.

4. The solution of claim 1, wherein said fine particles are super fine particles having an average particle diameter of from 1 to 1000 nanometers.

5. The solution of claim 1, wherein said fine particles are ultrafine particles having an average particle diameter of from 1 to 200 nanometers.

6. The solution of claim 1, wherein 50% or more of the total number of said fine particles have 200 nanometer or smaller ultrafine structures comprising at least one of pores, dents or bumps.

7. The solution of claim 1, wherein said fine particles of a medicinal compound are active in at least one medicinal effect of:

anti-cancer, anti-inflammatory, anti-carcinogenic, hypocholesterolemic, anti-microbial, anti-viral, antioxidant, hepato-protective, nephro-protective, thrombosis suppressing, myocardial infarction protective, hypoglycemic, anti-rheumatic, and protective against Alzheimer'"'"'s disease.

8. The solution of claim 2, wherein said bulk material of an amorphous solid of said medicinal compound is prepared via a process which includes at least one physical treatment wherein an initial crystalline structure of said medicinal compound undergoes at least one phase transition thereby converting it into an amorphous solid.

9. A medicinal compound containing the solution of claim 1.

10. A medicinal compound made from precursors wherein at least one of said precursors comprises the solution of claim 1.

27. The solution of claim 1, wherein amorphicity of said amorphous solid medicinal compound is characterized by an x-ray diffraction pattern exhibiting a smooth background having no distinct Bragg peaks representative of a crystalline structure.

11. Fine particles of a medicinal compound comprising:

a plurality of fine particles of an amorphous solid medicinal compound, said fine particles having an average particle diameter of from 1 to 5000 nanometers, wherein said fine particles are derived from a poorly water soluble bulk material of said medicinal compound by pulsed-laser-ablation processing of said bulk material in a liquid, and wherein said fine particles retain the chemical composition of said bulk material.

12. The fine particles of claim 11, wherein said bulk material comprises an amorphous solid of said medicinal compound.

13. The fine particles of claim 11, wherein said plurality of fine particles of said medicinal compound have a degree of amorphicity of at least 50%.

14. The fine particles of claim 11, wherein said fine particles are super fine particles having an average particle diameter of from 1 to 1000 nanometers.

15. The fine particles of claim 11, wherein said fine particles are ultrafine particles having an average particle diameter of from 1 to 200 nanometers.

16. The fine particles of claim 11, wherein 50% or more of the total number of said fine particles have 200 nanometer or smaller ultrafine structures comprising at least one of pores, dents or bumps.

17. The fine particles of claim 11, wherein said fine particles of a medicinal compound are active in at least one medicinal effect of:

anti-cancer, anti-inflammatory, anticarcinogenic, hypocholesterolemic, anti-microbial, anti-viral, antioxidant, hepato-protective, nephro-protective, thrombosis suppressing, myocardial infarction protective, hypoglycemic, anti-rheumatic, and protective against Alzheimer'"'"'s disease.

18. The fine particles of claim 14, wherein said bulk material of an amorphous solid of said medicinal compound is prepared via a process which includes at least one physical treatment wherein an initial crystalline structure of said medicinal compound undergoes at least one phase transition thereby converting it into an amorphous solid.

19. A medicinal compound containing the fine particles of claim 11.

20. A medicinal compound made from precursors wherein at least one of said precursors comprises the fine particles of claim 11.

28. The fine particles of claim 11, wherein amorphicity of said amorphous solid medicinal compound is characterized by an x-ray diffraction pattern exhibiting a smooth background having no distinct Bragg peaks representative of a crystalline structure.

21. A method of fabricating a solution of fine particles of a medicinal compound comprising the steps of:

a) providing a poorly water soluble bulk target material of a medicinal compound comprising an amorphous solid with at least a portion of said target material being in contact with at least a portion of a liquid; and

b) irradiating said target material with a pulsed-laser-ablation beam and forming a plurality of fine particles of said amorphous medicinal compound, said fine particles having an average particle diameter of from 1 to 5000 nanometers, wherein said fine particles retain the chemical composition of said bulk target material.

22. The method of claim 21, wherein said provided bulk target in step a) has a degree of amorphicity of at least 50%.

23. The method of claim 21, wherein step a) comprises providing a bulk target material prepared via a process which includes at least one physical treatment wherein an initial crystalline structure of said medicinal compound undergoes at least one phase transition thereby converting it to an amorphous solid.

24. The method of claim 21, wherein step a) further comprises forming said bulk target material from micron to millimeter sized powder of said medicinal compound by at least one of pressing, melting, or mixing with at least one binder material thereby forming the bulk target material.

25. The method of claim 21, wherein step b) comprises forming super fine particles having an average particle diameter of from 1 to 1000 nanometers.

26. The method of claim 21, wherein step b) comprises forming ultrafine particles having an average particle diameter of from 1 to 200 nanometers.

29. The method of claim 21, wherein amorphicity of said amorphous solid medicinal compound is characterized by an x-ray diffraction pattern exhibiting a smooth background having no distinct Bragg peaks representative of a crystalline structure.

30. The method of claim 21, comprising the further step of separating said plurality of fine particles from said liquid.