DRUG INTRODUCING AGENT FOR ADMINISTRATION INTO A LIVING BODY AND MANUFACTURING METHOD

• US 20170128377A1
• Filed: 11/08/2016
• Published: 05/11/2017
• Est. Priority Date: 11/09/2015
• Status: Active Grant

• Current Assignee: Medical Corporation Ijunkai
• Original Assignee: Medical Corporation Ijunkai
• Inventors: Nakanishi, Hiroyuki
• Granted Patent: US 10,449,155 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/501 Inorganic compounds
• CPC Class Codes: C12N 2310/141 MicroRNAs, miRNAs
• CPC Class Codes: C12N 2320/32 Special delivery means, e.g. tissue-specific

Abstract

The present invention provides carbonate apatites with a suitable particle size (average particle size and maximum particle size) as well as small variance (σ²) of particle sizes.

Provided is a method of manufacturing a carbonate apatite, the method comprising the step of incubating a mixture comprising a calcium ion, a phosphate ion, and a hydrocarbon ion, wherein an incubation temperature is 10° C. or lower and an incubation time of 10 minutes or less. Further, a carbonate apatite made by this method (e.g., carbonate apatite with a maximum particle size of 700 nm, average particle size of 30 nm and drug encapsulation rate of 98%, all in nanometer size) is provided.

Claims

1. A method of administrating a drug, comprising the step of administering a composition comprising carbonate apatites encapsulating the drug, wherein 90% or more of a population of the carbonate apatites have a particle size of 700 nm or less.

2. The method of claim 1, wherein 95% or more of the population of carbonate apatites have a particle size of 700 nm or less.

3. The method of claim 1, wherein 98% or more of the population of carbonate apatites have a particle size of 700 nm or less.

4. The method of claim 1, wherein the average particle size of the population of carbonate apatites is 30 nm or less.

5. The method of claim 1, wherein the average particle size of the population of carbonate apatites is 20 nm or less.

6. The method of claim 1, wherein the composition comprises an emulsifying oily substance.

7. The method of claim 6, wherein the composition comprises 0.5% (w/w) or more of the emulsifying oily substance and the composition has an HLB value of 3-16.

8. The method of claim 1, wherein the composition comprises a thickener.

9. The method of claim 1, wherein a viscosity of the composition is 1.3 mPa·

s or more.

10. The method of claim 1, wherein an encapsulation rate of the drug in the composition is 90% or greater.

11. The method of claim 1, wherein the composition comprises an electrophilic agent.

12. The method of claim 1, wherein the composition comprises a nucleophilic agent.

13. The method of claim 1, wherein the drug is an miRNA.

14. A method of treating or preventing cancer, comprising the step of administering a composition comprising carbonate apatites encapsulating a drug, wherein 90% or more of a population of the carbonate apatites have a particle size of 700 nm or less.

15. The method of claim 14, wherein the drug is an miRNA.

16. The method of claim 14, wherein the drug is an anticancer agent.

17. A method of manufacturing a carbonate apatite encapsulating a drug, the method comprising the step of incubating a mixture comprising a calcium ion, a phosphate ion, a hydrogen carbonate ion, and a drug, wherein an incubation temperature is 10°

C. or lower and an incubation time is 10 minutes or less.

18. The method of claim 17, wherein the incubation time is 1 minute or less.

19. The method of claim 17, wherein the mixture comprises an emulsifying oily substance.

20. A method of preparing an aqueous solution with carbonate apatites encapsulating a drug dispersed therein, comprising the steps of:

(a) incubating a mixture comprising a calcium ion, a phosphate ion, a hydrogen carbonate ion, and a drug, wherein an incubation temperature is 10°

C. or lower and an incubation time is 10 minutes or less;

(b) subjecting the mixture after completion of incubation to high-speed centrifugation; and

(c) dispersing a precipitate obtained by the high-speed centrifugation in an aqueous solution having a viscosity of 1.3 mPa·

s or more.

21. The method of claim 20, wherein the incubation time is 1 minute or less.

22. The method of claim 20, wherein the mixture comprises an emulsifying oily substance.

23. The method of claim 20, wherein a voltage is applied to the mixture at least in a part of step (a).

24. A method of manufacturing a carbonate apatite encapsulating a drug, comprising the steps of:

(a) loading water manufactured by an RO water manufacturing apparatus or a distilled water manufacturing apparatus into a stirrer;

(b) loading a phosphate ion and a hydrogen carbonate ion into the stirrer;

(c) adjusting a pH of a mixture loaded in by step (a) and step (b);

(d) loading a calcium ion and a drug into the mixture whose pH was adjusted in step (c) and incubating the resulting mixture at 10°

C. or lower for 10 minutes or less;

(e) adding an emulsifying oily substance to the mixture before or after incubating in step (d);

(f) centrifuging a mixture obtained in step (e) in a centrifuge having an inner cylinder applied with polypropylene or an inner cylinder equipped with a polypropylene cylinder to obtain a precipitate; and

(g) spraying a substance selected from the group consisting of air, distilled water, saline, and a thickener with a nozzle that is automatically inserted from a top or bottom portion of the cylinder and collecting the precipitate obtained in step (f).

25. The method of claim 24, further comprising the step of:

(h) bottling and lyophilizing the precipitate collected in step (g).