Drug introducing agent for administration into a living body and manufacturing method

• US 10,449,155 B2
• Filed: 11/08/2016
• Issued: 10/22/2019
• Est. Priority Date: 11/09/2015
• Status: Active Grant

• Current Assignee: Medical Corporation Ijunkai
• Original Assignee: Medical Corporation Ijunkai
• Inventors: Nakanishi, Hiroyuki
• Primary Examiner(s): Barham, Bethany P
• Assistant Examiner(s): Anthopolos, Peter
• Application Number:
  US15/346,401
• Publication Number:
  US 20170128377A1
• Time in Patent Office: 1,078 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 manufacturing a carbonate apatite encapsulating a drug, the method comprising the step of incubating, without treating with ultrasound waves, a mixture comprising a calcium ion, a phosphate ion, a hydrogen carbonate ion, and a drug at an incubation temperature of 1°

C. to 8°

C. and an incubation time of 1 minute or less to obtain a population of carbonate apatites encapsulating the drug, and wherein at least one of;

(i) 90% or more of the population of carbonate apatites have a particle size of 700 nm or less, and (ii) average particle size of the population of carbonate apatites is 50 nm or less.

2. The method of claim 1, wherein the mixture further comprises an emulsifying oily substance.

3. The method of claim 1, wherein 90% 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 50 nm or less.

5. A method of preparing an aqueous dispersion comprising a population of carbonate apatites which comprise a drug encapsulated therein, comprising the steps of:

(a) incubating, without treating with ultrasound waves, a mixture comprising a calcium ion, a phosphate ion, a hydrogen carbonate ion, and a drug at an incubation temperature of 1°

C. to 8°

C. and an incubation time of 1 minute or less, to produce in the mixture a population of carbonate apatites encapsulating the drug;

(b) subjecting the mixture after completion of incubation to high-speed centrifugation to produce a precipitate which comprises the population of carbonate apatites encapsulating the drug; and

(c) dispersing the precipitate produced in step (b) in an aqueous solution to obtain the aqueous dispersion, and wherein at least one of;

(i) 90% or more of the population of carbonate apatites have a particle size of 700 nm or less, and (ii) average particle size of the population of carbonate apatites is 50 nm or less.

6. The method of claim 5, wherein the mixture further comprises an emulsifying oily substance.

7. The method of claim 5, wherein a voltage is applied to the mixture while the mixture is incubating.

8. The method of claim 5, wherein 90% or more of the population of carbonate apatites have a particle size of 700 nm or less.

9. The method of claim 5, wherein the average particle size of the population of carbonate apatites is 50 nm or less.

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

(a) loading water, which is manufactured by an RO water manufacturing apparatus or by a distilled water manufacturing apparatus, into a container for stirring;

(b) loading a phosphate ion and a hydrogen carbonate ion into the water of step (a) to produce a mixture;

(c) adjusting pH of the mixture produced in step (b) to a pH value of 6.0 to 9.0, to obtain a pH-adjusted mixture;

(d) loading a calcium ion and a drug into the pH-adjusted mixture obtained in step (c) and incubating the mixture at a temperature of 1°

C. to 8°

C. for 1 minute or less;

(e) adding an emulsifying oily substance to the pH-adjusted mixture obtained in step (c) before or after said incubating in step (d);

(f) centrifuging the pH-adjusted mixture to which the emulsifying oily substance has been added in step (e) in a centrifuge and discarding a supernatant to obtain a precipitate that comprises a population of carbonate apatites comprising the carbonate apatite-encapsulated drug; and

(g) dispersing, without treating with ultrasound waves, the precipitate obtained in step (f) in a substance selected from air, distilled water, saline, and a thickener to obtain a dispersion comprising the population of carbonate apatites, and therefrom collecting the carbonate apatite-encapsulated drug, and wherein at least one of;

(i) 90% or more of the population of carbonate apatites have a particle size of 700 nm or less, and (ii) average particle size of the population of carbonate apatites is 50 nm or less.

11. The method of claim 10, further comprising the step of:

(h) bottling and lyophilizing the carbonate apatite-encapsulated drug collected in step (g).

12. The method of claim 10, wherein 90% or more of the population of carbonate apatites have a particle size of 700 nm or less.

13. The method of claim 10, wherein the average particle size of the population of carbonate apatites is 50 nm or less.