JP3148769B2 - Pro-nanosphere and its manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pronanosphere which gives a drug-containing aqueous nanosphere solution when redispersed in water, and a method for producing the same.

[0002]

2. Description of the Related Art Fine particles such as liposomes, microspheres or nanospheres finer than microspheres are selectively collected in the liver, lungs or inflammatory sites when administered by injection, and release drugs, thereby reducing side effects. And so on. In addition, when these microparticles are taken orally, it is expected that the absorption of the poorly-absorbable drug in the digestive tract is increased. However, these fine particles have a major drawback of being unstable in aqueous solution.

In order to overcome this drawback, Japanese Patent Publication No. Sho 62-5
No. 2724 discloses a method of freeze-drying liposomes and providing them in a preparation, and a method of stabilizing liposomes as proliposomes is also known (J. Pharm. Sc.
i., 75, 325, 1986). The proliposome means a dried granular substance which becomes a liposome solution which can be dissolved or dispersed by adding water to be administered. Furthermore, Japanese Patent Application No. Hei 3-2022
No. 16 discloses a pro-nanosphere characterized in that a nanosphere containing a drug is coated by a fluidized-bed granulation method using a sugar substance as a nucleus.

[0004]

However, it is very difficult to control the particle size of the fine particles after the dried product obtained by these methods is dispersed in water, and it is very difficult to control the particle size of water, especially various salts. Has the disadvantage that the diameter of the fine particles increases when they are redispersed in an aqueous solution in which is dissolved.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in order to obtain a stable and redispersible pro-nanosphere. As a result, they have found that the following means can solve the problem and completed the present invention. did.

That is, according to the present invention, a fluidized bed granulation is carried out by spraying a nanosphere- containing liquid having a molar ratio of a drug to phospholipid 1 of 0.15 to 0.5 on a nuclear substance which is a sugar substance.
This is a pro-nanosphere obtained by performing the method or a method for producing the same. In addition, the present invention relates to a phospholipid 1 in a molar ratio of 0.1 to 0.3 cholesterol or its induction.
Nanospheres containing the drug in the body and 0.15 to 0.5
The fluid is sprayed onto the core substance, a sugar substance, to perform fluidized-bed granulation.
Is a pro nanospheres or the method obtained by Ukoto.

In the present invention, the term “pro-nanosphere” means a powder or a granular substance that gives a nanosphere when dispersed in water or an aqueous solution. What is a nanosphere?
Fine particles whose particle size is appropriate to be measured in nanometer units. The sugar substance used as a core in the present invention is preferably sorbitol, sucrose, lactose, mannitol, maltose, trehalose, etc., and particularly preferably sorbitol. Can be. The pro-nanosphere according to the present invention can be made into an aqueous solution containing a nanosphere having substantially the same particle size as before fluidized bed granulation when redispersed in water. Furthermore, the pro-nanosphere according to the present invention obtains a nanosphere having almost the same particle diameter as before fluidized bed granulation even in a solution in which coalescence of fine particles is likely to occur, such as an aqueous solution in which a salt is dissolved. be able to.

Accordingly, an object of the present invention is to provide a pro-nanosphere which gives a nanosphere having substantially the same particle size as before fluidized-bed granulation even after redispersion in water or an aqueous solution in which a salt is dissolved. . In order to obtain the pro-nanosphere according to the present invention, first, it is necessary to obtain an aqueous solution containing the nanosphere. The nanosphere has a drug and a phospholipid as essential components, but the drug in the present invention is not particularly limited, and any drug can be used as long as it is a drug incorporated into the nanosphere. Examples thereof include analgesics, antitumor agents, and fat-soluble drugs such as tocopherols, ubidecarenone, vitamins A and vitamins K. Examples of the phospholipid include soybean phospholipid, egg yolk phospholipid, hydrogenated soybean phospholipid, and the like, and one or a combination of two or more thereof can be used.

In the present invention, the molar ratio of the drug to the phospholipid 1 needs to be 0.15 to 0.5. The particle size of the nanospheres can be kept equal to the size of the nanospheres before the preparation of pro-nanospheres. In the present invention, when producing nanospheres, cholesterol, a derivative thereof, or a substance that changes the surface charge of particles is added, and cholesterol or a derivative thereof is a sterol skeleton. And specifically includes cholesterol. Specific examples of the substance that changes the surface charge of the particles include higher fatty acid phosphates such as dicetyl phosphate, phosphatidyl glycerol, and phosphatidylinositol. .

The amount of cholesterol, a derivative thereof, or a substance that changes the surface charge to phospholipid 1 is desirably 0.1 to 0.3 in a molar ratio. The effect of adding cholesterol and the like, that is, the effect of preventing cholesterol and the like from increasing the particle size of the nanospheres after the re-dispersion of pronanospheres becomes more pronounced as the drug content in the nanospheres increases. In addition, the effect appears in an aqueous solution containing a salt. That is, the present invention controls the particle size of the nanospheres after redispersion in water by limiting the ratio of the phospholipid to the drug, and further increases the concentration of the drug by adding cholesterol. It is intended to suppress an increase in the particle size when the contained pro-nanosphere is redispersed in an aqueous solution containing a salt. Conventionally, it has been known that the addition of cholesterol or the like to the liposome stabilizes the film. However, adding cholesterol or a derivative thereof to the pronanosphere reduces the increase in the particle diameter after redispersion. What can be suppressed is a completely unexpected and significant effect.

The method for producing a pro-nanosphere in the present invention is specifically described as follows. To obtain an aqueous solution containing nanospheres, a commonly used method is applied, a phospholipid and water are added to the drug, and cholesterol and its derivatives are added if necessary, and the mixture is heated. And emulsify to obtain a solution containing fine particles. In order to obtain finer particles, if necessary, emulsification is performed by, for example, an ultrasonic emulsifier. The heating is preferably at least the phase transition temperature of the phospholipid, usually 60 ° C.
It is preferable to set the above.

As disclosed in Japanese Patent Application No. 3-202216, a drug is obtained by adding a saccharide or an aqueous saccharide solution to the nanosphere-containing solution and spraying it onto a core material such as sorbitol, if necessary, to perform fluidized bed granulation. The resulting pro-nanosphere can be obtained. Fluidized bed granulation can be carried out by a commonly used apparatus, but good results can be obtained particularly with a Wurster granulator and a tumbling fluidized bed granulator. Examples of the sugar substance to be added to the aqueous solution containing nanospheres include sorbitol, sucrose, lactose, mannitol, maltose, trehalose, and the like, and preferably sorbitol.

The amount of the drug to be added depends on the nature of the drug, the phospholipid used, the saccharide used, and the equipment used, and cannot be determined unconditionally. For example, if the amount of the phospholipid used is increased, the amount of the drug to be added can be increased, and it can be appropriately prepared according to the purpose. Hereinafter, the present invention will be described in more detail with reference to specific examples of the present invention. However, the present invention is not limited to these examples.

[0014]

【Example】

Example 1 A thin film composed of 0.562 g of partially hydrogenated soybean lecithin and 0.203 g of vitamin A palmitate prepared from a mixed solvent of methanol and chloroform (1: 2) was hydrated with purified water, and a high-speed homogenizer ( 15000 rpm, 5 mi
n) and then sonicated (90W, 1) after emulsification.
0 min) to obtain nanospheres. 5 g of D-sorbitol was added to this nanosphere, and this solution was used as a spray liquid to prepare a pro-nanosphere using a tumbling fluidized-granulation apparatus (MP-01). As nuclear material,
100 g of sorbitol was used.

Example 2 0.507 g of partially hydrogenated soybean lecithin, 0.203 g of vitamin A palmitate and 0.1 ml of cholesterol prepared from a mixed solvent of methanol and chloroform (1: 2).
The thin film consisting of 030 g was hydrated with purified water, stirred and emulsified with a high-speed homogenizer (15000 rpm, 5 min), and then subjected to ultrasonic treatment (90 W, 10 min) to obtain a nanosphere. 5 g of D-sorbitol was added to this nanosphere, and this solution was used as a spray liquid to prepare a pro-nanosphere using a tumbling fluidized-granulation apparatus (MP-01). As nuclear material, pharmacopoeia D-sorbitol 10
0 g was used.

Example 3 A thin film composed of 0.562 g of partially hydrogenated soybean lecithin and 0.081 g of vitamin A palmitate prepared from a mixed solvent of methanol and chloroform (1: 2) was hydrated with purified water, Homogenizer (15000 rpm, 5 mi
n) and then sonicated (90W, 1) after emulsification.
0 min) to obtain nanospheres. 5 g of D-sorbitol was added to this nanosphere, and this liquid was used as a spray liquid to prepare a pro-nanosphere using a tumbling fluidized-granulation apparatus (MP-01). As nuclear material,
100 g of sorbitol was used.

[0017]

Next, experimental examples will be described in order to explain the effects of the present invention in detail. Experimental Example 1 Nanosphere particles before preparation of pronanosphere in the same manner as in Example 1 except that the amount of vitamin A palmitate was changed from 0 to 0.8 parts by weight per 1 part by weight of phospholipid. FIG. 1 shows the diameters and the particle diameters of the nanospheres redispersed in water after the preparation of the pronanosphere. The particle size of the nanosphere was measured by a dynamic light scattering method. The circles in the figure indicate the particle diameter of the nanospheres before the preparation of the pro-nanosphere, and the triangles indicate the particle diameter of the nanospheres after re-dispersion in water after the preparation of the pro-nanosphere.

As apparent from FIG. 1, the particle size of the nanosphere when the pronanosphere is redispersed in water after the preparation thereof is such that the drug amount with respect to the phospholipid 1 is 0.15 to 0.15 in molar ratio.
When the particle diameter was 0.5, the particle diameter became almost the same as the particle diameter before the preparation of the pronanosphere.

Experimental Example 2 The same operation as in Example 2 was repeated, except that the amount of cholesterol was changed from 0 to 0.43 in terms of the molar ratio of phospholipid 1 to 1 solution or 2 solutions of the Japanese Pharmacopoeia. FIG. 2 shows the change in the particle size of the nanospheres after dispersion. In the figure, white circles indicate the ratio of the nanosphere particle diameter after redispersion in the Japanese Pharmacopoeia 1 solution to the particle size after redispersion in water, and white triangles indicate the nanosphere particles after redispersion in the Japanese Pharmacopoeia 2 solution. It is the ratio of the particle size to the particle size after redispersion in water. The black mark is the particle size of the nanosphere after redispersion in water.

As is apparent from FIG. 2, when the cholesterol ratio is 0.1 to 0.3, the increase in the particle diameter in the first or second liquid in Japan is suppressed. The Japanese Pharmacopoeia Solution 1 or Solution 2 is an aqueous solution prepared by dissolving a salt adjusted to pH 1.2 or 6.8, respectively. The pro-nanosphere according to the present invention is conventionally considered to cause an increase in the particle diameter of fine particles. It is clear that the inhibition is exhibited in the aqueous solution in which the salt is dissolved.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram showing the particle size of nanospheres before preparation of pronanospheres and the particle size of nanospheres after redispersion of pronanospheres in water. FIG. 2 is a diagram showing the ratio of the particle size after re-dispersion of the pro-nanosphere in one or two liquids of JP to the particle size when re-dispersed in water.

──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Hiroshi Ozawa 1226-59 Inaba, Niwa, Ichinomiya-shi, Aichi Examiner Reiko Imamura (58) Field surveyed (Int.Cl. ⁷ , DB name) A61K 9/51, 9/16 A61K 47 / 24,47 / 26,47 / 28

Claims (6)

(57) [Claims] 1. A nanosphere- containing liquid having a molar ratio of drug to phospholipid 1 of 0.15 to 0.5 by a sugar substance .
Pro-nanosphere obtained by spraying a certain nuclear material and performing fluidized-bed granulation . 2. The method according to claim 1, wherein the molar ratio of the phospholipid is 0.1 to 0.1.
3 cholesterol or its derivative and 0.15-
Nanosphere-containing liquid containing 0.5 drug with sugar substance
It is obtained by spraying a certain nuclear material and performing fluidized bed granulation.
Professional nanospheres to be. 3. A nuclear material is a sugar substance, sorbitol, sucrose, lactose, mannitol, maltose, claim 1 or one or more saccharides selected from trehalose
2. The pro-nanosphere according to 2 . 4. A nanosphere- containing liquid having a molar ratio of drug to phospholipid 1 of 0.15 to 0.5 with a sugar substance .
A method for producing a pro-nanosphere obtained by spraying a certain nuclear substance and performing fluidized-bed granulation . 5. A phospholipid having a molar ratio of 0.1 to 0.1 to 1.0.
3 cholesterol or its derivative and 0.15-
Nanosphere-containing liquid containing 0.5 drug with sugar
It is obtained by spraying a certain nuclear material and performing fluidized bed granulation.
Method of manufacturing a professional nanospheres to be. 6. nuclear material is a sugar substance, sorbitol, sucrose, lactose, mannitol, maltose, claim 4 or one or more saccharides selected from trehalose
6. The method for producing a pro-nanosphere according to 5 .