JPH0667824B2 - Microcapsule manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention freely designs a particle size distribution, a particle diameter, and a particle shape by granulating core particles from a powder serving as a core of a microcapsule. The present invention relates to a method for producing microcapsules that can be used for industrial mass production of microcapsules used for chemoembolization and other treatments.

[Conventional technology]

 Conventionally, as a method for producing microcapsules, (1) a chemical method such as an interfacial polymerization method or an in situ polymerization method.

(2) Physicochemical methods such as a phase separation method from an aqueous solution system, a phase separation method from an organic solution system, and a submerged drying method.

(3) Mechanical methods such as an air suspension coating method and a spray drying method.

Etc. are known (for example, see Granulation Handbook, Japan Powder Technology Association, Ohmsha, Capsule Granulation Method).

[Problems to be Solved by the Invention]

According to the first chemical method of the related art, it is difficult to make the microcapsules have a required minute particle size (50 to 150 μm), and it is difficult to produce microcapsules usable for living bodies. There was a point. In particular, there is a drawback that the toxicity of the reaction initiator and the residual monomer becomes a problem.

Further, in the second physicochemical method, the content of the active ingredient in the microcapsules depends on the properties such as whether the active ingredient is hydrophilic or lipophilic, so that the content of the active ingredient can be controlled. There is a problem that not only becomes difficult, but also a considerable amount of microcapsules containing no active ingredient are produced.

Further, the third mechanical method has an advantage that the particle size and the coating amount can be freely adjusted and mass production can be performed. However, when handling fine particles, the force of Wanderwerth and vigorous particle movement cause Since agglomeration occurs due to electrostatic force, there is a problem that it is difficult to efficiently obtain microcapsules of a desired size.

The present invention has been made in view of such problems of the prior art, and its purpose is, for example, in the chemical embolization therapy described below, for example, by stagnation of the anticancer agent in the local vascular bed An object of the present invention is to provide a method for producing microcapsules satisfying the shape, particle size, and particle size distribution required for the particles of the microcapsule during therapy.

Next, the above chemoembolization therapy and the conditions required for microcapsules in this therapy will be described.

First, chemoembolization is a combination of arterial embolization and drug arterial infusion. For example, an anticancer agent is retained in the local vascular bed to enhance the chemotherapeutic effect, and a powerful antitumor effect is also provided. It is a treatment method that seeks to obtain an effect.

Specifically, the tip of a catheter that is inserted from a peripheral artery under fluoroscopy is left as close as possible to a labeled organ, and microcapsules suspended in physiological saline are injected from the catheter. The injected microcapsules
Since the drug is gradually released from the embolized local blood vessel, a high concentration of the drug can be locally distributed even with a small dose compared with the systemic administration. Further, since the dose is small, it can be expected to reduce systemic side effects such as anticancer agents.

In the above chemoembolization therapy, for example, the conditions required for the microcapsules when the anticancer agent is retained in the local vascular bed for the chemical treatment are as follows.

(1) The particles have a shape that does not impede blood flow.

(2) It is appropriate that the particle size is centered around 100 μm and distributed by 50% before and after this. However, in order to enable the intermittent repeated administration method, it is desirable that the particle size be 150 μm or less. Further, considering an AV shunt that connects arteries and veins by bypass, it is required that particles of about 50 μm or less are not included. However, since the required particle size varies depending on each patient and medical condition, it is desired that the particle size can be freely controlled.

(3) The particles can control the amount of the active ingredient and control the release of various active ingredients by changing the film thickness.

[Means for Solving the Problems]

In order to achieve the above object, in the method for producing a microcapsule of the present invention, at least one of an active ingredient and a carrier which does or does not contain an air suspending agent, or a powder of a mixture thereof is suspended in an air stream. In the air, and the binder, or a binder and an air suspending agent, is sprayed onto the flowing powder to prevent the powder from excessively agglomerating. A coating layer which is formed of the same or different components and which protects and controls the release of the powder that forms the core particles on the surface of the granulated core particles. Finished particle diameter after formation is approximately 250μ
The value is set to m or less.

Examples of the binder and the film forming agent include sodium carboxymethyl cellulose, ethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, methacrylic acid / methacrylic acid ester copolymer, pregelatinized starch, dextrin, etc. , Water,
A single substance such as methanol, ethanol, isopropyl alcohol, toluene, hexane, carbon tetrachloride, chloroform, acetone, methylene chloride, or the one dissolved or dispersed in a mixed liquid thereof is used.

Further, as the above-mentioned air suspending agent, sterols such as cholesterol and ergosterol; phospholipids such as lecithin and kephalin; hydrogenated vegetable oils;
Paraffin; fatty acids such as myristic acid, palmitic acid, stearic acid, arahidic acid, behenic acid; higher fatty acids such as beeswax, carnauba wax; synthetic polymer polyethylene glycol; polyoxyethylene glycol fatty acid ester, polyoxyethylene sorbitan fatty acid Nonionic surfactants such as esters and sucrose fatty acid esters; Anionic surfactants such as alkyl esters and dialkylsulfosuccinates; silicic anhydride, hydrous silicic acid, hydrous magnesium silicate, synthetic aluminum silicate It is effective that silicic acid and salts thereof such as and the like are used alone or in combination.

[Work]

According to the method for producing a microcapsule described above, the raw material powder flowing in the suspension airflow is suspended in the binder or in the air with the binder regardless of the presence or absence of the air suspending agent. When sprayed with the agent, several to 10 raw material particles are produced due to the binding action of the binder and the excessive aggregation inhibiting action of the air suspending agent.
Agglomerates formed by agglomeration of about several particles, or agglomerates formed by agglomeration of small particles having a particle size of 1/10 or less on the surface of relatively large raw material particles.

Moreover, since the shape and particle size of these aggregates are closely related to the shape and particle size of the raw material powder, the particle design from the powder can be controlled by the combination of the active ingredient and the carrier.

In addition, one or more coating layers formed on the surface of the core particles are a reinforcing layer for preventing particle crushing when forming a coating depending on its purpose and application, and a layer for fixing powder such as active ingredient or carrier. , A layer that protects the contents or controls the radiation rate of the contents, and a surface-modifying layer that improves the dispersibility when used as a suspending agent, etc.,
Or, it acts to act as a combination thereof.

〔Example〕

Prior to the description of the examples, an apparatus used in the method for producing microcapsules of the present invention will be described.

FIG. 1 (a) is an example of an apparatus used for carrying out the present invention. An inner cylinder 2 is vertically arranged in a central portion of a lower part of a vertical outer cylinder 1, and below the inner cylinder 2. A perforated plate 4 having a spray nozzle 3 at the center is held by the outer cylinder 1 at the periphery. The spray nozzle 3 is connected to the spray liquid 6 in the liquid tank 5 below the porous plate 4 via the liquid feed pump 7, and is also connected to a high pressure air source 8 for atomizing the spray liquid 6. An exhaust fan 9 that exhausts the air inside the outer cylinder 1 is connected to the upper end portion of the outer cylinder 1, and the air sucked from the side of the lower end portion of the outer cylinder 1 by the exhaust fan 9 is in the side passage. It is heated by the heater 10 provided in the. Reference numeral 11 denotes a particle trap provided in the upper portion of the outer cylinder 1, and a wiping means 12 for dropping the particles trapped by the particle trap 11 is provided outside the upper end surface of the outer cylinder 1.

The porous plate 4 is provided with a large number of small holes so that the opening ratio of the lower part of the inner cylinder 2 is larger than the lower opening ratio between the inner cylinder 2 and the outer cylinder 1. The velocity of the gas passing through the plate 4 is adjusted so as to be faster inside the inner cylinder 2 than outside the inner cylinder 2, as shown in FIG. 1 (b).

However, a device capable of producing such a gas velocity difference between the inner side and the outer side of the inner cylinder 2 is shown in FIG.
In addition to the case of using the perforated plate 4 shown in (b), it can be easily obtained by a spouted bed type apparatus as shown in FIG.

The device for carrying out the method of the present invention is not limited to the case of the above two configurations, and other devices capable of suspending the powder in the air can also be used.

The method for producing a microcapsule according to the present invention uses the spray liquid 6 sprayed from the spray nozzle 3 to fluidize the powder raw material charged in the device having the above-described characteristics in the rising air flow in the device, and thereby the third process is performed. The core particles a as shown in the figure are granulated. In this granulation process, the powder is blown up in the inner cylinder 2 by a fast upward flow, and when it passes through the inner cylinder 2 and the gas velocity decreases, it falls between the inner cylinder 2 and the outer cylinder 1 due to gravity. Is guided to the lower part of the inner cylinder 2, and the above-mentioned movement is regularly repeated again.

However, during granulation of the core particles a, it is possible to prevent unnecessary excessive aggregation from occurring due to the action of various binders and air suspending agents described in the section of means for solving the problem. And the nuclear particle a
Is composed of agglomerates of several to more than 10 raw material particles, and the particle diameter is 1
It is configured as an agglomerate covering particles of / 10 or less so that the shape and particle diameter of the core particle a can be designed. The above air suspending agent can be used by dispersing it in the raw material powder, or can also be used by dispersing it in the spray liquid 6.

The granulated core particles a are successively provided in the same device on the outer side thereof, depending on the purpose and application, a reinforcing layer b for preventing the particles from being crushed when forming the core particles a, an active ingredient, a carrier, etc. A layer c for fixing the powder, a layer d for protecting the contents and controlling the release rate of the contents, and a coating layer such as a surface modification layer e for improving the dispersibility when a suspending agent is used. Properly combined to form one or more layers. Cellulose-based or resin-based substances are often used as these coating materials, and here again, the air-suspending agent has a major cause of inhibiting the adhesion of the core particles a to each other and the film formation on the core particles a. It works effectively to remove it.

In each of the examples of the present invention shown below, for the release of the contents from the microcapsules, the dissolution rate was measured by the dissolution tester NTR5S3 manufactured by Toyama Sangyo Co., Ltd., Japan Pharmacopoeia method No. 2 liquid, 37 ° C, 200 rpm paddle method. It was measured. Unless otherwise specified,% in each Example represents% by weight.

Example 1 500 g of corn starch having a size of about 10 μm was granulated using 500 ml of a 1.5% sodium carboxymethyl cellulose aqueous solution, and 100 g was sieved to 37 to 105 μm to obtain 100 g as a granulation nucleus. An ethanol solution containing 2.5% each of ethyl cellulose and cholesterol (hereinafter referred to as ECE
250 ml was sprayed to form a first coating layer. Next, as an active ingredient, 20 g of isoniazid suspended in 500 ml of ECE solution was sprayed to form a second coating layer. Further, as a diffusion barrier, ECE liquid was sprayed to form a third coating layer.

Fig. 4 (a) is a columnar diagram showing the particle size distribution of the granulation nuclei used, and solid line A in Fig. 4 (b) is the microcapsules obtained by coating 150% ethyl cellulose and cholesterol on the surface of the granulation nuclei. Fig. 5 is a column diagram showing the particle size distribution of Fig. 5, and Fig. 5 is a diagram showing the elution rate of isoniazid from the microcapsules when the coating amount was changed. The yield of microcapsules in this case was 97.1%.

In this example, only ethyl cellulose was 2.
The particle size distribution of the microcapsules produced in the same manner using an ethanol solution containing 5% is as shown by the dotted line B in FIG. 4 (b), which contains 2.5% ethyl cellulose and polyethylene glycol # 4000.1%. The particle size distribution of the microcapsules produced in the same manner using the ethanol solution was as shown by the chain line C in FIG. 4 (b).

Example 2. To 22.5 g of the granulation nucleus shown in Example 1 above, 4.5 g of solid powder of an ethanol solution (hereinafter abbreviated as EPE solution) containing 1.7% each of ethyl cellulose and polyethylene glycol # 4000 was sprayed. To obtain a first coating layer. Then solids
11 g of cisplatin was suspended in an EPE solution corresponding to 13.5 g, and this was sprayed to form a second coating layer. Furthermore, as a diffusion barrier, an ethanol solution containing 2.5% ethyl cellulose and 0.1% polyethylene glycol # 400 was sprayed to produce a third
It was a coating layer.

The particle size distribution of the microcapsules in this case was 75 μm or less 13.6% 75 to 106 μm 61.0% 106 to 150 μm 25.4% 150 μm or more. The outer shape of the microcapsules photographed by an electron microscope is as shown in FIG. 6, and the elution rate of cisplatin from the microcapsules when the coating amount is changed is as shown in the diagram in FIG. 7.

Example 3. Maruo Calcium Co. 08 heavy calcium carbonate 32-44 μm 300
g, ethyl cellulose and cholesterol respectively
Granulation was performed with 500 ml of an ethanol solution (ECE liquid) containing 1.5%, and a liquid in which 50 g of phenacetin was suspended in 1000 ml of ECE liquid was sprayed on the granulation nucleus to form a first coating layer. Next, an ECE liquid was sprayed as a diffusion barrier to form a second coating layer.

The particle size distribution of the microcapsules in this case was 44 μm or less 7.8% 44 to 75 μm 41.0% 75 to 149 μm 49.6% 149 μm to 1.6%. The elution rate of phenacetin from the microcapsules when the coating amount was changed is as shown in the diagram in FIG. 8, and the outer shape of the microcapsules photographed by an electron microscope is as shown in FIG.

The binder, the air suspending agent, and the coating agent in each of the above-mentioned examples are a single item appropriately selected from each of the other groups described in the section of means for solving the problem, or a single item thereof. Almost the same result can be obtained by using an appropriate combination.

〔The invention's effect〕

Since the present invention is configured as described above, it has the following effects as seen in each example.

According to the production method of the present invention, the distribution of microcapsule particle size can be freely controlled. When clinically applied as a microcapsule such as chemoembolization, 50-
150 μm is suitable, and not only intermittent repeated administration can be achieved but also microcapsules can be efficiently dispersed in the local vascular bed at the target site in consideration of AV shunt.

Moreover, according to the method of the present invention, not only can the microcapsules be made to have a required particle size, but also the film thickness can be adjusted, so that the release of the active ingredient in the microcapsules can be controlled.

In addition, the shape of the microcapsules has irregularities formed on the surface, so that there is no possibility of impeding blood flow even in clinical application.

[Brief description of drawings]

FIG. 1 (a) is a vertical cross-sectional view showing an example of an apparatus for carrying out the method of the present invention, FIG. 1 (b) is a main-part cross-sectional view showing the distribution of the air flow velocity inside and outside the inner cylinder, and FIG. FIG. 3 is a vertical sectional view showing the structure of another device, FIG. 3 is a sectional view schematically showing the structure of a microcapsule obtained by carrying out the method of the present invention, and FIGS. 4 (a) and 4 (b) are the first. FIG. 5 is a column diagram showing the particle nucleus and particle size distribution of the microcapsules in the example, and FIG. 5 is a diagram showing the elution rate of isoniazid in the first example.
FIG. 6 is a perspective view showing the outer shape of the microcapsules of the second embodiment, FIG. 7 is a diagram showing the elution rate of cisplatin from the microcapsules of the second embodiment, and FIG. 8 is a microcapsule of the third embodiment. FIG. 9 is a diagram showing the dissolution rate of phenacetin from the capsule, and FIG. 9 is a perspective view showing the outer shape of the microcapsule.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Yumiko Yamaoka, 1-23-23 Nori, Nori Nishi-Yodogawa-ku, Osaka-shi, Osaka 301-72 (72) Inventor, Tetsuma Fujimoto 8-23, Kawane-cho, Neyagawa-shi, Osaka (72) Inventor Yoshifumi Ohsako 109-54 Kubo, Kumatori-cho, Sennan-gun, Osaka Prefecture

Claims (3)

[Claims] 1. A powder of at least one of an active ingredient and a carrier, which does or does not contain an air suspending agent, or a mixture thereof, is made to flow in a suspension air flow, and a binder is added to the flowing powder. Or, a binder and an air-suspending agent are sprayed to prevent excessive agglomeration of the powder, and then the air-suspension coating method is used to granulate the core particles of the required size. At least one coating layer that protects and controls the release of powder that forms core particles on the surface of the particles is formed with the same or different components so that the finished diameter of the particles after forming the coating layer is approximately 250 μm or less. A method for producing a microcapsule, which is characterized in that 2. A binder and a film forming agent include sodium carboxymethyl cellulose, ethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, methacrylic acid / methacrylic acid ester copolymer, and pregelatinized starch. , Dextrin, water,
A microcapsule according to claim 1, wherein a simple substance such as methanol, ethanol, isopropyl alcohol, toluene, hexane, carbon tetrachloride, chloroform, acetone, methylene chloride, or a mixture or a mixture thereof dissolved therein is used. Manufacturing method. 3. Air suspension agents include sterols such as cholesterol and ergosterol; phospholipids such as lecithin and kephalin; hydrogenated vegetable oils; paraffin;
Fatty acids such as myristic acid, palmitic acid, stearic acid, arahydric acid and behenic acid; higher fatty acids such as beeswax, carnauba wax; synthetic polymer polyethylene glycol; polyoxyethylene glycol fatty acid ester, polyoxyethylene sorbitan fatty acid ester,
Nonionic surfactants such as sucrose fatty acid ester;
Anionic surfactants such as alkyl ester and dialkyl sulfosuccinate; silicic acid such as anhydrous silicic acid, hydrous silicic acid, hydrous magnesium silicate, and synthetic aluminum silicate and salts thereof are used individually or in combination. The method for producing a microcapsule according to claim 1 or 2.