JPH01249718A - Production of microcapsule - Google Patents

Abstract

PURPOSE:To obtain a microcapsule having freely controllable particle diameter distribution, by flowing powder consisting of active ingredient and carrier in suspended air current, spraying binder and granulating nucleus particle of desired size, then forming a film coating layer on the surface of the nucleus particle. CONSTITUTION:Powder consisting of active ingredient containing or not containing suspending agent in air (e.g., sterols, phospholipids or fatty acids) and carrier or mixture thereof is flowed in suspended current, said powder in flowing is sprayed binder or binder and suspending agent in air, then nucleus particle of desired size is granulated in a preventing too condensed state of powder. Next, at least one skin layer such as a layer fixing powder such as active ingredient or carrier, a layer protecting the content or controlling exhausting speed of content, etc., is formed on the surface of the granulated nucleus particle to afford a microcapsule of <=250mum resultant diameter.

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention allows the particle size distribution, particle diameter, and particle shape to be freely designed by granulating core particles from powder that serves as the core of microcapsules. The present invention relates to a method for producing microcapsules that can be used for industrial mass production of microcapsules used in chemoembolization therapy and other treatments.

[Conventional technology]

Conventionally, methods for producing microcapsules include (1) chemical methods such as interfacial polymerization and in situ polymerization.

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

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

etc. are known (for example, see Granulation Handbook, Japan Powder Technology Association, Ohmsha, capsule granulation method section).

[Problem to be solved by the invention]

With the conventional first chemical method, it is difficult to prepare microcapsules with the required fine particle size (50-150 μm), and it is also difficult to produce microcapsules that can be used in living organisms. There was a point. In particular, there was a drawback in that the toxicity of the reaction initiator and residual monomers became a problem.

In addition, in the second physicochemical method, the content of the active ingredient in the microcapsules is influenced by the properties of the active ingredient, such as whether it is hydrophilic or lipophilic, so it is difficult to control the content of the active ingredient. Not only is this difficult, but a considerable amount of microcapsules containing no active ingredient are also produced.

Furthermore, although the third mechanical method has the advantage of being able to freely adjust the particle size and amount of coating, and can also be mass-produced, when handling fine particles, Since aggregation occurs due to electrostatic force, there is a problem in that it is difficult to efficiently obtain microcapsules of a desired size.

The present invention has been made in view of the above-mentioned problems of the conventional technology, and its purpose is to, for example, stagnate an anticancer drug in the local vascular bed and use it in chemoembolization therapy, which will be described later. The present invention aims to provide a method for producing microcapsules that satisfies the shape, particle size, and particle size distribution required for microcapsule particles in the case of therapy.

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

First, chemoembolization is a combination of arterial embolization and arterial injection of drugs. For example, anticancer drugs are stagnated in the local vascular bed to enhance the chemotherapy effect, and in combination with the embolization effect, it is a powerful antitumor drug. This is a treatment method that attempts to achieve an effect.

Specifically, the tip of a catheter inserted through a peripheral artery is placed as close as possible to the target organ under X-ray fluoroscopy, and microcapsules suspended in physiological saline are injected through the catheter. The injected microcapsules are
Since the drug is gradually released from the embolized local blood vessels, it is possible to distribute the drug locally at a high concentration even with a smaller dose than when administered systemically. In addition, since the dose required is small, it is expected that systemic side effects of anticancer drugs and the like will be reduced.

In the chemoembolization therapy described above, for example, when chemotherapy is performed by causing an anticancer drug to stagnate in a local vascular bed, the conditions required for microcapsules are as follows.

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

(2) It is appropriate for the particle diameter to be distributed around 100 μm, with a distribution of 50% before and after this. However, in order to enable intermittent repeated administration, it is desirable that the diameter be 150 μm or less. Furthermore, considering the 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 this required particle size differs depending on each patient and disease state, it is desired that it can be freely controlled.

(3) Particles can be used to control the release of various active ingredients by adjusting the amount of active ingredients and controlling the film thickness.

[Means to solve the problem]

In order to achieve the above object, in the method for producing microcapsules of the present invention, a powder of an active ingredient with or without an air suspending agent, at least one of a carrier, or a mixture thereof is suspended in an air stream. A binder, or a binder and an air suspending agent are sprayed onto the flowing powder to prevent excessive agglomeration of the powder, and the required size is coated using an air suspension coating method. The core particles are granulated, and one or more coating layers are formed on the surface of the granulated core particles using the same or different ingredients to protect and control the release of the powder that forms the core particles, and after the coating layer is formed, The finished diameter of the particles is approximately 250
It is designed to be less than μm.

The binders and coating agents mentioned above include sodium carboxymethyl cellulose, ethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, methacrylic acid/methacrylic acid ester copolymer, pregelatinized starch, dextrin, etc. may be dissolved or dispersed in water, methanol, ethanol, isopropyl alcohol, toluene, hexane, carbon tetrachloride, chloroform, acetone, methylene chloride, or a mixture thereof.

In addition, the above air suspending agents include sterols such as cholesterol and ergosterol; phospholipids such as lecithin and cephalin; hydrogenated vegetable oils; paraffin; myristic acid, palmitic acid, stearic acid, arahidic acid, Fatty acids such as behenic acid; Higher fatty acids such as beeswax and carnauba wax; Synthetic polymer polyethylene glycol; Nonionic surfactants such as polyoxyethylene glycol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, and sucrose fatty acid ester anionic surfactants such as alkyl acid esters and dialkyl sulfosuccinates; silicic anhydride,
Silicic acids and their salts, such as hydrated silicic acid, hydrated magnesium silicate, and synthetic aluminum silicate, are effective when used alone or in combination.

[Function] According to the above-mentioned method for producing microcapsules, the raw material powder flowing in the suspending air stream is mixed with the binder or the binder and the air, regardless of the presence or absence of an air suspending agent. When sprayed with an airborne suspending agent, due to the binding effect of the binder and the excessive agglomeration prevention effect of the airborne suspending agent, the raw material particles range from a few to 1 liter.
It is formed into an aggregate in which about several O particles are aggregated, or an aggregate in which small particles having a particle diameter of 1/10 or less are aggregated 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 carrier.

In addition, one or more coating layers formed on the surface of the core particles can be formed, depending on the purpose and use, as follows: ■ A reinforcing layer to prevent particle fragmentation during coating; ■ An adhering layer for powders such as active ingredients and carriers. - a layer that protects the contents or controls the release rate of the contents, and - a surface modification layer that improves the dispersibility when used as a suspending agent, etc.
or a combination thereof.

〔Example〕

Prior to describing Examples, the apparatus used in the method for manufacturing microcapsules of the present invention will be described.

FIG. 1(a) shows an example of a device used for carrying out the present invention, in which an inner cylinder 2 is vertically disposed at the center of the lower part of a vertical outer cylinder l, and the lower part of the inner cylinder 2 is A perforated plate 4 having a spray nozzle 3 in the center is held by the outer cylinder 1 at its periphery. The spray nozzle 3 is connected to the liquid feed pump 7 under the perforated plate 4.
It is connected to the spray liquid 6 in the liquid tank 5 via a high-pressure air source 8 that atomizes the spray liquid 6. An exhaust fan 9 for exhausting the air inside the outer cylinder 1 is connected to the upper end of the outer cylinder 1, and the air sucked in from the side of the upper end of the outer cylinder 1 by the exhaust fan 9 is drawn into the side passage. It is heated by a heater lO provided in the. 1) is a particle trap provided in the upper part of the outer cylinder 1, and on the outside of the upper end surface of the outer cylinder 1 is provided a brush-off means 12 for dropping the particles captured by the particle trap 1). .

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

However, the devices that can create such a difference in gas velocity between the inside and outside of the inner cylinder 2 are those shown in Fig. 1 (a) and (
In addition to using the perforated plate 4 shown in b), it can also be easily obtained using a spouted bed type device as shown in FIG.

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

In the method for producing microcapsules of the present invention, a powder raw material introduced into an apparatus having the above-mentioned characteristics is fluidized in an ascending air current within the apparatus, and a third Core particles a as shown in the figure are granulated. In this granulation process, the powder is blown up by a fast upward flow inside the inner cylinder 2, 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 l due to gravity. is guided to the lower part of the inner cylinder 2, and the above-mentioned movement is repeated regularly.

However, during the granulation of core particles a, unnecessary excessive aggregation can be prevented by the action of various binders and air suspending agents mentioned in the section of means for solving the problem. In this case, the core particle a is made up of an aggregate of several to about 10 raw material particles, or the surface of a relatively large powder particle has a particle diameter of 1.
Constructed into an aggregate coated with particles of 710 or less, with core particles a
This makes it possible to design particles in terms of shape and particle size. The above air suspending agent can be used by dispersing it in the raw material powder, or it can be used as a spray liquid.
It can also be used by dispersing it in

The granulated core particles a are subsequently coated with a reinforcing layer b, an active ingredient, a carrier, etc. on the outside in the same device, depending on the purpose and use, to prevent particle crushing when forming the core particles a into a film. Suitable coating layers include a layer C1 that fixes the powder, a layer d that protects the contents and controls the release rate of the contents, and a surface modification layer e that improves the dispersibility when a suspending agent is used. are combined to form one or more layers. Cellulose-based and resin-based substances are often used as these coating materials, but even here, air suspending agents are a major cause of inhibiting adhesion of core particles a to each other and film formation on core particles a. It works effectively to remove it.

In each of the embodiments of the present invention shown below, the release of the contents from the microcapsules was performed using a dissolution tester NTR5S.
Type 3 manufactured by Toyama Sangyo Co., Ltd., Japanese Pharmacopoeia Law 2nd liquid, 37℃, 200
The dissolution rate was measured by the rpm paddle method. The percentages in each example represent percentages by weight unless otherwise specified.

Example 1 500g of cornstarch with a size of about 10μm was mixed into 1.
5% sodium carboxymethyl cellulose aqueous solution 5
0 (LD) and sieved to 37 to 105 μm, 100 g was used as a granulation nucleus. To this, an ethanol solution containing 2.5% each of ethyl cellulose and cholesterol (hereinafter abbreviated as ECE solution) was added. )250mZ
was sprayed to form the first coating layer. Next, a suspension of 20 g of isoniacite as an active ingredient in a 500-mL ECE liquid was sprayed to form a second coating layer. Further, as a diffusion barrier, an ECE liquid was sprayed to form a third coating layer.

Figure 4 (a) is a columnar diagram showing the particle size distribution of the granulation nuclei used. Figure 4 (solid line A in BL is a microcapsule obtained by coating the surface of the granulation nuclei with 150% ethyl cellulose and cholesterol). Fig. 5 is a graph showing the elution rate of isoniasite from microcapsules when the coating amount is varied.The yield of microcapsules in this case was 97.1%. Ta.

In addition, in this example, only ethyl cellulose was
．． The particle size distribution of microcapsules produced in the same manner as above using an ethanol solution containing 5% ethyl cellulose is as shown by the dotted line B in Figure 4 (Figure 4). ．． The particle size distribution of microcapsules produced in the same manner using an ethanol solution containing 5% polyethylene glycol #4000 and 0.1% polyethylene glycol #400 was as shown by the dashed line C in FIG. 4(b).

Example 2 To 22.5 g of the granulation cores shown in Example 1 above, 4.5 g of solid content of an ethanol solution (hereinafter abbreviated as EPE liquid) containing 1.7% each of ethyl cellulose and polyethylene glycol #4000 was added. A corresponding amount was sprayed to form the first coating layer. Next, 1) g of cisplatin was suspended in an EPE liquid corresponding to 13.5 g of solid content, and this was sprayed to form a second coating layer.

Furthermore, as a diffusion barrier, 2.5% ethyl cellulose
An ethanol solution containing 0.1% of polyethylene glycol #400 and polyethylene glycol #400 was sprayed to form a third 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 Trace. The external shape of the microcapsules photographed with an electron microscope is as shown in FIG. 6, and the elution rate of cisplatin from the microcapsules when the coating amount is varied is as shown in the diagram in FIG. 7.

Example 3゜Maruo Calcium Co., Ltd. 08 Heavy Calcium Carbonate 32-44
300 g of μm was granulated with 500 Inl of ethanol solution (ECE solution) containing 1.5% each of ethyl cellulose and cholesterol, and 100 μm of ECE solution was added to the granulation cores.
00- was sprayed with a suspension of 50 g of zenacetin to form a first coating layer.

Next, ECE liquid was sprayed as a diffusion barrier to form a second coating layer.

In this case, the particle size distribution of the microcapsules is 44 μm or less 7.8% 44-75, crm 41.0% 75-149
μm 49.6% 149 μm or more 1.6%. The elution rate of zenacetin from the microcapsules when the coating amount was changed is as shown in the diagram in FIG. 8, and the external shape of the microcapsules photographed with an electron microscope is as shown in FIG. 9.

In addition, the binder, air suspending agent, and coating agent in each of the above examples may include single items appropriately selected from the other groups described in the section of means for solving the problems, or these single items. Similar results can be obtained using appropriate combinations.

〔Effect of the invention〕

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

According to the production method of the present invention, the distribution of microcapsule particle diameters can be freely controlled. When used clinically as microcapsules for chemoembolization therapy, etc., 50
~150 μm is appropriate, which not only allows for intermittent repeated administration, but also enables efficient delivery of the microcapsules to the local vascular bed at the target site (even considering AV shunts).
Can be dispersed.

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

Moreover, since the shape of the microcapsules has irregularities formed on the surface, there is no risk of inhibiting blood flow even when used clinically.

[Brief explanation of the drawing]

FIG. 1(a) is a longitudinal cross-sectional view showing an example of an apparatus for carrying out the method of the present invention, FIG. 3 is a longitudinal sectional view showing the structure of another device, FIG. 3 is a sectional view schematically showing the structure of microcapsules obtained by implementing the method of the present invention, and FIGS. A histogram showing the particle size distribution of particle nuclei and microcapsules in Examples, FIG. 5 is a diagram showing the elution rate of isoniasite in Example 1, and FIG. 6 is a perspective view showing the external shape of microcapsules in Example 2. Figure 7 is a diagram showing the elution rate of cisplatin from the microcapsules in the second example, Figure 8 is a diagram showing the elution rate of zenacetin from the microcapsules in the third example, and Figure 9 is a diagram showing the elution rate of zenacetin from the microcapsules in the third example. FIG. 3 is a perspective view showing the outer shape of the same microcapsule. Figure 1 ((1) Figure 3 Figure 4 (a) g>14a #-1&#m ('1rkWIfL) Figure 4 (b)

Claims (3)

[Claims] (1) Fluidizing a powder of an active ingredient and at least one of a carrier, or a mixture thereof, with or without an air suspending agent, in a suspending air stream, and adding a binder, or A binder and an air-suspending agent are sprayed to prevent excessive agglomeration of the powder, and core particles of a desired size are granulated by an air-suspension coating method, and the granulated core particles are One or more coating layers are formed with the same or different components to protect and control the release of the powder that forms the core particles on the surface, and the finished diameter of the particles after the coating layer is formed is approximately 250 μm or less. Characteristic method for producing microcapsules. (2) Binders and coating agents include sodium carboxymethyl cellulose, ethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, methacrylic acid/methacrylic acid ester copolymer, pregelatinized starch, and dextrin. water, methanol, ethanol, isopropyl alcohol, toluene, etc.
2. The method for producing microcapsules according to claim 1, wherein hexane, carbon tetrachloride, chloroform, acetone, methylene chloride, or the like alone or dissolved or dispersed in a mixed solution thereof is used. (3) Air suspending agents include styrenes such as cholesterol and ergosterol; phospholipids such as lecithin and cephalin; hydrogenated vegetable oils; paraffin; myristic acid, palmitic acid, stearic acid, arahidic acid, and behenin. Fatty acids such as acids; Higher fatty acids such as beeswax and carnauba wax; Synthetic polymer polyethylene glycol; Polyoxyethylene glycol fatty acid ester,
Nonionic surfactants such as polyoxyethylene sorbitan fatty acid ester and sucrose fatty acid ester; anionic surfactants such as alkyl acid ester and dialkyl sulfosuccinate; anhydrous silicic acid, hydrated silicic acid, and hydrated magnesium silicate 3. The method for producing microcapsules according to claim 1 or 2, wherein silicic acid such as synthetic aluminum silicate and its salts are used singly or in combination.