JP2006102558A - Coating method for particle - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To solve a problem of dissolution and permeation of a particle component into a covering layer by a water based membrane agent liquid, to shorten a treatment time and to realize enhancement of productivity. <P>SOLUTION: A first covering layer L1 is formed on a surface of a chemical particle P by dry coating of a hydrophobic powder P'. Thereafter, a second covering layer L2 is formed on a surface of the particle P forming the first covering layer L1 by wet coating of the water based membrane agent liquid. The dry coating and the wet coating are successively performed in a single fluidized bed device. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for forming a coating layer on a water-soluble particle such as a drug-containing core particle having high water solubility by wet coating with an aqueous film agent solution.

  For example, in the pharmaceutical industry, research on formulation design for drug delivery is underway, and control of drug substance elution is an important issue. As elution control, various functional coatings such as enteric, gastric, sustained release, moisture-proof, photodegradable, bitterness mask, etc. are widely formed on the surface of drug particles. In many cases, such functional coating is performed using a fluidized bed apparatus. In recent years, the fluidized bed apparatus has been improved to enable direct coating on a fine drug substance. Various formulation designs such as microencapsulation are possible. On the other hand, the coating of fine drug substance requires a large amount of film agent and processing time due to the large total surface area of raw materials, and there are few problems related to production efficiency and product quality. Absent.

  In addition, the coating operation using a fluidized bed apparatus is generally wet coating by spraying droplets of a film agent solution. However, in recent years, from the viewpoint of safety and environmental protection, it has been replaced with an organic solvent-based film agent solution. The use of aqueous film solutions is increasing (aqueous coating). However, when an aqueous film agent solution is used for coating water-soluble particles such as drug particles with high water solubility, the particles are sprayed until the droplets of the sprayed film agent solution adhere to the particle surface and are sufficiently dried. In many cases, the component (drug) dissolves and penetrates into the coating layer, making it difficult to control the target elution. On the other hand, the particle component concentration in the coating layer can be reduced by further advancing the coating operation, but a large amount of coating is required to obtain the target elution control performance, leading to a reduction in production efficiency.

In relation to the above point, the following Patent Document 1 discloses that a water-insoluble polymer fine powder is added in a powder state to the surface of a solid molded product containing a pharmacologically active substance to form a film, followed by an aqueous coating method. A method for producing a coated preparation to be coated is disclosed.
JP-A-9-143056

  The manufacturing method disclosed in Patent Document 1 includes a step of forming a first coating layer by adding fine powder of water-insoluble polymer in a powder state to the surface of a solid molded product, and an aqueous film agent solution on the surface of the first coating layer. In which the second coating layer is formed by spraying, but each step is performed separately by different apparatuses. For example, in the example of this document, the first coating layer is formed by a rolling granulator, and the second coating layer is formed by a fluidized bed apparatus. Therefore, there is a problem that the processing time increases because it is necessary to transfer raw materials between processes and to prepare and monitor the operation of each device.

  Further, in the step of forming the first coating layer, the binder liquid is sprayed to adhere the water-insoluble polymer powder to the surface of the solid molded product. For such fine particles, the particles tend to aggregate and it is difficult to ensure good coating quality. Moreover, since the binder liquid is sprayed, the above-described problems occur. That is, when water-based binders are used, there is a problem of dissolution / penetration of particle components (drugs) into the coating layer, and when organic solvent-based binders are used, there are safety and environmental problems. Occurs.

  An object of the present invention is to dissolve and permeate particle components into a coating layer with an aqueous film agent solution when forming a coating layer on the water-soluble particles such as drug particles with high water solubility by wet coating of the aqueous film agent solution. It is to solve the problem, shorten the processing time, and improve the productivity.

  In order to solve the above problems, the present invention provides a step of forming a first coating layer on the surface of water-soluble particles by dry coating of hydrophobic powder, and an aqueous film agent solution on the surface of the particles on which the first coating layer has been formed. Forming a second coating layer by wet coating.

  Here, the water-soluble particles in the present invention are highly water-soluble so that the particle component is dissolved and transferred (penetrated) into the coating layer when the coating layer is formed by directly spraying the aqueous film agent liquid on the surface thereof. The particle which shows. The dry coating in the present invention refers to an operation of forming a coating layer by directly attaching a film agent powder to the surface of particles without adding a liquid such as a binder solution. Furthermore, the wet coating in the present invention refers to an operation of forming a coating layer by spraying droplets of an aqueous film agent solution on the surface of particles (aqueous wet coating).

  By forming the first coating layer by the dry coating of the hydrophobic powder under the second coating layer by the water-based wet coating, dissolution / penetration of the water-soluble particle component into the second coating layer is prevented or suppressed, Elution control of the water-soluble particle component is effectively performed.

  By continuously performing the process of forming the first coating layer and the process of forming the second coating layer in a single fluidized bed apparatus, transfer of raw materials between processes and individual operation for each apparatus Preparation / monitoring work is unnecessary, and the processing time can be shortened.

  Examples of the fluidized bed apparatus include a fluidized bed container, a particle size adjusting mechanism that disperses aggregation of particles flowing and circulating in the fluidized bed container by mechanical crushing force, and particles flowing and circulating in the fluidized bed container. A fluidized bed apparatus equipped with a spray nozzle for spraying an aqueous film agent solution can be used (see Japanese Patent Application Laid-Open No. 2004-148291 previously proposed by the present applicant). Here, the mechanical crushing force is a collision force, impact force, repulsive force, crushing force, shearing force, stirring force, frictional force, etc. given to the granular particles by the movement of the members constituting the sizing mechanism. It is power. As a sizing mechanism that disperses the agglomeration of the granular particles by such mechanical pulverization force, for example, an impeller having pulverization blades and a predetermined gap between the impeller pulverization blades and a predetermined gap are arranged. The thing provided with the installed screen can be employ | adopted. Further, as the above sizing mechanism, a mechanism provided with a rotor and a stator arranged concentrically and having a plurality of teeth can be employed. Such a sizing mechanism including a rotor and a stator is also called a homogenizer, and is generally used in a dispersion emulsifier (for example, “Universal Mixer SR Series” manufactured by POWREC Co., Ltd.). Alternatively, as the sizing mechanism, a relatively rotating disk provided with a large number of pins (so-called pin mill), a disk-shaped hammer plate provided with a large number of swing hammers, and an involute-type recessed lining plate are provided. (For example, “Powrex Atomizer” manufactured by POWREC Co., Ltd.) or the like can also be employed.

  According to the present invention, when a coating layer is formed on a water-soluble particle such as a drug particle having high water solubility by wet coating of an aqueous film agent solution, dissolution / penetration of the particle component into the coating layer by the aqueous film agent solution is performed. In addition to solving problems, the processing time can be shortened and productivity can be improved.

  Hereinafter, embodiments of the present invention will be described with reference to the drawings.

  FIG. 1 conceptually shows the overall configuration of the fluidized bed apparatus used in this embodiment.

  The fluidized bed container 1 has, for example, a conical cylinder in the upper part and a cylindrical shape in the lower part (the upper part may be cylindrical and the lower part may be conical), and the filter system 2 is installed in the upper space. A gas dispersion plate 3 made of a perforated plate such as punching metal is disposed at the bottom. In addition, the rotary rotor 4 is disposed at the center of the bottom, the granulating mechanism 5 is disposed above the rotating rotor 4, and the cylindrical draft tube 6 is disposed above the granulating mechanism 5. Furthermore, one or a plurality of spray nozzles 7 are disposed on the side of the sizing mechanism 5.

  FIG. 2 shows the lower part of the fluidized bed container 1. The draft tube 6 is fixed to the side wall of the fluidized bed container 1 through the attachment member 6a together with the screen 5b of the granulating mechanism 5, and the upper end thereof is open. For example, the upper portion 6b of the draft tube 6 has a cylindrical shape, and the lower portion 6c has a conical shape whose diameter decreases downward.

  The particle size adjusting mechanism 5 includes a plurality of, for example, two impellers 5a having crushing blades 5a1 and a screen (sieving) 5b having a large number of holes having a predetermined diameter. The screen 5b has a truncated cone shape with a diameter decreasing downward, and is adapted to the lower end portion of the draft tube 6. The impeller 5a is detachably fixed to the upper portion of the rotating shaft 5c with a bolt 5d, and the side edge of the crushing blade 5a1 has a predetermined gap with the inner surface of the screen 5b. The rotating shaft 5 c passes through the central portion of the gas dispersion plate 3, extends below the fluidized bed container 1, and is rotatably supported by a bearing 9 on a housing 9 fixed to the stand 8 of the fluidized bed container 1. The interior of the housing 9 is sealed with a seal member 11. Further, a gap between the rotating shaft 5c and the gas dispersion plate 3 is sealed with a labyrinth seal.

  The spacer 13, the air cap 14, and the rotary rotor 4 are fixed to a portion below the impeller 5a of the rotary shaft 5c. The rotary rotor 4 has a predetermined gap from the upper surface of the gas dispersion plate 3 and is disposed so as to cover the upper surface of the gas dispersion plate 3.

  The rotation shaft 5c is connected to an appropriate rotation driving unit (not shown) and is driven to rotate by the rotation driving unit. As the rotating shaft 5c rotates, the impeller 5a, the air cap 14, and the rotating rotor 4 are integrally rotated at a high speed. The lower end opening of the screen 5b forms a labyrinth seal (or contact seal) between the impeller 5a and the air cap 14. Further, the impeller 5a and the rotating rotor 4 may be rotated at different speeds (for example, the rotating speed of the rotating rotor 4 is made slower than the rotating speed of the impeller 5a).

  For example, the spray nozzle 7 is disposed so as to spray the spray liquid in a tangential direction with respect to a circle having a predetermined radius centered on the axis of the rotation shaft 5c (so-called tangential spray).

  Fluidized gas (for example, hot air) is supplied into the fluidized bed container 1 through the gas dispersion plate 3. The fluidized gas ejected from the gas dispersion plate 3 into the fluidized bed container 1 passes through a gap between the lower surface of the rotary rotor 4 and the upper surface of the gas dispersion plate 3, and the outer periphery of the rotary rotor 4 and the fluidized bed container 1. The gap between the bottom inner wall and the inner wall of the fluidized bed container 1 between the granulating mechanism 5 and the inner wall of the fluidized bed container 1, and between the outer periphery of the draft tube 6 and the inner wall of the fluidized bed container 1 are raised. The space is raised and reaches the filter system 2. And after filtering fine powder etc. with the filter system 2, it exhausts outside the apparatus. Further, an air flow from the inside to the outside of the screen 5b is generated by the fan effect caused by the rotation of the impeller 5a of the granulating mechanism 5. Thereby, the inside of the draft tube 6 becomes a very weak negative pressure compared with the circumference | surroundings, and the effect of attracting | sucking the surrounding granular material particle | grains inside is acquired in the upper end part of the draft tube 6.

  As shown in FIG. 1, the powder particles P introduced into the fluidized bed container 1 are a gap between the outer periphery of the rotating rotor 4 and the inner wall of the bottom of the fluidized bed container 1, the particle size adjusting mechanism 5 and the fluidized particles. The space portion between the inner wall of the layered container 1 and the space portion between the outer periphery of the draft tube 6 and the inner wall of the fluidized bed container 1 are lifted by an ascending air current, and rise in the fluidized bed container 1 to some extent. Thereafter, it descends due to its own weight and further flows into the draft tube 6 under the above suction effect. And the granular material particle | grains P which flowed in in the draft tube 6 descend | fall in the draft tube 6, reach the sizing mechanism 5, receive the centrifugal effect accompanying rotation of the impeller 5a, and have many holes of a predetermined diameter. When passing through the screen 5b, the secondary agglomerated part and the aggregated part are crushed and dispersed into particles having a single particle shape or a predetermined particle size (size adjusting action).

  The particulate particles P that have passed through the sizing mechanism 5 are returned again to the above-described updraft by the centrifugal effect of the rotating rotor 4. In this way, the gap between the outer periphery of the rotating rotor 4 and the inner wall at the bottom of the fluidized bed container 1, the sizing mechanism 5 and the inner wall of the fluidized bed container 1 is added to the granular particles P in the fluidized bed container 1. A fluidized bed that floats and circulates in the direction of descending along the interior of the draft tube 6 is formed by ascending the space between the outer periphery of the draft tube 6 and the space between the outer periphery of the draft tube 6 and the inner wall of the fluidized bed container 1. .

  Using the fluidized bed apparatus described above, a water-soluble particle, for example, a water-soluble drug particle is coated.

  First, a hydrophobic powder as a film agent is added to a water-soluble drug raw material, mixed, and then charged into the fluidized bed container 1. Then, the fluidized bed apparatus is operated in the above-described manner, and the drug particles and the hydrophobic powder are fluidly circulated in the fluidized bed container 1. As shown in FIG. 3, when the drug particles P and the hydrophobic powder P ′ flow and circulate in the fluidized bed container 1 in a mixed state and repeatedly pass through the sizing mechanism 5, mechanical shearing from the sizing mechanism 5, In response to the spreading action, the hydrophobic powder P ′ spreads and adheres to the surface of the drug particles P to form the first coating layer L1 (dry coating).

  The supply air amount of the fluidized gas in the dry coating operation is set to a low air amount that does not separate the drug particles P and the hydrophobic powder P ′ in the fluidized bed container 1, for example. Further, the supply temperature of the fluidizing gas is set in the range from room temperature to the softening point of the hydrophobic powder, depending on the thermal characteristics of the hydrophobic powder. Alternatively, only the drug raw material may be charged into the fluidized bed container 1 first, and the hydrophobic powder may be added in an appropriate amount from the lower part of the fluidized bed while fluidly circulating the drug particles in the fluidized bed container 1.

  After the first coating layer L1 of the hydrophobic powder P ′ is formed on the surface of the drug particle P by the dry coating, the process proceeds to the wet coating. As shown in FIG. 3, the wet coating is included in the aqueous film preparation liquid by spraying droplets of the aqueous film preparation liquid onto the surface of the drug particles P on which the first coating layer L1 of the hydrophobic powder P ′ is formed. In this step, the film agent component (solid content) is attached to the surface of the drug particles P and dried to form the second coating layer L2 made of the film agent component. The transition from the dry coating to the wet coating is performed by switching the operating conditions while continuing the operation state of the fluidized bed apparatus. This wet coating operation can be performed under the same conditions as a normal spray coating operation using a fluidized bed apparatus.

  As shown in FIG. 1, in this embodiment, the drug particles P that have passed through the sizing mechanism 5 and returned to the above-described updraft by the centrifugal effect of the rotating rotor 4 (the first of the hydrophobic powder P ′ by dry coating). The drug particles P) on which the coating layer L1 is formed are sprayed with the aqueous film agent solution from the spray nozzle 7 at this position. Then, the drug particles P that have been sprayed with the aqueous film agent liquid are dried when rising in the space between the outer periphery of the draft tube 6 and the inner wall of the fluidized bed container 1, and again enter the draft tube 6. It flows into the sizing mechanism 5 and receives a sizing action. In this way, the film agent component contained in the droplets of the aqueous film agent liquid without causing secondary aggregation of the drug particles P by repeating the cycle of the aqueous film agent liquid spray → drying → size control. Adheres to the surface of the drug particles P and is dried to form the second coating layer L2 (aqueous wet coating).

Anhydrous caffeine powder having a fine particle size (average particle size D50 = 53 μm) and a relatively high water solubility (solubility) was used as a water-soluble drug, and carnauba wax (wax) powder was added as a hydrophobic powder and mixed. Then, it charged in the fluidized bed container 1 of said fluidized bed apparatus, and performed dry coating-> wet coating continuously in the aspect mentioned above. The coating amount was 5% for dry coating and 90% for wet coating (ratio of the weight of anhydrous caffeine and the weight of solid content in the sprayed aqueous film solution) relative to the weight of anhydrous caffeine. The operating conditions are as shown in Table 1.

  The SEM observation results of the anhydrous caffeine bulk powder, the particles after dry coating, and the particles after wet coating are shown in FIGS. From the observation results shown in FIG. 5, it was confirmed that a hydrophobic powder coating layer (first coating layer) was formed on the particle surface after the dry coating operation. Moreover, the observation result shown in FIG. 6 confirmed that the coating layer (second coating layer) of the aqueous film agent solution was formed on the particle surface after the wet coating operation. In addition, it is confirmed that both the particles after dry coating and the particles after wet coating are sized to a relatively uniform particle size without causing secondary aggregation due to the sizing action of the sizing mechanism 5. It was done.

  FIG. 7 shows particles after wet coating shown in FIG. 6 (example product: indicated by ◆) and particles that were subjected only to wet coating under the same operating conditions using the above fluidized bed apparatus (comparative example product: ◇). The result of the dissolution test conducted for (Display) is shown. From the results shown in the figure, in the example product (♦), the hydrophobic dry coating layer (first coating layer) dissolves the core particle component (caffeine) into the wet coating layer (second coating layer). It was confirmed that permeation was prevented or suppressed, and better elution control performance was exhibited compared to the comparative product (◇).

  FIG. 8 shows the relationship between the 80% elution time and the coating rate. The amount of wet coating required for an elution time of 80% for 5 minutes is 82% for the comparative product (◆) (ratio of the weight of anhydrous caffeine and the weight of the solid content in the sprayed aqueous film solution). The example product (（) is 45%, and the example product (◇) can obtain the same elution control performance as the comparative product (◆) with a smaller amount of wet coating.

  Compared with the operation time, as shown in FIG. 9, in the example (left side), the dry coating requires 20 minutes, but by performing the wet coating continuously, it is about 90% compared to the comparative example (right side). Minute time savings were realized. That is, in the example, it was possible to realize a significant time reduction of about 37% with respect to the total coating time required in the comparative example.

[Dry coating operation]
As in Example 1, anhydrous caffeine powder having a fine particle size (average particle size D50 = 53 μm) and relatively high water solubility (solubility) was used as the water-soluble drug. 500 g of anhydrous caffeine powder is mixed with one of 7 types of dry film agents (glyceric acid fatty acid ester, edible oil and fat, wax, hardened oil, sustained-release coating powder) with different physical properties at a weight ratio of 10%. Then, dry coating was performed by circulating and flowing in the fluidized bed container 1 of the fluidized bed apparatus for 20 minutes. Table 2 shows the operating conditions at this time.

In the dry coating operation described above, the flow state of the particles in the fluidized bed container 1 was observed. As a result, the flow state of the particles could be classified into three modes shown in Table 3 depending on the type of the dry film agent.

  The SEM observation results of the anhydrous caffeine bulk powder and the particles after dry coating are shown in FIG. There is a relationship between the flow state of the particles and the film formability, and the deterioration of the flow state is considered to indicate the spread of the dry film agent film on the particle surface. In the dry film agent A, it is considered that the film is spread at the initial stage of operation, and the most uniform film is formed. The dry film agent B spreads the film at a later stage of operation. In the dry film agent C, although there was no flow deterioration state and a slight change in the particle surface was observed, many unattached film agent powders were mixed with the caffeine powder particles. Further, the film powder was scattered on the surface of the raw powder particles, resulting in an irregular surface shape.

  FIG. 11 shows the results of a dissolution test on particles that were only subjected to the dry coating described above. In addition, since the particle surface of the dry coating particles became hydrophobic and some particles floated in the test solution and could not be evaluated, they were compression molded at a low pressure of 2 (KN) to obtain test samples. Further, half of the molded product 500 (mmg) was prepared by mixing the disintegrant L-HPC so that it would disintegrate immediately. For comparison, a molded product was similarly prepared and evaluated for caffeine bulk powder. The dissolution test was carried out according to the Japanese Pharmacopoeia test (paddle method) with paddle rotation speed of 50 rpm and dissolution test solution with 900 ml of 37 ° C purified water.

  As shown in FIG. 11, up to 2 minutes elution time, elution of dry film products A, B, and C is suppressed as compared with the raw powder molded product. In the products B and C, the results were eluted quickly. As for the dry film product A, elution was delayed as a whole compared with the bulk molded product. As described above, the dry film agent product A has the entire particle surface hydrophobized, and water penetration into the drug is suppressed. On the other hand, in the case of the dry film agents B and C, the performance of the film can be confirmed up to a certain time.

[Wet coating operation]
Wet coating using the above-mentioned dry-coated particles (dry-type film products A, B, C) using ethyl cellulose aqueous solution {Aquacoat (Dainippon Pharmaceutical) 93%, Triacetin (Organic Synthetic Chemicals) 7%} went. Table 4 shows the operating conditions at this time.

  The coating amount (coating rate) was 60% with respect to the weight of anhydrous caffeine (the ratio between the weight of anhydrous caffeine and the weight of the solid content in the sprayed aqueous film solution), and sampling was performed during 40% coating. . The obtained coating particles were cured at 60 ° C. for 2 hours in a shelf dryer. Moreover, the sample which performed only the wet coating on the same operating conditions as a comparative example product without performing dry coating was produced. And the elution test was done about the Example goods and the comparative example goods with a coating rate of 40% and 60%, and the elution control performance was compared. The dissolution test was carried out according to the Japanese Pharmacopoeia test (paddle method) with paddle rotation speed of 50 rpm and dissolution test solution with 900 ml of 37 ° C purified water. The results are shown in FIGS. In addition, in order to confirm elution controllability, the dissolution test result of anhydrous caffeine bulk powder is also shown.

  From the test results shown in FIGS. 12 and 13, it was confirmed that the dry film preparation B (◯) exhibited higher elution control performance than the comparative example (Δ). For dry film product A (black square), improvement in elution control performance was observed up to 40% coating, but elution control performance decreased as the coating rate was increased. When the surface of the particles of the dry film agent A was observed with an SEM, the ethyl cellulose film was broken, which is considered to be caused by a decrease in the fixing property of the ethyl cellulose film due to the coating of the dry film agent A. For dry film product C (□), the effect of the dry coating operation was not recognized. This is presumably because the dry film agent that was not adhered or the dry film agent that was scattered and adhered to the surface of the raw powder particles reduced the coating performance of ethyl cellulose. In addition, since the dry film agent dissolves in water, it is considered that the drug has moved to the film side.

It is a figure which shows notionally the whole structure of the fluidized bed apparatus used by embodiment. It is an expanded sectional view which shows the principal part of the fluidized bed container 1 of FIG. It is a schematic diagram which shows the formation process of a coating layer. It is a figure which shows the SEM observation result of the anhydrous caffeine bulk particle. It is a figure which shows the SEM observation result of the particle | grains after dry coating. It is a figure which shows the SEM observation result of the particle | grains after wet coating. It is a figure which shows the result of a dissolution test. It is a figure which shows the relationship between 80% elution time and a coating rate. It is a figure which shows the comparison of operation time. It is a figure which shows the SEM observation result of the particle | grains after an anhydrous caffeine bulk powder and dry-type coating. It is a figure which shows the result of a dissolution test. It is a figure which shows the result of a dissolution test. It is a figure which shows the result of a dissolution test.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Fluidized bed container 5 Size control mechanism 7 Spray nozzle P Water-soluble particle P 'Hydrophobic powder L1 1st coating layer L2 2nd coating layer

Claims (3)

  Forming a first coating layer on the surface of the water-soluble particles by dry coating of hydrophobic powder, and forming a second coating layer on the surface of the particles on which the first coating layer has been formed by wet coating with an aqueous film agent solution. A method of coating particles comprising the steps of:   The particle coating method according to claim 1, wherein the step of forming the first coating layer and the step of forming the second coating layer are continuously performed in a single fluidized bed apparatus.   The fluidized bed apparatus includes a fluidized bed container, a sizing mechanism that disperses agglomeration of particles flowing and circulating in the fluidized bed container by mechanical crushing force, and an aqueous system toward the particles flowing and circulating in the fluidized bed container. The particle coating method according to claim 2, further comprising a spray nozzle for spraying the film agent solution.