JPH0117376B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is a new method for producing true spherical gelatin particles or gelatin microcapsules by improving the deficiencies of the conventional method described below, and is suitable for mass production using simple equipment and means. Relating to advocating for. Generally, in order to produce true spherical gelatin particles or gelatin microcapsules, a gelatin aqueous solution 1 (hereinafter referred to as "gelatin solution") in which a necessary drug is dissolved or dispersed is prepared at a gelatin temperature of (approximately 40°C) or higher and is poured into a hydrophobic solvent tank (dropping tank) 3 filled with a hydrophobic solvent (e.g. oil, especially vegetable oil) 2, and stirred or dispersed with a stirring blade 4 for dispersion in a liquid. As shown in FIG. 2, the gelatin solution 1 is passed through a nozzle 5 (a dropper in FIG. 2) and heated to a predetermined temperature in a heating tank 6 and a cooling tank 7, respectively, as in the case of the dispersion method in liquid. This method is based on a method called a submerged dropping method, in which the liquid is discharged under pressure into a hydrophobic solvent 2 held in a hydrophobic solvent 2 and then cut by mechanical or electrical means at the tip of the nozzle. Although the above-mentioned in-liquid dispersion method is simple,
If the product has a wide particle size distribution and the desired particle size, the yield rate is poor and it is unsuitable for manufacturing small preparations such as granules, and in such cases, the submerged drop method is exclusively used. However, in the conventional submerged dropping method, a third
As shown in the figure, an electric pulse 10 is generated from a discharge generator 9 installed below the double cylindrical tube nozzle 5, and an electric means for cutting with the pulse 10 is provided. As shown in FIG.
There is a mechanical means to flow and cut the hydrophobic solvent 2 by moving it up and down, but all of these require a special cutting device and its auxiliary equipment to be installed at the nozzle tip. The reality is that there are obstacles to increasing the number of nozzles in the production industry, and there is a natural limit to mass production. The present invention was conceived in order to improve the production industrial defects of the conventional submerged dropping method, and instead of installing various cutting devices on the nozzle tip of the conventional method, the nozzle tip itself was made hydrophobic. The purpose is to cut gelatin solution into appropriate sizes by moving it in a solvent. When producing true spherical gelatin particles or gelatin microcapsules by the method of the present invention, the particle size is determined in relation to the amplitude and frequency of the nozzle, the shape and diameter of the nozzle, the discharge pressure of the gelatin solution from the nozzle, etc. However, if the shape and diameter of the nozzle are constant, fine adjustment of the product particle size can be easily performed by manipulating the amplitude and frequency of the nozzle and the pressure at which the gelatin solution is discharged from the nozzle. In the method of the present invention, the movement locus of the nozzle in the hydrophobic solution includes a pendulum-type left and right reciprocating movement by hanging from one fulcrum (see Figure 6), and a horizontal movement by reciprocating back and forth or left and right between two fulcrums (see Figure 8). )
Alternatively, any movement such as curved movement may be used, but in practice, either of the former two movements is simple and convenient, and it is sufficient to use conventional drive means for these movements. , does not require anything special. In addition, even in the method of the present invention, it is necessary to maintain the temperature of the hydrophobic solvent that receives the gelatin solution pressure-discharged from the nozzle at a temperature higher than the gelatin temperature. A W/O type emulsion is formed in between, and the gelatin particles become spherical. If the temperature of the hydrophobic solvent is the same as or lower than the gelation temperature of gelatin, the gelatin solution will gel at the nozzle tip, which may clog the nozzle or cause the nozzle tip to not cut properly and cause threads to be drawn. An evil phenomenon occurs. Next, a description will be given of an apparatus used for producing the true spherical gelatin particles or gelatin microcapsules described in detail above. As shown in FIG. 5 and FIG.
a drug container 22 for containing capsule coating material 23 in liquid form at a predetermined temperature; a coating agent container 24 for containing capsule coating material 23 in liquid form; a nozzle 25 consisting of a concentric double tube; A liquid feeding pipe 26 for supplying the drug or gelatin solution 21 in liquid form from the container 22 into the inner pipe 25A of the double-tube nozzle 25;
A liquid feeding pipe 28 for supplying the coating agent 23 in liquid form into the outer pipe 25B of No. A hydrophobic solvent tank (dropping tank) 31 for immersing the hydrophobic solvent in the hydrophobic solvent tank, and a heat-retaining means for maintaining the hydrophobic solvent 30 in the hydrophobic solvent tank at a predetermined temperature, that is, the temperature near the nozzle is higher than the gelatin temperature of gelatin. The apparatus of the present invention has a hot water tank 32 for maintaining the temperature, and a cooling tank 33 near the bottom of the solvent tank for maintaining the hydrophobic solvent 30 inside at about 5° C. or lower. The double-tube nozzle 25 is configured to be movable, and the double-tube nozzle 25 is connected to the hydrophobic solvent 3
A nozzle drive mechanism 34 is provided for repeatedly moving the tip at a predetermined period while keeping the tip immersed in zero. As shown in the figure, it is advantageous for the hot water tank 32 to have a system in which hot water is forcibly circulated therein by a pump 35. Further, the swing of the nozzle is a so-called pendulum amplitude vibration with a one-point fulcrum as illustrated in FIGS. 5 and 6, or a horizontal amplitude vibration with a two-point fulcrum as illustrated in FIGS. 7 and 8. It is mechanically advantageous to use vibration. In addition to the illustrated crank system, a cam mechanism may be used as the nozzle swing drive source. In addition, 27 and 29 in FIGS. 5 to 8 indicate pumps for delivering the gelatin solution 21 and the coating agent 23, respectively. The apparatus of the present invention has the above-described configuration, and when the gelatin solution 21 and the coating agent 23 are discharged from the double-tube nozzle 25 into the hydrophobic solvent 30, the nozzle is activated at a predetermined period (pitch). The gelatin solution (and coating agent)
are cut to form true spherical gelatin grains or gelatin microcapsules 36 of substantially uniform size. The embodiments of the present invention will be described below with reference to Examples, and the effects of the present invention will also be shown.
Keep the temperature at ~45℃, cool the lower part to below 5℃, and attach the nozzle so that the tip is immersed in the salad oil. Dissolve 50g of gelatin in 100ml of warm water at 40-50℃.
This was degassed and injected into the nozzle, and the nozzle tip was vibrated left and right in a pendulum manner with an amplitude of 15 to 20 mm, producing granules in the salad oil layer. The particle size distribution was as follows.

[Table] Example 2 (Cytochrome C-containing gelatin granules) Place 1000 ml of liquid paraffin in a dropping tank, keep the upper part warm at 40 to 45°C, and cool the lower part to 5°C or less. Attach the nozzle so that its tip is submerged in the liquid paraffin layer. Add 20g of gelatin to 40-45℃ warm water from the top of the nozzle.
Add 1.5 g of dissolved cytochrome C to 40 ml, inject the degassed solution, and shake the nozzle tip with horizontal amplitude vibration for 15 to 20 minutes.
Upon reciprocating motion of 1 mm, cytochrome C-containing gelatin granules were formed in the liquid paraffin layer. The particle size distribution was as follows.

[Table] Example 3 (Gelatin Microcapsules) Approximately 1000 ml of liquid paraffin is placed in a dropping tank, the upper part is kept warm at 40-45°C, and the lower part is cooled to below 10°C. The tip of a double nozzle containing a small-diameter nozzle is immersed in a layer of liquid paraffin, and vegetable oil as the main ingredient is injected into the small-diameter nozzle. Dissolve 30g of gelatin in 100ml of warm water at 40-45℃, deaerate it, inject it into the outer nozzle, and vibrate the nozzle tip with a pendulum amplitude vibration method of 20-30mm.
By making a left-right reciprocating motion and applying weak pressure to a small diameter (main ingredient) nozzle, vegetable oil-containing gelatin microcapsules with a particle size of 0.5 to 1.0 mm were created. The method of manufacturing true spherical gelatin particles using the horizontal vibration method in liquid according to the method of the present invention is superior to the conventional nozzle vertical vibration method, since the latter produces one true sphere for each round trip of the vertical vibration of the nozzle. On the other hand, in the former case, two perfect spheres are produced per round trip of the left and right amplitude vibration, which is twice the production efficiency, and in the latter case, pulsating flow occurs, particles are naturally separated from the pulsating flow, and the particles are separated In contrast, in the former case, the process from the nozzle tip to the nozzle tip is forced to take a long time, so it is necessary to make the heated part of the hydrophobic solvent layer large (long). Since the jet has already been cut, a heating section is only needed to make the particles into true spheres, which has the advantage that the device can be made very compact.

[Brief explanation of drawings]

Figure 1 is a diagram schematically showing the principle of manufacturing gelatin granules by the in-liquid dispersion method, Figure 2 is a diagram also schematically illustrating the principle of manufacturing gelatin granules by the in-liquid dropping method, Figure 3 and Figure 4 shows the method of cutting gelatin particles using the submerged drip method, Figure 3 shows the mechanical method, Figure 4 shows the electric method, and Figure 5 shows an outline of the apparatus of the present invention. 6 is an enlarged view of the main part of FIG. 5, FIG. 7 is a side view showing another embodiment of the present invention, and FIG. 8 is an enlarged view of the main part of FIG. 7. 21... Gelatin solution, 22... Pharmaceutical container,
23...Capsule coating material, 24...Coating agent container, 25...Double tube nozzle, 26...Liquid feeding pipe,
28...Liquid feeding pipe, 30...Hydrophobic solvent, 31...
Hydrophobic solvent tank, 34...nozzle rocking mechanism.

Claims (1)

[Claims] 1. A gelatin aqueous solution in which a desired chemical is dispersed or dissolved is forced out into a hydrophobic solvent maintained at a temperature higher than the gelation temperature of gelatin through a nozzle tube installed to the extent that it is submerged in the surface layer of the solvent. 1. A method for producing true spherical gelatin particles or gelatin microcapsules, etc., in which the mouth of the nozzle is reciprocated with a constant horizontal amplitude in the submerged dropping method. 2. The method for producing true spherical gelatin particles or gelatin microcapsules, etc. according to claim 1, wherein the reciprocating motion of the nozzle opening with a constant horizontal amplitude is a pendulum amplitude vibration. 3. A drug container for accommodating the drug to be encapsulated or an aqueous gelatin solution in which the drug is dissolved or dispersed in liquid form at a predetermined temperature, and a coating agent container for accommodating capsule coating material in liquid form, concentrically. a nozzle made of a double cylindrical tube; a liquid feeding tube for supplying a drug or an aqueous gelatin solution in liquid form from the drug container into the inner tube of the double cylindrical nozzle; and a liquid feeding tube from the coating agent container to the double cylindrical tube. a liquid supply pipe for supplying a coating agent in liquid form into the outer tube of the nozzle;
A hydrophobic solvent tank located below the double cylindrical nozzle for immersing the lower end of the nozzle in a hydrophobic solvent, and a heat insulator for maintaining the solvent in the hydrophobic solvent tank at a predetermined temperature. In the apparatus for producing true spherical gelatin particles or gelatin microcapsules, the double-tube nozzle is configured to be swingable, and at least the tip of the double-tube nozzle is in contact with the hydrophobic solvent. An apparatus for producing true spherical gelatin grains or gelatin microcapsules, characterized by comprising a nozzle drive mechanism for repeatedly vibrating in the horizontal direction at a predetermined period while soaked.