JP6913976B1 - Seamless capsule and its manufacturing method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for efficiently producing a seamless capsule having a low-viscosity inner layer, which has extremely little uneven thickness and does not generate large eyes which may affect the quality.
SOLUTION: A capsule containing a substance having a viscosity at 20 ° C. of 30 mPa · s or less as an inner layer, containing gelatin, a plasticizer and water, and having a viscosity at 40 ° C. of 70 to 400 mPa · s. Seamless capsule with skin composition as the outer layer.
[Selection diagram] None

Description

The present invention relates to a seamless capsule having improved product quality and manufacturing efficiency, and a method for manufacturing the same.

Seamless capsules are characterized in that the compositional uniformity of each capsule is extremely high and the shape can be easily reduced. Since it does not require extreme heat or pressure during production, it can be stabilized by seamlessly encapsulating the unstable composition. Furthermore, by selecting the composition of the outer layer of the granular material or the like, it is possible to change the surface performance and control the release. In addition to being used in oral medicines, seamless capsules should be used in surgical procedures such as indwelling release control preparations, tissue damage repair and improvement agents, and blood flow control agents by utilizing the release control function. Is also possible. It can also be shaped for industrial use such as food and chemical products.

Seamless capsules are generally manufactured as follows (drop method). That is, a jet flow including a flow of a filling substance having fluidity is formed in a flow of a film-forming substance having fluidity, and is ejected into air or liquid to form droplets. The surface of the droplet is cured by the curing liquid, and the liquid on the center side is enclosed inside the cured surface.
In order to obtain capsules having a uniform particle size, some conventional seamless capsule manufacturing devices vibrate the capsule-forming liquid when forming droplets from a jet stream, and the applicant has included waveform control. We have devised a seamless capsule manufacturing apparatus and manufacturing method having a vibration mechanism (Patent Document 1).

During the manufacture of multi-layer seamless capsules, capsules with inner and outer layers are formed by supplying fluids that do not mix with each other in a short time to the inner and outer nozzles to form a composite jet flow and cutting at regular intervals. Although it is formed, when the composite jet flow is cut at regular intervals, the physical properties of the fluid supplied to the inner and outer layers have a great influence on the product quality. Stable production has been ensured by adding agents and the like.
However, in particular, when the fluid supplied to the inner layer has an extremely low viscosity (for example, a viscosity of less than 30 mPa · s) such as free fatty acids and derivatives thereof, liquid paraffins and organic solvents, the liquid is fed. Stabilization and cutting of the jet flow at equal intervals become difficult, and problems such as uneven thickness of the outer layer and "eyes" in which a plurality of droplets of the inner layer are generated in the outer layer are likely to occur. Further, the use of an interfacial tension adjusting agent or a gelation accelerator has a problem that the stability of the capsule contents is adversely affected and the high content of the capsule contents is hindered.

Patent Document 2 describes an invention relating to a method for producing a seamless capsule comprising a shell composition containing no interfacial tension adjusting agent or a gelation accelerator and a capsule content and containing EPA ethyl ester and DHA ethyl ester as the contents. However, in this case, strict temperature control of the capsule contents, the shell composition aqueous solution and the carrier solution (curing solution) is required. In order to strictly control the temperature of the supplied fluid, large-scale support equipment is required, and limited industrial equipment is often required, making it difficult to design equipment with general-purpose equipment.
Further, Patent Document 3 describes a method for manufacturing a seamless capsule in which the tip of the nozzle is arranged above the liquid surface of the curing liquid instead of the nozzle in the liquid, and the merged liquid flow is eccentric with the center of the forming tube. Although disclosed, limiting the nozzle position requires precise device design, eligibility for installation and installation, and impedes the ease of relocation, limiting the versatility of the device, such as device manufacturing and It interferes with the operation of the device.

Japanese Patent No. 5922512 Japanese Patent No. 5047285 Japanese Patent No. 4778639

The present invention relates to providing a method for efficiently producing a seamless capsule having a low-viscosity inner layer with extremely little uneven thickness and without causing large eyes that may affect the quality.

In the case of producing a seamless capsule while applying a constant vibration during droplet formation, the present inventors use a capsule skin composition having a predetermined viscosity characteristic to cause a seamless capsule that does not cause eyesight. Was found to be able to be manufactured efficiently.

That is, the present invention relates to the following 1) to 13).
1) Capsule skin composition containing a substance containing a substance having a viscosity at 20 ° C. of 30 mPa · s or less as an inner layer, containing gelatin, a plasticizer and water, and having a viscosity at 40 ° C. of 70 to 400 mPa · s. Seamless capsule with an outer layer.
2) The capsule skin composition further has a viscosity at 50 ° C. of 50 to 230 mPa · s, a viscosity at 45 ° C. of 60 to 260 mPa · s, and a viscosity at 35 ° C. of 100 to 600 mPa · s, whichever is one or more. The seamless capsule according to 1).
3) The seamless capsule according to 1) or 2), wherein the capsule skin composition further comprises a viscosity at 45 ° C. of 60 to 260 mPa · s and / or a viscosity at 50 ° C. of 50 to 230 mPa · s.
4) Capsule The seamless capsule according to any one of 1) to 3), wherein the skin composition contains 20 to 35% by mass of a solid content composed of gelatin and a plasticizer in the composition.
5) The seamless capsule according to any one of 1) to 4), wherein the substance having a viscosity of 30 mPa · s or less at 20 ° C. of the capsule contents is an ω3 fatty acid having 18 to 22 carbon atoms or an alkyl ester thereof.
6) A method for producing a seamless capsule having a capsule content containing a substance having a viscosity of 30 mPa · s or less at 20 ° C. as an inner layer by a dropping method, wherein the viscosity at 40 ° C. is 70 to 400 mPa · s. A method for producing a seamless capsule, which comprises forming droplets while applying a constant vibration using a capsule skin composition.
7) The method according to 6), which applies vibration of a sine wave or a pulse wave.
8) When the ratio of the viscosity of the capsule content to the viscosity of the capsule skin composition (capsule content / capsule skin composition) measured near the nozzle is 5 to 20, sine wave vibration is applied. 5, The method according to 7), wherein the vibration of the pulse wave is applied when it is less than 5 or larger than 20.
9) The capsule skin composition further has a viscosity at 50 ° C. of 50 to 230 mPa · s, a viscosity at 45 ° C. of 60 to 260 mPa · s, and a viscosity at 35 ° C. of 100 to 600 mPa · s, whichever is one or more. The method according to any one of 6) to 8).
10) The capsule skin composition further comprises any of 6) -9), further comprising a viscosity at 45 ° C. of 60-260 mPa · s and / or a viscosity at 50 ° C. of 50-230 mPa · s. Method.
11) The method according to any one of 6) to 10), wherein the capsule skin composition contains 20 to 35% by mass of a solid content composed of gelatin and a plasticizer in the composition.
12) The method according to any one of 6) to 11), wherein the substance having a viscosity of 30 mPa · s or less at 20 ° C. of the capsule contents is an ω3 fatty acid having 18 to 22 carbon atoms or an alkyl ester thereof.
13) The method according to any one of 6) to 11), wherein the temperature near the nozzle of the capsule skin composition is controlled to 30 to 50 ° C.

According to the method of the present invention, it is possible to efficiently produce a seamless capsule containing a low-viscosity substance having no uneven thickness, no eyes, or extremely small thickness in the inner layer. That is, according to the method of the present invention, it is possible to stably manufacture high-quality and highly efficient seamless capsules even if the temperature control range is wide, without limiting the nozzle position, and the versatility and installation of peripheral devices. Versatility and device operability are improved.

Temperature-viscosity properties of the capsule skin composition. The figure which shows typically the seamless capsule manufacturing apparatus. The figure which shows typically the seamless capsule manufacturing apparatus.

In the capsule contents and the capsule skin composition of the present invention, "viscosity" refers to the viscosity measured using a tuning fork type vibration viscometer.

The seamless capsule of the present invention has a capsule content containing a substance having a viscosity at 20 ° C. of 30 mPa · s or less as an inner layer, contains gelatin, a plasticizer and water, and has a viscosity at 40 ° C. of 70 to 400 mPa · s. A certain capsule skin composition is used as an outer layer.

The capsule contents constituting the inner layer of the seamless capsule of the present invention contain a substance having a viscosity of 30 mPa · s or less at 20 ° C.
The "capsule content" is a substance supplied to the inner layer of the double nozzle and constituting the inner core (inner layer) of the capsule, and is also referred to as "content" or "core liquid".

The substance having a viscosity at 20 ° C. of 30 mPa · s or less is preferably 15 mPa · s or less, and more preferably 10 mPa · s or less. Here, the temperature of 20 ° C. indicates the standard temperature of the contents supplied near the multiple nozzles (for example, 121 in FIGS. 2 and 3) of the seamless capsule manufacturing apparatus, and the viscosity at 20 ° C. is It can be said that the viscosity is suitable for capsule filling of the present invention.

The substance having a viscosity of 30 mPa · s or less at 20 ° C. may be a single compound or a composition. The type of substance is not limited, and may be any of pharmaceuticals, cosmetics, foods, chemical products, and the like.
For example, fatty acids (for example, ω3-fatty acids having 18 to 22 carbon atoms (for example, octadecatrienoic acid, octadecatetetraenoic acid, eikosatetraenoic acid, eikosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid, etc.) Docosapentaenoic acid) or its alkyl ester), free fatty acids (for example, oleic acid, etc., which has 18 or less carbon atoms and is in solution at room temperature) and its derivatives, vegetable oils (olive oil, perilla oil, sesame oil, rapeseed oil, sunflower oil, etc.) Derived fats and oils that are in solution at room temperature), surfactants (nonionic surfactants that are in solution at room temperature such as glycerin fatty acid ester, polysorbate, and sucrose fatty acid ester), liquid paraffins (fluid) Examples thereof include olefin fatty acids such as paraffin, which are liquid at room temperature and non-volatile substances), and organic solvents (saturated alcohols which are liquid at room temperature such as octanol, lauryl alcohol, and myristyl alcohol). In addition, additives such as stabilizers can be appropriately added to the capsule contents.
Examples of the stabilizer include α-tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, tocotrienol and the like.

The capsule skin composition constituting the outer layer in the seamless capsule of the present invention contains gelatin, a plasticizer and water, and has a viscosity at 40 ° C. of 70 to 400 mPa · s.
Here, gelatin is a major substance that constitutes a temperature-dependent reversible sol-gel form.
There are various grades of gelatin depending on the raw material of origin and the treatment method at the time of production, but in the present invention, any grade of gelatin can be used. For example, alkali-treated gelatin derived from bovine bone and skin and acid-treated gelatin derived from pig skin are easily available. It is also possible to use amberized gelatin that has been subjected to amberizing treatment to improve the solubility of gelatin over time.

Gelatin is a composite material of high molecular weight components and low molecular weight components, and its properties change depending on the distribution of these. In particular, jelly strength and viscosity are greatly related to physical properties, and these properties are effective guidelines when selecting gelatin. The method for measuring the jelly strength and viscosity of gelatin is generalized, and is defined in, for example, Japanese Industrial Standards "Gelatin and Gelatin" JIS K6503.
In the seamless capsule of the present invention, if the capsule skin composition has a characteristic that the viscosity at 40 ° C. is 70 to 400 mPa · s, the grade of the raw material gelatin is not limited, but the viscosity is extremely high. Things are not suitable.

The content of gelatin in the capsule skin composition is 10 to 40% by mass, preferably 20 to 30% by mass.

Examples of the plasticizer include sugar alcohols (for example, concentrated glycerin; tetritor such as erythritol and treitol; pentitol such as xylitol, arabinitol, ribitol and adonitol; hexitol such as mannitol, sorbitol, iditol, zurcitol and galactitol; maltitol, Examples thereof include dodecitol such as lactitol) and sugars (for example, glucose, lactose, sucrose, maltitol, oligosaccharide, etc.), and one of these may be used alone or in combination of two or more. ..
The content of the plasticizer in the capsule skin composition is 0.5 to 10% by mass, preferably 1 to 5% by mass.
The solid content of gelatin and the plasticizer in the capsule skin composition is 20 to 35% by mass, preferably 22 to 30% by mass.

In addition to the above components, thickening polysaccharides such as carrageenan, agar, and sodium alginate can be added to the capsule skin composition.
Since such thickening polysaccharides have a high gelation temperature, it is desirable that the coolant temperature be high when they are blended, and the temperature is set 10 to 60 ° C. lower than the gelation temperature of the capsule skin composition. It is preferable to do so.
Further, since sodium alginate has a property of gelling by divalent cations such as calcium ions, it is also possible to use a calcium chloride solution as a curing solution when this is blended.

Further, it is also possible to add a coloring agent or a preservative to the capsule skin composition as appropriate.

The capsule skin composition of the present invention is adjusted so that the viscosity at 40 ° C. is 70 to 400 mPa · s. The viscosity can be adjusted by appropriately changing the amounts of the plasticizer and water. The content of water is 50 to 90% by mass, preferably 60 to 85% by mass, and more preferably 70 to 80% by mass in the composition.

The capsule skin composition of the present invention has a viscosity at 40 ° C. of 70 to 400 mPa · s, and further has a viscosity at 50 ° C. of 50 to 230 mPa · s, a viscosity at 45 ° C. of 60 to 260 mPa · s, and 35. It is preferable that the viscosity at ° C. is 100 to 600 mPa · s, whichever is 1 or more. Further, it is more preferable that the viscosity at 45 ° C. is 60 to 260 mPa · s and / or the viscosity at 50 ° C. is 50 to 230 mPa · s, and further, the viscosity at 50 ° C. is 50 to 230 mPa · s, 45 ° C. It is more preferable that the viscosity at 35 ° C. is 60 to 260 mPa · s and the viscosity at 35 ° C. is 100 to 600 mPa · s.

The mass ratio of the capsule skin composition to the capsule contents at the time of capsule filling is usually 10: 1 to 1:10, preferably 2: 1 to 1: 1.

The seamless capsule of the present invention can be produced by using the above-mentioned capsule contents and capsule skin composition and forming droplets while applying constant vibration by a dropping method.
Specifically, for example, the capsule contents are applied from the inner nozzle of the multiple nozzle, and the capsule skin composition is applied from the outside at a constant rate while applying constant vibration (for example, medium chain fatty acid triglyceride (MCT)). , Olive oil, soybean oil, corn oil, oily base materials derived from animals and plants such as squalane, mineral oils such as liquid rosefin, non-mineral oils obtained by chemical synthesis such as hydrogenated polyisoptene, and mixtures thereof. Sometimes it flows out into a liquid that forms an interface with the capsule skin composition), the two layers of running liquid are cut at regular intervals, droplets are formed by interfacial tension, and then the outer shell layer is gelled by cooling. , Seamless capsule.
Such seamless capsule manufacturing can be performed by using a capsule manufacturing apparatus provided with vibration applying means, and the apparatus is not particularly limited, but for example, it is preferable to use the apparatus described in Patent Document 1. Figures 2 and 3).

The vibration may be applied so as to act on droplet formation, and the mode thereof is not limited, but for example, the capsule solution (capsule contents and capsule skin composition) supplied to the multiple nozzles, and the vicinity of the multiple nozzles. Examples thereof include a mode of applying the curing liquid to one or more objects selected from the curing liquid supplied to the nozzle and the skeleton in the vicinity of the nozzle.
Here, examples of the skeleton in the vicinity of the nozzle include the nozzle itself, a flexible portion provided in a part of the pipeline, a pulsator, and the like.

Vibration is applied by a vibration mechanism having a function generator and a drive unit driven based on a voltage signal generated by the function generator. A function generator is a device that can freely generate various voltage waveforms, that is, functions of time, and can control frequency, amplitude, waveform, and the like.
In the method for manufacturing a seamless capsule of the present invention, it is preferable to control the waveform of vibration in addition to voltage and frequency. The waveform may be a sine wave (sine wave), a square wave, a triangular wave, a sawtooth wave, a pulse wave or a combination thereof, and is preferably a pulse wave or a sine wave.
The voltage is ± several tens of V, the frequency is DC, and the upper limit is several ten to several hundred MHz.

Further, according to the production method of the present invention, the eyes can be controlled, but the viscosity of the capsule contents measured near the nozzle (for example, 120 in FIGS. 1 and 2) and the capsule skin composition measured in the same manner. When the viscosity ratio of the substance (capsule content / capsule skin composition) is 5 to 20, sine wave vibration is applied, and outside the range of this viscosity ratio (less than 5 or greater than 20). Then, by applying the vibration of the pulse wave, the eyes can be made smaller or extinguished more effectively. Therefore, it is preferable to appropriately select the vibration waveform to be applied according to the viscosity of the capsule content to be used and the capsule skin composition.

In the production of seamless capsules, the temperature conditions near the nozzle where the capsule is formed have a great influence on the quality of the final capsule. Above all, a high degree of temperature control is required while the capsule skin composition cools and gels to form the capsule skin.

It is desirable that the capsule contents be supplied to the nozzle in a state where the temperature and pressure are constant without pulsation during the liquid feeding. Under certain conditions, the viscosity of the capsule contents can be made constant, and defects caused by the viscosity can be reduced.
The temperature of the capsule contents is standardized at room temperature near the nozzle (for example, 121 in FIGS. 2 and 3), and is, for example, 0 ° C to 50 ° C, more preferably 10 ° C to 30 ° C, still more preferably 15 ° C to 25. It is controlled in the temperature range.

As described above, the capsule skin composition has a characteristic of having a viscosity of 70 to 400 mPa · s at 40 ° C., but it is necessary to maintain the solution state during the liquid feeding and to stably feed the liquid to the nozzle. .. It is desirable that the liquid feeding state is pulsation-free and the temperature and pressure are constant. Under certain conditions, the viscosity of the capsule skin composition can also be made constant, and defects caused by the viscosity can be reduced.
In the method of the present invention, the temperature near the nozzle of the capsule skin composition (for example, 122 in FIGS. 2 and 3) does not need to be high and is less than 50 ° C, preferably less than 48 ° C, more preferably 46 ° C. It is less than ° C., 30 ° C. or higher, preferably 35 ° C. or higher, and more preferably 40 ° C. or higher.

The cooling solidification (gelation) of the capsule skin composition is carried out by placing a cut piece from a continuously formed double jet stream at a temperature of 0 to 15 ° C. using a curing liquid. In this case, it is more desirable that the temperature change is small, and a fluctuation of about ± 1 to 2 ° C. is acceptable, although it depends on the cooling equipment and the buffer environment.
When gelling the capsule skin composition, there is a suitable ratio between the rate of spheroidization due to interfacial tension and the rate of cooling solidification from the cutting of the jet flow. It affects the yield, such as the formation of capsules with shaped protrusions. On the contrary, when the cooling and solidification is slow, the gelation becomes insufficient, and the capsules collide with each other to generate two balls or large balls, or the capsules are deformed due to the collision in the flow path pipe. These phenomena can be identified by observing the sample immediately after encapsulation.

Due to the mechanism of capsule filling, it is essential that the capsule contents and the capsule skin composition form a good interface between the two materials. In the production of the seamless capsule of the present invention, when the interface formation is insufficient, alcohol or a surfactant is added to the capsule contents and / or the capsule skin composition to adjust the interfacial tension, or A nozzle may be provided between the inner nozzle and the outer nozzle to supply a third solution, or the like. Here, as the third solution, it is possible to use a solution that forms an interface with both the capsule contents such as lecithin, isobutyl sculose acetate, or a dilution of these medium-chain fatty acid triglycerides and vegetable oils, and the capsule skin composition. Is.

Thus, according to the present invention, it is possible to efficiently produce a seamless capsule containing a low-viscosity substance having no uneven thickness, no eyes, or extremely small thickness in the inner layer.

Production Example 1 Preparation of Capsule Skin Composition (1) Gelatin, concentrated glycerin, sorbitol and purified water are mixed in the compositions shown in Table 1-1 and Table 1-2, and then gelatin is sufficiently swollen at room temperature. Then, it was heated and dissolved until the whole solution became a uniform solution without lumps and the like to obtain a capsule skin composition.

(2) Temperature / Viscosity Characteristics of Capsule Skin Composition The viscosity of the capsule skin composition prepared in (1) at each temperature was measured using a sound fork type vibration viscous meter (SV-10; manufactured by A & D Co., Ltd.). It was measured.
The results are shown in Table 2 and FIG.

Example Production of Seamless Capsules Using the seamless capsule production apparatus shown in FIG. 3, the capsule skin compositions 1 to 14, comparative compositions 1 to 3 and the capsule contents (omega-3 fatty acid ethyl, equosapentic acid) prepared in Production Example 1 were used. Using ethyl, medium-chain fatty acid triglyceride), seamless capsules were produced under the conditions shown in Table 3-1 and Table 3-2.
As the curing liquid, edible oil (medium chain fatty acid triglyceride specified as a pharmaceutical additive) was used and applied to FIG. 3103. A function generator manufactured by Tektronix (Model: AFG3022B) was used (Fig. 3 310). As the drive unit, a general-purpose device that converts the electric signal of the function generator into vibration was used for 330, and a power amplifier (manufactured in-house) for strength adjustment was used as 320. The produced capsules were collected as 104, and the presence or absence and size of eyes, the degree of uneven thickness of the capsule skin, and the state of deformation were observed. After that, the capsules were dried and 100% visually inspected to calculate the defective rate.

The evaluation results of the manufactured seamless capsules are also shown in Tables 3-1 and 3-2.
In the table, the viscosities of the contents and the capsule composition correspond to the temperature near the nozzle during capsule filling. In Examples 1 to 16, it was possible to control the size so as not to affect the quality even if there were no eyes. In addition, the uneven thickness and deformation were appropriate, and the product defect rate was extremely suppressed. At this time, the temperature near the nozzle (122 in FIG. 3) of the capsule skin composition was in the range of 40 to 49 ° C., and good production was achieved. On the other hand, in the comparative example, since the capsule skin composition has a high viscosity at 40 ° C., the temperature near the nozzle has to be higher than 50 ° C., which causes uneven thickness and deformation, resulting in a product defect rate. Also increased significantly.

1,2: Seamless capsule manufacturing equipment, 101: Core liquid, 102: Coating liquid, 103: Hardening liquid, 104: Capsule, 120: Nozzle, 121: Inner nozzle, 122: Outer nozzle, 1
33: Curing liquid discharge part, 141: Core liquid supply pipe, 142: Coating liquid supply pipe, 143: Hardening liquid supply pipe, 200, 300: Wave imparting part, 210, 310: Function generator, 22
0,320: Power amplification unit, 230,330: Drive unit, 231,3311: Core liquid drive unit, 23
2,332: Film liquid drive unit, 233: Curing liquid drive unit.

Claims (6)

A method for producing a seamless capsule having a capsule content containing a substance having a viscosity at 20 ° C. of 30 mPa · s or less as an inner layer by a dropping method, which contains gelatin, a plasticizer and water, and contains gelatin and a plasticizer. Using a capsule skin composition having a solid content of 20 to 35% by mass and a viscosity at 40 ° C. of 70 to 400 mPa · s, the temperature near the nozzle of the capsule skin composition is set to 30 or more and less than 48 ° C. A method for manufacturing a seamless capsule, which comprises controlling and forming droplets while applying constant vibration. Applying vibration of a sine wave or a pulse wave, a method according to claim 1. When the ratio of the viscosity of the capsule content to the viscosity of the capsule skin composition (capsule content / capsule skin composition) measured near the nozzle is 5 to 20, sine wave vibration is applied to 5 The method according to claim 2 , wherein the vibration of the pulse wave is applied when the value is less than or greater than 20. The capsule skin composition further comprises one or more of a viscosity at 50 ° C. of 50 to 230 mPa · s, a viscosity at 45 ° C. of 60 to 260 mPa · s, and a viscosity of 35 ° C. of 100 to 600 mPa · s. The method according to any one of claims 1 to 3. The one according to any one of claims 1 to 4 , wherein the capsule skin composition further comprises a viscosity at 45 ° C. of 60 to 260 mPa · s and / or a viscosity at 50 ° C. of 50 to 230 mPa · s. Method. The method according to any one of claims 1 to 5 , wherein the substance having a viscosity of 30 mPa · s or less at 20 ° C. of the capsule contents is an ω3 fatty acid having 18 to 22 carbon atoms or an alkyl ester thereof.

Images