JP7698176B2 - Gelatin particle manufacturing method and gelatin particle manufacturing device - Google Patents

Description

The present invention relates to a method and an apparatus for producing gelatin particles, and more specifically to a method and an apparatus for producing gelatin particles in which liquid gelatin is sprayed and dried to form granules.

Gelatin has been used in the fields of food and industry, and granulated gelatin particles are used as a form of gelatin.
Known methods for producing such gelatin particles include the spray-drying method (Patent Document 1), in which liquid gelatin is sprayed and dried, and the emulsion method (Patent Document 2), in which gelatin droplets are ejected into a hydrophobic solvent, the hydrophobic solvent is dehydrated and washed, and then dried.

Japanese Patent Application Publication No. 1-245074 Patent No. 5307490

Here, the gelatin particles as described above are also used in the medical field. For example, they are used as sustained-release carriers that impregnate medicinal ingredients and gradually release the ingredients inside the body, or as a culture substrate to be placed between each sheet when multiple cell sheets such as myocardial sheets are stacked.
From the viewpoints of ease of handling and affinity with cells, gelatin particles for such medical use are required to have a particle size of about several tens of μm. However, when the method described in Patent Document 1 was used, the particle size was large at 250 to 350 μm, which was inappropriate.
On the other hand, according to the method described in Patent Document 2, although it is possible to reduce the particle size, highly toxic solvents such as acetone are used for dehydration and drying, and therefore there are safety concerns about using the resulting gelatin particles for medical purposes.
In view of such problems, the present invention provides a method and an apparatus for producing gelatin particles which are highly safe and capable of obtaining gelatin particles having a desired particle size.

That is, the method for producing gelatin particles according to the invention of claim 1 has a granulation step in which liquid gelatin is sprayed and dried to form granules, and the granulated gelatin particles are collected as gelatin particles having a desired size within the range of upper and lower limits of several tens of μm,
a first sorting step of sorting the gelatin particles obtained by the granulation step using a first sieve having a first mesh size selected in the range of 90 to 45 μm for sorting gelatin particles below the upper limit of the desired range;
a grinding step of grinding gelatin particles exceeding the upper limit of the desired range that did not pass through the first sieve in the first screening step;
a second sorting step of sorting the gelatin particles pulverized in the crushing step using the first sieve;
a third sorting step in which the gelatin particles that have passed through the first sieve in the first sorting step and the second sorting step are sorted using a second sieve having a second opening selected in the range of 40 to 10 μm for sorting gelatin particles that are smaller than the first opening and are equal to or smaller than the lower limit of a desired range;
a recovery step of recovering gelatin particles exceeding the lower limit of a desired range which did not pass through the second sieve in the third screening step;
and a heating step for heat-treating the recovered gelatin particles.
The gelatin particle manufacturing apparatus according to the invention of claim 4 is provided with a granulating means for spraying and drying liquid gelatin to form granules, and recovers the granulated gelatin particles as gelatin particles having a desired size within a range of upper and lower limits of several tens of μm,
The gelatin particle sorting apparatus comprises a first sorting means having a first sieve with a first opening selected in the range of 90 to 45 μm for sorting gelatin particles below the upper limit of a desired range, a second sorting means having a second sieve with a second opening selected in the range of 40 to 10 μm for sorting gelatin particles below the lower limit of a desired range that is smaller than the first opening, a crushing means for crushing the gelatin particles, and a heating means for heat-treating the gelatin particles,
The gelatin particles granulated by the granulating means are sorted by the first sorting means, and the gelatin particles which do not pass through the first sieve are pulverized by the pulverizing means.
Further, the gelatin particles pulverized by the pulverizing means are selected by the first selecting means,
The second sorting means sorts gelatin particles that have been sorted by the first sorting means and passed through the first sieve,
The gelatin particles which did not pass through the second sieve by the sorting by the second sorting means are recovered and heat-treated by the heating means.

According to the above invention, liquid gelatin is sprayed and dried to produce gelatin particles granulated containing particles larger than the desired particle size, and gelatin particles exceeding the desired particle size range are selected and crushed using a first sieve, and the crushed gelatin particles are again selected using the first sieve to remove gelatin particles exceeding the desired particle size range. This makes it possible to recover more gelatin particles within the desired particle size range than when gelatin particles within the desired particle size range are selected directly from the granulated gelatin particles or when the granulated gelatin particles are crushed directly and gelatin particles within the desired particle size range are selected.
Furthermore, because the gelatin is granulated by the spray drying method, in which liquid gelatin is sprayed and dried, no toxic components remain and the gelatin can be used safely for medical purposes.

Plan view of the gelatin particle manufacturing apparatus according to the present embodiment. Flow showing a method for producing gelatin particles according to this embodiment A graph showing the frequency distribution of particle sizes of gelatin particles granulated by a granulation means.

The illustrated embodiment will now be described. FIG. 1 shows a gelatin particle manufacturing apparatus 1, which is an apparatus for obtaining gelatin particles having a particle size suitable for medical use.
The medical gelatin particles produced in this embodiment can be used as a sustained-release carrier that is impregnated with medicinal ingredients and gradually releases the ingredients inside the body, and can also be used as a culture substrate to be placed between multiple cell sheets, such as myocardial sheets, when multiple sheets are stacked together, making it possible to use them in a variety of clinical applications.
Here, when gelatin particles are used for medical purposes, it is desirable for the particle size to be approximately several tens of μm from the standpoint of operability and affinity with cells, and the gelatin particle manufacturing apparatus 1 of this embodiment is designed to manufacture such gelatin particles for medical use.

The gelatin particle manufacturing apparatus 1 of this embodiment includes a granulating means 2 for granulating gelatin particles, a sorting means 3 for sorting gelatin particles of a desired particle size from the granulated gelatin particles, a crushing means 4 for crushing gelatin particles larger than the desired particle size, and a heating means 5 for vacuum heat-treating the sorted gelatin particles.
The gelatin particle manufacturing apparatus 1 also includes a clean room 6 whose interior is maintained at a predetermined air cleanliness level to form a clean space, and an isolator 7 which similarly forms a clean space whose interior is maintained at a predetermined air cleanliness level and can maintain a sterile state by decontaminating the interior. The granulation means 2, sorting means 3, and crushing means 4 are housed inside the clean room 6, and the isolator 7 is provided between the clean room 6 and the heating means 5.
At one end of the clean room 6, there is provided an entrance door 6a for carrying in liquid gelatin, which is the raw material for gelatin particles, and at the side, there are provided gloves 6g for workers to wear.

The granulation means 2 is well known and detailed description will be omitted, but it comprises a cylindrical processing tube 2a, spraying means 2b provided at the bottom of the processing tube 2a for spraying liquid gelatin, and airflow generating means having an air nozzle (not shown) for generating an airflow of dry air inside the processing tube 2a.
The inside of the processing tube 2a is set to a predetermined temperature. For example, the inside temperature of the processing tube 2a can be set to 70 to 150.degree.
The spray means 2b sprays liquid gelatin, which is obtained by dissolving solid gelatin in water, in the form of a mist. As the liquid gelatin, liquid gelatin dissolved at a concentration of 1 to 30 wt % can be used.
The spraying means 2b can spray the liquid gelatin into the inside of the processing cylinder 2a at a rate of 0.5 to 10 g/min, and the airflow generating means can inject dry air into the inside of the processing cylinder 2a at a rate of 20 to 100 L/min.

With this configuration, the liquid gelatin in the form of fine droplets sprayed by the spraying means 2b is dried while suspended inside the processing tube 2a by the dry air supplied by the airflow generating means, forming small seed particles.
New liquid gelatin collides with these seed particles, and as the collided liquid gelatin dries, the particle size of the seed particles increases, and then the collision and drying of the liquid gelatin are repeated, forming gelatin particles.
Here, the method of granulating gelatin particles using such granulation means 2 is known as the spray drying method, which is also described in the above Patent Document 1. Compared with the emulsion method described in Patent Document 2, no drugs are used, and therefore the obtained gelatin particles are highly safe for medical use.
However, when the above-mentioned spray drying method is used, as described in Patent Document 1, the particle size of the gelatin particles obtained is most frequently 250 to 350 μm, and the particle size is too large to be suitable for medical use. As described in detail below, the gelatin particles granulated by the granulation means 2 of this embodiment also have an average particle size exceeding 100 μm.

The sorting means 3 includes two sorting means, a first sorting means 11 and a second sorting means 12. The first sorting means 11 has a first sieve 11a with a first mesh size, and the second sorting means 12 has a second sieve 12a with a second mesh size smaller than the first mesh size of the first sieve 11a.
These first and second sorting means 11 and 12 are each adapted to sort the input gelatin particles by minute vibrations caused by ultrasonic vibrations.
That is, the first sorting means 11 and the second sorting means 12 are equipped with ultrasonic vibration means 11b, 12b for vibrating the first and second sieves 11a, 12a, and recovery containers 11c, 12c for recovering gelatin particles that have passed through the first and second sieves 11a, 12a.
The openings of the first and second sieves 11a and 12b may be those specified by the ISO standard, and any openings may be used depending on the particle size of the desired gelatin particles.
When selecting gelatin particles having a particle size of several tens of μm for medical use, it is desirable to select the first mesh size for the first sieve 11a in the range of 90 to 45 μm and the second mesh size for the second sieve 12a in the range of 40 to 10 μm.

The crushing means 4 can adopt a conventionally known configuration, and is provided with an injection means (not shown) for jetting sterile air therein, and also includes a hopper 4a for feeding gelatin particles before crushing.
With this configuration, the ejection means causes sterile air to collide at high speed against the gelatin particles fed by the hopper 4a, thereby pulverizing the gelatin particles.

In this embodiment, the granulation means 2, the sorting means 3 (first sorting means 11 and second sorting means 12), and the crushing means 4 are arranged such that the sorting means 3 is disposed between the granulation means 2 and the crushing means 4.
This improves the workability when moving gelatin particles from the granulation means 2 to the first sorting means 11, from the first sorting means 11 to the crushing means 4, from the crushing means 4 to the first sorting means 11, and from the first sorting means 11 to the second sorting means 12.
The above arrangement is particularly effective when the respective means are arranged close to each other in the clean room 6 and the gelatin particles are moved by operation with the glove 6g. Note that, as long as the sorting means 3 is located between the granulating means 2 and the crushing means 4, it is not necessary to arrange them in a line, and each means may be laid out according to the shape and size of the clean room 6.

The heating means 5 may be a conventionally known one, and heats the gelatin particles contained therein at a required temperature under a vacuum state, thereby causing a crosslinking reaction in the gelatin particles.
In addition, since the gelatin particles are sterilized by such heat treatment, the gelatin particles after heating by the heating means 5 are in a sterile state and can be used for treatment, etc. after being removed from the heating means 5.

The isolator 7 is equipped with a sterile air supply means (not shown) for supplying sterile air to the internal space, and a decontamination means 13 for decontaminating the internal space, and is provided on the side with gloves 7g for an operator to use when working.
In addition, a transfer chamber 14 is provided adjacent to the isolator 7 so as to communicate with the clean room 6. A glove 14g is also provided in this transfer chamber 14, and the gelatin particles processed in the clean room 6 are once accommodated in this transfer chamber 14.
The isolator 7 is provided with a plurality of opening and closing doors, including a delivery door 7a between the isolator 7 and the delivery chamber 14, a communication door 7b between the isolator 7 and the vacuum heating means 5, and an exit door 7c for transporting the gelatin particles contained in the container from the isolator 7 after heat treatment.
The decontamination means 13 fills the internal space with a decontamination medium such as hydrogen peroxide vapor to decontaminate the parts exposed within the internal space, and a conventionally known configuration can be used.

Hereinafter, a method for producing gelatin particles using the gelatin particle production device 1 having the above-mentioned configuration will be described with reference to Figures 1 and 2. Here, liquid gelatin as a raw material and materials necessary for the work are carried into the clean room 6 in advance.
First, a granulation step is carried out to granulate gelatin particles from liquid gelatin.
In this embodiment, liquid gelatin with a concentration of 15 wt % is charged into the granulation means 2, the internal temperature of the processing tube 2a is set to 90°C, the liquid gelatin is sprayed into the inside of the processing tube 2a at a rate of 2 g/min, while the airflow generating means injects dry air into the inside of the processing tube 2a at a rate of 70 L/min, and the granulation means 2 is operated for 90 minutes under the above conditions.
Then, the droplets of liquid gelatin dry inside the processing tube 2a to form seed particles, and new liquid gelatin that collides with these seed particles dries and expands in particle size, thereby obtaining gelatin particles G.
Here, FIG. 3 shows a graph in which the frequency distribution of the particle size of the gelatin particles G granulated by the above-mentioned granulation means 2 was analyzed using a laser diffraction/scattering method, and the particle size range showing the most frequent value ((4) in the figure) was 133.103 μm to 152.453 μm, the frequency of which was 8.799%, and the cumulative frequency until the particle size was obtained was 63.901%.
In this way, when gelatin particles G are granulated using the so-called spray drying method, the particle size exceeds 100 μm, and it can be understood that only a small amount of gelatin particles in the desired range of several tens of μm, for example, 53 μm to 20 μm, can be obtained.

Next, a first sorting step is carried out in which the gelatin particles G obtained in the granulation step are sorted using the first sieve 11a.
When the gelatin particles G obtained by the granulation means 2 are fed into the first sieve 11a of the first sorting means 11, the first sieve 11a selects gelatin particles having a particle size of 53 μm or less, and gelatin particles G1 having a particle size exceeding 53 μm remain on the first sieve 11a, while gelatin particles g having a particle size of 53 μm or less that pass through the first sieve 11a are collected in a collection container 11c.

Next, a crushing step is carried out in which the gelatin particles G1 remaining on the first sieve 11a in the first screening step are crushed using the crushing means 4. That is, in this crushing step, gelatin particles G1 having a particle size exceeding 53 μm are crushed.
In the crushing means 4, the hopper 4a supplies the gelatin particles G1 with 28 m ³ /h of supply air, and the jetting means jets 48 m ³ /h of crushing air to crush the gelatin particles G1. The processing capacity of the crushing means 4 at this time was 1 to 10 g/min.

Next, a second sorting step is carried out in which the gelatin particles G2 pulverized in the above-mentioned crushing step are sorted again by the above-mentioned first sieve 11a.
The gelatin particles G2 crushed in the crushing process are those that did not pass through the first sieve 11a in the first sorting process, but by being crushed in the crushing process, most of them have a particle size that can pass through the first sieve 11a.
As in the first sorting step, when the gelatin particles G2 are sorted by the first sieve 11a of the first sorting means 11, a small amount of gelatin particles G3 having a particle size exceeding 53 μm remain on the first sieve 11a, and gelatin particles g1 having a particle size of 53 μm or less pass through the first sieve 11a and are recovered.
Gelatin particles G3 that do not pass through the first sieve 11a in this second sorting process can be discarded or dissolved and reused, or they can be subjected to a crushing process again to make them into a particle size that can pass through the first sieve 11a, and then the second sorting process can be performed again.

Next, a third sorting step is carried out in which the gelatin particles g which have passed through the first sieve 11a in the first sorting step and the gelatin particles g1 which have passed through the first sieve 11a in the second sorting step are sorted by a second sieve 12.
In this third sorting step, gelatin particles having a particle size of 53 μm or less, consisting of the gelatin particles g and the gelatin particles g1, are put into the second sieve 12 a of the second sorting means 12 .
The second sieve 12a has a mesh size smaller than that of the first sieve 11a, for example, 20 μm. Therefore, of the gelatin particles g and g1 introduced into the second sieve 12a, gelatin particles g2 having a particle size exceeding 20 μm will remain on the second sieve 12a.

Next, a recovery step is carried out in which the gelatin particles g2 selected in the third selection step are recovered as gelatin particles having a particle size in a desired range.
In other words, gelatin particles g2 that do not pass through the second sieve 12a in the second sorting means 12 are collected in a required container, and gelatin particles g3 that pass through the second sieve 12a are discarded or dissolved and reused because their particle size is too small for medical use.

Next, a heating step is carried out in which the gelatin particles g2 which did not pass through the second sieve 12a in the third screening step and were recovered in the recovery step are heat-treated in a vacuum non-oxidizing state using a heating means 5.
The gelatin particles g2 contained in the required container in the above recovery process are transferred from the clean room 6 to a delivery room 14 provided adjacent to the isolator 7, and then moved to the internal space of the isolator 7 through the delivery door 7a of the isolator 7.
Thereafter, the gelatin particles g2 are received in the heating means 5 through the communication door 7b, and are heated in the heating means 5 in an oxygen-free environment at a temperature of 160° C., a heating time of 0.5 to 24 hours, and a pressure of 100 Pa or less.
As a result, a cross-linking reaction occurs in the gelatin particles g2 due to the heat, changing them into a state suitable for medical use, and sterilization is also carried out by heating.

In parallel with the heating process by the heating means 5, a decontamination process for decontaminating the internal space of the isolator 7 is carried out.
Before the decontamination process, a container such as a vial for storing gelatin particles g2 is loaded in advance through the discharge door 7c of the isolator 7, and in this state, with all of the opening and closing doors of the isolator 7 closed, the internal space is decontaminated by the decontamination means 13.
This decontaminates the internal space of the isolator 7 and the container.

Finally, a packaging step is carried out in which the gelatin particles g2 that have been subjected to the heating step are placed in a container and sealed.
When the heating and decontamination steps are completed, the communication door 7b with the heating means 5 is opened, and the heat-treated gelatin particles g2 are moved into the internal space of the isolator 7.
The gelatin particles g2 are then manually placed in each container by an operator and then sealed, so that the gelatin particles g2 are stored in all containers under sterile conditions, and the containers can be taken out by opening the discharge door 7c.

According to the above embodiment, it is possible to efficiently collect gelatin particles g2 having a desired particle size range from the highly safe gelatin particles G granulated by the granulating means 2.
In other words, by crushing large gelatin particles G1 that did not pass through the first sieve 11a in the first sorting step by the crushing means 4, and then re-sorting the crushed gelatin particles G2 in the second sorting step, it is possible to obtain a large number of gelatin particles having a predetermined particle size or smaller that can pass through the first sieve 11a.
Thereafter, in the third sorting step, gelatin particles g and g1 are sorted by a second sieve 12a, whereby gelatin particles g2 exceeding a predetermined particle size can be obtained, and gelatin particles g2 having a particle size within the desired range can be efficiently obtained.
On the other hand, if the granulated gelatin particles are pulverized as they are without carrying out the first sorting step from the above-mentioned operation, those having a particle size exceeding the desired range will be pulverized to an appropriate size, but those having a particle size within the desired range will be pulverized to a smaller particle size, falling below the desired range.
Specifically, when gelatin particles g2 were obtained through the first to third screening steps according to this embodiment, about 26% of the gelatin particles G granulated by the granulation means 2 could be recovered as gelatin particles g2 having a desired particle size range.
In contrast, when the pulverization step was carried out without carrying out the first screening step, only about 5.6% of the gelatin particles G granulated by the granulating means 2 could be recovered.

In the above embodiment, the granulating means 2, sorting means 3 and pulverizing means 4 are provided inside the clean room 6, but these may also be installed inside the isolator 7.
In addition, in the above embodiment, a decontamination process is performed to decontaminate the inside of the isolator 7 during the heating process by the heating means 5. However, if the heat-treated gelatin particles g2 can be moved to the decontaminated and sterile isolator 7, it is not necessary to perform the heating process and the decontamination process in parallel. If the gelatin particles g2 are contained in the heating means 5 or in a state where they are not affected by the decontamination medium, they can be decontaminated before or after the heating process.

Reference Signs List 1 Gelatin particle manufacturing device 2 Granulation means 3 Selection means 4 Crushing means 5 Heating means 6 Clean room 7 Isolator 11 First sieve 12 Second sieve 13 Decontamination means

Claims (6)

A method for producing gelatin particles, comprising a granulation step of spraying liquid gelatin and drying it to form granules, and recovering the granulated gelatin particles as gelatin particles having a desired size within the range of upper and lower limits of several tens of μm,
a first sorting step of sorting the gelatin particles obtained by the granulation step using a first sieve having a first mesh size selected in the range of 90 to 45 μm for sorting gelatin particles below the upper limit of the desired range;
a grinding step of grinding gelatin particles exceeding the upper limit of the desired range that did not pass through the first sieve in the first screening step;
a second sorting step of sorting the gelatin particles pulverized in the crushing step using the first sieve;
a third sorting step in which the gelatin particles that have passed through the first sieve in the first sorting step and the second sorting step are sorted using a second sieve having a second opening selected in the range of 40 to 10 μm for sorting gelatin particles that are smaller than the first opening and are equal to or smaller than the lower limit of a desired range;
a recovery step of recovering gelatin particles exceeding the lower limit of a desired range which did not pass through the second sieve in the third screening step;
and a heating step of heat-treating the recovered gelatin particles. The method for producing gelatin particles according to claim 1, characterized in that the concentration of the liquid gelatin sprayed in the granulation process is 1 to 30 wt %. The method for producing gelatin particles according to claim 2, characterized in that in the granulation process, liquid gelatin of the above concentration is sprayed at 0.5 to 10 g/min, and dried by spraying dry air at 20 to 100 L/min. A gelatin particle manufacturing apparatus is provided with a granulating means for spraying and drying liquid gelatin to form granules, and the granulated gelatin particles are collected as gelatin particles having a desired size within a range of upper and lower limits of several tens of μm,
The gelatin particle sorting apparatus comprises a first sorting means having a first sieve with a first opening selected in the range of 90 to 45 μm for sorting gelatin particles below the upper limit of a desired range, a second sorting means having a second sieve with a second opening selected in the range of 40 to 10 μm for sorting gelatin particles below the lower limit of a desired range that is smaller than the first opening, a crushing means for crushing the gelatin particles, and a heating means for heat-treating the gelatin particles,
The gelatin particles granulated by the granulating means are sorted by the first sorting means, and the gelatin particles which do not pass through the first sieve are pulverized by the pulverizing means.
Further, the gelatin particles pulverized by the pulverizing means are selected by the first selecting means,
The second sorting means sorts gelatin particles that have been sorted by the first sorting means and passed through the first sieve,
The gelatin particle manufacturing apparatus is characterized in that gelatin particles which did not pass through the second sieve by the selection by the second selection means are recovered and heat-treated by the heating means. The gelatin particle manufacturing apparatus according to claim 4, characterized in that the granulating means, the first sorting means, the second sorting means and the pulverizing means are provided in a clean space, and the first sorting means and the second sorting means are disposed between the granulating means and the pulverizing means. an isolator whose internal space is maintained in a sterile state is connected to the heating means, and a decontamination means for decontaminating the internal space is provided in the isolator;
6. The gelatin particle manufacturing apparatus according to claim 4 or 5 , characterized in that the gelatin particles heat-treated by the heating means are conveyed to a decontaminated internal space of the isolator.

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