JPS6139925B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for encapsulating oral preparations such as lactic acid bacteria and enzymes while maintaining high potency, and to oral preparations produced by this method. Traditionally, this type of preparation has been available in tablets or capsules, but in order to create such an easy-to-take dosage form, it is unavoidable that the potency of the drug decreases to some extent during the manufacturing process. The reality was that this was the case. In addition, when these oral preparations are freeze-dried and then mechanically turned into powder and packed into capsules, it is difficult to measure the highly hygroscopic powder after freeze-drying and fill it into capsules in minute amounts, which may cause moisture absorption. For reasons such as preventing a drop in titer, the entire filling process must be performed aseptically and in a dry state, which increases the size of the equipment and ultimately increases the cost of the formulation, making it impractical. do not have. In addition, mechanical pressure and impact during the powdering process and weighing and filling operation process cause a significant drop in the titer of viable bacteria and a decrease in the number of viable bacteria, which poses a major problem. Furthermore, a tablet molding machine, the aforementioned powder machine,
The entire equipment, including the weighing machine, must be sterilized and installed under dry conditions, which is difficult to implement. This invention fundamentally improves such methods,
This is a method for making capsules as they are without damaging the freeze-dried form,
Moreover, in this way, capsules with high potency can be obtained. This invention is an oral capsule in which the liquid oral preparation is injected into a capsule made of a water-soluble material and then freeze-dried before the capsule is dissolved. Another feature is that a large number of capsules made of water-soluble material are placed in a large number of depressions of a support plate with good thermal conductivity, with their openings facing upward, and these are kept at temperatures below freezing. Under these conditions, a predetermined amount of the liquid oral preparation was dispensed into all the capsules at the same time, immediately frozen, and then lyophilized. This method for producing oral capsules is characterized in that each capsule is closed with a capsule lid made of the same material or in another capsule, and then the capsules are sealed in an appropriately sealed container while maintaining a dry state. By employing the above method (claim 7), since the oral drug is still in liquid form when dispensed into each capsule, it is easy to inject a predetermined amount and the measurement is accurate. Furthermore, since the capsule is frozen and dried before being dissolved, the capsule maintains its function as an outer shell even after freeze-drying, and serves to protect the form of the freeze-dried oral drug inside. It is convenient to seal it in a sealed container or to take it as is. Furthermore, in the method invention, a large number of capsules are supported in a large number of depressions of a support plate made of a good thermal conductor, and these are kept at a temperature below the freezing temperature of the liquid oral drug, and the liquid oral drug is injected into the large number of capsules almost simultaneously. Because we adopted a method of injecting a predetermined amount of the capsule, all the oral preparations in the capsules freeze immediately, without dissolving the outer shell of the capsule. Also serves as a mold material, and further in this method invention,
By keeping it dry and packaging it in a sealed container, it retains its potency for a longer period of time. In particular, in the oral capsules manufactured by the method invention, that is, the product invention in this patent application, the oral preparations are not subjected to strong compressive force or impact during the process of packaging the oral preparations into capsules. After freeze-drying, mechanical pressure, humidification,
Since it is not subjected to heating, it has the effect of not losing its potency, especially when pelletizing live bacteria such as lactic acid bacteria. In addition, the dosage can be accurately determined by the number of capsules, making it particularly excellent as a continuous medication. Furthermore, since it can be carried out with a comparatively inexpensive dispenser and support plate, there is also the advantage that there is no need to provide a very expensive capsule filling machine. The method of this invention will now be specifically explained. First of all,
As the support plate 1, a good heat conductor such as aluminum, rust-proofed brass copper, or stainless steel or a thin plastic plate is used.
For this purpose, use one that has a large number (usually 100 to 200) of depressions 2 into which the capsule can be inserted. Capsule 3 was molded from gelatin, polyvinylpyrrolidone (PVP), sodium carboxylmethylcellulose (CMC), methylcellulose (MC), and other materials capable of forming a water-soluble film, either singly or in combination. The outer diameter of the recess is such that it can be easily inserted into and removed from the recess 2, and the length of the recess corresponds to the depth of the recess. The dispenser 9 has injection needle-like injection beaks 8 corresponding to the number of depressions 2 in the support plate 1, and is provided corresponding to the positions of the plurality of depressions 2, and the injection beaks 8 are provided in correspondence with the positions of the plurality of depressions 2, and the injection beaks 8 are provided in the shape of injection needles corresponding to the number of depressions 2 in the support plate 1. It is designed so that it can be dispensed into capsule 3 inside. The freeze dryer used is one that can accommodate a large number of the support plates and freeze-dry them at once. The method of the present invention is carried out in the following manner using the above-mentioned instruments and devices. First, capsules 3 made of the above material are sufficiently dried (moisture content is 5% or less) and inserted one by one into each depression 2 of the support plate 1 with the opening facing upward.
The support plate 1 is placed on the pedestal of the dispenser, and the liquid oral drug 5 is cooled to below the freezing temperature of the liquid oral drug to be injected, usually about -30°C. Inject a predetermined amount into capsule 3 all at once. The injected liquid oral preparation 5 is immediately frozen in each capsule 3. Then, this frozen capsule-filled drug is placed in a tank of a freeze dryer together with the support plate 1, and frozen in the same manner as normal freeze drying. Alternatively, the capsules are set on the uncooled support plate 1 and the liquid oral preparation 5 is
If injected in portions, place directly into a pre-cooled tank of a freeze dryer and freeze. After sufficiently freezing, the pressure inside the tank is reduced and the support plate is heated to sublimate the moisture and dry it. The sufficiently dried capsule 3a containing the freeze-dried drug usually has a size that is 10 to 15% smaller than its original size. Then, the group of capsules containing the freeze-dried oral medication was taken out from the tank along with the support plate, and the capsules were removed from the support plate 1. Next, each of the capsules 3a was closed with a capsule lid made of the same material as the capsule 3, and these capsules were closed. Either place it in a suitable container such as a bottle, synthetic resin film, or plate in a dry atmosphere and seal it, or cover the outside of the capsule 3a without a lid with a pair of packaging capsules 7, Place in a suitable airtight container and seal. Example 1 A bacterial solution of 1 to 2 x ^{10 lactic} acid bacteria (Bifidus bacteria)/ml containing a dispersion medium consisting of 20% sucrose, 5% sodium glutamate, and 3% dexdran was prepared in advance, and the solution was prepared in advance with a diameter of 6 mm and a depth of 15 mm. A capsule (small container) made of a mixture of gelatin and starch having a diameter of 6 mm and a length of 15 mm is inserted in advance into each of the above-mentioned depressions 2, and the capsules (small containers) made of a mixture of gelatin and starch having a diameter of 6 mm and a length of 15 ^mm are inserted into each of the depressions 2 described above. /
0.33 ml of bacterial solution to each capsule 3 at the same time with dispenser 9
Dispense in ml. After dispensing, the support plate is immediately placed in a freeze dryer tank that has been previously cooled to -30°C or lower and frozen. Once freezing is complete, water is sublimed and dried using a conventional freeze-drying method. At the end of freeze-drying, capsule 3a has a diameter of approximately 5 mm.
It shrinks to about 15mm in length and becomes a cylindrical pellet. The support plate is taken out from the tank of the freeze dryer, the pellet-shaped capsules are removed from the support plate, and each of these capsules 3a without a lid is wrapped with a capsule lid made of the same material or another packaging capsule (see Figure 5) 7 Packed by. These operations are performed manually or mechanically. Then, the product is further bottled in vacuum or in dry air and nitrogen gas, and airtightly packaged with synthetic resin film foil. The experimental results of this example are shown in the following table.

[Table] In the above table, 1 is the same as 1, using Bifidus bacterium as the oral preparation of the patented method, capping each capsule 3a after freeze-drying, and storing it in a vial under vacuum. Packed in aluminum foil and airtight at normal pressure. The control was freeze-dried, powdered, and airtightly packaged in aluminum foil at normal pressure. As is clear from the table above, it is powdered after freeze-drying, which is considered to have the best shelf life.
In some cases, lactic acid bacteria preparations with a viable cell count of 5 to 10 x 10 ⁹ have an order of magnitude better shelf life than those mixed with starch, etc. and sealed in aluminum foil at normal pressure. Moreover, even when stored at room temperature at 37°C for a long period of time, the number of viable bacteria decreases only slightly, and has a marked difference in storage stability compared to conventionally known products. Example 2 Fresh royal jelly that had been frozen and transported from the production area was once thawed, and water-soluble capsules made of gelatin were placed in advance on a support plate 1 having a number of holes with a diameter of 6 mm and a depth of 15 mm, with the opening facing upward. , cool them in advance to the extent that the royal jelly freezes, and add 0.35 g of jelly into these small containers.
Dispense royal jelly in ml portions and immediately lyophilize using a conventional method. After drying, the capsule 3a is placed on the support plate 1.
Take it out. Each of these capsules 3a is then closed with a capsule lid made of the same material.
or each of the freeze-dried capless capsules 3a;
are further placed in another pair of packaging capsules and closed. Thereafter, by the same method as in Example 1, it is bottled or airtightly packaged with synthetic resin film foil or the like. In this way, high quality dried royal jelly containing 0.11 to 0.12 g of pure royal jelly in the dried capsules 3a is obtained. In terms of storage stability, better results were obtained than with conventional tablet bottling. Similar effects can be obtained when the above-mentioned examples and capsule materials include polyvinyl pyrrolidone, sodium chloride, carboxymethyl cellulose, and methyl cellulose. Even if other water-soluble agents are not exemplified, as long as they meet the above objectives, they fall within the scope of this invention, regardless of whether they are used in the preparation of this invention or in this method. . Other items that can be freeze-dried include enzymes,
When we tested antibiotics, we found that regular tablets had high potency and had excellent shelf life.

[Brief explanation of the drawing]

The drawings show what is related to this invention, and FIG. 1 is a partially longitudinal side view of a state in which a capsule is inserted into a recess in a support plate and a liquid oral preparation is being dispensed, and FIG. FIG. 3 is a partially enlarged cross-sectional view after completion of injection of the liquid oral drug; FIG. 4 is an enlarged cross-sectional view of the capped capsule after freeze-drying; FIG. The figure is an enlarged sectional view of the product packaged in a packaging capsule, and FIG. 6 is a perspective view of the product packaged in an airtight packaging material. In the figure, 1... support plate, 2... depression, 3... capsule, 4... pedestal, 9... dispensing machine, 6... packaging material, 7... packaging capsule.

Claims (1)

[Scope of Claims] 1. An oral capsule in which a liquid oral preparation is injected into a capsule made of a water-soluble material and then frozen before the capsule dissolves to lyophilize the liquid oral preparation. 2 The water-soluble agent is gelatin, polyvinyl pyrrolidone, sodium carboxyl methyl cellulose,
2. The oral capsule according to claim 1, which is made of one of the group consisting of methylcellulose and other materials capable of forming a water-soluble film. 3. The oral capsule according to claim 1 or 2, wherein the liquid oral preparation contains lactic acid bacteria as a main ingredient. 4. Claim 1 or 2, characterized in that the liquid oral preparation contains an enzyme as the main ingredient.
Oral capsules as described in Section. 5. The oral capsule according to claim 1 or 2, wherein the liquid oral preparation is an antibiotic. 6. The oral capsule according to claim 1 or 2, wherein the liquid oral preparation is royal jelly. 7 Capsules made of a water-soluble material are inserted into a number of depressions provided in a support plate with good thermal conductivity, with the openings facing upward, and a predetermined amount of liquid oral preparation is dispensed into these capsules almost simultaneously. The capsules are immediately frozen and then lyophilized, the capsules are removed from the support plate, each lyophilized capsule without a lid is placed in the same capsule lid or another capsule, and then closed, and then placed in a sealed container in a dry state. A method for producing an oral capsule, characterized by encapsulating the oral capsule while maintaining the 8. Oral capsule according to claim 7, characterized in that one or a mixture of two or more of gelatin, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, and methyl cellulose is used as the water-soluble material. How to manufacture. 9. The oral capsule preparation according to claim 7 or 8, characterized in that the liquid oral preparation is based on one of the group consisting of lactic acid bacteria, enzymes, antibiotics, and royal jelly. Production method.