JP2023172963A - Soft formulation containing lipophilic drug - Google Patents

Abstract

To provide a soft capsule that contains a lipophilic drug such as eldecalcitol, calcitriol, alfacalcidol, cyclosporin, menatetrenone, where the capsule has high strength while retaining formulation stability.SOLUTION: A soft capsule is filled with a content liquid containing a lipophilic drug. Its capsule coating contains sucrose and a gelator.SELECTED DRAWING: None

Description

The present invention relates to soft capsules stably containing lipophilic drugs.

Lipophilic drugs that are unstable in the presence of water and pose problems in the preparation manufacturing process and storage quality during preparation include vitamin D derivatives such as eldecalcitol, alfacalcidol, and calcitriol, prostaglandin E2, dinoprostone, Alphaprostadil, latanoprost and 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentan-1-yl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran- There are prostaglandin derivatives such as 5-yl]heptanoic acid).
Among these, 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentan-1-yl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl ]Heptanoic acid (hereinafter referred to as "Compound A") has the effect of promoting intestinal fluid secretion, is a therapeutic agent for chronic constipation, and is commercially available in the form of soft capsules.
However, such soft capsules have a problem in that they have insufficient plasticity compared to ordinary soft capsules and are easily damaged by impact, especially at high temperatures in winter.

In soft capsule preparations, a plasticizer such as glycerin or sugar alcohol is generally added to the base of the capsule film in order to impart plasticity to the capsule film. For example, Patent Document 1 describes a soft capsule preparation in which the capsule film contains a sugar alcohol derived from corn starch and the soft capsule is filled with a compound A solution. Patent Document 2 describes a soft capsule in which a film made of gelatin and trehalose is filled with a liquid content made of compound A and medium-chain fatty acid triglyceride.

Patent No. 4783794 JP 2021-172663 Publication

An object of the present invention is to provide a soft capsule formulation containing a lipophilic drug such as Compound A that has excellent strength while maintaining formulation stability.

The present inventor has investigated ingredients other than glycerin, sugar alcohol, and trehalose as plasticizers for the shell of soft capsules containing lipophilic drugs, and has found that they have been found to have problems such as browning and delayed disintegration. The present invention was completed by discovering that by using sucrose, which is rarely used as a plasticizer, it is possible to produce soft capsules with excellent strength while maintaining formulation stability.

That is, the present invention relates to the following 1) to 16).
1) A soft capsule filled with a liquid containing a lipophilic drug, the capsule film of which contains sucrose and a gelling agent.
2) Lipophilic drugs include vitamin D derivatives consisting of eldecalcitol, calcitriol and alphacalcidol, prostaglandin E2, dinoprostone, alphaprostadil, latanoprost and 7-[(2R,4aR,5R,7aR)-2- (1,1-difluoropentan-1-yl)-2-hydroxy-6-oxo-octahydrocyclopenta[b]pyran-5-yl]heptanoic acid), cyclosporin, and menatetrenone. The soft capsule according to claim 1.
3) The lipophilic drug is 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentan-1-yl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran- 5-yl]heptanoic acid) according to 1).
4) The soft capsule according to 3), wherein the gelling agent is one or two selected from gelatin and succinated gelatin.
5) The soft capsule according to 3), wherein the content of sucrose in the capsule film is 30 to 100 parts by mass based on 100 parts by mass of the gelling agent.
6) The soft capsule according to 3), wherein the content of sucrose in the capsule film is 40 to 60 parts by mass based on 100 parts by mass of the gelling agent.
7) The soft capsule according to 3), wherein the content of the lipophilic drug in the capsule is 0.01 to 10,000 μg.
8) The soft capsule according to 3), wherein the lipophilic drug-containing liquid contains the lipophilic drug and saturated fatty acid triglyceride.
9) The soft capsule according to 8), wherein the saturated fatty acid is capric acid and/or caprylic acid.
10) The soft capsule according to 3), wherein the ratio of the capsule film to the content liquid is 20 to 200 parts by mass of the content liquid per 100 parts by mass of the film.
11) The soft capsule according to 3), which has a soft capsule strength of 200N or more.
12) The soft capsule according to 3), which has a disintegration time of 20 minutes or less after being held at 40°C for one month.
13) The soft capsule according to 3), wherein the soft capsule film further contains a plasticizer.
14) The soft capsule according to 13), wherein the plasticizer is one or more selected from sucrose fatty acid ester, povidone, crospovidone, and vinyl acetate/vinylpyrrolidone copolymer.
15) The soft capsule according to 13), wherein the content of the plasticizer is 1 to 100 parts by mass based on 100 parts by mass of the gelling agent.
16) A soft capsule formed by filling a capsule film containing sucrose and a gelling agent with a liquid content containing a lipophilic drug by a punching method.

According to the present invention, there is provided a lipophilic drug-containing soft capsule that maintains formulation stability and has excellent strength. In addition, the soft capsules of the present invention have excellent productivity because capsules can be easily molded and the amount of film used can be reduced.

The soft capsule of the present invention is a soft capsule filled with a liquid containing a lipophilic drug, and the capsule film contains sucrose and a gelling agent.

The sucrose contained in the film of the soft capsule of the present invention is a compound represented by the following formula [I], and is also called sucrose, sucrose or refined white sugar, and glucose (glucose) and fructose (fructose) are It is a sugar with -1,2-glycosidic bonds. Sucrose is a type of disaccharide and is a non-reducing sugar, so sucrose itself does not undergo the Maillard reaction. However, sucrose is converted into glucose and fructose due to heat, pH, the presence of acids and alkalis, and changes over time, causing a Maillard reaction, and due to the effects of reducing sugars and amino acids contained as impurities, a Maillard reaction occurs, so gelatin is not used. It is not used industrially as a plasticizer for the soft capsule film that is the base material. It is believed that when the Maillard reaction occurs in the film, problems such as browning and delayed disintegration occur.
In the soft capsules of the present invention, even when sucrose is blended, the capsule strength can be improved without causing such problems.

In the present invention, sucrose may be either food-grade or pharmaceutical-grade, but from the viewpoint of stability of the lipophilic drug, it is preferably naturally derived and contains no more than a certain amount of impurities derived from the manufacturing process. It is more preferable to use a product that satisfies the standards listed in the official compendium, such as a product listed in the Japanese Pharmacopoeia.

In the present invention, the gelling agent is used as a base for the capsule film, and is a pharmaceutically acceptable polymeric compound having sol-gel transition ability, such as gelatin, carrageenan, agar, pullulan, starch, etc. Can be mentioned. Among them, gelatins are preferred, and in addition to normal gelatin, acid-treated gelatin and chemically modified gelatin can be used. It is also possible to use gelatin alone, modified gelatin alone, or a mixture of gelatin and modified gelatin.
The origin of gelatin is not particularly limited, and gelatin obtained from bones, cartilage, tendons, skin, etc. of animals such as cows, pigs, birds, and fish can be used. Gelatin includes hydrolyzed gelatin and enzymatically decomposed gelatin. Modified gelatin is a product in which the properties of gelatin are changed by reacting the amino groups of gelatin with various substances, and is produced by reacting with succinic acid, phthalic acid, acetic acid, etc. Succinated gelatin, phthalate, etc. Examples include gelatin.
As the gelling agent, one selected from gelatin and succinated gelatin among the above-mentioned gelatins is selected from gelatin and succinated gelatin from the viewpoint of maintaining particularly excellent strength, disintegration properties, and formulation stability of soft capsules when sucrose is used as a plasticizer. One species or two species are more preferred.

When the gelling agent is gelatin and/or succinated gelatin, the jelly strength is, for example, 130 to 280 g, preferably 130 to 200 g, and more preferably 130 to 170 g. When using gelatin and succinated gelatin as a gelling agent, the blending ratio of gelatin and succinated gelatin is preferably 0 to 2000 parts by mass of succinified gelatin per 100 parts by mass of gelatin, more preferably 0 to 2000 parts by mass of succinified gelatin per 100 parts by mass of gelatin. The amount of succinated gelatin is 20 to 1000 parts by weight, and more preferably 200 to 600 parts by weight of succinated gelatin per 100 parts by weight of gelatin. Here, the jelly strength can be measured by the test method of JIS K6503 and/or the Japanese Pharmacopoeia.

The content (content ratio) of sucrose in the film is set to 100 parts by mass of the gelling agent from the viewpoint of the strength, disintegration, and stability of the soft capsule, as well as sucrose precipitation, powder blowing, stickiness, and coloring after forming the film. It is preferably 20 to 200 parts by weight, more preferably 30 to 150 parts by weight, even more preferably 30 to 120 parts by weight, and most preferably 30 to 70 parts by weight.

Among these, when gelatin is used as the gelling agent, the content of sucrose is preferably 20 to 100 parts by weight, more preferably 30 to 80 parts by weight, and still more preferably 40 to 100 parts by weight, based on 100 parts by weight of gelatin. It is 70 parts by mass. Further, when using succinated gelatin, the content of sucrose is preferably 20 to 90 parts by weight, more preferably 30 to 80 parts by weight, and even more preferably 40 to 60 parts by weight, based on 100 parts by weight of succinated gelatin. be.

In addition to sucrose, the capsule film of the present invention may contain a plasticizer as long as it does not affect the effects of the present invention. By including a plasticizer, depending on the desired formulation design, the stickiness of soft capsules that occurs when the content of sucrose is too high, changes in the appearance of the film due to precipitation of sucrose over time, and soft capsules. The disintegrative delay of can be suppressed.
The plasticizer is preferably one or more selected from the group consisting of sucrose fatty acid ester, povidone, crospovidone, and vinyl acetate/vinylpyrrolidone copolymer, and more preferably povidone or sucrose fatty acid ester. The content of the plasticizer is preferably 0 to 100 parts by weight, more preferably 1 to 100 parts by weight, and even more preferably 5 to 30 parts by weight, based on 100 parts by weight of the gelling agent.

The capsule film of the present invention may contain additives commonly used in soft capsule films. Such additives include, for example, coloring agents such as titanium oxide, iron sesquioxide, yellow iron sesquioxide, and yellow No. 5, preservatives, sweeteners, fragrances, pH adjusters, disintegration delay inhibitors, and antioxidants. , surface treatment agents, and plasticizers other than sucrose.

Examples of the surface treatment agent include carnauba wax, lecithin, hydrogenated castor oil, polyoxyethylene hydrogenated castor oil, hydrogenated rapeseed oil, hydrogenated oil, magnesium stearate, starch, and wheat flour.

Thus, sucrose is used as a plasticizer in the capsule film of the present invention, and there is no need to use other plasticizers. Sugars other than sucrose, such as lactose, have a problem in that they do not dissolve in the gelling agent and mix with powder, and trehalose has a problem in that the film sheet is hard, the bonding between the films is weak, and the strength is low. It is also preferable that corn-derived sugar alcohol liquid and polyhydric alcohols such as sorbitol, glycerin, and maltitol are substantially free. "Substantially not containing" means that polyhydric alcohol is not actively added to the film, and even if it is contained, it is in a small amount that does not affect the effects of the present invention. For example, if a small amount of polyhydric alcohol is included, if it is mixed in as an impurity, if it is generated in a small amount due to some kind of chemical reaction or decomposition of the contained ingredients, or if it is used to change the properties of soft capsules such as changes in flexibility or hardness. Examples include addition. The blending amount of the polyhydric alcohol is preferably 50 parts by mass or less, more preferably 30 parts by mass or less, more preferably 10 parts by mass or less, and most preferably 5 parts by mass or less, for example, per 100 parts by mass of sucrose.

The soft capsule of the present invention is filled with a liquid containing a lipophilic drug.
Lipophilic drugs are drugs that do not dissolve in water but dissolve in oils, fats, and organic solvents. Furthermore, they tend to generate impurities through hydrolysis or addition reactions in the presence of water, and are unstable in terms of long-term stability. , for example, vitamin D derivatives such as eldecalcitol, calcitriol, alphacalcidol, prostaglandin E2, dinoprostone, alphaprostadil, latanoprost and 7-[(2R,4aR,5R,7aR)-2-(1 , 1-difluoropentan-1-yl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl]heptanoic acid) (compound A), cyclosporin, and menatetrenone. Examples include. Among these, the soft capsules of the present invention are 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentan-1-yl)-2-hydroxy-6-oxooctahydrocyclopenta [b] Pyran-5-yl]heptanoic acid) (Compound A) It has a prostaglandin structure and opens the ring in an equilibrium manner, so it is suitable for Compound A, which requires strong pharmaceutical stability. is preferable.

7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentan-1-yl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl]heptane Acid) "Compound A" includes the compound represented by the following formula [II], as well as its pharmaceutically acceptable salts and solvates thereof. The pharmaceutically acceptable salt of compound A refers to a salt formed from a compound represented by the following formula [II] and an organic or inorganic base and is acceptable for administration to mammals including humans. . Pharmaceutically acceptable salts of Compound A include, for example, alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, etc.), ammonium salts, amine salts (methylamine salts, etc.). Examples include dimethylamine salts, cyclohexylamine salts, benzylamine salts, triethanolamine salts, procaine salts, caffeine salts, etc.), basic amine salts (arginine salts, lysine salts, etc.), and tetraalkylammonium salts.

A pharmaceutically acceptable solvate of Compound A or a pharmaceutically acceptable salt thereof is a compound represented by the above formula [II] or a pharmaceutically acceptable salt thereof, and a mammal including a human. A solid molecule formed from a certain amount of solvent that is allowed to be ingested. Such solvents include, for example, ethanol, propanol, hexane, and acetone.

The content of the lipophilic drug in the soft capsule may be the usual dosage per preparation, and is preferably 0.1 to 100,000 μg per soft capsule, for example. Further, it is preferable that the amount of alfacalcidol is 0.25 to 3 μg, eldecalcitol is 0.3 μg, and calcitriol is 0.5 to 0.75 μg, and for compound A, it is preferably 1 μg or more and 100 μg or less, More preferably it is 12 μg or 24 μg.

Internal solutions containing lipophilic drugs are prepared by dissolving or dispersing the lipophilic drug in a solvent that does not adversely affect the stability of the lipophilic drug. Such a solvent can be appropriately selected from aqueous and non-aqueous media that are normally used for the contents of soft capsules, and may be a mixture of a plurality of them, but it is preferable to use a non-aqueous medium. Examples of the aqueous medium include ethanol. For example, examples of the non-aqueous medium include fatty acid triglycerides, vegetable or animal fats and oils, waxes, hydrogenated oils, mineral oils, and the like.
Examples of fatty acid triglycerides include triglycerides of medium-chain or long-chain saturated fatty acids, such as caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, and Examples include one or more types selected from behenic acids. Examples of vegetable or animal fats and oils include olive oil, sesame oil, soybean oil, camellia oil, castor oil, and fish oil. Examples of the waxes include beeswax, carnauba wax, and lanolin. Examples of hydrogenated oils include hydrogenated oils and fats such as hydrogenated hydrogenated castor oil. Examples of the mineral oil include paraffin. Preferred solvents are medium-chain fatty acid triglycerides, such as triglycerides of caprylic acid and/or capric acid, and those that meet pharmaceutical excipient standards, the European Pharmacopoeia, and the United States Pharmacopoeia are more preferred. More preferably, the ratio of caprylic acid to capric acid is 25 to 100 parts by mass, preferably 30 to 70 parts by mass of capric acid per 100 parts by mass of caprylic acid.

The amount of solvent can be selected as appropriate by taking into consideration the amount that the drug can be dissolved in, the effect on the absorption of lipophilic drugs into the body, the size of the soft capsule, etc. For example, the amount of solvent can be selected from 40 to It is 300 mg. When the lipophilic drug is Compound A, the amount of solvent is preferably 40 to 150 mg, more preferably 60 to 120 mg per capsule.

In the soft capsules of the present invention, the ratio of the coating film to the internal liquid is 20 to 200 parts by weight, preferably 60 to 120 parts by weight, per 100 parts by weight of the coating.

The soft capsule of the present invention can be produced by filling a capsule film containing sucrose and a gelling agent with a liquid content containing a lipophilic drug. Specifically, the above-mentioned liquid content and capsule coating composition are supplied to a rotary die molding device, a flat plate punching device, or a seamless molding device to form soft capsules filled with an internal liquid.
In a rotary die molding device, the coating composition solution is cooled and gelled to form a sheet, and the coating sheet is sandwiched between a pair of die rolls while filling the space between the two formed coating sheets. By pressing and punching, a soft capsule filled with liquid is formed. In seamless molding equipment, the coating composition solution is poured out from the outside of concentric multiple nozzles, and the liquid content is simultaneously poured out from the inside to form a combined liquid stream, and the combined liquid stream is shredded and released into cooling oil. As a result, soft capsules filled with the liquid content are formed.
The film composition solution can be prepared by stirring and dispersing the gelling agent and sucrose in water, stirring and dissolving them at 60 to 98°C, and defoaming in vacuum.
After drying, the filled and molded soft capsules are finished by surface treatment using a tumbler or the like, if necessary.

The film containing sucrose and a gelling agent of the present invention has good plasticity and is easy to form a film during the molding process.Since the film has good plasticity, it has a sufficient adhesion area during the filling process, and because of its good adhesion, it does not break at the adhesive surface. The drying process is also good because there is no stickiness on the surface of the film. In particular, in the case of a rotary die type molding device, the time required to bond the films is short, for example, about 100 pieces/minute, and the bondability of the films is important. In the present invention, the film can be made thin, and the thickness of the film is adjusted by adjusting the shutter height of the spreader box, but the film thickness is 0.5 to 1.5 mm, preferably 0.8 mm. ~1.2mm.

The shape of the soft capsule of the present invention is not particularly limited, and may be any shape such as spherical, elliptical, elongated elliptical, tube, suppository, fish, acorn, and eggplant shape. The size of the capsule may be any size that can be taken orally, and the weight of the soft capsule is preferably 100 to 500 mg, more preferably 100 to 300 mg.
Since the soft capsules of the present invention are preferably used in a method in which one capsule is administered at a time, it is preferable that the soft capsules are manufactured by a punching method and can be filled with a fixed volume of liquid. preferable.
The formed soft capsules may be packaged by PTP packaging, bottle filling, aluminum packaging, etc.

The soft capsule of the present invention thus obtained has sufficient strength, for example, 200 N or more in a hardness test, so that it will not be damaged during transportation, packaging, or during the preparation process.
In addition, the soft capsule of the present invention has a disintegration property in which the disintegration time is within 20 minutes even after being kept at 40°C for one month in a disintegration test. Here, the disintegration time is the time when the joint surfaces of the soft capsule separate and the contents come out.

Moreover, the soft capsule of the present invention has formulation stability. Formulation stability refers to the stability of the drug itself and the stability of the capsule. The stability of the drug itself is defined by the fact that the lipophilic drug itself contained in the soft capsule does not decompose during production and its residual rate does not change much over time, and there is little delay in the disintegration of the soft capsule over time. It meets the requirements as a drug after being stored at room temperature for 2 or 3 years. Specifically, the drug has drug stability with a drug survival rate of 90% or more in 2 years or 90% or more in 3 years.
The stability of the capsules is determined by, for example, no discoloration such as brown when stored at 40°C for one month, no precipitation due to plasticizer insolubility or recrystallization, no powdering of the film surface, and no damage to soft capsules due to a decrease in film strength. There must be no damage.

Furthermore, the soft capsules of the present invention have higher productivity than when saccharides other than sucrose are used as plasticizers. That is, the moldability of the film is high, the adhesive strength is high, the molding speed and the thickness of the film can be reduced, and the production amount can be increased.
Although the mode for carrying out the invention has been described above, this description clearly shows a specific example, and is not limited to this description. Includes elements that will have a similar effect when replaced in the future.

An example of the method for manufacturing a soft capsule containing Compound A according to the present invention is shown below, but this description is only an example and is not limited thereto.

Example 1
(Manufacture of soft capsules containing compound A)
Table 1 shows the formulation (amount of ingredients per capsule) of the soft capsule of Example 1. In the table, the mass of purified water is not included in the total. Note that the succinated gelatin used in Example 1 is derived from bovine and has a jelly strength of 150 to 170 g. Further, in Example 1, the mass of sucrose is 100 parts by mass relative to 100 parts by mass of gelatin.
An appropriate amount of water was added to sucrose, stirred and heated to obtain a sucrose solution. An appropriate amount of water was added to the succinated gelatin, stirred and heated, a sucrose solution was added, and a titanium oxide solution dispersed in water was added to obtain a coating solution. Compound A was dissolved in medium chain fatty acid triglyceride to obtain a content liquid. The coating solution and the content liquid were encapsulated in the coating using a soft capsule forming and filling machine, and then dried to obtain a soft capsule.

(Hardness test and disintegration test)
Hardness tests and disintegration tests were conducted on the soft capsules at the start of storage and after storage at 40°C for one month. The hardness test was performed by applying a load of 200 N to the short diameter side of the soft capsule and crushing it using a digital hardness meter (KHT-40N, manufactured by Fujiwara Seisakusho) to see if any cracks would occur. The disintegration test was conducted in accordance with the section of "Disintegration test method 2.1 Immediate release preparation" of the Japanese Pharmacopoeia. Using water as the test liquid, the disintegration tester was operated at 37±2°C, and the time taken for the capsule contents to finish being released into the test liquid was measured as the disintegration time. The hardness test was conducted on 3 capsules, and the disintegration test was conducted on 6 capsules.

The results of the hardness test and disintegration test are shown in Table 2. "Starting time" in the table indicates the results at the time when storage of the soft capsules started. The upper limit of measurement by the hardness test measuring device is 392N, and "no cracking" means that no cracking occurred even at the upper limit of pressure. The disintegration time is the average value of 6 capsules, the shortest time and the longest time. The minimum and maximum times are shown in parentheses.

As shown in Table 2, even when stored at 40° C. for one month, there was no noticeable increase in the disintegration time of the soft capsules, and there was no change in disintegration properties.

(Measurement of survival rate)
The soft capsule containing Compound A of Example 1 was stored at 40° C. for one month, and the residual rate of the active ingredient before and after storage was compared. The test was performed independently three times using the method described below, and the average value of the three tests was calculated as the residual rate of the active ingredient. The residual rate (%) was calculated by setting the quantitative value at the time when storage of the soft capsule was started ("starting time") as 100%.

(1) Preparation of sample solution One soft capsule was taken, exactly 2 mL of purified water was added thereto, and the mixture was stirred for 1 hour. Ethanol (99.5%) was added to make exactly 20 mL. The solution was filtered to obtain a sample solution.
(2) Preparation of standard solution Approximately 30 mg of Compound A was accurately weighed, and ethanol (99.5%) was added to make exactly 100 mL. 2 mL of this liquid was accurately measured and ethanol (99.5%) was added to make exactly 50 mL. 5 mL of this solution was accurately weighed, ethanol (99.5%) was added to make 20 mL, and this was used as a standard solution.
(3) Quantitative method 20 μL of each of the sample solution and standard solution was subjected to a quantitative test of the active ingredient by liquid chromatography under the following conditions.
<Test conditions>
- Detector: Mass spectrometer - Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 150 mm was filled with 5 μm octadecysilyl silica gel for liquid chromatography.
・Column temperature: constant temperature around 20°C ・Mobile phase A: 10mM ammonium acetate solution ・Mobile phase B: acetonitrile ・Flow rate: 1.0 mL per minute

Table 3 shows the residual rate (%) of Compound A in the soft capsules of Example 1 at the start of storage and after one month. The residual rate (%) was calculated by setting the quantitative value at the time when storage of the soft capsule was started ("starting time") as 100%. Table 3 shows the residual rate (%) of Compound A in the soft capsules of Example 1 at the start of storage and one month later.

As shown in Table 3, there was no change in the residual rate of Compound A in the soft capsule of Example 1 even after storage at 40°C for one month.

Example 2
(Manufacture of soft capsules containing compound A)
Table 4 shows the formulation (amount of ingredients per capsule) of the soft capsule of Example 2. In the table, the mass of purified water is not included in the total. Note that the succinated gelatin used in Example 2 is derived from bovine and has a jelly strength of 150 to 170 g. Also, the gelatin is of bovine origin and has a jelly strength of 135-165g. Further, in Example 2, the mass of sucrose was 100 parts by mass with respect to 100 parts by mass of the total amount of gelatin and succinated gelatin. Moreover, the mass ratio of gelatin and succinated gelatin was 20:80.
The soft capsule of Example 2 was prepared by adding an appropriate amount of water to the amount of sucrose shown in Table 4, stirring and heating. Separately, a solution was prepared by adding an appropriate amount of water to succinated gelatin and gelatin, stirring and heating, and adding an aqueous solution of sucrose to obtain a gelatin solution. A coating solution was obtained by adding a titanium oxide solution dispersed in water to a gelatin solution. Compound A is dissolved in medium chain fatty acid triglyceride to obtain a solution. Soft capsules were obtained using a capsule forming and filling machine.

(Hardness test and disintegration test)
Hardness tests and disintegration tests were performed on the soft capsules at the start of storage and after storage for one month at 40°C. Each test was conducted in the same manner as for the soft capsule formulation of Example 1.
The results of the hardness test and disintegration test are shown in Table 5. "Starting time" in the table indicates the results at the time when storage of the soft capsules started. In the hardness test, the upper limit of measurement by the hardness tester was 392N, and the soft capsule could not be broken at the upper limit of 392N. The disintegration time is the average value of 6 capsules, the shortest time and the longest time.

As shown in Table 5, it had good hardness as a soft capsule before and after storage. In addition, it had good disintegration properties as a soft capsule before and after storage.

(Measurement of survival rate)
The soft capsule containing Compound A of Example 2 was stored at 40° C. for one month, and the residual rate of the active ingredient before and after storage was compared. The test was conducted independently three times in the same manner as the soft capsule formulation of Example 1, and the average value of the three tests was calculated as the residual rate of the active ingredient. The residual rate (%) was calculated by setting the quantitative value at the time when storage of the soft capsule was started ("starting time") as 100%. Table 6 shows the residual rate (%) of Compound A in the soft capsules of Example 2 at the start of storage and after one month.

As shown in Table 6, there was no change in the residual rate of Compound A in the soft capsule of Example 2 even after storage at 40°C for one month.

Example 3
(Manufacture of soft capsules containing compound A)
Soft capsules containing Compound A were manufactured so as to have the formulation shown in Table 7.
An appropriate amount of water was added to sucrose, stirred and heated to obtain a sucrose solution. An appropriate amount of water was added to the succinated gelatin, stirred and heated, a sucrose solution was added, and a suspension of titanium oxide and Yellow No. 5 was added to obtain a coating solution. Compound A was dissolved in medium chain fatty acid triglyceride to obtain a content liquid. The film solution and the content liquid were punched out using a rotary die-type soft capsule forming and filling machine, and the content liquid was encapsulated in the film and dried to obtain a soft capsule.

(shape, weight, moisture)
The major axis, minor axis, and film weight of 10 soft capsules were measured. Moisture content was measured using an infrared moisture meter (manufactured by Kett Co., Ltd., FD-660) under conditions of 0.5 g of sample, 110° C., and 120 minutes.

(Hardness test and disintegration test)
A hardness test and a disintegration test were measured in the same manner as in Example 2.

(Measurement of compound A content)
Compound A content was measured in the same manner as in Example 2.

Reference example 1
(Manufacture of soft capsule film)
An appropriate amount of water was added to 60 parts by mass of sucrose, stirred and heated to obtain a sucrose solution. An appropriate amount of water was added to 100 parts by mass of succinated gelatin and 10 parts by mass of povidone, stirred and heated, and a sucrose solution was added and degassed to obtain a coating solution. This coating solution was rolled out into a plate shape with a thickness of 1 mm to obtain a coating sheet.

The film sheet did not crack, was not too soft, and was sufficiently usable as a film.

Reference examples 2 to 5
An appropriate amount of water was added to 50 parts by mass of the sugars shown in Table 11, and the mixture was stirred and heated to obtain a sugar solution. An appropriate amount of water was added to 100 parts by mass of succinated gelatin, stirred and heated, and a sugar solution was added and degassed to obtain a coating solution. This coating solution was rolled out into a plate shape with a thickness of 1 mm to obtain a coating sheet, which was maintained at a temperature of 40° C. for one week. Table 11 shows the results.

The film using sucrose as a plasticizer used in the present invention could be used as a film for soft capsules. On the other hand, trehalose and lactose, which are disaccharides, and glucose, which is a monosaccharide, have problems such as insufficient sheets and coloring, and are not sufficient as a film for soft capsules.

Reference examples 6 to 10
An appropriate amount of water was added to sucrose and povidone according to the blending ratio in Table 12, and the mixture was stirred and heated to obtain a sugar solution. An appropriate amount of water was added to the succinated gelatin, stirred and heated, and a sugar solution was added and degassed to obtain a coating solution. This coating solution was rolled out into a plate shape with a thickness of 1 mm to obtain a coating sheet. The evaluation results are shown in Table 13. The disintegration time here is the time during which a section of the film dissolves.

Plasticity of the film sheet and the presence of precipitates were not confirmed, and the disintegration time in the stability test was 7 minutes or less, which was a sufficient disintegration time and could be used as a film for soft capsules.

Claims (16)

A soft capsule filled with a liquid containing a lipophilic drug, the capsule film comprising sucrose and a gelling agent. Lipophilic drugs include vitamin D derivatives consisting of eldecalcitol, calcitriol and alphacalcidol, prostaglandin E2, dinoprostone, alphaprostadil, latanoprost and 7-[(2R,4aR,5R,7aR)-2-(1 , cyclosporin, and menatetrenone, The soft capsule according to claim 1. The lipophilic drug is 2. The soft capsule according to claim 1, wherein the soft capsule is a polyheptanoic acid). The soft capsule according to claim 3, wherein the gelling agent is one or two selected from gelatin and succinated gelatin. The soft capsule according to claim 3, wherein the content of sucrose in the capsule film is 30 to 100 parts by mass based on 100 parts by mass of the gelling agent. The soft capsule according to claim 3, wherein the content of sucrose in the capsule film is 40 to 60 parts by mass based on 100 parts by mass of the gelling agent. The soft capsule according to claim 3, wherein the content of the lipophilic drug in the capsule is 0.01 to 10,000 μg. The soft capsule according to claim 3, wherein the content liquid containing the lipophilic drug contains the lipophilic drug and saturated fatty acid triglyceride. The soft capsule according to claim 8, wherein the saturated fatty acid is capric acid and/or caprylic acid. The soft capsule according to claim 3, wherein the ratio of the capsule film to the content liquid is 20 to 200 parts by weight of the content liquid per 100 parts by weight of the capsule. The soft capsule according to claim 3, having a soft capsule strength of 200N or more. The soft capsule according to claim 3, which has a disintegration time of 20 minutes or less after being kept at 40°C for one month. The soft capsule according to claim 3, wherein the soft capsule film further contains a plasticizer. The soft capsule according to claim 13, wherein the plasticizer is one or more selected from sucrose fatty acid ester, povidone, crospovidone, and vinyl acetate/vinylpyrrolidone copolymer. The soft capsule according to claim 13, wherein the content of the plasticizer is 1 to 100 parts by mass based on 100 parts by mass of the gelling agent. A soft capsule formed by filling a capsule film containing sucrose and a gelling agent with a liquid content containing a lipophilic drug by a punching method.