Soft capsule containing lubiprostone and method for producing same

Abstract

To provide a lubiprostone-containing gelatin agent having a coat of a novel composition and a method for producing the same.SOLUTION: A gelatin agent has a gelatin coat containing a gelator and trehalose, the gelatin coat filled with a content liquid containing lubiprostone and a solvent.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a soft capsule formulation containing lubiprostone as an active ingredient in a soft capsule shell containing trehalose, and a method for producing the same. [Background technology]

[0002] Lubiprostone is a compound represented by the following formula (I), and its chemical name is 7-[(2R, 4aR, 5R, 7aR)-2-(1, 1-difluoropentan-1-yl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl]heptanoic acid. Lubiprostone promotes intestinal fluid secretion and is used to treat chronic constipation. Currently, lubiprostone is commercially available in the form of soft capsules.

[0003] [ka]

[0004] In the manufacture of soft capsules, a plasticizer is generally added to the base of the soft capsule shell (hereinafter simply referred to as the "shell") to impart plasticity to the shell. Glycerin and sugar alcohols are often used as plasticizers. For example, Patent Document 1 describes a soft capsule in which a lubiprostone solution is filled in a shell containing a sugar alcohol liquid derived from corn starch. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 4783794 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a lubiprostone-containing soft capsule having a coating film with a novel composition. [Means for solving the problem]

[0007] The present inventors have newly found that trehalose can be used as a plasticizer in the coating of a lubiprostone-containing soft capsule. Furthermore, the present inventors have found that a lubiprostone-containing soft capsule having a coating containing trehalose has good hardness and disintegrability, and have completed the present invention.

[0008] Therefore, the present invention provides a soft capsule in which a content liquid containing lubiprostone and a solvent is filled in a soft capsule shell containing a gelling agent and trehalose. The present invention also provides a method for producing a soft capsule, the method including a step of filling a content liquid containing lubiprostone and a solvent in a soft capsule shell containing a gelling agent and trehalose. Effect of the Invention

[0009] According to the present invention, there are provided a lubiprostone-containing soft capsule having good hardness and disintegrability, and a method for producing the same. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In this specification, the term "lubiprostone" includes the compound represented by the above formula (I), as well as its pharma- ceutically acceptable salts and solvates thereof. The pharma- ceutically acceptable salts of lubiprostone refer to salts formed from the compound represented by the above formula (I) and an organic or inorganic base, which are acceptable for administration to mammals, including humans. Examples of pharma- ceutically acceptable salts of lubiprostone include alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium salts, amine salts (methylamine salt, dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidine salt, ethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino)ethane salt, monomethyl-monoethanolamine salt, procaine salt, caffeine salt, etc.), basic amino acid salts (arginine salt, lysine salt, etc.), and tetraalkylammonium salts.

[0011] The pharma- ceutically acceptable solvate of lubiprostone or a pharma- ceutically acceptable salt thereof refers to a solid molecule formed from the compound represented by the above formula (I) or a pharma- ceutically acceptable salt thereof and a solvent that is acceptable for administration to mammals, including humans, such as ethanol.

[0012] The soft capsule of the present embodiment is filled with a liquid content containing lubiprostone and a solvent. The content of lubiprostone per capsule is, for example, 1 μg to 100 μg, preferably 5 μg to 50 μg, more preferably 12 μg or 24 μg.

[0013] The solvent is not particularly limited as long as it is a medium capable of dissolving or dispersing lubiprostone. Such a solvent can be appropriately selected from aqueous and non-aqueous media used in the content liquid of soft capsules. Examples of aqueous media include ethanol. Examples of non-aqueous media include fatty acid triglycerides, vegetable and animal fats and oils, waxes, hardened oils, mineral oils, and the like. It is preferable that the solvent is selected from non-aqueous media. Examples of fatty acid triglycerides include triglycerides of medium- or long-chain (e.g., carbon number 6 to 24) saturated fatty acids. Examples of vegetable and animal fats and oils include olive oil, sesame oil, wheat germ oil, safflower oil, perilla oil, soybean oil, camellia oil, corn oil, peppermint oil, castor oil, cottonseed oil, coconut oil, peanut oil, fish oil, egg yolk oil, beef tallow, lard, and the like. Examples of waxes and waxes include beeswax, carnauba wax, lanolin, and the like. The hardened oil may be hydrogenated oils such as hydrogenated hardened castor oil. The mineral oil may be liquid paraffin, paraffin, etc. In a preferred embodiment, the solvent is a medium chain triglyceride. The solvent may be one type or a combination of two or more types.

[0014] The liquid content containing lubiprostone and a solvent can be obtained by mixing lubiprostone with the solvent in a conventional manner to dissolve or disperse lubiprostone in the solvent.

[0015] In the soft capsule of this embodiment, the shell contains a gelling agent and trehalose. The gelling agent may be a polymeric compound having sol-gel transition ability and being pharma- ceutically acceptable. Examples of such gelling agents include gelatin, carrageenan, agar, sodium alginate, pullulan, glucomannan, and the like. Among them, gelatin is particularly preferred. The origin of gelatin is not particularly limited, and gelatin obtained from bones, cartilage, tendons, skins, and the like of animals such as cows, pigs, chickens, and salmon can be used. The gelling agent may be one type or a combination of two or more types.

[0016] In this embodiment, in addition to or instead of gelatin, a gelatin hydrolysate, an enzymatic decomposition product of gelatin, a modified gelatin, etc. may be used. Examples of modified gelatin include succinated gelatin and phthalated gelatin. Among them, succinated gelatin is particularly preferred.

[0017] In this embodiment, when gelatin and / or succinated gelatin is used as the gelling agent, the jelly strength is preferably 150 to 280 g.

[0018] In a preferred embodiment, the gelling agent contains gelatin and / or succinated gelatin. The mass ratio of gelatin to succinated gelatin in the gelling agent (gelatin: succinated gelatin) is usually 100:0 to 20:80, and preferably 90:10 to 20:80.

[0019] As described above, trehalose is added as a plasticizer to the shell of the soft capsule of this embodiment. The content of trehalose in the shell is not particularly limited, but for example, the shell may contain trehalose in a ratio of 5 parts by mass to 50 parts by mass, preferably 10 parts by mass to 45 parts by mass, per 100 parts by mass of the gelling agent. In this specification, the term "trehalose" includes trehalose and its hydrates.

[0020] If necessary, the shell of the soft capsule of the present embodiment may contain additives that are commonly used in soft capsule shells, such as colorants such as titanium oxide and Yellow No. 5, preservatives such as paraben, sweeteners, and flavors.

[0021] In this embodiment, it is preferable that the shell of the soft capsule does not substantially contain sugar alcohol. Here, "substantially does not contain" means that the shell contains only a small amount of sugar alcohol, even if any, and sugar alcohol is not actively added. Examples of cases in which a small amount of sugar alcohol is contained include cases in which it is mixed in as an impurity in a small amount, and cases in which a small amount is generated by some chemical reaction or decomposition of a contained component. Examples of sugar alcohol include sugar alcohol solution derived from corn starch, sorbitol, mannitol, maltitol, sorbitan, etc.

[0022] In this embodiment, the soft capsule preferably has a hardness of 200 N or more in the hardness test described below. In addition, in this embodiment, the soft capsule preferably disintegrates within 20 minutes in the disintegration test described below.

[0023] In this embodiment, the shape of the soft capsule is not particularly limited, and examples thereof include a spherical (round), oval, oblong, tube, and suppository shape.

[0024] The soft capsule of the present embodiment can be produced by filling a content liquid containing lubiprostone and a solvent into a soft capsule shell containing a gelling agent and trehalose. Specifically, the process is as follows. First, lubiprostone and a solvent are mixed to prepare a content liquid. Also, a gelling agent and trehalose are mixed while being heated to obtain a shell solution. Trehalose may be dissolved in purified water in advance to obtain an aqueous trehalose solution. If necessary, an additive such as a colorant may be added to the aqueous trehalose solution or the shell solution. The obtained content liquid and shell solution are then fed to a rotary or seamless filling machine to form and fill a soft capsule, thereby obtaining the soft capsule of the present embodiment.

[0025] In the rotary filling machine, the coating solution is cooled and gelled to form a sheet, and the liquid content is filled between the two formed coating sheets, while the coating sheets are sandwiched between a pair of die rolls to press and punch out, forming a soft capsule filled with the liquid content. In the seamless filling machine, the coating solution is poured out from the outside of a concentric double nozzle, and the liquid content is simultaneously poured out from the inside, and the nozzle is vibrated by a pulsator to cut off the outflowing liquid, thereby forming a soft capsule filled with the liquid content. In a preferred embodiment, the liquid content is filled into the coating by the rotary filling machine. The formed soft capsule may be packaged by PTP packaging, bottle filling, aluminum packaging, etc.

[0026] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. EXAMPLES

[0027] [Example 1] 1. Manufacture of lubiprostone-containing soft capsules Table 1 shows the formulation of the soft capsule of Example 1 (amount of ingredients per capsule). In the table, the weight of purified water is not included in the total. The gelatin used in Example 1 is derived from bovine and has a jelly strength of 230 to 280 g. In Example 1, the mass of trehalose hydrate per 100 parts by mass of gelatin, which is a gelling agent, is 40 parts by mass.

[0028] [Table 1]

[0029] The soft capsule of Example 1 was produced as follows. Lubiprostone was added to the medium-chain fatty acid triglyceride and dissolved to obtain a content liquid. Purified water was added to a gelatin degassing tank, and trehalose was added and dissolved. A liquid in which titanium oxide and Yellow No. 5 were dispersed in purified water was added while sieving and mixed. Gelatin was added and dissolved. After dissolution, the viscosity was adjusted by degassing and adding water as necessary. The obtained solution was sieved to obtain a solution of the soft capsule shell. The content liquid and the solution of the soft capsule shell were fed to a rotary filling machine, and the soft capsules were formed and filled to form soft capsules. The filling was carried out while applying medium-chain fatty acid triglyceride as a mold release agent to the surface of the formed shell. The medium-chain fatty acid triglyceride applied to the surface of the formed soft capsule was wiped off and tumble dried. Furthermore, the soft capsule was shelf-dried using a drying plate to obtain the soft capsule of Example 1.

[0030] 2.Hardness test and disintegration test The hardness test and disintegration test were performed on the soft capsules after one month of storage under 40°C 75% RH conditions and at the start of storage. The hardness was measured by crushing the major axis of the soft capsules using a Kiya hardness tester. The hardness test was performed on 10 capsules for Example 1. The disintegration test was performed according to Section 1 of "Disintegration Test Method 2.1 Immediate Release Preparations" of the Japanese Pharmacopoeia. Using water as the test liquid, the tester was operated at 37±2°C to measure the disintegration time of the soft capsules. The disintegration time refers to the time until the release of the content liquid into the test liquid is completed. The disintegration test was performed on 6 capsules for Example 1.

[0031] The results of the hardness test and disintegration test are shown in Table 2. In the table, "Start time" indicates the result at the start of storage of each soft capsule. In the table, the average value and standard deviation of 10 capsules for hardness are shown. The standard deviation value is shown in parentheses. In addition, the average value, shortest time, and longest time for disintegration time of 6 capsules are shown. The shortest time and longest time are shown in parentheses.

[0032] [Table 2]

[0033] As shown in Table 2, the soft capsule of Example 1 had good hardness as a soft capsule formulation before and after storage. Regarding the disintegration time, the soft capsule of Example 1 disintegrated within 15 minutes before and after storage, and had good disintegration property as a soft capsule formulation.

[0034] 3. Measurement of the remaining rate (3.1) Remaining rate of active ingredient after one month The lubiprostone-containing soft capsule preparation of Example 1 was stored for one month under conditions of 40°C and 75% RH, and the remaining rate of the active ingredient before and after storage was compared. The test was carried out three times independently by the following methods (1) to (3), and the remaining rate of the active ingredient was calculated as the average value of the three tests.

[0035] (1) Preparation of sample solution Ten soft capsules of Example 1 were used as samples. Ten samples were mixed with a water / acetonitrile mixture (1:1) (hereinafter referred to as a dissolving agent) to make exactly 100 mL. This liquid was centrifuged, and 2.5 mL of the supernatant was taken exactly, and a dissolving agent was added to make exactly 50 mL. 5 mL of this liquid was taken exactly, and a dissolving agent was added to make exactly 50 mL, and then the liquid was filtered to obtain a sample solution.

[0036] (2) Preparation of standard solutions Approximately 24 mg of lubiprostone was weighed out accurately, and a solubilizing agent was added to make exactly 100 mL. 2 mL of this solution was accurately weighed out, and a solubilizing agent was added to make exactly 100 mL. 2 mL of this solution was accurately weighed out, and a solubilizing agent was added to make exactly 100 mL. 2.5 mL of this solution was accurately weighed out, and a solubilizing agent was added to make exactly 20 mL, to create the standard solution.

[0037] (3) Quantitative method Quantitative testing of the active ingredient was performed using 10 μL of each of the sample solution and standard solution by liquid chromatography under the following conditions.

[0038] <Test conditions> Detector: Mass spectrometer Column: A stainless steel tube with an inner diameter of 2.1 mm and a length of 5 cm was packed with 1.8 μm octadecylsilylated silica gel for liquid chromatography. Column temperature: constant temperature around 25℃ Mobile phase A: Formic acid solution (1 → 1000) Mobile phase B: Acetonitrile ·Flow rate: 0.3mL per minute

[0039] Table 3 shows the remaining rate (%) of lubiprostone in the soft capsule of Example 1 at the start of storage and after one month. The remaining rate (%) was calculated by setting the quantitative value at the start of storage of the soft capsule ("start time") as 100%.

[0040] [Table 3]

[0041] As shown in Table 3, even after storage for one month under conditions of 40° C. and 75% RH, there was no change in the residual rate of lubiprostone in the soft capsule preparation of Example 1.

[0042] (3.2) Residual rate of active ingredient after 6 months The lubiprostone-containing soft capsule of Example 1 was stored for 6 months under conditions of 40°C and 75% RH, and the remaining rate of the active ingredient before and after storage was compared. The test was performed three times independently using the above methods (1) to (3), and the average value of the three tests was calculated as the remaining rate of the active ingredient. Table 4 shows the remaining rate (%) of lubiprostone in the soft capsule of Example 1 at the start of storage and after 6 months. The remaining rate (%) was calculated by setting the quantitative value at the start of storage of the soft capsule ("start time") as 100%.

[0043] [Table 4]

[0044] As shown in Table 4, even after storage for 6 months under conditions of 40° C. and 75% RH, the residual rate of lubiprostone in the soft capsule preparation of Example 1 hardly changed.

[0045] [Example 2] 1. Manufacture of lubiprostone-containing soft capsules Table 5 shows the formulation of the soft capsule of Example 2 (amount of ingredients per capsule). In the table, the weight of purified water is not included in the total. In Example 2, the gelatin is derived from bovine and has a jelly strength of 230 to 280 g. The succinated gelatin is derived from bovine and has a jelly strength of 150 to 170 g. In Example 2, the mass of trehalose hydrate is 40 parts by mass relative to 100 parts by mass of the total amount of gelatin and succinated gelatin, which are gelling agents. The mass ratio of gelatin to succinated gelatin is 20:80.

[0046] [Table 5]

[0047] The soft capsule of Example 2 was produced as follows. Lubiprostone was added to the medium-chain fatty acid triglyceride and dissolved to obtain a content liquid. Purified water was added to a gelatin degassing tank, and trehalose was added and dissolved. A liquid in which titanium oxide and Yellow No. 5 were dispersed in purified water was added while sieving and mixed. Gelatin and succinated gelatin were added and dissolved. After dissolution, the viscosity was adjusted by degassing and adding water as necessary. The obtained solution was sieved to obtain a solution of the soft capsule shell. The content liquid and the solution of the soft capsule shell were fed to a rotary filling machine, and the soft capsules were formed and filled to form soft capsules. The filling was carried out while applying medium-chain fatty acid triglyceride as a mold release agent to the surface of the formed shell. The medium-chain fatty acid triglyceride applied to the surface of the formed soft capsule was wiped off and tumble dried. Furthermore, the soft capsule was shelf-dried using a drying plate to obtain the soft capsule of Example 2.

[0048] 2.Hardness test and disintegration test For the soft capsules of Example 2, hardness tests and disintegration tests were conducted at the start of storage and after storage for 1 month and 6 months under conditions of 40°C and 75% RH. Each test was conducted in the same manner as for the soft capsules of Example 1. The results at the start of storage are shown in Table 6, and the results after storage for 1 month and 6 months are shown in Table 7. In the table, the average value and standard deviation of 10 capsules for hardness are shown. The standard deviation value is shown in parentheses. In addition, the average value, the shortest time, and the longest time for disintegration time of 6 capsules are shown. The shortest time and the longest time are shown in parentheses.

[0049] [Table 6]

[0050] [Table 7]

[0051] As shown in Table 6, the soft capsule of Example 2 at the start of storage had good hardness as a soft capsule formulation. As for the disintegration time, the soft capsule of Example 2 at the start of storage disintegrated in about 10 minutes, and had good disintegration properties as a soft capsule formulation. As shown in Table 7, the soft capsule of Example 2 stored for 1 month or 6 months also had good hardness as a soft capsule formulation. As for the disintegration time, the soft capsule of Example 2 stored for 1 month or 6 months disintegrated in about 10 minutes, and had good disintegration properties as a soft capsule formulation.

[0052] 3. Measurement of remaining rate The lubiprostone-containing soft capsule of Example 2 was stored under conditions of 40°C and 75% RH for 1 month and 6 months, and the remaining rate of the active ingredient before and after storage was compared. The test was performed three times independently in the same manner as for the soft capsule of Example 1, and the average value of the three tests was calculated as the remaining rate of the active ingredient. Table 8 shows the remaining rate (%) of lubiprostone in the soft capsule of Example 2 at the start of storage, after 1 month, and after 6 months. The remaining rate (%) was calculated by setting the quantitative value at the start of storage of the soft capsule ("start time") as 100%.

[0053] [Table 8]

[0054] As shown in Table 8, even after storage under conditions of 40° C. and 75% RH for 1 month or 6 months, the residual rate of lubiprostone in the soft capsule preparation of Example 2 hardly changed.

Claims

1. A soft capsule comprising a soft capsule shell containing a gelling agent and trehalose, and a liquid content containing lubiprostone and a solvent, the soft capsule shell being substantially free of sugar alcohol.

2. 2. The soft capsule according to claim 1, wherein the soft capsule shell contains trehalose in a ratio of 5 parts by mass to 50 parts by mass to 100 parts by mass of the gelling agent.

3. The soft capsule according to claim 1 or 2, wherein the gelling agent comprises gelatin and / or succinylated gelatin.

4. The soft capsule according to claim 3, wherein the gelling agent comprises gelatin and succinated gelatin in a mass ratio of 100:0 to 20:

80.

5. The soft capsule according to any one of claims 1 to 4, wherein the solvent is a medium-chain fatty acid triglyceride.

6. A method for producing a soft capsule, comprising the step of filling a content liquid containing lubiprostone and a solvent into a soft capsule shell containing a gelling agent and trehalose, wherein the soft capsule shell is substantially free of sugar alcohol.

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