WO2015045037A1

WO2015045037A1 - Capsule preparation

Info

Publication number: WO2015045037A1
Application number: PCT/JP2013/075926
Authority: WO
Inventors: 秋山　英郎
Original assignee: テムリック株式会社
Priority date: 2013-09-25
Filing date: 2013-09-25
Publication date: 2015-04-02

Abstract

This capsule preparation is such that a filling liquid, which contains tamibarotene and a propylene glycol monocaprylate ester, is coated by a coating film component.

Description

Capsule formulation

The present invention relates to a capsule preparation containing tamibarotene.

Retinoic acid (vitamin A acid) is a substance having physiological functions that are extremely important for life-supporting action, such as differentiating developing immature cells into mature cells having a specific function, or promoting cell proliferation. It is. Clinically, retinoic acid has been found useful for the treatment of vitamin A deficiency, epithelial keratosis, leukemia and certain cancers.
Drugs using such physiological functions of retinoids have been developed. One of these is tamibarotene, which is known as a therapeutic agent for cancers such as leukemia (for example, JP-A-7-17584).

On the other hand, taking into consideration the improvement of in-vivo absorbability and bioavailability of drugs, storage stability, and the like, drug dosage forms may be used as capsule preparations. Capsule preparations are filled with glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, propylene glycol fatty acid ester, ethylene glycol fatty acid ester, decaglycerin fatty acid ester, etc. in order to dissolve a poorly soluble drug in water and fill the capsule. It has been proposed to use it as a liquid base (for example, JP-A-5-25037).
Tamibarotene is also known to be excellent in stability and easy to take by making into a capsule formulation. For example, WO 2008/056073 pamphlet contains propylene glycol monooleate as a filling liquid. A capsule formulation based on the above is disclosed.

However, when a highly versatile propylene glycol monooleate is used as a base of a filling liquid for a tamibarotene capsule preparation, the stability over time of the capsule preparation may not be sufficient.
Accordingly, an object of the present invention is to provide a capsule preparation containing tamibarotene and having excellent stability over time.

The present invention is as follows.
[1] A capsule preparation in which a filling liquid containing tamibarotene and propylene glycol monocaprylate is coated with a coating component.
[2] The capsule preparation according to [1], wherein the filling liquid contains 0.1% by mass to 10.0% by mass of tamibarotene.
[3] The capsule formulation according to [1], wherein the filling liquid contains 0.1% by mass to 8.0% by mass of tamibarotene.
[4] The capsule preparation according to any one of [1] to [3], containing 0.1 mg to 10 mg of tamibarotene.
[5] The capsule preparation according to any one of [1] to [4] for the treatment of blood cancer or solid cancer.

According to the present invention, it is possible to provide a capsule preparation containing tamibarotene and having excellent temporal stability.

The capsule formulation of the present invention is a capsule formulation in which a filling liquid containing tamibarotene and propylene glycol monocaprylate is coated with a coating component.
According to the knowledge of the inventor of the present invention, when tamibarotene is combined with propylene glycol monooleate, which is widely used as a base in capsule formulations of poorly water-soluble drugs, the stability over time of the capsule formulation is impaired. It was found that there is a case.
In the present invention, the use of propylene glycol monocaprylate as a base of a tamibarotene capsule preparation can improve the stability over time of the capsule preparation.
In this specification, the term “process” is not limited to an independent process, and is included in the term if the intended purpose of the process is achieved even when it cannot be clearly distinguished from other processes. .
In the present specification, a numerical range indicated by using “to” indicates a range including the numerical values described before and after that as the minimum value and the maximum value, respectively.
Furthermore, in this specification, the amount of each component in the composition is the total amount of the plurality of substances present in the composition unless there is a specific indication when there are a plurality of substances corresponding to each component in the composition. means.
The present invention will be described below.

[Filling liquid]
Tamibarotene which is an active ingredient of the present invention is 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid. As tamibarotene, either a crystal obtained by normal production or a crystalline powder can be used. Examples of the method for producing tamibarotene include the methods described in Japanese Patent No. 3001632, Japanese Patent Laid-Open No. 61-76440, and WO2002 / 018322.

The filling liquid preferably contains tamibarotene in a content (mass ratio) of 0.1% by mass to 10.0% by mass. If it is 0.1% by mass or more, the number of capsule preparations for taking a desired amount of tamibarotene is not excessively increased, and if it is 10.0% by mass or less, the solubility of tamibarotene is improved. There is a tendency to maintain. The content of tamibarotene in the filling liquid is more preferably 0.1% by mass to 8.0% by mass from the viewpoint of stability over time of the capsule preparation.

Further, the content per volume of the tamibarotene filling liquid can be 1 mg / mL to 100 mg / mL, preferably 1 mg / mL to 80 mg / mL. If Tamibarotene is 1 mg / mL or more, the effect of Tamibarotene tends to be sufficiently obtained, and if it is 100 mg / mL or less, good solubility tends to be obtained.

The filling liquid contains propylene glycol monocaprylate (propylene glycol monooctanoate) as a base. Thereby, the temporal stability of the capsule preparation containing tamibarotene becomes good. In addition, a capsule preparation containing a higher concentration of tamibarotene can be provided under normal conditions.
The propylene glycol monocaprylate used as the base is preferably a grade approved for use as a pharmaceutical additive.

The filling liquid may contain an oily base other than propylene glycol monocaprylate from the viewpoint of imparting desired properties to the capsule preparation, such as dissolution of a poorly soluble drug in water.

Examples of the other oily bases include propylene glycol fatty acid esters other than propylene glycol monocaprylate, sucrose fatty acid esters, sorbitan fatty acid esters, fatty acid triglycerides, polyethylene glycols, animal and vegetable oils, and surfactants. These can be used alone or in combination of two or more.

Examples of the propylene glycol fatty acid ester include monooleic acid ester and di (capryl, capric acid) ester. Specifically, Riquemar PO-100V (propylene glycol monooleate, manufactured by Riken Vitamin Co., Ltd.), Sunsoft No. 25-ODV (manufactured by Taiyo Chemical Co., Ltd.), NIKKOL Sefsol-228 (Nikko Chemicals Co., Ltd.), NIKKOL Sefsol PDD (Nikko Chemicals Co., Ltd.) and the like.

Examples of the fatty acid triglycerides include C8-C12 medium chain fatty acid triglycerides. Specifically, 1-capryloyl-2,3-dilauroyl glyceride, trinonanoyl glyceride, tricaproyl glyceride, 1-lauroyl-2,3-dicaproyl glyceride, 2-lauroyl-1,3-dicapro Ilyl glyceride, 1-caproyl-2,3-dilauroyl glyceride, 2-caproyl-1,3-dilauroyl glyceride, trilauroyl glyceride and the like can be mentioned.

Examples of the polyethylene glycol (PEG) include polyethylene glycol and methoxy polyethylene glycol. The average molecular weight of the polyethylene glycols is preferably 200 to 1540. Specific examples of polyethylene glycols include polyethylene glycol (macrogol) 200, 300, 400, 600, 1000, 1500, and 1540 described in the Japanese Pharmacopoeia and the Japanese Pharmacopoeia Pharmaceutical Component Standards. .
Among these, from the viewpoint of absorbability after oral administration, PEG-200 (freezing point-50 ° C.), PEG-300 (freezing point-13 ° C.), PEG-400 (freezing point 7 ° C.), PEG-600 (freezing point 20 ° C.) and Five types of PEG-1000 (freezing point: 37 ° C.) are preferable, and those having a mean molecular weight of 300 PEG-300, 400 PEG-400, and 600 PEG-600 at room temperature are preferable.

Examples of the sucrose fatty acid ester include esters of fatty acids having 12 to 20 carbon atoms and sucrose.
Examples of the sorbitan fatty acid ester include esters of fatty acids having 12 to 20 carbon atoms and sorbitan.
Examples of the animal and vegetable oils include olive oil, sunflower seed oil, soybean oil, corn oil, fennel oil, sesame oil, safflower oil, wheat germ oil, perilla oil, camellia oil, and whale oil.
Examples of the surfactant include polyoxyethylene hydrogenated castor oil and polysorbate. In addition, a base having a low molecular weight may be used.

The filling liquid may contain a base having a high melting point from the viewpoint of adjusting the viscosity of the oily base and the dispersibility of the drug. Examples of the high melting point base include wax, for example, beeswax, tree wax, whale wax, hydrogenated plant wax, and the like.

[Coating component]
The film component of the capsule preparation is not particularly limited as long as it is a component usually used in capsule preparations. As the base of the coating component, gelatin, agar, pullulan, cellulose, carrageenan and the like can be used alone or in combination.

The film component includes additives such as glycerin, sorbitol, mannitol, polyethylene glycol, maltitol, erythritol, xylitol, alginic acid, sodium alginate, and dextrin from the viewpoint of adjusting the strength, disintegration or release characteristics of the film. It may be included. If necessary, colorants such as caramel, β-carotene, tar dyes; preservatives such as methylparaben, ethylparaben, propylparaben; BHT, BHA, tocopherol, gallic acid, propyl gallate, ascorbic acid, ascorbic acid Antioxidants or stabilizers such as sodium and stearic esters of ascorbic acid; thickeners or dispersants such as fatty acid monoglycerides and beeswax; solubilizers and solubilizers such as ethanol, ethyl acetate and surfactants; One or more kinds can be added.

The coating component is preferably gelatin from the viewpoint of stability over time. When gelatin is contained as a coating component, the gelatin content can generally be 30% to 90% by mass, preferably 55% to 85% by mass, based on the total mass of the coating component.
Further, the coating component may contain glycerin, sorbitol, etc. in order to give elasticity to gelatin.

Gelatin may be acid-treated gelatin, alkali-treated gelatin, or chemically modified gelatin. Examples of the chemically modified gelatin include succinylated gelatin. As gelatin, succinylated gelatin is preferable because it is easily soluble and hardly causes a delay in disintegration.

The moisture content of the coating component is preferably 1% by mass to 20% by mass, more preferably 5% by mass to 15% by mass, and further preferably 7% by mass to 13% by mass.

[Shape of capsule preparation]
The shape of the capsule preparation of the present invention is not particularly limited, and is oval type (football type), oblong type (long oval type), round type (spherical type), acorn type, long eggplant type, triangular type. , Diamond type, tube type and the like. From the viewpoint of easy pinching and ease of swallowing, an oval type, an oblong type, or a round type is preferable.

The capsule preparation may be a soft capsule or a hard capsule, but is preferably a soft capsule in order to encapsulate a poorly soluble drug in water dissolved in an oil base.
For clinical application, for example, a capsule size having a major axis of about 5 mm to about 12 mm is preferable as a soft capsule, and a Japanese standard No. 1 to No. 4 capsule is preferable as a hard capsule.
Moreover, there is no restriction | limiting in particular about the quantity of tamibarotene contained in a capsule formulation. From the viewpoint of convenience of taking the capsule preparation, it is preferable that 0.1 mg to 10 mg of tamibarotene is contained in one capsule, and more preferably 0.1 mg to 8 mg.

[Production method]
The capsule preparation can be produced by blending each of the above components by a usual method. For example, it can be obtained as follows.
At room temperature, the tamibarotene drug substance is added to a propylene glycol monocaprylate ester or a mixed solution with other components as necessary, and the mixture is stirred and dissolved to prepare a filling solution.
On the other hand, the coating is formed into a desired shape by heating / dissolving a base such as gelatin and an additional component as necessary, if necessary. Moreover, after shaping | molding, it dries as needed.
Filling can be performed using a filling machine generally used according to the type of capsule. At the time of filling, the filling liquid is filled into the film formed into the desired shape by a filling machine.

When the capsule preparation is a soft capsule, for example, after forming a film into a sheet having a desired thickness, a filling machine is used to fill a certain amount of the above filling liquid into the capsule and dry it. Get the desired soft capsule.
When the capsule preparation is a hard capsule, after filling the capsule with a filling liquid, a gelatin-based solution is used to seal the joint between the capsule head and the body in a band shape. Get a hard capsule.
Thereby, the capsule formulation which coat | covered the filling liquid containing a tamibarotene with the film component is obtained.

[Usage]
The capsule preparation of the present invention is preferably used for an application according to the application application of tamibarotene, for example, for the treatment of blood cancer or solid cancer. Although it does not specifically limit as a hematological cancer and solid cancer, Specifically, hematological cancer, such as acute promyelocytic leukemia (APL), adult T cell leukemia (ATL), multiple myeloma (MM); liver cancer And solid cancers such as gastric cancer, breast cancer, esophageal cancer, prostate cancer, gynecological cancer, pancreatic cancer, lung cancer and colon cancer.

The present invention also includes a method for treating blood cancer or solid cancer. The treatment method includes administering (specifically, orally administering) the capsule preparation containing tamibarotene to a subject in need of treatment for blood cancer or solid cancer. The capsule preparation may be administered once or multiple times. One or more capsule preparations may be administered at one time.
When the capsule preparation as a therapeutic agent for blood cancer or solid cancer is used, the daily dose of tamibarotene is preferably 1 mg to 16 mg.

In the present invention, when the capsule preparation is used for the above-described uses, an amount of tamibarotene necessary for treatment per day may be included in one capsule preparation, and multiple administrations or multiple administrations may be performed at one time. As possible, a reduced amount of tamibarotene may be included in one capsule formulation.

Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to them. Unless otherwise specified, “%” and “part” are based on mass.

[Example 1]
(1) Insolubilization evaluation The insolubilization of capsule preparations by a combination of a base material for a filling liquid of capsule preparations and a film was examined.
Propylene glycol monocaprylate (NIKKOL Sefsol-218, Nikko Chemicals), propylene glycol monooleate (Riquemar PO-100V, Riken Vitamin), propylene glycol dicaprate (NIKKOL Sefsol PDD) , Nikko Chemicals Co., Ltd., and propylene glycol dicaprylate (NIKKOL Sefsol-228, Nikko Chemicals Co., Ltd.) Packing obtained by adding Tamibarotene to these polypropylene glycol fatty acid esters to a final concentration of 2% by mass A liquid and a filling liquid composed only of a polypropylene glycol fatty acid ester not containing tamibarotene were prepared as filling liquid samples.
As a coating, 100 parts of gelatin, 28 parts of concentrated glycerin and 200 parts of purified water were stirred and dissolved at room temperature (25 ° C.) to prepare a capsule coating solution.

The capsule coating solution 25 g was spread evenly on a stainless steel vat (about 15 cm × about 11 cm) and allowed to stand at room temperature to obtain a capsule skin sheet. From the obtained sheet, a circular sample having a diameter of 1 cm was punched out and dried in the drying chamber until the moisture content of the soft capsule (9% by mass or less) was obtained, thereby obtaining a test coating sample.

The obtained film sample was dipped in 5 g of each filling liquid sample in a glass standard bottle (10 mL), sealed, and stored in a thermostatic bath at 50 ° C. for 4 weeks. After the start of storage, capsule coating samples were taken out at 2 weeks and 4 weeks, the content components were wiped off, and a disintegration test was performed without an auxiliary board (n = 6).
In the disintegration test, a capsule film sample taken out from each filling liquid sample is subjected to a disintegration test at 37 ± 2 ° C. using a disintegration tester (NT-4H, Toyama Sangyo Co., Ltd.), and the film is completely dissolved. As the time of disintegration, the time from the start of the test to the disintegration was measured.
The results are shown in Table 1.

As shown in Table 1, in the filling liquid sample containing no tamibarotene, the disintegration time was extended in all the filling samples, and in the filling liquid sample containing 2% by mass of tamibarotene, other than propylene glycol monocaprylate ester In the filled sample containing, extended decay time was observed for all filled samples.
On the other hand, when a filling liquid sample containing propylene glycol monocaprylate as a propylene glycol fatty acid ester was used, an extension of the disintegration time due to the addition of tamibarotene was not specifically observed.

Moreover, in the filling liquid sample containing propylene glycol monooleate, insolubilization of the film occurred at 2 weeks after the start of the test, and insolubilized portions were observed in the film at all of the second and fourth weeks.
On the other hand, in the filling liquid sample containing propylene glycol monocaprylate, insolubilization of the film was not observed even after 4 weeks from the start of the test.

From these facts, it was suggested that propylene glycol monooleate, which is widely used in pharmaceuticals as a base for filling liquid, causes insolubilization of a coating based on gelatin when combined with tamibarotene. In contrast, when combined with tamibarotene, propylene glycol monocaprylate ester did not specifically cause insolubilization of the gelatin-based film, and showed good disintegration of the capsule preparation.

(2) Solubility Evaluation Next, the solubility of tamibarotene in propylene glycol monocaprylate, propylene glycol dicaprylate, and propylene glycol dicaprate was confirmed.
A predetermined concentration of tamibarotene was added to each propylene glycol fatty acid ester, and the mixture was allowed to stand for 4 hours while shaking at a temperature of 20 ° C. ± 5 ° C. to prepare a tamibarotene solution. Each tamibarotene solution was centrifuged and the supernatant was collected and analyzed using a high performance liquid chromatograph analyzer to quantify tamibarotene in each propylene glycol fatty acid ester.

As a result, the dissolution concentration of tamibarotene at 20 ° C. ± 5 ° C. was 6.3% by mass for propylene glycol monocaprylate, 0.8% by mass for propylene glycol dicaprylate, and propylene glycol dicaprate. It was 0.5 mass% with respect to the phosphonate ester.
Therefore, it was found that the solubility of tamibarotene at the specific temperature in propylene glycol monocaprylate was significantly higher than the solubility in propylene glycol dicaprylate and propylene glycol dicaprate.

From the results of insolubilization evaluation and solubility evaluation, when preparing a capsule preparation containing tamibarotene as an active ingredient, propylene glycol monocaprylate is used in terms of stability over time and the ability to formulate tamibarotene at a high concentration. It has been found that it is best to use the base of the filling liquid.

(3) Manufacture of capsule formulation 2 g of tamibarotene drug substance was added to 98 g of propylene glycol monocaprylate and dissolved uniformly while stirring to prepare a filling solution.
A coating solution was prepared by dissolving 80 g of gelatin, 20 g of concentrated glycerin, and an appropriate amount of purified water while stirring at 70 ° C., forming into a sheet, and drying to a moisture content of 9% by mass to obtain a coating.
The coating was loaded into a rotary capsule automatic filling machine (manufactured by Toyo Capsule Co., Ltd.), and the filling solution was filled so as to be equivalent to 100 mg per soft capsule to obtain a Tamibarotene capsule containing 2 mg Tamibarotene. Thereafter, PTP packaging was performed to obtain a product.

According to the present invention, it is possible to provide a tamibarotene-containing capsule preparation having excellent stability over time.

All documents, patent applications, and technical standards mentioned in this specification are to the same extent as if each individual document, patent application, and technical standard were specifically and individually described to be incorporated by reference, Incorporated herein by reference.

Claims

Capsule formulation in which a filling liquid containing tamibarotene and propylene glycol monocaprylate is coated with a coating component.
The capsule preparation according to claim 1, wherein the filling liquid contains 0.1% by mass to 10.0% by mass of tamibarotene.
The capsule preparation according to claim 1, wherein the filling liquid contains 0.1% by mass to 8.0% by mass of tamibarotene.
The capsule preparation according to any one of claims 1 to 3, which contains 0.1 mg to 10 mg of tamibarotene.
The capsule preparation according to any one of claims 1 to 4, for the treatment of blood cancer or solid cancer.