WO2014010008A1 - Capsule-filling composition of candesartan cilexetil - Google Patents

Description

Candesartan cilexetil capsule filling composition

The present invention relates to a capsule filling composition containing candesartan cilexetil as an active ingredient and having an increased elution rate of the active ingredient.

Candesartan cilexetil is an antihypertensive agent that exhibits angiotensin II (AII) receptor antagonism. Commercially available preparations are tablets for oral administration, but because candesartan cilexetil is extremely poorly soluble in water (solubility of less than 0.05 μg / ml), it has a low dissolution rate and thus low bioavailability.

In order to increase the dissolution rate and bioavailability, a solid preparation for oral administration containing this compound in a substantially amorphous form has been proposed. See Special Table 2010-502698 (Patent Document 1). Specifically, this compound is polyvinyl pyrrolidone (PVP), or this compound, PVP and nonionic surfactant are dissolved in ethanol, and then the formed component is granulated using this solution as a binder, and then compressed into tablets. Made up of. In this document, for the purpose of obtaining a solid dispersion of substantially amorphous candesartan cilexetil, an experiment is performed in which a mixture of a compound and poloxamer or polyethylene glycol 6000 is melted and solidified by cooling to obtain a solid dispersion. However, in all cases, the drug in the dispersion was reported to be crystalline.

Japanese Patent No. 2682353 (Patent Document 2) proposes the use of polyethylene glycol 6000 as a stabilizer that suppresses the degradation of the active ingredient over time in solid preparations such as tablets containing candesartan cilexetil (Compound V). ing. However, this technique is not concerned with improving dissolution rates related to drug bioavailability.

Special table 2010-502698 Japanese Patent No. 2682353

The aforementioned solid dosage form for oral administration comprising candesartan cilexetil in substantially amorphous form and a solubilizer requires a number of steps including the use of organic solvents such as ethanol and is resistant to heat. There has not been sufficient consideration for the manufacturing process and storage stability of formulations of this unstable compound. Furthermore, when compared with the candesartan cilexetil drug substance, it is difficult to say that the dissolution rate is sufficiently improved. The object of the present invention is therefore to provide new formulations for oral administration of candesartan cilexetil in which these drawbacks are at least partly improved, in particular a formulation which is even higher than was possible by the prior art with regard to dissolution rate. That is.

According to the present invention, there is provided a capsule filling composition containing candesartan cilexetil dissolved in polyethylene glycol which is liquid at room temperature and an antioxidant. Polyethylene glycol (abbreviated as PEG), which is liquid at normal temperature (25 ° C.) as a solvent, has functions such as drug dissolution assistance and / or dissolution rate and / or viscosity adjustment of the preparation and / or drug stabilization. Can be included.

The present invention also provides a capsule filled with the capsule filling composition described above. In addition to normal soft capsules and hard capsules, capsules include the capsule filling composition of the present invention as a core, and encapsulate an intermediate layer and an intermediate layer composed of a lipophilic surfactant and an oil covering the core. It may be a capsule having a multilayer structure including a covering.

The present invention provides a higher drug elution rate than was possible with the prior art. This is because candesartan cilexetil exists in a state dissolved in PEG.

In addition, it is known that candesartan cilexetil is unstable to heat. However, in the present invention, when it is dissolved in PEG, it may be heated to 40 to 50 ° C., which is lower than before. Stabilization in the manufacturing process is achieved. Moreover, since the preparation contains an antioxidant, storage stability after production is also ensured.

The graph which compared the elution rate of the composition of the prescription 1 and the prescription 2 which were tested in the test example 3 with the elution rate of the control | contrast (candesartan cilexetil raw material).

PEG has the formula H- (OCH ₂ CH ₂ ) _n -OH
And n is 4 or more. Generally, PEG is called with a numerical value corresponding to its average molecular weight. For example, PEG having an average molecular weight of 400 is called “polyethylene glycol 400”, and in the pharmaceutical field, it is called “macrogol 400”.

PEGs that are liquid at room temperature (25 ° C.) are PEG200, PEG400, and PEG600. PEG400 (mp4-8 ° C) is preferred. Although PEG 6000, which is solid at room temperature, cannot be used alone, it can be used as an auxiliary agent for adjusting its viscosity and the like by adding it to liquid PEG at room temperature.

Candesartan cilexetil dissolves in liquid PEG at room temperature to form a solution. In order to promote dissolution, it is preferable to heat the mixture of candesartan cilexetil and PEG. As described above, the heating temperature at this time is preferably up to 50 ° C. in order to avoid thermal decomposition. At this time, it is preferable to add an antioxidant to the PEG at the same time. After dissolution, it waits for the temperature to drop to room temperature and is used for capsule filling.

Candesartan cilexetil dissolves well in liquid PEG. However, since the dose per dose is 2 to 12 mg, it is difficult to fill the capsule with a solution dissolved up to or near its maximum solubility because the amount of the solution per dose is too small. . Therefore, the drug may be dissolved in liquid PEG so that the amount of liquid administered at one time is at least 80 mg.

The dose per dose of candesartan cilexetil is subdivided up to a maximum of 12 mg. Therefore, the drug concentration in the PEG can be increased in proportion to the dose of the drug so that the liquid volume per one dose, and hence the number of capsules, is equal in all doses. However, in this case, a plurality of capsules filled with solutions having different concentrations depending on the number of drug administration levels must be prepared, and there is a risk of under- or over-administration of the drug if selected incorrectly. Therefore, it is preferable to prepare only one type of capsule having a constant drug concentration in the capsule filling solution, and the dose of the drug can be selected according to the number of capsules. For this reason, it is not necessary to dissolve the drug in PEG at a high concentration above a certain concentration, and a drug concentration expressed by the drug / PEG weight ratio may be 1/20.

The amount of liquid suitable for filling the capsule can be adjusted by adding an auxiliary agent. The adjuvant must be miscible with PEG and a pharmaceutically acceptable ingredient. The auxiliary agent can also have other functions such as drug dissolution assistance, viscosity adjustment, drug stabilization, and drug elution rate control. Examples of adjuvants that can be used include:

PEG solid at normal temperature such as PEG6000; polyalcohol fatty acid ester such as prolene glycol fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, polyethylene glycol fatty acid ester; medium chain fatty acid triglyceride, saturated polyglycolation Nonionic surfactants containing polyoxyethylene chains such as glycerides (transesterification reaction product of hydrogenated vegetable oil and PEG); polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil and the like.

Adjuvants can be added from 5% to 150%, preferably 100% of the liquid PEG by weight, and can be pre-mixed with PEG prior to warming, as with other components.

The capsule filling composition of the present invention must contain an antioxidant. You can choose from antioxidants that are approved as pharmaceutical or food additives. Examples are tocopherol, ascorbic acid and its salts, dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), propyl gallate, sodium edetate, citric acid, soy lecithin and the like. Dibutylhydroxytoluene or butylhydroxyanisole is preferred. The amount depends on the antioxidant power of the specific antioxidant, but in the case of dibutylhydroxytoluene, 0.05 to 0.5 parts by weight per 1 part by weight of candesartan cilexetil is appropriate. Antioxidants can be mixed into PEG prior to warming as well as other ingredients.

The pharmaceutical composition of the present invention is a capsule and may be a soft capsule or a hard capsule. The soft capsule can be produced by filling a soft capsule film such as gelatin by any one of a seamless method, a flat plate method, and a rotary die method. Moreover, a hard capsule can be manufactured by enclosing in a hard capsule such as gelatin by a method of filling a liquid or paste-like content.

When the pharmaceutical composition of the present invention is used as a seamless capsule, an intermediate layer that is difficult to mix with water can be interposed between the film and the contents. Since the polyethylene glycol used in the present invention is a hydrophilic substance, the capsule may be softened due to the compatibility with the film at the time of capsule filling or the moisture transfer after the capsule filling, and may not be able to be encapsulated in a stable state. In this case, by providing an intermediate layer that is difficult to mix with water between the film and the contents, it becomes possible to form a stable capsule by preventing contact between the contents and the film. Such a three-layer seamless capsule uses a concentric triple nozzle to simultaneously extrude the contents from the center, the intermediate layer from the inner annular nozzle, and the capsule film from the outer annular nozzle to form a three-layer droplet. And can be obtained by solidification.

Examples of the lipophilic surfactant constituting the intermediate layer include glycerin fatty acid ester, polyhydric alcohol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, saturated polyglycolized glyceride, polyoxyethylene Polyoxypropylene glycol, acetyl glycerin fatty acid ester, polyglycerin fatty acid ester, lecithin, polyoxyethylene hydrogenated castor oil and the like, or a mixture thereof can be used. Preferably, condensed ricinoleic acid ester, propylene glycol fatty acid ester, palmitic acid ester, isostearic acid ester, linoleic acid ester, stearic acid ester, oleic acid ester, sucrose acetate isobutyric acid, or a mixture thereof can be used. . Examples of the fats and oils constituting the intermediate layer include fatty acids, vegetable oils, and synthetic oils. Preferred is a medium chain fatty acid triglyceride. The mixing ratio of the lipophilic surfactant to the fat is preferably 19: 1 to 1: 1, more preferably 9: 1 to 7: 3, by weight.

It is also possible to wrap and wrap seamless capsules for each dose. Candesartan cilexetil contains only a small amount of one pharmaceutical unit, and the dosage is finely adjusted between 2 mg and 12 mg. Since seamless capsules can be filled with a small amount of contents with high accuracy, capsules with a small amount of active ingredient in one preparation unit can be accurately prepared. By packaging and packaging this for each dose, it is possible to provide a preparation capable of accurately administering a minute amount and a fine dose. Providing a preparation in which a single dose of a patient is packaged is advantageous from the viewpoint of prevention of mistakes in dosage and ease of administration. The packaging is not particularly limited, but a shape considering ease of taking is desirable, and stick-shaped packaging is preferable.

Hereinafter, the present invention is illustrated by test examples and examples. In these, unless otherwise indicated, parts and percentages are based on weight.

Test example 1
First, in order to examine the solubility and storage stability of candesartan cilexetil (hereinafter simply referred to as “drug”) in various additives, the following accelerated stability test was conducted.
30 mg of the drug and 0.9 g of various additive components were weighed in a transparent glass container, heated at about 80 ° C. for several minutes, and visually observed whether the drug was dissolved in these components. Next, the liquid was transferred to a glass bottle, sealed, and stored for 1 week in an environment of temperature 50 ° C. and humidity 75% RH, and the drug content after storage was quantified by HPLC to calculate the residual rate. The results are shown in Table 1.

Test example 2
Next, in order to investigate the stability of drugs in various additives in the presence of an antioxidant, the same accelerated stability test as in Test Example 1 was performed. The test method is the same as the test method of Test Example 1 except that the sample contains an antioxidant. The amount of antioxidant was set to about 10 mg of dibutylhydroxytoluene, 24 mg of tocopherol, and 10 mg of citric acid in consideration of the maximum daily dose of each component. When two kinds of antioxidants were used in combination, the total amount shown above was added. The results are shown in Table 2.

From the above results, it was confirmed that the solubility of candesartan cilexetil in various additives was confirmed, and the stability in the various additives was greatly improved by the addition of an antioxidant.

Test example 3
The effect on drug dissolution was observed. The formulation shown in Table 3 was filled into hard capsules and subjected to a dissolution test. The dissolution test was conducted by the Japanese Pharmacopoeia, General Test, and dissolution test paddle method. The test solution was 20% 1.0% polysorbate solution, 900 mL, and the rotation speed was 50 rpm. In addition, since the hard capsule floats in the test solution, a sinker was used. 20 mL was sampled at a specified time, and the content of candesartan cilexetil was measured by HPLC. Formulations 1 and 2 were tested at an active ingredient amount of 2 mg, and the control was tested at 10 mg for convenience of collection. About each result, it converted into the elution rate with respect to the amount of active ingredients, and the elution property was compared.

The results are shown in the graph of FIG. As can be seen, in the AUC of the dissolution rate curve, Formula 1 and Formula 2 show at least a 3-fold increase over the control.

The present invention will be described below with reference to non-limiting examples. In addition, the numerical value of the various components in a formulation example means a weight part.

[Prescription Example 1]
Composition for soft capsule filling The ingredients for the composition shown below are mixed, stirred at a temperature of 40 to 50 ° C until dissolved, and stirred and cooled to 15 to 25 ° C to produce a capsule filling composition. did.

[Prescription Example 2]
Composition for soft capsule filling The ingredients for the composition shown below are mixed, stirred at a temperature of 40 to 50 ° C until dissolved, and stirred and cooled to 15 to 25 ° C to produce a capsule filling composition. did.

[Prescription Example 3]
Composition for soft capsule filling The ingredients for the composition shown below are mixed, stirred at a temperature of 40 to 50 ° C until dissolved, and stirred and cooled to 15 to 25 ° C to produce a capsule filling composition. did.

[Prescription Example 4]
Composition for soft capsule filling The ingredients for the composition shown below are mixed, stirred at a temperature of 40 to 50 ° C until dissolved, and stirred and cooled to 15 to 25 ° C to produce a capsule filling composition. did.

[Prescription Example 5]
Composition for soft capsule filling The ingredients for the composition shown below are mixed, stirred at a temperature of 40 to 50 ° C until dissolved, and stirred and cooled to 15 to 25 ° C to produce a capsule filling composition. did.

[Prescription Example 6]
Composition for soft capsule filling The ingredients for the composition shown below are mixed, stirred at a temperature of 40 to 50 ° C until dissolved, and stirred and cooled to 15 to 25 ° C to produce a capsule filling composition. did.

[Prescription Example 7]
Composition for soft capsule filling The ingredients for the composition shown below are mixed, stirred at a temperature of 40 to 50 ° C until dissolved, and stirred and cooled to 15 to 25 ° C to produce a capsule filling composition. did.

[Prescription Example 8]
Hard capsule filling composition The ingredients of the composition shown below are mixed, stirred at a temperature of 40 to 50 ° C until dissolved, and cooled to 15 to 25 ° C to produce a capsule filling composition. did.

[Prescription Example 9]
Hard capsule filling composition The ingredients of the composition shown below are mixed, stirred at a temperature of 40 to 50 ° C until dissolved, and cooled to 15 to 25 ° C to produce a capsule filling composition. did.

[Prescription Example 10]
Seamless capsule filling composition

[Prescription Example 11]
Seamless capsule filling composition

The compositions of Formulation Examples 1 to 7 and Formulation Examples 8 and 9 are filled in soft capsules or hard capsules according to a conventional method in such an amount that the content of the drug per capsule is 2 mg, for example.

The seamless capsules containing the compositions of Formulation Examples 10 and 11 were produced by the operation described above so that the active ingredient per capsule was 1 mg or 0.5 mg.

The produced capsules containing 1 mg and 0.5 mg of active ingredient per capsule are packaged in the number corresponding to the single dose shown in Table 4, for example, in a stick-shaped package.

Claims (14)

A capsule filling composition comprising a solution of candesartan cilexetil and an antioxidant dissolved in polyethylene glycol which is liquid at room temperature. 2. The capsule filling composition according to claim 1, wherein the polyethylene glycol which is liquid at room temperature is polyethylene glycol 200, polyethylene glycol 400, polyethylene glycol 600, or a mixture thereof. 3. The composition for filling capsules according to claim 1 or 2, wherein the polyethylene glycol that is liquid at room temperature is polyethylene glycol 400. The composition for capsule filling according to claim 1, 2 or 3, wherein candesartan cilexetil is dissolved in at least 20 parts by weight of polyethylene glycol which is liquid at room temperature per part by weight of candesartan cilexetil. Capsule filling according to any one of claims 1 to 4, wherein the antioxidant is selected from tocopherol, ascorbic acid and salts thereof, dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, sodium edetate, citric acid, or soybean lecithin Composition. The composition according to any one of claims 1 to 5, wherein the antioxidant is contained in an amount of 0.05 to 1 part by weight per 1 part by weight of candesartan cilexetil. 7. The capsule filling composition according to any one of claims 1 to 6, further comprising a pharmaceutically acceptable adjuvant miscible with polyethylene glycol which is liquid at room temperature. Auxiliary agents are polyethylene glycol, propylene glycol fatty acid ester, sucrose fatty acid ester, polyethylene glycol fatty acid ester, medium chain fatty acid triglyceride, saturated polyglycolized glyceride, polyoxyethylene sorbitan fatty acid ester, or polyoxyethylene castor oil that is solid at room temperature The composition for capsule filling of Claim 7 chosen from these. Soft capsule formed by filling the composition according to any one of claims 1 to 8. Hard capsule formed by filling the composition according to any one of claims 1 to 8. (A) a core comprising the composition of claims 1 to 8;
(B) a non-water miscible intermediate layer;
(C) Capsule having a multilayer structure composed of a seamless capsule shell containing a core and an intermediate layer. The capsule according to claim 11, wherein the intermediate layer is composed of a mixture of fats and oils and a lipophilic surfactant. Lipophilic surfactants include glycerin fatty acid esters, polyhydric alcohol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, saturated polyglycolized glycerides, poloxamers (block copolymers of ethylene oxide and propylene oxide) ), Acetylglycerin fatty acid ester, lecithin, or polyoxyethylene hydrogenated castor oil. A pharmaceutical preparation in which the seamless capsule according to any one of claims 11 to 13 is packaged and packaged in a number corresponding to a single dose.

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