KR100592687B1 - Formulation and manufacturing process of amlodipine soft capsules - Google Patents

Abstract

The present invention relates to the preparation of a novel amlodipine solubilizing formulation using the Self-MicroEmulsifying Drug Delivery System (SMEDDS), a solubilization technique for poorly soluble drugs. Amlodipine is a drug that works to block calcium ions from entering the cell membranes of heart and peripheral vascular smooth muscle, and is widely used for the treatment of hypertension, but has a very poorly soluble property in water.

The amlodipine solubilization technology using the SMEDDS technique of the present invention has the advantage that the solubility can be increased as compared to the solubility in water. It was also possible to prepare a microemulsion spontaneously when dispersing the SMEDDS in the water phase, it is also possible to prepare an injectable microemulsion of amlodipine through the solubilization technique of the present invention. Amlodipine mesylate, which is water-soluble in water, can be used as an agent that can secure stability against water. SMEDDS is an excellent formulation technology that can improve solubility and stability of drugs. In addition, the present invention can be said to be an advanced formulation that can be applied to various drugs by forming a homogeneous and transparent mixed solution with or without amlodipine.

Amlodipine, self-emulsifying drug delivery system, bioavailability, soft capsule

Description

Soft capsule composition containing amlodipine and its manufacturing method {Formulation and manufacturing process of amlodipine soft capsules}

The present invention relates to the preparation of a novel amlodipine solubilizing formulation using the Self-MicroEmulsifying Drug Delivery System (SMEDDS), a solubilization technique for poorly soluble drugs.

In general, in order for a drug to be absorbed into the human body and exhibit high pharmacological activity in vivo, it must first be eluted quickly. The dissolution rate of the drug determines the rate of absorption in the body and is an important indicator of the drug concentration in the blood in proportion. It depends on the solubility of. However, since the solubility of the drug is poorly soluble in water, various methods have been studied to improve the solubility.

Typical solubilization methods include reducing the size of particles to increase the surface area, changing the crystalline form to amorphous, adding salts to acids or bases by adding ions to poorly soluble materials, and making soluble by combining water-soluble polymers. There is a way. In addition, a method of increasing the solubility by forming a micelle using a surfactant and taking a poorly soluble material therein has been studied in recent years. In particular, the self-emulsifying drug delivery system (SMEDDS) is one of the methods to compensate for the shortcomings of the emulsion, when a mixture of oil and surfactant is in contact with the water phase to form a fine oil-in-water emulsion with only light mixing. SMEDDS is encapsulated in soft gelatin capsules and when administered orally, is rapidly emulsified in the gastric aqueous phase into an emulsion in the gastrointestinal tract. At this time, since the particles of the resulting emulsion are fine, they have a very wide interface, which facilitates the diffusion of the drug.

The chemical name of amlodipine is 3-ethyl-5-methyl-2- [2-aminoethoxymethyl] -4- [2-chlorophenyl] -6-methyl-1,4-dihydropyridine-3,5 It is a dicarboxylate, a powerful Calcium Channel Blocker in the form of dihydropyridine-dicarboxylate, which acts to block calcium ions from entering the cell membranes of the heart and peripheral vascular smooth muscle. This amlodipine base is generally administered in the form of a salt because of its pharmaceutical stability.

Amlodipine besylate is a generic name for benzenesulfonate salt of amlodipine. When oral administration of a therapeutic dose occurs, the lowest drug concentration reaches 6–12 hours after drug administration and the distribution is about 20 L / kg. The final excretion half-life of the drug in plasma is known to be about 35-50 hours. Amlodipine mesylate is a generic name for methanesulfonic acid salt of amlodipine and is known to be relatively stable with besylate and has higher solubility than other materials.

Solution formulations and SMEDDS can be designed to improve the low solubility of amlodipine and its salts and to improve water stability, thereby increasing the dissolution and stability of amlodipine and encapsulating it in soft gelatin capsules to increase absorption. To develop a formulation.

Self-emulsification was first discovered in 1878 by J. Gad and has been used for years in herbicides, pesticides, and industry. Because herbicides and insecticides are solubilized in water, they cannot be prepared in concentrated aqueous solutions. Although there was a problem of growing, it was possible to reduce the volume by dispersing in water to make a self-emulsifying formulation using an organic solvent and a surfactant. These characteristics make SMEDDS a good drug carrier for oral administration of poorly soluble drugs that can be dissolved in surfactants and oils.

In addition, SMEDDS is applied to solubilization and formulation of cyclosoluble A, halophantrin, and poorly soluble drugs such as biphenyldimethyl dicarboxylate (DDB) and indomethacin to improve drug absorption and bioavailability. It was. SMEDDS is a homogeneous mixture of oils and nonionic surfactants that delivers drugs that can easily form O / W type microemulsions, even by relatively gentle agitation such as gastrointestinal motility when exposed to body water such as body fluids when administered to the human body. Known as the system. The properties of SMEDDS are determined by the self-emulsifying ability of the mixture to form an emulsion of microparticles (<5 μm) and the polarity of the oil droplets which rapidly release the drug into the water phase, and the stability of the resulting microemulsion is the volume of the dispersed oil phase. When it is small, it is known to increase when the particle size distribution is narrow.

The present invention relates to the preparation of a novel amlodipine solubilizing agent using a self-emulsifying drug delivery system (SMEDDS), which is a solubilization technique of poorly soluble drugs, wherein the amlodipine solubilization technique using the SMEDDS technique of the present invention has a solubility in water compared to solubility in water. The aim of the present invention is to prepare amlodipine soft capsules having excellent dissolution characteristics by formulating amlodipine SMEDDS which can be increased and prepared based on such a solubilization technique into soft capsules. It is also an object of the present invention to prepare a microemulsion for injection of amlodipine through the solubilization technique of the present invention, and to form a homogeneous and transparent mixed solution with or without amlodipine, to prepare a formulation applicable to various drugs.

The present invention relates to an amlodipine formulation having improved solubility and stability, and specifically, a method of solubilizing amlodipine and its pharmaceutically acceptable salts, which are poorly soluble in water, using a hydrophilic solvent, a lipophilic solvent and a surfactant, and an active ingredient thereof. It relates to a formulation containing. That is, the present invention relates to a preparation and a method for preparing the same, which can provide high pharmacological activity and secure stability against water by solubilizing amlodipine and its salts which are poorly soluble in water to increase solubility and improve dissolution rate. Due to its fast absorption and excellent stability, high therapeutic effects can be expected.

SMEDDS designs typically use oil components, surfactants, dispersants and dissolution aids. The solubilization method of amlodipine and its salts is to solubilize amlodipine in surfactants, co-solvents, oils to enhance the solubility of the drug to obtain a composition of soft capsule compositions. The present invention is a novel amlodipine solubilizing agent using a self-emulsifying drug delivery system having the above-mentioned advantages, and comprises a pharmaceutical composition comprising the following components (1) to (4),

(1) As the surfactant, polyoxyl castor oil, polyethylene glycol stearate, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ether, sorbitan fatty acid, glyceryl monooleate (glyceryl momooleate) Glyceryl monostearate and polyvinyl alcohol, dimethyl isosorbid,

(2) polyethylene glycol, propylene glycol, triacetin, diethylene glycol monoethyl ether, glycerin,

(3) as an oil medium chain triglycerides (MCT), propylene glycol laurate (Lauroglycol ^R ), isopropyl myristate, isopropyl palmitate and ethyl oleate,

(4) Polyvinylpyrrolidone (PVP, polyvinylpyrrolidone) or the like is used as the dispersing agent.

In order to produce SMEDDS, component (1) is suitably present in an amount of 10 to 70%, preferably 20 to 60%, based on the total weight of the composition of the invention, component (2) of the invention Suitably present in the total weight of the composition in the range of 1 to 100%. In addition, component (3) is suitably present in an amount of 1 to 70% with respect to the total weight of the composition of the present invention, and preferably in an amount of 1 to 30%. Component (4) is suitably present in an amount of 1.0 to 5.0% relative to the total weight of the composition of the present invention.

In the present invention, the design of amlodipine solution and SMEDDS as one of the formulations to minimize the in vivo side effects of amlodipine and to promote absorption to increase the bioavailability, solubility in the oil and surfactant of amlodipine, the transparency after the water phase addition of SMEDDS from SMEDDS Amlodipine release was measured. In addition, it was prepared as a gelatin soft capsule to evaluate the stability.

First, solubility was measured in representative oils and surfactants to combine oils and surfactants suitable for solubilization of amlodipine and its salts.

TABLE 1 Solubility of Amlodipine with Solvents

Solvent Solubility (mg / mL) water 1.582 Isopropyl myristate 0.004 Ethyl oleate 0.844 Lauroglycol ^r 0.087 MCT 0.158 glyceryl momooleate 16.743 Cremophor ^R RH 40 76.657

As can be seen in Table 1, amlodipine and its salts do not dissolve well in water, but likewise have properties insoluble in oil components. However, the surfactant showed about 10 to 50 times better solubility than water. PEG also had better solubility than Cremophor ^R RH 40, a surfactant.

Based on the solubility, SMEDDS was designed using MCT, ethyl oleate as oil, PEG as cosolvent, Cremophor ^R RH 40 as surfactant, and Cremophor ^R EL as surfactant.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, this does not limit the scope of the invention.

Example 1

6.158 g of amlodipine mesylate was added to 100 g of PEG 400, dissolved with stirring, and used as a solution for preparing a soft capsule.

Example 2

6.158 g of amlodipine mesylate was added to 97.7 g of PEG400 and 97.7 g of Cremophor ^R RH40 and dissolved with stirring. 14.7 g of MCT was added to the solution and stirred to prepare a SMEDDS preparation.

Example 3

6.158 g of amlodipine mesylate was added to 81.6 g PEG 400, 40.8 g Cremophor ^R RH 40 and 77.6 g Cremophor ^R EL and dissolved with stirring. 12.2 g of ethyl oleate was added to the solution and stirred to prepare a SMEDDS preparation.

Example 4

6.158 g of amlodipine mesylate was added to 85.1 g of PEG400, 39.7 g of Cremophor ^R RH40 and 79.4 g of Cremophor ^R EL and dissolved with stirring. 6.4 g of MCT was added to the solution and stirred to prepare a SMEDDS preparation.

Example 5

6.158 g of amlodipine mesylate was added to 17.3 g of PEG400 and 96.3 g of Cremophor ^R EL and dissolved with stirring. 96.3 g of ethyl oleate was added to the solution and stirred to prepare a SMEDDS preparation.

Example 6

6.158 g of amlodipine mesylate was added to 11.5 g of PEG400 and 106.0 g of Cremophor ^R EL and dissolved with stirring. 182.5 g of ethyl oleate was added to the solution and stirred to prepare a SMEDDS preparation.

Example 7

6.158 g of amlodipine mesylate was added to 6.0 g of PEG 400 and 174.3 g of Cremophor ^R EL and dissolved with stirring. 119.7 g of MCT was added to the solution and stirred to prepare a SMEDDS preparation.

Example 8

Example 1, Example 3 and Example 4 above were prepared, filtered with a 1.0 μm filter, and filled into gelatin capsules to prepare amlodipine soft capsules. On the other hand, the coating formulation of the soft capsule was used the most commonly used prescription and the contents of the prescription are shown in Table 2 below.

[Table 2] Composition of soft capsule film

Name weight % gelatin 58.2 Concentrated glycerin 28.0 D-sorbitol 12.5 antiseptic 0.4 Flavor 0.9 system 100

 Soft capsule molding of amlodipine and a salt-containing preparation of the present invention is molded into Oval 6 type by a conventional filling method using a rotary automatic charger, which is generally used, and then subjected to drying and screening to produce a prototype.

[Test Example 1]

In order to evaluate the stability of the preparation, the samples were stored under accelerated conditions (40 ° C, 75% RH) to visually check for color change, phase separation, and precipitation. 2 months after preparation to confirm the stability of amlodipine. Then, a certain amount was taken, diluted with methanol, and the concentration of amlodipine was measured by HPLC. As in the case of Example 2, it could be observed that the solution became turbid when used alone with Cremophor ^R RH 40. This turbidity did not occur when Cremophor ^R RH 40 and Cremophor ^R EL were used simultaneously. In addition, it can be seen that the content of amlodipine is greatly reduced when an excess oil is used.

[Table 3] Results of stability test of amlodipine-containing soft capsule

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Change of color - muddiness - - - - - Tops - - - - - - - Sedimentation - - - - - - - content(%) 93.89 91.64 98.47 97.68 92.46 76.88 86.12

[Test Example 2]

The self-emulsified liquid prepared in each Example was diluted 10-fold with distilled water, and the absorbance was measured at 540 nm to evaluate the transparency by light transmittance (%). In the case of dispersing SMEDDS in water, as the amount of PEG, which is a water-soluble component, was increased, almost dissolved or finely dispersed, the permeability was high, and the amount of oil component was opaque, resulting in low permeability.

 Table 4 Evaluation of transparency of self-emulsifying amlodipine composition

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 T (%) 99.74 98.66 98.72 98.69 77.72 0.83 68.82

[Test Example 3]

In order to evaluate the dissolution characteristics of the amlodipine soft capsules, the test solution was purified water, and the test method was the second dissolution test method of the 8 KPs. The temperature of the test solution was 37 ± 0.5 ° C. and the stirring speed was 50 rpm. . The content of amlodipine was measured for absorbance at 237 nm using HPLC method.

TABLE 5 Dissolution Evaluation of Amlodipine Soft Capsules

Example 1 Example 3 Example 4 5 minutes 85.7 88.2 87.3 10 minutes 95.4 98.3 97.2 15 minutes 100.2 100.5 100.6

Amlodipine soft capsules are affected by the disintegration time of the soft capsule film, but it can be observed that most drugs are eluted as the film disintegrates. Therefore, amlodipine soft capsule developed as a SMEDDS formulation is excellent in dissolution rate can be expected high physiological activity when administered in vivo.

In the case of amlodipine base, when not solubilized, it shows some solubility at pH 1.2, but gelling phenomenon is observed in other eluents pH 4.0 and 6.8 and hardly dissolved in water. Therefore, SMEDDS technology was able to produce a formulation that is excellent in dissolution in the stomach as well as in the intestine. Amlodipine mesylate has better solubility than other salts, but is concerned about the water solubility, but the SMEDDS technology has improved the stability to water.

As described above, the SMEDDS technology of amlodipine is an excellent formulation technology that can be applied to solubility of amlodipine and its salts which are poorly soluble, and in the case of amlodipine mesylate, which is water-soluble in water, it is a formulation technology that can improve stability to water.

The present invention relates to the preparation of a novel amlodipine solubilizing agent using a self-emulsifying drug delivery system that is a solubilization technique of a poorly soluble drug, wherein the amlodipine solubilization technique using the SMEDDS technique in the present invention will increase the solubility compared to the solubility in water. It has the advantage that can be, by formulating the amlodipine SMEDDS prepared on the basis of such a solubilization technique into a soft capsule can be produced a soft amlodipine soft capsule excellent in dissolution properties. In addition, since the microemulsion can be spontaneously formed when the SMEDDS is dispersed in an aqueous phase, an injectable microemulsion of amlodipine can also be prepared through the solubilization technique of the present invention. Amlodipine mesylate, which is water-soluble in water, can be used as an agent that can secure stability against water. SMEDDS is an excellent formulation technology that can improve solubility and stability of drugs. In addition, the present invention can be applied to various drugs by forming a homogeneous and transparent mixed solution with or without amlodipine.

While the invention has been described in detail only with respect to the described embodiments, it will be apparent to those skilled in the art that various modifications and variations are possible within the spirit of the invention, and such modifications and variations belong to the appended claims. .

Claims (8)

Amlodipine containing 6.158 parts by weight of amlodipine mesylate, 81.6 parts by weight of polyethylene glycol-400 as a cosolvent, 40.8 parts by weight of cremepore RH40 as a surfactant, 77.6 parts by weight of cremerpore EL and 12.2 parts of ethyl oleate as oil Composition. A soft capsule comprising the amlodipine-containing composition of claim 1. An injection comprising the amlodipine-containing composition of claim 1. delete delete delete delete delete