KR101136075B1 - Pharmaceutical composition for treating hypertension - Google Patents

Abstract

The present invention relates to a hypertension therapeutic composition. Lacidipine or a pharmaceutically acceptable salt thereof; Hydroxypropylmethylcellulose (HMC); And a pharmaceutically acceptable additive, wherein the therapeutic composition for hypertension has a very high solubility in the water-soluble medium of the active ingredient, lacidipine, and shows an excellent dissolution rate.

Lacidipine, hydroxypropylmethylcellulose, additives, crospovidone, solubility, dissolution rate

Description

Hypertension Therapeutic Composition {PHARMACEUTICAL COMPOSITION FOR TREATING HYPERTENSION}

The present invention relates to a hypertension therapeutic composition, and more particularly, to a hypertension therapeutic composition in which the active ingredient lashidipine has a considerably high solubility in an aqueous medium and exhibits an excellent dissolution rate.

Lacidipine (C ₂₆ H ₃₃ NO ₆ ) has the chemical name (E) -4- {2- [3- (1,1-dimethylethoxy) -3-oxo-1-propenyl] phenyl} -1 , 4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester ((E) -4- {2- [3- (1,1-dimethylethoxy) -3-oxo-1-propenyl ] phenyl} -1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester), a calcium channel antagonist (Calcium channel antagonist or Calcium channel blocker) having the structure of formula (1).

<Formula 1>

Lacidipine inhibits calcium ions from entering slow channels, or inhibits calcium ions from entering into voltage-sensitive sites in myocardium and vascular smooth muscle during depolarization, thereby limiting intracellular ion concentrations and coronary vessels. Induces relaxation of smooth muscle and expansion of coronary blood vessels, thereby lowering blood pressure. Because of this pharmacological effect, it is generally used for the treatment of hypertension and other cardiovascular diseases.

Lacidipine is known as a poorly soluble drug that exhibits significantly low solubility in aqueous media. Solubility of the drug is one of several factors affecting the absorption of the drug in the body, the dissolution of the drug in an aqueous medium is an important step in systemic absorption. In particular, the rate of dissolution in the gastrointestinal tract is often a factor that determines the rate of systemic absorption, so the bioavailability of the drug is predicted according to the results of the dissolution test. Thus, a drug must have adequate solubility in an aqueous medium in order to achieve the desired bioavailability and therapeutic effect. Low solubility compounds or poorly soluble compounds exhibit irregular absorption, so it is difficult to expect effective therapeutic effects. Especially, low solubility drugs in the gastrointestinal tract are absorbed except in the case of the formulation specially designed for the drug. There is a disadvantage that is not made completely.

Thus, in order to improve the solubility of poorly soluble drugs such as lacidipine, a method of obtaining a pharmaceutical composition using a water-soluble polymer such as polyvinylpyrrolidone (PVP) or polyethylene glycol (PEG) has been considered. However, the mixing of such water-soluble polymers alone does not sufficiently improve the solubility of the lacidipine and the like, and thus the bioavailability.

The present invention aims to provide a hypertension therapeutic composition which can be prepared by a simple process and that the active ingredient, lacidipine, has a considerably high solubility in water-soluble media and shows an excellent dissolution rate.

The present invention relates to lacidipine or a pharmaceutically acceptable salt thereof; Hydroxypropylmethylcellulose (HMC); And it provides a high blood pressure therapeutic composition comprising a pharmaceutically acceptable additive.

Hereinafter, the hypertension therapeutic composition according to the specific embodiment of the present invention will be described.

According to one embodiment of the invention, lacidipine, C ₂₆ H ₃₃ NO _{6 ,} (E) -4- {2- [3- (1,1-dimethylethoxy) -3-oxo-1-propenyl] phenyl } -1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylic acid diethyl ester) or a pharmaceutically acceptable salt thereof; Hydroxypropylmethylcellulose (HMC); And a pharmaceutically acceptable additive, and a high blood pressure therapeutic composition having high solubility of lacidipine in an aqueous medium can be provided.

As a result of the experiments of the present inventors, one example of the antihypertensive therapeutic composition of the present invention can be prepared by mixing rashidipine with hydroxypropylmethylcellulose and a pharmaceutically acceptable additive and proceeding through a conventional tablet manufacturing process, and the active ingredient recidi It was found that the fins had a significantly higher solubility in water soluble media and a good dissolution rate. The pharmaceutical composition of the commercially available lacidipine is provided in the form of a solid dispersion using a water-soluble polymer such as polyvinylpyrrolidone (PVP) or polyethylene glycol (PEG) in order to increase the solubility of the lacidipine in the water-soluble medium. As can be seen, such pharmaceutical compositions require special and complex processes and apparatus for the preparation of solid dispersions, and such preparation methods have not reached sufficient levels of solubility and dissolution rate of the lacidipine in the aqueous medium. On the contrary, as shown in the following Experimental Examples and FIGS. 1 and 2, the hypertension therapeutic composition according to one embodiment of the present invention has a significantly higher solubility and dissolution rate of recidipine in comparison with a comparative example using polyvinylpyrrolidone. It can be manufactured by a simple process.

Meanwhile, in one embodiment of the present invention, the antihypertensive therapeutic composition may include lacidipine in the form of a free base or a pharmaceutically acceptable salt.

In general, the pharmaceutical composition includes the active ingredient in the form of a salt to improve solubility and dissolution rate, or after mixing and mixing the salt of the active ingredient in an aqueous solution to improve the efficacy, the crystal form of the free base of the active ingredient is mixed from the mixed solution. Including the filter separated to increase the purity of the pharmaceutical composition. However, in one embodiment of the present invention, by simply mixing hydroxydipine freebase with hydroxypropylmethylcellulose and a pharmaceutically acceptable additive, it is possible to obtain a very high solubility, dissolution rate, bioavailability and efficacy of recidipine. Therefore, a high purity hypertension therapeutic composition can be produced without including complicated manufacturing processes, such as filtering off the aqueous solution of a mixture.

The pharmaceutically acceptable salts of lassidipine may include conventional lassidipine acid addition salts that are harmless to living organisms. Such acid addition salts of lassidipine may be any suitable inorganic acid such as hydrochloric acid, phosphoric acid or sulfuric acid, or ascorbic acid. , Such as citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, oxalic acid, benzenesulfonic acid, camposulfonic acid, cinnamic acid, adipic acid, cyclamic acid or methanesulfonic acid It cannot be obtained by reacting an organic acid with lacidin. However, acid addition salts of lacidipine are not limited thereto, and salts of lacidipine combined with pharmaceutically acceptable acids may be used without any particular limitation.

On the other hand, the hydroxypropyl methyl cellulose serves to facilitate the solubilization of the lacidipine by allowing the water-soluble medium to be easily introduced into the hypertension therapeutic composition. As can be seen in the following Experimental Examples and Figures 1 and 2, in one embodiment of the invention by simply mixing hydroxypropylmethylcellulose with lashidipine and pharmaceutically acceptable additives without using complex processes or large amounts of organic solvents Lassidipine, the active ingredient of the therapeutic composition for hypertension, has a very high solubility in water-soluble media and can exhibit excellent dissolution rate.

In addition, the hypertension therapeutic composition may comprise lasidipine: hydroxypropylmethylcellulose in a weight ratio of 1: 4 to 1:30, preferably 1: 7 to 1:10. Within the weight ratio range above, the active ingredient lassidipine has a significantly higher solubility in water-soluble media, simply by mixing in a conventional manner the assicipine, hydroxypropylmethylcellulose and pharmaceutically acceptable additives. And excellent dissolution rate.

On the other hand, the high blood pressure therapeutic composition according to one embodiment of the invention may further comprise crospovidone (Crospovidone) in order to further improve the dissolution rate of lacidipine. Crospovidone helps to disperse the active ingredient easily in the medium, etc. In one embodiment of the present invention, in addition to HPMC, the water-soluble medium can be easily introduced into the hypertension therapeutic composition to promote the solubilization of lassipidine. Seems to be. As shown in the following Experimental Example and Figure 3, the hypertension therapeutic composition may exhibit an excellent dissolution rate due to the synergy of the combination of crospovidone and hydroxypropylmethylcellulose.

In addition, the hypertension therapeutic composition may include lacidipine: crospovidone in a weight ratio of 1: 1 to 1:15, preferably in a weight ratio of 1: 3 to 1:10. Mixing lacidipine and crospovidone in the above weight ratio range can provide a hypertension therapeutic composition with higher solubility and dissolution rate of lacidipine without the addition of complex manufacturing processes.

On the other hand, the pharmaceutically acceptable additive may include an excipient, a binder, a disintegrant or a lubricant. Excipients may include starch, lactose, white sugar, mannitol, sorbitol, glucose, microcrystalline cellulose or calcium dihydrogen phosphate, and the like. The binder may include cellulose derivatives such as methyl cellulose, ethyl cellulose, carboxymethyl cellulose sodium, starch, gelatin, povidone or gum arabic. Disintegrants may include starch, starch derivatives such as sodium starch glycolate, carboxymethylcellulose calcium, carboxymethylcellulose derivatives such as crosslinked carboxymethylcellulose, microcrystalline cellulose or crosslinked povidone, and the like. Glidants may include stearic acid and its pharmaceutically acceptable alkali metal salts or amine salts, colloidal silicon dioxide, silicates or talc. However, without being limited thereto, additives that can be used in the composition for treating hypertension may be used without limitation.

In one embodiment of the invention, the hypertension therapeutic composition can be prepared by a simple process without having to include the complicated step of preparing a solid dispersion. For example, 1) mixing rasidipine with hydroxypropylmethylcellulose, conventional excipients, etc., 2) granulating the mixture, drying at high temperature, and then sizing in a conventional manner. And 3) it is possible to prepare a hypertension therapeutic composition according to an embodiment of the invention by a simple manufacturing method comprising the step of mixing and tableting the lubricant in the formulation mixture.

The antihypertensive composition according to one embodiment of the present invention may be formulated in any form administered orally or parenterally. When the hypertension therapeutic composition is in the form of a liquid formulation for oral administration, conventional emulsions, suspensions or syrups may be included, and various additives other than water or liquid paraffin, which are commonly used simple diluents, for example, Sweeteners, wetting agents, fragrances or preservatives may also be included. And, if the hypertension therapeutic composition is a preparation for parenteral administration, sterile aqueous solution, suspension, emulsion, non-aqueous solvent or suppository may be included. More specifically, the non-aqueous solvent or suspending agent may be used vegetable oils such as propylene glycol, polyethylene glycol or olive oil, injectable esters such as ethyl oleate, etc. As a base of suppositories, Witepsol, Macrogol, Tween 61, cacao butter, laurin butter or glycerogelatin can be used.

The hypertension therapeutic composition may be administered to the human body in an appropriate amount depending on the weight, health status, diet, age, sex, administration method, administration time, excretion rate or severity of the disease of the patient. For example, the antihypertensive therapeutic composition may include 0.001 to 50 mg, preferably 0.005 to 20 mg, of the active ingredient lashidipine, which is administered once, and such unit dosage form is used once in an adult. Or multiple times.

According to the present invention, there is provided a hypertension therapeutic composition prepared by a simple process, wherein the active ingredient, lacidipine, has a very high solubility in an aqueous medium and exhibits an excellent dissolution rate.

The invention is explained in more detail in the following examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

< Example : Hypertension therapeutic composition>

Example  One

4 g of lassidipine was dissolved in 80 g of ethanol and completely dissolved, followed by mixing with 265.2 g of lactose hydrate and 30.0 g of hydroxypropylmethylcellulose (hypromellose 2910, DOW chemical). This mixture was granulated, dried at 60 ° C., and then sieved in a conventional manner. 0.8 g of magnesium stearate was added to the prepared mixture, mixed, compressed, and a high blood pressure therapeutic composition was prepared.

Example  2

A hypertension therapeutic composition was prepared in the same manner as in Example 1 except that lactose hydrate was mixed with 235.2 g of hydroxypropylmethylcellulose and 60 g.

Example  3

4 g of lassidipine was added to 110 g of ethanol and completely dissolved. Then, 255.2 g of lactohydrate, 30.0 g of hydroxypropylmethylcellulose, and 10 g of crospovidone were mixed. This mixture was granulated, dried at 60 ° C. and then stipulated in a conventional manner. 0.8 g of magnesium stearate was added to the squeezed mixture, mixed and compressed to prepare a hypertension therapeutic composition.

Example  4

A hypertension therapeutic composition was prepared in the same manner as in Example 3 except that the content of ethanol, lactohydrate and crospovidone was 120g, 245.2g, and 20g, respectively.

Example 5

A hypertension therapeutic composition was prepared in the same manner as in Example 4 except that the content of ethanol, lactohydrate and crospovidone was 120g, 225.2g, and 40g, respectively.

Comparative example  One

4 g of racidipine was dissolved in 80 g of ethanol and completely dissolved, and then mixed with 255.2 g of lactohydrate and 40.0 g of polyvinylpyrrolidone. This mixture was granulated, dried at 60 ° C. and then stipulated in a conventional manner. 0.8 g of magnesium stearate was added to the squeezed mixture, mixed and compressed to prepare a hypertension therapeutic composition.

Comparative example  2

4 g of lassicipine was added to 80 g of ethanol to completely dissolve it, and then 20 g of polyvinylpyrrolidone was added and mixed. This mixture was added to 275.2 g of lactohydrate and mixed, dried at 60 ° C. and then stipulated in a conventional manner. 0.8 g of magnesium stearate was added to the squeezed mixture, mixed and compressed to prepare a hypertension therapeutic composition.

Comparative example  3

A hypertension therapeutic composition was prepared in the same manner as in Comparative Example 2 except that the content of lactose and polyvinylpyrrolidone was 255.2 g and 40.0 g, respectively.

The composition of the hypertension therapeutic composition prepared in Examples 1 to 5 and Comparative Examples 1 to 3 is shown in Table 1 below. Each example is a 1,000T quantity manufactured and the unit is g.

[Table 1]

Ingredient Name Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 3 Lacidipine 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 Lactose Carb 265.2 235.2 255.2 245.2 225.2 255.2 275.2 255.2 Hypromellose2910 30.0 60.0 30.0 30.0 30.0 Crospovidone 10.0 20.0 40.0 Polyvinylpyrrolidone 40.0 20.0 40.0 Magnesium stearate 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 Ethanol (g) 80.0 80.0 110.0 120.0 120.0 80.0 80.0 80.0 system 300.0 300.0 300.0 300.0 300.0 300.0 300.0 300.0

< Experimental Example  1: Solubility Experiment

Each of 300 mg (4 mg as lassipidine) and 20 mg of the hypertension therapeutic composition of Examples 1 to 5 and Comparative Examples 1 to 3 and 20 mg of the raw material were put in 200 mL of aqueous solution and tween80 0.05% solution (ICI Americas, Inc.) for 24 hours. Magnetic stirring. Thereafter, the supernatant was collected by centrifugation, filtered with a 0.45 μm membrane filter, and the absorbance was measured at 284 nm using a UV spectrophotometer (VAS model of JASCO Corporation). The saturation concentration of Lassidipine was calculated according to the formula according to the calibration curve of Lassidipine standard solution.

The saturation concentrations of the lacidipine in the aqueous solution and the Tween80 0.05% solution measured in the above experiment are shown in Table 2 below. In addition, these results are shown in FIGS. 1 and 2.

TABLE 2

division In aqueous solution
Saturated Concentration of Racidipine (ug / mL) Tween80 in 0.05% solution
Saturated Concentration of Racidipine (ug / mL) Rassidipine Raw Material ND 1.497 Commercial Drugs (Ph.D.) 0.793 2.756 Example 1 0.376 4.266 Example 2 0.667 4.483 Example 3 0.280 4.231 Example 4 0.356 4.067 Example 5 0.789 4.969 Comparative Example 1 0.038 2.016 Comparative Example 2 0.016 2.064 Comparative Example 3 0.069 2.027

As shown in Table 2, Figures 1 and 2, the hypertension of Examples 3 to 5 further comprising crospovidone in Examples 1 and 2, including hydroxypropylmethylcellulose and lassidipine In the therapeutic composition, the saturation concentration of the lacidipine in the aqueous solution showed high solubility ranging from 4 to 49 times as compared with Comparative Examples 1 to 3 using polyvinylpyrrolidone. In addition, the antihypertensive composition of Examples 1 to 5 in Tween80 0.05% solution showed more than two times higher solubility of radidipine than Comparative Examples 1 to 3, and 1.5 to 1.8 times higher than commercial drugs.

These results indicate that the therapeutic composition for hypertension comprising lassidipine, hydroxypropylmethylcellulose and pharmaceutically acceptable additives is easily prepared by a simple process, and the solubility of lassidipine in an aqueous medium is higher than in the prior art. It can be seen that it is significantly high.

< Experimental Example  2: Comparative Dissolution Test>

Tablets having the compositions of Examples 1 and 5 were placed in a water solution containing 900 mL of 1% of Tween80, respectively, and proceeded at 37 ° C. by paddle method (50 rpm). The comparative dissolution test results measured in the above experiment are shown in Table 3 below.

[Table 3] Dissolution Rate of Lassidipine by Extraction Time (%)

Minutes 0 5 10 15 30 45 60 Example 1 0.0 12.5 26.3 37.9 63.6 76.0 78.8 Example 5 0.0 19.0 39.3 56.7 76.0 84.3 87.9

As shown in Table 3 and FIG. 3, the composition of Example 1 including hydroxypropylmethylcellulose and the composition of Example 5 further including crospovidone show excellent dissolution rates, and in particular, the composition of Example 5 It was confirmed that the dissolution rate was superior to that of the composition of Example 1.

Figure 1 shows the saturation concentration of the lacidipine in the aqueous solution according to Experimental Example 1.

Figure 2 shows the saturation concentration of the lacidipine in 0.05% solution of Tween80 according to Experimental Example 1.

Figure 3 shows the dissolution rate of the lacidipine for each time according to Experimental Example 2.

Claims (8)

Lacidipine free base; Hydroxypropylmethylcellulose; Crospovidone; And A high blood pressure therapeutic composition comprising a pharmaceutically acceptable additive. delete The method of claim 1, A high blood pressure therapeutic composition comprising lassipinepine freebase: hydroxypropylmethylcellulose in a weight ratio of 1: 4 to 1:30. The method of claim 1, A high blood pressure therapeutic composition comprising lassipinepine freebase: hydroxypropylmethylcellulose in a weight ratio of 1: 7 to 1:10. The method of claim 1, The pharmaceutically acceptable additive is at least one selected from the group consisting of excipients, binders, disintegrants and lubricants. delete The method of claim 1, Rasidipine free base: high blood pressure therapeutic composition comprising crospovidone in a weight ratio of 1: 1 to 1:15. The method of claim 1, A composition for treating high blood pressure comprising lacidipine free base: crospovidone in a weight ratio of 1: 3 to 1:10.

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