KR20100069170A - Lacidipine containing granules and pharmaceutical composition comprising the same - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing lacidipine-containing granule is provided to ensure high elution rate and solubility and to enhance accumulated elution rate. CONSTITUTION: A lacidipine-containing granule is formed by coating lacidipine, surfactant, and polyvinyl pyrrolidone on the surface of water-soluble saccharide particle. The content of surfactant is 5-200 weight parts based on 100 weight parts of lacidipine. The content of polyvinylpyrrolidone is 50-1500 weight parts based on 100 weight parts of lacidipine. The coating is performed by spray-coating on the water-soluble saccharide.

Description

Lacidipine containing granules and pharmaceutical composition comprising the same}

The present invention relates to lacidipine-containing granules and pharmaceutical compositions comprising the same. More particularly, it relates to lacidipine-containing granules and pharmaceutical compositions comprising them which exhibit good dissolution rates and solubility in aqueous media and thus can exhibit high bioavailability.

Lacidipine is (E) -4- [2- [3- (1,1-dimethylethoxy) -3-oxo-1-propenyl] phenyl] -1,4-dihydro having the structure of formula (1). As -2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester, it is a 1,4-dihydropyridine derivative useful as a therapeutic agent for hypertension (British Patent Publication No. 2,164,336).

Lassidipine reduces intracellular calcium concentration by limiting the large influx of calcium through the membrane, thus reducing cardiovascular disorders such as hypertension, arteriosclerosis, angina pectoris, myocardial ischemia, congestive heart failure, cerebrovascular and peripheral disorders, aorta It is useful for the prevention and treatment of sclerosis, atherosclerotic aneurysms and renal atherosclerosis.

On the other hand, lacidipine is a poorly water-soluble drug, which is almost insoluble in water and hardly absorbed in the gastrointestinal tract, and thus has low bioavailability. Therefore, there is a need in the art to formulate it as an oral preparation to improve dissolution rate and solubility in aqueous media.

Various formulation methods for solubilizing poorly soluble drugs, for example, using a co-solvent, increasing the surface area by reducing the size of particles through grinding or powder drying, changing the crystalline form to amorphous, The method of making a salt of an acid or a base by attaching counterion to a soluble substance, the method of making into a soluble solid dispersion, etc. are known. However, no effective pharmaceutical method has been reported to improve the dissolution rate and solubility of racidipine.

The inventors have conducted various studies on pharmaceutical methods for improving the dissolution rate and solubility of the poorly soluble drug, lacidipine in the aqueous medium. As a result, it was found that the dissolution rate and solubility of lacidipine is greatly improved when lacidipine is coated with the surfactant and the water-soluble polymer on the surface of the water-soluble sugars and granulated, and formulated into a solid preparation.

Therefore, an object of the present invention is to provide a lacidipine-containing granule with improved dissolution rate and solubility.

It is also an object of the present invention to provide an oral solid preparation formulated from the lacidipine-containing granules.

According to one aspect of the present invention, a lacidipine; Surfactants; And lacidipine-containing granules formed by coating a surface of the particles of water-soluble sugars with a mixture of polyvinylpyrrolidone.

The amount of the surfactant may be in the range of 5 to 200 parts by weight based on 100 parts by weight of lacidipine, and the content of the water-soluble polymer may be in the range of 50 to 1500 parts by weight based on 100 parts by weight of lacidipine. The content of the saccharide may be 1 to 1000 parts by weight based on 1 part by weight of lacidipine. The coating can be carried out by spray-coating the solution obtained by dissolving the mixture in C ₁ -C ₄ alcohols, for example ethanol, onto the water soluble sugars.

According to another aspect of the present invention, there are provided oral solid preparations comprising such radidipine-containing granules, for example oral solid preparations such as tablets, capsules.

Lacidipine-containing granules according to the present invention exhibit excellent dissolution rates and solubility in aqueous media and thus can exhibit high bioavailability. Particularly, solid preparations such as tablets obtained from the lacidipine-containing granules according to the present invention can increase the cumulative dissolution rate up to 30 minutes or more compared with the conventional formulations, and thus exhibit not only rapid pharmacological activity but also excellent bioavailability. Can be represented.

The present invention Lacidipine; Surfactants; And a mixture of polyvinylpyrrolidone is coated on the surface of the particles of water-soluble sugars to provide lacidipine-containing granules.

The lacidipine-containing granules according to the present invention significantly improved the solubility of the insoluble drug rashidipine by formulating a combination of a surfactant and a water-soluble polymer, and particularly a solid preparation such as a tablet obtained from the lacidipine-containing granules was 30 Since the cumulative dissolution rate up to 2 times or more can be increased, not only rapid pharmacological activity but also excellent bioavailability can be expected.

The surfactants contained in the lacidipine-containing granules of the present invention include polyoxyethylene sorbitan fatty acid esters (eg, polysorbates 20, 40, 60, 80, etc.); Sucrose fatty acid esters; Polyoxyethylene glycol esters (eg, Solutol HS15, etc.); polyoxyethylene glycolated natural or hydrogenated castor oils (eg, Cremophor EL, RH40, RH60, etc.); Polyoxylglycerides (eg, Gelucire 44/14, 50/13, etc.); Polyethylene glycol 400 monostearate (eg, Myrj 45); Polyoxyethylene-polyoxypropylene block copolymers (eg, poloxamer 188, poloxamer 407, etc.); Sodium dioctylsulfosuccinate; Vitamin E TPGS (D-alpha tocopheryl polyethylene glycol succinate); And caprylocaproyl macrogol glyceride (eg, Labrasol). Preferably the surfactant may be polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester, polyoxyethylene glycol ester, polyoxylglyceride, polyoxyethylene glycolated natural or hydrogenated castor oil, or sodium dioctylsulfosuccinate More preferably, the surfactant may be polyoxyethylene sorbitan fatty acid ester.

The amount of the surfactant may be in the range of 5 to 200 parts by weight, more preferably 25 to 150 parts by weight based on 100 parts by weight of lacidipine. When the amount of the surfactant is less than 5 parts by weight, the dissolution rate may not be improved to a satisfactory level. When the amount of the surfactant is used in excess of 200 parts by weight, liquid or semi-solid surfactant may be present in excess, so that sticking and And / or problems such as reduced hardness.

The lacidipine-containing granules of the present invention comprise polyvinylpyrrolidone as the water soluble polymer. The polyvinylpyrrolidone, in combination with a surfactant, not only reduces the interfacial tension of the poorly soluble drug, radicipine, but also enhances the permeability of moisture, thereby effectively improving the rapid dissolution and solubility of the lacidipine. In addition, as shown in the following test example, when formulated using another water-soluble polymer, for example, a water-soluble polymer such as hydroxypropyl cellulose widely used in the field of formulation, the effect of improving the dissolution rate of lassicipine does not appear. In view of this, it is assumed that polyvinylpyrrolidone in the granules according to the present invention performs a different function from other water soluble polymers.

The amount of the water-soluble polymer may be 50 to 1500 parts by weight, more preferably about 1000 parts by weight based on 100 parts by weight of lacidipine. If the amount of the water-soluble polymer is less than 50 parts by weight, the dissolution rate and / or solubility may not be improved to a satisfactory level. If the amount of the water-soluble polymer exceeds 1500 parts by weight, the size of the granules may be too large, and sticking may be performed. A tableting disorder can occur.

Lacidipine-containing granules of the present invention include lacidipine; Surfactants; And a mixture of polyvinylpyrrolidone is formed by coating the particle surface of the water-soluble sugars. The water-soluble sugars may be water-soluble carriers commonly used in the pharmaceutical field, for example, from the group consisting of lactose, sucrose, mannitol, erythritol, isomalt, maltitol, xylitol, sorbitol, trehalose and dextrose. One or more may be selected. Preferably, a high density and easily soluble lactose can be used. The amount of the water-soluble sugars may be 1 to 1000 parts by weight, more preferably 20 to 100 parts by weight based on 1 part by weight of lacidipine, but is not limited thereto.

The coating comprises lacidipine; Surfactants; And spray-coating on the water-soluble sugars in a solvent capable of dissolving a mixture of polyvinylpyrrolidone, for example C ₁ -C ₄ alcohol, preferably ethanol. The amount of the solvent used is not particularly limited and may be used in an appropriate range for preparing a spray-coating solution. For example, when ethanol is used as the solvent, about 4000 parts by weight may be used based on 100 parts by weight of lacidipine. When the amount of the solvent is too low, lacidipine; Surfactants; And it may be difficult to completely dissolve the mixture of polyvinylpyrrolidone, and if too large (eg, in excess of about 6000 parts by weight), the drying time may be long and the manufacturing process may be inefficient.

The present invention also provides an oral solid preparation comprising the above-mentioned lacidipine-containing granules.

Oral solid preparations according to the present invention may include additives commonly used in the pharmaceutical art, for example, excipients (diluents), binders, glidants and the like. The excipient (diluent) is lactose, white sugar, glucose, fructose, mannitol, corn starch, potato starch, wheat starch, pregelatinized starch, microcrystalline cellulose, cellulose derivatives, dextrin, calcium dihydrogen phosphate, calcium dihydrogen phosphate, Calcium carbonate, potassium polyacrylic acid, acetic acid, ammonium carbonate, ammonium phosphate, boric acid, lactic acid, citric acid, potassium phosphate, sodium phosphate, sodium acetate, sodium citrate, sodium lactate, ascorbic acid, ascorbyl parmitate and the like Glidants include colloidal silicon dioxide, talc, sodium stearyl fumarate, stearic acid, rotoesters, hydrogenated castor oil, and the like. In addition, oral solid preparations according to the present invention may further include a conventional film coating, a coating layer by sugar coating.

The oral solid preparations include tablets, capsules and the like, preferably tablets. Tablets may be prepared according to conventional tablet preparation methods and may be prepared, for example, by mixing the lacidipine-containing granules with excipients, glidants and then tableting (ie, direct tableting). In addition, the amount of lacidipine contained in the oral solid preparation may include a content known as a therapeutically effective amount, and may be appropriately adjusted according to the usage. The daily dosage of the oral solid preparation may range from 0.1 to 50 mg, and may be administered in one or more times. The dosage can be adjusted by one skilled in the art according to the age and condition of the patient.

Hereinafter, the present invention will be described in more detail through Examples and Test Examples. However, these Examples and Test Examples are for illustrating the present invention, and the scope of the present invention is not limited to these Examples and Test Examples.

Example 1.

Radidipine-containing granules were prepared according to the ingredients and contents in Table 1 below. In other words, lacidipine, polysorbate 80, and polyvinylpyrrolidone were dissolved in ethanol. Granules were prepared by spray-coating the solution under the following conditions while flowing lactose into the spray dryer: Inlet Temp. 50 ° C., Outlet Temp. -35 ℃

ingredient weight % Lacidipine 1.3 Polysorbate 80 1.3 Polyvinylpyrrolidone 13.3 Lactose (granulated) 70.7 Lactose (tablet manufacturing) 7.9 Hydroxypropyl cellulose 5.0 Magnesium stearate 0.5 Ethanol anhydride 52.7

The obtained granules were mixed with hydroxypropyl cellulose, lactose and magnesium stearate, and compressed into tablets.

Examples 2-4

According to the ingredients and contents (% by weight) of Table 2 below, a radidipine-containing granule and a tablet were prepared in the same manner as in Example 1.

ingredient Example 2 Example 3 Example 4 Lacidipine 1.3 1.3 1.3 Polysorbate 80 0.3 0.6 2.0 Polyvinylpyrrolidone 13.3 13.3 13.3 Lactose (granulated) 70.7 70.7 70.7 Lactose (tablet manufacturing) 8.9 8.6 70.2 Hydroxypropyl cellulose 5.0 5.0 5.0 Magnesium stearate 0.5 0.5 0.5 Ethanol anhydride 52.7 52.7 52.7

Example 5-18

According to the components and contents of Tables 3 to 11 below, the radidipine-containing granules and tablets were prepared in the same manner as in Example 1. In Tables 3 to 11, each content represents the content per tablet.

ingredient Example 5 Example 6 Lacidipine 4mg 6mg Sucrose Fatty Acid Ester 4mg 12mg Polyvinylpyrrolidone 40mg 30mg Lactose (granulated) 218 mg 302mg Lactose (tablet manufacturing) 21mg 27mg Hydroxypropyl cellulose 15 mg 19mg Magnesium stearate 1.5mg 4mg Ethanol anhydride 52.7 mg 52.7 mg

ingredient Example 7 Example 8 Lacidipine 2mg 6mg Gelushi 44/14 1mg 6mg Polyvinylpyrrolidone 20mg 60mg Lactose (granulated) 108mg 270mg Lactose (tablet manufacturing) 10mg 27mg Hydroxypropyl cellulose 7.5mg 27mg Magnesium stearate 1.5mg 4mg Ethanol anhydride 26.35mg 79.05mg

ingredient Example 9 Example 10 Lacidipine 4mg 8mg Solutol HS15 4mg 4mg Polyvinylpyrrolidone 40mg 85 mg Lactose (granulated) 218 mg 419 mg Lactose (tablet manufacturing) 21.8mg 48mg Hydroxypropyl cellulose 15.3mg 30mg Magnesium stearate 1.5mg 6mg Ethanol anhydride 52.7 mg 105.4 mg

ingredient Example 11 Example 12 Lacidipine 4mg 6mg Cremophor EL 4mg 10mg Polyvinylpyrrolidone 40mg 58mg Lactose (granulated) 218 mg 356 mg Lactose (tablet manufacturing) 21.8mg 40mg Hydroxypropyl cellulose 15 mg 25mg Magnesium stearate 1.5mg 5mg Ethanol anhydride 52.7 mg 79.05mg

ingredient Example 13 Example 14 Lacidipine 6mg 4mg Dioctylsulfosuccinate sodium 0.3mg 4mg Polyvinylpyrrolidone 90 mg 40mg Lactose (granulated) 255.7 mg 218 mg Lactose (tablet manufacturing) 24mg 21mg Hydroxypropyl cellulose 20mg 15 mg Magnesium stearate 4mg 1.5mg Ethanol anhydride 79.05mg 52.7 mg

ingredient Example 15 Lacidipine 4mg Labrasol 10mg Polyvinylpyrrolidone 60mg Lactose (granulated) 365.5 mg Lactose (tablet manufacturing) 44 mg Hydroxypropyl cellulose 15 mg Magnesium stearate 1.5mg Ethanol anhydride 52.7 mg

ingredient Example 16 Lacidipine 3mg Vit E TPGS 1.5mg Polyvinylpyrrolidone 1.5mg Lactose (granulated) 255 mg Lactose (tablet manufacturing) 24mg Hydroxypropyl cellulose 12.5mg Magnesium stearate 2.5mg Ethanol anhydride 50.5mg

ingredient Example 17 Lacidipine 6mg Myrj 45 1.5mg Polyvinylpyrrolidone 90.5mg Lactose (granulated) 257mg Lactose (tablet manufacturing) 24mg Hydroxypropyl cellulose 17.5mg Magnesium stearate 3.5mg Ethanol anhydride 79.05mg

ingredient Example 18 Lacidipine 6mg Poloxamer 188 12mg Polyvinylpyrrolidone 90 mg Lactose (granulated) 244mg Lactose (tablet manufacturing) 24mg Hydroxypropyl cellulose 20mg Magnesium stearate 4mg Ethanol anhydride 79.05mg

Test Example 1: Comparative Dissolution Test

Examples 1 to 5, 8, 9, 11, and commercially available tablets [Paksar tablet 4mg, GSK] dissolution test was carried out according to the method of the Korean Pharmacopeia 9 tablet dissolution test method 2 under the conditions of pH 4.0 acetate buffer eluate. . The sample solution was filtered and diluted with methanol, and HPLC analysis conditions were as follows.

[Analysis Condition]

Column: Luna C18 (4.6 × 30 mm, 3 μm)

Detector: UV absorbance (measured wavelength: 284 nm)

Flow rate: 1.5 ml / min

Column temperature: 40 ℃

Mobile phase: Mixed solution of 2 mM acetic acid buffer and methanol (25:75, v / v)

The dissolution rate after 30 minutes is shown in Table 12 below, and the cumulative dissolution rate change for each 30 minutes is as shown in FIGS. 1 to 3.

division Dissolution rate after 30 minutes Example 1 66% Example 2 42% Example 3 53% Example 4 64% Example 5 45% Example 8 43% Example 9 40% Example 11 56% Commercially available 33%

Test Example 2 Comparative Test of Water-Soluble Polymer

Granules were prepared in the same manner as in Example 1 using hydroxypropylcellulose as a water-soluble polymer instead of polypyrrolidone, and tablets (Comparative Example 1) were prepared using the same (see Table 13).

ingredient Comparative Example 1 (% by weight) Lacidipine 1.3 Polysorbate 80 1.3 Hydroxypropyl cellulose (granulated) 13.3 Lactose (granulated) 70.7 Lactose (tablet manufacturing) 7.9 Hydroxypropyl cellulose 5.0 Magnesium stearate 0.5 Ethanol anhydride 52.7

The dissolution test of the tablets obtained in Example 1 and Comparative Example 1 in the same manner as in Test Example 1 is the same as FIG. As can be seen in Figure 4, it can be seen that the effect of improving the dissolution rate when hydroxypropyl cellulose is used as the water-soluble polymer.

Test Example 3: Pharmacokinetic Study

After the oral administration of the tablet and the commercially available product [Ph.D. tablet 4mg, GSK] obtained in Example 1 to human (n = 6), blood was collected from the vein at a predetermined time to determine the blood drug concentration in a known method (Ramakrishna NV, Vishwottam KN). , Puran S, Manoj S, Santosh M, Koteshwara M, Siple, Sensitive and rapid liquid chromatographic / electrospray ionization tandem mass spectrometric method for the quantification of lacidipine in human plasma.J Mass Spectrom ., 824-32, 39 (7), 2004).

The blood drug concentrations of the tablets and commercial preparations obtained in Example 1 are as shown in FIG. ml and 10.959 ng.hr/ml for commercially available formulations. Thus, the tablets obtained from the lacidipine-containing granules according to the present invention exhibited an excellent bioavailability since the AUC was increased by at least about 43% compared to commercially available formulations.

1 to 4 show the results of the dissolution test performed on the tablets prepared according to the present invention, comparative preparations, and commercially available formulations. (FIG. 1: tablet and commercial formulation of Example 1, FIG. 2: tablet and commercial formulation of Examples 2-4, FIG. 3: tablet and commercial formulation of Examples 5, 8, 9, and 11, FIG. 4: practice Tablet of Example 1 and Comparative Example 1)

Figure 5 shows the pharmacokinetic test results for tablets and commercial preparations prepared according to the present invention.

Claims (6)

Lacidipine; Surfactants; And lacidipine-containing granules formed by coating a surface of the particles of water-soluble sugars with a mixture of polyvinylpyrrolidone. According to claim 1, wherein the content of the surfactant is a lacidipine-containing granules, characterized in that from 5 to 200 parts by weight based on 100 parts by weight of lacidipine. According to claim 1, wherein the polyvinylpyrrolidone content of the lasidipine-containing granules, characterized in that 50 to 1500 parts by weight based on 100 parts by weight of lacidipine. According to claim 1, wherein the content of the water-soluble sugar is a rashidipine-containing granules, characterized in that 1 to 1000 parts by weight with respect to 1 part by weight of rashidipine. The granidipine-containing granules according to claim 1, wherein the coating is carried out by spray-coating the solution obtained by dissolving the mixture in C ₁ -C ₄ alcohols on the water-soluble sugars. Oral solid preparation comprising the lacidipine-containing granules according to any one of claims 1 to 5.

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