KR101798184B1 - Composition for Controlled Release of Drug - Google Patents

Abstract

The present invention relates to a composition for controlling drug release. Specifically, the drug release controlling composition of the present invention expands the controllability of release of the polymer for western blotting to a carbomer in which matrix type western blending polymer forms a basic skeleton and sol-gel conversion occurs according to pH. The present invention is particularly characterized in that a solubilizing agent is suitably used in the case where the drug to be released is highly soluble and further contains a disintegrant for sufficient initial release. The composition for controlling drug release of the present invention can be prepared by introducing a carbomer having a sol-gel conversion property while retaining the sustained release of the conventional matrix structure of the polymer for sustained release to prevent the rapid release of the drug due to collapse of the late matrix structure have. In addition, solubilization of the high solubility drug due to the introduction of the solubilizer was solved even after the release, and the initial release rate, which is the limit of the sustained release preparation, was improved by introducing the disintegrant.

Description

[Composition for Controlled Release of Drug]

The present invention relates to a composition for controlling drug release. Specifically, the drug release controlling composition of the present invention expands the controllability of release of the polymer for western blotting to a carbomer in which matrix type western blending polymer forms a basic skeleton and sol-gel conversion occurs according to pH. The present invention is particularly characterized in that a solubilizing agent is suitably used in the case where the drug to be released is highly soluble and further contains a disintegrant for sufficient initial release.

Compared to conventional rapid release formulations, controlled release formulations provide sustained release of the drug over a period of time in the body, thus maintaining the effective blood level of the drug for a prolonged period of time. Therefore, it is possible to reduce the amplitude of the blood concentration caused by frequent administration of a conventional preparation, thereby reducing the side effect, and further reducing the frequency of administration, thereby improving the compliance of the patient with the medication.

Many methods have been used to prepare sustained-release preparations having high efficacy and stability, and among them, the most easily formulated formulation is a sustained-release matrix tablet. Sustained-release matrix tablets are mainly used in the pharmaceutical industry because they can be manufactured using common manufacturing techniques and equipments, and refers to forms in which drugs dissolve gradually from the outside in the gastric juice. Examples of such a base material include a western polymer, for example, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), Carbopol, polyethylene oxide (PEO) .

However, once the matrix structure is collapsed, the sustained-release matrix preparation has a problem that the drug is rapidly released and the blood concentration temporarily increases.

In addition, when the drug itself is highly solubilized, some of the drug may remain in a non-dissolved state even after the matrix structure collapses, which is uneconomical.

In addition, due to the nature of the matrix structure, there is a low initial release rate, which may be a disadvantage in situations where rapid expression is required.

Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made in order to solve the above-mentioned problems, and it is an object of the present invention to provide a drug delivery system capable of suppressing rapid release of a drug even after collapse of a matrix structure, And to provide a novel drug release control composition with improved drug release control.

It is another object of the present invention to provide a cilostazol sustained-release tablet which can appropriately control the release by the drug release controlling composition to prevent side effects due to rapid release.

It is another object of the present invention to provide a levamidase sustained-release tablet which can appropriately control the release by the drug release controlling composition and prevent side effects due to rapid release.

It is still another object of the present invention to provide a sustained-release sustained-release pharmaceutical composition which can appropriately control the release by the drug release controlling composition and prevent side effects due to rapid release.

The composition for controlling drug release of the present invention, in order to achieve the above object,

100 parts by weight of a western polymer,

5 to 100 parts by weight of a carbomer,

10 to 200 parts by weight of a solubilizing agent, and

30 to 70 parts by weight of a disintegrant

And a control unit.

In addition, the above-mentioned polymer for the sustained release is preferably a polymer such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), Carbopol, polyethylene oxide (PEO) May be hydroxypropyl methylcellulose (HPMC).

In addition, the viscosity of the polymer for the sustained release may be 50,000 to 150,000 cps, preferably 80,000 to 120,000 cps.

The solubilizing agent may also be sodium lauryl sulfate, Labrafil, Labrasol, Tween 60 or a mixture thereof, preferably sodium lauryl sulfate.

The disintegrant may also be selected from the group consisting of Crosscamellose-Na, Sodium starch glycolate, Pregelatinized Starch, microcrystalline cellulose, Crospovidone , cross-linked povidone) and other commercially useful polyvinylpyrrolidone (PVP), low substituted hydroxypropyl cellulose (low substituted), alginic acid, carboxymethylcellulose, calcium salt And sodium salt, colloidal silica collidal silica, guar gum, magnesium alumimum silicate, methylcellulose, powdered cellulose, starch, sodium alginate, alginate, and mixtures thereof.

The drug may also be cilostazol, rebamipide, aripiperazole, irbesartan, atazanavir or lubuconazole.

The content of the drug may be 10 to 2000 parts by weight, preferably 20 to 1900 parts by weight, per 100 parts by weight of the polymer for sustained release.

Meanwhile, the cilostazol sustained-

100 parts by weight of a western polymer,

5 to 100 parts by weight of a carbomer,

10 to 200 parts by weight of a solubilizing agent,

30 to 70 parts by weight of a disintegrant, and

1000 to 1900 parts by weight of cilostazol

And a control unit.

Meanwhile, the levamidipedia sustained-release tablet of the present invention

100 parts by weight of a western polymer,

5 to 100 parts by weight of a carbomer,

10 to 200 parts by weight of a solubilizing agent,

30 to 70 parts by weight of a disintegrant, and

Rebamipide 750 to 1500 parts by weight

And a control unit.

Meanwhile, the sustained release of aripiperazole of the present invention

100 parts by weight of a western polymer,

5 to 100 parts by weight of a carbomer,

10 to 200 parts by weight of a solubilizing agent,

30 to 70 parts by weight of a disintegrant, and

20 to 100 parts by weight of < RTI ID = 0.0 >

And a control unit.

The composition for controlling drug release of the present invention can be prepared by introducing a carbomer having a sol-gel conversion property while retaining the sustained release of the conventional matrix structure of the polymer for sustained release to prevent the rapid release of the drug due to collapse of the late matrix structure have. In addition, solubilization of the high solubility drug due to the introduction of the solubilizer was solved even after the release, and the initial release rate, which is the limit of the sustained release preparation, was improved by introducing the disintegrant.

Fig. 1 is a graph showing the dissolution rate test results in a state in which the solubilizer and the disintegrant are not contained.
2 is a graph showing a dissolution rate test result in a state in which a solubilizing agent is contained.
Fig. 3 is a graph showing the dissolution rate test results in the state that the solubilizer and the disintegrant are contained. Fig.
Figure 4 is a graph showing the results of the nonclinical test of the present invention containing solubilizing agent and disintegrant.
Figure 5 is a graph showing the results of a single clinical trial of the present invention comprising a solubilizer and a disintegrant.
FIG. 6 is a graph showing dissolution rate test results of another drug containing a solubilizing agent and a disintegrant. FIG.

Hereinafter, preferred embodiments of the present invention will be described in detail. In the following description, numerous specific details, such as specific elements, are set forth in order to provide a thorough understanding of the present invention, and it is to be understood that the present invention may be practiced without these specific details, It will be obvious to those who have knowledge of. In the following description of the present invention, a detailed description of known functions and configurations incorporated herein will be omitted when it may make the subject matter of the present invention rather unclear.

The drug release controlling composition of the present invention comprises

100 parts by weight of a western polymer,

5 to 100 parts by weight of a carbomer,

10 to 200 parts by weight of a solubilizing agent, and

30 to 70 parts by weight of a disintegrant

And a control unit.

The preparation for delaying the elution of the pharmacologically active ingredient is prepared by mixing a polymer for sustained release. In the present invention, the sustained-release polymer may be any polymer that is pharmaceutically acceptable. Examples of the polymer include methylcellulose, ethylcellulose, Cellulose derivatives such as cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, propylene oxide and derivatives thereof, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, polyvinyl acetate phthalate , Polymethacrylates and derivatives thereof, Carbopol, polyethylene oxide, glycerol monostearate, poloxamer and copolymers or mixtures thereof, preferably hydroxypropylmethylcellulose.

Preferably, it may be hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and copolymers or mixtures thereof, and more preferably hydroxypropylcellulose.

The inventors of the present invention found that, in the case of a preparation requiring sustained release, a long release time and a constant drug elution pattern are observed when carbomers are mixed with a common sustained-release polymer in comparison with a single-component sustained release polymer. It has also been found that the release pattern can be controlled by controlling the weight ratio of the polymer for western use to that of carbomer.

Rapid dissolution of the drug may cause tachycardia, headache or headache, so maintaining and controlling a constant dissolution rate is also an important factor in Western medicine. A sustained-release polymer such as hydroxypropyl methylcellulose can form a matrix that prevents the rapid elution of the pharmacologically active ingredient within the tablet, thereby securing a long elution time. In addition, it exhibits a certain elution pattern compared to other western polymers.

However, in the case of the sustained-release tablet containing a pharmacologically active ingredient, the tablet exhibits a swelling phenomenon upon elution. In this case, if the matrix of the western polymer is not rigid, the matrix may be partially damaged and the tablet may be disintegrated, leading to rapid drug release, which may cause headache or flushing to the patient. In order to solve such a problem, in the present invention, a polymer for western blending and a carbomer were mixed.

The carbomer may be solely used as a solubilized polymer, but sol-gel conversion is caused according to pH, and in the present invention, it is mixed with another solubilized polymer. Specifically, the carbomer exists in a sol state from an acidic state, and the drug release is maintained by the sustained-release polymer. In the case of the small intestine, which is an alkaline condition, the drug exists in a hydrogel state to control the drug release. It also has the effect of strengthening the matrix in the drug when used together with the polymer for sustained release. It keeps the shape of the tablet expansion and maintains the matrix of the tablet, thereby preventing the tablets from falling off and maintaining a constant dissolution rate.

The sustained-release polymer used in the present invention is preferably a sustained-release polymer having a viscosity of 50,000 to 150,000 cps, preferably 80,000 to 120,000 cps. If the viscosity is less than 50,000 cps, a large amount of a sustained-release polymer is required, which leads to a large size of the tablet. When the viscosity exceeds 150,000 cps, uniform mixing with the pharmacological component becomes difficult. Even if the same viscosity is used, products with better physical shape with better dispersion and better grinding of particles are used.

It is preferable that the weight ratio of the polymer for release to the carbohydrate in the drug release controlling composition according to the present invention is a ratio of 5 to 100 parts by weight of carbomer per 100 parts by weight of the polymer for sustained release. When the amount of the carbomer is less than the above range, sustained release in an alkali condition is difficult to be ensured. If the amount of the carbomer is more than the above range, the dissolution rate of the drug is excessively lowered under alkaline conditions, and uniform mixing of the drug and the western polymer is difficult.

The formulation containing the drug release controlling composition according to the present invention exhibits a constant dissolution rate depending on the change in pH. Surfactants administered orally will remain in the human body for more than 8 hours, and the gastric and small intestine residing in the intestine for a long time should have a very high pH change, so that the sustained release agent should maintain a constant dissolution rate depending on the pH. The formulation containing the drug release controlling composition according to the present invention maintains a uniform dissolution rate at pH 1.2 (artificial gastric juice) and pH 6.8 (artificial intestinal fluid).

Meanwhile, the drug to which the composition for controlling drug release according to the present invention is applied may include substances having very low solubility. In this case, the solubility of the drug may be further deteriorated due to the addition of the sustained release system of the present invention. This results in a rapid release of the drug after administration, making it difficult to expect the initial pharmacological effect.

The main feature of the present invention is to add a solubilizing agent for solving the problem of solubility of poorly soluble drugs. The solubilizing agent usable in the present invention may be any pharmaceutically acceptable solubilizing agent, and specifically includes sodium lauryl sulfate, Labrafil, Labrasol, Tween 60 (Tween 60 ) Or a mixture thereof, preferably sodium lauryl sulfate.

The amount of the solubilizing agent is preferably 10 to 200 parts by weight per 100 parts by weight of the sustained-release polymer. If the amount is less than the above range, the drug can not reach the critical micelle concentration, On the other hand, when the concentration exceeds the above range, the concentration of the free drug may decrease and the absorption of the drug may decrease.

On the other hand, the above-mentioned low initial release rate can be attributed to the matrix structure itself formed by the sustained-release polymer. To prevent this, when the sustained release polymer itself is contained in a small amount, the release is controlled by the collapse of the preparation itself Which can not be solved. To solve this problem, the present invention has been able to achieve overall release control while maintaining an initial release rate above a certain level by introducing an appropriate proportion of the disintegrant. Disintegrants which can be used in the present invention may be any pharmaceutically acceptable solubilizing agent, and specifically include Crosscamellose-Na, sodium starch glycolate, pregelatinized starch glycolate, It is also possible to use pregelatinized starch, microcrystalline cellulose, crospovidone (cross-linked povidone) and other commercially available polyvinylpyrrolidone (PVP), low-substituted hydroxypropylcellulose alginic acid, carboxymethylcellulose, calcium salt and sodium salt, fumed silica collidal silica, guar gum, magnesium alumimum silicate, Methylcellulose, powdered cellulose, starch, sodium alginate alginate, and mixtures thereof.

It is preferable that the content of the disintegrant is 30 to 70 parts by weight per 100 parts by weight of the sustained release polymer. If the amount is less than the above range, water will not penetrate into the tablet and cause a sufficient wetting action through capillary action, On the other hand, if the amount exceeds the above range, rapid expansion of the tablet and simultaneous drug release are promoted, leading to an increase in dissolution of the initial drug and promotion of absorption, which may cause side effects.

The drug to be delivered through the drug release controlling composition of the present invention can be used without limitation as long as it is a drug that requires sustained release. Particularly, cilostazol, rebamipide, aripiperazole, irbesartan, atazanavir, In the case of labuconazole, the advantages of the present invention are significantly expressed.

The content of the drug may be 10 to 2000 parts by weight, preferably 20 to 1900 parts by weight, per 100 parts by weight of the polymer for sustained release. If the amount of the drug is less than the above range, the release time is long and the drug elution amount per unit time is small, so that sufficient effect can not be expected. On the contrary, if the above range is exceeded, the release time of the drug is shortened and the elution amount per unit time is increased.

Meanwhile, the cilostazol sustained-

100 parts by weight of a western polymer,

5 to 100 parts by weight of carbomer,

10 to 200 parts by weight of a solubilizing agent,

30 to 70 parts by weight of a disintegrant, and

1000 to 1900 parts by weight of cilostazol

And a control unit.

Meanwhile, the levamidipedia sustained-release tablet of the present invention

100 parts by weight of a western polymer,

5 to 100 parts by weight of carbomer,

10 to 200 parts by weight of a solubilizing agent,

30 to 70 parts by weight of a disintegrant, and

Rebamipide 750 to 1500 parts by weight

And a control unit.

Meanwhile, the sustained release of aripiperazole of the present invention

100 parts by weight of a western polymer,

5 to 100 parts by weight of carbomer,

10 to 200 parts by weight of a solubilizing agent,

30 to 70 parts by weight of a disintegrant, and

20 to 100 parts by weight of < RTI ID = 0.0 >

And a control unit.

Hereinafter, embodiments of the present invention will be described.

Example

Test Example  1: dissolution rate experiment

The elution test was carried out according to the seventh revised elution test method described in Korean Pharmacopoeia. PH 7.8 phosphate buffer solution was used as the eluent, and the paddle method was used for the elution. The eluent was 900 ml, the stirring rate was 100 rpm, and the elution temperature was 37 ± 0.5 ° C. 5 ml of sample was taken at 0, 5, 10, 15, 30, 45, and 60 minutes, and the same amount of eluate was added. For the analysis conditions, the solution obtained from the above dissolution test was filtered with 0.45 ㎛ membrane filter, and aceclofenac was quantified by HPLC. The analytical wavelength was 277 nm, the mobile phase was acetonitrile: pH 7.4 phosphate buffer = 68:32 solution, the flow rate was 1.0 ml / min and the column was C18 ODS.

Comparative Example  : With solubilizing agent The disintegrant  No formulations

Each formulation described in Table 1 below was prepared using the following manufacturing process. First, povidone K-30 and carbomer (50%) were dispersed and dissolved in ethanol to prepare a binding solution. Next, cilostazol, microcrystalline cellulose, carbomer (50%) and hydroxypropylmethylcellulose were mixed well using a speed mixer and wet granulation was carried out in a cylindrical granulator using a binding liquid. The granules thus obtained were dried in a drying oven (40 ° C.) for 12 hours or more and sieved with a 40-mesh sieve. Light anhydrous silicic acid and magnesium stearate were further mixed with the semi-finished product and the mixture was weighed to the weight per one unit described below. A constant amount of cilostazol sustained release prepared in the following Examples was subjected to a dissolution test according to the above Test Example. A 0.5 W / W% aqueous solution of sodium lauryl sulfate was used as the eluent. The elution was carried out by the paddle method, the eluent was 900 ml, the stirring speed was 75 rpm, and the elution temperature was 37 ± 0.5 ° C. 5 ml of the sample was taken at 15, 30, 60, 90, 120, 240, 360, 480, 600, 720 minutes and the same amount of the eluate was added. For the analysis conditions, the solution obtained by the above elution test was filtered with 0.45 ㎛ membrane filter, and cilostazol was quantified by HPLC. The analytical wavelength of the 257 nm mobile phase was acetonitrile: water = 40:60 and octadecylsilylated column was used.

Classification
ingredient Prescription 1 Prescription 2 Prescription 3 Prescription 4 content
(mg) Content ratio
(%) content
(mg) Content ratio
(%) content
(mg) Content ratio
(%) content
(mg) Content ratio
(%) Pharmacological
Active ingredient Cilostazol 200 40 200 38.46 200 42.55 200 33.33
Western Dragon
Polymer Carbomer 50 10 70 13.46 10 4.25 50 8.33 Hydroxypropyl
Fill methyl cellulose
(100,000 cps) 100 20 100 19.23 100 21.27 200 33.33 Binder Povidone K-30 25 5 25 4.8 25 5.31 25 4.16 Filler Microcrystalline cellulose 100 20 100 19.23 100 21.27 100 16.66 Light anhydrous silicic acid 10 2 10 1.92 10 2.12 10 1.66 Lubricant Stearic acid
magnesium 15 3 15 2.88 15 3.19 15 2.5 1 Total weight 500 100 520 100 470 100 600 100

The dissolution rate results for the prescriptions of the comparative example are shown in FIG. 1, and it was confirmed that sufficient elution was not obtained from the FIG. 1 and the pharmacokinetic data.

Example  1: formulation with solubilizing agent

In order to confirm the addition effect of the solubilizing agent, a dissolution test was carried out using a tablet having a mixing ratio as shown in Table 2.

ingredient Content (mg) Content ratio (%) Cilostazol 200 52.77 Carbomer 3 0.79 Hydroxypropyl methylcellulose 13 3.43 Sodium lauryl sulfate 20 5.28 Croscarmellose sodium 4 1.06 Povidone K-30 6 1.58 Microcrystalline cellulose 115 30.34 Light anhydrous silicic acid 10 2.64 Magnesium stearate 8 2.11 1 Total weight 379 100

200.0 mg of the drug cilostazol and each of the excipients were thoroughly mixed, and HPMC and sodium lauryl sulfate as a solubilizing agent were added in a powder mixer, and wet granules were prepared using ethanol as a polymer base . Normally, 10 ml of ethanol was used to prepare 100 tablets of tablets. If necessary, a small amount of the polymer base in the formulation may be dissolved in a mixed solvent of water or alcohol to granulate the powder. The prepared granules were sufficiently dried in an oven at 60 ° C and then milled evenly. Magnesium stearate was further mixed for the preparation of the preparation by postmixing, and tablets containing cilostazol were prepared using a rotary purifier Respectively.

The elution test was carried out according to the Seventh revised elution test method described in Korean Pharmacopoeia. The test solution was prepared by dissolving 900 ml of sodium lauryl sulfate (0.5%) in 50 rounds per minute according to Method 2 of the dissolution test described in the FDA 37 ± 0.5 ° C. After the start of the dissolution test, the eluate 5 from each of the containers at time 0, 15, 30, 60, 90, 120, 180, 300, 360, 480, 600, 720, 840, 960, 1080, 1220, The solution was filtered through a 0.45 ㎛ membrane filter, and this solution was used as the sample solution. The absorbance values At and As were measured at 257 nm using UV (spectrophotometer, Shimadzu, Japan). The dissolution results are shown in Fig.

Compared with FIG. 1, it can be seen that the initial elution of the drug is better performed in FIG. 2, which is more advantageous in achieving the initial pharmacological effect.

Example  2: solubilizing agent and The disintegrant  The added preparation (1)

In order to confirm the effect of addition of the solubilizing agent and disintegrant, a dissolution test was carried out using tablets having the mixing ratios shown in Table 3.

200.0 mg of the drug cilostazol and each of the excipients were mixed thoroughly according to the mixing ratio shown in Table 3, and the HPMC was uniformly mixed with the polymer base and the wet granules were mixed with ethanol. Normally, 10 ml of ethanol was used to prepare 100 tablets of tablets. If necessary, a small amount of the polymer base in the formulation may be dissolved in a mixed solvent of water or alcohol to granulate the powder. The prepared granules were sufficiently dried in an oven at 60 ° C and then milled evenly. Magnesium stearate was further mixed for the preparation of the preparation by postmixing, and tablets containing cilostazol were prepared using a rotary purifier Respectively.

The degree of fluidity was measured by the angle of repose and the hardness was measured and its suitability was examined. Then, a dissolution test was carried out as in Test Example and Example 1, and the results are shown in FIG.

ingredient Content (mg) Cilostazol 200 Carbomer 5 Hydroxypropyl methylcellulose 15 Sodium lauryl sulfate 20 Croscarmellose sodium 5 Povidone K-30 6 Microcrystalline cellulose 115 Light anhydrous silicic acid 10 Magnesium stearate 8

Compared with FIG. 2, FIG. 3 shows that not only the initial dissolution of the drug is well performed, but also a smooth curve of the dissolution rate, indicating that the dissolution is uniform over the entire dissolution process.

Test Example  2 : Nonclinical  exam

Non-clinical studies were conducted to determine the pharmacokinetics of the drug after oral administration of Example 2 and a control substance (Pretal® tablet) to beagle dogs.

The beagle dogs were orally administered Example 2 and one control substance, and the blood plasma was separated after a predetermined time, and the concentration of cilostazol in the beagle blood plasma was measured. Pharmacokinetic parameters were calculated using AUCt (area under the plasma concentration-time curve from dosing time to final blood concentration time t), AUCi (area under the plasma concentration-time curve from dosing time to infinite time) , Cmax (maximum blood concentration), Tmax (maximum blood concentration reaching time), and t1 / 2 (blood withdrawal half-life). AUCi / dose and Cmax / dose were calculated by dividing AUCi and Cmax by the dose, respectively, and the ratio of AUCt to AUCi was expressed as AUCt / AUCi. The results were confirmed by Student t-test (SPSS) at 95% confidence interval, and the results are shown in Table 4 and FIG.

Control substance Example 2 Cmax / dose (ng / mL) 0.87 ± 0.28 0.62 + - 0.12 Tmax (h) 2.75 ± 0.61 4.17 ± 0.41 T1 / 2 (h) 7.25 ± 6.18 8.34 ± 1.56 AUCt (hng / mL) 307.63 + - 86.14 683.77 ± 90.68 AUC∞ (hng / mL) 333.72 ± 88.73 720.93 + - 95.01 AUC (0-t) / AUC (0-inf),% 92.41 + - 7.59 94.88 ± 3.28 F * (%) - 108.0

Cilostazol in beagle dog plasma was detected from the first sampling time of 1 hour after the administration of the test substance and the control substance, and 5 out of 6 animals in the test substance group were detected up to 36 hours. In 6 of the control group, Were detected up to 36 hours and 2 were detected up to 24 hours, while the remaining 3 were detected up to 12 hours or less.

The AUCt / AUCi of the administration group of Example 2 and the control group were 0.949 and 0.924, respectively, and 94.9% and 92.4% of the cilostazol in the plasma were lost within 36 hours after the administration of the drug.

The AUCi / dose of Example 2 and the control group was 3.60 and 3.34 hr * ng / mL, the Cmax / dose was 0.62 and 0.87 ng / mL, the Tmax was 4.17 and 2.75 hr, the t1 / 2 was 8.34 and 7.25 hr, .

The AUCi / dose ratio and the Cmax / dose ratio of the Example 2 administration group and the control substance administration group were 108.0% and 71.7%, respectively.

The P-values of the pharmacokinetic parameters were 0.530 (AUCi / dose), 0.071 (Cmax / dose), 0.001 (Tmax) and 0.690 (t1 / 2).

In summary, no significant difference was found between AUCi / dose, Cmax / dose, and t1 / 2 of Example 2 and the control substance (Pretal® 100 mg), but there was a significant difference in Tmax. Therefore, it was judged that Example 2 had a pharmacokinetic difference from the control substance, and when the average concentration of cilostazol in the plasma was compared with that of Example 2 and the control substance administration group, the same tendency was observed until 3 hours after administration From then on, it was confirmed that the administration group of Example 2 was maintained at a higher concentration than the control substance administration group.

Test Example  3: One-time clinical  exam

To evaluate the pharmacokinetic properties of cilostazol and cilostazol in oral administration of cilostazol in healthy male subjects with nonclinical formulations, randomized, open, single, fasting, group 2, Cross-over studies were conducted as follows.

- randomly assigned two treatments (fasting) and test drugs (fasting) in random order

- Period of withdrawal: 7 days from the start date of the first dose

- Blood collection time:

13, 14, 15, 16, 17 (first dose after blood collection), 1, 2, 3, 4, 5, 8 and 12 (second dose after blood collection) , 20, 24, 36, 48, 60, 72 (total 19 times)

Test drug (fasting): Before each dose (0h), 1, 2, 3, 4, 5, 6, 8, 12, 24,

- Assessment Methods

(1) Safety evaluation

The adverse events were compared by Fisher's exact test (Mann-Whitney U test) and by non-parametric comparison (Mann-Whitney U test). Other safety assessment items were reviewed for individual values.

1) Adverse reactions: Observe subjective symptoms or signs of embolism.

2) vital signs, physical examination, electrocardiogram, clinical laboratory test

 ① Vital signs: blood pressure (left), heart rate, body temperature (eardrum)

 ② Physical examination

 ③ Electrocardiogram: 12-lead-ECG

 ④ Clinical Laboratory Test

Hematology: Hemoglobin, Hematocrit, RBC, WBC (Leucocytes), Neutrophils, Eosinophils, Basophils, Lymphocytes, Monocytes, Platelet

- Blood chemistry: Creatinine, Total protein, Albumin, sGOT (AST), sGPT (ALT), total bilirubin, Glucose (fast), Total cholesterol, Alkaline phophatase (ALP), BUN, Ca, P, Gamma GT, Triglyceride, HDL-Cholesterol, LDL-Cholesterol, Uric acid, LDH

- Blood coagulation test: PT, aPTT

- Urine test: Specific gravity, Color, pH, Glucose, Albumin,

  (2) Evaluation of pharmacokinetic properties

The pharmacokinetic parameters were calculated after the drug concentration analysis, and the primary endpoint values of the control drug (fasting) and the test drug (fasting) were calculated for the primary endpoints Cmax and AUC72h

- Cilostazol and two active metabolites (OPC-13015; 3,4-dehydro-cilostazol, OPC-13213; 4'-trans-hydroxy-cilostazol) over the 72 hours after cilostazol in- Is measured. The treatment and analysis of clinical specimens are performed using LC-MS / MS according to the analysis conditions established by the laboratory of Hopkins Bio Research Center, Inc. Once established, validation of specificity, linearity, accuracy, precision and sensitivity is completed and applied to sample analysis and the following pharmacokinetic parameters are evaluated.

- Evaluation variable:

Single dose: - Primary endpoint - Cmax, AUCt (t = 72)

- Secondary endpoints - tmax, t1 / 2, AUC∞ Fasting single administration compared the pharmacokinetic properties of the two agents.

(3) Statistical analysis

- demographic information

Statistical analysis was performed to confirm the age, height, body weight, and drinking and smoking status of subjects participating in clinical trials. In the case of continuous variables, either independent Student's t-test or non-parametric comparison (Mann-Whitney U test) was used. For categorical variables, chi-square analysis or Fisher's exact test was used

The total number of subjects was divided as shown in Table 5 below. In the following Table 5, the A treatment is a single administration of Cilostazol 100 mg as a control treatment after one meal twice a day, and the B treatment is the same as that of Example 2 (Cilostazol 200 mg) was administered once a day, followed by a single 7-day withdrawal period. Based on the results of a study by SL Bramer et al. (1999), the AUC ∞ was 8956 ± 2440 ㎍ / L * hr and the Cmax was 625.01 ± 168 ㎍ / L, and the mutation coefficients were 27.2% and 26.9%, respectively. Therefore, the total number of subjects with 80% , A total of 26 people. In this test, three subjects were added to each group considering the number of dropouts, and a total of 32 subjects, 16 subjects per group, were tested.

Sequence test group Number of subjects Test therapy First Second Ⅰ 16 people A B Ⅱ 16 people B A

The results of oral administration of Example 2 in this clinical study are shown in Table 6, and the changes in plasma concentration over time are shown in FIG.

Pharmacokinetic
variable Cilostazol OPC-13015 OPC-13213 Control substance Example 2 Control substance Example 2 Control substance Example 2 Cmax (μg / mL) 1413.052 1414.551 297.159 259.463 145.438 120.872 AUC [infinity (h [mu] g / mL) 26482.49 24738.445 7833.247 7107.002 2889 2363.514

Cmax and AUC were 1414.55 ng / mL, 24738.45 hr-ng / mL for Cilostazol, 259.463 ng / mL and 7107.002 hr-ng / mL for OPC- 13015, 120.872 ng / mL for OPC- 13213, 2363.514 hr- ng / mL, and Cilostazol 1413.05 ng / mL, 26482.49 hr-ng / mL, OPC-13213 297.159 ng / mL, 7833.247 hng / mL, OPC- 13213 145.438 ng / mL, 2889 hng / mL, . The point estimate of the Cmax geometric mean ratio was 1.001 and the 90% confidence interval was 0.8217 to 1.2195. The point estimate of the AUCt geometric mean ratio was 0.934 and the 90% confidence interval ranged from 0.880 to 1.0791, ranging from 0.8 to 1.25. When the test drug used in this trial was clinically applied, its effect would be more closely related to total exposure, ie AUC, and less likely to be related to tmax. Therefore, the efficacy and safety of the drug are not different even if they are used alternately between the two formulations. Thirty-two subjects participated in the study, but there were no statistically significant differences in the number of adverse events and the number of subjects who experienced adverse events when the control material was administered according to Example 2. Clinical laboratory tests, electrocardiograms, vital signs, and physical examinations were not statistically significant and clinically significant differences were not observed, and similar pharmacokinetic characteristics were shown for Cmax and AUCt values.

Example  3: solubilizing agent and The disintegrant  The added formulations (2, 3)

In order to confirm the suitability of the technology for other drugs by using the composition for controlling release of the present invention, each of the excipients was thoroughly mixed with levamidipa and aripiperazoles in the mixing ratios shown in Table 7, Were mixed in a powder mixer and uniformly mixed to prepare wet granules with ethanol. Normally, 10 ml of ethanol was used to prepare 100 tablets of tablets. If necessary, a small amount of the polymer base in the formulation may be dissolved in a mixed solvent of water or alcohol to granulate the powder. The prepared granules were sufficiently dried in an oven at 60 ° C and then milled evenly. Magnesium stearate was further mixed for the preparation of the preparation by postmixing, and tablets containing cilostazol were prepared using a rotary purifier Respectively. The dissolution test of each preparation is the same as the dissolution test described above.

ingredient Content (mg) Rebamipide 300 - Aripiperazole 5 Carbomer 10 3 Hydroxypropyl methylcellulose 28 10 Sodium lauryl sulfate 5 5 Croscarmellose sodium 15 4 Povidone K-30 10 9 Microcrystalline cellulose 100 60 Light anhydrous silicic acid - 2 Magnesium stearate 12 2

Each drug exhibited controlled release over 24 hours as shown in Figure 6, and the trend of its release was also significant with cilostazol.

While the present invention has been described in connection with what is presently considered to be practical exemplary embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, Of course it is possible. Accordingly, the scope of the present invention should not be construed as being limited to the above-described embodiments, but should be determined by equivalents to the appended claims, as well as the following claims.

Claims (8)

100 parts by weight of hydroxypropyl methylcellulose (HPMC) as a polymer for the sustained release,
5 to 100 parts by weight of a carbomer,
30 to 70 parts by weight of a disintegrant,
10 to 200 parts by weight of a solubilizing agent, and
10 to 2000 parts by weight of cilostazol
Wherein the composition exhibits the following pharmacokinetic profile when orally administered to a beagle dog:
(a) C _max / dose (ng / mL): 0.62 ± 0.12,
(b) T _max (h): 4.17 + -0.41, and
(c) T _1/2 (h): 8.34 + 1.56.
The method according to claim 1,
Wherein the solubilizing agent is sodium lauryl sulfate.
The method according to claim 1,
Wherein the amount of the polymer for sustained release is 50,000 to 150,000 cps.
The method according to claim 1,
The disintegrant may be selected from the group consisting of Crosscamellose-Na, Sodium starch glycolate, Pregelatinized Starch, Microcrystalline cellulose, Crospovidone cross -linked povidone, polyvinylpyrrolidone (PVP), hydroxypropylcellulose (low substituted), alginic acid, calcium or sodium salts of carboxymethylcellulose, colloidal It is also possible to use fumed silica collidal silica, guar gum, magnesium alumimum silicate, methylcellulose, powdered cellulose, starch, sodium alginate and mixtures thereof. Lt; RTI ID = 0.0 > of: < / RTI > delete delete delete delete

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