WO2019245150A1 - Pharmaceutical composition comprising cilostazol and statin-based drug - Google Patents

Abstract

The present invention relates to a sustained-release complex formulation comprising, as active ingredients, a statin-based drug which is an HMG-CoA reductase inhibitor, and cilostazol. More specifically, the sustained-release complex formulation consists of an HMG-CoA reductase inhibitor mixture part containing the HMG-CoA reductase inhibitor, and a cilostazol mixture part containing cilostazol, wherein the cilostazol mixture part contains immediate-release granules and sustained-release granules, and thus, the sustained-release complex formulation shows minimal side effects while allowing for immediate pharmacological activity, and has sustained-release properties which provide sufficient pharmacological effects even when orally administered only once daily.

Description

Pharmaceutical composition containing cilostazol and statin contract

This application claims the benefit of priority based on Korean Patent Application No. 10-2018-0069955 dated June 19, 2018, and all content disclosed in the literature of that Korean patent application is incorporated as part of this specification.

The present invention relates to a sustained release combination preparation containing a statin-based drug and cilostazol, which are HMG-CoA reductase inhibitors as an active ingredient.

Cilostazol inhibits primary aggregation of platelets induced by ADP, epinephrine and the like in platelets isolated from mice, rats, rabbits, dogs and humans and dissociates platelet aggregates. In addition, oral administration to beagle dogs inhibits aggregation of platelets induced by ADP and collagen, and when administered orally to patients with chronic arterial obstruction (Berger's disease, obstructive atherosclerosis, diabetic peripheral angiopathy, etc.). Inhibits platelet aggregation induced by ADP, collagen, arachidonic acid and epinephrine in isolated platelets. The platelet aggregation inhibitory effect of cilostazol is expressed rapidly after administration, and the effect is maintained even in repeated administration. Inhibition of platelet aggregation at the time of discontinuation is restored to pre-administration values with a decrease in plasma concentration, and no rebound phenomenon is observed.

The mechanism of action of cilostazol is as follows. It inhibits the release of serotonin from platelets in rabbits but does not affect the entry of serotonin, adenosine, into platelets. It inhibits platelet aggregation by TXA2 (thromboxane A2) without affecting arachidonic acid metabolism of platelets. This is due to the inhibition of cAMP-PDE (cyclic AMP phosphodiesterase) activity of platelets and vascular smooth muscle, which eventually exerts antiplatelet action and vasodilation.

Existing cilostazol formulations are not only poor patient compliance, but also cilostazol immediate release formulations result in rapid and uneven drug release upon oral administration, resulting in a rapid rise in blood concentration. It is known to cause side effects such as headache, headache, tachycardia and the like (see Am J Cardiol 2001; 87 (suppl): 28D-33D and US Patent Publication No. 2002/0058066). In addition, since cilostazol is poorly soluble and its absorption rate decreases toward the lower part of the small intestine, the overall bioavailability may be reduced in the case of conventional release control formulations, and PCT Patent Publication No. WO 2000/57881 discloses cilostas in the form of fine powder. A method is disclosed for increasing the small intestinal uptake of cilostazol using a formulation in the form in which the sol is dispersed and / or dissolved in combination with a dispersing agent and / or a solubilizing agent.

The present invention improves the shortcomings of the conventional cilostazol sustained release formulation having a large dissolution deviation, and is manufactured in a tablet form to significantly increase productivity, and further improves bioavailability by adding an HMG-CoA reductase inhibitor as an active ingredient. will be.

The present invention comprises an HMG-CoA reductase inhibitor mixing unit containing an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient; And a cilostazol mixed portion containing cilostazol or a pharmaceutically acceptable salt thereof as an active ingredient. Meanwhile, the cilostazol mixing unit includes a release regulator for controlling the amount of cilostazol active ingredient eluted in the body, and the content of the release regulator is 3 to 9 parts by weight based on 100 parts by weight of the cilostazol active ingredient. desirable.

The pharmaceutical composition according to the present invention is a complex preparation containing a cilostazol and HMG-CoA reductase inhibitor, and has a very high bioavailability, and controls the release regulator content of the cilostazol mixed part containing cilostazol 1 day 1 Dose alone has sufficient sustained release and shows an excellent effect of reducing side effects of cilostazol.

At this time, if the content of the release controlling agent is less than 3 parts by weight based on 100 parts by weight of the cilostazol active ingredient, the initial release amount of cilostazol is not sufficient to exhibit sufficient sustained release, and side effects such as headaches may occur. On the other hand, when the content of the release controlling agent exceeds 9 parts by weight with respect to 100 parts by weight of the cilostazol active ingredient, the dissolution of the cilostazol active ingredient is delayed too much to achieve a sufficient pharmacological effect.

HMG-CoA reductase inhibitors used in the present invention can be used by selecting one or two or more from the group consisting of rosuvastatin, simvastatin, atorvastatin, pitavastatin, pravastatin, fluvastatin, lovastatin, The active ingredient content of the HMG-CoA reductase inhibitor mixture is preferably 3 to 40 mg, and the effective ingredient content of the cilostazol mixture is preferably 160 to 240 mg.

If the active ingredient content of the HMG-CoA reductase inhibitor mixture is less than 3 mg or the active ingredient content of the cilostazol mixture is less than 160 mg, sufficient pharmacological activity is not observed, and the active ingredient content of the HMG-CoA reductase inhibitor mixture is 40 mg. Excess or, if the active ingredient content of the cilostazol mixture exceeds 240mg, the blood concentration of the active ingredient is excessively increased may cause side effects.

On the other hand, the cilostazol mixing portion of the sustained release composite preparation according to the present invention can be used by mixing the hypromellose and carbomer as a release control agent, in this case the hypromellose and carbomer having a viscosity of 75,000 to 140,000cps It is preferable to mix and use in the weight ratio of 1: 1 to 2.5: 1. If the mixing ratio of the release controlling agent is out of the above range, the stability of the sustained release matrix may be inferior.

In addition, the cilostazol mixing unit, immediate release granules containing cilostazol and disintegrant and a binder as an active ingredient; And it may comprise a sustained-release granules comprising cilostazol and a release control agent and a binder as an active ingredient, the active ingredient content of the sustained-release granules is 50 to 90% by weight, more preferably based on the active ingredient content of the immediate release granules Preferably it is 60 to 80% by weight.

As described above, when the immediate release granules containing cilostazol containing cilostazol and the sustained release granules are prepared, and then mixed and used, the rapid pharmacological activity of the immediate release granules and the sustained effect of the sustained release granules All of these expressions can reduce side effects. At this time, the active ingredient content ratio of the immediate release and the western part is very important, if the active ingredient content of the immediate release may cause side effects due to too fast dissolution. On the other hand, in the West, the content of the active ingredient should be adjusted while considering the dissolution characteristics by the release control agent so that the pharmacological effect can be sustained for a long time. After repeated studies, the applicant was able to find the optimum content ratio of the immediate and western active ingredients as described above, and in order to uniformly control the dissolution rate, the active ingredients of the mixing part containing the respective active ingredients. In consideration of the content, the type and content of disintegrants, binders and release control agents were optimized. This resulted in the rapid pharmacological activity and the long-term effects, while reducing the side effects.

As the disintegrant, one or two or more selected from the group consisting of carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, 1-hydroxypropyl cellulose, and crosslinked polyvinylpyrrolidone may be used, and the binder may be a binder. 1 or 2 or more selected from the group consisting of hydroxypropyl cellulose, hydroxy cellulose, hydroxypropyl methyl cellulose, hydroxypropyl starch, polyvinyl alcohol, hydroxymethyl cellulose, polyvinylpyrrolidone may be used. have. In addition, as the release control agent, hypromellose and carbomer may be used alone, or a combination thereof may be used. However, when using a mixture of hypromellose and carbomer as described above was the most preferable results.

The active ingredient contained in the cilostazol mixing portion of the sustained release complex preparation according to the present invention is dissolved in 0.4% sodium lauryl sulfate (SLS) eluate according to the second method (paddle method) of the Korean Pharmacopoeia Dissolution Test Method. 20% or less of the total weight of the active ingredient of the stasol mixing part, 20 to 50% of the total weight of the active ingredient of the cilostazol mixing part after 90 minutes, and 80% or more of the total weight of the active ingredient of the cilostazol mixing part after 300 minutes It has a characteristic that satisfies the dissolution profile, thereby showing a rapid pharmacological activity, while reducing the side effects due to over-dissolution, after 300 minutes, the total active ingredient was completed the formulation is mostly eluted.

In addition, the immediate release granules and the sustained-release granules according to the present invention use those having a diameter of 350 to 450 μm, which affects the dissolution characteristics, so that the dissolution is too fast or does not exhibit sufficient pharmacological effects. Can be.

 On the other hand, the sustained-release complex preparation of the present invention is preferably prepared with a diameter of 5 to 10mm, the total weight of 350 to 550mg, if the diameter is less than 5mm there is a possibility that the formulation is collapsed during tableting, if the patient exceeds 10mm Medication convenience may be reduced. In addition, when the total weight is less than 350mg may not add enough excipients, the stability may be lowered, and when the total weight exceeds 550mg, the dosage form is too large to reduce the patient's medication convenience.

It is preferable that the sustained release composite preparation of the present invention has a hardness of 10 to 30 kg / cm 2, and when the hardness is less than 10 kg / cm 2, the formulation may collapse or deteriorate in stability when tableting. The problem of more delayed dissolution may occur.

Sustained release complex preparations according to the present invention comprises an HMG-CoA reductase inhibitor mixing unit containing an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient; And a cilostazol mixing portion containing cilostazol or a pharmaceutically acceptable salt thereof as an active ingredient, the first layer comprising the HMG-CoA reductase inhibitor mixing portion; And a second layer consisting of a cilostazol mixing unit; when prepared in a single tablet formulation of a two-layer structure consisting of a fast mass production is excellent in stability and preferable in terms of productivity and preservation.

Meanwhile, the sustained release complex preparation containing the HMG-CoA reductase inhibitor and cilostazol according to the present invention may be prepared through the following steps.

Preparing a HMG-CoA reductase inhibitor mixing unit granules by mixing an HMG-CoA reductase inhibitor, an excipient, a binder, and a disintegrant; Mixing cilostazol, excipients and binder to produce immediate release granules; Preparing sustained-release granules by mixing cilostazol, excipient, release controlling agent, binder and glidant; Mixing the immediate release granules and the sustained release granules to form a cilostazol mixed part granule containing cilostazol; Tableting the HMG-CoA reductase inhibitor mixing unit granules and cilostazol mixing unit granules to produce a sustained release composite formulation; comprising the tableting sequence of the HMG-CoA reductase inhibitor mixing unit and cilostazol mixing unit And the manufacturing order of the immediate release and sustained-release granules can be changed.

The present invention is a sustained release combination preparation including an HMG-CoA reductase inhibitor and cilostazol, which has a fast pharmacological activity and few side effects, and has a sustained release showing sufficient pharmacological effect by oral administration once a day.

The pharmaceutical composition according to the present invention includes immediate release granules containing cilostazol as an active ingredient, so that an effective amount of cilostazol active ingredient is rapidly eluted in the body to exhibit pharmacological activity after oral administration. This leads to a rapid rise in early blood levels to achieve a rapid pharmacological effect. In addition, including sustained-release granules containing cilostazol, once daily administration shows sufficient long-term pharmacological activity.

In addition, it contains a HMG-CoA reductase inhibitor as an active ingredient, characterized in that the bioavailability is further improved than administration of cilostazol alone. The HMG-CoA reductase inhibitor is a statin-based drug, one or two or more may be selected from the group consisting of rosuvastatin, simvastatin, atorvastatin, pitavastatin, pravastatin, fluvastatin, and lovastatin, In consideration of pharmacological effects, long-term storage stability and marketability, it is preferable to use one or two or more selected from rosuvastatin, simvastatin, and atorvastatin, and most preferably rosuvastatin.

<Method for Producing Sustained Release Composite Preparation>

According to one embodiment of the present invention, the sustained release complex preparation according to the present invention is prepared in accordance with the preparation method of the tablet term of the Korean Pharmacopoeia General Formulation, but HMG-CoA by mixing an HMG-CoA reductase inhibitor, an excipient, a binder and a disintegrant Preparing a reductase inhibitor mixture part granule; Mixing cilostazol, excipients and binder to produce immediate release granules; Preparing sustained-release granules by mixing cilostazol, excipient, release controlling agent, binder and glidant; Mixing the immediate release granules and the sustained release granules to form a cilostazol mixed part granule containing cilostazol; Tableting the HMG-CoA reductase inhibitor mixing unit granules and cilostazol mixing unit granules to produce a sustained release composite formulation; comprising the tableting sequence of the HMG-CoA reductase inhibitor mixing unit and cilostazol mixing unit And the manufacturing order of the immediate release and sustained-release granules can be changed.

In addition, the specific composition, such as the type, content, etc. of the raw materials used in each step according to the following Examples and Comparative Examples, the formulation of each composite formulation was prepared as a bilayer tablet by the direct stroke method.

Content and Composition Design of Release Controlling Agent

In order to reduce the side effects of cilostazol and statin-based drugs and improve bioavailability during oral administration, in order to derive an optimal composition for the preparation of a sustained release combination formulation showing sufficient effects only once daily administration, As shown in the Examples and Comparative Examples, the sustained release composite formulation was prepared by varying the content and composition of the release control agent, and thereby adjusting the amount of other excipients.

(Unit: mg)

division	Usage	Ingredient Name	Example 1	Example 2	Example 3	Comparative Example 1	Comparative Example 2
Cilostazol	chief ingredient	Cilostazol	120.00	120.00	120.00	120.00	120.00
	Excipient	Microcrystalline Cellulose 101	20.00	20.00	20.00	20.00	20.00
	Disintegrant	Croscarmellose sodium	4.00	4.00	4.00	4.00	4.00
	Binder	Povidone K-30	6.00	6.00	6.00	6.00	6.00
	Cilostazol immediate release weight		150.00	150.00	150.00	150.00	150.00
West Cilostazol	chief ingredient	Cilostazol	80.00	80.00	80.00	80.00	80.00
	Excipient	Microcrystalline Cellulose 101	52.00	49.00	44.00	55.00	40.00
	Release regulator	Hypromellose 2208 (viscosity 100,000 cps)	5.00	7.00	10.00	3.00	14.00
	Release regulator	Carbomer 971	3.00	4.00	6.00	2.00	6.00
	Binder	Povidone K-30	10.00	10.00	10.00	10.00	10.00
	Lubricant	Magnesium stearate	10.00	10.00	10.00	10.00	10.00
	Cilostazol Western Weight		160.00	160.00	160.00	160.00	160.00
Statin floor	chief ingredient	Rosuvastatin Calcium	20.80	20.80	20.80	20.80	20.80
	Excipient	Lactose Carb	42.00	42.00	42.00	42.00	42.00
	Excipient	Microcrystalline Cellulose 102	22.00	22.00	22.00	22.00	22.00
	Excipient	Calcium hydrogen phosphate dihydrate	52.00	52.00	52.00	52.00	52.00
	Binder	Copovidone	4.60	4.60	4.60	4.60	4.60
	Disintegrant	Crospovidone	4.60	4.60	4.60	4.60	4.60
	Lubricant	Magnesium stearate	2.00	2.00	2.00	2.00	2.00
Coating layer	Coating	Opadray AMB II white	23.00	23.00	23.00	23.00	23.00
Total weight			481.00	481.00	481.00	481.00	481.00

<Experiment 1> Measurement of dissolution rate of cilostazol active ingredient

By dissolution rate according to the eleventh revised dissolution test method for each Example and Comparative Example was shown in Table 2 below. As the eluate, 0.4% SLS aqueous solution was used. The elution method was a paddle method.

Dissolution rate in 0.4% SLS eluate (%)

	15 minutes	30 minutes	60 minutes	90 minutes	120 minutes	180 minutes	300 minutes	420 minutes
Example 1	12.3 ± 0.7	20.7 ± 0.5	35.5 ± 0.8	45.8 ± 1.7	55.4 ± 1.7	69.7 ± 3.1	99.1 ± 1.8	99.1 ± 1.2
Example 2	10.1 ± 0.5	13.7 ± 0.5	22.1 ± 1.1	35.1 ± 1.3	45.2 ± 2.0	62.3 ± 1.5	95.1 ± 1.3	100.1 ± 0.3
Example 3	8.0 ± 0.6	12.8 ± 0.9	20.5 ± 1.5	30.6 ± 2.2	39.6 ± 1.8	56.1 ± 2.4	87.9 ± 1.3	94.9 ± 0.5
Comparative Example 1	20.3 ± 2.3	35.3 ± 1.1	57.2 ± 2.2	71.2 ± 1.5	85.7 ± 3.4	98.1 ± 2.2	99.5 ± 0.8	99.8 ± 1.2
Comparative Example 2	4.3 ± 1.7	7.4 ± 1.2	14.5 ± 3.2	18.2 ± 2.3	25.6 ± 2.4	35.4 ± 3.4	65.4 ± 2.5	85.1 ± 1.7

Review

In Examples 1 to 3, after 30 minutes after administering cilostazol to the eluate, 20% or less of the active ingredient is eluted, and then a certain amount of drug is continuously eluted. On the other hand, in the case of Comparative Example 1, the sustained-release property indicates an excessively rapid dissolution of the active ingredient, and there is a fear that side effects occur due to a sharp rise in blood concentration. In Comparative Example 2, the elution is too slow to show sufficient pharmacological activity during the stay in the body, so the effect may be reduced.

In addition, in the case of Examples 1 to 3, about 20 to 50% of the active ingredient is eluted after 90 minutes, and after 300 minutes, 80% or more of the active ingredient is eluted. Oral administration in the body is expected to produce a desirable dissolution pattern for a long time.

Experiment 2 Measurement of Dissolution Rate of Statin Active Ingredients

Since the pharmaceutical composition according to the present invention is a sustained-release complex preparation containing two different active ingredients, the dissolution rate of the active ingredient may change depending on the combination properties of the active ingredients having different properties or the characteristics of the formulation.

Accordingly, Applicant has selected rosuvastatin, simvastatin, atorvastatin, among the statin-based drugs available as a control, to determine whether the formulation properties of the combined or sustained release formulation with cilostazol affect the elution of the statin component. Single tablets according to Comparative Examples 3 to 5 were prepared. Meanwhile, Examples 4 and 5 having the same composition as in Example 2 were prepared except for the types of statins. Compared.

Preparation of Comparative Examples 3 to 5 : Statin-containing mono-formulation

As a control for comparing the dissolution rate of the statin component, a single tablet containing rosuvastatin, simvastatin, atorvastatin as an active ingredient was prepared according to the component content of Table 3 below.

Unit: mg

Usage	Ingredient Name	Comparative Example 3	Comparative Example 4	Comparative Example 5
chief ingredient	Rosuvastatin Calcium	20.80	-	-
chief ingredient	Simvastatin	-	20.00	-
chief ingredient	Atorvastatin	-	-	20.00
Excipient	Lactose Carb	42.00	42.80	42.80
Excipient	Microcrystalline Cellulose 102	22.00	22.00	22.00
Excipient	Calcium hydrogen phosphate dihydrate	52.00	52.00	52.00
Binder	Copovidone	4.60	4.60	4.60
Disintegrant	Crospovidone	4.60	4.60	4.60
Lubricant	Magnesium stearate	2.00	2.00	2.00
Total weight		148.00	148.00	148.00

Examples 2, 4, 5 : sustained-release complex preparations containing cilostazol and statins

According to the ingredient content of Table 4, except for the statin type, the composition was the same as in Example 2 to prepare a sustained release composite preparation of Examples 4 to 5.

Unit: mg

division	Usage	Ingredient Name	Example 2	Example 4	Example 5
Cilostazol	chief ingredient	Cilostazol	120.00	120.00	120.00
	Excipient	Microcrystalline Cellulose 101	20.00	20.00	20.00
	Disintegrant	Croscarmellose sodium	4.00	4.00	4.00
	Binder	Povidone K-30	6.00	6.00	6.00
	Cilostazol immediate release weight		150.00	150.00	150.00
West Cilostazol	chief ingredient	Cilostazol	80.00	80.00	80.00
	Excipient	Microcrystalline Cellulose 101	49.00	49.00	49.00
	Release regulator	Hypromellose 2208 (viscosity 100,000 cps)	7.00	7.00	7.00
	Release regulator	Carbomer 971	4.00	4.00	4.00
	Binder	Povidone K-30	10.00	10.00	10.00
	Lubricant	Magnesium stearate	10.00	10.00	10.00
	Cilostazol Western Weight		160.00	160.00	160.00
Statin floor	chief ingredient	Rosuvastatin Calcium	20.80	-	-
	chief ingredient	Simvastatin	-	20	-
	chief ingredient	Atorvastatin	-	-	20
	Excipient	Lactose Carb	42.00	42.80	42.80
	Excipient	Microcrystalline Cellulose 102	22.00	22.00	22.00
	Excipient	Calcium hydrogen phosphate dihydrate	52.00	52.00	52.00
	Binder	Copovidone	4.60	4.60	4.60
	Disintegrant	Crospovidone	4.60	4.60	4.60
	Lubricant	Magnesium stearate	2.00	2.00	2.00
Coating layer	Coating	Opadray AMB II white	23.00	23.00	23.00
Total weight			481.00	481.00	481.00

Comparison of elution patterns of Examples 2, 4, and 5 and Comparative Examples 3 to 5

The statin active ingredient dissolution rates of the statin single tablets according to Comparative Examples 3 to 5 and the sustained release combination preparations according to Examples 2, 4 and 5 are shown in Tables 5 to 7 below.

PH 6.6, 7.0 aqueous buffer and water were used as the eluent. The elution was performed using the paddle method.

% elution in citric acid buffer

Statin types		5 minutes	10 minutes	15 minutes	30 minutes	45 minutes
Example 2	Rosuvastatin Calcium	85.0 ± 10.0	96.0 ± 3.3	97.5 ± 2.4	99.6 ± 1.7	100.8 ± 1.3
Comparative Example 3		80.4 ± 10.1	90.0 ± 7.8	93.7 ± 6.2	98.1 ± 3.1	100.4 ± 2.1

Dissolution rate in 0.5% SLS, pH 7.0 phosphate buffer eluate (%)

Statin types		5 minutes	10 minutes	15 minutes	30 minutes
Example 4	Simvastatin	24.5 ± 3.7	61.3 ± 6.6	80.4 ± 3.9	92.7 ± 2.6
Comparative Example 4		24.6 ± 4.6	62.5 ± 6.4	81.8 ± 3.4	96.8 ± 3.2

Dissolution rate in water eluate (%)

Statin types		5 minutes	10 minutes	15 minutes	30 minutes
Example 5	Atorvastatin	58.4 ± 5.7	85.7 ± 3.3	96.3 ± 2.1	100.3 ± 2.7
Comparative Example 5		56.2 ± 6.3	82.1 ± 2.4	97.2 ± 1.0	101.2 ± 2.8

Review

As shown in Tables 5 to 7, the dissolution rate of the sustained release complex preparation and the statin single tablet according to the present invention is very similar to show substantially the same dissolution rate. As a result, the sustained-release complex preparation according to the present invention can be seen that the effect is rapid because there is no effect on the dissolution of the contained statins in the body even though the formulation and composition differ from the control containing the statin single component.

As a result, when the results of the dissolution rate of cilostazol shown in Table 2 and the dissolution rate of rosuvastatin shown in Tables 5 to 7, the sustained-release complex preparations according to the present invention had the best dissolution profiles of two different effective ingredients. It is suitable as a sustained release combination preparation once daily.

<Experiment 3> Comparative experiment of dissolving single tablet formulation and dissolution

A single tablet (Comparative Examples 6 to 8) according to Table 8 was prepared by simple mixing to include all of the cilostazol sustained-release granules, immediate-release granules and statin components, and sustained-release composite formulations according to the present invention Examples 2, 4 and The formulation of 5 and the effective ingredient dissolution rate for 120 minutes in 0.4% SLS eluate conditions are shown in Table 9 below.

Comparative Examples 6 to 8 : Single tablet containing statins and cilostazol (unit: mg)

division	Usage	Ingredient Name	Comparative Example 6	Comparative Example 7	Comparative Example 8
Cilostazol immediate release granule	chief ingredient	Cilostazol	120.00	120.00	120.00
	Excipient	Microcrystalline Cellulose 101	20.00	20.00	20.00
	Disintegrant	Croscarmellose sodium	4.00	4.00	4.00
	Binder	Povidone K-30	6.00	6.00	6.00
	Cilostazol immediate release weight		150.00	150.00	150.00
Cilostazol Western Granule	chief ingredient	Cilostazol	80.00	80.00	80.00
	Excipient	Microcrystalline Cellulose 101	49.00	49.00	49.00
	Release regulator	Hypromellose 2208 (viscosity 100,000 cps)	7.00	7.00	7.00
	Release regulator	Carbomer 971	4.00	4.00	4.00
	Binder	Povidone K-30	10.00	10.00	10.00
	Lubricant	Magnesium stearate	10.00	10.00	10.00
	Cilostazol Western Weight		160.00	160.00	160.00
Statins	chief ingredient	Rosuvastatin Calcium	20.80	-	-
	chief ingredient	Simvastatin	-	20	-
	chief ingredient	Atorvastatin	-	-	20
Coating layer	Coating	Opadray AMB II white	23.00	23.00	23.00
Total weight			353.80	353.00	353.00

 0.4% SLS Elution Elution Rate (%)

division	Active ingredient	15 minutes	30 minutes	60 minutes	90 minutes	120 minutes
Example 2	Cilostazol	10.1 ± 0.5	13.7 ± 0.5	22.1 ± 1.1	35.1 ± 1.3	45.2 ± 2.0
	Rosuvastatin Calcium	97.5 ± 2.4	99.6 ± 1.7
Comparative Example 6	Cilostazol	11.2 ± 1.1	14.5 ± 2.1	21.7 ± 3.1	36.7 ± 1.2	44.4 ± 1.8
	Rosuvastatin Calcium	6.8 ± 2.2	11.3 ± 3.6	18.6 ± 2.8	25.3 ± 2.0	32.8 ± 3.3
Example 4	Cilostazol	12.3 ± 2.3	13.5 ± 2.1	23.5 ± 3.6	36.8 ± 1.5	46.1 ± 1.9
	Simvastatin	80.4 ± 3.9	92.7 ± 2.6
Comparative Example 7	Cilostazol	11.3 ± 2.1	14.2 ± 1.1	21.8 ± 2.1	33.7 ± 2.1	43.1 ± 2.6
	Simvastatin	10.5 ± 1.1	15.2 ± 2.1	22.0 ± 2.5	31.2 ± 1.5	41.2 ± 3.0
Example 5	Cilostazol	12.3 ± 1.0	15.4 ± 0.8	21.9 ± 0.7	33.5 ± 2.1	43.9 ± 2.5
	Atorvastatin	96.3 ± 2.1	100.3 ± 2.7
Comparative Example 8	Cilostazol	12.2 ± 2.1	16.1 ± 2.1	23.1 ± 1.7	32.8 ± 1.5	44.5 ± 2.7
	Atorvastatin	7.7 ± 0.5	13.5 ± 0.8	20.7 ± 1.8	38.9 ± 0.9	55.2 ± 2.4

Review

While the sustained-release complex preparations of the present invention exhibited an excellent early dissolution rate of all active ingredients, there was a problem that the statin active ingredient was almost eluted at the beginning due to the viscosity of the sustained-release matrix in the case of a simple mixed single tablet. As a result, the sustained release co-formulation of the present invention composed of a double layer containing statins and cilostazol in different layers, respectively, was found to be an excellent formulation having sustained release while excellent initial dissolution rate of the active ingredients included.

<Experiment 4> Experiment of dissolution deviation with reference drug for cilostazol active ingredient

Meanwhile, in order to confirm the effect of minimizing dissolution deviation of cilostazol, a sustained-release active ingredient of the sustained-release complex preparation according to the present invention, the dissolution rate deviation between the formulation of Example 2 of the present invention and the preservative SR capsule, which is a reference drug, was compared. Table 10 shows.

Minutes	Example 2		Total SR Capsule
	Average(%)	Deviation	Average(%)	Deviation
15	10.1	0.5	3.1	0.8
30	13.7	0.5	5.6	0.2
60	22.1	1.1	21.0	7.6
90	35.1	1.3	35.2	8.8
120	45.2	2.0	56.7	12.6
180	62.3	1.5	72.2	13.4
300	95.1	1.3	89.0	10.5
420	100.1	0.3	95.4	7.9

Review

As shown in Table 10, the formulation according to Example 2 of the present invention showed a significantly less variation than the conventional phthalal SR, thereby showing excellent pharmacological activity and significantly reducing side effects. .

<Experiment 5> Elution test for cilostazol active ingredient of a sustained release combination preparation containing 10 mg of statin active ingredient

As another formulation of the sustained release co-formulation according to the present invention, a sustained-release co-formulation formulation containing 10 mg of rosuvastatin (10.4 mg of rosuvastatin calcium) in a statin-based drug and designed to dissolve the cilostazol active ingredient Was done.

The composition of each Example and a comparative example is as Table 11 below.

Unit: mg

division	Usage	Ingredient Name	Example 6	Example 7	Example 8	Comparative Example 9	Comparative Example 10
Cilostazol	chief ingredient	Cilostazol	120.00	120.00	120.00	120.00	120.00
	Excipient	Microcrystalline Cellulose 101	20.00	20.00	20.00	20.00	20.00
	Disintegrant	Croscarmellose sodium	4.00	4.00	4.00	4.00	4.00
	Binder	Povidone K-30	6.00	6.00	6.00	6.00	6.00
	Cilostazol immediate release weight		150.00	150.00	150.00	150.00	150.00
West Cilostazol	chief ingredient	Cilostazol	80.00	80.00	80.00	80.00	80.00
	Excipient	Microcrystalline Cellulose 101	52.00	49.00	44.00	55.00	40.00
	Release regulator	Hypromellose 2208 (viscosity 100,000 cps)	5.00	7.00	10.00	3.00	14.00
	Release regulator	Carbomer 971	3.00	4.00	6.00	2.00	6.00
	Binder	Povidone K-30	10.00	10.00	10.00	10.00	10.00
	Lubricant	Magnesium stearate	10.00	10.00	10.00	10.00	10.00
	Cilostazol Western Weight		160.00	160.00	160.00	160.00	160.00
Statin floor	chief ingredient	Rosuvastatin Calcium	10.40	10.40	10.40	10.40	10.40
	Excipient	Lactose Carb	21.00	21.00	21.00	21.00	21.00
	Excipient	Microcrystalline Cellulose 102	11.00	11.00	11.00	11.00	11.00
	Excipient	Calcium hydrogen phosphate dihydrate	26.00	26.00	26.00	26.00	26.00
	Binder	Copovidone	2.30	2.30	2.30	2.30	2.30
	Disintegrant	Crospovidone	2.30	2.30	2.30	2.30	2.30
	Lubricant	Magnesium stearate	1.00	1.00	1.00	1.00	1.00
Coating layer	Coating	Opadray AMB II white	19.00	19.00	19.00	19.00	19.00
Total weight			403.00	403.00	403.00	403.00	403.00

By dissolution rate according to the eleventh revised dissolution test method for each of the Examples and Comparative Examples was shown in Table 12 below. As the eluate, 0.4% SLS aqueous solution was used. The elution method was a paddle method.

Dissolution rate in 0.4% SLS eluate (%)

	15 minutes	30 minutes	60 minutes	90 minutes	120 minutes	180 minutes	300 minutes	420 minutes
Example 6	12.3 ± 0.7	20.7 ± 0.5	35.5 ± 0.8	45.8 ± 1.7	55.4 ± 1.7	69.7 ± 3.1	99.1 ± 1.8	99.1 ± 1.2
Example 7	10.1 ± 0.5	13.7 ± 0.5	22.1 ± 1.1	35.1 ± 1.3	45.2 ± 2.0	62.3 ± 1.5	95.1 ± 1.3	100.1 ± 0.3
Example 8	8.0 ± 0.6	12.8 ± 0.9	20.5 ± 1.5	30.6 ± 2.2	39.6 ± 1.8	56.1 ± 2.4	87.9 ± 1.3	94.9 ± 0.5
Comparative Example 9	20.3 ± 2.3	35.3 ± 1.1	57.2 ± 2.2	71.2 ± 1.5	85.7 ± 3.4	98.1 ± 2.2	99.5 ± 0.8	99.8 ± 1.2
Comparative Example 10	4.3 ± 1.7	7.4 ± 1.2	14.5 ± 3.2	18.2 ± 2.3	25.6 ± 2.4	35.4 ± 3.4	65.4 ± 2.5	85.1 ± 1.7

Review

In Examples 6 to 8, the same dissolution patterns were observed as in Examples 1 to 3 of Experiment 1, whereas Comparative Examples 9 and 10 showed too fast or slow dissolution.

Experiment 6 Measurement of Dissolution Rate of Statin Active Ingredients

For the sustained release combination preparation containing 10 mg of statin active ingredient as in Experiment 5, the statin-based drug was changed to rosuvastatin, simvastatin, and atorvastatin, respectively, to proceed in the same manner as in Experiment 2.

Preparation of Comparative Examples 11 to 13 : Statin-containing single formulation

As a control for comparing the dissolution rate of the statin component, a single tablet containing rosuvastatin, simvastatin, atorvastatin as an active ingredient was prepared according to the component content of Table 13 below.

Unit: mg

Usage	Ingredient Name	Comparative Example 11	Comparative Example 12	Comparative Example 13
chief ingredient	Rosuvastatin Calcium	10.40	-	-
chief ingredient	Simvastatin	-	10.00	-
chief ingredient	Atorvastatin	-	-	10.00
Excipient	Lactose Carb	21.00	21.40	21.40
Excipient	Microcrystalline Cellulose 102	11.00	11.00	11.00
Excipient	Calcium hydrogen phosphate dihydrate	26.00	26.00	26.00
Binder	Copovidone	2.30	2.30	2.30
Disintegrant	Crospovidone	2.30	2.30	2.30
Lubricant	Magnesium stearate	1.00	1.00	1.00
Total weight		74.00	74.00	74.00

Examples 7, 9 and 10 : sustained release combination preparation containing cilostazol and statins

According to the ingredient content of Table 14, the sustained-release composite preparation of Examples 9 to 10 were prepared in the same manner as in Example 7 except for the statin type.

division	Usage	Ingredient Name	Example 7	Example 9	Example 10
Cilostazol	chief ingredient	Cilostazol	120.00	120.00	120.00
	Excipient	Microcrystalline Cellulose 101	20.00	20.00	20.00
	Disintegrant	Croscarmellose sodium	4.00	4.00	4.00
	Binder	Povidone K-30	6.00	6.00	6.00
	Cilostazol immediate release weight		150.00	150.00	150.00
West Cilostazol	chief ingredient	Cilostazol	80.00	80.00	80.00
	Excipient	Microcrystalline Cellulose 101	49.00	49.00	49.00
	Release regulator	Hypromellose 2208 (viscosity 100,000 cps)	7.00	7.00	7.00
	Release regulator	Carbomer 971	4.00	4.00	4.00
	Binder	Povidone K-30	10.00	10.00	10.00
	Lubricant	Magnesium stearate	10.00	10.00	10.00
	Cilostazol Western Weight		160.00	160.00	160.00
Statin floor	chief ingredient	Rosuvastatin Calcium	10.40	-	-
	chief ingredient	Simvastatin	-	10	-
	chief ingredient	Atorvastatin	-	-	10
	Excipient	Lactose Carb	21.00	21.40	21.40
	Excipient	Microcrystalline Cellulose 102	11.00	11.00	11.00
	Excipient	Calcium hydrogen phosphate dihydrate	26.00	26.00	26.00
	Binder	Copovidone	2.30	2.30	2.30
	Disintegrant	Crospovidone	2.30	2.30	2.30
	Lubricant	Magnesium stearate	1.00	1.00	1.00
Coating layer	Coating	Opadray AMB II white	19.00	19.00	19.00
Total weight			403.00	403.00	403.00

Comparison of elution patterns of Examples 7, 9, and 10 and Comparative Examples 11 to 13

The statin active ingredient dissolution rates of the statin single tablets according to Comparative Examples 11 to 13 and the sustained release combination preparations according to Examples 7, 9 and 10 are shown in Tables 15 to 17 below.

Eluent was used as aqueous buffer and water of pH 6.6, 7.0 and elution method was used paddle method, eluent 900ml, stirring speed was 50rpm, elution temperature was performed at 37 ± 0.5 ℃.

% elution in citric acid buffer

Statin types		5 minutes	10 minutes	15 minutes	30 minutes	45 minutes
Example 7	Rosuvastatin Calcium	85.0 ± 10.0	96.0 ± 3.3	97.5 ± 2.4	99.6 ± 1.7	100.8 ± 1.3
Comparative Example 11		80.4 ± 10.1	90.0 ± 7.8	93.7 ± 6.2	98.1 ± 3.1	100.4 ± 2.1

Dissolution rate in 0.5% SLS, pH 7.0 phosphate buffer eluate (%)

Statin types		5 minutes	10 minutes	15 minutes	30 minutes
Example 9	Simvastatin	24.5 ± 3.7	61.3 ± 6.6	80.4 ± 3.9	92.7 ± 2.6
Comparative Example 12		24.6 ± 4.6	62.5 ± 6.4	81.8 ± 3.4	96.8 ± 3.2

Dissolution rate in water eluate (%)

Statin types		5 minutes	10 minutes	15 minutes	30 minutes
Example 10	Atorvastatin	58.4 ± 5.7	85.7 ± 3.3	96.3 ± 2.1	100.3 ± 2.7
Comparative Example 13		56.2 ± 6.3	82.1 ± 2.4	97.2 ± 1.0	101.2 ± 2.8

Review

As shown in Tables 15 to 17, the dissolution rate of the sustained release complex preparation and the statin single tablet according to the present invention is very similar, showing substantially the same dissolution rate. As a result, the sustained-release complex preparation according to the present invention can be seen that the effect is rapid because there is no effect on the dissolution of the contained statins in the body even though the formulation and composition differ from the control containing the statin single component.

As a result, the same results as in Experiment 2, the sustained-release complex preparation according to the present invention shows an optimal dissolution profile of the two different active ingredients, it is suitable as a sustained-release complex preparation to be taken once a day.

<Experiment 7> Comparison between dissolution of single tablet formulation and dissolution

Single tablets (Comparative Examples 14 to 16) according to Table 18 were prepared by simple mixing to include all of the cilostazol sustained-release granules, immediate-release granules and statin components, and the sustained-release complex preparations according to the present invention Examples 7, 9 and The effective ingredient dissolution rate for 120 minutes in the formulation of 10 and 0.4% SLS eluate is shown in Table 19 below.

Comparative Examples 14 to 16 : Single tablet containing statins and cilostazol (unit: mg)

division	Usage	Ingredient Name	Comparative Example 14	Comparative Example 15	Comparative Example 16
Cilostazol immediate release granule	chief ingredient	Cilostazol	120.00	120.00	120.00
	Excipient	Microcrystalline Cellulose 101	20.00	20.00	20.00
	Disintegrant	Croscarmellose sodium	4.00	4.00	4.00
	Binder	Povidone K-30	6.00	6.00	6.00
	Cilostazol immediate release weight		150.00	150.00	150.00
Cilostazol Western Granule	chief ingredient	Cilostazol	80.00	80.00	80.00
	Excipient	Microcrystalline Cellulose 101	49.00	49.00	49.00
	Release regulator	Hypromellose 2208 (viscosity 100,000 cps)	7.00	7.00	7.00
	Release regulator	Carbomer 971	4.00	4.00	4.00
	Binder	Povidone K-30	10.00	10.00	10.00
	Lubricant	Magnesium stearate	10.00	10.00	10.00
	Cilostazol Western Weight		160.00	160.00	160.00
Statins	chief ingredient	Rosuvastatin Calcium	10.40	-	-
	chief ingredient	Simvastatin	-	10	-
	chief ingredient	Atorvastatin	-	-	10
Coating layer	Coating	Opadray AMB II white	19.00	19.00	19.00
Total weight			339.40	339.00	339.00

0.4% SLS Elution Elution Rate (%)

division	Active ingredient	15 minutes	30 minutes	60 minutes	90 minutes	120 minutes
Example 7	Cilostazol	10.1 ± 0.5	13.7 ± 0.5	22.1 ± 1.1	35.1 ± 1.3	45.2 ± 2.0
	Rosuvastatin Calcium	97.5 ± 2.4	99.6 ± 1.7
Comparative Example 14	Cilostazol	11.2 ± 1.1	14.5 ± 2.1	21.7 ± 3.1	36.7 ± 1.2	44.4 ± 1.8
	Rosuvastatin Calcium	6.8 ± 2.2	11.3 ± 3.6	18.6 ± 2.8	25.3 ± 2.0	32.8 ± 3.3
Example 9	Cilostazol	12.3 ± 2.3	13.5 ± 2.1	23.5 ± 3.6	36.8 ± 1.5	46.1 ± 1.9
	Simvastatin	80.4 ± 3.9	92.7 ± 2.6
Comparative Example 15	Cilostazol	11.3 ± 2.1	14.2 ± 1.1	21.8 ± 2.1	33.7 ± 2.1	43.1 ± 2.6
	Simvastatin	10.5 ± 1.1	15.2 ± 2.1	22.0 ± 2.5	31.2 ± 1.5	41.2 ± 3.0
Example 10	Cilostazol	12.3 ± 1.0	15.4 ± 0.8	21.9 ± 0.7	33.5 ± 2.1	43.9 ± 2.5
	Atorvastatin	96.3 ± 2.1	100.3 ± 2.7
Comparative Example 16	Cilostazol	12.2 ± 2.1	16.1 ± 2.1	23.1 ± 1.7	32.8 ± 1.5	44.5 ± 2.7
	Atorvastatin	7.7 ± 0.5	13.5 ± 0.8	20.7 ± 1.8	38.9 ± 0.9	55.2 ± 2.4

Review

As in Experiment 3, in the case of simple mixed single tablets, the problem of the early release of statin active ingredient was almost eluted due to the viscosity of the western matrix.

<Experiment 8> Dissolution deviation test with reference drug for cilostazol active ingredient

Meanwhile, in order to confirm the effect of minimizing elution deviation of cilostazol, a sustained-release active ingredient of the sustained-release complex preparation according to the present invention, the dissolution rate deviation between the formulation of Example 7 of the present invention and the prepreg SR capsule as a reference drug was compared. Table 20 shows.

Minutes	Example 7		Total SR Capsule
	Average(%)	Deviation	Average(%)	Deviation
15	10.1	0.5	3.1	0.8
30	13.7	0.5	5.6	0.2
60	22.1	1.1	21.0	7.6
90	35.1	1.3	35.2	8.8
120	45.2	2.0	56.7	12.6
180	62.3	1.5	72.2	13.4
300	95.1	1.3	89.0	10.5
420	100.1	0.3	95.4	7.9

Review

As shown in Table 20, the formulation according to Example 7 of the present invention showed significantly less variation than the conventional phthalal SR, thereby showing excellent pharmacological activity and significantly reducing side effects. .

Claims (16)

1. HMG-CoA reductase inhibitor mixing unit containing an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient; And

   A sustained-release complex preparation comprising a cilostazol mixed portion containing cilostazol or a pharmaceutically acceptable salt thereof as an active ingredient,

   The cilostazol mixed portion is a sustained-release complex preparation containing 3 to 9 parts by weight of the release control agent based on 100 parts by weight of the cilostazol active ingredient.
2. The method of claim 1,

   The HMG-CoA reductase inhibitor is a sustained-release complex preparation of one or two or more selected from the group consisting of rosuvastatin, simvastatin, atorvastatin, pitavastatin, pravastatin, fluvastatin, and lovastatin.
3. The method of claim 1,

   The active ingredient content of the HMG-CoA reductase inhibitor mixture is 3 to 40mg of a sustained-release complex preparation.
4. The method of claim 1,

   The active ingredient content of the cilostazol mixed portion is a sustained-release composite preparation of 160 to 240mg.
5. The method of claim 1,

   The release controlling agent is a sustained release complex preparation comprising a hypromellose having a viscosity of 75,000 to 140,000cps and carbomer in a weight ratio of 1: 1 to 2.5: 1.
6. The method of claim 1,

   The cilostazol mixing unit,

   Immediate release granules including cilostazol, a disintegrant, and a binder as an active ingredient; And

   Western active granules comprising cilostazol and a release control agent, a binder as an active ingredient;

   The active ingredient content of the sustained-release granules is a sustained-release complex preparation 50 to 90% by weight based on the active ingredient content of the immediate release granules.
7. The method of claim 6,

   The disintegrant is a sustained-release complex preparation of one or two or more selected from the group consisting of carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, 1-hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone.
8. The method of claim 6,

   The binder is one or two or more selected from the group consisting of hydroxypropyl cellulose, hydroxy cellulose, hydroxypropyl methyl cellulose, hydroxypropyl starch, polyvinyl alcohol, hydroxymethyl cellulose, polyvinylpyrrolidone Phosphorus sustained release combinations.
9. The method of claim 6,

   The release modulator is a sustained release combination formulation of one or two selected from the group consisting of hypromellose and carbomer.
10. The method of claim 1,

    The active ingredient contained in the cilostazol mixed portion of the sustained-release composite formulation in the 0.4% sodium lauryl sulfate eluate according to the second method (paddle method) of the Korea Pharmacopoeia Dissolution Test Method,

    After 30 minutes, 20% or less of the total weight of the active ingredient of the cilostazol mixed part,

    20 to 50% of the total weight of the active ingredient of the cilostazol mixture after 90 minutes,

    Sustained release composite formulation that satisfies an elution profile eluting at least 80% of the total weight of the active ingredient of the cilostazol mixture after 300 minutes.
11. The method of claim 6,

    The immediate release granules and the sustained release granules are sustained-release composite preparation having a diameter of 350 to 450㎛.
12. The method of claim 1,

    The sustained release composite preparation is a sustained release composite preparation having a diameter of 5 to 10mm.
13. The method of claim 1,

    The total weight of the sustained-release complex preparations is 350 to 550mg.
14. The method of claim 1,

    The sustained release composite preparation is a sustained release composite preparation having a hardness of 10 to 30kg / ㎠.
15. The method of claim 1,

    The sustained release complex preparations

    A first layer consisting of an HMG-CoA reductase inhibitor mixture; And

    A sustained-release complex preparation comprising a second layer comprising a cilostazol mixing unit.
16. In the manufacturing method of a sustained release complex preparation containing a HMG-CoA reductase inhibitor and cilostazol,

    Preparing a HMG-CoA reductase inhibitor mixing unit granules by mixing an HMG-CoA reductase inhibitor, an excipient, a binder, and a disintegrant;

    Mixing cilostazol, excipients and binder to produce immediate release granules;

    Preparing sustained-release granules by mixing cilostazol, excipient, release controlling agent, binder and glidant;

    Mixing the immediate release granules and the sustained release granules to form a cilostazol mixed part granule containing cilostazol;

    Tableting the HMG-CoA reductase inhibitor mixing unit granules and cilostazol mixing unit granules to produce a sustained release composite preparation; a method of producing a sustained-release complex preparation comprising a.