This combination product contains statins and cilostazol.

Abstract

According to the example schemes, the invention relates to a combination product. This combination product contains a statin and cilostazol, in which the sustained-release index of cilostazol, calculated according to Formula 1 below, is in the range of 16.652% to 28.400%.

Description

Combination drugs containing statins and cilostazol

[0001] This disclosure claims the benefit of priority to Republic of Korea Patent Application No. 10-2023-0143923, filed October 25, 2023, the entire contents of which are incorporated by reference herein.

[0002] The present invention relates to a composite preparation comprising two or more effective ingredients.

[0003] More specifically, the present invention relates to a combination comprising an HMG-CoA reductase inhibitor and cilostazol.

[0004]

[0005] Ischemic cardiovascular disease (ICD) caused by metabolic diseases such as hypertension, hyperlipidemia, diabetes, and obesity is characterized by progressive, chronic, and complex course. Its prevalence is increasing, leading to a decline in quality of life and a major cause of death. Furthermore, it is often accompanied by multiple comorbidities with other metabolic diseases and various complications. Therefore, specific treatments for a single metabolic disease are difficult to cure, and their effectiveness in alleviating complications and managing comorbidities is limited. To effectively treat and prevent ICD, the development of multi-drug combination therapies that can reduce multiple risk factors, including metabolic diseases and comorbidities, is urgently needed. In particular, the incidence and morbidity of ICD are significantly higher in the elderly than in the general population, making adult drug treatments vulnerable (25-49% mortality rate) and limiting their effectiveness. Therefore, the development of multi-drug combination therapies tailored to the physiological and pathological characteristics of the elderly is urgently needed.

[0006] Due to metabolic diseases and vascular damage, the formation of thrombi through the activation of platelet aggregation through the interaction of platelets and plasma coagulation factors in the arteries causes ischemic cardiovascular diseases such as arteriosclerosis, angina pectoris, myocardial infarction, and cerebral infarction. Therefore, antiplatelet agents that inhibit platelet aggregation are pharmacologically effective in the treatment and prevention of ischemic cardiovascular diseases by inhibiting platelet-mediated thrombosis and vascular occlusion. In particular, cilostazol is an antiplatelet agent with a phosphodiesterase III inhibitory mechanism that has vasodilatory, antiproliferative, and lipid-regulating effects. It is frequently used to improve ischemic symptoms due to chronic arterial occlusive diseases such as occlusive arteriosclerosis and diabetic peripheral angiopathy, and to prevent recurrence after cerebral infarction. In addition, cilostazol has been clinically proven to be effective in secondary prevention of acute and chronic ischemic stroke by preventing restenosis after vascular procedures, in improving inflammation and oxidative stress in hypertensive type 2 diabetic patients, and in protecting the kidneys in the treatment of nephropathy, and has much lower drug resistance than antiplatelet agents such as aspirin or clopidogrel.

[0007] Hyperlipidemia, which is caused by an abnormal increase in lipids such as cholesterol and triglycerides in the plasma due to excessive intake of fat and carbohydrates, obesity, diabetes, kidney disease, hypothyroidism, genetic factors, etc., can form blood clots in the arteries, causing ischemic cardiovascular symptoms. Therefore, ischemic cardiovascular disease can be prevented by treating hyperlipidemia. Among hyperlipidemia treatments, statins, which control cholesterol synthesis by inhibiting HMG-CoA reductase, are the most effective in lowering plasma low-density lipoprotein and are mainly used to prevent cardiovascular disease in patients with metabolic disorders. It has been clinically proven to be effective in reducing ischemic cardiovascular symptoms such as arteriosclerosis, angina pectoris, myocardial infarction, cerebral infarction, and mortality.

[0008] Combination therapy with cilostazol and statins is currently being used to treat and prevent ischemic cardiovascular disease associated with hyperlipidemia and ischemic cardiovascular disease associated with hyperlipidemia secondary to other metabolic diseases. It has been shown to offer superior clinical therapeutic and preventive effects compared to cilostazol or statin monotherapy. The development of combinations of cilostazol and statins could yield additive or synergistic therapeutic and preventive effects from the combined antiplatelet, antihyperlipidemic, and antithrombotic effects of different mechanisms. Furthermore, the simplified single-dose solid combination formulation, formulated in a single formulation, could improve the convenience of taking both drugs and patient compliance.

[0009] Since cilostazol is administered twice daily and statin drugs are administered once daily, in order to ensure effective once-daily administration of fixed doses of cilostazol and statin selected with a specific dose ratio of both drugs, the development of an optimized formulation is required, including individually controlling the release and dissolution of each drug from a single formulation to maintain or improve the original pharmacokinetic behavior (absorption, distribution, metabolism, and excretion) of both drugs, clarifying and simplifying the formulation composition and manufacturing method that are suitable for the properties of both drugs, preventing physicochemical interactions between the two drugs and with excipients to be used to ensure the safety of the combination formulation, and minimizing the increase in formulation size due to the combination of the two drugs to minimize the size of the combination formulation.

[0010]

[0011] The technical idea of ​​the present invention is to provide an optimized combination drug comprising a statin and cilostazol.

[0012]

[0013] According to exemplary embodiments of the present invention for solving the above-described problems, a combination formulation is provided. The combination formulation comprises a statin and cilostazol, wherein the sustained-release index of cilostazol, calculated using the following mathematical formula 1, is 16.652% to 28.400%.

[0014] [Mathematical Formula 1]

[0015]

[0016] The above statin may include at least one selected from the group consisting of rosuvastatin, simvastatin, atorvastatin, pitavastatin, pravastatin, fluvastatin, lovastatin, and cerivastatin.

[0017] The above statins may include rosuvastatin.

[0018] The above complex may be a two-layer tablet.

[0019] The above statin may be included in the first layer and the above cilostazol may be included in the second layer.

[0020] The second layer may include a cilostazol immediate-release portion and a cilostazol sustained-release portion.

[0021] The first layer may further include excipients, binders, disintegrants and lubricants.

[0022] The cilostazol immediate-release portion of the second layer may further include excipients, a disintegrant, and a binder.

[0023] The cilostazol sustained-release portion of the second layer may further include excipients, a sustained-release agent, a binder, and a lubricant.

[0024]

[0025] The combination preparation according to exemplary embodiments of the present invention has sufficient pharmacological effects with only one daily administration due to the sustained release of cilostazol, thereby providing high convenience and compliance with administration.

[0026] In addition, the composite formulation according to exemplary embodiments of the present invention has excellent bioavailability.

[0027] The effects that can be obtained from the exemplary embodiments of the present invention are not limited to the effects mentioned above, and other effects not mentioned can be clearly derived and understood by those skilled in the art to which the exemplary embodiments of the present disclosure pertain from the following description. In other words, unintended effects resulting from practicing the exemplary embodiments of the present disclosure can also be derived by those skilled in the art from the exemplary embodiments of the present disclosure.

[0028]

[0029] The terms or words used in this specification should not be interpreted as limited to their usual or dictionary meanings, but should be interpreted as meanings and concepts that conform to the technical idea of ​​the present invention based on the principle that the inventor can appropriately define the concept of the term to explain his or her invention in the best way.

[0030] In this specification, terms such as "include" or "have" are intended to specify the presence of a feature, number, step, operation, component, part, or combination thereof described in the specification, and should be understood as not excluding in advance the possibility of the presence or addition of one or more other features, numbers, steps, operations, components, parts, or combinations thereof. In addition, when a part such as a layer, film, region, or plate is said to be "on" another part, this includes not only the case where it is "directly above" the other part, but also the case where there is another part in between. Conversely, when a part such as a layer, film, region, or plate is said to be "under" another part, this includes not only the case where it is "directly below" the other part, but also the case where there is another part in between. In addition, in this application, being disposed "on" may include the case where it is disposed below as well as above.

[0031] The embodiments described in this specification and the configurations illustrated in the drawings are only the most preferred embodiments of the present invention and do not represent all of the technical ideas of the present invention. Therefore, it should be understood that there may be various equivalents and modified examples that can replace them at the time of filing this application.

[0032] When describing the present invention, if it is determined that a detailed description of a related known configuration or function may obscure the gist of the present invention, the detailed description will be omitted.

[0033]

[0034] The following describes the terms used in this specification.

[0035] "AUC (area under curve)" is the area under the drug blood concentration-time curve calculated using the trapezoidal method, and "AUC (A h ~ B h)" refers to the area under the drug blood concentration-time curve from hour A to hour B after drug administration. For example, "AUC (0 h ~ 24 h)" refers to the area under the drug blood concentration-time curve from hour 0 to 24 after drug administration.

[0036] "Time to reach peak blood concentration (t max, Tmax) is the highest blood concentration (C) after drug administration. max ) means the time to reach.

[0037] "Maximum blood concentration (C max )" refers to the highest blood concentration after drug administration.

[0038]

[0039] Hereinafter, specific details for carrying out the present invention will be described.

[0040] In order for a formulation to exhibit a rapid effect when administered orally and to maintain its effect for a long period of time, a certain amount of the active ingredient must be rapidly released and absorbed into the body as the formulation passes through the gastrointestinal tract, while the remaining active ingredient must remain in the gastrointestinal tract for a long period of time and be slowly released and absorbed into the body.

[0041] The present invention provides a novel parameter, a sustained-release index, calculated as in the following mathematical formula 1, which can confirm that a formulation exhibits a rapid effect upon oral administration while maintaining the effect for a long period of time.

[0042] [Mathematical Formula 1]

[0043]

[0044] The release index is the area under the blood concentration curve of the active ingredient (AUC (0 h ~ 48 h)) from 0 to 48 hours after oral administration of the preparation, expressed as Tmax-1.0 hours to T max+2.0 hours is the ratio of the area under the blood concentration curve of the active ingredient (AUC(Tmax-1.0 h ~ Tmax+2.0 h)). However, in some subjects, the blood concentration of the active ingredient 48 hours after oral administration of the preparation may be 0. In this case, when calculating the sustained-release index, the value of AUC(0 h ~ 24 h) rather than AUC(0 h ~ 48 h) can be entered in the denominator. In other words, the sustained-release index can be calculated as in the following mathematical equation 2.

[0045] [Equation 2]

[0046]

[0047] If the blood concentration of the active ingredient 48 hours after oral administration of the preparation is 0, then t is 24.

[0048] If the blood concentration of the active ingredient is not 0 at 48 hours after oral administration of the preparation, t is 48.

[0049] The sustained-release index can be a useful index for predicting the sustained-release ability of a formulation, i.e., whether the formulation can exhibit rapid effects and maintain its effects for a long period of time when administered orally.

[0050] According to exemplary embodiments, the combination formulation may have a sustained-release index of cilostazol of 16.652% to 28.400%.

[0051] According to exemplary embodiments, the combination formulation may have a sustained release index of cilostazol of 20.919% to 24.134%.

[0052]

[0053] The upper and lower limits of the numerical range of the sustained-release index of a sustained-release formulation can be calculated using the following method. The clinical trial details are described in detail in the experimental examples below.

[0054] Pharmacokinetic data for each male subject obtained from a clinical trial conducted on 42 healthy adults were input into the above calculation formula, and the resulting values ​​were collected and the mean and standard deviation were calculated. The mean was calculated as 22.526% and the standard deviation was calculated as 5.874%. Therefore, the lower limit of the numerical range was set to 16.652%, which is the mean minus the standard deviation, and the upper limit was set to 28.400%, which is the mean plus the standard deviation.

[0055] Meanwhile, since the number of samples is 42, which is greater than 30, and the sample is assumed to follow a normal distribution according to the central limit theorem, the 90% confidence interval of the mean was calculated to be 20.919% to 24.134%. In this case, the upper and lower limits of the numerical range can be regarded as 20.919% and 24.134%, respectively.

[0056]

[0057] According to exemplary embodiments, the combination may comprise a statin and cilostazol.

[0058] According to exemplary embodiments, the statin may include at least one selected from the group consisting of rosuvastatin, simvastatin, atorvastatin, pitavastatin, pravastatin, fluvastatin, lovastatin, and cerivastatin. According to exemplary embodiments, the statin may include rosuvastatin.

[0059] Rosuvastatin, a drug with the same mechanism of action, is more effective in lowering blood low-density lipoprotein (LDL) levels than commercially available drugs like atorvastatin or simvastatin, and research reports have shown that it is also superior in raising beneficial high-density lipoprotein (HDL) levels in the body, which has led to increasing interest in rosuvastatin. Pitavastatin has been reported to be the only statin that can lower blood sugar levels rather than increase them, and thus does not cause the 'increased blood sugar' side effect of statins, which has recently become a hot topic, and is widely used in patients with hyperlipidemia accompanied by diabetes. Atorvastatin is one of the drugs used in high-intensity statin therapy, including rosuvastatin, and is actively recommended for the treatment of atherosclerotic cardiovascular disease. Additionally, it is widely used because it has been reported to have fewer adverse effects on renal function decline. Since the characteristics of the present invention do not lie in the type of statin drug, a description of the remaining statin drugs will be omitted.

[0060] Cilostazol inhibits primary platelet aggregation induced by ADP, epinephrine, etc. in platelets isolated from mice, rats, rabbits, dogs, and humans, and dissociates platelet aggregates. In addition, when administered orally to beagles, it inhibits platelet aggregation induced by ADP and collagen. When administered orally to patients with chronic arterial occlusive disease (such as Buerger's disease, atherosclerosis obliterans, and diabetic peripheral angiopathy), it inhibits platelet aggregation induced by ADP, collagen, arachidonic acid, and epinephrine in isolated platelets. The platelet aggregation inhibition effect of cilostazol appears rapidly after administration and is maintained even with repeated administration. When administration is discontinued, the inhibited platelet aggregation returns to the pre-administration level along with a decrease in plasma concentration, and there is no rebound phenomenon (enhanced aggregation).

[0061] Cilostazol's mechanism of action is as follows: it inhibits the release of serotonin from rabbit platelets, but does not affect the uptake of serotonin or adenosine into platelets. It inhibits platelet aggregation induced by thromboxane A2 (TXA2) without affecting arachidonic acid metabolism in platelets. This is due to inhibition of cAMP-PDE (cyclic AMP phosphodiesterase) activity in platelets and vascular smooth muscle, ultimately exerting antiplatelet and vasodilatory effects.

[0062] According to exemplary embodiments, the combination formulation may be a bilayer tablet. The bilayer tablet may be one type of combination formulation. The bilayer tablet may include two or more types of active ingredients. The bilayer tablet may include two layers, each referred to as a first layer and a second layer. The positional relationship between the first layer and the second layer is not particularly limited as long as they are separated from each other. As non-limiting examples, the first layer may be located above the second layer, the first layer may be located below the second layer, the first layer may be located to the left of the second layer, and the first layer may be located to the right of the second layer. The bilayer tablet may include two types of active ingredients, one active ingredient may be included in the first layer and the other active ingredient may be included in the second layer. The bilayer tablet may prevent chemical interactions between different active ingredients while improving interference in drug release.

[0063] According to exemplary embodiments, the statin may be included in the first layer of the bilayer tablet and cilostazol may be included in the second layer of the bilayer tablet.

[0064] As a non-limiting example, the diameter of a bilayer tablet may range from 5 mm to 10 mm. A bilayer tablet with a diameter less than 5 mm may be prone to disintegration during compression. A bilayer tablet with a diameter exceeding 10 mm may reduce patient compliance.

[0065] As a non-limiting example, the weight of a bilayer tablet may range from 350 mg to 550 mg. If the weight of a bilayer tablet is less than 350 mg, insufficient excipients may be added, resulting in poor stability. If the weight of a bilayer tablet exceeds 550 mg, the dosage form may become excessively large, which may reduce patient convenience.

[0066] As a non-limiting example, the statin content in the first layer may range from 3 mg to 40 mg. If the statin content in the first layer is less than 3 mg, sufficient pharmacological activity may not be observed. If the statin content in the first layer exceeds 40 mg, the blood statin concentration may increase excessively, resulting in adverse effects.

[0067] As a non-limiting example, the statin content of the first layer may be 5 mg or more. As a non-limiting example, the statin content of the first layer may be 10 mg or more. As a non-limiting example, the statin content of the first layer may be 15 mg or more. As a non-limiting example, the statin content of the first layer may be 35 mg or less. As a non-limiting example, the statin content of the first layer may be 30 mg or less. As a non-limiting example, the statin content of the first layer may be 25 mg or less.

[0068] As a non-limiting example, the cilostazol content of the second layer may range from 160 mg to 240 mg. If the cilostazol content of the second layer is less than 160 mg, sufficient pharmacological activity may not be observed. If the cilostazol content of the second layer exceeds 240 mg, the blood concentration of cilostazol may increase excessively, resulting in adverse effects.

[0069] As a non-limiting example, the content of cilostazol in the second layer may be 170 mg or more. As a non-limiting example, the content of cilostazol in the second layer may be 180 mg or more. As a non-limiting example, the content of cilostazol in the second layer may be 190 mg or more. As a non-limiting example, the content of cilostazol in the second layer may be 230 mg or less. As a non-limiting example, the content of cilostazol in the second layer may be 220 mg or less. As a non-limiting example, the content of cilostazol in the second layer may be 210 mg or less.

[0070] According to exemplary embodiments, the second layer of the bilayer tablet may include a cilostazol immediate-release portion and a cilostazol sustained-release portion.

[0071] As a non-limiting example, the cilostazol content of the cilostazol extended-release portion may range from 50% to 90% of the cilostazol content of the cilostazol immediate-release portion. Since the cilostazol content of the cilostazol extended-release portion is in the range from 50% to 90% of the cilostazol content of the cilostazol immediate-release portion, both the rapid pharmacological activity of the immediate-release portion and the sustained effect of the extended-release portion can be achieved while reducing side effects.

[0072] As a non-limiting example, the cilostazol content of the cilostazol extended-release portion may be 55% or greater based on the cilostazol content of the cilostazol immediate-release portion. As a non-limiting example, the cilostazol content of the cilostazol extended-release portion may be 60% or greater based on the cilostazol content of the cilostazol immediate-release portion. As a non-limiting example, the cilostazol content of the cilostazol extended-release portion may be 65% or greater based on the cilostazol content of the cilostazol immediate-release portion. As a non-limiting example, the cilostazol content of the cilostazol extended-release portion may be 80% or less based on the cilostazol content of the cilostazol immediate-release portion. As a non-limiting example, the cilostazol content of the cilostazol extended-release portion may be 75% or less based on the cilostazol content of the cilostazol immediate-release portion. As a non-limiting example, the cilostazol content of the extended-release cilostazol may be 70% or less of the cilostazol content of the immediate-release cilostazol.

[0073] According to exemplary embodiments, the first layer may further comprise excipients, binders, disintegrants and lubricants.

[0074] As a non-limiting example, the excipient content of the first layer may range from 90 mg to 140 mg. If the excipient content of the first layer is less than 90 mg, the compound may not be properly expanded or may cause sticking, in which the mixture adheres to the punches of the tableting machine. If the excipient content of the first layer exceeds 140 mg, the compound may be expanded excessively.

[0075] As a non-limiting example, the content of the excipient in the first layer may be 95 mg or more. As a non-limiting example, the content of the excipient in the first layer may be 100 mg or more. As a non-limiting example, the content of the excipient in the first layer may be 110 mg or more. As a non-limiting example, the content of the excipient in the first layer may be 135 mg or less. As a non-limiting example, the content of the excipient in the first layer may be 130 mg or less. As a non-limiting example, the content of the excipient in the first layer may be 120 mg or less.

[0076] As a non-limiting example, the binder content of the first layer may range from 1 mg to 8 mg. If the binder content of the first layer is less than 1 mg, the binding force of the formulation may be weakened, which may result in reduced flowability and tabletability of the granules. If the binder content of the first layer exceeds 8 mg, the dissolution rate may be relatively slow, which may significantly affect the control of the dissolution rate of cilostazol.

[0077] As a non-limiting example, the binder content of the first layer may be 2 mg or more. As a non-limiting example, the binder content of the first layer may be 3 mg or more. As a non-limiting example, the binder content of the first layer may be 4 mg or more. As a non-limiting example, the binder content of the first layer may be 7 mg or less. As a non-limiting example, the binder content of the first layer may be 6 mg or less. As a non-limiting example, the binder content of the first layer may be 5 mg or less.

[0078] As a non-limiting example, the content of the disintegrant in the first layer may range from 1 mg to 8 mg. If the content of the disintegrant in the first layer is less than 1 mg, the dissolution rate of the formulation may be slow. Even if the content of the disintegrant in the first layer exceeds 8 mg, the dissolution rate may not be significantly increased, which may be uneconomical.

[0079] As a non-limiting example, the content of the disintegrant in the first layer may be 2 mg or more. As a non-limiting example, the content of the disintegrant in the first layer may be 3 mg or more. As a non-limiting example, the content of the disintegrant in the first layer may be 4 mg or more. As a non-limiting example, the content of the disintegrant in the first layer may be 7 mg or less. As a non-limiting example, the content of the disintegrant in the first layer may be 6 mg or less. As a non-limiting example, the content of the disintegrant in the first layer may be 5 mg or less.

[0080] As a non-limiting example, the content of the lubricant in the first layer may range from 0.5 mg to 3.5 mg. If the content of the lubricant in the first layer is less than 0.5 mg, the lubricant may be insufficient, which may increase the risk of tableting failure and make tableting difficult. If the content of the lubricant in the first layer exceeds 3.5 mg, the dissolution profile of the tablet may be affected due to the coating phenomenon of the lubricant granules.

[0081] As a non-limiting example, the content of the lubricant in the first layer may be 1.0 mg or more. As a non-limiting example, the content of the lubricant in the first layer may be 1.5 mg or more. As a non-limiting example, the content of the lubricant in the first layer may be 3.0 mg or less. As a non-limiting example, the content of the lubricant in the first layer may be 2.5 mg or less.

[0082] According to exemplary embodiments, the cilostazol immediate-release portion of the second layer may further include excipients, a disintegrant, and a binder.

[0083] As a non-limiting example, the excipient content of the cilostazol immediate-release part may range from 5 mg to 40 mg. If the excipient content of the cilostazol immediate-release part is less than 5 mg, the dosage form may not be properly expanded or the mixture may stick to the punches of the tableting machine. If the excipient content of the cilostazol immediate-release part exceeds 40 mg, the dosage form may be excessively expanded.

[0084] As a non-limiting example, the amount of excipients in the cilostazol immediate-release portion may be 10 mg or more. As a non-limiting example, the amount of excipients in the cilostazol immediate-release portion may be 15 mg or more. As a non-limiting example, the amount of excipients in the cilostazol immediate-release portion may be 35 mg or less. As a non-limiting example, the amount of excipients in the cilostazol immediate-release portion may be 30 mg or less. As a non-limiting example, the amount of excipients in the cilostazol immediate-release portion may be 25 mg or less.

[0085] As a non-limiting example, the disintegrant content of the cilostazol immediate-release portion may range from 1 mg to 10 mg. If the disintegrant content of the cilostazol immediate-release portion is less than 1 mg, the dissolution rate of the formulation may be slow. Even if the disintegrant content of the cilostazol immediate-release portion exceeds 10 mg, the dissolution rate may not be significantly accelerated, which may be uneconomical.

[0086] As a non-limiting example, the content of disintegrant in the cilostazol immediate-release portion may be 2 mg or more. As a non-limiting example, the content of disintegrant in the cilostazol immediate-release portion may be 3 mg or more. As a non-limiting example, the content of disintegrant in the cilostazol immediate-release portion may be 8 mg or less. As a non-limiting example, the content of disintegrant in the cilostazol immediate-release portion may be 6 mg or less.

[0087] As a non-limiting example, the binder content of the cilostazol immediate-release portion may range from 1 mg to 10 mg. If the binder content of the cilostazol immediate-release portion is less than 1 mg, the binding force of the formulation may be weakened, which may result in reduced granule flowability and tableting properties. If the binder content of the cilostazol immediate-release portion exceeds 10 mg, the dissolution rate may be relatively slow, which may significantly affect the dissolution rate control of cilostazol.

[0088] As a non-limiting example, the binder content of the cilostazol immediate-release portion may be 3 mg or more. As a non-limiting example, the binder content of the cilostazol immediate-release portion may be 5 mg or more. As a non-limiting example, the binder content of the cilostazol immediate-release portion may be 8 mg or less. As a non-limiting example, the binder content of the cilostazol immediate-release portion may be 7 mg or less.

[0089] According to exemplary embodiments, the cilostazol sustained-release portion of the second layer may further include excipients, a release agent, a binder, and a lubricant.

[0090] As a non-limiting example, the excipient content of the cilostazol extended-release formulation may range from 30 mg to 70 mg. If the excipient content of the cilostazol extended-release formulation is less than 30 mg, the dosage form may not be properly expanded or the mixture may stick to the punches of the tableting machine. If the excipient content of the cilostazol extended-release formulation exceeds 70 mg, the dosage form may be excessively expanded.

[0091] As a non-limiting example, the excipient content of the cilostazol extended-release may be 35 mg or more. As a non-limiting example, the excipient content of the cilostazol extended-release may be 40 mg or more. As a non-limiting example, the excipient content of the cilostazol extended-release may be 45 mg or more. As a non-limiting example, the excipient content of the cilostazol extended-release may be 65 mg or less. As a non-limiting example, the excipient content of the cilostazol extended-release may be 60 mg or less. As a non-limiting example, the excipient content of the cilostazol extended-release may be 55 mg or less.

[0092] As a non-limiting example, the content of the sustained-release agent in the cilostazol extended-release portion may be in the range of 3% to 9% based on the weight of the cilostazol in the second layer. If the content of the sustained-release agent in the cilostazol extended-release portion is less than 3% based on the weight of the cilostazol in the second layer, the initial release amount of cilostazol may be excessive, which may prevent sufficient sustained-release, and side effects such as headache may occur. If the content of the sustained-release agent in the cilostazol extended-release portion is more than 9% based on the weight of the cilostazol in the second layer, the dissolution of cilostazol may be excessively delayed, making it difficult to achieve sufficient pharmacological effects.

[0093] As a non-limiting example, the content of the sustained-release agent in the cilostazol sustained-release portion may be 4% or more, based on the weight of the cilostazol in the second layer. As a non-limiting example, the content of the sustained-release agent in the cilostazol sustained-release portion may be 5% or more, based on the weight of the cilostazol in the second layer. As a non-limiting example, the content of the sustained-release agent in the cilostazol sustained-release portion may be 8% or less, based on the weight of the cilostazol in the second layer. As a non-limiting example, the content of the sustained-release agent in the cilostazol sustained-release portion may be 7% or less, based on the weight of the cilostazol in the second layer. As a non-limiting example, the content of the sustained-release agent in the cilostazol sustained-release portion may be 6% or less, based on the weight of the cilostazol in the second layer.

[0094] As a non-limiting example, the binder content of the cilostazol extended-release formulation may range from 1 mg to 20 mg. If the binder content of the cilostazol extended-release formulation is less than 1 mg, the binding force of the formulation may be weakened, which may result in reduced granule flowability and tableting properties. If the binder content of the cilostazol extended-release formulation exceeds 20 mg, the dissolution rate may be relatively slow, which may significantly affect the dissolution rate control of cilostazol.

[0095] As a non-limiting example, the binder content of the cilostazol extended-release may be 5 mg or more. As a non-limiting example, the binder content of the cilostazol extended-release may be 7 mg or more. As a non-limiting example, the binder content of the cilostazol extended-release may be 9 mg or more. As a non-limiting example, the binder content of the cilostazol extended-release may be 15 mg or less. As a non-limiting example, the binder content of the cilostazol extended-release may be 13 mg or less. As a non-limiting example, the binder content of the cilostazol extended-release may be 11 mg or less.

[0096] As a non-limiting example, the content of the lubricant in the second layer may range from 1 mg to 20 mg. If the content of the lubricant in the second layer is less than 1 mg, the lubricant may be insufficient, increasing the risk of tableting failure and making tableting difficult. If the content of the lubricant in the second layer exceeds 20 mg, the dissolution profile of the tablet may be affected due to the coating phenomenon of the lubricant granules.

[0097] As a non-limiting example, the amount of the lubricant in the second layer may be 5 mg or more. As a non-limiting example, the amount of the lubricant in the second layer may be 7 mg or more. As a non-limiting example, the amount of the lubricant in the second layer may be 9 mg or more. As a non-limiting example, the amount of the lubricant in the second layer may be 15 mg or less. As a non-limiting example, the amount of the lubricant in the second layer may be 13 mg or less. As a non-limiting example, the amount of the lubricant in the second layer may be 11 mg or less.

[0098] As a non-limiting example, the first layer can be manufactured by compressing granules prepared by mixing the statin, excipients, and binder and then post-mixing the lubricant.

[0099] As a non-limiting example, the second layer can be manufactured by compressing cilostazol granules prepared by post-mixing cilostazol immediate-release granules and cilostazol sustained-release granules with a lubricant. As a non-limiting example, cilostazol immediate-release granules can be manufactured by mixing cilostazol, an excipient, and a disintegrant, mixing them with a binder, granulating, drying, and sizing. As a non-limiting example, cilostazol sustained-release granules can be manufactured by mixing cilostazol, an excipient, and a sustained-release agent, mixing them with a binder, granulating, drying, and sizing.

[0100] As described above, the cilostazol immediate-release granules and the cilostazol sustained-release granules are post-mixed with a lubricant, so the boundary between the cilostazol immediate-release granules and the cilostazol sustained-release granules in the second layer may not be clear. The cilostazol immediate-release granules may be understood to be derived from the cilostazol immediate-release granules, and the cilostazol sustained-release granules may be understood to be derived from the cilostazol sustained-release granules.

[0101] As a non-limiting example, the diameter of the cilostazol immediate-release granules and cilostazol extended-release granules may be in the range of 350 μm to 450 μm. If the diameter of the cilostazol immediate-release granules and cilostazol extended-release granules is less than 350 μm or greater than 450 μm, the dissolution may be too rapid or the pharmacological effect may not be sufficient.

[0102] Excipients are substances used to increase the volume of solid dosage forms and can include all substances commonly used in the pharmaceutical industry. As non-limiting examples, excipients include lactose monohydrate, microcrystalline cellulose, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, powdered cellulose, starch, pregelatinized starch, modified pregelatinized starch, tapioca starch, wheat starch, corn starch, potato starch, dextrates, dextrin, dextrose additives, wheat starch, sodium alginate, lactose, lactose monohydrate, anhydrous lactose, methylcellulose, sucrose, compressible sucrose, refined sucrose, sodium carboxymethylcellulose, glucose, kaolin, fructose, maltose, sucrose, urea, mannitol, d-mannitol, sorbitol, colloidal silica gel, precipitated calcium carbonate, hydroxypropyl starch, synthetic aluminum silicate, hydroxypropyl methylcellulose, It may include at least one selected from the group consisting of calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium sulfate, propylene glycol, sodium chloride, casein, sodium bicarbonate, calcium lactate, purified lanolin, and Primogel.

[0103] Disintegrants are substances that are necessary to expand solid dosage forms so that they can be broken down in the digestive tract before they are absorbed, and can include any substance commonly used in the pharmaceutical industry. As non-limiting examples, disintegrants include crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, maltose, potassium polycrylin, starch, corn starch, potato starch, pregelatinized starch, modified pregelatinized starch, tapioca starch, wheat starch, agar powder, methylcellulose, bentonite, hydroxypropyl starch, sodium carboxymethylcellulose, sodium alginate, calcium carboxymethylcellulose, calcium citrate, sodium lauryl sulfate, anhydrous silicic acid, 1-hydroxypropyl cellulose, dextran, ion exchange resin polyvinyl acetate, formaldehyde-treated casein and gelatin alginate, amylose, guar gum, It may include at least one selected from the group consisting of baking soda, polyvinylpyrrolidone (povidone), calcium phosphate, gelled starch, gum arabic, amylopectin, pectin, sodium polyphosphate, ethylcellulose, sucrose, magnesium aluminum silicate, di-sorbitol solution, and light anhydrous silicic acid.

[0104] A binder is a substance that imparts a certain absorption, solidification or consistency to a mixture and can include any substance commonly used in the pharmaceutical industry. As non-limiting examples, binders include polysorbates, hydroxypropylcellulose, polyvinyl alcohol, gelatin, glucose, gum arabic, sodium caseinate, agar powder, glycerin (concentrated glycerin), cellulose acetate phthalate, stearic acid, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium methylcellulose, methylcellulose, refined shellac, microcrystalline cellulose, starch starch, corn starch, potato starch, pregelatinized starch, modified pregelatinized starch, tapioca starch, wheat starch, syrup, dextrin, maltodextrin, maltose, hydroxycellulose, hydroxypropylmethylcellulose, hydroxypropyl starch, polyvinyl alcohol, hydroxymethylcellulose, It may include at least one selected from the group consisting of methylcellulose, ethylcellulose, hypromellose acetate succinate, gelatin acetate, liquid glucose, guar gum, low-substituted hydroxypropyl cellulose, polyethylene oxide, polyvinylpyrrolidone (povidone), copovidone, acacia, alginic acid, ammoniomethacrylic acid copolymer, ammoniomethacrylic acid copolymer dispersion, carbomer copolymer, carbomer homopolymer, and carbomer interpolymer. The binder can be used by dissolving it in a solvent such as purified water and ethanol.

[0105] Lubricants are substances used to provide slip and reduce friction during tablet manufacturing, and can include all substances commonly used in the pharmaceutical industry. As a non-limiting example, the lubricant may include at least one selected from the group consisting of magnesium stearate, colloidal silicon dioxide, calcium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopodium dentata, kaolin, petrolatum, sodium stearate, cocoa butter, sodium salicylate, magnesium salicylate, polyethylene glycol 4000, 6000, liquid paraffin, hydrogenated soybean oil (Lubri wax), aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, macrogol, synthetic aluminum silicate, anhydrous silicic acid, calcium silicate, magnesium silicate, higher fatty acids, higher alcohols, silicone oil, paraffin oil, polyethylene glycol fatty acid ethers, starch, sodium chloride, sodium acetate, sodium oleate, dl-leucine, and light anhydrous silicic acid. Can be.

[0106] As a non-limiting example, the release agent may include one or more selected from the group consisting of hypromellose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, carboxymethylethylcellulose, hydroxypropylmethylcellulose acetylsuccinate, sodium carboxymethylcellulose, polyethylene glycol, carbomer, Kollidon SR, polyvinyl alcohol, polyvinyl acetate, and xanthan gum.

[0107] As a non-limiting example, a mixture of hypromellose and carbomer having a viscosity of 75,000 cps to 140,000 cps and a weight ratio of 1:1 to 2.5:1 can be used as a sustained-release agent. When hypromellose having a viscosity of 75,000 cps to 140,000 cps and carbomer are mixed in a weight ratio of 1:1 to 2.5:1, the stability of the sustained-release matrix can be improved.

[0108]

[0109] Hereinafter, the contents for carrying out the present invention will be described in more detail through examples and comparative examples, but the examples are only examples, and the present invention is not limited thereto.

[0110]

[0111] Example

[0112] Cilostazol immediate-release granules were prepared by mixing a mixture of cilostazol, microcrystalline cellulose 101, and croscarmellose sodium with a povidone binding solution dissolved in ethanol, granulating, drying, and sizing.

[0113] Cilostazol sustained-release granules were prepared by mixing a mixture of cilostazol, microcrystalline cellulose 101, hypromellose, and carbomer with a povidone binding solution dissolved in ethanol, granulating, drying, and sizing.

[0114] The above cilostazol immediate-release granules and the above cilostazol sustained-release granules were post-mixed with magnesium stearate to prepare cilostazol granules.

[0115] Rosuvastatin granules were prepared by mixing rosuvastatin calcium, lactose monohydrate, microcrystalline cellulose 102, calcium hydrogen phosphate monohydrate, copovidone, and crospovidone, and then post-mixing with magnesium stearate.

[0116] The above cilostazol granules and the above rosuvastatin granules were compressed into tablets to produce a bilayer tablet, and then coated.

[0117] At this time, the content of each substance is as shown in Table 1 below.

[0118] Classification, Mixing Purpose, Material Name, Example (Unit: mg) Cilostazol Layer (2nd Layer) Cilostazol immediate-release granules, Active ingredient, Cilostazol 120.00, Excipient, Microcrystalline cellulose 10120.00, Disintegrant, Croscarmellose sodium 4.00, Binder, Povidone 6.00, Cilostazol sustained-release granules, Active ingredient, Cilostazol 80.00, Excipient, Microcrystalline cellulose 10149.00, Sustained-release agent, Hypromellose 7.00, Sustained-release agent, Carbomer 4.00, Binder, Povidone 10.00, Lubricant, Magnesium stearate 10.00, Rosuvastatin Layer (1st Layer) Active ingredient, Rosuvastatin calcium 20.80, Excipient, Lactose monohydrate 42.00, Excipient, Microcrystalline cellulose 10222.00 Excipients: Calcium hydrogen phosphate monohydrate 52.00 Binder: Copovidone 4.60 Disintegrant: Crospovidone 4.60 Lubricant: Magnesium stearate 2.00 Coating layer: Film coating agent: Opadry amb II 88A180040 White 23.00 Total weight 481.00

[0119]

[0120] Comparative example

[0121] Pretal SR capsules (cilostazol 100 mg, Korea Otsuka Pharmaceutical Co., Ltd.) and Crestor tablets 20 mg (rosuvastatin 20 mg, Korea AstraZeneca Co., Ltd.) were prepared.

[0122]

[0123] Experimental example

[0124] A randomized, open-label, single-dose, six-sequence, three-treatment, three-period clinical trial was conducted on 42 healthy adults. One bilayer tablet of the example was administered as a single dose, and two Pletal SR capsules and one 20 mg Crestor tablet of the comparative example were administered concurrently.

[0125] Pharmacokinetic analysis was performed using PK software (WinNonlin® Phoenix (Pharsight, CA, USA; ver. 6.3)), and pharmacokinetic parameters were calculated using the actual blood sampling time. The following pharmacokinetic evaluation items were calculated for each subject through non-compartmental analysis using the above PK software. However, the pharmacokinetic evaluation items below are based on fasting administration. The calculation results are shown in Tables 2 and 3 below. The values ​​listed in Tables 2 and 3 are the arithmetic mean, standard deviation, and coefficient of variation calculated from the values ​​for each subject.

[0126]

[0127] C max : Highest concentration after a single dose.

[0128] AUC t : After a single dose, the area under the concentration-time curve was calculated by adding the linear trapezoidal for the increasing concentration range and the log-linear trapezoidal (or linear trapezoidal) for the decreasing concentration range. Concentration values ​​below the LLOQ were excluded from the calculation.

[0129] T max : Time to reach peak blood concentration after single administration

[0130]

[0131] Cilostazol pharmacokinetic evaluation items, comparative example, implementation budget, arithmetic mean, standard deviation, coefficient of variation, arithmetic mean, standard deviation, coefficient of variation, C max (ng / mL)928.4464.450.0932.4338.536.3AUC t (h*ng / mL)13074.55496.342.012026.33701.030.8T max (h)6.0 [4.0 ~ 25.3]3.0 [1.0 ~ 8.0]

[0132]

[0133] Rosuvastatin pharmacokinetic evaluation items, comparative example, implementation budget, arithmetic mean, standard deviation, coefficient of variation, arithmetic mean, standard deviation, coefficient of variation, C max(ng / mL)19.98.542.823.211.147.6AUC t (h*ng / mL)195.683.042.4206.185.941.7T max (h)4.0 [2.0 ~5.0]3.5 [0.5 ~ 6.0]

[0134]

[0135] The results of the pharmacokinetic equivalence evaluation for the examples and comparative examples are shown in Tables 4 and 5 below. The evaluation was performed on the AUC of the examples. t and C max AUC of the comparative example after log transformation t and C max The ratio was calculated and the 90% confidence interval thereof was evaluated to determine whether it was within the range of 0.8 to 1.25. As shown in Tables 4 and 5 below, the evaluation results showed that all values ​​were within the range of 0.8 to 1.25, confirming that the examples and comparative examples had similar pharmacokinetic characteristics.

[0136]

[0137] Cilostazol Pharmacokinetic Evaluation ItemsGeometric Mean ± Standard DeviationPoint Estimate90% Confidence IntervalComparison ExampleExample C max (ng / mL)831.2±464.4875.6±338.51.04910.9080-1.2121AUC t (h*ng / mL)12116.9±5496.311466.7±3701.00.94350.8654-1.0287

[0138]

[0139] Rosuvastatin Pharmacokinetic Evaluation ItemsGeometric Mean ± Standard DeviationPoint Estimate90% Confidence IntervalComparisonExampleExample C max (ng / mL)18.2±8.520.9±11.11.15301.0698-1.2427AUC t (h*ng / mL)178.2±83.0188.4±85.91.05821.0074-1.1116

[0140]

[0141] Meanwhile, the pharmacokinetic data for 42 healthy adults obtained from the above clinical trial were input into the following mathematical formula 1, and the resulting values ​​were collected and the mean and standard deviation were calculated. At this time, the mean was calculated as 22.526% and the standard deviation was calculated as 5.874%. Meanwhile, since the number of samples was 30 or more, and it was assumed that the samples followed a normal distribution according to the central limit theorem, the 90% confidence interval of the mean was calculated as 20.919% to 24.134%.

[0142]

[0143] [Mathematical Formula 1]

[0144]

[0145]

[0146] The above description merely exemplifies the technical concepts of the present invention. Those skilled in the art will appreciate that various modifications and variations can be made without departing from the essential characteristics of the present invention. The scope of protection of the present invention should be interpreted in accordance with the claims, and all technical concepts within the scope equivalent thereto should be construed as being included within the scope of the present invention.

Claims

1. Including statins and cilostazol, A combination preparation characterized in that the sustained-release index of cilostazol calculated by the following mathematical formula 1 is 16.652% to 28.400%. [Mathematical Formula 1] 2. In paragraph 1, A combination drug, characterized in that the statin comprises at least one selected from the group consisting of rosuvastatin, simvastatin, atorvastatin, pitavastatin, pravastatin, fluvastatin, lovastatin, and cerivastatin.

3. In paragraph 1, A combination drug characterized in that the statin comprises rosuvastatin.

4. In paragraph 1, The above complex is characterized in that it is a two-layer tablet.

5. In paragraph 4, A combination drug, characterized in that the statin is included in the first layer and the cilostazol is included in the second layer.

6. In paragraph 5, A combination preparation characterized in that the second layer comprises a cilostazol immediate-release part and a cilostazol sustained-release part.

7. In paragraph 6, A composite composition characterized in that the first layer further comprises an excipient, a binder, a disintegrant, and a lubricant.

8. In paragraph 6, A composite formulation characterized in that the cilostazol immediate-release part of the second layer further comprises an excipient, a disintegrant, and a binder.

9. In paragraph 6, A composite formulation characterized in that the cilostazol sustained-release portion of the second layer further comprises an excipient, a sustained-release agent, a binder, and a lubricant.