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WO2008069546A1 - Oral administrative preparation for treating cardiovascular system disease - Google Patents

Oral administrative preparation for treating cardiovascular system disease Download PDF

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Publication number
WO2008069546A1
WO2008069546A1 PCT/KR2007/006248 KR2007006248W WO2008069546A1 WO 2008069546 A1 WO2008069546 A1 WO 2008069546A1 KR 2007006248 W KR2007006248 W KR 2007006248W WO 2008069546 A1 WO2008069546 A1 WO 2008069546A1
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WO
WIPO (PCT)
Prior art keywords
preparation
pellet
acid
oral administrative
administrative preparation
Prior art date
Application number
PCT/KR2007/006248
Other languages
French (fr)
Inventor
Sang-Lin Kim
Hyun-Kwang Tan
Sung-Bum La
Sin-Tack Kang
Jong-Hwa Song
Man-Ki Kim
Keun Lee
Original Assignee
Boryung Pharmaceutical Co., Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boryung Pharmaceutical Co., Ltd filed Critical Boryung Pharmaceutical Co., Ltd
Publication of WO2008069546A1 publication Critical patent/WO2008069546A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Definitions

  • the present invention relates to oral administrative preparation for treating cardiovascular disease.
  • Cyclooxygenases are essential substance in the synthesis of prostaglandin, thromboxane A2, prostacyclin, and the like.
  • Prostaglandin is an inflammatory substance
  • thromboxane A2 is synthesized in platelets and causes aggregation of platelets and thrombosis.
  • prostacyclin shows platelet aggregation inhibiting activity.
  • Cyclooxygenases are generated in epithelial cells, not in platelets. Low-dose of aspirin can selectively inhibit cyclooxygenase in platelets maintaining synthesis of cyclooxygenase and prostaglandin in epithelial cells. That is, the main pharmacological effects of aspirin are inhibition of inflammation, reduction of platelet aggregation and reduction of thrombosis in blood vessel.
  • Fat absorbed in blood stream such as neutral fats, cholesterols, phospholipids, free fatty acids, and the like, are coupled with proteins to form lipoproteins, which is called as serum lipids.
  • Hyperlipidemia refers to a state in which concentration of serum lipid are above the normal range.
  • fat such as cholesterol cannot be dissolved in water, in order to be circulated in blood, it should be surrounded with proteins so that the complex is circulated in blood.
  • Such complex of fat and protein is called as lipoprotein.
  • Lipoprotein delivering cholesterol is divided into high density lipoprotein(HDL) and low density lipoprotein(LDL). HDL removes cholesterol from tissues and consequently lowers the risk of atherosclerosis, while LDL plays a role in stacking cholesterol on blood vessel wall, which leads to increase the risk of atherosclerosis.
  • Hyperlipidemia contributes to the changes of blood coagulation mechanism such as acceleration of platelet aggregation, decreasing the platelet coagulation time, inhibition of fibrinolytic system, etc.. This leads to increase the viscosity of blood, and finally to cause pathological changes in the property and states of blood and peripheral circulatory disturbance due to vasculitis. Also, hyperlipidemia causes atherosclerosis to make thrombus and to block blood vessels. Blockage of blood vessel in brain or coronary artery of heart results in cerebral infarction or myocardial infarction, respectively, which becomes to be the direct causes of death. Hyperlipidemia is main causes of angina pectoris, myocardial infarction, stroke, fatty liver, pancreatitis, etc., particularly closely involved in arteriosclerosis. It is known that a high concentration of cholesterol not only accelerates the occurrence arteriosclerosis but also makes arteriosclerosis be unstable, which rapidly progress arteriosclerosis to acute myocardial infarction.
  • HMG-CoA reductase inhibitor lowers the concentration of cholesterol required to synthesize cholic acid etc. by inhibiting HMG-CoA reductase which relates to the rate-limiting step in the synthesis of cholesterol in liver cells. As a result, to compensate this, the number of LDL receptors which causes the atherosclerosis is increased, which leads to a fall of in LDL blood level. This is the way HMG-CoA reductase inhibitor works.
  • US Patent 5,622,985 discloses a method for reducing the risk of a second attack in a patient having a substantially normal serum cholesterol level by administering an
  • HMG-CoA reductase Inhibitor such as especially pravastatin, alone or in combination with an ACE inhibitor.
  • US Patent 5,140,012 discloses the method to prevent the risk or restenosis following angioplasty by administering pravastatin alone or in combination with an ACE inhibitor, however, there is also an inconvenience in administration, and no further study for prevention or treatment of other cardiovascular disease than the said use, whereby the applicability had a limit.
  • EP 457,514 discloses a similar use to US Patent 5,622,985 and US Patent
  • US Patent 6,248,729 suggests a combined formulation of an ADP-receptor blocking antiplatelet drug and angiotensin receptor antagonist and its use, and a combined formulation of an ADP-receptor blocking antiplatelet drug and an ACE inhibitor and the use thereof.
  • a combined formulation of cholesterol lowering agent and aspirin and its use there is no description for a combined formulation of cholesterol lowering agent and aspirin and its use.
  • KR Publication No. 10-2006-0091762 suggests a combined pellet containing HMG-CoA reductase inhibitors and enteric coated aspirin for the prevention of atherosclerosis in hyperlipidemia patients.
  • the said pellet comprised of multi-layers consisting of a main layer in which an inert sugar sphere is coated with aspirin, a enteric coated layer on the main layer, and an outer layer coated with HMG-CoA reductase on the enteric coated layer.
  • this kind of formulation with multi-layers has many difficulties in a large scale production. For example, in order to prepare such formulation, expensive special equipments are required, and the coating performed at high temperature for a long time can fatally affect the stability of active ingredient.
  • production yield is decreased, compared with those of the way to coat each drugs independently.
  • direct contact of HMG-CoA reductase inhibitor and aspirin in the coating procedure can be an immediate cause to lower the dissolution rate due to their physical interaction, which greatly lowers the stability of drug.
  • aspirin as an acidic drug can react with basic compound or basic ester to cause hydrolysis of aspirin or disintegration of other compounds, and can react with acid-labile compound such as pravastatin, which results in the degradation of the compound.
  • US Patent 6,235,311 discloses a bilayered tablet consisting of first layer containing aspirin, second layer containing statins and a layer containing buffering agent between two layers to block interactions of the both active ingredients.
  • first layer containing aspirin second layer containing statins
  • second layer containing statins a layer containing buffering agent between two layers to block interactions of the both active ingredients.
  • buffering agent between two layers to block interactions of the both active ingredients.
  • the present inventors intended to develop a formulation which can dramatically improve or prevent drug hydrolysis or unstable drug reaction due to drug interaction between an antithrombotic agent and cholesterol lowering agent, while maximizing the therapeutic effect, and thereby came to complete the present invention.
  • the present invention provides an oral administrative preparation for treating cardiovascular disease comprising: (a) a first pellet comprising a core containing an antithrombotic agent and an enteric coating layer; and (b) a second pellet comprising a core containing an inert particle, a middle layer containing a cholesterol lowering agent and an outer coating layer.
  • the antithrombotic agent can be a platelet aggregation inhibitor.
  • the platelet aggregation inhibitor can be a derivative of salicylic acid.
  • the derivative of salicylic acid comprises one or more selected from a group consisting of salicylic acid sodium, salicylic acid magnesium including salicylic acid magnesium tetrahydrate, salicylsalicylic acid(salsalate), and aspirin.
  • the derivative of salicylic acid is preferably aspirin.
  • the platelet aggregation inhibitor can be an agent inhibiting binding of ADP to platelet.
  • an agent inhibiting binding of ADP to platelet can be ticlopidine, anagrelide, dipyridamole, clopidogrel, clopidogrel bisulfate, clopidogrel (+)-camphorsulfonic acid salt, clopidogrel besylate, and clopidogrel sulfosalicylic acid salt.
  • the platelet aggregation inhibitor can be a nonsteroidal anti-inflammatory drug(NSAID) inhibiting cyclooxygenase.
  • nonsteroidal anti-inflammatory drug can be one or more selected from a group consisting of ibuprofen, ibuprofen lysinate, dexibuprofen, ibuproxam, ketoprofen, ketoprofen lysinate, loxoprofen, loxoprofen sodium, flubiprofen, alminoprofen, zaltoprofen, fenoprofen calcium, pranoprofen, ketololac, ketololac tromethamin, sulindac, sulindac sulfide, sulindac sulfone, etodolac, diclofenac, diclofenac sodium, diclofenac beta-dimethylarninoethanol, diclofenac potassium, lonazolac
  • the cholesterol lowering agent can be a pharmaceutically acceptable HMG-CoA reductase inhibitor.
  • the pharmaceutically acceptable HMG-CoA reductase inhibitor can be rosuvastatin, rosuvastatin calcium, atorvastatin, atorvastatin calcium, atorvastatin sodium, cerivastatin, fluindostatin, fluvastatin, lovastatin, mevastatin, pravastatin, compactin, dihydrocompactin, dalvastatin, simvastatin and velostatin; a pharmaceutically acceptable salt thereof. They can be administered alone or in combination of 2 or more ingredients.
  • the weight ratio of the core: the enteric coating layer in the first pellet can be 70-90 weight% : 10-30 weight%.
  • the core in the first pellet can comprise an antithrombotic agent, binder, and excipient.
  • the excipient in the first pellet can be any one used in the art of the present invention.
  • the excipient can be lactose, microcrystalline cellulose, starch, etc.
  • the excipient is preferably microcrystalline ellulose.
  • the binder in the first layer can be any one used in the art of the present invention.
  • the binder can be hydroxypropylcellulose, carboxymethylcellulose sodium, pregelatinized starch, povidone, and the like.
  • the binder is preferably hydroxypropylcellulose.
  • the enteric coating layer in the first pellet can be excipient, binder, and disintegrant.
  • the coating agent used in the enteric coating layer can be any one used in the present art.
  • the coating agent can be cellulosebutratephthalate, cellulosehydrogenphthalate, cellulosepropionatephthalate, polyvinylacetatephthalate, celluloseacetatephthalate, celluloseacetatetrimellitate, hydroxypropylmethylcellulosephthalate, hydroxypropylmethylacetate, dioxypropylmethylcellulosesuccinate, carboxymethylethylcellulose, hydroxypropylmethylcelluloseacetatesuccinate, or copolymer prepared from polymer and acrylic acid, methacrylic acid, or their ester, etc.
  • the weight ratio of the core: the middle layer: the outer coating layer in the second pellet can be 30-70 weight%: 10-40 weight%: 1-10 weight%.
  • the core in the second pellet can be inert sugar sphere, wax particle, etc., preferably inert sugar sphere.
  • the middle layer in the second pellet can be cholesterol lowering agent, excipient, and antioxidant. Also, the middle layer in the second pellet can further be disintegrant.
  • the excipient referred in the first pellet can be employed as the excipient in the second pellet.
  • the excipient in the second pellet can be hydroxypropylmethylcellulose.
  • the antioxidant in the second pellet can be any one used as a pharmaceutically acceptable antioxidant in the art of present invention.
  • the antioxidant can comprise tocopherol, dibutylhydroxytoluene, butylated hydroxyanisole, ascorbic acid, citric acid, sodium sulfite, sodium pyrosulfite, sodium hydro sulfite, etc.
  • the antioxidant can be one or more selected from a group consisting of butylated hydroxyanisole, ascorbic acid, and citric acid.
  • the outer coating layer of the second pellet can be any one employed as coating layer of cholesterol lowering agent in the art of present invention.
  • the outer coating layer can be made by using coating materials comprising polymer, plasticizer, anti-sticking agent, pigment and light-blocking agent. If necessary, flavoring, sweetener etc. can be further added.
  • the polymer used in outer coating layer can be one or more selected from a group consisting of cellulose ethers ⁇ ex. hydroxypropylmethyl cellulose (Hypromellose), hydroxypropyl cellulose, methyl cellulose, ethyl cellulose etc. ⁇ , vinyl polymers ⁇ ex.
  • the anti-sticking agent can be any pharmaceutically acceptable anti-sticking agent used in the present art:, for example, talc, etc.
  • the pigment and light-blocking agent can be one or more selected from water soluble pigment(Dye), synthetic pigment ⁇ for example, aluminium lakes, titanium dioxide, iron oxides, talc, calcium sulphate, calcium carbonate, magnesium carbonate, etc. ⁇ and natural pigment ⁇ for example, riboflavin, carotenoids, anthocyanins, carmine, curcumin, chlorophyll, etc. ⁇ .
  • flavoring such as vanillin, or sweetener, etc. can be used.
  • Opadry Colorcon; 415 Moyer Blvd., P.O. Box 4, West Point, PA 19486-0024, U.S.A.
  • the formulation of the present invention can be prepared by filling a hard capsule while providing two active drug simultaneously.
  • the first pellet can be provided by preparing asprin core using Extruder and Spheronizer, then forming enteric coating for improvement of gastric disorders, and the second pellet can be prepared by coating cholesterol inhibitor to inert sugar sphere. Then, each pellet can be mixed and then filled in a hard capsule.
  • the amount of the antithrombotic agent in a unit dose can be 1 to 500 mg, preferably, 30 to 300 mg.
  • the amount of aspirin per capsule is preferably 75-120 mg.
  • the amount of cholesterol lowering agent of the second pellet in a unit dose can be 1 to 300 mg, preferably, 5 to lOOmg, most preferably, 10 to 50mg per capsule.
  • the above unit dose can be varied depending on severity of patient's symptom, age, sex, complication, etc.
  • the formulation can be in form of hard capsule or soft capsule.
  • the formulation of the present invention improves prior inconvenience that an antithrombotic agent and a cholesterol lowering agent should be taken separately.
  • the formulation of the present invention provides mutual stability between the two drugs by preparing each pellet separately, mixing and filling, without using buffering agent used in prior mixed formulations.
  • cholesterol lowering agent is first released to lower lipids such as cholesterol excessively existing in blood, and then enteric coated aspirin is released at the upper part of intestine to inhibit the aggregation of platelets, thereby preventing genesis of thrombus.
  • enteric coated aspirin is released at the upper part of intestine to inhibit the aggregation of platelets, thereby preventing genesis of thrombus.
  • Fig. 1 shows the comparative dissolution rates of simvastatin from the formulation of Example 5 and the formulation of Comparative Example 1.
  • Fig. 2 shows the retention time of aspirin and simvastatin in D-700 High Performance Liquid Chromatography (HPLC).
  • Fig. 3 shows the content of aspirin in the formulation of Example 5 and the formulation of Comparative Example 1 after the stability test.
  • Fig. 4 shows the content of simvastatin in the formulation of Example 5 and the formulation of Comparative Example 1 after the stability test.
  • Fig. 5 shows cross sections of the aspirin pellet and simvastatin pellet according to the present invention.
  • Fig. 6 shows a cross section of the capsule according to the present invention.
  • GPCGl fluidized bed coater Germany, Glatt was used in the preparations of the pellet of the cholesterol lowering agent and of Comparative Examples.
  • the operation condition of the instrument was controlled as follows: in-let air temperature of 55 0 C, out-let air temperature of 40 ° C, air flow amount of 30%, nozzle diameter of 1.0 mm, jet pressure of 1.8 bar, and inflowing velocity of coating liquid of 15 g/min.
  • the inert sugar spheres added into the Examples and Comparative Examples were selected from those with a particle size of 0.2-0.5 mm.
  • the pellets containing an antithrombotic agent and the pellets containing a cholesterol lowering agent were prepared as follows.
  • composition of Table 1 aspirin and microcrystalline cellulose were mixed in High Speed Mixer(manufacturer: Sejong Machine), and a preliminarily prepared binding solution (a solution prepared by dissolving hydroxypropylcellulose in purified water) was added thereto in order to make granulates.
  • the granulates were extruded with Extruder(manufacturer: Sejong Machine), and then were rotated with Spheronizer (manufacturer: Sejong Machine) to prepare spherical shape of pellets.
  • enteric coating agents hydroxypropylmethylcellulose phthalate, diethylphthalate, wheat starch and magnesium stearate
  • enteric coating agents hydroxypropylmethylcellulose phthalate, diethylphthalate, wheat starch and magnesium stearate
  • the entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using 75 mg of clopidogrel, an agent inhibiting binding of ADP to platelet, instead of aspirin lOOmg in Table 1 of Preparation Example A-I.
  • the entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using clopidogrel (+)-camphorsulfonic acid salt (equal to 75mg clopidogrel), an agent inhibiting binding of ADP to platelet, instead of aspirin lOOmg in Table 1 of Preparation Example A-L
  • Example A-I by using clopidogrel bisulfate (equal to 75mg clopidogrel), an agent inhibiting binding of ADP to platelet, instead of aspirin lOOmg in Table 1 of Preparation Example A-I.
  • Example A-I by using clopidogrel besylate (equal to 75mg clopidogrel), an agent inhibiting binding of ADP to platelet, instead of aspirin lOOmg in Table 1 of Preparation Example A-I.
  • the entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using clopidogrel subsalicylate (equal to 75mg clopidogrel), an agent inhibiting binding of ADP to platelet, instead of aspirin lOOmg in Table 1 of Preparation Example A-I.
  • Preparation Example A-7 (Preparation of loxoprofen pellet) The entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using 60mg of loxoprofen, a nonsteroidal anti-inflammatory drug, instead of aspirin lOOmg in Table 1 of Preparation Example A-L
  • Preparation Example A-8 (Preparation of loxoprofen sodium salt pellet)
  • the entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using 68.1mg of loxoprofen sodium salt (equal to 60mg loxoprofen), a nonsteroidal anti-inflammatory drug, instead of aspirin lOOmg in Table 1 of Preparation Example A-L
  • Preparation Example A-9 (Preparation of aceclofenac pellet)
  • the entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using lOOmg of aceclofenac, a nonsteroidal anti-inflammatory drug, instead of aspirin lOOmg in Table 1 of Preparation Example A-I.
  • the entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using lOOmg of nimesulide, a nonsteroidal anti-inflammatory drug, instead of aspirin lOOmg in Table 1 of Preparation Example A-L
  • the entitled pellets were prepared according to the preparation method of Preparation Example A-I 5 by using 200mg of celecoxib, a nonsteroidal anti-inflammatory drug, instead of aspirin lOOmg in Table 1 of Preparation Example A-I ,
  • the entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using 125mg of clonixin lysinate, a nonsteroidal anti-inflammatory drug, instead of aspirin lOOmg in Table 1 of Preparation Example A-L
  • the entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using 250mg of clonixin lysinate, a nonsteroidal anti-inflammatory drug, instead of aspirin lOOmg in Table 1 of Preparation Example A-I.
  • the pellets containing simvastatin were prepared according to the composition described in the following Table 2 (constitution of simvastatin pellet).
  • the coating solution was prepared by suspending simvastatin in purified water. Butylated hydroxyanisole, ascorbic acid and citric acid as antioxidant were added to the coating solution.
  • the core comprising inert sugar sphere was coated with the coating solution by using GPCGl fluidized bed coater to form middle layer.
  • the outer coating layer was prepared by using Opadry 03F43036(manufacturer : Colorcon) on the middle layer.(see Fig 5)
  • the entitled pellets were prepared according to the same preparation method as in Preparation Example B-I, based on the composition described in Table 3 (constitution of simvastatin pellet).
  • Preparation Example B-3 (Preparation of simvastatin pellet) The entitled pellets were prepared according to the same preparation method as Preparation Example B-I, based on the composition described in Table 4(constitution
  • the entitled pellets were prepared according to the same preparation method as in Preparation Example B-I 5 based on the composition described in Table 5 (constitution of simvastatin pellet) .
  • the entitled pellets were prepared according to the same preparation method as in Preparation Example B-I, based on the composition described in Table 6(constitution of simvastatin pellet).
  • the entitled pellets were prepared according to the same preparation method as in
  • the entitled pellets were prepared by using lovastatin 20mg instead of simvastatin in tables of from Preparation Example B-I to Preparation Example B-6.
  • the coating solution was prepared by suspending lovastatin (solubility in water: 0.4 X 10 " mg/mL) in purified water. Butylated hydroxyanisole, ascorbic acid and citric acid as antioxidant were added to the coating solution.
  • the core comprising inert sugar sphere was coated with the coating solution by using GPCGl fluidized bed coater to form middle layer.
  • the outer coating layer was prepared by using Opadry 03F43036(manufacturer : Colorcon) on the middle layer to obtain the pellets containing lovastatin 20mg.
  • Preparation Example B-13 to Preparation Example B-18 The entitled pellets were prepared by using fluvastatin 20mg instead of simvastatin in each table of from Preparation Example B-I to Preparation Example B-6.
  • the coating solution was prepared by suspending fluvastatin (solubility in water: 0.4 X 10 "3 mg/mL) in purified water. Butylated hydroxyanisole, ascorbic acid and citric acid as antioxidant were added to the coating solution.
  • the core comprising inert sugar sphere was coated with the coating solution by using GPCGl fluidized bed coater to form middle layer.
  • the outer coating layer was prepared by using Opadry 03F43036(manufacturer : Colorcon) on the middle layer to obtain the pellets containing fluvastatin 20mg.
  • the entitled pellets containing fluvastatin 40mg were prepared according to the preparation method of Preparation Example 14, by doubling the amounts of all ingredients in each table of from Preparation Example B-13 to Preparation Example B-18.
  • Preparation Example B-25 to Preparation Example B-30 Preparation of atorvastatin pellet
  • the entitled pellets containing atorvastatin 20mg were prepared according to the preparation method of Preparation Example B-I, by using atorvastatin 20mg instead of simvastatin in each table of from Preparation Example B-I to Preparation Example B-6.
  • Preparation Example B-31 to Preparation Example B-36 (Preparation of atorvastatin potassium pellet)
  • the entitled pellets containing atorvastatin potassium were prepared according to the preparation method of Preparation Example B-I, by using atorvastatin potassium (equal to atorvastatin 20mg) instead of simvastatin in each table of from Preparation Example B-I to Preparation Example B-6.
  • the entitled pellets containing atorvastatin sodium were prepared according to the preparation method of Preparation Example B-I, by using atorvastatin sodium (equal to atorvastatin 20mg) instead of simvastatin in each table of from Preparation Example B-I to Preparation Example B-6.
  • the entitled pellets containing atorvastatin 40mg were prepared according to the preparation method of Preparation Example B- 13, by doubling the amounts of all ingredients in each table of from Preparation Example B-25 to Preparation Example B-30.
  • Preparation Example B-49 to Preparation Example B-54 (Preparation of atorvastatin potassium pellet)
  • the entitled pellets containing atorvastatin potassium (equal to atorvastatin 40mg) were prepared according to the preparation method of Preparation Example B-13, by doubling the amounts of all ingredients in each table of Preparation Example B-31 to Preparation Example B-36.
  • Preparation Example B-55 to Preparation Example B-60 (Preparation of atorvastatin sodium pellet)
  • the entitled pellets containing atorvastatin sodium were prepared according to the preparation method of Preparation Example B- 13, by doubling the amounts of all ingredients in each table of from Preparation Example B-37 to Preparation Example B-42.
  • the entitled pellets containing atorvastatin lOmg were prepared according to the preparation method of Preparation Example B-13, by using half(l/2) amounts of all ingredients in each table of from Preparation Example B-25 to Preparation Example B-30.
  • the entitled pellets containing atorvastatin potassium (equal to atorvastatin lOmg) were prepared according to the preparation method of Preparation Example B- 13, by using half(l/2) amounts of all ingredients in each table of from Preparation Example B-31 to Preparation Example B-36.
  • Preparation Example B-73 to Preparation Example B-78 (Preparation of atorvastatin sodium pellet)
  • the entitled pellets containing atorvastatin sodium(equal atorvastatin lOmg) were prepared according to the preparation method of Preparation Example B- 13, by using half(l/2)amounts of all ingredients in each table of from Preparation Example B-37 to Preparation Example B-42.
  • the entitled pellets were prepared by using pravastatin sodium 21.09mg (amount corresponding to pravastatin 20mg) instead of simvastatin in each table of from Preparation Example B-I to Preparation Example B-6.
  • the coating solution was prepared by suspending pravastatin sodium (solubility in water: 0.4 X 10 "3 mg/mL) in purified water. Butylated hydroxyanisole, ascorbic acid and citric acid as antioxidant were added to the coating solution.
  • the core comprising inert sugar sphere was coated with the coating solution by using GPCGl fluidized bed coater to form middle layer.
  • the outer coating layer was prepared by using Opadry Q3F43036(manufacturer : Colorcon) on the middle layer to obtain the pellets containing pravastatin sodium.
  • the entitled pellets containing pravastatin sodium (amount corresponding to pravastatin 40mg) were prepared according to the preparation method of Preparation Example B-13, by doubling the amounts of all ingredients in each table of from Preparation Example B-79 to Preparation Example B-84.
  • the entitled pellets containing pravastatin sodium (amount corresponding to pravastatin lOmg) were prepared according to the preparation method of Preparation Example B- 13, by using half(l/2) amounts of all ingredients in each table of from Preparation Example B-79 to Preparation Example B-84.
  • the entitled pellets containing pravastatin sodium (amount corresponding to pravastatin 5mg) were prepared according to the preparation method of Preparation Example B- 13, by using quarter (1/4) amounts of all ingredients in each table of from Preparation Example B-79 to Preparation Example B-84.
  • the pellets containing aspirin and simvastatin were prepared according to the composition described in the following Table 8 (constitution of combination pellet of aspirin and simvastatin).
  • the coating solution was prepared by suspending simvastatin in purified water. Butylated hydroxyanisole, ascorbic acid and citric acid as antioxidant were added to the coating solution.
  • the core comprising enteric coated aspirin granule (manufacturer: Boryung Phamaceutical Co., Ltd) was coated with the coating solution by using GPCGl fluidized bed coater to form middle layer.
  • the outer coating layer was prepared by using Opadry 03F43036(manufacturer : Colorcon) on the middle layer to obtain the entitled pellets.
  • the formulations according to the present invention were prepared as follows.
  • Examplelto Example ⁇ ( " Preparation of the capsule comprising aspirin pellet and simvastatin pellet)
  • the entitled capsules were prepared by filling the enteric coated aspirin pellet prepared in Preparation Example A-I and each of the simvastatin pellet prepared in from Preparation Example B-I to Preparation Example B-6 into hard capsules (manufacturer: Seoheung Capsule) wherein, the capsule of Example 1 was prepared by filling the enteric coated aspirin pellet prepared in Preparation Example A-I and the simvastatin pellet prepared in Preparation Example B-I; the capsule of Example 2 was prepared by filling the enteric coated aspirin pellet prepared in Preparation Example A-I; the simvastatin pellet prepared in Preparation Example B-2;the capsule of Example 3 was prepared by filling the enteric coated aspirin pellet prepared in Preparation ExampleA-1 and the simvastatin pellet prepared in Preparation Example B-3; the capsule of Example 4 was prepared by filling the enteric coated aspirin pellet prepared in Preparation Example A-I and the simvastatin pellet prepared in Preparation Example B-4; the capsule
  • the simvastatin dissolution rates of the capsules of Example 2 to Example 6 were much superior to that of Comparative Example 1.
  • the capsule of Example 5 showed that more than 80% of drug was released at about 15 min of dissolution time as shown in Fig. 1 (Fig. 1 : Comparative simvastatin dissolution test of Example5 and Comparative Examplel).
  • the capsules of Example 1 to Example 6 maintained stable state for 6 months without a significant change of contents.
  • the pellet of Comparative Example 1 was unstable that the contents of aspirin was lowered by about 2.9% and the content of simvastatin was lowered by about 3% as shown in Table 12, Fig. 3 (the contents of aspirin in the capsule of Example5 and the pellet of Comparative Example 1 after 6 months from the stability experiment), and Fig. 4(the contents of simvastatin in the capsule of Example 5 and the pellet of Comparative Example 1 after 6 months stability test).
  • Expiration dates was calculated by Arrhenius equation from the loss rate constant(k) calculated with each temperature storage condition and temperature. That is, since when natural logarithm of the loss rate constant k for the reciprocal of the absolute temperature(273 +storage temperature) was plotted, the plotted points shows a straight line, the linear equation is calculated from the plotted points, and then 1/(273+25 "C) was substituted for x of the linear equation to determine In k 25 t at 25 ° C . The k 25 t is substituted for the following algebraic expression to calculate the expiration dates.
  • Example 5 showed much longer than 3 years of expiration dates while the formulation of Comparative Example 1 showed shorter than 3 years that is general expiration of medicinal product. Thus, it is confirmed that the formulation of the Example 5 according to the present invention have superior drug stability to that of Comparative Example 1.
  • the formulation of the present invention improves inconvenience that an antithrombotic agent and a cholesterol lowering agent should be taken separately.
  • the formulation of the present invention provides mutual stability between the two drags by preparing each pellet separately, mixing and filling, without using buffering agent used in prior mixed formulations.
  • cholesterol lowering agent is first released to lower lipids such as cholesterol excessively existed in blood, and then enteric coated aspirin is released at the upper part of intestine to inhibit the arrogation of platelets, thereby preventing genesis of thrombus.
  • enteric coated aspirin is released at the upper part of intestine to inhibit the arrogation of platelets, thereby preventing genesis of thrombus.

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Abstract

The present invention provides an oral administrative preparation for treating cardiovascular disease comprising: (a) a first pellet comprising a core containing an antithrombotic agent and an enteric coating layer; and (b) a second pellet comprising a core containing an inert particle, a middle layer containing a cholesterol lowering agent and an outer coating layer. The present preparation makes to improve compliance in combined prescription and reduce risk of accidence relating to cardiovascular disease.

Description

1
ORAL ADMINISTRATIVE PREPARATION FOR TREATING CARDIOVASCULAR SYSTEM DISEASE
TECHNICAL FIELD The present invention relates to oral administrative preparation for treating cardiovascular disease.
BACKGROUND ART
It is known that long term administration of a low dose aspirin (acetylsalicylic acid) prevents myocardial infarction or stroke due to thrombosis in patients with high risk cardiovascular diseases or related disorders. In order to achieve this, 100 mg of aspirin is orally administrated as tablet or sustained release capsule once a day. It is also reported that once a day administration of low-dose (about 80 mg) aspirin can reduce the death rate by at least 25% due to cardiac crisis, stroke, or cardiovascular disease. The preventing effect of aspirin on cardiovascular disease is based on various pharmacological mechanisms of action, among which the key mechanism is inhibition of thrombosis. This mechanism is as follows.
Aspirin irreversibly acetylates cyclooxygenases to be inactive. Cyclooxygenases are essential substance in the synthesis of prostaglandin, thromboxane A2, prostacyclin, and the like. Prostaglandin is an inflammatory substance, and thromboxane A2 is synthesized in platelets and causes aggregation of platelets and thrombosis. Also, prostacyclin shows platelet aggregation inhibiting activity. Cyclooxygenases are generated in epithelial cells, not in platelets. Low-dose of aspirin can selectively inhibit cyclooxygenase in platelets maintaining synthesis of cyclooxygenase and prostaglandin in epithelial cells. That is, the main pharmacological effects of aspirin are inhibition of inflammation, reduction of platelet aggregation and reduction of thrombosis in blood vessel.
Fat absorbed in blood stream, such as neutral fats, cholesterols, phospholipids, free fatty acids, and the like, are coupled with proteins to form lipoproteins, which is called as serum lipids. Hyperlipidemia refers to a state in which concentration of serum lipid are above the normal range. Because fat such as cholesterol cannot be dissolved in water, in order to be circulated in blood, it should be surrounded with proteins so that the complex is circulated in blood. Such complex of fat and protein is called as lipoprotein. Lipoprotein delivering cholesterol is divided into high density lipoprotein(HDL) and low density lipoprotein(LDL). HDL removes cholesterol from tissues and consequently lowers the risk of atherosclerosis, while LDL plays a role in stacking cholesterol on blood vessel wall, which leads to increase the risk of atherosclerosis.
Hyperlipidemia contributes to the changes of blood coagulation mechanism such as acceleration of platelet aggregation, decreasing the platelet coagulation time, inhibition of fibrinolytic system, etc.. This leads to increase the viscosity of blood, and finally to cause pathological changes in the property and states of blood and peripheral circulatory disturbance due to vasculitis. Also, hyperlipidemia causes atherosclerosis to make thrombus and to block blood vessels. Blockage of blood vessel in brain or coronary artery of heart results in cerebral infarction or myocardial infarction, respectively, which becomes to be the direct causes of death. Hyperlipidemia is main causes of angina pectoris, myocardial infarction, stroke, fatty liver, pancreatitis, etc., particularly closely involved in arteriosclerosis. It is known that a high concentration of cholesterol not only accelerates the occurrence arteriosclerosis but also makes arteriosclerosis be unstable, which rapidly progress arteriosclerosis to acute myocardial infarction.
To treat hyperlipidemia, several therapies have been applied. Among them, cholesterol synthesis inhibitor, 3-hydroxy-3methyglutaryl-CoenzymeA(HMG-CoA) reductase inhibitor is known as the most effective drug for treating hyperlipidemia.
HMG-CoA reductase inhibitor lowers the concentration of cholesterol required to synthesize cholic acid etc. by inhibiting HMG-CoA reductase which relates to the rate-limiting step in the synthesis of cholesterol in liver cells. As a result, to compensate this, the number of LDL receptors which causes the atherosclerosis is increased, which leads to a fall of in LDL blood level. This is the way HMG-CoA reductase inhibitor works.
Thus, as a method of treating cardiovascular disease, methods of combining and administrating an antithrombotic agent and an antihyperlipidemic agent have been disclosed as follows.
For example, US Patent 5,622,985 discloses a method for reducing the risk of a second attack in a patient having a substantially normal serum cholesterol level by administering an
HMG-CoA reductase Inhibitor such as especially pravastatin, alone or in combination with an ACE inhibitor. However, according to the invention, there is an inconvenience to take two kinds of medications.
Also, US Patent 5,140,012 discloses the method to prevent the risk or restenosis following angioplasty by administering pravastatin alone or in combination with an ACE inhibitor, however, there is also an inconvenience in administration, and no further study for prevention or treatment of other cardiovascular disease than the said use, whereby the applicability had a limit.. Also, EP 457,514 discloses a similar use to US Patent 5,622,985 and US Patent
5,140,012. This patent was merely in their extension of both patents, and did not provide any study for a combination of other cholesterol lowering agent and aspirin to introduce a novel concept or to stretch it.
US Patent 6,248,729 suggests a combined formulation of an ADP-receptor blocking antiplatelet drug and angiotensin receptor antagonist and its use, and a combined formulation of an ADP-receptor blocking antiplatelet drug and an ACE inhibitor and the use thereof. However, there is no description for a combined formulation of cholesterol lowering agent and aspirin and its use.
KR Publication No. 10-2006-0091762 suggests a combined pellet containing HMG-CoA reductase inhibitors and enteric coated aspirin for the prevention of atherosclerosis in hyperlipidemia patients. In detail, the said pellet comprised of multi-layers consisting of a main layer in which an inert sugar sphere is coated with aspirin, a enteric coated layer on the main layer, and an outer layer coated with HMG-CoA reductase on the enteric coated layer. However, this kind of formulation with multi-layers has many difficulties in a large scale production. For example, in order to prepare such formulation, expensive special equipments are required, and the coating performed at high temperature for a long time can fatally affect the stability of active ingredient. Also, production yield is decreased, compared with those of the way to coat each drugs independently. In particular, direct contact of HMG-CoA reductase inhibitor and aspirin in the coating procedure can be an immediate cause to lower the dissolution rate due to their physical interaction, which greatly lowers the stability of drug. Because aspirin as an acidic drug, can react with basic compound or basic ester to cause hydrolysis of aspirin or disintegration of other compounds, and can react with acid-labile compound such as pravastatin, which results in the degradation of the compound.
In order to minimize the interaction of aspirin and statins, US Patent 6,235,311 discloses a bilayered tablet consisting of first layer containing aspirin, second layer containing statins and a layer containing buffering agent between two layers to block interactions of the both active ingredients. However, in order to prepare such bilayered tablet, expensive exclusive production equipments are required, and even prepared bilayered tablet has a limit in completely blocking the interaction by the contact of the drugs.
DISCLOSURE OF THE INVENTION
TECHNICAL PROBLEM
Therefore, the present inventors intended to develop a formulation which can dramatically improve or prevent drug hydrolysis or unstable drug reaction due to drug interaction between an antithrombotic agent and cholesterol lowering agent, while maximizing the therapeutic effect, and thereby came to complete the present invention.
TECHNICAL SOLUTION
The present invention provides an oral administrative preparation for treating cardiovascular disease comprising: (a) a first pellet comprising a core containing an antithrombotic agent and an enteric coating layer; and (b) a second pellet comprising a core containing an inert particle, a middle layer containing a cholesterol lowering agent and an outer coating layer.
According to the present invention, the antithrombotic agent can be a platelet aggregation inhibitor. According to the present invention, the platelet aggregation inhibitor can be a derivative of salicylic acid.
In accordance with the present invention, the derivative of salicylic acid comprises one or more selected from a group consisting of salicylic acid sodium, salicylic acid magnesium including salicylic acid magnesium tetrahydrate, salicylsalicylic acid(salsalate), and aspirin. In particular, the derivative of salicylic acid is preferably aspirin.
Also, according to the present invention, the platelet aggregation inhibitor can be an agent inhibiting binding of ADP to platelet. In the present invention, an agent inhibiting binding of ADP to platelet can be ticlopidine, anagrelide, dipyridamole, clopidogrel, clopidogrel bisulfate, clopidogrel (+)-camphorsulfonic acid salt, clopidogrel besylate, and clopidogrel sulfosalicylic acid salt.
In accordance with the present invention, the platelet aggregation inhibitor can be a nonsteroidal anti-inflammatory drug(NSAID) inhibiting cyclooxygenase. In accordance with the present invention, nonsteroidal anti-inflammatory drug can be one or more selected from a group consisting of ibuprofen, ibuprofen lysinate, dexibuprofen, ibuproxam, ketoprofen, ketoprofen lysinate, loxoprofen, loxoprofen sodium, flubiprofen, alminoprofen, zaltoprofen, fenoprofen calcium, pranoprofen, ketololac, ketololac tromethamin, sulindac, sulindac sulfide, sulindac sulfone, etodolac, diclofenac, diclofenac sodium, diclofenac beta-dimethylarninoethanol, diclofenac potassium, lonazolac calcium, aceclofenac, indomethacin, naproxen, naproxen sodium, proglumetacin maleate, acemetacin, mefenamic acid, meclofenamic acid, meclofenamic acid sodium, tolfenamic acid, flufenamic, flufenamic aluminum, tiaprofenic acid, tiaprofenic acid trometamol, enfenamic acid, piroxicam, piroxicam potassium, piroxicambetacyclodextrin, meloxicam, lornoxicam, cinnoxicam, tenoxicam, morniflumate, talniflumate, benorylate, etofenamate, glucametacin, nabumetone, nimesulide, niflumic acid, diflunisal, diflunisal lysinate, mepirizole, bumadizone calcium, celecoxib, benzydamine hydrochloride, tiaramide hydrochloride, oxaprozin, imidazole-2- hydroxybenzoate, clonixin, clonixin lysinate, fentiazac and pyrazinobutazone. According to the present invention, the cholesterol lowering agent can be a pharmaceutically acceptable HMG-CoA reductase inhibitor. For example, the pharmaceutically acceptable HMG-CoA reductase inhibitor can be rosuvastatin, rosuvastatin calcium, atorvastatin, atorvastatin calcium, atorvastatin sodium, cerivastatin, fluindostatin, fluvastatin, lovastatin, mevastatin, pravastatin, compactin, dihydrocompactin, dalvastatin, simvastatin and velostatin; a pharmaceutically acceptable salt thereof. They can be administered alone or in combination of 2 or more ingredients.
According to the present invention, the weight ratio of the core: the enteric coating layer in the first pellet can be 70-90 weight% : 10-30 weight%.
According to the present invention, the core in the first pellet can comprise an antithrombotic agent, binder, and excipient.
In accordance with the present invention, the excipient in the first pellet can be any one used in the art of the present invention. For example, the excipient can be lactose, microcrystalline cellulose, starch, etc. In particular, the excipient is preferably microcrystalline ellulose. In the present invention, the binder in the first layer can be any one used in the art of the present invention. For example, the binder can be hydroxypropylcellulose, carboxymethylcellulose sodium, pregelatinized starch, povidone, and the like. In particular, the binder is preferably hydroxypropylcellulose.
In the present invention, the enteric coating layer in the first pellet can be excipient, binder, and disintegrant. The coating agent used in the enteric coating layer can be any one used in the present art. For example, the coating agent can be cellulosebutratephthalate, cellulosehydrogenphthalate, cellulosepropionatephthalate, polyvinylacetatephthalate, celluloseacetatephthalate, celluloseacetatetrimellitate, hydroxypropylmethylcellulosephthalate, hydroxypropylmethylacetate, dioxypropylmethylcellulosesuccinate, carboxymethylethylcellulose, hydroxypropylmethylcelluloseacetatesuccinate, or copolymer prepared from polymer and acrylic acid, methacrylic acid, or their ester, etc. According to the present invention, the weight ratio of the core: the middle layer: the outer coating layer in the second pellet can be 30-70 weight%: 10-40 weight%: 1-10 weight%.
According to the present invention, the core in the second pellet can be inert sugar sphere, wax particle, etc., preferably inert sugar sphere. According to the present invention, the middle layer in the second pellet can be cholesterol lowering agent, excipient, and antioxidant. Also, the middle layer in the second pellet can further be disintegrant.
According to the present invention, the excipient referred in the first pellet can be employed as the excipient in the second pellet. In particular, the excipient in the second pellet can be hydroxypropylmethylcellulose.
In accordance with the present invention, the antioxidant in the second pellet can be any one used as a pharmaceutically acceptable antioxidant in the art of present invention. For example, the antioxidant can comprise tocopherol, dibutylhydroxytoluene, butylated hydroxyanisole, ascorbic acid, citric acid, sodium sulfite, sodium pyrosulfite, sodium hydro sulfite, etc. In particular, in accordance with the present invention, the antioxidant can be one or more selected from a group consisting of butylated hydroxyanisole, ascorbic acid, and citric acid.
According to the present invention, the outer coating layer of the second pellet can be any one employed as coating layer of cholesterol lowering agent in the art of present invention. The outer coating layer can be made by using coating materials comprising polymer, plasticizer, anti-sticking agent, pigment and light-blocking agent. If necessary, flavoring, sweetener etc. can be further added. The polymer used in outer coating layer can be one or more selected from a group consisting of cellulose ethers {ex. hydroxypropylmethyl cellulose (Hypromellose), hydroxypropyl cellulose, methyl cellulose, ethyl cellulose etc.}, vinyl polymers{ex. polyvinyl alcohol, polyvinyl acetate phthalate, polyvinyl pyrrolidone etc.}, and acrylic polymers{ex. methacrylic acid co-polymers, etc. }. The plasticizer used in outer coating layer can be water soluble plasticizer such as polyethylene glycols, glycerol, propyleneglycol, phthalate esters, triacetin, acetylated monoglyceride, citrate esters, etc. and water insoluble plasticizer such as lecithin, etc. In accordance with the present invention, the anti-sticking agent can be any pharmaceutically acceptable anti-sticking agent used in the present art:, for example, talc, etc. In accordance with the present invention, the pigment and light-blocking agent can be one or more selected from water soluble pigment(Dye), synthetic pigment{for example, aluminium lakes, titanium dioxide, iron oxides, talc, calcium sulphate, calcium carbonate, magnesium carbonate, etc.} and natural pigment{for example, riboflavin, carotenoids, anthocyanins, carmine, curcumin, chlorophyll, etc.}. Also, flavoring such as vanillin, or sweetener, etc. can be used. In particular, in the present invention, Opadry (Colorcon; 415 Moyer Blvd., P.O. Box 4, West Point, PA 19486-0024, U.S.A.) can be used to prepare the coating layer.
The formulation of the present invention can be prepared by filling a hard capsule while providing two active drug simultaneously. For example, the first pellet can be provided by preparing asprin core using Extruder and Spheronizer, then forming enteric coating for improvement of gastric disorders, and the second pellet can be prepared by coating cholesterol inhibitor to inert sugar sphere. Then, each pellet can be mixed and then filled in a hard capsule.
According to the present invention, the amount of the antithrombotic agent in a unit dose can be 1 to 500 mg, preferably, 30 to 300 mg. In detail, the amount of aspirin per capsule is preferably 75-120 mg.
According to the present invention, the amount of cholesterol lowering agent of the second pellet in a unit dose can be 1 to 300 mg, preferably, 5 to lOOmg, most preferably, 10 to 50mg per capsule.
The above unit dose can be varied depending on severity of patient's symptom, age, sex, complication, etc.
In the present invention, the formulation can be in form of hard capsule or soft capsule. ADVANTAGEOUS EFFECTS
In the administration of oral administrative preparation for cardiovascular disease, the formulation of the present invention improves prior inconvenience that an antithrombotic agent and a cholesterol lowering agent should be taken separately. In addition, the formulation of the present invention provides mutual stability between the two drugs by preparing each pellet separately, mixing and filling, without using buffering agent used in prior mixed formulations. In other words, at the time of administrating the formulation of the present invention, cholesterol lowering agent is first released to lower lipids such as cholesterol excessively existing in blood, and then enteric coated aspirin is released at the upper part of intestine to inhibit the aggregation of platelets, thereby preventing genesis of thrombus. Thus it does not lead to lowering of the dissolution rate and bioavailability to be low by direct contact of the two drugs.
DESCRIPTION OF THE DRAWINGS
Fig. 1 shows the comparative dissolution rates of simvastatin from the formulation of Example 5 and the formulation of Comparative Example 1.
Fig. 2 shows the retention time of aspirin and simvastatin in D-700 High Performance Liquid Chromatography (HPLC).
Fig. 3 shows the content of aspirin in the formulation of Example 5 and the formulation of Comparative Example 1 after the stability test.
Fig. 4 shows the content of simvastatin in the formulation of Example 5 and the formulation of Comparative Example 1 after the stability test.
Fig. 5 shows cross sections of the aspirin pellet and simvastatin pellet according to the present invention.
Fig. 6 shows a cross section of the capsule according to the present invention. MODE FOR INVENTION
The following Examples, Experimental Examples and Comparative Examples are provided to explain the present invention in more detail. However, the following Examples are only examples to help understanding the present invention, and are not intended to limit the scope of the present invention in any manner.
Instruments used in the preparation of pellets and operation condition of the instruments
GPCGl fluidized bed coater (Germany, Glatt) was used in the preparations of the pellet of the cholesterol lowering agent and of Comparative Examples. The operation condition of the instrument was controlled as follows: in-let air temperature of 55 0C, out-let air temperature of 40 °C, air flow amount of 30%, nozzle diameter of 1.0 mm, jet pressure of 1.8 bar, and inflowing velocity of coating liquid of 15 g/min. Also, the inert sugar spheres added into the Examples and Comparative Examples were selected from those with a particle size of 0.2-0.5 mm.
1. Preparation Example
To prepare the formulation of the present invention, the pellets containing an antithrombotic agent and the pellets containing a cholesterol lowering agent were prepared as follows.
A. Preparation of the pellet containing an antithrombotic agent
Preparation Example A-I (Preparation of aspirin pellet) The composition to prepare aspirin pellet of the present invention are shown in Table 1
(constitution of aspirin pellet). [Table 1]
Figure imgf000010_0001
Figure imgf000011_0001
1) Preparation of core
According to the composition of Table 1, aspirin and microcrystalline cellulose were mixed in High Speed Mixer(manufacturer: Sejong Machine), and a preliminarily prepared binding solution (a solution prepared by dissolving hydroxypropylcellulose in purified water) was added thereto in order to make granulates. The granulates were extruded with Extruder(manufacturer: Sejong Machine), and then were rotated with Spheronizer (manufacturer: Sejong Machine) to prepare spherical shape of pellets.
2) Preparation of enteric coated layer
According to the composition of Table 1, pharmaceutically acceptable enteric coating agents (hydroxypropylmethylcellulose phthalate, diethylphthalate, wheat starch and magnesium stearate) were mixed and dissolved in ethanol and methylene chloride solvent, and then the pellets were coated with the solution by the fluidized bed coater(manufacturer: Sejong Machine). (see Fig. 5)
Preparation Example A-2 (Preparation of clopidogrel pellet)
The entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using 75 mg of clopidogrel, an agent inhibiting binding of ADP to platelet, instead of aspirin lOOmg in Table 1 of Preparation Example A-I.
Preparation Example A-3 (Preparation of clopidogrel (+)-camphorsulfonic acid salt pellet)
The entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using clopidogrel (+)-camphorsulfonic acid salt (equal to 75mg clopidogrel), an agent inhibiting binding of ADP to platelet, instead of aspirin lOOmg in Table 1 of Preparation Example A-L
Preparation Example A-4 (Preparation of clopidogrel bisulfate pellet) The entitled pellets were prepared according to the preparation method of Preparation
Example A-I, by using clopidogrel bisulfate (equal to 75mg clopidogrel), an agent inhibiting binding of ADP to platelet, instead of aspirin lOOmg in Table 1 of Preparation Example A-I.
Preparation Example A-5 (Preparation of clopidogrel besylate pellet) The entitled pellets were prepared according to the preparation method of Preparation
Example A-I, by using clopidogrel besylate (equal to 75mg clopidogrel), an agent inhibiting binding of ADP to platelet, instead of aspirin lOOmg in Table 1 of Preparation Example A-I.
Preparation Example A-6 (Preparation of clopidogrel sulfonsalicylic acid salt pellet)
The entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using clopidogrel subsalicylate (equal to 75mg clopidogrel), an agent inhibiting binding of ADP to platelet, instead of aspirin lOOmg in Table 1 of Preparation Example A-I.
Preparation Example A-7 (Preparation of loxoprofen pellet) The entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using 60mg of loxoprofen, a nonsteroidal anti-inflammatory drug, instead of aspirin lOOmg in Table 1 of Preparation Example A-L
Preparation Example A-8 (Preparation of loxoprofen sodium salt pellet) The entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using 68.1mg of loxoprofen sodium salt (equal to 60mg loxoprofen), a nonsteroidal anti-inflammatory drug, instead of aspirin lOOmg in Table 1 of Preparation Example A-L
Preparation Example A-9 (Preparation of aceclofenac pellet) The entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using lOOmg of aceclofenac, a nonsteroidal anti-inflammatory drug, instead of aspirin lOOmg in Table 1 of Preparation Example A-I.
Preparation Example A-IO (Preparation of nimesulide pellet)
The entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using lOOmg of nimesulide, a nonsteroidal anti-inflammatory drug, instead of aspirin lOOmg in Table 1 of Preparation Example A-L
Preparation Example A-Il (Preparation of celecoxib pellet)
The entitled pellets were prepared according to the preparation method of Preparation Example A-I5 by using 200mg of celecoxib, a nonsteroidal anti-inflammatory drug, instead of aspirin lOOmg in Table 1 of Preparation Example A-I ,
Preparation Example A-12 (Preparation of clonixin lysinate pellet)
The entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using 125mg of clonixin lysinate, a nonsteroidal anti-inflammatory drug, instead of aspirin lOOmg in Table 1 of Preparation Example A-L
Preparation Example A-13 (preparation of clonixin lysinate pellet)
The entitled pellets were prepared according to the preparation method of Preparation Example A-I, by using 250mg of clonixin lysinate, a nonsteroidal anti-inflammatory drug, instead of aspirin lOOmg in Table 1 of Preparation Example A-I.
B. Preparation of pellets containing cholesterol lowering agent
Preparation Example B-I (Preparation of simvastatin pellet)
The pellets containing simvastatin were prepared according to the composition described in the following Table 2 (constitution of simvastatin pellet). The coating solution was prepared by suspending simvastatin in purified water. Butylated hydroxyanisole, ascorbic acid and citric acid as antioxidant were added to the coating solution. The core comprising inert sugar sphere was coated with the coating solution by using GPCGl fluidized bed coater to form middle layer. The outer coating layer was prepared by using Opadry 03F43036(manufacturer : Colorcon) on the middle layer.(see Fig 5)
[Table 2]
Figure imgf000014_0001
Preparation Example B-2 (Preparation of simvastatin pellet)
The entitled pellets were prepared according to the same preparation method as in Preparation Example B-I, based on the composition described in Table 3 (constitution of simvastatin pellet).
[Table 3]
Figure imgf000014_0002
Preparation Example B-3 (Preparation of simvastatin pellet) The entitled pellets were prepared according to the same preparation method as Preparation Example B-I, based on the composition described in Table 4(constitution
[Table 4]
Figure imgf000015_0001
Preparation Example B-4 (Preparation of simvastatin pellet)
The entitled pellets were prepared according to the same preparation method as in Preparation Example B-I5 based on the composition described in Table 5 (constitution of simvastatin pellet) .
[Table 5]
Figure imgf000015_0002
Figure imgf000016_0001
Preparation Example B-5 (Preparation of simvastatin pellet)
The entitled pellets were prepared according to the same preparation method as in Preparation Example B-I, based on the composition described in Table 6(constitution of simvastatin pellet).
[Table 6]
Figure imgf000016_0002
Preparation Example B-6 (Preparation of simvastatin pellet)
The entitled pellets were prepared according to the same preparation method as in
Preparation Example B-I, based on the composition described in Table 7(constitution of simvastatin pellet).
[Table 7]
Figure imgf000016_0003
Figure imgf000017_0001
Preparation Example B-7 to Preparation Example B-12(Treparation of lovastatin pellef)
The entitled pellets were prepared by using lovastatin 20mg instead of simvastatin in tables of from Preparation Example B-I to Preparation Example B-6. The coating solution was prepared by suspending lovastatin (solubility in water: 0.4 X 10" mg/mL) in purified water. Butylated hydroxyanisole, ascorbic acid and citric acid as antioxidant were added to the coating solution. The core comprising inert sugar sphere was coated with the coating solution by using GPCGl fluidized bed coater to form middle layer. The outer coating layer was prepared by using Opadry 03F43036(manufacturer : Colorcon) on the middle layer to obtain the pellets containing lovastatin 20mg.
Preparation Example B-13 to Preparation Example B-18(Preparation of fluvastatin pellet)) The entitled pellets were prepared by using fluvastatin 20mg instead of simvastatin in each table of from Preparation Example B-I to Preparation Example B-6. The coating solution was prepared by suspending fluvastatin (solubility in water: 0.4 X 10"3 mg/mL) in purified water. Butylated hydroxyanisole, ascorbic acid and citric acid as antioxidant were added to the coating solution. The core comprising inert sugar sphere was coated with the coating solution by using GPCGl fluidized bed coater to form middle layer. The outer coating layer was prepared by using Opadry 03F43036(manufacturer : Colorcon) on the middle layer to obtain the pellets containing fluvastatin 20mg.
Preparation Example B-19 to Preparation Example B-24 (Preparation of fluvastatin pellet)
The entitled pellets containing fluvastatin 40mg were prepared according to the preparation method of Preparation Example 14, by doubling the amounts of all ingredients in each table of from Preparation Example B-13 to Preparation Example B-18. Preparation Example B-25 to Preparation Example B-30 (Preparation of atorvastatin pellet)
The entitled pellets containing atorvastatin 20mg were prepared according to the preparation method of Preparation Example B-I, by using atorvastatin 20mg instead of simvastatin in each table of from Preparation Example B-I to Preparation Example B-6.
Preparation Example B-31 to Preparation Example B-36 (Preparation of atorvastatin potassium pellet) The entitled pellets containing atorvastatin potassium were prepared according to the preparation method of Preparation Example B-I, by using atorvastatin potassium (equal to atorvastatin 20mg) instead of simvastatin in each table of from Preparation Example B-I to Preparation Example B-6.
Preparation Example B-37 to Preparation Example B-42 (Preparation of atorvastatin sodium pellet)
The entitled pellets containing atorvastatin sodium were prepared according to the preparation method of Preparation Example B-I, by using atorvastatin sodium (equal to atorvastatin 20mg) instead of simvastatin in each table of from Preparation Example B-I to Preparation Example B-6.
Preparation Example B-43 to Preparation Example B-48 (Preparation of atorvastatin pellet)
The entitled pellets containing atorvastatin 40mg were prepared according to the preparation method of Preparation Example B- 13, by doubling the amounts of all ingredients in each table of from Preparation Example B-25 to Preparation Example B-30.
Preparation Example B-49 to Preparation Example B-54 (Preparation of atorvastatin potassium pellet) The entitled pellets containing atorvastatin potassium (equal to atorvastatin 40mg) were prepared according to the preparation method of Preparation Example B-13, by doubling the amounts of all ingredients in each table of Preparation Example B-31 to Preparation Example B-36.
Preparation Example B-55 to Preparation Example B-60(Preparation of atorvastatin sodium pellet) The entitled pellets containing atorvastatin sodium (equal to atorvastatin 40mg) were prepared according to the preparation method of Preparation Example B- 13, by doubling the amounts of all ingredients in each table of from Preparation Example B-37 to Preparation Example B-42.
Preparation Example B-61 to Preparation Example B-66 (Preparation of atorvastatin pellet)
The entitled pellets containing atorvastatin lOmg were prepared according to the preparation method of Preparation Example B-13, by using half(l/2) amounts of all ingredients in each table of from Preparation Example B-25 to Preparation Example B-30.
Preparation Example B-67 to Preparation Example B-72 (Preparation of atorvastatin potassium pellet)
The entitled pellets containing atorvastatin potassium (equal to atorvastatin lOmg) were prepared according to the preparation method of Preparation Example B- 13, by using half(l/2) amounts of all ingredients in each table of from Preparation Example B-31 to Preparation Example B-36.
Preparation Example B-73 to Preparation Example B-78 (Preparation of atorvastatin sodium pellet) The entitled pellets containing atorvastatin sodium(equal atorvastatin lOmg) were prepared according to the preparation method of Preparation Example B- 13, by using half(l/2)amounts of all ingredients in each table of from Preparation Example B-37 to Preparation Example B-42.
Preparation Example B-79 to Preparation Example B-84 (Preparation of pravastatin sodium pellet)
The entitled pellets were prepared by using pravastatin sodium 21.09mg (amount corresponding to pravastatin 20mg) instead of simvastatin in each table of from Preparation Example B-I to Preparation Example B-6. The coating solution was prepared by suspending pravastatin sodium (solubility in water: 0.4 X 10"3 mg/mL) in purified water. Butylated hydroxyanisole, ascorbic acid and citric acid as antioxidant were added to the coating solution. The core comprising inert sugar sphere was coated with the coating solution by using GPCGl fluidized bed coater to form middle layer. The outer coating layer was prepared by using Opadry Q3F43036(manufacturer : Colorcon) on the middle layer to obtain the pellets containing pravastatin sodium.
Preparation Example B-85 to Preparation Example B-90 (Preparation of pravastatin sodium pellet)
The entitled pellets containing pravastatin sodium (amount corresponding to pravastatin 40mg) were prepared according to the preparation method of Preparation Example B-13, by doubling the amounts of all ingredients in each table of from Preparation Example B-79 to Preparation Example B-84.
Preparation Example B-91 to Preparation Example B-96 (Preparation of pravastatin sodium pellet)
The entitled pellets containing pravastatin sodium (amount corresponding to pravastatin lOmg) were prepared according to the preparation method of Preparation Example B- 13, by using half(l/2) amounts of all ingredients in each table of from Preparation Example B-79 to Preparation Example B-84.
Preparation Example B-97 to Preparation Example B-102 (preparation of pravastatin sodium pellet)
The entitled pellets containing pravastatin sodium (amount corresponding to pravastatin 5mg) were prepared according to the preparation method of Preparation Example B- 13, by using quarter (1/4) amounts of all ingredients in each table of from Preparation Example B-79 to Preparation Example B-84.
2. Comparative Example (Combination pellet of aspirin and simvastatin)
The pellets containing aspirin and simvastatin were prepared according to the composition described in the following Table 8 (constitution of combination pellet of aspirin and simvastatin). The coating solution was prepared by suspending simvastatin in purified water. Butylated hydroxyanisole, ascorbic acid and citric acid as antioxidant were added to the coating solution. The core comprising enteric coated aspirin granule (manufacturer: Boryung Phamaceutical Co., Ltd) was coated with the coating solution by using GPCGl fluidized bed coater to form middle layer. The outer coating layer was prepared by using Opadry 03F43036(manufacturer : Colorcon) on the middle layer to obtain the entitled pellets.
[Table 8]
Figure imgf000021_0001
3. Examples
The formulations according to the present invention were prepared as follows.
Examplelto Exampleό ("Preparation of the capsule comprising aspirin pellet and simvastatin pellet)
The entitled capsules were prepared by filling the enteric coated aspirin pellet prepared in Preparation Example A-I and each of the simvastatin pellet prepared in from Preparation Example B-I to Preparation Example B-6 into hard capsules (manufacturer: Seoheung Capsule) wherein, the capsule of Example 1 was prepared by filling the enteric coated aspirin pellet prepared in Preparation Example A-I and the simvastatin pellet prepared in Preparation Example B-I; the capsule of Example 2 was prepared by filling the enteric coated aspirin pellet prepared in Preparation Example A-I; the simvastatin pellet prepared in Preparation Example B-2;the capsule of Example 3 was prepared by filling the enteric coated aspirin pellet prepared in Preparation ExampleA-1 and the simvastatin pellet prepared in Preparation Example B-3; the capsule of Example 4 was prepared by filling the enteric coated aspirin pellet prepared in Preparation Example A-I and the simvastatin pellet prepared in Preparation Example B-4; the capsule of Example 5 was prepared by filling the enteric coated aspirin pellet prepared in Preparation ExampleA-1 and the simvastatin pellet prepared in Preparation Example B-5; and the capsule of Example 6 was prepared by filling the enteric coated aspirin pellet prepared in Preparation Example A-I and the simvastatin pellet prepared in Preparation Example B-6).(see Fig. 6)
4 . Experimental Examples
To compare the effect of the formulations of Examples and Comparative Examples, the following experiments were performed.
Experimental Example 1 (Confirmation of drug dissolution rate of simvastatin)
Drug dissolution rate(%) of the simvastatin capsules of Example 1 to Example 6 and pellet of Comparative Examplel were measured (Table 9. simvastatin dissolution rate). The measurements were performed based on USP 28 'Simvastatin tablets.'
[Table 9]
Figure imgf000022_0001
The simvastatin dissolution rates of the capsules of Example 2 to Example 6 were much superior to that of Comparative Example 1. Particularly, the capsule of Example 5 showed that more than 80% of drug was released at about 15 min of dissolution time as shown in Fig. 1 (Fig. 1 : Comparative simvastatin dissolution test of Example5 and Comparative Examplel).
Experimental Example 2 (Confirmation of drug dissolution rate ofaspirin)
Aspirin dissolution rates(%) of the capsules of Example 1 to Example 6 and pellet of Comparative Examplel were measured (Table 10. aspirin dissolution rate). The measurements were performed based on USP 28 'Aspirin Delayed Release Capsule'.
[Table 10]
Figure imgf000023_0001
All Examples and Comparative Example had met standard resolution of aspirin in USP 28 Aspirin Delayed Release Capsule' (at pH 1.2, 120 min: <10%; at pH 6.8, 90 min: 80%>).
Experimental Example 3 (Confirmation of stability of formulations)
The stability tests of the capsules of Example 1 to Example 6 and the pellet of Comparative Examplel were preformed on the following conditions (long-term storage test condition: 25 °C, 60 % RH, accelerated test condition: 40 °C, 75 % RH). Each amount was measured by using D-7000 HPLC(High Performance Liquid Chromatography, manufacturer: Hitachi) (The standard data are as shown in Fig. 2(chromatogram of aspirin and simvastatin), wherein the peak at 3.56 min of Retention Time (RT) indicates aspirin, and the another peak at 15.79 min of RT indicates simvastatin). The results were as shown in Table 11 (the early release(%) of aspirin and simvastatin in the capsules of Example 1 to Example 6 and the pellet of Comparative Example 1 tested in long-term storage test and accelerated test) and Table 12 (the amounts(%) after 6 month from the stability test of aspirin and simvastatin in the capsules of Example 1 to Example 6 and the pellet of Comparative Example 1).
Figure imgf000024_0001
[Table 12]
Figure imgf000024_0002
As the result of stability experiment of 6 months, the capsules of Example 1 to Example 6 maintained stable state for 6 months without a significant change of contents. However, the pellet of Comparative Example 1 was unstable that the contents of aspirin was lowered by about 2.9% and the content of simvastatin was lowered by about 3% as shown in Table 12, Fig. 3 (the contents of aspirin in the capsule of Example5 and the pellet of Comparative Example 1 after 6 months from the stability experiment), and Fig. 4(the contents of simvastatin in the capsule of Example 5 and the pellet of Comparative Example 1 after 6 months stability test).
Experimental Example 4 (Calculation of expiration date of formulation)
The expiration dates of the capsule of Example 5 and the pellet of Comparative Example 1 were calculated. The results are shown in Table 13.
1) Method of calculation Loss of drug according to the length of time under each of storage condition was regarded as first order rate, natural logarithm of the amount of drug for elapsed days were plotted. From the plotted points, the linear equation was calculated using least Square Method, and then loss rate constant was calculated from the slope of linear plot.
rate constant (k) = -slope
Expiration dates was calculated by Arrhenius equation from the loss rate constant(k) calculated with each temperature storage condition and temperature. That is, since when natural logarithm of the loss rate constant k for the reciprocal of the absolute temperature(273 +storage temperature) was plotted, the plotted points shows a straight line, the linear equation is calculated from the plotted points, and then 1/(273+25 "C) was substituted for x of the linear equation to determine In k25t at 25 °C . The k25t is substituted for the following algebraic expression to calculate the expiration dates.
2) Calculation of the expiration dates of the capsule of Example 5
A. aspirin
-Λ- x ln(-τ?-) %. Expiration dates T95o/0 = *∞r- c Co : early concentration(%)
C : minimum allowance concentration within expiration dates (95%)
In k25°c = -11.54338467 k25t = 0.0000097 1 x ln ( 100% ) Expiration dates T95O70 (Shelf-life) - 0.0000097 95% = about 14.69 years
B. simvastatin
1 C
* Expiration dates T95»/o = **« ° c C0 : early concentration(%)
C : minimum allowance concentration within expiration dates (95%)
In k25t = -11.84142953 k25t = 0.0000072
_L ln 1 ro/ /
Expiration dates T95o/O (Shelf-life) == 0.0000072 111(V n00% ) about 19.79 years
3) Calculation of expiration dates of the pellet of Comparative Example 1 The expiration dates of the pellet of Comparative Example 1 were calculated by the same method to calculation of the expiration dates of the capsules of Example5. [Table 13]
Figure imgf000026_0001
The formulation of Example 5 showed much longer than 3 years of expiration dates while the formulation of Comparative Example 1 showed shorter than 3 years that is general expiration of medicinal product. Thus, it is confirmed that the formulation of the Example 5 according to the present invention have superior drug stability to that of Comparative Example 1.
INDUSTRIAL APPLICABILITY
In the administration of oral administrative preparation for cardiovascular disease, the formulation of the present invention improves inconvenience that an antithrombotic agent and a cholesterol lowering agent should be taken separately. In addition, the formulation of the present invention provides mutual stability between the two drags by preparing each pellet separately, mixing and filling, without using buffering agent used in prior mixed formulations.
In other words, at the time of administrating the formulation of the present invention, cholesterol lowering agent is first released to lower lipids such as cholesterol excessively existed in blood, and then enteric coated aspirin is released at the upper part of intestine to inhibit the arrogation of platelets, thereby preventing genesis of thrombus. Thus it does not lead the lowering of dissolution rate and bioavailability by direct contact of the two drugs.

Claims

WHAT IS CLAIMED IS:
1. An oral administrative preparation for treating cardiovascular disease comprising:
(a) a first pellet comprising a core containing antithrombotic agent(s) and an enteric coating layer; and
(b) a second pellet comprising a core containing an inert particle, a middle layer containing a cholesterol lowering agent, and an outer coating layer.
2. The oral administrative preparation of claim 1, wherein the antithrombotic agent is a platelet aggregation inhibitor.
3. The oral administrative preparation of claim 2, wherein the platelet aggregation inhibitor is a derivative of salicylic acid.
4. The oral administrative preparation of claim 3, wherein the derivative of salicylic acid is one or more selected from a group consisting of salicylic acid sodium, salicylic acid magnesium including salicylic acid magnetium tetrahydrate, salicyl salicylic acid(salsalate), and aspirin.
5. The oral administrative preparation of claim 4, wherein the derivative of salicylic acid is aspirin.
6. The oral administrative preparation of claim 2, wherein the platelet aggregation inhibitor is an agent inhibiting binding of ADP to platelet.
7. The oral administrative preparation of claim 6, wherein the agent inhibiting binding of ADP to platelet is one or more selected from a group consisting of ticlopidine, anagrelide, dipyridamole, clopidogrel, clopidogrel bi sulfate, clopidogrel (+)-camphorsulfonic acid salt, clopidogrel besylate and clopidogrel sulfosalicylic acid salt.
8. The oral administrative preparation of claim 2, wherein the platelet aggregation inhibitor is a nonsteroidal anti-inflammatory drug (NSAID) inhibiting cyclooxygenase.
9. The oral administrative preparation of claim 8, wherein the nonsteroidal anti-inflammatory drug is one or more selected from a group consisting of ibuprofen, ibuprofen lysinate, dexibuprofen, ibuproxam, ketoprofen, ketoprofen lysinate, loxoprofen, loxoprofen sodium, flubiprofen, alminoprofen, zaltoprofen, fenoprofen calcium, pranoprofen, ketololac, ketololac tromethamin, sulindac, sulindac sulfide, sulindac sulfone, etodolac, diclofenac, diclofenac sodium, diclofenac beta-dimethylaminoethanol, diclofenac potassium, lonazolac calcium, aceclofenac, indomethacin, naproxen, naproxen sodium, proglumetacin maleate, acemetacin, mefenamic acid, meclofenamic acid, meclofenamic acid sodium, tolfenamic acid, fiufenamic acid, fiufenamic acid aluminum, tiaprofenic acid, tiaprofenic acid trometamol, enfenamic acid, piroxicam, piroxicam potassium, piroxicam betacyclodextrin, meloxicam, lornoxicam, cinnoxicam, tenoxicam, morniflumate, talniflumate, benorylate, etofenamate, glucametacin, nabumetone, nimesulide, niflumic acid, diflunisal, diflunisal lysinate, mepirizole, bumadizone calcium, celecoxib, benzydamine hydrochloride, tiaramide hydrochloride, oxaprozin, imidazole-2-hydroxybenzoate, clonixin, clonixin lysinate, fentiazac, and pyrazinobutazone.
10. The oral administrative preparation of claim 1, wherein the cholesterol lowering agent is a pharmaceutically acceptable HMG-CoA reductase inhibitor.
11. The oral administrative preparation of claim 10, wherein the cholesterol lowering agent is one or more selected from a group consisting of rosuvastatin, rosuvastatin calcium, atorvastatin, atorvastatin calcium, atorvastatin sodium, cerivastatin, fluindostatin, fluvastatin, lovastatin, mevastatin, pravastatin, compactin, dihydrocompactin, dalvastatin, simvastatin and velostatin; and a pharmaceutically acceptable salt thereof.
12. The oral administrative preparation of any one of claims 1 to 11 , wherein the weight ratio of the core: the enteric coating layer in the first pellet is 70-90 weight% : 10-30 weight%.
13. The oral administrative preparation of claim 12, wherein the core in the first pellet comprises an antithrombotic agent, binder, and excipient.
14. The oral administrative preparation of claim 13, wherein the excipient of the core in the first pellet is microcrystalline cellulose.
15. The oral administrative preparation of claim 13, wherein the binder of the core in the first pellet is hydroxypropylcellulose.
16. The oral administrative preparation of claim 12, wherein the enteric coating layer in the first pellet comprises excipient, binder and disintegrant.
17. The oral administrative preparation of any one of claims 1 to 11, wherein the weight ratio of the core: the middle layer: the outer coating layer in the second pellet is 30-70 weight%: 10-40 weight%: l~10 weight%.
18. The oral administrative preparation of claim 17, wherein the core in the second pellet is an inert sugar sphere.
19. The oral administrative preparation of claim 17, wherein the middle layer in the second pellet comprises cholesterol lowering agent, excipient and antioxidant.
20. The oral administrative preparation of claim 19, wherein the middle layer in the second pellet further comprises disintegrant.
21. The oral administrative preparation of claim 19, wherein the binder in second pellet is hydroxypropylmethylcellulose.
22. The oral administrative preparation of claim 19, wherein the antioxidant in the second pellet is one or more selected from a group consisting of butylated hydroxyanisole, ascorbic acid and citric acid.
23. The oral administrative preparation of claim 17, wherein the outer coating layer comprises polymer, plasticizer, anti-sticking agent, pigment and light-blocking agent.
24. The oral administrative preparation of any one of claims 1 to 11, wherein an amount of the antithrombotic agent in a unit dose is 1 to 500 mg.
25. The oral administrative preparation of any one of claims 1 to 11, wherein the amount of cholesterol lowering agent in a unit dose is 1 to 300 mg.
26. The oral administrative preparation of any one of claims 1 to 11, wherein the oral administrative preparation is capsule.
PCT/KR2007/006248 2006-12-07 2007-12-04 Oral administrative preparation for treating cardiovascular system disease WO2008069546A1 (en)

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