WO2019245150A1 - Composition pharmaceutique comprenant du cilostazol et un médicament à base de statine - Google Patents

Composition pharmaceutique comprenant du cilostazol et un médicament à base de statine Download PDF

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Publication number
WO2019245150A1
WO2019245150A1 PCT/KR2019/004743 KR2019004743W WO2019245150A1 WO 2019245150 A1 WO2019245150 A1 WO 2019245150A1 KR 2019004743 W KR2019004743 W KR 2019004743W WO 2019245150 A1 WO2019245150 A1 WO 2019245150A1
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Prior art keywords
cilostazol
release
sustained
active ingredient
granules
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PCT/KR2019/004743
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English (en)
Korean (ko)
Inventor
최연웅
장재상
이남송
전형준
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한국유나이티드제약 주식회사
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Publication of WO2019245150A1 publication Critical patent/WO2019245150A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present invention relates to a sustained release combination preparation containing a statin-based drug and cilostazol, which are HMG-CoA reductase inhibitors as an active ingredient.
  • Cilostazol inhibits primary aggregation of platelets induced by ADP, epinephrine and the like in platelets isolated from mice, rats, rabbits, dogs and humans and dissociates platelet aggregates.
  • oral administration to beagle dogs inhibits aggregation of platelets induced by ADP and collagen, and when administered orally to patients with chronic arterial obstruction (Berger's disease, obstructive atherosclerosis, diabetic peripheral angiopathy, etc.).
  • the platelet aggregation inhibitory effect of cilostazol is expressed rapidly after administration, and the effect is maintained even in repeated administration. Inhibition of platelet aggregation at the time of discontinuation is restored to pre-administration values with a decrease in plasma concentration, and no rebound phenomenon is observed.
  • cilostazol The mechanism of action of cilostazol is as follows. It inhibits the release of serotonin from platelets in rabbits but does not affect the entry of serotonin, adenosine, into platelets. It inhibits platelet aggregation by TXA2 (thromboxane A2) without affecting arachidonic acid metabolism of platelets. This is due to the inhibition of cAMP-PDE (cyclic AMP phosphodiesterase) activity of platelets and vascular smooth muscle, which eventually exerts antiplatelet action and vasodilation.
  • cAMP-PDE cyclic AMP phosphodiesterase
  • cilostazol formulations are not only poor patient compliance, but also cilostazol immediate release formulations result in rapid and uneven drug release upon oral administration, resulting in a rapid rise in blood concentration. It is known to cause side effects such as headache, headache, tachycardia and the like (see Am J Cardiol 2001; 87 (suppl): 28D-33D and US Patent Publication No. 2002/0058066).
  • cilostazol is poorly soluble and its absorption rate decreases toward the lower part of the small intestine, the overall bioavailability may be reduced in the case of conventional release control formulations, and PCT Patent Publication No. WO 2000/57881 discloses cilostas in the form of fine powder.
  • a method is disclosed for increasing the small intestinal uptake of cilostazol using a formulation in the form in which the sol is dispersed and / or dissolved in combination with a dispersing agent and / or a solubilizing agent.
  • the present invention improves the shortcomings of the conventional cilostazol sustained release formulation having a large dissolution deviation, and is manufactured in a tablet form to significantly increase productivity, and further improves bioavailability by adding an HMG-CoA reductase inhibitor as an active ingredient. will be.
  • the present invention comprises an HMG-CoA reductase inhibitor mixing unit containing an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient; And a cilostazol mixed portion containing cilostazol or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the cilostazol mixing unit includes a release regulator for controlling the amount of cilostazol active ingredient eluted in the body, and the content of the release regulator is 3 to 9 parts by weight based on 100 parts by weight of the cilostazol active ingredient. desirable.
  • the pharmaceutical composition according to the present invention is a complex preparation containing a cilostazol and HMG-CoA reductase inhibitor, and has a very high bioavailability, and controls the release regulator content of the cilostazol mixed part containing cilostazol 1 day 1 Dose alone has sufficient sustained release and shows an excellent effect of reducing side effects of cilostazol.
  • the content of the release controlling agent is less than 3 parts by weight based on 100 parts by weight of the cilostazol active ingredient, the initial release amount of cilostazol is not sufficient to exhibit sufficient sustained release, and side effects such as headaches may occur.
  • the content of the release controlling agent exceeds 9 parts by weight with respect to 100 parts by weight of the cilostazol active ingredient, the dissolution of the cilostazol active ingredient is delayed too much to achieve a sufficient pharmacological effect.
  • HMG-CoA reductase inhibitors used in the present invention can be used by selecting one or two or more from the group consisting of rosuvastatin, simvastatin, atorvastatin, pitavastatin, pravastatin, fluvastatin, lovastatin,
  • the active ingredient content of the HMG-CoA reductase inhibitor mixture is preferably 3 to 40 mg, and the effective ingredient content of the cilostazol mixture is preferably 160 to 240 mg.
  • the active ingredient content of the HMG-CoA reductase inhibitor mixture is less than 3 mg or the active ingredient content of the cilostazol mixture is less than 160 mg, sufficient pharmacological activity is not observed, and the active ingredient content of the HMG-CoA reductase inhibitor mixture is 40 mg. Excess or, if the active ingredient content of the cilostazol mixture exceeds 240mg, the blood concentration of the active ingredient is excessively increased may cause side effects.
  • the cilostazol mixing portion of the sustained release composite preparation according to the present invention can be used by mixing the hypromellose and carbomer as a release control agent, in this case the hypromellose and carbomer having a viscosity of 75,000 to 140,000cps It is preferable to mix and use in the weight ratio of 1: 1 to 2.5: 1. If the mixing ratio of the release controlling agent is out of the above range, the stability of the sustained release matrix may be inferior.
  • the cilostazol mixing unit immediate release granules containing cilostazol and disintegrant and a binder as an active ingredient; And it may comprise a sustained-release granules comprising cilostazol and a release control agent and a binder as an active ingredient, the active ingredient content of the sustained-release granules is 50 to 90% by weight, more preferably based on the active ingredient content of the immediate release granules Preferably it is 60 to 80% by weight.
  • the rapid pharmacological activity of the immediate release granules and the sustained effect of the sustained release granules can reduce side effects.
  • the active ingredient content ratio of the immediate release and the western part is very important, if the active ingredient content of the immediate release may cause side effects due to too fast dissolution.
  • the content of the active ingredient should be adjusted while considering the dissolution characteristics by the release control agent so that the pharmacological effect can be sustained for a long time.
  • the applicant was able to find the optimum content ratio of the immediate and western active ingredients as described above, and in order to uniformly control the dissolution rate, the active ingredients of the mixing part containing the respective active ingredients.
  • the type and content of disintegrants, binders and release control agents were optimized. This resulted in the rapid pharmacological activity and the long-term effects, while reducing the side effects.
  • the disintegrant one or two or more selected from the group consisting of carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, 1-hydroxypropyl cellulose, and crosslinked polyvinylpyrrolidone may be used, and the binder may be a binder. 1 or 2 or more selected from the group consisting of hydroxypropyl cellulose, hydroxy cellulose, hydroxypropyl methyl cellulose, hydroxypropyl starch, polyvinyl alcohol, hydroxymethyl cellulose, polyvinylpyrrolidone may be used. have.
  • the release control agent hypromellose and carbomer may be used alone, or a combination thereof may be used. However, when using a mixture of hypromellose and carbomer as described above was the most preferable results.
  • the active ingredient contained in the cilostazol mixing portion of the sustained release complex preparation according to the present invention is dissolved in 0.4% sodium lauryl sulfate (SLS) eluate according to the second method (paddle method) of the Korean Pharmacopoeia Dissolution Test Method.
  • SLS sodium lauryl sulfate
  • immediate release granules and the sustained-release granules according to the present invention use those having a diameter of 350 to 450 ⁇ m, which affects the dissolution characteristics, so that the dissolution is too fast or does not exhibit sufficient pharmacological effects. Can be.
  • the sustained-release complex preparation of the present invention is preferably prepared with a diameter of 5 to 10mm, the total weight of 350 to 550mg, if the diameter is less than 5mm there is a possibility that the formulation is collapsed during tableting, if the patient exceeds 10mm Medication convenience may be reduced.
  • the stability may be lowered, and when the total weight exceeds 550mg, the dosage form is too large to reduce the patient's medication convenience.
  • the sustained release composite preparation of the present invention has a hardness of 10 to 30 kg / cm 2, and when the hardness is less than 10 kg / cm 2, the formulation may collapse or deteriorate in stability when tableting. The problem of more delayed dissolution may occur.
  • Sustained release complex preparations comprises an HMG-CoA reductase inhibitor mixing unit containing an HMG-CoA reductase inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient; And a cilostazol mixing portion containing cilostazol or a pharmaceutically acceptable salt thereof as an active ingredient, the first layer comprising the HMG-CoA reductase inhibitor mixing portion; And a second layer consisting of a cilostazol mixing unit; when prepared in a single tablet formulation of a two-layer structure consisting of a fast mass production is excellent in stability and preferable in terms of productivity and preservation.
  • sustained release complex preparation containing the HMG-CoA reductase inhibitor and cilostazol according to the present invention may be prepared through the following steps.
  • Preparing a HMG-CoA reductase inhibitor mixing unit granules by mixing an HMG-CoA reductase inhibitor, an excipient, a binder, and a disintegrant; Mixing cilostazol, excipients and binder to produce immediate release granules; Preparing sustained-release granules by mixing cilostazol, excipient, release controlling agent, binder and glidant; Mixing the immediate release granules and the sustained release granules to form a cilostazol mixed part granule containing cilostazol; Tableting the HMG-CoA reductase inhibitor mixing unit granules and cilostazol mixing unit granules to produce a sustained release composite formulation; comprising the tableting sequence of the HMG-CoA reductase inhibitor mixing unit and cilostazol mixing unit And the manufacturing order of the immediate release and sustained-release granules can be
  • the present invention is a sustained release combination preparation including an HMG-CoA reductase inhibitor and cilostazol, which has a fast pharmacological activity and few side effects, and has a sustained release showing sufficient pharmacological effect by oral administration once a day.
  • the pharmaceutical composition according to the present invention includes immediate release granules containing cilostazol as an active ingredient, so that an effective amount of cilostazol active ingredient is rapidly eluted in the body to exhibit pharmacological activity after oral administration. This leads to a rapid rise in early blood levels to achieve a rapid pharmacological effect.
  • sustained-release granules containing cilostazol once daily administration shows sufficient long-term pharmacological activity.
  • HMG-CoA reductase inhibitor as an active ingredient, characterized in that the bioavailability is further improved than administration of cilostazol alone.
  • the HMG-CoA reductase inhibitor is a statin-based drug, one or two or more may be selected from the group consisting of rosuvastatin, simvastatin, atorvastatin, pitavastatin, pravastatin, fluvastatin, and lovastatin, In consideration of pharmacological effects, long-term storage stability and marketability, it is preferable to use one or two or more selected from rosuvastatin, simvastatin, and atorvastatin, and most preferably rosuvastatin.
  • the sustained release complex preparation according to the present invention is prepared in accordance with the preparation method of the tablet term of the Korean Pharmacopoeia General Formulation, but HMG-CoA by mixing an HMG-CoA reductase inhibitor, an excipient, a binder and a disintegrant Preparing a reductase inhibitor mixture part granule; Mixing cilostazol, excipients and binder to produce immediate release granules; Preparing sustained-release granules by mixing cilostazol, excipient, release controlling agent, binder and glidant; Mixing the immediate release granules and the sustained release granules to form a cilostazol mixed part granule containing cilostazol; Tableting the HMG-CoA reductase inhibitor mixing unit granules and cilostazol mixing unit granules to produce a sustained release composite formulation; comprising the tableting sequence
  • each composite formulation was prepared as a bilayer tablet by the direct stroke method.
  • the sustained release composite formulation was prepared by varying the content and composition of the release control agent, and thereby adjusting the amount of other excipients.
  • the pharmaceutical composition according to the present invention is a sustained-release complex preparation containing two different active ingredients
  • the dissolution rate of the active ingredient may change depending on the combination properties of the active ingredients having different properties or the characteristics of the formulation.
  • Applicant has selected rosuvastatin, simvastatin, atorvastatin, among the statin-based drugs available as a control, to determine whether the formulation properties of the combined or sustained release formulation with cilostazol affect the elution of the statin component.
  • Single tablets according to Comparative Examples 3 to 5 were prepared. Meanwhile, Examples 4 and 5 having the same composition as in Example 2 were prepared except for the types of statins. Compared.
  • a single tablet containing rosuvastatin, simvastatin, atorvastatin as an active ingredient was prepared according to the component content of Table 3 below.
  • Example 2 According to the ingredient content of Table 4, except for the statin type, the composition was the same as in Example 2 to prepare a sustained release composite preparation of Examples 4 to 5.
  • Cilostazol chief ingredient Cilostazol 120.00 120.00 120.00 Excipient Microcrystalline Cellulose 101 20.00 20.00 20.00 Disintegrant Croscarmellose sodium 4.00 4.00 4.00 Binder Povidone K-30 6.00 6.00 6.00 Cilostazol immediate release weight 150.00 150.00 150.00 West Cilostazol chief ingredient Cilostazol 80.00 80.00 Excipient Microcrystalline Cellulose 101 49.00 49.00 49.00 Release regulator Hypromellose 2208 (viscosity 100,000 cps) 7.00 7.00 7.00 7.00 Release regulator Carbomer 971 4.00 4.00 4.00 Binder Povidone K-30 10.00 10.00 10.00 10.00 Lubricant Magnesium stearate 10.00 10.00 10.00 Cilostazol Western Weight 160.00 160.00 160.00 160.00 Statin floor chief ingredient Rosuvastatin Calcium 20.80 - - chief ingredient Simvastatin - 20 - chief ingredient Atorvastatin - - 20 Excipient Lactose Carb
  • statin active ingredient dissolution rates of the statin single tablets according to Comparative Examples 3 to 5 and the sustained release combination preparations according to Examples 2, 4 and 5 are shown in Tables 5 to 7 below.
  • PH 6.6, 7.0 aqueous buffer and water were used as the eluent.
  • the elution was performed using the paddle method.
  • the dissolution rate of the sustained release complex preparation and the statin single tablet according to the present invention is very similar to show substantially the same dissolution rate.
  • the sustained-release complex preparation according to the present invention can be seen that the effect is rapid because there is no effect on the dissolution of the contained statins in the body even though the formulation and composition differ from the control containing the statin single component.
  • the sustained-release complex preparations according to the present invention had the best dissolution profiles of two different effective ingredients. It is suitable as a sustained release combination preparation once daily.
  • a single tablet (Comparative Examples 6 to 8) according to Table 8 was prepared by simple mixing to include all of the cilostazol sustained-release granules, immediate-release granules and statin components, and sustained-release composite formulations according to the present invention Examples 2, 4 and The formulation of 5 and the effective ingredient dissolution rate for 120 minutes in 0.4% SLS eluate conditions are shown in Table 9 below.
  • Comparative Examples 6 to 8 Single tablet containing statins and cilostazol (unit: mg) division Usage Ingredient Name Comparative Example 6 Comparative Example 7 Comparative Example 8 Cilostazol immediate release granule chief ingredient Cilostazol 120.00 120.00 120.00 Excipient Microcrystalline Cellulose 101 20.00 20.00 20.00 Disintegrant Croscarmellose sodium 4.00 4.00 4.00 Binder Povidone K-30 6.00 6.00 6.00 Cilostazol immediate release weight 150.00 150.00 150.00 Cilostazol Western Granule chief ingredient Cilostazol 80.00 80.00 80.00 Excipient Microcrystalline Cellulose 101 49.00 49.00 49.00 Release regulator Hypromellose 2208 (viscosity 100,000 cps) 7.00 7.00 7.00 Release regulator Carbomer 971 4.00 4.00 4.00 Binder Povidone K-30 10.00 10.00 10.00 Lubricant Magnesium stearate 10.00 10.00 10.00 Cilostazol Western Weight 160.00 160.00 160.00 Statins chief ingredient Rosuvastatin Calcium
  • sustained-release complex preparations of the present invention exhibited an excellent early dissolution rate of all active ingredients, there was a problem that the statin active ingredient was almost eluted at the beginning due to the viscosity of the sustained-release matrix in the case of a simple mixed single tablet.
  • the sustained release co-formulation of the present invention composed of a double layer containing statins and cilostazol in different layers, respectively, was found to be an excellent formulation having sustained release while excellent initial dissolution rate of the active ingredients included.
  • Example 2 of the present invention showed a significantly less variation than the conventional phthalal SR, thereby showing excellent pharmacological activity and significantly reducing side effects. .
  • sustained-release co-formulation As another formulation of the sustained release co-formulation according to the present invention, a sustained-release co-formulation formulation containing 10 mg of rosuvastatin (10.4 mg of rosuvastatin calcium) in a statin-based drug and designed to dissolve the cilostazol active ingredient was done.
  • composition of each Example and a comparative example is as Table 11 below.
  • statin-based drug was changed to rosuvastatin, simvastatin, and atorvastatin, respectively, to proceed in the same manner as in Experiment 2.
  • a single tablet containing rosuvastatin, simvastatin, atorvastatin as an active ingredient was prepared according to the component content of Table 13 below.
  • the sustained-release composite preparation of Examples 9 to 10 were prepared in the same manner as in Example 7 except for the statin type.
  • Cilostazol chief ingredient Cilostazol 120.00 120.00 120.00 Excipient Microcrystalline Cellulose 101 20.00 20.00 20.00 Disintegrant Croscarmellose sodium 4.00 4.00 4.00 Binder Povidone K-30 6.00 6.00 6.00 Cilostazol immediate release weight 150.00 150.00 150.00 West Cilostazol chief ingredient Cilostazol 80.00 80.00 Excipient Microcrystalline Cellulose 101 49.00 49.00 49.00 Release regulator Hypromellose 2208 (viscosity 100,000 cps) 7.00 7.00 7.00 7.00 Release regulator Carbomer 971 4.00 4.00 4.00 Binder Povidone K-30 10.00 10.00 10.00 Lubricant Magnesium stearate 10.00 10.00 10.00 Cilostazol Western Weight 160.00 160.00 160.00 160.00 Statin floor chief ingredient Rosuvastatin Calcium 10.40 - - chief ingredient Simvastatin - 10 - chief ingredient Atorvastatin - - 10 Excipient Lactose Carb 21.00 21.
  • statin active ingredient dissolution rates of the statin single tablets according to Comparative Examples 11 to 13 and the sustained release combination preparations according to Examples 7, 9 and 10 are shown in Tables 15 to 17 below.
  • Eluent was used as aqueous buffer and water of pH 6.6, 7.0 and elution method was used paddle method, eluent 900ml, stirring speed was 50rpm, elution temperature was performed at 37 ⁇ 0.5 °C.
  • the dissolution rate of the sustained release complex preparation and the statin single tablet according to the present invention is very similar, showing substantially the same dissolution rate.
  • the sustained-release complex preparation according to the present invention can be seen that the effect is rapid because there is no effect on the dissolution of the contained statins in the body even though the formulation and composition differ from the control containing the statin single component.
  • the sustained-release complex preparation according to the present invention shows an optimal dissolution profile of the two different active ingredients, it is suitable as a sustained-release complex preparation to be taken once a day.
  • Comparative Examples 14 to 16 Single tablet containing statins and cilostazol (unit: mg) division Usage Ingredient Name Comparative Example 14 Comparative Example 15 Comparative Example 16 Cilostazol immediate release granule chief ingredient Cilostazol 120.00 120.00 120.00 Excipient Microcrystalline Cellulose 101 20.00 20.00 20.00 Disintegrant Croscarmellose sodium 4.00 4.00 4.00 Binder Povidone K-30 6.00 6.00 6.00 Cilostazol immediate release weight 150.00 150.00 150.00 Cilostazol Western Granule chief ingredient Cilostazol 80.00 80.00 80.00 Excipient Microcrystalline Cellulose 101 49.00 49.00 49.00 Release regulator Hypromellose 2208 (viscosity 100,000 cps) 7.00 7.00 7.00 Release regulator Carbomer 971 4.00 4.00 4.00 Binder Povidone K-30 10.00 10.00 10.00 Lubricant Magnesium stearate 10.00 10.00 10.00 Cilostazol Western Weight 160.00 160.00 160.00 Statins chief ingredient Rosuvastatin Calcium
  • Example 7 of the present invention showed significantly less variation than the conventional phthalal SR, thereby showing excellent pharmacological activity and significantly reducing side effects. .

Abstract

La présente invention concerne une formulation complexe à libération prolongée comprenant, en tant que principes actifs, un médicament à base de statine qui est un inhibiteur de la HMG-CoA réductase, et du cilostazol. Plus spécifiquement, la formulation complexe à libération prolongée consiste en une partie de mélange inhibiteur de la HMG-CoA réductase contenant l'inhibiteur de la HMG-CoA réductase, et une partie de mélange cilostazol contenant du cilostazol, la partie de mélange cilostazol contenant des granules à libération immédiate et des granules à libération prolongée, et ainsi, la formulation complexe à libération prolongée présente des effets secondaires minimaux tout en permettant une activité pharmacologique immédiate, et a des propriétés de libération prolongée qui fournissent des effets pharmacologiques suffisants même lorsqu'elle est administrée par voie orale uniquement une fois par jour.
PCT/KR2019/004743 2018-06-19 2019-04-19 Composition pharmaceutique comprenant du cilostazol et un médicament à base de statine WO2019245150A1 (fr)

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