WO2019182276A1 - Pharmaceutical combination preparation comprising ezetimibe and rosuvastatin - Google Patents

Pharmaceutical combination preparation comprising ezetimibe and rosuvastatin Download PDF

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Publication number
WO2019182276A1
WO2019182276A1 PCT/KR2019/002769 KR2019002769W WO2019182276A1 WO 2019182276 A1 WO2019182276 A1 WO 2019182276A1 KR 2019002769 W KR2019002769 W KR 2019002769W WO 2019182276 A1 WO2019182276 A1 WO 2019182276A1
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WO
WIPO (PCT)
Prior art keywords
ezetimibe
pharmaceutically acceptable
acceptable salt
rosuvastatin
pharmaceutical combination
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PCT/KR2019/002769
Other languages
French (fr)
Inventor
Hyuk Jun Cho
Jeong Hyeon Kim
Ho Taek IM
Yong Il Kim
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Hanmi Pharm. Co., Ltd.
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Application filed by Hanmi Pharm. Co., Ltd. filed Critical Hanmi Pharm. Co., Ltd.
Priority to SG11202007869WA priority Critical patent/SG11202007869WA/en
Priority to MX2020009492A priority patent/MX2020009492A/en
Priority to EA202092189A priority patent/EA202092189A1/en
Priority to CN201980020077.6A priority patent/CN111886003A/en
Publication of WO2019182276A1 publication Critical patent/WO2019182276A1/en
Priority to ZA2020/04982A priority patent/ZA202004982B/en
Priority to CONC2020/0010204A priority patent/CO2020010204A2/en
Priority to PH12020500656A priority patent/PH12020500656A1/en

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/2072—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

Definitions

  • the present invention relates to a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin. More specifically, the present invention relates to a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin, wherein water activity is 0.40 or less.
  • Rosuvastatin or a pharmaceutically acceptable salt thereof is one of the HMG-CoA reductase inhibitors that inhibit the synthesis of cholesterol to treat dyslipidemia.
  • Crestor Tab. rosuvastatin calcium salt, AstraZeneca
  • rosuvastatin containing rosuvastatin as a main ingredient are widely used in the treatment of dyslipidemia and related diseases at home and abroad.
  • studies have shown that rosuvastatin not only has an excellent effect in lowering the blood LDL cholesterol levels, compared to atorvastatin or simvastatin, which is commonly used as a drug having the same mechanism, but also has an excellent effect in increasing the HDL cholesterol levels beneficial to the body.
  • atorvastatin or simvastatin which is commonly used as a drug having the same mechanism
  • the HMG-CoA reductase inhibitors are generally administrated in combination with therapeutic agents for dyslipidemia having other mechanism to enhance the therapeutic effect.
  • the HMG-CoA reductase inhibitors have an excellent interaction with ezetimibe, a drug that inhibits cholesterol reabsorption in the small intestine, and thus, studies on combination formulation with the two ingredients are active.
  • Vytorin Tab. which is a combination formulation of simvastatin and ezetimibe, has already proved its superior pharmacological effect and stability, and thus, is in commercial use with excellent sales.
  • Non-Patent Document 1 Brandon Ason et al., J Lipid Res. Apr 2011; 52(4): 679-687
  • Non-Patent Document 2 Torimoto et al., Lipids in Health and Disease 2013, 12:137
  • the present inventors intend to provide a pharmaceutical combination preparation having improved stability of the active ingredients due to the inhibited production of impurities, by experimentally confirming the correlation between water activity and impurities in a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin as active ingredients, and providing a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin, wherein water activity is 0.40 or less.
  • the present invention provides a pharmaceutical combination preparation comprising ezetimibe or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof, wherein water activity is 0.40 or less.
  • the ezetimibe or a pharmaceutically acceptable salt thereof is present in a physically separated state from the rosuvastatin or a pharmaceutically acceptable salt thereof.
  • the ezetimibe or a pharmaceutically acceptable salt thereof is present in admixture with the rosuvastatin or a pharmaceutically acceptable salt thereof in granular form.
  • the granule comprising the ezetimibe or a pharmaceutically acceptable salt thereof further comprises a solubilizer.
  • the solubilizer is sodium lauryl sulfate.
  • the weight ratio of sodium lauryl sulfate to ezetimibe in the granule comprising the ezetimibe or a pharmaceutically acceptable salt thereof is 0.15:1 to 0.3:1.
  • the pharmaceutical combination preparation further comprises one or more ingredients selected from the group consisting of amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and combinations thereof.
  • the ezetimibe or a pharmaceutically acceptable salt thereof is present in a physically separated state from the rosuvastatin or a pharmaceutically acceptable salt thereof, the amlodipine or a pharmaceutically acceptable salt thereof, and the losartan or a pharmaceutically acceptable salt thereof, respectively.
  • the pharmaceutical combination preparation is present in the form of a bilayer tablet consisting of: a first layer comprising the ezetimibe or a pharmaceutically acceptable salt thereof, the rosuvastatin or a pharmaceutically acceptable salt thereof, and the amlodipine or a pharmaceutically acceptable salt thereof; and a second layer comprising the losartan or a pharmaceutically acceptable salt thereof.
  • the ezetimibe or a pharmaceutically acceptable salt thereof in the first layer is present in admixture with the rosuvastatin or a pharmaceutically acceptable salt thereof, and the amlodipine or a pharmaceutically acceptable salt thereof in granular form.
  • the losartan or a pharmaceutically acceptable salt thereof in the second layer is present in granular form.
  • the present invention provides a method of preparing a pharmaceutical combination preparation comprising the steps of: i) producing an ezetimibe granule comprising ezetimibe or a pharmaceutically acceptable salt thereof; ii) mixing the ezetimibe granule with rosuvastatin or a pharmaceutically acceptable salt thereof to producing a mixture; iii) allowing the mixture to stand under conditions of 15 to 25% relative humidity to reduce water activity to 0.40 or less; and iv) tableting the mixture with reduced water activity.
  • the rosuvastatin or a pharmaceutically acceptable salt thereof in step ii) is mixed with the ezetimibe granule, together with amlodipine or a pharmaceutically acceptable salt thereof.
  • step iv) comprises being tableted into a bilayer tablet consisting of the mixture with reduced water activity as a first layer and a losartan granule with reduced water activity as a second layer.
  • the losartan granule with reduced water activity is prepared by the steps of: a) producing a losartan granule comprising losartan or a pharmaceutically acceptable salt thereof; and b) allowing the produced losartan granule to stand under conditions of 15 to 25% relative humidity to reduce water activity to 0.40 or less.
  • the present invention provides a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin, wherein water activity is 0.40 or less, thereby inhibiting the production of impurities in the pharmaceutical combination preparation to be able to improve stability of the active ingredients in the pharmaceutical combination preparation.
  • the stability and dissolution rate of the active ingredients in the pharmaceutical combination preparation can be improved by physically separating ezetimibe from amlodipine, losartan, and rosuvastatin, respectively.
  • Fig. 1 is a graph showing the bulk densities and tapped densities measured for the products obtained immediately prior to tableting in examples 1, 2, 8, and 9 and comparative examples 1 to 4.
  • Fig. 2 is a graph showing the hardness measured according to the tableting pressure for the products obtained immediately prior to tableting in examples 1 to 3 and 8 to 10 and comparative examples 1 to 6.
  • Fig. 3 is a graph showing the amount of impurities measured according to the purification time for the products obtained from examples 3 and 10 and comparative examples 5 and 6, which have different water activities.
  • Fig. 4 is a graph showing the dissolution rate of amlodipine measured according to the purification time for the products obtained from examples 3 to 5 and comparative examples 7, 8, and 14.
  • Fig. 5 is a graph showing the dissolution rate of losartan measured according to the purification time for the products obtained from examples 3 to 5 and comparative examples 7, 8, and 15.
  • Fig. 6 is a graph showing the dissolution rate of rosuvastatin measured according to the purification time for the products obtained from examples 3 to 5 and comparative examples 7, 8, and 16.
  • Fig. 7 is a graph showing the dissolution rate of ezetimibe measured according to the purification time for the products obtained from examples 3 to 5 and comparative examples 7, 8, and 17.
  • Fig. 8 is a graph showing the dissolution rate of ezetimibe measured according to the purification time for the products obtained from examples 3, 6, and 7 and comparative examples 12, 13, and 17.
  • the present invention provides a pharmaceutical combination preparation comprising ezetimibe or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination preparation according to the present invention comprises ezetimibe or pharmaceutically acceptable salt thereof as a first active ingredient.
  • the ezetimibe plays a role of mainly inhibiting cholesterol absorption to treat and prevent arteriosclerosis.
  • the daily dose of the ezetimibe or a pharmaceutically acceptable salt thereof is 5 mg to 15 mg.
  • the pharmaceutical combination preparation according to the present invention comprises rosuvastatin or pharmaceutically acceptable salt thereof as a second active ingredient.
  • the pharmaceutically acceptable salt of rosuvastatin include, but are not limited to, calcium salt, magnesium salt, strontium salt, etc., and preferably rosuvastatin calcium salt.
  • the rosuvastatin inhibits HMG-CoA reductase, which is essential for the synthesis of cholesterol, to lower the blood LDL cholesterol levels, while increasing the HDL cholesterol levels, thereby contributing to the treatment of dyslipidemia.
  • the daily dose of the rosuvastatin or a pharmaceutically acceptable salt thereof is 10 mg to 20 mg.
  • the water activity can affect the production of impurities during storage of the pharmaceutical combination preparation. Since the water activity of the pharmaceutical combination preparation can not be confirmed at all by the measurement of the moisture content or density of the pharmaceutical combination preparation, the correlation between water activity and impurities is less predictable through other physical properties and this correlation can also appear in completely different forms depending on the kind of the active ingredients.Taking these points into consideration, properties of water activity and impurities can be more important in the pharmaceutical combination preparation of the present invention. In addition, since a general manufacturing method of a pharmaceutical combination preparation is difficult to satisfy the water activity criteria required in the present invention, a separate process is required to control water activity.
  • the pharmaceutical combination preparation can have a water activity of 0.40 or less, preferably 0.35 or less, more preferably 0.30 or less.
  • Water activity refers to the availability of water (i.e., free water) (water availability) in a sample, which can be used by microorganisms for growth.
  • free water water availability
  • the water activity herein was measured using a water activity meter (Labmaster, novasina).
  • the impurities due to the specific ingredient increase as the water activity increases.
  • An impurity which increases in a significant level with increasing water activity in the pharmaceutical combination preparation can be EP impurity D resulting from rosuvastatin. If the pharmaceutical combination preparation has water activity of more than 0.40, it can easily exceed the impurity criteria of the ICH guideline according to storage conditions.
  • the water activity should be controlled to 0.40 or less by the water activity evaluation, not by the general moisture content evaluation.
  • the method for controlling the water activity of the pharmaceutical combination preparation is not especially limited, but the water activity of the pharmaceutical combination preparation according to the present invention can be controlled by allowing the pharmaceutical combination preparation to stand under the conditions of a certain level of relative humidity for a period of time.
  • the pharmaceutical combination preparation in order to control the water activity of the pharmaceutical combination preparation to 0.40 or less, can be allowed to stand under conditions of 15 to 25% relative humidity for 6 hours or more, preferably 8 to 15 hours.
  • the water activity of the pharmaceutical combination preparation is controlled according to the above conditions, the water activity can be effectively controlled while minimizing the physical and chemical changes of the pharmaceutical combination preparation.
  • ezetimibe and rosuvastatin which are active ingredients in the pharmaceutical combination preparation, have different stable pH conditions, they can cause problems with the stability of the active ingredients, such as increased impurities of ezetimibe and rosuvastatin, when prepared as a pharmaceutical combination preparation.
  • impurities such as (3R,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3-hydroxy-5-oxo-hept-6-enoate calcium (hereinafter referred to as "5-Oxo impurity") or N-[4-(4-fluorophenyl)-6-(1-methylethyl)-5-[(1E)-2-[(2S,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethenyl]-2-pyrimidinyl]-N-methylmethanesulfonamide (hereinafter referred to as "lactone impourity”), which are the major metabolites, can be increased.
  • lactone impourity N-[4-(4-fluorophenyl)-6-(1-methylethyl)-5-[
  • the ezetimibe and rosuvastatin be present in a physically separated state.
  • the physically separated state indicates that the reference active ingredients are kept in a state of being distinguished from other active ingredients in the final pharmaceutical combination preparation obtained through the processing step, which is carried out to separate the reference active ingredients from other active ingredients.
  • the physically separated state can be achieved through, for example, physical separation using granulation, physical separation by multilayer tableting, physical separation by tablets each tableted separately, physical separation using a core-shell structure, etc.
  • ezetimibe in order to physically separate ezetimibe and rosuvastatin, can be processed into a separate granular form and then mixed with rosuvastatin.
  • the state in which the active ingredient (rosuvastatin) other than ezetimibe is not substantially present in the granules is maintained as in the processing step even after the completion of the pharmaceutical combination preparation, even if there is an interface at which the ezetimibe is in contact with rosuvastatin on the surface of each of the ezetimibe granules in the pharmaceutical combination preparation, it can be said that the ezetimibe is present in a physically separated state from rosuvastatin in the pharmaceutical combination preparation as described in the present invention.
  • the pharmaceutical combination preparation is obtained by mixing rosuvastatin and amlodipine with the ezetimibe granule produced after granulation processing of ezetimibe.
  • the other active ingredients rosuvastatin and amlodipine
  • the ezetimibe can be regarded as being present in a physically separated state from rosuvastatin and amlodipine.
  • the method for producing an ezetimibe granule is not especially limited, but it can be preferable to produce granules in a wet state.
  • Ezetimibe is a poorly soluble drug having a low saturation solubility of about 1 ppm under acidic to weakly basic conditions such as body fluids.
  • the saturation solubility and the dissolution rate from the start of dissolution to the point of saturation can be an important indicator for evaluating the bioavailability of the poorly soluble drug. Since wet granules can reach saturation solubility at a faster rate, high bioavailability can be achieved for the poorly soluble drug ezetimibe. However, since wet granules can have high water activity, the overall water activity of the pharmaceutical combination preparation can be controlled by lowering the water activity of the other ingredients.
  • the pharmaceutical combination preparation of the present invention can further comprise one or more pharmaceutically acceptable additives necessary for preparation in addition to the active ingredients.
  • the ezetimibe wet granule part or the rosuvastatin mixing part can comprise one or more pharmaceutically acceptable additives selected from the group consisting of excipients, binders, disintegrants, and glidants.
  • each of the ezetimibe granule part and the rosuvastatin mixing part can further comprise 0.5 to 50 parts by weight of an excipient, 0.1 to 20 parts by weight of a binder, 0.1 to 10 parts by weight of a disintegrant, and 0.1 to 3 parts by weight of a glidant, per 1 part by weight of ezetimibe.
  • the excipient is selected from the group consisting of, but is not limited to, lactose, starch, mannitol, microcrystalline cellulose, carboxymethylcellulose, and combinations thereof;
  • the binder is selected from the group consisting of, but is not limited to, povidone, hypromellose, hydroxypropylcellulose, copovidone, and combinations thereof;
  • the disintegrant is selected from the group consisting of, but is not limited to, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropylcellulose, and combinations thereof;
  • the glidant is selected from the group consisting of, but is not limited to, magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof.
  • the ezetimibe granules can further comprise a solubilizer.
  • a solubilizer Preferably, sodium lauryl sulfate (SLS) can be used as the solubilizer.
  • sodium lauryl sulfate can be used within the weight ratio of sodium lauryl sulfate to ezetimibe in ezetimibe granules ranging from 0.15:1 to 0.3:1. When the amount of sodium lauryl sulfate is used in the weight ratio of less than 0.15, the dissolution rate of ezetimibe is remarkably lowered.
  • the pharmaceutical combination preparation according to the present invention can further comprise one or more ingredients selected from the group consisting of amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and combinations thereof.
  • the pharmaceutical combination preparation according to the present invention can comprise amlodipine or pharmaceutically acceptable salt thereof as a third active ingredient.
  • the pharmaceutically acceptable salt of amlodipine include, but is necessarily limited to, hydrochloride, hydrobromide, sulfate, phosphate, acetate, malate, fumarate, lactate, tartrate, citrate, gluconate, besilate, and camsylate, preferably amlodipine besilate salt and amlodipine camsylate salt.
  • the amlodipine of the present invention includes amlodipine racemates and (S)-amlodipine. The amlodipine blocks the calcium channel, thereby being used in the treatment of cardiovascular diseases such as angina, hypertension, and congestive heart failure.
  • the daily dose of the amlodipine or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg.
  • the pharmaceutical combination preparation according to the present invention can comprise losartan or pharmaceutically acceptable salt thereof as a forth active ingredient.
  • the pharmaceutically acceptable salt of losartan include, but are not necessarily limited to, losartan potassium salt.
  • the losartan blocks angiotensin II, which is a vasoconstrictor substance, from binding to the receptor, thereby contributing to the treatment of hypertension and heart failure, the treatment of ischemic peripheral circulatory disorder and myocardial ischemia (angina pectoris), the prevention of the progression of heart failure after myocardial infarction, and the treatment of diabetic neuropathy, glaucoma, etc.
  • the daily dose of the losartan or a pharmaceutically acceptable salt thereof is 45 mg to 100 mg.
  • the ezetimibe can also react with amlodipine or losartan as well as rosuvastatin to produce impurities, the ezetimibe is present in a physically separated state from rosuvastatin, amlodipine, and losartan, respectively.
  • the physically separated state follows the above description.
  • the pharmaceutical combination preparation comprises losartan
  • the pharmaceutical combination preparation does not comprise losartan, it can be formulated in more various forms.
  • the pharmaceutical combination preparation may be present in the form of a bilayer tablet consisting of: a first layer comprising the ezetimibe or a pharmaceutically acceptable salt thereof, the rosuvastatin or a pharmaceutically acceptable salt thereof, and the amlodipine or a pharmaceutically acceptable salt thereof; and a second layer comprising the losartan or a pharmaceutically acceptable salt thereof.
  • the ezetimibe or a pharmaceutically acceptable salt thereof in the first layer is present in admixture with the rosuvastatin or a pharmaceutically acceptable salt thereof, and the amlodipine or a pharmaceutically acceptable salt thereof in granular form.
  • the losartan or a pharmaceutically acceptable salt thereof in the second layer is present in granular form.
  • the first and second layers in the bilayer tablet can comprise one or more pharmaceutically acceptable additives selected from the group consisting of excipients, binders, disintegrants, and glidants.
  • the present invention provides a method of preparing a pharmaceutical combination preparation comprising ezetimibe or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.
  • the method of preparing a pharmaceutical combination preparation comprises the steps of: i) producing an ezetimibe granule comprising ezetimibe or a pharmaceutically acceptable salt thereof; ii) mixing the ezetimibe granule with rosuvastatin or a pharmaceutically acceptable salt thereof to producing a mixture; iii) allowing the mixture to stand under conditions of 15 to 25% relative humidity to reduce water activity to 0.40 or less; and iv) tableting the mixture with reduced water activity.
  • the rosuvastatin or a pharmaceutically acceptable salt thereof in step ii) may be mixed with the ezetimibe granule, together with amlodipine or a pharmaceutically acceptable salt thereof.
  • Step iv) may comprise being tableted into a bilayer tablet consisting of the mixture with reduced water activity as a first layer and a losartan granule with reduced water activity as a second layer.
  • the losartan granule with reduced water activity may be prepared by the steps of: a) producing a losartan granule comprising losartan or a pharmaceutically acceptable salt thereof; and b) allowing the produced losartan granule to stand under conditions of 15 to 25% relative humidity to reduce water activity to 0.40 or less.
  • the details of the preparation method are supplemented by the above-mentioned descriptions and the following examples.
  • Example 1 Preparation of a tablet comprising ezetimibe and rosuvastatin
  • a tablet comprising ezetimibe and rosuvastatin as active ingredients was prepared according to the composition shown in Table 1 below.
  • ezetimibe was placed in a fluidized bed granulator with lactose hydrate, microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate and was mixed for 3 minutes.
  • a binder solution in which povidone was dissolved in water was added to the mixture and the mixture was combined to perform granulation for about 50 minutes.
  • the granulated product was dried in a fluidized bed drier at 45°C and was sieved with a sieve of 0.6 mm size to produce an ezetimibe granule.
  • the produced ezetimibe granule was placed in a mixer with a mixture having the composition described in the mixing part of Table 1 and was mixed for 15 minutes. Then, 4 mg of magnesium stearate was added as a glidant and was further mixed for 5 minutes. The mixed product was exposed under conditions of about 20% relative humidity at 25°C for about 12 hours, and the resulting product was subject to a pressure of about 950 kgf with a tableting machine (Autotab-200TR, ichihashi seiki) to prepare a tablet having a hardness of about 13 kp.
  • a tableting machine Autotab-200TR, ichihashi seiki
  • Example 2 Preparation of a tablet comprising ezetimibe , rosuvastatin , and amlodipine
  • a tablet comprising ezetimibe, rosuvastatin, and amlodipine as active ingredients was prepared according to the composition shown in Table 1 below.
  • the tablet was prepared in the same manner as in example 1, except that amlodipine besilate was added to the mixing part compared with example 1.
  • the hardness of the tablet prepared was about 13 kp.
  • Example 3 Preparation of a bilayer tablet comprising ezetimibe , rosuvastatin, amlodipine , and losartan
  • a bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan as active ingredients was prepared according to the composition shown in Table 1 below.
  • losartan potassium was placed in a mixer with lactose hydrate, microcrystalline cellulose, and crospovidone, and was mixed for 20 minutes.
  • the mixed product was pressed under the conditions of an oil pressure of 2 MPa, a feeder speed of 5 rpm, and a roller speed of 1 rpm using a roller compressor (TF-1-A60, Freund vector) to form flakes.
  • the formed flakes was sieved with a sieve of 0.8 mm size to produce a losartan granule.
  • the prepared upper layer and bottom layer mixtures were exposed under the conditions of a temperature of 25°C and a relative humidity of about 20% for about 12 hours, and were then subject to a pressure of about 1,200 kgf with a tableting machine to prepare a bilayer tablet having a hardness of about 20 kp.
  • Example 4 Preparation of a bilayer tablet comprising ezetimibe , rosuvastatin, amlodipine , and losartan
  • a bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan as active ingredients was prepared according to the composition shown in Table 1 below.
  • the bilayer tablet was prepared in the same manner as in example 3, except that the ezetimibe granule was prepared in the same manner as the method of preparing the losartan granule in example 3, compared with example 3.
  • the hardness of the prepared bilayer tablet was about 20 kp.
  • Example 5 Preparation of a capsule comprising ezetimibe , rosuvastatin , amlodipine, and losartan
  • a bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan as active ingredients was prepared according to the composition shown in Table 1 below.
  • Ezetimibe granule and losartan granule were prepared in the same manner as in example 3.
  • the prepared losartan granules and 1.5 mg of magnesium stearate were placed in a mixer and were mixed for 5 minutes.
  • a tablet having a hardness of about 13 kp was prepared with a tableting machine.
  • the ingredients having the composition described in the mixing part of Table 1 below were placed in a mixer and were mixed for 15 minutes. 2 mg of magnesium stearate was further placed in the mixer and was mixed for 5 minutes, and the mixed product was exposed under the condition of about 20% relative humidity for about 12 hours.
  • a tablet having a hardness of about 7 kp was prepared with a tableting machine. The prepared two tablets were filled into a capsule of capsule No. 0 together with the ezetimibe granules to prepare a capsule.
  • compositions of the pharmaceutical combination preparations according to examples 1 to 5 are shown in Table 1 below.
  • Example 1 (mg) Example 2 (mg) Example 3 (mg) Example 4 (mg) Example 5 (mg) Losartan Granule Losartan potassium - - 100.0 100.0 100.0 Microcrystalline cellulose(Avicel PH101) - - 125.0 125.0 62.5 Lactose hydrate (#200) - - 60.0 60.0 30.0 Crospovidone (XL-10) - - 15.0 15.0 7.5 Total granule mass - - 300.0 300.0 200.0 Ezetimibe Granule Ezetimibe 10.0 10.0 10.0 10.0 10.0 10.0 Microcrystalline cellulose(Avicel PH101) 90.0 90.0 90.0 90.0 44.0 Lactose hydrate (#200) 35.0 35.0 35.0 35.0 17.5 Croscarmellose sodium 15.0 15.0 15.0 15.0 7.5 Sodium lauryl sulfate 2.0 2.0 2.0 2.0 2.0 2.0 Povidone (k-30) 5.0 5.0 5.0 5.0 2.5 Purified water (70.0) - - -
  • Example 6 Preparation of a bilayer tablet comprising ezetimibe , rosuvastatin, amlodipine , and losartan
  • a bilayer tablet comprising ezetimibe, rosuvastatin, and amlodipine as active ingredients was prepared according to the composition shown in Table 2 below.
  • the tablet was prepared in the same manner as in example 3, except that in the ezetimibe granule, the amount of microcrystalline cellulose was adjusted to 90.5 mg and the amount of sodium lauryl sulfate was adjusted to 1.5 mg, compared with example 3.
  • the hardness of the tablet prepared was about 20 kp.
  • Example 7 Preparation of a bilayer tablet comprising ezetimibe , rosuvastatin, amlodipine , and losartan
  • a bilayer tablet comprising ezetimibe, rosuvastatin, and amlodipine as active ingredients was prepared according to the composition shown in Table 2 below.
  • the tablet was prepared in the same manner as in example 3, except that in the ezetimibe granule, the amount of microcrystalline cellulose was adjusted to 89 mg and the amount of sodium lauryl sulfate was adjusted to 3 mg, compared with example 3.
  • the hardness of the tablet prepared was about 20 kp.
  • compositions of the pharmaceutical combination preparations according to examples 6 and 7 are shown in Table 2 below.
  • Example 6 (mg) Example 7 (mg) Losartan Granule Losartan potassium 100.0 100.0 Microcrystalline cellulose(Avicel PH101) 125.0 125.0 Lactose hydrate (#200) 60.0 60.0 Crospovidone (XL-10) 15.0 15.0 Total granule mass 300.0 300.0 Ezetimibe Granule Ezetimibe 10.0 10.0 Microcrystalline cellulose(Avicel PH101) 90.5 89.0 Lactose hydrate (#200) 35.0 35.0 Croscarmellose sodium 15.0 15.0 Sodium lauryl sulfate 1.5 3.0 Povidone (k-30) 5.0 5.0 Purified water (70.0) - Total granule mass 157.0 157.0 Mixing Part Amlodipine besilate(as amlodipine) 6.94(5.0) 6.94(5.0) Rosuvastatin calcium(as rosuvastatin) 20.8(20.0) 20.8(20.0) Mannitol (SD200) 120.0 120.0 Lactol
  • Example 8 Preparation of a tablet comprising ezetimibe and rosuvastatin, with high water activity
  • the product after the final mixing obtained from example 1 was exposed under condition of about 20% relative humidity for 8 hours, and was then subject to a pressure of about 1,200 kgf with a tableting machine to prepare a tablet having a hardness of about 20 kp.
  • Example 9 Preparation of a tablet comprising ezetimibe , rosuvastatin , and amlodipine , with high water activity
  • the product after the final mixing obtained from example 2 was exposed under condition of about 20% relative humidity for 8 hours, and was then subject to a pressure of about 950 kgf with a tableting machine to prepare a tablet having a hardness of about 13 kp.
  • Example 10 Preparation of a bilayer tablet comprising ezetimibe , rosuvastatin, amlodipine , and losartan , with high water activity
  • the product after the final mixing obtained from example 3 was exposed under condition of about 20% relative humidity for 8 hours, and was then subject to a pressure of about 950 kgf with a tableting machine to prepare a tablet having a hardness of about 13 kp.
  • Comparative Examples 1 Preparation of a tablet comprising ezetimibe and rosuvastatin , with high water activity
  • the product after the final mixing obtained from example 1 was exposed under condition of about 20% relative humidity for 4 hours, and was then subject to a pressure of about 1,200 kgf with a tableting machine to prepare a tablet having a hardness of about 20 kp.
  • Comparative Examples 2 Preparation of a tablet comprising ezetimibe and rosuvastatin , with high water activity
  • the product after the final mixing obtained from example 1 was subject to a pressure of about 1,200 kgf with a tableting machine to prepare a tablet having a hardness of about 20 kp.
  • Comparative Examples 3 Preparation of a tablet comprising ezetimibe , rosuvastatin, and amlodipine , with high water activity
  • the product after the final mixing obtained from example 2 was exposed under condition of about 20% relative humidity for 4 hours, and was then subject to a pressure of about 950 kgf with a tableting machine to prepare a tablet having a hardness of about 13 kp.
  • Comparative Examples 4 Preparation of a tablet comprising ezetimibe , rosuvastatin, and amlodipine , with high water activity
  • the product after the final mixing obtained from example 2 was subject to a pressure of about 950 kgf with a tableting machine to prepare a tablet having a hardness of about 13 kp.
  • Comparative Examples 5 Preparation of a bilayer tablet comprising ezetimibe, rosuvastatin , amlodipine , and losartan , with high water activity
  • the product after the final mixing obtained from example 3 was exposed under condition of about 20% relative humidity for 4 hours, and was then subject to a pressure of about 950 kgf with a tableting machine to prepare a tablet having a hardness of about 13 kp.
  • Comparative Examples 6 Preparation of a bilayer tablet comprising ezetimibe, rosuvastatin , amlodipine , and losartan , with high water activity
  • the product after the final mixing obtained from example 3 was subject to a pressure of about 950 kgf with a tableting machine to prepare a tablet having a hardness of about 13 kp.
  • Comparative Examples 7 Preparation of a single layer tablet comprising ezetimibe, rosuvastatin , amlodipine , and losartan
  • the prepared ezetimibe granule and losartan granule were mixed for 15 minutes in a mixer with the mixture having the composition described in the mixing part of example 3 in Table 1 above. 7 mg of magnesium stearate was further added and mixed for 5 minutes, and then a tablet having a hardness of about 20 kp was prepared with a tableting machine.
  • Comparative Examples 8 Preparation of a bilayer tablet comprising ezetimibe, rosuvastatin , amlodipine , and losartan
  • the prepared ezetimibe granule and losartan granule were mixed for 15 minutes in a mixer. 3 mg of magnesium stearate was added and further mixed in a mixer for 5 minutes to prepare an upper layer mixture of the bilayer tablet. 4 mg of magnesium stearate was added to the mixture having the composition described in the mixing part of example 3 in Table 1 above, and was further mixed in a mixer for 5 minutes to prepare a bottom layer mixture of a bilayer tablet.
  • the prepared upper layer and bottom layer mixtures were subject to a pressure of about 1,200 kgf with a tableting machine to prepare a bilayer tablet having a hardness of about 20 kp.
  • a bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan was prepared according to the composition shown in Table 3 below.
  • the bilayer tablet was prepared in the same manner as in example 3, except that amlodipine besilate and rosuvastatin calcium were added not to the mixing part but to the ezetimibe granule, compared with example 3.
  • the hardness of the prepared bilayer tablet was about 20 kp.
  • Comparative Examples 10 Preparation of a bilayer tablet comprising ezetimibe, rosuvastatin , amlodipine , and losartan
  • a bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan was prepared according to the composition shown in Table 3 below.
  • the bilayer tablet was prepared in the same manner as in example 3, except that amlodipine besilate was added not to the mixing part but to the ezetimibe granule, compared with example 3.
  • the hardness of the prepared bilayer tablet was about 20 kp.
  • a bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan was prepared according to the composition shown in Table 3 below.
  • the bilayer tablet was prepared in the same manner as in example 3, except that rosuvastatin calcium were added not to the mixing part but to the ezetimibe granule, compared with example 3.
  • the hardness of the prepared bilayer tablet was about 20 kp.
  • compositions of the pharmaceutical combination preparations according to comparative examples 9 and 11 are shown in Table 3 below.
  • Comparative Examples 12 Preparation of a bilayer tablet comprising ezetimibe, rosuvastatin , amlodipine , and losartan
  • a bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan was prepared according to the composition shown in Table 4 below.
  • the tablet was prepared in the same manner as in example 3, except that in the ezetimibe granule, the amount of microcrystalline cellulose was adjusted to 92.0 mg and the amount of sodium lauryl sulfate was adjusted to 0 mg, compared with example 3.
  • the hardness of the tablet prepared was about 20 kp.
  • a bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan was prepared according to the composition shown in Table 4 below.
  • the tablet was prepared in the same manner as in example 3, except that in the ezetimibe granule, the amount of microcrystalline cellulose was adjusted to 91.0 mg and the amount of sodium lauryl sulfate was adjusted to 1.0 mg, compared with example 3.
  • the hardness of the tablet prepared was about 20 kp.
  • compositions of the pharmaceutical combination preparations according to comparative examples 12 and 13 are shown in Table 4 below.
  • Norvasc Tab. comprising amlodipine besilate salt was used as a control drug.
  • Cozaar Tab. comprising losartan potassium was used as a control drug.
  • Crestor Tab. comprising rosuvastatin calcium was used as a control drug.
  • Exetrol Tab. comprising ezetimibe was used as a control drug.
  • Test Example 1 Measurement of the moisture content of examples 1 to 3 and 8 to 10 and comparative examples 1 to 6
  • comparative examples 2, 4, and 6 were not left under the condition of about 20% relative humidity. Under the same condition, comparative examples 1, 3, and 5 were left for 4 hours each, examples 8 to 10 were left for 8 hours each, and examples 1 to 3 were left for 12 hours each. According to Table 5 above, it can be confirmed that the moisture content is 2.76% to 3.06% at 4 hours exposure, 2.63% to 3.19% at 8 hours exposure, and 2.63% to 2.94% at 12 hours exposure.
  • Test Example 2 Measurement of the water activity of examples 1 to 3 and 8 to 10 and comparative examples 1 to 6
  • Water activity of the tablets obtained from examples 1 to 3 and 8 to 10 and comparative examples 1 to 6 was measured using a water activity meter (Labmaster, novasina). Specifically, four tablets were pulverized into particles having a size smaller than size No. 20 at 25°C and placed in a cylindrical container having a diameter of 4 cm and a height of 13 mm. Then, the change in value was observed using a water activity meter. The values measured when the change in value stays at the level of ⁇ 0.001 for about 1 minute are shown in Table 6 below.
  • comparative examples 2, 4, and 6 were not left under the condition of about 20% relative humidity. Under the same condition, comparative examples 1, 3, and 5 were left for 4 hours each, examples 8 to 10 were left for 8 hours each, and examples 1 to 3 were left for 12 hours each. According to Table 6 above, it can be confirmed that water activity is 0.411 to 0.428 at 4 hours exposure, 0.338 to 0.349 at 8 hours exposure, and 0.196 to 0.208 at 12 hours exposure.
  • Test Example 3 Measurement of the density of examples 1, 2, 8, and 9 and comparative examples 1 to 4
  • the bulk densities (g/ml) and tapped densities (g/ml) measured for the products obtained immediately prior to tableting in examples 1, 2, 8, and 9 and comparative examples 1 to 4 are shown in Fig. 1.
  • the bulk density was calculated by measuring the granular mass of about 5 to 10 g, carefully placing the granules into a 50 mL measuring cylinder, and measuring the bulk volume.
  • the tap density was calculated by measuring the volume of the granules in a compact state by tapping the measuring cylinder 100 times.
  • test example 3 The evaluation of the granular properties in test example 3 is conducted for the purpose of confirming whether a specific issue occurs during the production of the semi-finished product (granule or final mixture) to be produced in the process, not after the completion of the production of the preparation in the pharmaceutical field.
  • Fig. 1 when the products were left under the condition of about 50% relative humidity, the density of the products was not significantly affected by the standing time. In other words, it can be confirmed that the change in water activity during the production process is difficult to confirm by the density measurement method.
  • Test Example 4 Measurement of the hardness of examples 1 to 3 and 8 to 10 and comparative examples 1 to 6
  • test example 4 The tabletability evaluation of test example 4 is conducted for the purpose of confirming whether a specific issue occurs during the production of the tablets. According to Fig. 2, when the products were left to stand under the condition of about 50% relative humidity and then tableted, the hardness of the tablets was not significantly affected by the standing time. In other words, it can be confirmed that the change in water activity during the production process is difficult to confirm by the hardness measurement method.
  • Test Example 5 Measurement of impurities of examples 1 to 3 and 8 to 10 and comparative examples 1 to 6
  • Test Example 6 Dissolution test of examples 3 to 5 and comparative examples 7, 8, and 14 to 16 ( amlodipine , losartan , rosuvastatin )
  • amlodipine and rosuvastatin of examples 3 to 5 and comparative example 8 were confirmed to have different dissolution rates from losartan.
  • the amlodipine and rosuvastatin of comparative example 7 in which all ingredients were mixed showed a slow dissolution profile in a pattern similar to losartan due to the effect of losartan, which was also significantly different from the dissolution profile of the control drugs for each ingredients (comparative examples 14 and 16).
  • Test Example 7 Dissolution test of examples 3 to 7 and comparative examples 7, 8, 12, 13, and 17 ( ezetimibe )
  • ezetimibe was a poorly soluble drug and showed a dissolution rate of about 10% or less, dissolution of ezetimibe was confirmed by dissolution conditions different from those of test example 6.
  • Dissolution solution 0.1% polysorbate 80, 900 mL
  • amlodipine, rosuvastatin, and ezetimibe should be present in a physically separated state from losartan in the development of a pharmaceutical combination preparation comprising amlodipine, losartan, rosuvastatin, and ezetimibe.
  • ezetimibe As a result of dissolution test of ezetimibe according to the amount of sodium lauryl sulfate widely used as a solubiliser, ezetimibe was confirmed to show a dissolution profile similar to comparative example 17, which is a control drug, when the amount of sodium lauryl sulfate was 1.5 to 3 mg. It is judged that the amount of sodium lauryl sulfate as a solubiliser is required to be more than a certain amount for the dissolution rate of the poorly soluble drug ezetimibe.
  • Test Example 8 Measurement of impurities of examples 3 to 5 and comparative examples 7 to 11
  • ezetimibe needs to be present in a physically separated state from amlodipine, losartan, and rosuvastatin.

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Abstract

The present invention relates to a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin. The pharmaceutical combination preparation has a water activity of 0.40 or less. The pharmaceutical combination preparation can further comprise one or more ingredients selected the group consisting of amlodipine, losartan, and combinations thereof, and the ezetimibe is present in a physically separated state from rosuvastatin, amlodipine, and losartan, respectively.

Description

PHARMACEUTICAL COMBINATION PREPARATION COMPRISING EZETIMIBE AND ROSUVASTATIN
The present invention relates to a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin. More specifically, the present invention relates to a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin, wherein water activity is 0.40 or less.
Rosuvastatin or a pharmaceutically acceptable salt thereof is one of the HMG-CoA reductase inhibitors that inhibit the synthesis of cholesterol to treat dyslipidemia. Crestor Tab. (rosuvastatin calcium salt, AstraZeneca) containing rosuvastatin as a main ingredient are widely used in the treatment of dyslipidemia and related diseases at home and abroad. In particular, studies have shown that rosuvastatin not only has an excellent effect in lowering the blood LDL cholesterol levels, compared to atorvastatin or simvastatin, which is commonly used as a drug having the same mechanism, but also has an excellent effect in increasing the HDL cholesterol levels beneficial to the body. Thus, there is growing interest in formulation of rosuvastatin.
The HMG-CoA reductase inhibitors are generally administrated in combination with therapeutic agents for dyslipidemia having other mechanism to enhance the therapeutic effect. The HMG-CoA reductase inhibitors have an excellent interaction with ezetimibe, a drug that inhibits cholesterol reabsorption in the small intestine, and thus, studies on combination formulation with the two ingredients are active. For example, Vytorin Tab., which is a combination formulation of simvastatin and ezetimibe, has already proved its superior pharmacological effect and stability, and thus, is in commercial use with excellent sales.
In the case of rosuvastatin, the superiority of the pharmacological effect when administered in combination with ezetimibe has been proved by many studies (see non-patent literatures 1 and 2). Thus, there is a need for the development of combination formulations with excellent pharmaceutical properties for the combination of rosuvastatin and ezetimibe which have proven pharmacological effects as a combination. Furthermore, in order to effectively treat cardiovascular diseases, a combination preparation which further comprises amlodipine and/or losartan in addition to rosuvastatin and ezetimibe is required. It is also necessary to develop a combination preparation having excellent pharmaceutical properties for the combination preparation comprising the combination of rosuvastatin, ezetimibe, amlodipine, and losartan.
[Prior-art Documents]
[Non-Patent Documents]
(Non-Patent Document 1) Brandon Ason et al., J Lipid Res. Apr 2011; 52(4): 679-687
(Non-Patent Document 2) Torimoto et al., Lipids in Health and Disease 2013, 12:137
The present inventors intend to provide a pharmaceutical combination preparation having improved stability of the active ingredients due to the inhibited production of impurities, by experimentally confirming the correlation between water activity and impurities in a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin as active ingredients, and providing a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin, wherein water activity is 0.40 or less.
According to a first aspect of the present invention,
the present invention provides a pharmaceutical combination preparation comprising ezetimibe or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof, wherein water activity is 0.40 or less.
In one embodiment of the present invention, the ezetimibe or a pharmaceutically acceptable salt thereof is present in a physically separated state from the rosuvastatin or a pharmaceutically acceptable salt thereof.
In one embodiment of the present invention, the ezetimibe or a pharmaceutically acceptable salt thereof is present in admixture with the rosuvastatin or a pharmaceutically acceptable salt thereof in granular form.
In one embodiment of the present invention, the granule comprising the ezetimibe or a pharmaceutically acceptable salt thereof further comprises a solubilizer.
In one embodiment of the present invention, the solubilizer is sodium lauryl sulfate.
In one embodiment of the present invention, the weight ratio of sodium lauryl sulfate to ezetimibe in the granule comprising the ezetimibe or a pharmaceutically acceptable salt thereof is 0.15:1 to 0.3:1.
In one embodiment of the present invention, the pharmaceutical combination preparation further comprises one or more ingredients selected from the group consisting of amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and combinations thereof.
In one embodiment of the present invention, the ezetimibe or a pharmaceutically acceptable salt thereof is present in a physically separated state from the rosuvastatin or a pharmaceutically acceptable salt thereof, the amlodipine or a pharmaceutically acceptable salt thereof, and the losartan or a pharmaceutically acceptable salt thereof, respectively.
In one embodiment of the present invention, the pharmaceutical combination preparation is present in the form of a bilayer tablet consisting of: a first layer comprising the ezetimibe or a pharmaceutically acceptable salt thereof, the rosuvastatin or a pharmaceutically acceptable salt thereof, and the amlodipine or a pharmaceutically acceptable salt thereof; and a second layer comprising the losartan or a pharmaceutically acceptable salt thereof.
In one embodiment of the present invention, the ezetimibe or a pharmaceutically acceptable salt thereof in the first layer is present in admixture with the rosuvastatin or a pharmaceutically acceptable salt thereof, and the amlodipine or a pharmaceutically acceptable salt thereof in granular form.
In one embodiment of the present invention, the losartan or a pharmaceutically acceptable salt thereof in the second layer is present in granular form.
According to a second aspect of the present invention,
the present invention provides a method of preparing a pharmaceutical combination preparation comprising the steps of: i) producing an ezetimibe granule comprising ezetimibe or a pharmaceutically acceptable salt thereof; ii) mixing the ezetimibe granule with rosuvastatin or a pharmaceutically acceptable salt thereof to producing a mixture; iii) allowing the mixture to stand under conditions of 15 to 25% relative humidity to reduce water activity to 0.40 or less; and iv) tableting the mixture with reduced water activity.
In one embodiment of the present invention, the rosuvastatin or a pharmaceutically acceptable salt thereof in step ii) is mixed with the ezetimibe granule, together with amlodipine or a pharmaceutically acceptable salt thereof.
In one embodiment of the present invention, step iv) comprises being tableted into a bilayer tablet consisting of the mixture with reduced water activity as a first layer and a losartan granule with reduced water activity as a second layer.
In one embodiment of the present invention, the losartan granule with reduced water activity is prepared by the steps of: a) producing a losartan granule comprising losartan or a pharmaceutically acceptable salt thereof; and b) allowing the produced losartan granule to stand under conditions of 15 to 25% relative humidity to reduce water activity to 0.40 or less.
The present invention provides a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin, wherein water activity is 0.40 or less, thereby inhibiting the production of impurities in the pharmaceutical combination preparation to be able to improve stability of the active ingredients in the pharmaceutical combination preparation.
In addition, when a pharmaceutical combination preparation further comprising amlodipine and losartan in addition to ezetimibe and rosuvastatin is provided, the stability and dissolution rate of the active ingredients in the pharmaceutical combination preparation can be improved by physically separating ezetimibe from amlodipine, losartan, and rosuvastatin, respectively.
Fig. 1 is a graph showing the bulk densities and tapped densities measured for the products obtained immediately prior to tableting in examples 1, 2, 8, and 9 and comparative examples 1 to 4.
Fig. 2 is a graph showing the hardness measured according to the tableting pressure for the products obtained immediately prior to tableting in examples 1 to 3 and 8 to 10 and comparative examples 1 to 6.
Fig. 3 is a graph showing the amount of impurities measured according to the purification time for the products obtained from examples 3 and 10 and comparative examples 5 and 6, which have different water activities.
Fig. 4 is a graph showing the dissolution rate of amlodipine measured according to the purification time for the products obtained from examples 3 to 5 and comparative examples 7, 8, and 14.
Fig. 5 is a graph showing the dissolution rate of losartan measured according to the purification time for the products obtained from examples 3 to 5 and comparative examples 7, 8, and 15.
Fig. 6 is a graph showing the dissolution rate of rosuvastatin measured according to the purification time for the products obtained from examples 3 to 5 and comparative examples 7, 8, and 16.
Fig. 7 is a graph showing the dissolution rate of ezetimibe measured according to the purification time for the products obtained from examples 3 to 5 and comparative examples 7, 8, and 17.
Fig. 8 is a graph showing the dissolution rate of ezetimibe measured according to the purification time for the products obtained from examples 3, 6, and 7 and comparative examples 12, 13, and 17.
The embodiments provided according to the present invention can be all achieved by the following description. It is to be understood that the following description describes preferred embodiments of the present invention and the present invention is not necessarily limited thereto.
The present invention provides a pharmaceutical combination preparation comprising ezetimibe or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.
The pharmaceutical combination preparation according to the present invention comprises ezetimibe or pharmaceutically acceptable salt thereof as a first active ingredient. The ezetimibe plays a role of mainly inhibiting cholesterol absorption to treat and prevent arteriosclerosis. The daily dose of the ezetimibe or a pharmaceutically acceptable salt thereof is 5 mg to 15 mg.
The pharmaceutical combination preparation according to the present invention comprises rosuvastatin or pharmaceutically acceptable salt thereof as a second active ingredient. Examples of the pharmaceutically acceptable salt of rosuvastatin include, but are not limited to, calcium salt, magnesium salt, strontium salt, etc., and preferably rosuvastatin calcium salt. The rosuvastatin inhibits HMG-CoA reductase, which is essential for the synthesis of cholesterol, to lower the blood LDL cholesterol levels, while increasing the HDL cholesterol levels, thereby contributing to the treatment of dyslipidemia. The daily dose of the rosuvastatin or a pharmaceutically acceptable salt thereof is 10 mg to 20 mg.
In a pharmaceutical combination preparation comprising ezetimibe and rosuvastatin as active ingredients, the water activity can affect the production of impurities during storage of the pharmaceutical combination preparation. Since the water activity of the pharmaceutical combination preparation can not be confirmed at all by the measurement of the moisture content or density of the pharmaceutical combination preparation, the correlation between water activity and impurities is less predictable through other physical properties and this correlation can also appear in completely different forms depending on the kind of the active ingredients.Taking these points into consideration, properties of water activity and impurities can be more important in the pharmaceutical combination preparation of the present invention. In addition, since a general manufacturing method of a pharmaceutical combination preparation is difficult to satisfy the water activity criteria required in the present invention, a separate process is required to control water activity. According to one embodiment of the present invention, the pharmaceutical combination preparation can have a water activity of 0.40 or less, preferably 0.35 or less, more preferably 0.30 or less. Water activity refers to the availability of water (i.e., free water) (water availability) in a sample, which can be used by microorganisms for growth. As described above, it is difficult to confirm water activity by a general moisture content test. In the case of the general moisture content test, both the free water and the bonded water are measured, whereas in the case of the water activity test, the only free water which is directly related to the stability of main ingredients, the crystal form, the moisture migration, etc., is measured. Therefore, a more precise measurement is required in the water activity test and the correlation with impurities can be confirmed only by the thus measured water activity. Specifically, the water activity herein was measured using a water activity meter (Labmaster, novasina). In the pharmaceutical combination preparation comprising ezetimibe and rosuvastatin according to the present invention, the impurities due to the specific ingredient increase as the water activity increases. An impurity which increases in a significant level with increasing water activity in the pharmaceutical combination preparation can be EP impurity D resulting from rosuvastatin. If the pharmaceutical combination preparation has water activity of more than 0.40, it can easily exceed the impurity criteria of the ICH guideline according to storage conditions. Therefore, for the stability of the pharmaceutical combination preparation, the water activity should be controlled to 0.40 or less by the water activity evaluation, not by the general moisture content evaluation. The method for controlling the water activity of the pharmaceutical combination preparation is not especially limited, but the water activity of the pharmaceutical combination preparation according to the present invention can be controlled by allowing the pharmaceutical combination preparation to stand under the conditions of a certain level of relative humidity for a period of time. According to one embodiment of the present invention, in order to control the water activity of the pharmaceutical combination preparation to 0.40 or less, the pharmaceutical combination preparation can be allowed to stand under conditions of 15 to 25% relative humidity for 6 hours or more, preferably 8 to 15 hours. When the water activity of the pharmaceutical combination preparation is controlled according to the above conditions, the water activity can be effectively controlled while minimizing the physical and chemical changes of the pharmaceutical combination preparation.
Since ezetimibe and rosuvastatin, which are active ingredients in the pharmaceutical combination preparation, have different stable pH conditions, they can cause problems with the stability of the active ingredients, such as increased impurities of ezetimibe and rosuvastatin, when prepared as a pharmaceutical combination preparation. In the case of rosuvastatin, the production of impurities such as (3R,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3-hydroxy-5-oxo-hept-6-enoate calcium (hereinafter referred to as "5-Oxo impurity") or N-[4-(4-fluorophenyl)-6-(1-methylethyl)-5-[(1E)-2-[(2S,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethenyl]-2-pyrimidinyl]-N-methylmethanesulfonamide (hereinafter referred to as "lactone impourity"), which are the major metabolites, can be increased. Accordingly, it can be preferable that the ezetimibe and rosuvastatin be present in a physically separated state. Wherein, the physically separated state indicates that the reference active ingredients are kept in a state of being distinguished from other active ingredients in the final pharmaceutical combination preparation obtained through the processing step, which is carried out to separate the reference active ingredients from other active ingredients. However, it does not include the case where the ingredients themselves are mixed into the mixing process in advance without going through this processing step. The physically separated state can be achieved through, for example, physical separation using granulation, physical separation by multilayer tableting, physical separation by tablets each tableted separately, physical separation using a core-shell structure, etc. According to one embodiment of the present invention, in order to physically separate ezetimibe and rosuvastatin, ezetimibe can be processed into a separate granular form and then mixed with rosuvastatin. At this time, in the case where the state in which the active ingredient (rosuvastatin) other than ezetimibe is not substantially present in the granules is maintained as in the processing step even after the completion of the pharmaceutical combination preparation, even if there is an interface at which the ezetimibe is in contact with rosuvastatin on the surface of each of the ezetimibe granules in the pharmaceutical combination preparation, it can be said that the ezetimibe is present in a physically separated state from rosuvastatin in the pharmaceutical combination preparation as described in the present invention. In another embodiment, the pharmaceutical combination preparation is obtained by mixing rosuvastatin and amlodipine with the ezetimibe granule produced after granulation processing of ezetimibe. At this time, in the case where the other active ingredients (rosuvastatin and amlodipine) are not substantially present in the ezetimibe granule, the ezetimibe can be regarded as being present in a physically separated state from rosuvastatin and amlodipine.
The method for producing an ezetimibe granule is not especially limited, but it can be preferable to produce granules in a wet state. Ezetimibe is a poorly soluble drug having a low saturation solubility of about 1 ppm under acidic to weakly basic conditions such as body fluids. The saturation solubility and the dissolution rate from the start of dissolution to the point of saturation can be an important indicator for evaluating the bioavailability of the poorly soluble drug. Since wet granules can reach saturation solubility at a faster rate, high bioavailability can be achieved for the poorly soluble drug ezetimibe. However, since wet granules can have high water activity, the overall water activity of the pharmaceutical combination preparation can be controlled by lowering the water activity of the other ingredients.
The pharmaceutical combination preparation of the present invention can further comprise one or more pharmaceutically acceptable additives necessary for preparation in addition to the active ingredients. Specifically, the ezetimibe wet granule part or the rosuvastatin mixing part can comprise one or more pharmaceutically acceptable additives selected from the group consisting of excipients, binders, disintegrants, and glidants. According to one embodiment of the present invention, each of the ezetimibe granule part and the rosuvastatin mixing part can further comprise 0.5 to 50 parts by weight of an excipient, 0.1 to 20 parts by weight of a binder, 0.1 to 10 parts by weight of a disintegrant, and 0.1 to 3 parts by weight of a glidant, per 1 part by weight of ezetimibe.
The kind and content of such an additive can be appropriately selected according to the type of the specific formulation to be prepared by one skilled in the art. For example, the excipient is selected from the group consisting of, but is not limited to, lactose, starch, mannitol, microcrystalline cellulose, carboxymethylcellulose, and combinations thereof; the binder is selected from the group consisting of, but is not limited to, povidone, hypromellose, hydroxypropylcellulose, copovidone, and combinations thereof; the disintegrant is selected from the group consisting of, but is not limited to, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropylcellulose, and combinations thereof; and the glidant is selected from the group consisting of, but is not limited to, magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof.
Since ezetimibe is a poorly soluble drug as described above, the ezetimibe granules can further comprise a solubilizer. Preferably, sodium lauryl sulfate (SLS) can be used as the solubilizer. According to one embodiment of the present invention, sodium lauryl sulfate can be used within the weight ratio of sodium lauryl sulfate to ezetimibe in ezetimibe granules ranging from 0.15:1 to 0.3:1. When the amount of sodium lauryl sulfate is used in the weight ratio of less than 0.15, the dissolution rate of ezetimibe is remarkably lowered. On the other hand, when the amount of sodium lauryl sulfate is used in the weight ratio of more than 0.3, the effect of improving the dissolution rate of ezetimibe according to the increase of sodium lauryl sulfate is insignificant. In addition, when the solubilizer is used in an excessive amount, the stability of the ezetimibe granules can be lowered.
The pharmaceutical combination preparation according to the present invention can further comprise one or more ingredients selected from the group consisting of amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and combinations thereof.
The pharmaceutical combination preparation according to the present invention can comprise amlodipine or pharmaceutically acceptable salt thereof as a third active ingredient. Examples of the pharmaceutically acceptable salt of amlodipine include, but is necessarily limited to, hydrochloride, hydrobromide, sulfate, phosphate, acetate, malate, fumarate, lactate, tartrate, citrate, gluconate, besilate, and camsylate, preferably amlodipine besilate salt and amlodipine camsylate salt. In addition, the amlodipine of the present invention includes amlodipine racemates and (S)-amlodipine. The amlodipine blocks the calcium channel, thereby being used in the treatment of cardiovascular diseases such as angina, hypertension, and congestive heart failure. The daily dose of the amlodipine or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg.
The pharmaceutical combination preparation according to the present invention can comprise losartan or pharmaceutically acceptable salt thereof as a forth active ingredient. Examples of the pharmaceutically acceptable salt of losartan include, but are not necessarily limited to, losartan potassium salt. The losartan blocks angiotensin II, which is a vasoconstrictor substance, from binding to the receptor, thereby contributing to the treatment of hypertension and heart failure, the treatment of ischemic peripheral circulatory disorder and myocardial ischemia (angina pectoris), the prevention of the progression of heart failure after myocardial infarction, and the treatment of diabetic neuropathy, glaucoma, etc. The daily dose of the losartan or a pharmaceutically acceptable salt thereof is 45 mg to 100 mg.
Since the ezetimibe can also react with amlodipine or losartan as well as rosuvastatin to produce impurities, the ezetimibe is present in a physically separated state from rosuvastatin, amlodipine, and losartan, respectively. Wherein, the physically separated state follows the above description. According to one embodiment of the present invention, when the pharmaceutical combination preparation comprises losartan, it may be preferable to prepare a bilayer tablet consisting of a layer comprising ezetimibe and rosuvastatin and a layer comprising losartan. However, when the pharmaceutical combination preparation does not comprise losartan, it can be formulated in more various forms.
When the pharmaceutical combination preparation comprises all of ezetimibe, rosuvastatin, amlodipine, and losartan as active ingredients, the pharmaceutical combination preparation may be present in the form of a bilayer tablet consisting of: a first layer comprising the ezetimibe or a pharmaceutically acceptable salt thereof, the rosuvastatin or a pharmaceutically acceptable salt thereof, and the amlodipine or a pharmaceutically acceptable salt thereof; and a second layer comprising the losartan or a pharmaceutically acceptable salt thereof. the ezetimibe or a pharmaceutically acceptable salt thereof in the first layer is present in admixture with the rosuvastatin or a pharmaceutically acceptable salt thereof, and the amlodipine or a pharmaceutically acceptable salt thereof in granular form. The losartan or a pharmaceutically acceptable salt thereof in the second layer is present in granular form. The first and second layers in the bilayer tablet can comprise one or more pharmaceutically acceptable additives selected from the group consisting of excipients, binders, disintegrants, and glidants.
The present invention provides a method of preparing a pharmaceutical combination preparation comprising ezetimibe or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof.
The method of preparing a pharmaceutical combination preparation according to the present invention comprises the steps of: i) producing an ezetimibe granule comprising ezetimibe or a pharmaceutically acceptable salt thereof; ii) mixing the ezetimibe granule with rosuvastatin or a pharmaceutically acceptable salt thereof to producing a mixture; iii) allowing the mixture to stand under conditions of 15 to 25% relative humidity to reduce water activity to 0.40 or less; and iv) tableting the mixture with reduced water activity. The rosuvastatin or a pharmaceutically acceptable salt thereof in step ii) may be mixed with the ezetimibe granule, together with amlodipine or a pharmaceutically acceptable salt thereof. Step iv) may comprise being tableted into a bilayer tablet consisting of the mixture with reduced water activity as a first layer and a losartan granule with reduced water activity as a second layer. Wherein, the losartan granule with reduced water activity may be prepared by the steps of: a) producing a losartan granule comprising losartan or a pharmaceutically acceptable salt thereof; and b) allowing the produced losartan granule to stand under conditions of 15 to 25% relative humidity to reduce water activity to 0.40 or less. The details of the preparation method are supplemented by the above-mentioned descriptions and the following examples.
Hereinafter, preferred examples will be described to facilitate understanding of the present invention. However, the following examples are provided not to limit the present invention but to facilitate the understanding of the present invention.
EXAMPLES
Example 1: Preparation of a tablet comprising ezetimibe and rosuvastatin
A tablet comprising ezetimibe and rosuvastatin as active ingredients was prepared according to the composition shown in Table 1 below.
Specifically, ezetimibe was placed in a fluidized bed granulator with lactose hydrate, microcrystalline cellulose, croscarmellose sodium, and sodium lauryl sulfate and was mixed for 3 minutes. A binder solution in which povidone was dissolved in water was added to the mixture and the mixture was combined to perform granulation for about 50 minutes. The granulated product was dried in a fluidized bed drier at 45℃ and was sieved with a sieve of 0.6 mm size to produce an ezetimibe granule.
The produced ezetimibe granule was placed in a mixer with a mixture having the composition described in the mixing part of Table 1 and was mixed for 15 minutes. Then, 4 mg of magnesium stearate was added as a glidant and was further mixed for 5 minutes. The mixed product was exposed under conditions of about 20% relative humidity at 25℃ for about 12 hours, and the resulting product was subject to a pressure of about 950 kgf with a tableting machine (Autotab-200TR, ichihashi seiki) to prepare a tablet having a hardness of about 13 kp.
Example 2: Preparation of a tablet comprising ezetimibe , rosuvastatin , and amlodipine
A tablet comprising ezetimibe, rosuvastatin, and amlodipine as active ingredients was prepared according to the composition shown in Table 1 below.
Specifically, the tablet was prepared in the same manner as in example 1, except that amlodipine besilate was added to the mixing part compared with example 1. The hardness of the tablet prepared was about 13 kp.
Example 3: Preparation of a bilayer tablet comprising ezetimibe , rosuvastatin, amlodipine , and losartan
A bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan as active ingredients was prepared according to the composition shown in Table 1 below.
Specifically, losartan potassium was placed in a mixer with lactose hydrate, microcrystalline cellulose, and crospovidone, and was mixed for 20 minutes. The mixed product was pressed under the conditions of an oil pressure of 2 MPa, a feeder speed of 5 rpm, and a roller speed of 1 rpm using a roller compressor (TF-1-A60, Freund vector) to form flakes.The formed flakes was sieved with a sieve of 0.8 mm size to produce a losartan granule.
3 mg of magnesium stearate was added to the produced losartan granules and was further mixed in a mixer for 5 minutes to prepare an upper layer mixture of the bilayer tablet. The ezetimibe granule produced in example 1 was placed in a mixer with a mixture having the composition described in the mixing part of Table 1 and was mixed for 15 minutes. 4 mg of magnesium stearate was added to the mixed product and was further mixed for 5 minutes to prepare a bottom layer mixture of the bilayer tablet. The prepared upper layer and bottom layer mixtures were exposed under the conditions of a temperature of 25℃ and a relative humidity of about 20% for about 12 hours, and were then subject to a pressure of about 1,200 kgf with a tableting machine to prepare a bilayer tablet having a hardness of about 20 kp.
Example 4: Preparation of a bilayer tablet comprising ezetimibe , rosuvastatin, amlodipine , and losartan
A bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan as active ingredients was prepared according to the composition shown in Table 1 below.
Specifically, the bilayer tablet was prepared in the same manner as in example 3, except that the ezetimibe granule was prepared in the same manner as the method of preparing the losartan granule in example 3, compared with example 3. The hardness of the prepared bilayer tablet was about 20 kp.
Example 5: Preparation of a capsule comprising ezetimibe , rosuvastatin , amlodipine, and losartan
A bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan as active ingredients was prepared according to the composition shown in Table 1 below.
Specifically, in order to fill the active ingredients into a capsule of capsule No. 0, the reduced amount of excipient in the composition of example 3 was applied. Ezetimibe granule and losartan granule were prepared in the same manner as in example 3. The prepared losartan granules and 1.5 mg of magnesium stearate were placed in a mixer and were mixed for 5 minutes. A tablet having a hardness of about 13 kp was prepared with a tableting machine. In addition, the ingredients having the composition described in the mixing part of Table 1 below were placed in a mixer and were mixed for 15 minutes. 2 mg of magnesium stearate was further placed in the mixer and was mixed for 5 minutes, and the mixed product was exposed under the condition of about 20% relative humidity for about 12 hours. A tablet having a hardness of about 7 kp was prepared with a tableting machine. The prepared two tablets were filled into a capsule of capsule No. 0 together with the ezetimibe granules to prepare a capsule.
The specific compositions of the pharmaceutical combination preparations according to examples 1 to 5 are shown in Table 1 below.
Elements Example 1 (mg) Example 2 (mg) Example 3 (mg) Example 4 (mg) Example 5 (mg)
Losartan Granule Losartan potassium - - 100.0 100.0 100.0
Microcrystalline cellulose(Avicel PH101) - - 125.0 125.0 62.5
Lactose hydrate (#200) - - 60.0 60.0 30.0
Crospovidone (XL-10) - - 15.0 15.0 7.5
Total granule mass - - 300.0 300.0 200.0
Ezetimibe Granule Ezetimibe 10.0 10.0 10.0 10.0 10.0
Microcrystalline cellulose(Avicel PH101) 90.0 90.0 90.0 90.0 44.0
Lactose hydrate (#200) 35.0 35.0 35.0 35.0 17.5
Croscarmellose sodium 15.0 15.0 15.0 15.0 7.5
Sodium lauryl sulfate 2.0 2.0 2.0 2.0 2.0
Povidone (k-30) 5.0 5.0 5.0 5.0 2.5
Purified water (70.0) - - - (50.0)
Total granule mass 157.0 157.0 157.0 157.0 83.5
Mixing Part Amlodipine besilate(as amlodipine) - 6.94(5.0) 6.94(5.0) 6.94(5.0) 6.94(5.0)
Rosuvastatin calcium(as rosuvastatin) 20.8(20.0) 20.8(20.0) 20.8(20.0) 20.8(20.0) 20.8(20.0)
Mannitol (SD200) 120.0 120.0 120.0 120.0 60.0
Lactose hydrate (supertab) 120.0 120.0 120.0 120.0 60.0
Microcrystalline cellulose (Avicel PH101) 30.0 30.0 30.0 30.0 15.0
Crospovidone (XL-10) 24.0 24.0 24.0 24.0 12.0
Final Mixing Magnesium stearate 4.0 4.0 3.0(Upper layer) 3.0(Upper layer) 1.5(Upper layer)
4.0(Bottom layer) 4.0(Bottom layer) 2.0(Bottom layer)
Total tablet mass 475.8 482.74 785.74 785.74 461.74
Example 6: Preparation of a bilayer tablet comprising ezetimibe , rosuvastatin, amlodipine , and losartan
A bilayer tablet comprising ezetimibe, rosuvastatin, and amlodipine as active ingredients was prepared according to the composition shown in Table 2 below.
Specifically, the tablet was prepared in the same manner as in example 3, except that in the ezetimibe granule, the amount of microcrystalline cellulose was adjusted to 90.5 mg and the amount of sodium lauryl sulfate was adjusted to 1.5 mg, compared with example 3. The hardness of the tablet prepared was about 20 kp.
Example 7: Preparation of a bilayer tablet comprising ezetimibe , rosuvastatin, amlodipine , and losartan
A bilayer tablet comprising ezetimibe, rosuvastatin, and amlodipine as active ingredients was prepared according to the composition shown in Table 2 below.
Specifically, the tablet was prepared in the same manner as in example 3, except that in the ezetimibe granule, the amount of microcrystalline cellulose was adjusted to 89 mg and the amount of sodium lauryl sulfate was adjusted to 3 mg, compared with example 3. The hardness of the tablet prepared was about 20 kp.
The specific compositions of the pharmaceutical combination preparations according to examples 6 and 7 are shown in Table 2 below.
Elements Example 6 (mg) Example 7 (mg)
Losartan Granule Losartan potassium 100.0 100.0
Microcrystalline cellulose(Avicel PH101) 125.0 125.0
Lactose hydrate (#200) 60.0 60.0
Crospovidone (XL-10) 15.0 15.0
Total granule mass 300.0 300.0
Ezetimibe Granule Ezetimibe 10.0 10.0
Microcrystalline cellulose(Avicel PH101) 90.5 89.0
Lactose hydrate (#200) 35.0 35.0
Croscarmellose sodium 15.0 15.0
Sodium lauryl sulfate 1.5 3.0
Povidone (k-30) 5.0 5.0
Purified water (70.0) -
Total granule mass 157.0 157.0
Mixing Part Amlodipine besilate(as amlodipine) 6.94(5.0) 6.94(5.0)
Rosuvastatin calcium(as rosuvastatin) 20.8(20.0) 20.8(20.0)
Mannitol (SD200) 120.0 120.0
Lactose hydrate (supertab) 120.0 120.0
Microcrystalline cellulose (Avicel PH101) 30.0 30.0
Crospovidone (XL-10) 24.0 24.0
Final Mixing Magnesium stearate 3.0(Upper layer) 3.0(Upper layer)
4.0(Bottom layer) 4.0(Bottom layer)
Total tablet mass 785.74 785.74
Example 8: Preparation of a tablet comprising ezetimibe and rosuvastatin, with high water activity
The product after the final mixing obtained from example 1 was exposed under condition of about 20% relative humidity for 8 hours, and was then subject to a pressure of about 1,200 kgf with a tableting machine to prepare a tablet having a hardness of about 20 kp.
Example 9: Preparation of a tablet comprising ezetimibe , rosuvastatin , and amlodipine , with high water activity
The product after the final mixing obtained from example 2 was exposed under condition of about 20% relative humidity for 8 hours, and was then subject to a pressure of about 950 kgf with a tableting machine to prepare a tablet having a hardness of about 13 kp.
Example 10: Preparation of a bilayer tablet comprising ezetimibe , rosuvastatin, amlodipine , and losartan , with high water activity
The product after the final mixing obtained from example 3 was exposed under condition of about 20% relative humidity for 8 hours, and was then subject to a pressure of about 950 kgf with a tableting machine to prepare a tablet having a hardness of about 13 kp.
Comparative Examples 1: Preparation of a tablet comprising ezetimibe and rosuvastatin , with high water activity
The product after the final mixing obtained from example 1 was exposed under condition of about 20% relative humidity for 4 hours, and was then subject to a pressure of about 1,200 kgf with a tableting machine to prepare a tablet having a hardness of about 20 kp.
Comparative Examples 2: Preparation of a tablet comprising ezetimibe and rosuvastatin , with high water activity
The product after the final mixing obtained from example 1 was subject to a pressure of about 1,200 kgf with a tableting machine to prepare a tablet having a hardness of about 20 kp.
Comparative Examples 3: Preparation of a tablet comprising ezetimibe , rosuvastatin, and amlodipine , with high water activity
The product after the final mixing obtained from example 2 was exposed under condition of about 20% relative humidity for 4 hours, and was then subject to a pressure of about 950 kgf with a tableting machine to prepare a tablet having a hardness of about 13 kp.
Comparative Examples 4: Preparation of a tablet comprising ezetimibe , rosuvastatin, and amlodipine , with high water activity
The product after the final mixing obtained from example 2 was subject to a pressure of about 950 kgf with a tableting machine to prepare a tablet having a hardness of about 13 kp.
Comparative Examples 5: Preparation of a bilayer tablet comprising ezetimibe, rosuvastatin , amlodipine , and losartan , with high water activity
The product after the final mixing obtained from example 3 was exposed under condition of about 20% relative humidity for 4 hours, and was then subject to a pressure of about 950 kgf with a tableting machine to prepare a tablet having a hardness of about 13 kp.
Comparative Examples 6: Preparation of a bilayer tablet comprising ezetimibe, rosuvastatin , amlodipine , and losartan , with high water activity
The product after the final mixing obtained from example 3 was subject to a pressure of about 950 kgf with a tableting machine to prepare a tablet having a hardness of about 13 kp.
Comparative Examples 7: Preparation of a single layer tablet comprising ezetimibe, rosuvastatin , amlodipine , and losartan
After producing the ezetimibe granule and losartan granule as in example 3, the prepared ezetimibe granule and losartan granule were mixed for 15 minutes in a mixer with the mixture having the composition described in the mixing part of example 3 in Table 1 above. 7 mg of magnesium stearate was further added and mixed for 5 minutes, and then a tablet having a hardness of about 20 kp was prepared with a tableting machine.
Comparative Examples 8: Preparation of a bilayer tablet comprising ezetimibe, rosuvastatin , amlodipine , and losartan
After producing the ezetimibe granule and losartan granule as in example 3, the prepared ezetimibe granule and losartan granule were mixed for 15 minutes in a mixer. 3 mg of magnesium stearate was added and further mixed in a mixer for 5 minutes to prepare an upper layer mixture of the bilayer tablet. 4 mg of magnesium stearate was added to the mixture having the composition described in the mixing part of example 3 in Table 1 above, and was further mixed in a mixer for 5 minutes to prepare a bottom layer mixture of a bilayer tablet. The prepared upper layer and bottom layer mixtures were subject to a pressure of about 1,200 kgf with a tableting machine to prepare a bilayer tablet having a hardness of about 20 kp.
Comparative Examples 9: Preparation of a bilayer tablet comprising ezetimibe, rosuvastatin , amlodipine , and losartan
A bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan was prepared according to the composition shown in Table 3 below.
Specifically, the bilayer tablet was prepared in the same manner as in example 3, except that amlodipine besilate and rosuvastatin calcium were added not to the mixing part but to the ezetimibe granule, compared with example 3. The hardness of the prepared bilayer tablet was about 20 kp.
Comparative Examples 10: Preparation of a bilayer tablet comprising ezetimibe, rosuvastatin , amlodipine , and losartan
A bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan was prepared according to the composition shown in Table 3 below.
Specifically, the bilayer tablet was prepared in the same manner as in example 3, except that amlodipine besilate was added not to the mixing part but to the ezetimibe granule, compared with example 3. The hardness of the prepared bilayer tablet was about 20 kp.
Comparative Examples 11: Preparation of a bilayer tablet comprising ezetimibe, rosuvastatin , amlodipine , and losartan
A bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan was prepared according to the composition shown in Table 3 below.
Specifically, the bilayer tablet was prepared in the same manner as in example 3, except that rosuvastatin calcium were added not to the mixing part but to the ezetimibe granule, compared with example 3. The hardness of the prepared bilayer tablet was about 20 kp.
The specific compositions of the pharmaceutical combination preparations according to comparative examples 9 and 11 are shown in Table 3 below.
Elements Comparative Example 9 (mg) Comparative Example 10 (mg) Comparative Example 11 (mg)
Losartan Granule Losartan potassium 100.0 100.0 100.0
Microcrystalline cellulose(Avicel PH101) 125.0 125.0 125.0
Lactose hydrate (#200) 60.0 60.0 60.0
Crospovidone (XL-10) 15.0 15.0 15.0
Total granule mass 300.0 300.0 300.0
Ezetimibe Granule Ezetimibe 10.0 10.0 10.0
Amlodipine besilate(as amlodipine) 6.94(5.0) 6.94(5.0) -
Rosuvastatin calcium (as rosuvastatin) 20.8(20.0) - 20.8(20.0)
Microcrystalline cellulose (Avicel PH101) 90.0 90.0 90.0
Lactose hydrate (#200) 35.0 35.0 35.0
Croscarmellose sodium 15.0 15.0 15.0
Sodium lauryl sulfate 2.0 2.0 2.0
Povidone (k-30) 5.0 5.0 5.0
Purified water (70.0) - -
Total granule mass 184.74 163.94 177.8
Mixing Part Amlodipine besilate(as amlodipine) - - 6.94(5.0)
Rosuvastatin calcium(as rosuvastatin) - 20.8(20.0) -
Mannitol (SD200) 120.0 120.0 120.0
Lactose hydrate (supertab) 120.0 120.0 120.0
Microcrystalline cellulose (Avicel PH101) 30.0 30.0 30.0
Crospovidone (XL-10) 24.0 24.0 24.0
Final Mixing Magnesium stearate 3.0(Upper layer) 3.0(Upper layer) 3.0(Upper layer)
4.0(Bottom layer) 4.0(Bottom layer) 4.0(Bottom layer)
Total tablet mass 785.74 785.74 785.74
Comparative Examples 12: Preparation of a bilayer tablet comprising ezetimibe, rosuvastatin , amlodipine , and losartan
A bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan was prepared according to the composition shown in Table 4 below.
Specifically, the tablet was prepared in the same manner as in example 3, except that in the ezetimibe granule, the amount of microcrystalline cellulose was adjusted to 92.0 mg and the amount of sodium lauryl sulfate was adjusted to 0 mg, compared with example 3. The hardness of the tablet prepared was about 20 kp.
Comparative Examples 13: Preparation of a bilayer tablet comprising ezetimibe, rosuvastatin , amlodipine , and losartan
A bilayer tablet comprising ezetimibe, rosuvastatin, amlodipine, and losartan was prepared according to the composition shown in Table 4 below.
Specifically, the tablet was prepared in the same manner as in example 3, except that in the ezetimibe granule, the amount of microcrystalline cellulose was adjusted to 91.0 mg and the amount of sodium lauryl sulfate was adjusted to 1.0 mg, compared with example 3. The hardness of the tablet prepared was about 20 kp.
The specific compositions of the pharmaceutical combination preparations according to comparative examples 12 and 13 are shown in Table 4 below.
Elements Comparative Examples 12 (mg) Comparative Examples 13 (mg)
Losartan Granule Losartan potassium 100.0 100.0
Microcrystalline cellulose(Avicel PH101) 125.0 125.0
Lactose hydrate (#200) 60.0 60.0
Crospovidone (XL-10) 15.0 15.0
Total granule mass 300.0 300.0
Ezetimibe Granule Ezetimibe 10.0 10.0
Microcrystalline cellulose(Avicel PH101) 92.0 91.0
Lactose hydrate (#200) 35.0 35.0
Croscarmellose sodium 15.0 15.0
Sodium lauryl sulfate 0.0 1.0
Povidone (k-30) 5.0 5.0
Purified water (70.0) -
Total granule mass 157.0 157.0
Mixing Part Amlodipine besilate(as amlodipine) 6.94(5.0) 6.94(5.0)
Rosuvastatin calcium(as rosuvastatin) 20.8(20.0) 20.8(20.0)
Mannitol (SD200) 120.0 120.0
Lactose hydrate (supertab) 120.0 120.0
Microcrystalline cellulose (Avicel PH101) 30.0 30.0
Crospovidone (XL-10) 24.0 24.0
Final Mixing Magnesium stearate 3.0(Upper layer) 3.0(Upper layer)
4.0(Bottom layer) 4.0(Bottom layer)
Total tablet mass 785.74 785.74
Comparative Examples 14: Control drug I
Norvasc Tab. comprising amlodipine besilate salt was used as a control drug.
Comparative Examples 15: Control drug II
Cozaar Tab. comprising losartan potassium was used as a control drug.
Comparative Examples 16: Control drug III
Crestor Tab. comprising rosuvastatin calcium was used as a control drug.
Comparative Examples 17: Control drug IV
Exetrol Tab. comprising ezetimibe was used as a control drug.
TEST EXAMPLES
Test Example 1: Measurement of the moisture content of examples 1 to 3 and 8 to 10 and comparative examples 1 to 6
The moisture content of the tablets obtained from examples 1 to 3 and 8 to 10 and comparative examples 1 to 6 was measured using a moisture content meter (MA45, sartorius). The results are shown in Table 5 below.
Sample Moisture Content (%) Sample Moisture Content (%) Sample Moisture Content (%)
Example 1 2.81 Example 2 2.63 Example 3 2.94
Example 8 3.19 Example 9 2.63 Example 10 3.16
Comparative Example 1 2.84 Comparative Example 3 2.76 Comparative Example 5 3.06
Comparative Example 2 3.26 Comparative Example 4 2.94 Comparative Example 6 2.92
In Table 5 above, comparative examples 2, 4, and 6 were not left under the condition of about 20% relative humidity. Under the same condition, comparative examples 1, 3, and 5 were left for 4 hours each, examples 8 to 10 were left for 8 hours each, and examples 1 to 3 were left for 12 hours each. According to Table 5 above, it can be confirmed that the moisture content is 2.76% to 3.06% at 4 hours exposure, 2.63% to 3.19% at 8 hours exposure, and 2.63% to 2.94% at 12 hours exposure.
As a result, when the products after the final mixing were left under the condition of about 20% relative humidity, the moisture content of the tablets was not significantly affected by the standing time.
Test Example 2: Measurement of the water activity of examples 1 to 3 and 8 to 10 and comparative examples 1 to 6
Water activity of the tablets obtained from examples 1 to 3 and 8 to 10 and comparative examples 1 to 6 was measured using a water activity meter (Labmaster, novasina). Specifically, four tablets were pulverized into particles having a size smaller than size No. 20 at 25℃ and placed in a cylindrical container having a diameter of 4 cm and a height of 13 mm. Then, the change in value was observed using a water activity meter. The values measured when the change in value stays at the level of ± 0.001 for about 1 minute are shown in Table 6 below.
Sample Water Activity Sample Water Activity Sample Water Activity
Example 1 0.196 Example 2 0.204 Example 3 0.208
Example 8 0.338 Example 9 0.341 Example 10 0.349
Comparative Example 1 0.419 Comparative Example 3 0.411 Comparative Example 5 0.428
Comparative Example 2 0.471 Comparative Example 4 0.472 Comparative Example 6 0.481
In Table 6 above, comparative examples 2, 4, and 6 were not left under the condition of about 20% relative humidity. Under the same condition, comparative examples 1, 3, and 5 were left for 4 hours each, examples 8 to 10 were left for 8 hours each, and examples 1 to 3 were left for 12 hours each. According to Table 6 above, it can be confirmed that water activity is 0.411 to 0.428 at 4 hours exposure, 0.338 to 0.349 at 8 hours exposure, and 0.196 to 0.208 at 12 hours exposure.
As a result, when the products after the final mixing were left under the condition of about 20% relative humidity, the water activity of the tablets decreased as a standing time increased.
Test Example 3: Measurement of the density of examples 1, 2, 8, and 9 and comparative examples 1 to 4
To compare the granular properties of each products immediately prior to tableting according to the water activity, the bulk densities (g/ml) and tapped densities (g/ml) measured for the products obtained immediately prior to tableting in examples 1, 2, 8, and 9 and comparative examples 1 to 4 are shown in Fig. 1. Wherein, the bulk density was calculated by measuring the granular mass of about 5 to 10 g, carefully placing the granules into a 50 mL measuring cylinder, and measuring the bulk volume. In addition, the tap density was calculated by measuring the volume of the granules in a compact state by tapping the measuring cylinder 100 times.
The evaluation of the granular properties in test example 3 is conducted for the purpose of confirming whether a specific issue occurs during the production of the semi-finished product (granule or final mixture) to be produced in the process, not after the completion of the production of the preparation in the pharmaceutical field. According to Fig. 1, when the products were left under the condition of about 50% relative humidity, the density of the products was not significantly affected by the standing time. In other words, it can be confirmed that the change in water activity during the production process is difficult to confirm by the density measurement method.
Test Example 4: Measurement of the hardness of examples 1 to 3 and 8 to 10 and comparative examples 1 to 6
To compare the tabletability of the granules according to the water activity, the hardness of the products obtained immediately prior to tableting in examples 1 to 3 and 8 to 10 and comparative examples 1 to 6 measured according to the tableting pressure with a hardness tester (TBH 425, Erweka) is shown in Fig. 2.
The tabletability evaluation of test example 4 is conducted for the purpose of confirming whether a specific issue occurs during the production of the tablets. According to Fig. 2, when the products were left to stand under the condition of about 50% relative humidity and then tableted, the hardness of the tablets was not significantly affected by the standing time. In other words, it can be confirmed that the change in water activity during the production process is difficult to confirm by the hardness measurement method.
Test Example 5: Measurement of impurities of examples 1 to 3 and 8 to 10 and comparative examples 1 to 6
The tablets obtained from examples 1 to 3 and 8 to 10 and comparative examples 1 to 6 were packed in HDPE bottles, respectively, and stored for 5 days and 10 days under the severe condition of 60℃. Then, impurities were analyzed under the following analytical conditions and the results of rosuvastatin EP impurity D are shown in Table 7 below.
- Analytical Conditions -
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 25 cm was packed with 3 μm of an octadecyl silylated silica gel for liquid chromatography.
Mobile phase: * 7 mM sodium hexanesulfonate/0.05%(v/v) phosphoric acid : acetonitrile (66:34, v/v)
(* 7 mM sodium hexanesulfonate/0.05%(v/v) phosphoric acid: Take 1.45 g of sodium hexanesulfonate (sodium 1-hexanesulfonate monohydrate) into a 1 L flask and carefully add 0.5 mL of phosphoric acid. Add purified water to dissolve, dilute and mix well.)
Detector: Ultraviolet-visible absorption spectrophotometer (measurement wavelength 239 nm)
Flow rate: 1.0 mL/min
Injection volume: 10 μL
Column temperature: 40℃
Sample Water Activity Initial Severe 5 days Severe 10 days
Example 1 0.196 0.02 0.12 0.19
Example 8 0.338 0.02 0.24 0.38
Comparative Example 1 0.419 0.02 0.36 0.64
Comparative Example 2 0.471 0.02 0.47 0.80
Example 2 0.204 0.02 0.13 0.20
Example 9 0.341 0.02 0.24 0.39
Comparative Example 3 0.411 0.02 0.37 0.62
Comparative Example 4 0.472 0.02 0.47 0.80
Example 3 0.208 0.02 0.13 0.20
Example 10 0.349 0.02 0.25 0.40
Comparative Example 5 0.428 0.02 0.38 0.65
Comparative Example 6 0.481 0.02 0.48 0.82
When the tablets obtained from examples 1 to 3 and 8 to 10 and comparative examples 1 to 6 were each stored under severe conditions, impurities resulting from amlodipine, losartan, and ezetimibe were confirmed to be less than LOQ (0.1%) at all time points. Among impurities resulting from rosuvastatin, all the remaining impurities other than EP impurity D also showed a similar pattern regardless of the types of the examples and the comparative examples. On the other hand, EP impurity D, which is an impurity resulting from rosuvastatin, exhibited an increase in the impurity as the water activity increased. Considering that the criterion of impurities according to the ICH guideline is 0.5%, comparative examples 1, 3 and 5, with a water activity of about 0.41 to 0.43, were confirmed to exceed the criterion on 10th day, and comparative examples 2, 4 and 6, with a water activity of about 0.47 to 0.48, were confirmed to have the results approximating the criterion on the severe 5th day.
In order to determine the correlation between the water activity and impurity D, the results of examples 3 and 10 and comparative examples 5 and 6 in Table 7 above are shown in FIG. 3. From Fig. 3, it was confirmed that the amount of impurity D increases with a steep slope under severe conditions as the tablet has a high water activity.
Test Example 6: Dissolution test of examples 3 to 5 and comparative examples 7, 8, and 14 to 16 ( amlodipine , losartan , rosuvastatin )
For the tablets produced in examples 3 to 5 and comparative examples 7 and 8, and the control drugs of comparative examples 14 (control drug for amlodipine), 15 (control drug for losartan), and 16 (control drug for rosuvastatin), the dissolution rates of amlodipine, losartan, and rosuvastatin over time were evaluated under the following dissolution conditions and analytical conditions and the results are shown in Figs. 4 to 6.
- Dissolution Conditions -
Dissolution solution: pH 6.8, 900 mL
Apparatus: USP paddle method, 50 rpm
Temperature: 37±0.5℃
- Analytical Conditions -
Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 25 cm was packed with 3 μm of an octadecyl silylated silica gel for liquid chromatography.
Mobile phase: * 9 mM sodium hexanesulfonate/0.05%(v/v) phosphoric acid : acetonitrile (52:48, v/v)
(* 9 mM sodium hexanesulfonate/0.13%(v/v) phosphoric acid: Take 1.86 g of sodium hexanesulfonate (sodium 1-hexanesulfonate monohydrate) into a 1 L flask and carefully add 1.3 mL of phosphoric acid. Add purified water to dissolve, dilute and mix well.)
Detector: Ultraviolet-visible absorption spectrophotometer (measurement wavelength 254 nm)
Flow rate : 1.3 mL/min
Injection volume: 10 μL
Column temperature: 45℃
According to Figs. 4 to 6, amlodipine and rosuvastatin of examples 3 to 5 and comparative example 8 were confirmed to have different dissolution rates from losartan. However, the amlodipine and rosuvastatin of comparative example 7 in which all ingredients were mixed showed a slow dissolution profile in a pattern similar to losartan due to the effect of losartan, which was also significantly different from the dissolution profile of the control drugs for each ingredients (comparative examples 14 and 16).
Test Example 7: Dissolution test of examples 3 to 7 and comparative examples 7, 8, 12, 13, and 17 ( ezetimibe )
Since ezetimibe was a poorly soluble drug and showed a dissolution rate of about 10% or less, dissolution of ezetimibe was confirmed by dissolution conditions different from those of test example 6.
For the tablets produced in examples 3 to 7 and comparative examples 7, 8, 12, and 13, and the control drugs of comparative example 17 (control drug for ezetimibe), the dissolution rate of ezetimibe over time was evaluated under the following dissolution conditions and the analytical conditions of test example 6, and the results are shown in Figs. 7 and 8.
- Dissolution Conditions -
Dissolution solution: 0.1% polysorbate 80, 900 mL
Apparatus: USP paddle method, 75rpm
Temperature: 37±0.5℃
As shown in test example 6, the dissolution patterns of ezetimibe according to the presence or absence of losartan were compared based on the results shown in Fig. 7. Ezetimibe of examples 3 to 7 were confirmed to have different dissolution patterns from losartan. However, ezetimibe of comparative example 7 in which all ingredients were mixed, and ezetimibe of comparative example 8 in which losartan was mixed, showed a slow dissolution profile in a pattern similar to losartan due to the effect of losartan, which was also significantly different from the dissolution profile of the control drug (comparative example 17).
As a result of test examples 6 and 7, it was confirmed that amlodipine, rosuvastatin, and ezetimibe should be present in a physically separated state from losartan in the development of a pharmaceutical combination preparation comprising amlodipine, losartan, rosuvastatin, and ezetimibe.
As a result of dissolution test of ezetimibe according to the amount of sodium lauryl sulfate widely used as a solubiliser, ezetimibe was confirmed to show a dissolution profile similar to comparative example 17, which is a control drug, when the amount of sodium lauryl sulfate was 1.5 to 3 mg. It is judged that the amount of sodium lauryl sulfate as a solubiliser is required to be more than a certain amount for the dissolution rate of the poorly soluble drug ezetimibe.
Test Example 8: Measurement of impurities of examples 3 to 5 and comparative examples 7 to 11
The tablets obtained from examples 3 to 5 and comparative examples 7 to 11 were packed in HDPE bottles, respectively, and stored for 5 days and 10 days under the severe condition of 60℃. Then, impurities were analyzed under the analytical conditions of test example 5 and the results are shown in Tables 8 to 11 below.
Amlodipine Impurity II Example 3 Example 4 Example 5 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11
Initial ND ND ND ND ND ND ND ND
Severe 5 days ND ND ND 0.07 ND 0.07 0.06 ND
Severe 10 days ND ND ND 0.18 ND 0.16 0.14 ND
Losartan Total Impurities Example 3 Example 4 Example 5 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11
Initial ND ND ND ND ND ND ND ND
Severe 5 days ND ND ND ND 0.05 ND ND ND
Severe 10 days ND ND ND 0.08 0.16 ND ND ND
Rosuvastatin Impurity D Example 3 Example 4 Example 5 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11
Initial ND ND ND ND ND ND ND ND
Severe 5 days 0.13 0.11 0.12 0.16 0.13 0.61 0.13 0.45
Severe 10 days 0.20 0.17 0.16 0.28 0.20 1.64 0.20 1.34
Ezetimibe Total Impurities Example 3 Example 4 Example 5 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11
Initial ND ND ND ND ND ND ND ND
Severe 5 days ND ND ND 0.21 0.17 ND ND ND
Severe 10 days ND ND ND 0.34 0.27 ND ND ND
In the case of amlodipine and rosuvastatin, the most commonly produced known impurities were compared. In the case of losartan and ezetimibe, since unknown peaks were generated, total impurities were compared.
In the case of amlodipine, comparative example 7, which was prepared by mixing all four ingredients together, and comparative examples 9 to 10, which were prepared by granulating together with ezetimibe, were poor in stability. In the case of amlodipine, since it is expected to react with ezetimibe, they require separate preparation to ensure stability.
In the case of losartan, comparative example 7, which was prepared by mixing all four ingredients together, and comparative example 8, which was prepared by granulating together with ezetimibe, were poor in stability. Since losartan is also expected to react with ezetimibe, they require separate preparation to ensure stability.
In the case of rosuvastatin, an increase in impurities was confirmed in comparative examples 7, 9, and 11. Especially, in comparative examples 9 and 11, which were prepared by granulating together with ezetimibe, the increase in impurities was significant. Since rosuvastatin is also expected to react with ezetimibe, they require separate preparation to ensure stability.
In the case of ezetimibe, an increase in impurities was confirmed in comparative examples 7 and 8, and it requires separate preparation from losartan to ensure stability.
Taking all the above results into consideration, to ensure stability, ezetimibe needs to be present in a physically separated state from amlodipine, losartan, and rosuvastatin.
It should be appreciated that all the simple modifications and variations of the present invention are within the scope of the present invention, and the specific scope of the present invention to be protected will be defined by the appended claims.

Claims (15)

  1. A pharmaceutical combination preparation comprising ezetimibe or a pharmaceutically acceptable salt thereof, and rosuvastatin or a pharmaceutically acceptable salt thereof,
    wherein water activity is 0.40 or less.
  2. The pharmaceutical combination preparation according to claim 1,
    wherein the ezetimibe or a pharmaceutically acceptable salt thereof is present in a physically separated state from the rosuvastatin or a pharmaceutically acceptable salt thereof.
  3. The pharmaceutical combination preparation according to claim 2,
    wherein the ezetimibe or a pharmaceutically acceptable salt thereof is present in admixture with the rosuvastatin or a pharmaceutically acceptable salt thereof in granular form.
  4. The pharmaceutical combination preparation according to claim 3,
    wherein the granule comprising the ezetimibe or a pharmaceutically acceptable salt thereof further comprises a solubilizer.
  5. The pharmaceutical combination preparation according to claim 4,
    wherein the solubilizer is sodium lauryl sulfate.
  6. The pharmaceutical combination preparation according to claim 5,
    wherein the weight ratio of sodium lauryl sulfate to ezetimibe in the granule comprising the ezetimibe or a pharmaceutically acceptable salt thereof is 0.15:1 to 0.3:1.
  7. The pharmaceutical combination preparation according to claim 1,
    wherein the pharmaceutical combination preparation further comprises one or more ingredients selected from the group consisting of amlodipine or a pharmaceutically acceptable salt thereof, losartan or a pharmaceutically acceptable salt thereof, and combinations thereof.
  8. The pharmaceutical combination preparation according to claim 7,
    wherein the ezetimibe or a pharmaceutically acceptable salt thereof is present in a physically separated state from the rosuvastatin or a pharmaceutically acceptable salt thereof, the amlodipine or a pharmaceutically acceptable salt thereof, and the losartan or a pharmaceutically acceptable salt thereof, respectively.
  9. The pharmaceutical combination preparation according to claim 8,
    wherein the pharmaceutical combination preparation is present in the form of a bilayer tablet consisting of:
    a first layer comprising the ezetimibe or a pharmaceutically acceptable salt thereof, the rosuvastatin or a pharmaceutically acceptable salt thereof, and the amlodipine or a pharmaceutically acceptable salt thereof; and
    a second layer comprising the losartan or a pharmaceutically acceptable salt thereof.
  10. The pharmaceutical combination preparation according to claim 9,
    wherein the ezetimibe or a pharmaceutically acceptable salt thereof in the first layer is present in admixture with the rosuvastatin or a pharmaceutically acceptable salt thereof, and the amlodipine or a pharmaceutically acceptable salt thereof in granular form.
  11. The pharmaceutical combination preparation according to claim 9,
    wherein the losartan or a pharmaceutically acceptable salt thereof in the second layer is present in granular form.
  12. A method of preparing the pharmaceutical combination preparation according to claim 1, comprising the steps of:
    i) producing an ezetimibe granule comprising ezetimibe or a pharmaceutically acceptable salt thereof;
    ii) mixing the ezetimibe granule with rosuvastatin or a pharmaceutically acceptable salt thereof to producing a mixture;
    iii) allowing the mixture to stand under conditions of 15 to 25% relative humidity to reduce water activity to 0.40 or less; and
    iv) tableting the mixture with reduced water activity.
  13. The method of preparing the pharmaceutical combination according to claim 12,
    wherein the rosuvastatin or a pharmaceutically acceptable salt thereof in step ii) is mixed with the ezetimibe granule, together with amlodipine or a pharmaceutically acceptable salt thereof.
  14. The method of preparing the pharmaceutical combination according to claim 12,
    wherein step iv) comprises being tableted into a bilayer tablet consisting of the mixture with reduced water activity as a first layer and a losartan granule with reduced water activity as a second layer.
  15. The method of preparing the pharmaceutical combination according to claim 14,
    wherein the losartan granule with reduced water activity is prepared by the steps of:
    a) producing a losartan granule comprising losartan or a pharmaceutically acceptable salt thereof; and
    b) allowing the produced losartan granule to stand under conditions of 15 to 25% relative humidity to reduce water activity to 0.40 or less.
PCT/KR2019/002769 2018-03-19 2019-03-11 Pharmaceutical combination preparation comprising ezetimibe and rosuvastatin WO2019182276A1 (en)

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MX2020009492A MX2020009492A (en) 2018-03-19 2019-03-11 Pharmaceutical combination preparation comprising ezetimibe and rosuvastatin.
EA202092189A EA202092189A1 (en) 2018-03-19 2019-03-11 PHARMACEUTICAL COMBINED PREPARATION CONTAINING EZETIMIB AND ROSUVASTATIN
CN201980020077.6A CN111886003A (en) 2018-03-19 2019-03-11 Pharmaceutical combination formulation containing ezetimibe and rosuvastatin
ZA2020/04982A ZA202004982B (en) 2018-03-19 2020-08-12 Pharmaceutical combination preparation comprising ezetimibe and rosuvastatin
CONC2020/0010204A CO2020010204A2 (en) 2018-03-19 2020-08-19 Preparation of a pharmaceutical combination comprising ezetimibe and rosuvastatin
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GB2622822A (en) * 2022-09-28 2024-04-03 Novumgen Ltd A rapidly disintegrating tablet of rosuvastatin and its process of preparation

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