WO2013157840A1 - Composition composite présentant une stabilité améliorée et contenant de l'amlodipine et du rozaltan - Google Patents

Composition composite présentant une stabilité améliorée et contenant de l'amlodipine et du rozaltan Download PDF

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WO2013157840A1
WO2013157840A1 PCT/KR2013/003231 KR2013003231W WO2013157840A1 WO 2013157840 A1 WO2013157840 A1 WO 2013157840A1 KR 2013003231 W KR2013003231 W KR 2013003231W WO 2013157840 A1 WO2013157840 A1 WO 2013157840A1
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amlodipine
content
composition
pharmaceutically acceptable
acceptable salt
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PCT/KR2013/003231
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English (en)
Korean (ko)
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이범진
정원태
최연웅
남규열
조상민
박진하
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한국유나이티드제약 주식회사
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Priority to BR112014025956-9A priority Critical patent/BR112014025956B1/pt
Priority to CN201380025567.8A priority patent/CN104394865B/zh
Priority to RU2014145827A priority patent/RU2628538C2/ru
Publication of WO2013157840A1 publication Critical patent/WO2013157840A1/fr
Priority to PH12014502326A priority patent/PH12014502326A1/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
    • A61K31/435—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
    • 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
    • A61K31/41—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
    • 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
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a combination composition containing amlodipine and rozatan with improved stability by including an antioxidant.
  • Drugs commonly used in the treatment of hypertension are divided into diuretics, sympathetic inhibitors, and vasodilators, depending on the mechanism of action of the drug.
  • Vasodilators which are widely used, are again used according to the mechanism of action.
  • Angiotensin II angiotensin II Angiotensin II receptor blocker (ARB) and calcium channel blocker.
  • ARB Angiotensin II receptor blocker
  • Amlodipine is a dihydropyridine calcium channel blocker and is a representative drug used in the treatment of hypertension or angina. Absorption of the drug relaxes the smooth muscle in the artery wall, thereby lowering blood pressure and increasing blood flow to the myocardium.
  • Amlodipine is commercially available in the form of various salts such as besylic acid, maleic acid, and camsylic acid, and amlodipine besylate is the most widely used.
  • Rosaltan is one of the earliest developed drugs in the Angiotensin II receptor blocker (ARB) family of hypertension drugs, and angiotensin II blocks the binding of the receptor.
  • ARB Angiotensin II receptor blocker
  • Amlodipine, a calcium channel blocker, and Rosaltan, an ARB have different mechanisms and could be effective in treating hypertension when two drugs are taken simultaneously.
  • the stability of such formulations is greatly degraded under accelerated conditions when a complex preparation is prepared by simply mixing amlodipine and rozatan.
  • Amlodipine formulations are generally made by combining amlodipine, an active ingredient, with salts that aid in the activation and formulation of the drug.
  • the salt is a part which helps stabilize the amlodipine, which is an active ingredient, and the amlodipine is useful in the free base form, but is preferably administered in the form of a salt with a pharmaceutically acceptable acid because of its low solubility in water.
  • a combination with another drug that can produce a synergistic effect is widely used, such as a combination of amlodipine besylate and atorvastatin calcium (US Pat. No.
  • amlodipine besylate and A combination formulation of valsartan (US Pat. No. 6,395,728) and a combination formulation of amlodipine camsylate and simvastatin (Korean Patent Registration No. 742432) are disclosed.
  • Amlodipine is an unstable free base that is greatly affected by light, heat and moisture, and thus has a disadvantage in that its therapeutic effect is poor.
  • amlodipine is marketed in combination with various acid addition salts described above, Its stability is maintained. However, there is still little achievement in achieving pharmaceutical stability.
  • Rosaltan is commonly used in the form of potassium salt and generally maintains a stable state, but has a disadvantage in that a decomposition product polymer is formed when heat is applied under acidic conditions. In other words. If it is made of a combination, the addition of amlodipine acid salts reduce the stability of Rosaltan.
  • the present invention minimizes the physical bonding of amlodipine and rozatan, and adds an antioxidant to maintain the stability of amlodipine and at the same time the formulation process is simplified, improved stability of amlodipine and rozatan It is an object to provide a composite composition containing.
  • the present invention provides a combination composition for the prevention and treatment of cardiovascular diseases, including amlodipine or a pharmaceutically acceptable salt thereof, rozatan or a pharmaceutically acceptable salt thereof and propyl gallate.
  • the combination composition for the prevention and treatment of cardiovascular diseases containing amlodipine and rozatan of the present invention minimizes physical binding of amlodipine and rozatan, and has excellent stability by containing propyl gallate, and has a simplified preparation process.
  • Fig. 2 is a graph showing the results of the dissolution test of lozatan for the composite agents of Examples 8 to 17.
  • the present invention relates to a pharmaceutical composition for the prevention and treatment of cardiovascular diseases, including amlodipine or a pharmaceutically acceptable salt thereof, rozatan or a pharmaceutically acceptable salt thereof and propyl gallate.
  • the propyl gallate (propyl gallate, C 10 H 12 O 5 ) is an antioxidant, a product having a high stability by increasing the stability of the active ingredient when the combination of rozatan and amlodipine is molded and mixed with other pharmaceutically acceptable additives It not only makes it possible to produce but also reduces the deformation of the active ingredient by temperature and moisture, thereby increasing the stability against changes over time. Propyl gallic acid is safe enough to show no toxicity compared to other antioxidants.
  • the combination composition may be prepared in the form of nucleated tablets, capsules, double tablets, multi-layered tablets, single tablets, but in the present invention, amlodipine or a pharmaceutically acceptable salt thereof and lozatan or a pharmaceutically acceptable salt thereof are physically separated from It is desirable to prepare a composite formulation with the greatest reduction in contact surface area, more preferably separated into an amlodipine layer comprising said amlodipine or a pharmaceutically acceptable salt thereof and a rozatantan layer comprising lozatan or a pharmaceutically acceptable salt thereof. It is preferable that it is a double tablet which comprises the double layer structure which is a state.
  • the method of manufacturing the double layer may be prepared by tableting using a tableting machine after forming a lower layer of potassium and a mixture of rosaltane and a mixture thereof, and then forming an upper layer of amlodipine and mixtures thereof, but is not limited thereto.
  • the propyl gallate is preferably included in the amlodipine layer comprising amlodipine or a pharmaceutically acceptable salt thereof.
  • the propyl gallate is preferably included in an amount of 0.001 to 1% by weight, more preferably 0.001 to 0.5% by weight, and most preferably 0.001 to 0.1% by weight based on the total weight of the composition.
  • propyl gallate is included in the above range, the stability of the active ingredient is increased to have high stability.
  • the total weight of the combination composition of the present invention preferably comprises 1 to 6% by weight of the amlodipine or a pharmaceutically acceptable salt thereof and 5 to 30% by weight of the rozatan or its pharmaceutically acceptable salt, more
  • amlodipine or a pharmaceutically acceptable salt thereof may be included in an amount of 1.2 to 3.5% by weight and lozatan or a pharmaceutically acceptable salt thereof in an amount of 10 to 20% by weight.
  • Amlodipine is preferably included in 3 to 12 mg of the combination, more preferably 5 to 10 mg, rozatan is preferably included in 30 to 120 mg of the combination, more preferably 50 to 100 mg May be included.
  • the pharmaceutically acceptable salt of amlodipine is formed from an acid which forms a nontoxic acid addition salt containing a pharmaceutically acceptable anion, for example hydrochloride, hydrobromide, sulfate, phosphate, acetate, malate, puma Latex, lactate, tartrate, citrate, gluconate, besylate and camsylate and the like, but most preferably the pharmaceutically acceptable salt of amlodipine is amlodipine besylate and the pharmaceutically acceptable salt of lozatan
  • the salt is preferably potassium salzatan.
  • the pharmaceutical composition of the present invention comprises an amlodipine layer comprising amlodipine besylate, microcrystalline cellulose, D-mannitol, starch glyconate, sodium povidone, magnesium stearate and propyl gallate, and potassium potassium, microcrystalline cellulose, crospovidone and magnesium stearate It is most preferably made of a Rosaltan layer, but is not limited thereto.
  • the pharmaceutical composition of the present invention may further include a coating base to ensure long-term stability, and may be used as long as it is commonly used in the art, but preferably the coating base is a polyvinyl alcohol derivative in a water-soluble coating base.
  • Coating bases including methacrylic acid derivatives and polyacrylic acid derivatives, Kollicoat Protect, Opadry And hydroxypropyl methyl cellulose (HPMC) may be used one or two or more selected from the group consisting of, more preferably Kollicoat Protect is available.
  • the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable additive.
  • the additive may be included in 5 to 90% by weight, more preferably 50 to 90% by weight relative to the total weight of the composition of the present invention.
  • examples of such additives include fillers, extenders, binders, disintegrators, lubricants, preservatives, antioxidants, isotonic agents, buffers, coatings, sweeteners, solubilizers, bases, dispersants, wetting agents, suspending agents.
  • a pharmaceutically acceptable thing normally used for each formulation such as a stabilizer, a coloring agent, a fragrance
  • disintegrants including microcrystalline cellulose, lactose, mannitol, sodium citrate, calcium phosphate, glycine and starch, sodium starch glycolate, crospovidone, croscarmellose sodium and certain composite silicides and the like; Povidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, acacia gum, macrogol, hard silicic anhydride, synthetic aluminum silicate, calcium silicate or magnesium metasilicate Binders comprising silicate derivatives such as aluminate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate and mixtures thereof; And metal stearates such as stearic acid, calcium stearate or magnesium stearate, talc, colloidal silica, sucrose fatty acid esters, hydrogenated vegetable oils, high melting point waxes, glyceryl fatty acid esters, glyce
  • the disintegrant of the present invention refers to a substance which promotes disintegration of the solid composition in the digestive fluid to help achieve a sufficient dissolution rate.
  • a suitable disintegrant is selected and an appropriate amount of disintegrant It is important to use the release. In case of lowering dissolution due to delayed disintegration, dissolution can be improved by increasing the amount of disintegrant.
  • excessive use of disintegrant can sufficiently maintain the properties of the tablet during the manufacture and packaging process of solid preparation or during transport and storage. As much as possible, the tablet may not show strong strength. Therefore, the selection of a suitable disintegrant is very important and there is a limit to the amount of disintegrant used.
  • the disintegrant is preferably included in an amount of 1 to 10% by weight, and more preferably 3 to 7% by weight, based on the total weight of the composition.
  • the disintegrant satisfies the above range, there is an effect of facilitating the pharmacologically effective concentration by promoting disintegration of the formulation to increase the dissolution of the formulation to improve the absorption of moisture and release of the main component.
  • the cardiovascular disease described in the present invention is selected from the group consisting of angina pectoris, hypertension, arterial spasm, deep vein, cerebral infarction, cardiac hypertrophy, congestive heart failure, thrombosis and myocardial infarction, but is not limited thereto.
  • the solid pharmaceutical composition of the present invention may be formulated in the form of tablets, capsules, multiparticulates, etc. according to conventional formulation methods, and may be administered by oral, oral, sublingual, or the like route.
  • the composition of the present invention may be formulated in the form of tablets and orally administered, and may be easily formulated in the form of tablets by simply mixing and then tableting the components constituting the composition of the present invention.
  • the method of administration will be determined by the physician after the evaluation of the subject's symptoms and requirements.
  • amlodipine and lozatan In order to measure the change of stability according to the interaction between the two drugs, amlodipine and lozatan, amlodipine and lozatan were physically mixed and exposed to an accelerated environment, and their contents were measured.
  • amlodipine and rozatan were measured by the following method.
  • rozatan potassium is precisely weighed into a 200 mL volumetric flask, filled with about 100 mL of mobile phase A (phosphate buffer: acetonitrile (85:15, v / v%)), ultrasonically extracted for about 10 minutes, and then mobile phase A is added. After precisely adjusting to 200mL and filtered with a 0.45 ⁇ m membrane filter, the content was measured using HPLC under the conditions shown in Table 3.
  • mobile phase A phosphate buffer: acetonitrile (85:15, v / v%)
  • amlodipine content described the value according to the following Equation 1
  • content of rozatan described the value according to the following Equation 2.
  • the mixture of amlodipine and rozatan is confirmed to be less stable over time due to physical mixing and heat and pressure of the two drugs.
  • select two antioxidants that can be used as pharmaceutical additives. The effects of antioxidants on the stability of amlodipine and rozatan were investigated.
  • antioxidants Two kinds of antioxidants were formed by combining with oxygen to form a radical, which is a chemical synthesis antioxidant that exhibits antioxidant effects.
  • Butylated Hydroxy Anisole (BHA) forms chelates with chelate antioxidants citric acid. Proceeded.
  • Amlodipine and rozaaltan were prepared in Comparative Example 4 and Comparative Example 6, respectively, in the physical mixture containing antioxidants, as shown in Table 5 below, and tablets of the same formulation were used in Comparative Example 5 and Comparative Example 7, respectively. Tableting was carried out using a rotary tablet press at a pressure of 10 kpa and a thickness of 5.10 mm.
  • the method of measuring the content of amlodipine and rozatan was carried out in the same manner as described in Test Example 1. At this time, the amlodipine content described the value according to the formula 1, the content of rozatan described the value according to the formula 2.
  • Amlodipine and rozatan were prepared in Example 1 and Comparative Examples 8 to 21, respectively, with physical mixtures containing 12 antioxidants, as shown in Table 7, Table 8, Table 9, and Table 10, two of which When using different kinds of antioxidants at the same time, a mixture of BHA and BHT mixed with additive effect was shown as Comparative Example 13, a mixture of citric acid and BHA was used as Comparative Example 14, and a complex containing no antioxidant as Comparative Example 8 Compared.
  • the formulations of each prescription were measured after exposure to an accelerated chamber under the conditions of Table 2 in the form of tablets using a physical tablet after mixing, and after 2 weeks and 5 weeks after manufacturing.
  • the formulations were prepared in a single tablet at 10 kPa pressure conditions.
  • Amlodipine and rozaaltan were prepared in Example 2, Comparative Example 22, and Comparative Example 23, respectively, including a physical mixture containing three kinds of antioxidants as shown in Table 12 below.
  • Each formulation was formulated as a two-layered tablet divided into an amlodipine layer and a losaltan layer containing antioxidants.
  • the two-layered tablet was tableted by setting the pressure to 12.5kpa and the thickness of 5.30 mm using a two-layer tablet press.
  • Each tablet was exposed to an acceleration chamber under the conditions shown in Table 2, and immediately after manufacture, after 2 weeks, after 4 weeks, and after 8 weeks, the contents were measured.
  • Example 4 was amlodipine and Rosaltan single tablets, Example 3 was tableted into double tablets divided into amlodipine layer and Rosaltan layer, each tablet accelerated to the conditions of Table 2 Immediately after the exposure to the chamber, after 2 weeks, 4 weeks, 8 weeks after the content was measured.
  • Example 3 (doublet)
  • Example 4 (single schedule) Content (mg) Content ratio (%) Content (mg) Content ratio (%)
  • Pharmacologically active ingredient Amlodipine Besylate Amlodipine layer 6.94 1.74 6.94 1.74
  • Example 3 As shown in Table 15, in both Example 3 and Example 4 was found to form a relatively stable composite even after 8 weeks, but the content of Example 3 formulated in double tablets with a small drop over time lost. Therefore, it can be seen that the single information shows improved stability when formulated with double tablets, which is considered to be due to preventing drug interaction by minimizing the contact surface between the two drugs.
  • Amlodipine and rozaaltan were refined into double tablets divided into amlodipine layer and rozatan layer as shown in Table 16 below, and each tablet had three coating bases (KollicoatProtect (BASF), Opadry, hydroxypropylmethylcellulose (HPMC, Hydroxypropyl methylcellulose)) and then exposed to the acceleration chamber under the conditions shown in Table 2, respectively, immediately after the manufacture, after 2 weeks, after 4 weeks, after 8 weeks the content was measured.
  • potassium lozatan is precisely weighed into a 200mL volumetric flask, filled with 100mL of mobile phase A, ultrasonically extracted for about 10 minutes, added to mobile phase A to exactly 200mL, and filtered with a 0.45 ⁇ m membrane filter. The content is measured using HPLC under the same conditions.
  • Example 5 Example 6
  • Example 7 Amlodipine Initial content 100.2% 97.7% 101.6% 2 weeks 100.4% 95.6% 99.4% 4 Weeks 99.6% 94.1% 98.8% 8 Weeks 98.9% 93.5% 95.2% Rosaltan Initial content 99.5% 99.5% 100.3% 2 weeks 99.3% 97.6% 98.4% 4 Weeks 99.9% 96.9% 96.5% 8 Weeks 99.5% 96.0% 95.3%
  • Example 5 the formulation coated with protect
  • Example 5 showed the best stability.
  • kollicoat Protect is thought to be because it can effectively block the hydrolysis of the drug by blocking the drug's contact with moisture.
  • HPMC and Opadry Kollicoat which serves to improve the stability of the drug in Examples 6 and 7 coated using It has been observed that protect is most effectively blocked.
  • Amlodipine and rozaaltan were prepared by tableting and coating into bilayer tablets divided into amlodipine and rozatan layers as shown in Tables 18 and 19.
  • Example 12 Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Amlodipine layer Pharmacologically active ingredient Amlodipine Besylate 6.94 1.72 6.94 1.70 6.94 1.72 6.94 1.72 Filler Microcrystalline Cellulose (101) 130.00 32.17 130.00 31.78 130.00 32.17 130.00 32.17 130.00 32.17 Excipient D-mannitol 40.00 9.90 40.00 9.78 40.00 9.90 40.00 9.90 40.00 9.90 Disintegrant Sodium Glyconate 12.00 2.97 17.00 4.16 20.00 4.95 12.00 2.97 17.00 4.21 Binder Povidone 5.00 1.24 5.00 1.22 5.00 1.24 5.00 1.24 5.00 1.24 Lubricant Magnesium stearate 3.00 0.74 3.00 0.73 3.00 0.74 3.00 0.74 3.00 0.74 0.74 0.74 0.74 Antioxidant Propyl
  • amlodipine besylate standard is precisely weighed and placed in a 250 mL brown volumetric flask to exactly 250 mL with 0.001 mol / L hydrochloric acid. Take 10 mL of this solution and place it in a 100 mL brown volume flask. Add 0.01 mol / L hydrochloric acid to mix to the mark, and filter the solution with a 0.45 ⁇ m membrane filter as standard solution.
  • sample solution and the standard solution are analyzed using HPLC under the same conditions as in Table 3.
  • sample solution and the standard solution are analyzed using HPLC under the same conditions as in Table 3.
  • FIG. 1 is a graph showing the results of the dissolution test of amlodipine for Examples 8 to 17
  • Figure 2 is a graph showing the results of the dissolution test of Rosaltan for Examples 8 to 17.
  • Example 9 As shown in the results of the dissolution test for amlodipine shown in Figure 1, all formulations initially showed a high dissolution rate, but the formulations satisfying 85% or more in the standard 5 minutes was Example 9 and Example 10. In the case of Rosaltan shown in FIG. 2, Example 8 and Example 9 also satisfied the criteria of 85% or more for 5 minutes. Therefore, the optimal formulation of the combination containing amlodipine and rozatan with improved stability was found to be Example 9.

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Abstract

La présente invention concerne une composition composite contenant de l'amlodipine et du rozaltan, et présentant une stabilité améliorée grâce à un antioxydant.
PCT/KR2013/003231 2012-04-17 2013-04-17 Composition composite présentant une stabilité améliorée et contenant de l'amlodipine et du rozaltan WO2013157840A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
BR112014025956-9A BR112014025956B1 (pt) 2012-04-17 2013-04-17 composição compreendendo anlodipino e losartana tendo uma estabilidade aperfeiçoada e uso da mesma
CN201380025567.8A CN104394865B (zh) 2012-04-17 2013-04-17 稳定性提高的包含氨氯地平和氯沙坦的组合物
RU2014145827A RU2628538C2 (ru) 2012-04-17 2013-04-17 Композиция, включающая амлодипин и лозартан, имеющая улучшенную стабильность
PH12014502326A PH12014502326A1 (en) 2012-04-17 2014-10-17 A composition compromising amlodipine and losartan having an improved stability

Applications Claiming Priority (2)

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KR1020120039708A KR101392364B1 (ko) 2012-04-17 2012-04-17 안정성이 향상된 암로디핀 및 로잘탄을 함유하는 복합제 조성물
KR10-2012-0039708 2012-04-17

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KR20200143914A (ko) * 2019-06-17 2020-12-28 주식회사유한양행 암로디핀 또는 이의 염 및 클로르탈리돈 또는 이의 염을 포함하는 다층 정제 형태의 약학 조성물

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KR20100086921A (ko) * 2009-01-23 2010-08-02 한미홀딩스 주식회사 암로디핀 및 로자탄을 함유하는 고형 약제학적 조성물
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CN104394865A (zh) 2015-03-04
KR20130117048A (ko) 2013-10-25
RU2628538C2 (ru) 2017-08-18
KR101392364B1 (ko) 2014-05-07
PH12014502326B1 (en) 2015-01-12
CN104394865B (zh) 2016-11-09
PH12014502326A1 (en) 2015-01-12
BR112014025956B1 (pt) 2019-10-29

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