WO2013157840A1 - Composite composition having improved stability and containing amlodipine and rozaltan - Google Patents

Composite composition having improved stability and containing amlodipine and 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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French (fr)
Korean (ko)
Inventor
이범진
정원태
최연웅
남규열
조상민
박진하
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한국유나이티드제약 주식회사
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Priority to CN201380025567.8A priority Critical patent/CN104394865B/en
Priority to RU2014145827A priority patent/RU2628538C2/en
Priority to BR112014025956-9A priority patent/BR112014025956B1/en
Publication of WO2013157840A1 publication Critical patent/WO2013157840A1/en
Priority to PH12014502326A priority patent/PH12014502326B1/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

The present invention relates to a composite composition containing amlodipine and rozaltan, and having improved stability by comprising an antioxidant.

Description

안정성이 향상된 암로디핀 및 로잘탄을 함유하는 복합제 조성물Complex composition containing amlodipine and rozatan with improved stability
본 발명은 항산화제를 포함함으로써, 안정성이 향상된 암로디핀 및 로잘탄을 함유하는 복합제 조성물에 관한 것이다.The present invention relates to a combination composition containing amlodipine and rozatan with improved stability by including an antioxidant.
고혈압은 혈압 그 자체를 치료하는 것보다 혈압을 정상범위로 유지시켜 생명을 위협하는 뇌졸중, 심부전증, 심근경색증 등의 관상동맥질환, 신부전과 같은 심혈관계 합병증을 예방하는 것이 중요하므로, 꾸준하게 혈압을 조절하는 것이 중요하다. 이처럼 혈압약은 장기간 복용할 것이 요구되므로 치료 약물 선택에 있어서도 신중을 기하게 된다. 따라서, 꾸준한 치료를 위해 한 가지 약물을 선택하기보다는 다른 메커니즘을 가진 약물을 서로 병용함으로써 보다 우수한 예방 및 치료 효과를 발휘할 수 있고, 병용 투여로 단일 약물의 사용량을 줄임으로써 약물의 장기 복용에 의해 발생할 수 있는 부작용을 감소시킬 수 있다.It is important to keep your blood pressure in a normal range rather than to treat the blood pressure itself, so it is important to prevent cardiovascular complications such as coronary artery disease such as life-threatening stroke, heart failure, myocardial infarction, and renal failure. It is important to do. As such, blood pressure medications are required to be taken for a long time, so careful selection of therapeutic drugs is also required. Therefore, by using drugs with different mechanisms in combination with each other, rather than selecting one drug for continuous treatment, a better prevention and treatment effect can be exerted. It can reduce side effects.
고혈압의 치료에 흔히 사용되는 약물은 약물의 작용 메커니즘에 따라 이뇨제, 교감신경억제제, 혈관확장제로 크게 구분되며, 현재 많이 사용되고 있는 혈관확장제는 다시 작용 메커니즘에 따라 ACE (angiotensin converting enzyme) 억제제, 안지오텐신 II 수용체 차단제(Angiotensin II receptor blocker, ARB) 및 칼슘 통로 차단제로 구분된다.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.
암로디핀(amlodipine)은 디히드로피리딘 계열의 칼슘통로 차단제로써 고혈압 또는 협심증의 치료에 사용되는 대표적인 약물이다. 약물이 흡수되면 동맥벽의 평활근을 이완시키고 이에 따라 혈압을 낮추며 심근으로 흐르는 혈류를 증가시키는 작용을 한다. 암로디핀은 베실산, 말레인산, 캠실산 등 다양한 염의 형태로 시판되고 있으며 암로디핀 베실레이트가 가장 널리 사용되고 있다.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.
로잘탄은 ARB(Angiotensin II receptor blocker) 계열의 고혈압치료제 중 가장 일찍 개발된 약물 중 하나로 안지오텐신 II (angiotensin II) 가 수용체에 결합을 차단하는 작용을 한다. 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.
칼슘통로차단제인 암로디핀과 ARB인 로잘탄은 서로 다른 기전을 가져 두 약물을 동시에 복용할 경우 고혈압치료에 상가적인 효과를 나타낼 수 있을 것으로 나타났다. 그러나, 암로디핀과 로잘탄을 단순 혼합 직타하여 복합제제를 제조할 경우에 이러한 제제의 안정성이 가속 조건에서 매우 저하되는 문제점이 남아있다.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. However, there is a problem that the stability of such formulations is greatly degraded under accelerated conditions when a complex preparation is prepared by simply mixing amlodipine and rozatan.
암로디핀 제제는 일반적으로 약효를 나타내는 성분인 암로디핀과 약효의 활성화 및 제형화를 돕는 염이 결합되어 만들어진다. 염은 유효성분인 암로디핀의 안정화를 돕는 부분으로서, 암로디핀은 유리 염기 형태인 것이 유용하나, 물에 대한 용해도가 낮기 때문에 약제학적으로 허용되는 산과의 염 형태로 투여되는 것이 바람직하다. 암로디핀 산부가염과 함께 사용하여 시너지 효과를 낼 수 있는 또 다른 약물과의 복합제제가 많이 이용되고 있으며, 이러한 예로 암로디핀 베실레이트와 아토바스타틴 칼슘의 복합제제(미국특허 제6,455,574호), 암로디핀 베실레이트와 발사르탄의 복합제제(미국특허 제6,395,728호) 및 암로디핀 캠실레이트와 심바스타틴의 복합제제(대한민국 특허등록 제742432호) 등이 개시되어 있다. 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. In combination with amlodipine acid addition salts, 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. 6,455,574), 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.
암로디핀은 불안정한 유리염기로써 빛, 열 및 수분에 의해 큰 영향을 받아 그 치료효과가 떨어지는 단점이 있기에 이를 극복하기 위하여 상기에 기술한 다양한 산부가염과 결합된 형태로 시판되어 포장 등의 방법을 사용하여 그 안정성을 유지하고 있다. 그러나 여전히 제제학적으로 안정성을 확보하는 것에 대한 성과는 미미하다.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. To overcome this problem, 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.
특히 암로디핀 산부가염의 경우 로잘탄과 물리적으로 혼합될 경우 로잘탄 및 부형제가 화학적 반응을 촉진시켜 암로디핀의 안정성을 떨어뜨리는 것이 확인되었다. In particular, in the case of amlodipine acid addition salts, it was confirmed that rozatan and excipients promote chemical reactions and decrease the stability of amlodipine when physically mixed with rozatan.
로잘탄은 보편적으로 칼륨염의 형태로 사용되고 있으며 일반적으로는 안정한 상태를 유지하나 산성조건에서 열이 가해질 경우 분해산물 중합체가 형성되는 단점이 있다. 즉. 복합제로 만들어질 경우 암로디핀의 산부가염에 의해 로잘탄의 안정성이 떨어지게 된다. 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.
예컨대, 암로디핀 캄실레이트와 로잘탄 칼륨염의 복합제제(대한민국 특허공개 제2008-0052852호)를 이용한 기존 시판 중인 암로디핀, 로잘탄 복합제제는 두 성분간의 안정성을 충분히 확보하지 못한 단점이 있다.For example, the existing commercially available amlodipine and rozatan combinations using a combination of amlodipine chamlate and rozatan potassium salt (Korean Patent Publication No. 2008-0052852) have a disadvantage of not sufficiently securing stability between the two components.
따라서, 상술한 문제점을 해결하기 위하여, 본 발명은 암로디핀과 로잘탄의 물리적 결합을 최소화하고, 암로디핀의 안정성을 유지시키기 위하여 항산화제를 첨가함과 동시에 제제공정이 간소화된, 안정성이 향상된 암로디핀 및 로잘탄을 함유하는 복합제 조성물을 제공하는데 목적이 있다.Therefore, in order to solve the above problems, 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.
본 발명은 암로디핀 또는 이의 약제학적 허용가능한 염, 로잘탄 또는 이의 약제학적 허용가능한 염 및 갈산프로필을 포함하는 심혈관계 질환의 예방 및 치료용 복합제 조성물을 제공한다.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.
본 발명의 암로디핀 및 로잘탄을 함유하는 심혈관계 질환의 예방 및 치료용 복합제 조성물은 암로디핀과 로잘탄의 물리적 결합을 최소화하고, 갈산프로필을 함유함으로써 안정성이 우수하며, 제제공정이 간소화된 장점이 있다.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.
도 1은 실시예 8 내지 실시예 17의 복합제에 대한 암로디핀의 용출 시험의 결과를 나타낸 그래프이며, 1 is a graph showing the results of the dissolution test of amlodipine for the composite agent of Examples 8 to 17,
도 2는 실시예 8 내지 실시예 17의 복합제에 대한 로잘탄의 용출 시험의 결과를 나타낸 그래프이다.Fig. 2 is a graph showing the results of the dissolution test of lozatan for the composite agents of Examples 8 to 17.
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명은 암로디핀 또는 이의 약제학적 허용가능한 염, 로잘탄 또는 이의 약제학적 허용가능한 염 및 갈산프로필을 포함하는 심혈관계 질환의 예방 및 치료용 약제학적 조성물에 관한 것이다.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.
상기 갈산프로필(propyl gallate, C10H12O5)은 항산화제로, 로잘탄과 암로디핀의 복합제제가 다른 약제학적으로 허용가능한 첨가제들과 혼합되어 성형될 때 활성성분의 안정성을 증가시켜 높은 안정성을 가진 제품이 생산될 수 있도록 할 뿐만 아니라 온도 및 수분에 의한 활성성분의 변형을 감소시켜 경시적 변화에 대한 안정성을 증가시키는 역할을 한다. 갈산프로필은 타 항산화제와 비교 시 피부 자극이 나타나지 않을 정도로 독성이 나타나지 않을 정도로 안전성을 나타낸다. 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.
상기 복합제 조성물은 유핵정, 캅셀제, 이중정, 다층정, 단일정 형태로 제조될 수 있으나, 본 발명에서는 암로디핀 또는 이의 약제학적 허용가능한 염과 로잘탄 또는 이의 약제학적 허용가능한 염을 물리적으로 분리시켜 이들의 접촉 표면적을 최대한 감소시킨 복합 제제를 제조하는 것이 바람직하며, 보다 바람직하게는 상기 암로디핀 또는 이의 약제학적 허용가능한 염을 포함하는 암로디핀 층 및 로잘탄 또는 이의 약제학적 허용가능한 염을 포함하는 로잘탄 층으로 분리된 상태인 이중층 구조를 이루는 이중정인 것이 바람직하다. 상기 이중층의 제조방법은 로잘탄 칼륨 및 그 혼합물이 하층을 형성하여 다져진 후 암로디핀 및 그 혼합물과립이 상층을 형성하여 타정기를 이용하여 타정하여 제조될 수 있으나, 이에 한정하는 것은 아니다.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.
이때, 상기 갈산프로필은 암로디핀 또는 이의 약제학적 허용가능한 염을 포함하는 암로디핀 층에 포함되는 것이 바람직하다.In this case, the propyl gallate is preferably included in the amlodipine layer comprising amlodipine or a pharmaceutically acceptable salt thereof.
상기 갈산프로필은 조성물 총 중량에 대하여 0.001 내지 1 중량%로 포함되는 것이 바람직하며, 보다 바람직하게는 0.001내지 0.5 중량%로 포함될 수 있으며, 0.001내지 0.1 중량%로 포함되는 것이 가장 바람직하다. 갈산프로필이 상기 범위로 포함될 때 활성성분의 안정성을 증가시켜 높은 안정성을 가진다. 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. When propyl gallate is included in the above range, the stability of the active ingredient is increased to have high stability.
또한, 본 발명의 복합제 조성물 총 중량에 대하여 상기 암로디핀 또는 이의 약제학적 허용가능한 염은 1 내지 6 중량% 및 상기 로잘탄 또는 이의 약제학적 허용가능한 염은 5 내지 30 중량%로 포함되는 것이 바람직하며, 보다 바람직하게는 암로디핀 또는 이의 약제학적 허용가능한 염은 1.2 내지 3.5 중량% 및 로잘탄 또는 이의 약제학적 허용가능한 염은 10 내지 20 중량%로 포함될 수 있다.In addition, 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 Preferably, 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.
암로디핀은 복합제제 중 3 내지 12 mg로 포함되는 것이 바람직하며, 보다 바람직하게는 5 내지 10 mg, 로잘탄은 복합제제 중 30 내지 120 mg로 포함되는 것이 바람직하며, 보다 바람직하게는 50 내지 100 mg로 포함될 수 있다.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.
상기 암로디핀의 약제학적으로 허용가능한 염은 약제학적으로 허용가능한 음이온을 함유하는 비독성 산부가염을 형성하는 산으로부터 형성된 것으로서, 예를 들어 염산염, 브롬화수소산염, 황산염, 인산염, 아세테이트, 말레이트, 푸마레이트, 락테이트, 타르트레이트, 시트레이트, 글루코네이트, 베실레이트 및 캄실레이트 등을 이용할 수 있으나, 가장 바람직하게는 상기 암로디핀의 약제학적 허용가능한 염은 암로디핀 베실레이트이며, 상기 로잘탄의 약제학적 허용가능한 염은 로잘탄 칼륨인 것이 바람직하다.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.
본 발명의 약제학적 조성물은 암로디핀 베실레이트, 미결정셀룰로오스, D-만니톨, 글리콘산전분 나트륨, 포비돈, 스테아린산 마그네슘 및 갈산프로필을 포함하는 암로디핀 층 및 로잘탄 칼륨, 미결정셀룰로오스, 크로스포비돈 및 스테아린산 마그네슘을 포함하는 로잘탄 층으로 이루어지는 것이 가장 바람직하나, 이에 한정되는 것은 아니다. 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.
본 발명의 약제학적 조성물은 보다 장기적인 안정성 확보를 위해 코팅기제를 더 포함할 수 있으며, 당 업계에서 통상적으로 이용하는 것이면 어느 것이나 이용할 수 있으나, 바람직하게는 상기 코팅기제는 수용성 코팅기제 중 폴리비닐 알코올유도체, 메타크릴산 유도체 및 폴리아크릴산 유도체를 포함한 코팅기제, Kollicoat Protect, Opadry 및 히드록시프로필메틸셀룰로오스(HPMC)로 이루어지는 군에서 선택되는 1종 또는 2종이상을 이용할 수 있으며, 보다 바람직하게는 Kollicoat Protect을 이용할 수 있다.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.
또한, 본 발명의 약제학적 조성물은 약제학적으로 허용가능한 첨가제를 추가로 더 포함할 수 있다. 상기 첨가제는 본 발명의 조성물 총 중량에 대하여 5 내지 90 중량%로 포함될 수 있으며, 보다 바람직하게는 50 내지 90 중량%로 포함될 수 있다. 상기 첨가제의 예로는 충진제, 증량제, 결합제, 붕해제(disintegrator), 윤활제, 방부제, 항산화제, 등장제 (isotonic agent), 완충제, 피막제, 감미제, 용해제, 기제 (base), 분산제, 습윤제, 현탁제, 안정제, 착색제, 방향제, 수용성 첨가제, 부형제 등 각 제형에 통상적으로 사용되는 약제학적으로 허용되는 것이면 어느 것이나 사용할 수 있다. 보다 상세하게는 미결정 셀룰로오스, 락토스, 만니톨, 나트륨 시트레이트, 칼슘 포스페이트, 글리신 및 전분, 글리콜산 전분나트륨, 크로스포비돈, 크로스카르멜로즈 나트륨 및 특정 복합 실리게이트 등을 포함하는 붕해제; 포비돈, 폴리비닐피롤리돈, 히드록시프로필메틸셀룰로오스 (HPMC), 히드록시프로필셀룰로오스 (HPC), 수크로스, 젤라틴, 아카시아 검, 마크로골, 경질 무수 규산, 합성 규산 알루미늄, 규산 칼슘 또는 마그네슘 메타실리케이트 알루미네이트와 같은 규산염 유도체, 인산수소칼슘과 같은 인산염, 탄산칼슘과 같은 탄산염 및 이들의 혼합물을 포함하는 결합제; 및 스테아르산, 스테아르산 칼슘 또는 스테아르산 마그네슘과 같은 스테아르산 금속염류, 탈크, 콜로이드 실리카, 자당지방산에스테르, 수소첨가된 식물성 오일, 고융점의 왁스, 글리세릴지방산에스테르류, 글리세롤디베헤네이트, 활석 및 이들의 혼합물을 포함하는 활택제가 포함될 수 있다.In addition, 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. As long as it is a pharmaceutically acceptable thing normally used for each formulation, such as a stabilizer, a coloring agent, a fragrance | flavor, a water-soluble additive, and an excipient, it can be used. More specifically, 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, glycerol dibehenate, talc And glidants including mixtures thereof.
본 발명의 붕해제는 소화액 중에서 고형 조성물의 붕해를 촉진시켜 충분한 용출률을 달성하도록 도와주는 물질을 지칭하는데, 고형제제, 특히 정제의 용해성을 개선하기 위하여 적절한 종류의 붕해제를 선정하고 적절한 양의 붕해제를 사용하는 것은 중요하다. 붕해 지연에 의한 용출 저하가 있을 경우 붕해제의 사용량을 높여 용출 저하를 개선시킬 수 있으나, 붕해제를 과도하게 사용하게 되면 고형제제의 제조와 포장 공정 시 또는 이송과 보관 중에 정제의 성상을 충분히 유지할 수 있을 만큼 정제가 강한 강도를 나타낼 수 없게 된다. 따라서, 적절한 붕해제의 선택은 매우 중요하며, 붕해제의 사용량에도 제한이 있다.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.In order to improve the solubility of the solid preparation, in particular, a tablet, 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. However, 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.
상기 붕해제는 조성물 총 중량에 대하여 1 내지 10 중량%로 포함되는 것이 바람직하며, 보다 바람직하게는 3 내지 7 중량%로 포함될 수 있다. 붕해제가 상기 범위를 만족한 경우, 수분의 흡수 및 주성분의 방출이 향상될 수 있도록 제제의 붕해를 촉진하여 주성분의 용출을 증가시킴에 따라 약리학적 유효농도 도달을 용이하게 하는 효과가 있다.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. When 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.
본 발명에 기재된 심혈관계 질환은 협심증, 고혈압, 동맥연축, 심부정맥, 뇌경색, 심비대, 울혈심부전, 혈전증 및 심근경색으로 이루어진 군으로부터 선택되는 것으로, 이에 한정되는 것은 아니다.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.
본 발명의 고형 약제학적 조성물은 통상의 제제화 방법에 따라 정제, 캡슐, 다중입자 등의 형태로 제제화되어 경구, 구강, 설하 등의 경로로 투여될 수 있다. 바람직하게는, 본 발명의 조성물은 정제의 형태로 제제화되어 경구투여될 수 있으며, 본 발명의 조성물을 구성하는 성분들을 간단히 혼합한 후 타정함으로써 쉽게 정제의 형태로 제제화될 수 있다. 투여 방법은 개체의 증상 및 요구치의 평가 후에 의사에 의해 측정될 것이다.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. Preferably, 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.
이하, 실시예 및 시험예를 통하여 본 발명을 더욱 상세히 설명하기로 한다. 이들 실시예 및 시험예는 단지 본 발명을 예시하기 위한 것이므로, 본 발명의 범위가 이들 실시예 및 시험예에 의해 제한되는 것으로 해석되지는 않는다.Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples. These examples and test examples are for illustrative purposes only, and thus the scope of the present invention is not to be construed as being limited by these examples and test examples.
시험예 1. 암로디핀 및 로잘탄 간의 안정성 시험Test Example 1 Stability Test Between Amlodipine and Rosaltan
암로디핀 및 로잘탄, 두 약물사이의 상호작용에 따른 안정성의 변화를 측정하기 위해 암로디핀 및 로잘탄을 물리적으로 혼합하여 가속환경에 노출시켜 그 함량을 측정해 보았다. 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.
(1) 시험 방법(1) test method
암로디핀과 로잘탄을 하기 표 1에 나타난 처방과 같은 중량으로 물리적 혼합을 하여 각각 비교예 1, 비교예 2 로 하였다. 또한 정제화 시 가해지는 압력과 열이 암로디핀과 로잘탄의 안정성에 미치는 영향을 알아보기 위하여 비교예 2를 정제화 한 것을 비교예 3으로 하였다. 비교예 3을 정제화하는 공정에서 20 kPa의 압력으로 처리하였다.Amlodipine and rozatan were physically mixed to the same weight as the formulation shown in Table 1 below to make Comparative Examples 1 and 2, respectively. In addition, in order to determine the effect of the pressure and heat applied during tabletting on the stability of amlodipine and rozatan, the tablet of Comparative Example 2 was used as Comparative Example 3. Comparative Example 3 was treated at a pressure of 20 kPa in the process of tableting.
표 1
분류 성분 비교예 1 비교예 2 비교예 3
함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%)
약리학적 유효성분 암로디핀 베실레이트 6.94 12.2 6.94 1.7 6.94 1.7
약리학적 유효성분 로잘탄 칼륨 50 87.8 50 12.5 50 12.5
충진제 미결정셀룰로오스 (101) - - 130 32.6 130 32.6
충진제 미결정셀룰로오스 (102) - - 135.1 33.9 135.1 33.9
부형제 D-만니톨 - - 40 10.0 40 10.0
붕해제 글리콘산전분 나트륨 - - 17 4.3 17 4.3
붕해제 크로스포비돈 - - 12 3.0 12 3.0
결합제 포비돈 - - 5 1.3 5 1.3
활택제 스테아린산마그네슘 - - 3 0.8 3 0.8
중량 56.94 100 399.04 100 399.04 100
State Powder Powder Tablet
Table 1
Classification ingredient Comparative Example 1 Comparative Example 2 Comparative Example 3
Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%)
Pharmacologically active ingredient Amlodipine Besylate 6.94 12.2 6.94 1.7 6.94 1.7
Pharmacologically active ingredient Rosaltan Potassium 50 87.8 50 12.5 50 12.5
Filler Microcrystalline Cellulose (101) - - 130 32.6 130 32.6
Filler Microcrystalline Cellulose (102) - - 135.1 33.9 135.1 33.9
Excipient D-mannitol - - 40 10.0 40 10.0
Disintegrant Starch sodium glyconate - - 17 4.3 17 4.3
Disintegrant Crospovidone - - 12 3.0 12 3.0
Binder Povidone - - 5 1.3 5 1.3
Lubricant Magnesium stearate - - 3 0.8 3 0.8
weight 56.94 100 399.04 100 399.04 100
State Powder Powder Tablet
암로디핀과 로잘탄의 안정성 시험을 위해, 상기 제조된 비교예 1 및 비교예 2의 각 혼합물 및 비교예 3의 정제를 하기 표 2의 조건으로 가속챔버에 노출 시킨 후 제조직후, 2주, 5주 후 함량을 측정하였다.For the stability test of amlodipine and rozatan, each mixture of Comparative Example 1 and Comparative Example 2 prepared above and the tablets of Comparative Example 3 were exposed to an accelerated chamber under the conditions of Table 2 immediately after the preparation, 2 weeks, 5 weeks after The content was measured.
표 2
온도 40 ± 2 ℃
상대 습도 75 ± 5 %
TABLE 2
Temperature 40 ± 2 ℃
Relative humidity 75 ± 5%
암로디핀 및 로잘탄의 함량은 하기와 같은 방법에 의하여 측정하였다.The contents of amlodipine and rozatan were measured by the following method.
① 암로디핀의 함량 측정 방법① How to measure the content of amlodipine
각 샘플 3정 또는 동일 분량을 취해 무게를 정밀히 달고 가루로 만들었다. 암로디핀으로서 5 mg 해당량을 달아 100mL 갈색용량플라스크에 넣고 이동상을 넣어 정확히 100mL가 되게 하였다. 상기 액 25mL를 취해 50mL 갈색용량플라스크에 넣어 이동상으로 표선까지 맞춘 후 0.45㎛ 멤브레인 필터로 여과하여 표 3과 같은 조건으로 HPLC를 이용하여 함량을 측정하였다. Three or equal portions of each sample were taken, precisely weighed and ground. 5 mg equivalent of amlodipine was weighed into a 100 mL brown volumetric flask and a mobile phase was added to exactly 100 mL. 25 mL of the solution was taken, placed in a 50 mL brown volumetric flask, adjusted to the mark with a mobile phase, filtered through a 0.45 μm membrane filter, and the content was measured using HPLC under the same conditions as in Table 3.
② 로잘탄의 함량 측정 방법② How to measure the content of lozatan
각 샘플 3정 또는 동일 분량을 취해 무게를 정밀히 달고 가루로 한다. 로잘탄칼륨으로서 50mg 해당량을 정밀히 달아 200mL 용량플라스크에 넣고, 이동상 A(인산염완충액: 아세토니트릴(85:15, v/v%))로 약 100mL을 채운 후 약 10분간 초음파 추출한 뒤 이동상 A를 가해 정확히 200mL로 맞춘 후 0.45㎛ 멤브레인 필터로 여과하여 표 3과 같은 조건으로 HPLC를 이용하여 함량을 측정하였다.Take 3 tablets or the same amount of each sample, weigh it precisely, and powder it. 50 mg of 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㎛ membrane filter, the content was measured using HPLC under the conditions shown in Table 3.
표 3
암로디핀 로잘탄
검출기 자외부흡광광도계 (측정파장350nm) 자외부흡광광도계 (측정파장250nm)
컬럼 안지름 4.6 mm, 길이 약 150 mm의 스테인레스 관에 5㎛의 액체크로마토그래프용 옥타데실실릴화한 실리카겔을 충진한 컬럼 안지름 4.6 mm, 길이 약 150 mm의 스테인레스 관에 5㎛의 액체크로마토그래프용 옥타데실실릴화한 실리카겔을 충진한 컬럼
동상 메탄올:0.03 mol/L 인산이수소칼륨액 (600:400,v/v) 이동상 A: 인산염완충액: 아세토니트릴(85:15, v/v%)이동상 B: 아세토니트릴
유속 1.5 mL/min 1.2 mL/min
칼럼온도 35
Gradient system 0분 : 이동상 A 80%, 이동상 B 20 %2분 : 이동상 A 80%, 이동상 B 20 %8분 : 이동상 A 40%, 이동상 B 60 %10분: 이동상 A 80%, 이동상 B 20 %15분: 이동상 A 80%, 이동상 B 20 %
TABLE 3
Amlodipine Rosaltan
Detector UV Absorbance Spectrometer (350nm wavelength) UV absorbance photometer (wavelength 250nm)
column A column filled with a octadecylsilylated silica gel for liquid chromatograph of 5 µm in a stainless steel tube having a diameter of 4.6 mm and a length of about 150 mm. A column filled with a octadecylsilylated silica gel for liquid chromatograph of 5 µm in a stainless steel tube having a diameter of 4.6 mm and a length of about 150 mm.
frostbite Methanol: 0.03 mol / L Potassium Dihydrogen Phosphate (600: 400, v / v) Mobile Phase A: Phosphate Buffer: Acetonitrile (85:15, v / v%) Mobile Phase B: Acetonitrile
Flow rate 1.5 mL / min 1.2 mL / min
Column temperature 35
Gradient system 0 minutes: Mobile phase A 80%, Mobile phase B 20% 2 minutes: Mobile phase A 80%, Mobile phase B 20% 8 minutes: Mobile phase A 40%, Mobile phase B 60% 10 minutes: Mobile phase A 80%, Mobile phase B 20% 15 minutes : Mobile phase A 80%, mobile phase B 20%
(2) 시험 결과(2) test result
상기 시험 방법에 따른 결과를 하기 표 4에 기재하였다. The results according to the test method are shown in Table 4 below.
이때, 암로디핀 함량은 하기 식 1에 따른 값을 기재하였으며, 로잘탄의 함량은 하기 식 2에 따른 값을 기재하였다. At this time, the amlodipine content described the value according to the following Equation 1, the content of rozatan described the value according to the following Equation 2.
수학식 1
Figure PCTKR2013003231-appb-M000001
 Equation 1
Figure PCTKR2013003231-appb-M000001
수학식 2
Figure PCTKR2013003231-appb-M000002
 Equation 2
Figure PCTKR2013003231-appb-M000002
표 4
함량 비교예 1 비교예 2 비교예 3
암로디핀 초기함량 97.9% 98.3% 89.3%
2주 83.1% 94.1% 43.7%
5주 19.4% 19.0% 18.8%
로잘탄 초기함량 99.7% 99.4% 105.5%
2주 97.1% 99.5% 103.1%
5주 98.4% 100.7% 111.3%
Table 4
content Comparative Example 1 Comparative Example 2 Comparative Example 3
Amlodipine Initial content 97.9% 98.3% 89.3%
2 weeks 83.1% 94.1% 43.7%
5 Weeks 19.4% 19.0% 18.8%
Rosaltan Initial content 99.7% 99.4% 105.5%
2 weeks 97.1% 99.5% 103.1%
5 Weeks 98.4% 100.7% 111.3%
상기 표 4에 나타난 바와 같이 암로디핀의 경우 로잘탄과 물리적 접촉만으로도 그 함량이 크게 떨어지는 것을 알 수 있었으며 5주만에 무려 20%까지 감소하는 것으로 보아 로잘탄 칼륨의 영향을 크게 받는 것으로 보였다. 또한 물리적 혼합물을 정제화한 비교예 3의 경우, 시간이 지남에 따른 함량의 감소폭은 더 커지는 경향을 보임으로써 암로디핀의 안정성에 열이나 압력 또한 큰 영향을 끼친다는 것을 알 수 있었다.As shown in Table 4, it was found that the content of amlodipine was greatly reduced only by physical contact with rozaaltan, and it was shown to be greatly affected by rozatan potassium as it was reduced by as much as 20% in 5 weeks. In addition, in the case of Comparative Example 3 in which the physical mixture was refined, the decrease in content over time tended to be larger, indicating that heat or pressure also significantly affected the stability of amlodipine.
시험예 2. 항산화제 효력 시험Test Example 2 Antioxidant Effect Test
암로디핀 및 로잘탄의 혼합물은 두 약물의 물리적 혼합 및 열과 압력에 의해 시간이 경과함에 따라 그 안정성이 떨어지는 것을 확인하여 안정성을 높일 수 있는 대안으로 약학적 첨가제로 사용이 가능한 2종의 항산화제를 선택하여 암로디핀 및 로잘탄의 안정성에 미치는 항산화제의 영향을 알아보았다.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. As an alternative to increase the stability, select two antioxidants that can be used as pharmaceutical additives. The effects of antioxidants on the stability of amlodipine and rozatan were investigated.
2종의 항산화제로 산소와 결합하여 라디칼을 형성함으로써 항산화효과를 나타내는 대표적인 화학적 합성 항산화제 Butylated Hydroxy Anisole(BHA)와 킬레이트를 형성하여 항산화효과를 나타내는 대표적 킬레이트 항산화제 시트르산(Citric acid)를 선택하여 실험을 진행하였다.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.
(1) 시험 방법(1) test method
암로디핀과 로잘탄을 하기 표 5에 나타난 처방과 같이 항산화제를 포함한 물리적 혼합물을 각각 비교예 4, 비교예 6으로 하였으며, 같은 제제 구성으로 정제화 시킨 것을 각각 비교예 5, 비교예 7로 하였다. 정제화는 로타리 타정기를 이용하여 압력 10kpa, 두께 5.10mm의 조건으로 수행하였다. 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.
각 혼합물 및 정제는 상기 표 2의 조건으로 가속챔버에 노출 시킨 후 제조직후, 5주 후 함량을 측정하였다.Each mixture and the tablets were exposed to an accelerated chamber under the conditions of Table 2, and immediately after manufacture, the contents were measured after 5 weeks.
암로디핀과 로잘탄의 함량 측정 방법은 시험예 1에 기재한 방법과 동일한 방법으로 실시하였다. 이때, 암로디핀 함량은 상기 식 1에 따른 값을 기재하였으며, 로잘탄의 함량은 상기 식 2에 따른 값을 기재하였다. 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.
표 5
분류 성분 비교예 4 비교예 5 비교예 6 비교예 7
함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%)
약리학적 유효성분 암로디핀 베실레이트 6.94 1.67 6.94 1.67 6.94 1.38 6.94 1.38
약리학적 유효성분 로잘탄 칼륨 50 12.02 50 12.02 50 9.96 50 9.96
충진제 미결정셀룰로오스 (101) 130 31.25 130 31.25 130 25.89 130 25.89
충진제 미결정셀룰로오스 (102) 135.1 32.47 135.1 32.47 135.1 26.91 135.1 26.91
부형제 D-만니톨 40 9.61 40 9.61 40 7.97 40 7.97
붕해제 글리콘산전분 나트륨 17 4.09 17 4.09 17 3.39 17 3.39
붕해제 크로스포비돈 12 2.88 12 2.88 12 2.39 12 2.39
결합제 포비돈 5 1.20 5 1.20 5 1.00 5 1.00
활택제 스테아린산마그네슘 3 0.72 3 0.72 3 0.60 3 0.60
항산화제 BHA 17 4.09 17 4.09 - - - -
시트르산 - - - - 103 20.52 103 20.52
중량 416.04 100.00 416.04 100.00 502.04 100.00 502.04 100.00
State Powder Tablet Powder Tablet
Table 5
Classification ingredient Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7
Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%)
Pharmacologically active ingredient Amlodipine Besylate 6.94 1.67 6.94 1.67 6.94 1.38 6.94 1.38
Pharmacologically active ingredient Rosaltan Potassium 50 12.02 50 12.02 50 9.96 50 9.96
Filler Microcrystalline Cellulose (101) 130 31.25 130 31.25 130 25.89 130 25.89
Filler Microcrystalline Cellulose (102) 135.1 32.47 135.1 32.47 135.1 26.91 135.1 26.91
Excipient D-mannitol 40 9.61 40 9.61 40 7.97 40 7.97
Disintegrant Starch sodium glyconate 17 4.09 17 4.09 17 3.39 17 3.39
Disintegrant Crospovidone 12 2.88 12 2.88 12 2.39 12 2.39
Binder Povidone 5 1.20 5 1.20 5 1.00 5 1.00
Lubricant Magnesium stearate 3 0.72 3 0.72 3 0.60 3 0.60
Antioxidant BHA 17 4.09 17 4.09 - - - -
Citric acid - - - - 103 20.52 103 20.52
weight 416.04 100.00 416.04 100.00 502.04 100.00 502.04 100.00
State Powder Tablet Powder Tablet
(2) 시험 결과(2) test result
상기 시험 결과를 하기 표 6에 기재하였다. The test results are shown in Table 6 below.
표 6
함량 비교예 4 비교예 5 비교예 6 비교예 7
암로디핀 초기함량 99.7% 91.9% 97.1% 90.4%
5주 93.3% 83.4% 102.7% 92.1%
로잘탄 초기함량 100.7% 101.0% 103.6% 101.3%
5주 105.5% 101.9% 100.0% 97.9%
Table 6
content Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7
Amlodipine Initial content 99.7% 91.9% 97.1% 90.4%
5 Weeks 93.3% 83.4% 102.7% 92.1%
Rosaltan Initial content 100.7% 101.0% 103.6% 101.3%
5 Weeks 105.5% 101.9% 100.0% 97.9%
상기 표 6에 나타난 바와 같이 항산화제가 첨가될 경우 물리적 접촉만으로도 큰 변화를 나타내었던 암로디핀의 함량이 지속적으로 유지되는 것을 관찰할 수 있었으며, 2종의 항산화제를 사용하였을 때 모두 안정성이 향상된 결과를 얻을 수 있었다. 또한 타정으로 인해 발생하는 열이나 압력이 가해지는 환경에서도 시간이 지남에 따라 함량이 유지되어 항산화제를 이용하여 암로디핀의 안정성을 향상시킬 수 있음을 알 수 있었다. 또한 로잘탄 칼륨의 경우 항산화제의 사용에 따라 그 함량이 크게 변하지 않으며 또한 열이나 압력에 대해서도 큰 변화없이 안정성을 유지하는 경향을 나타내었다.As shown in Table 6, when the antioxidant was added, it was observed that the content of amlodipine, which showed a great change only by physical contact, was continuously maintained, and the stability was improved when two kinds of antioxidants were used. Could. In addition, the contents were maintained over time even in the environment in which heat or pressure is generated due to tableting, and it was found that the stability of amlodipine can be improved by using an antioxidant. In addition, as for the Rosaltan potassium, the content of the antioxidant does not change significantly, and the stability of the heat or the pressure does not change significantly.
시험예 3. 항산화제 선정 시험Test Example 3 Antioxidant Selection Test
3.1 항산화제에 따른 안정성 시험3.1 Stability test according to antioxidant
상기 시험에서 확인한 항산화제의 안정성 향상 결과를 토대로 항산화제 12종을 이용하여 최적의 항산화제를 선정하는 시험을 수행하였다. Based on the results of improving the stability of the antioxidants identified in the test, a test for selecting an optimal antioxidant using 12 kinds of antioxidants was performed.
(1) 복합제 제조방법(1) Method of manufacturing a composite
암로디핀과 로잘탄을 하기 표 7, 표 8, 표 9 및 표 10에 나타난 처방과 같이 12종의 항산화제를 각각 포함한 물리적 혼합물을 실시예 1 및 비교예 8 내지 비교예 21로 제조하였으며, 그 중 두 종류의 항산화제를 동시에 사용할 경우 상가효과를 나타내는 BHA와 BHT를 혼용한 혼합물을 비교예 13, 시트르산과 BHA를 혼용한 혼합물을 비교예 14로 하였으며, 항산화제를 포함하지 않은 복합제를 비교예 8로 비교하였다. 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.
각각 처방의 제제는 물리적 혼합을 한 후 타정기를 이용하여 정제의 형태로 표 2의 조건으로 가속챔버에 노출 시킨 후 제조직후, 2주 후, 5주 후 함량을 측정하였다. 상기 제제는 단일정으로, 10kPa 압력 조건에서 제조되었다.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.
암로디핀과 로잘탄의 함량 측정 방법은 시험예 1에 기재한 방법과 동일한 방법으로 실시하였다. The method of measuring the content of amlodipine and rozatan was carried out in the same manner as described in Test Example 1.
표 7
분류 성분 실시예 1 비교예 8 비교예 9 비교예 10 비교예 11
함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%)
약리학적 유효성분 암로디핀 베실레이트 6.94 1.74 6.94 1.74 6.94 1.67 6.94 1.67 6.94 1.38
약리학적 유효성분 로잘탄 칼륨 50 12.53 50 12.53 50 12.02 50 12.02 50 9.96
충진제 미결정셀룰로오스 (101) 130 32.57 130 32.58 130 31.25 130 31.25 130 25.89
미결정셀룰로오스 (102) 135.1 33.85 135.1 33.86 135.1 32.47 135.1 32.47 135.1 26.91
부형제 D-만니톨 40 10.02 40 10.02 40 9.61 40 9.61 40 7.97
붕해제 글리콘산전분 나트륨 17 4.26 17 4.26 17 4.09 17 4.09 17 3.39
크로스포비돈 12 3.01 12 3.01 12 2.88 12 2.88 12 2.39
결합제 포비돈 5 1.25 5 1.25 5 1.20 5 1.20 5 1.00
활택제 스테아린산마그네슘 3 0.75 3 0.75 3 0.72 3 0.72 3 0.60
항산화제 BHA - - - - - - 17 4.09 - -
시트르산 - - - - - - - - 103 20.52
BHT - - - - 17 4.09 - - - -
갈산프로필 0.06 0.02 - - - - - - - -
중량 399.1 100 399.04 100 416.04 100 416.04 100 502.04 100
TABLE 7
Classification ingredient Example 1 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11
Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%)
Pharmacologically active ingredient Amlodipine Besylate 6.94 1.74 6.94 1.74 6.94 1.67 6.94 1.67 6.94 1.38
Pharmacologically active ingredient Rosaltan Potassium 50 12.53 50 12.53 50 12.02 50 12.02 50 9.96
Filler Microcrystalline Cellulose (101) 130 32.57 130 32.58 130 31.25 130 31.25 130 25.89
Microcrystalline Cellulose (102) 135.1 33.85 135.1 33.86 135.1 32.47 135.1 32.47 135.1 26.91
Excipient D-mannitol 40 10.02 40 10.02 40 9.61 40 9.61 40 7.97
Disintegrant Starch sodium glyconate 17 4.26 17 4.26 17 4.09 17 4.09 17 3.39
Crospovidone 12 3.01 12 3.01 12 2.88 12 2.88 12 2.39
Binder Povidone 5 1.25 5 1.25 5 1.20 5 1.20 5 1.00
Lubricant Magnesium stearate 3 0.75 3 0.75 3 0.72 3 0.72 3 0.60
Antioxidant BHA - - - - - - 17 4.09 - -
Citric acid - - - - - - - - 103 20.52
BHT - - - - 17 4.09 - - - -
Gallic acid profile 0.06 0.02 - - - - - - - -
weight 399.1 100 399.04 100 416.04 100 416.04 100 502.04 100
표 8
분류 성분 비교예 12 비교예 13 비교예 14 비교예 15
함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%)
약리학적유효성분 암로디핀베실레이트 6.94 1.73 6.94 1.34 6.94 1.47 6.94 1.66
약리학적유효성분 로잘탄 칼륨 50 12.50 50 9.63 50 10.58 50 11.93
충진제 미결정셀룰로오스 (101) 130 32.50 130 25.05 130 27.51 130 31.02
충진제 미결정셀룰로오스 (102) 135.1 33.77 135.1 26.03 135.1 28.59 135.1 32.24
부형제 D-만니톨 40 10.00 40 7.71 40 8.46 40 9.55
붕해제 글리콘산전분 나트륨 17 4.25 17 3.28 17 3.60 17 4.06
붕해제 크로스포비돈 12 3.00 12 2.31 12 2.54 12 2.86
결합제 포비돈 5 1.25 5 0.96 5 1.06 5 1.19
활택제 스테아린산마그네슘 3 0.75 3 0.58 3 0.63 3 0.72
항산화제 BHA - - 8.5 1.64 8.5 1.80 - -
항산화제 Citric acid - - - 65 13.76 - -
항산화제 BHT - - 8.5 1.64 - - - -
항산화제 Sodium Ascorbate 1 0.25 103 19.84 - - - -
항산화제 산화아연 - - - - - - 20 4.77
중량 400.04 100 519.04 100 472.54 100 419.04 100
Table 8
Classification ingredient Comparative Example 12 Comparative Example 13 Comparative Example 14 Comparative Example 15
Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%)
Pharmacologically active ingredient Amlodipine besylate 6.94 1.73 6.94 1.34 6.94 1.47 6.94 1.66
Pharmacologically active ingredient Rosaltan Potassium 50 12.50 50 9.63 50 10.58 50 11.93
Filler Microcrystalline Cellulose (101) 130 32.50 130 25.05 130 27.51 130 31.02
Filler Microcrystalline Cellulose (102) 135.1 33.77 135.1 26.03 135.1 28.59 135.1 32.24
Excipient D-mannitol 40 10.00 40 7.71 40 8.46 40 9.55
Disintegrant Starch sodium glyconate 17 4.25 17 3.28 17 3.60 17 4.06
Disintegrant Crospovidone 12 3.00 12 2.31 12 2.54 12 2.86
Binder Povidone 5 1.25 5 0.96 5 1.06 5 1.19
Lubricant Magnesium stearate 3 0.75 3 0.58 3 0.63 3 0.72
Antioxidant BHA - - 8.5 1.64 8.5 1.80 - -
Antioxidant Citric acid - - - 65 13.76 - -
Antioxidant BHT - - 8.5 1.64 - - - -
Antioxidant Sodium Ascorbate One 0.25 103 19.84 - - - -
Antioxidant Zinc oxide - - - - - - 20 4.77
weight 400.04 100 519.04 100 472.54 100 419.04 100
표 9
분류 성분 비교예 16 비교예 17 비교예 18 비교예 19 비교예 20 비교예 21
함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%)
약리학적 유효성분 암로디핀 베실레이트 6.94 1.66 6.94 1.66 6.94 1.69 6.94 1.66 6.94 1.66 6.94 1.74
약리학적 유효성분 로잘탄 칼륨 50 11.93 50 11.93 50 12.21 50 11.93 50 11.93 50 12.51
충진제 미결정셀룰로오스 (101) 130 31.02 130 31.02 130 31.74 130 31.02 130 31.02 130 32.54
충진제 미결정셀룰로오스 (102) 135.1 32.24 135.1 32.24 135.1 32.99 135.1 32.24 135.1 32.24 135.1 33.81
부형제 D-만니톨 40 9.55 40 9.55 40 9.77 40 9.55 40 9.55 40 10.01
붕해제 글리콘산전분 나트륨 17 4.06 17 4.06 17 4.15 17 4.06 17 4.06 17 4.25
붕해제 크로스포비돈 12 2.86 12 2.86 12 2.93 12 2.86 12 2.86 12 3.00
결합제 포비돈 5 1.19 5 1.19 5 1.22 5 1.19 5 1.19 5 1.25
활택제 스테아린산마그네슘 3 0.72 3 0.72 3 0.73 3 0.72 3 0.72 3 0.75
항산화제 산화아연 - - - - 8.5 2.08 - - - - - -
항산화제 아스코르빈산 20 4.77 - - - - - - - - - -
항산화제 아황산수소나트륨 - - 20 4.77 - - - - - - - -
항산화제 에데트산 나트륨 - - - - 2 0.49 - - - - - -
항산화제 초산토코페롤 - - - - - - 20 4.77 - - - -
항산화제 토코페롤 - - - - - - - - 20 4.77 - -
항산화제 피로아황산나트륨 - - - - - - - - - - 0.5 0.13
중량 419.04 100 419.04 100 409.54 100 419.04 100 419.04 100 399.54 100
Table 9
Classification ingredient Comparative Example 16 Comparative Example 17 Comparative Example 18 Comparative Example 19 Comparative Example 20 Comparative Example 21
Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%)
Pharmacologically active ingredient Amlodipine Besylate 6.94 1.66 6.94 1.66 6.94 1.69 6.94 1.66 6.94 1.66 6.94 1.74
Pharmacologically active ingredient Rosaltan Potassium 50 11.93 50 11.93 50 12.21 50 11.93 50 11.93 50 12.51
Filler Microcrystalline Cellulose (101) 130 31.02 130 31.02 130 31.74 130 31.02 130 31.02 130 32.54
Filler Microcrystalline Cellulose (102) 135.1 32.24 135.1 32.24 135.1 32.99 135.1 32.24 135.1 32.24 135.1 33.81
Excipient D-mannitol 40 9.55 40 9.55 40 9.77 40 9.55 40 9.55 40 10.01
Disintegrant Starch sodium glyconate 17 4.06 17 4.06 17 4.15 17 4.06 17 4.06 17 4.25
Disintegrant Crospovidone 12 2.86 12 2.86 12 2.93 12 2.86 12 2.86 12 3.00
Binder Povidone 5 1.19 5 1.19 5 1.22 5 1.19 5 1.19 5 1.25
Lubricant Magnesium stearate 3 0.72 3 0.72 3 0.73 3 0.72 3 0.72 3 0.75
Antioxidant Zinc oxide - - - - 8.5 2.08 - - - - - -
Antioxidant Ascorbic acid 20 4.77 - - - - - - - - - -
Antioxidant Sodium bisulfite - - 20 4.77 - - - - - - - -
Antioxidant Sodium Edetate - - - - 2 0.49 - - - - - -
Antioxidant Tocopherol Acetate - - - - - - 20 4.77 - - - -
Antioxidant Tocopherol - - - - - - - - 20 4.77 - -
Antioxidant Sodium pyrosulfite - - - - - - - - - - 0.5 0.13
weight 419.04 100 419.04 100 409.54 100 419.04 100 419.04 100 399.54 100
(2) 시험 결과(2) test result
상기 시험 결과를 하기 표 10 및 표 11에 기재하였다. The test results are shown in Tables 10 and 11 below.
표 10
함량 실시예 1 비교예 8 비교예 9 비교예 10 비교예 11 비교예 12 비교예 13 비교예 14
암로디핀 초기함량 93.1% 96.6% 92.8% 90.8% 91.1% 91.6% 94.1% 94.2%
2주 93.9% 93.4% 90.9% 92.3% 98.2% 90.9% 90.6% 99.0%
5주 95.8% 90.8% 94.6% 92.7% - 88.2% 93.5% -
로잘탄 초기함량 99.2% 96.9% 102.5% 96.4% 99.0% 94.5% 99.8% 59.4%
2주 98.3% 94.8% 99.0% 86.8% 53.2% 99.0% 95.3% 56.8%
5주 100.9% 92.3% 101.2% 96.2% - 99.9% 102.4% -
Table 10
content Example 1 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Comparative Example 12 Comparative Example 13 Comparative Example 14
Amlodipine Initial content 93.1% 96.6% 92.8% 90.8% 91.1% 91.6% 94.1% 94.2%
2 weeks 93.9% 93.4% 90.9% 92.3% 98.2% 90.9% 90.6% 99.0%
5 Weeks 95.8% 90.8% 94.6% 92.7% - 88.2% 93.5% -
Rosaltan Initial content 99.2% 96.9% 102.5% 96.4% 99.0% 94.5% 99.8% 59.4%
2 weeks 98.3% 94.8% 99.0% 86.8% 53.2% 99.0% 95.3% 56.8%
5 Weeks 100.9% 92.3% 101.2% 96.2% - 99.9% 102.4% -
표 11
함량 비교예 15 비교예 16 비교예 17 비교예 18 비교예 19 비교예 20 비교예 21
암로디핀 초기함량 97.3% 95.5% 91.5% 94.8% 96.2% 97.3% 98.2%
2주 90.1% 89.5% 88.5% 90.3% 95.4% 94.2% 93.1%
5주 81.5% 80.6% 75.7% 76.5% 80.8% 83.2% 77.5%
로잘탄 초기함량 95.9% 102.5% 100.4% 95.7% 94.5% 93.1% 97.2%
2주 92.8% 95.1% 80.8% 79.2% 98.3% 91.0% 95.3%
5주 90.3% 80.2% 65.2% 70.5% 95.3% 87.5% 90.4%
Table 11
content Comparative Example 15 Comparative Example 16 Comparative Example 17 Comparative Example 18 Comparative Example 19 Comparative Example 20 Comparative Example 21
Amlodipine Initial content 97.3% 95.5% 91.5% 94.8% 96.2% 97.3% 98.2%
2 weeks 90.1% 89.5% 88.5% 90.3% 95.4% 94.2% 93.1%
5 Weeks 81.5% 80.6% 75.7% 76.5% 80.8% 83.2% 77.5%
Rosaltan Initial content 95.9% 102.5% 100.4% 95.7% 94.5% 93.1% 97.2%
2 weeks 92.8% 95.1% 80.8% 79.2% 98.3% 91.0% 95.3%
5 Weeks 90.3% 80.2% 65.2% 70.5% 95.3% 87.5% 90.4%
상기 표 10 및 표 11에 나타난 것과 같이 12종의 항산화제 및 혼용된 항산화제는 암로디핀 및 로잘탄의 안정성에 영향을 끼쳤다. 하지만 시트르산(citric acid) 및 아황산수소나트륨, 에데트산 나트륨은 로잘탄의 함량을 저하시키는 경향을 보였으며, 산화아연, 아스코르빈산, 초산토코페롤, 토코페롤, 피로아황산나트륨은 암로디핀의 함량이 저하시켰다. 그 외의 항산화제인 BHA, BHT, 갈산프로필(proyl gallate)이 암로디핀 및 로잘탄의 안정성을 유지시켜 주었다. 따라서 항산화제 중 BHT, 갈산프로필, BHT 및 BHA을 혼합하여 사용한 경우, 상대적으로 항산화력을 나타냄을 알 수 있었다. As shown in Table 10 and Table 11, 12 kinds of antioxidants and mixed antioxidants affected the stability of amlodipine and rozatan. However, citric acid, sodium bisulfite and sodium edetate showed a tendency to reduce the content of rozatan, and zinc oxide, ascorbic acid, tocopherol, tocopherol and sodium pyrosulfite decreased the content of amlodipine. Other antioxidants, BHA, BHT and propyl gallate, helped to maintain the stability of amlodipine and rozatan. Therefore, it was found that the antioxidant activity of BHT, propyl gallate, BHT and BHA mixed with the antioxidant was shown relatively.
3.2 항산화제 선정 시험3.2 Antioxidant Selection Test
상기 시험예 3.1에서 안정성을 높게 나타내는 것으로 확인되었던 상위 3종의 항산화제 (BHT, 갈산프로필, BHT+BHA)를 이용하여 3종의 항산화제 중 최적의 안정화 효과를 나타내는 항산화제를 선정하는 시험을 수행하였다. Using the top three antioxidants (BHT, propyl gallate, BHT + BHA) that were found to exhibit high stability in Test Example 3.1, a test for selecting an antioxidant having an optimal stabilizing effect among three antioxidants was carried out. Was performed.
(1) 제조방법(1) manufacturing method
암로디핀과 로잘탄을 하기 표 12에 나타난 처방과 같이 3종의 항산화제를 각각 포함한 물리적 혼합물을 실시예 2 및 비교예 22, 비교예 23으로 제조하였다. 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.
각각 처방의 제제 각각 항산화제를 포함하는 암로디핀 층과 로잘탄 층으로 나누어지는 이층정으로 제제화하였으며 이층정은 이층정 타정기를 이용하여 각각 처방 중량을 맞춘 후 압력 12.5kpa, 두께 5.30 mm로 설정되어 타정하였다. 각각의 정제는 표 2의 조건으로 가속챔버에 노출 시킨 후 제조직후, 2주 후, 4주 후, 8주 후 함량을 측정하였다. 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.
① 암로디핀의 함량 측정① Determination of Amlodipine Content
각 샘플 3정 또는 동일 분량을 취해 무게를 정밀히 달고 가루로 한다. 암로디핀으로서 약 5 mg 해당량을 달아 100mL 갈색용량플라스크에 넣고 이동상을 넣어 정확히 100mL가 되게 한다. 이 액 25mL를 취해 50mL 갈색용량플라스크에 넣어 이동상으로 표선까지 맞춘 후 0.45㎛ 멤브레인 필터로 여과하여 표 3과 같은 조건으로 HPLC를 이용하여 함량을 측정한다. Take 3 tablets or the same amount of each sample, weigh it precisely, and powder it. Weigh about 5 mg of amlodipine in a 100 mL brown volumetric flask and add mobile phase to exactly 100 mL. Take 25 mL of this solution, place it in a 50 mL brown volumetric flask, adjust the mark to the mobile phase, and filter with 0.45 μm membrane filter. Measure the content using HPLC under the same conditions as in Table 3.
② 로잘탄의 함량 측정② Determination of the content of lozatan
각 샘플 3정 또는 동일 분량을 취해 무게를 정밀히 달고 가루로 한다. 로잘탄칼륨으로서 약 50mg 해당량을 정밀히 달아 200mL 용량플라스크에 넣고, 이동상 A로 약 100mL을 채운 후 약 10분간 초음파 추출한 뒤 이동상 A를 가해 정확히 200mL로 맞춘 후 0.45㎛ 멤브레인 필터로 여과하여 표 3과 같은 조건으로 HPLC를 이용하여 함량을 측정한다.Take 3 tablets or the same amount of each sample, weigh it precisely, and powder it. Precisely weigh about 50mg of rozatan potassium and place it in a 200mL volumetric flask, fill about 100mL with mobile phase A, ultrasonically extract for about 10 minutes, add mobile phase A to exactly 200mL, and filter with 0.45㎛ membrane filter. The content is measured using HPLC as conditions.
표 12
분류 성분 실시예 2 비교예 22 비교예 23
함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%)
약리학적유효성분 암로디핀베실레이트 암로디핀 층 6.94 1.74 6.94 1.66 6.94 1.66
충진제 미결정셀룰로오스 (101) 130 32.57 130 31.02 130 31.02
부형제 D-만니톨 40 10.02 40 9.55 40 9.55
붕해제 글리콘산전분 나트륨 17 4.26 17 4.06 17 4.06
결합제 포비돈 5 1.25 5 1.19 5 1.19
활택제 스테아린산마그네슘 1.5 0.38 3 0.72 3 0.72
항산화제 BHT 17 4.06 8.5 2.03
항산화제 BHA 8.5 2.03
항산화제 Propyl gallate 0.06 0.02
약리학적 유효성분 로잘탄 칼륨 로잘탄 층 50 12.53 50 11.93 50 11.93
충진제 미결정셀룰로오스 (102) 135.1 33.85 135.1 32.24 135.1 32.24
붕해제 크로스포비돈 12 3.01 12 2.86 12 2.86
활택제 스테아린산마그네슘 1.5 0.38 3 0.72 3 0.72
총중량 399.1 100.00 419.04 100.00 419.04 100.00
Table 12
Classification ingredient Example 2 Comparative Example 22 Comparative Example 23
Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%)
Pharmacologically active ingredient Amlodipine besylate Amlodipine layer 6.94 1.74 6.94 1.66 6.94 1.66
Filler Microcrystalline Cellulose (101) 130 32.57 130 31.02 130 31.02
Excipient D-mannitol 40 10.02 40 9.55 40 9.55
Disintegrant Starch sodium glyconate 17 4.26 17 4.06 17 4.06
Binder Povidone 5 1.25 5 1.19 5 1.19
Lubricant Magnesium stearate 1.5 0.38 3 0.72 3 0.72
Antioxidant BHT 17 4.06 8.5 2.03
Antioxidant BHA 8.5 2.03
Antioxidant Propyl gallate 0.06 0.02
Pharmacologically active ingredient Rosaltan Potassium Rosaltan floor 50 12.53 50 11.93 50 11.93
Filler Microcrystalline Cellulose (102) 135.1 33.85 135.1 32.24 135.1 32.24
Disintegrant Crospovidone 12 3.01 12 2.86 12 2.86
Lubricant Magnesium stearate 1.5 0.38 3 0.72 3 0.72
Gross weight 399.1 100.00 419.04 100.00 419.04 100.00
(2) 시험 결과(2) test result
상기 시험 결과를 표 13에 기재하였다.The test results are shown in Table 13.
표 13
함량 실시예 2 비교예 22 비교예 23
암로디핀 초기함량 93.6% 96.0% 99.6%
4주 90.4% 87.0% 91.1%
8주 84.6% 81.2%
로잘탄 초기함량 99.3% 96.8% 101.6%
4주 102.5% 103.5% 96.5%
8주 100% 97%
Table 13
content Example 2 Comparative Example 22 Comparative Example 23
Amlodipine Initial content 93.6% 96.0% 99.6%
4 Weeks 90.4% 87.0% 91.1%
8 Weeks 84.6% 81.2%
Rosaltan Initial content 99.3% 96.8% 101.6%
4 Weeks 102.5% 103.5% 96.5%
8 Weeks 100% 97%
상기 표 13에 나타난 것과 같이 각각의 처방으로 초기함량, 4주 8주의 함량을 측정한 결과, 각 처방은 비슷한 항산화력을 나타내었다. 하지만 BHT와 BHA 및 BHT가 함유된 처방인 비교예 22 및 비교예 23은 각각 4주, 8주 뒤 항산화제에 의한 정제의 갈변현상이 관찰되었다. 따라서 실시예 2에 함유된 항산화제인 갈산프로필(propyl gallate)이 정제에 물리화학적 영향을 최소화하면서 강력한 항산화력을 가지는 것으로 나타났다. As shown in Table 13, the initial content of each prescription, the content of 4 weeks 8 weeks was measured, each prescription showed similar antioxidant power. However, browning of tablets by antioxidants was observed in Comparative Example 22 and Comparative Example 23 containing BHT and BHA and BHT after 4 weeks and 8 weeks, respectively. Therefore, propyl gallate, an antioxidant contained in Example 2, was shown to have strong antioxidant power while minimizing physicochemical effects on the tablets.
시험예 4. 복합제 안정성 확보시험Experimental Example 4. Complex stability stability test
암로디핀과 로잘탄의 두 약물간 상호작용을 최소화하기 위하여, 수분에 대해 강력한 보호효과를 가지는 코팅기제를 이용한 제형을 적용하였으며, 그 코팅에 따른 안정성의 변화를 측정하였다. In order to minimize the interaction between the two drugs, amlodipine and lozatan, a formulation using a coating agent having a strong protective effect against water was applied, and the change in stability with the coating was measured.
4.1 제형 확인 시험4.1 Formulation Identification Test
상기 시험에서도 확인하였듯이 암로디핀과 로잘탄이 물리화학적으로 접촉할 경우 약물 또는 부형제간의 상호작용에 의하여 그 안정성이 떨어짐을 알 수 있다. 따라서 암로디핀과 로잘탄의 접촉면적을 최소화하기 위해 암로디핀 층과 로잘탄 층으로 나뉜 이층정과 물리적 혼합을 이용한 단일정과의 안정성을 비교 측정하였다.As confirmed in the above test, when amlodipine and rozatan contact with physicochemically, it can be seen that the stability of the drug or excipient is reduced due to the interaction between the drug and the excipient. Therefore, in order to minimize the contact area between amlodipine and rozatan, the stability of the bilayer tablet divided into amlodipine layer and rozatan layer and the single tablet using physical mixing were compared and measured.
(1) 제조방법(1) manufacturing method
암로디핀과 로잘탄을 하기 표 14에 나타난 처방과 같이 실시예 4은 암로디핀과 로잘탄 단일정이며, 실시예 3는 암로디핀 층과 로잘탄 층으로 나누지는 이중정으로 정제화하였으며, 각각의 정제는 표 2의 조건으로 가속챔버에 노출 시킨 후 제조직후, 2주 후, 4주 후, 8주 후 함량을 측정하였다. Amlodipine and Rosaltan as shown in Table 14, 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.
암로디핀과 로잘탄의 함량 측정 방법은 시험예 1에 기재한 방법과 동일한 방법으로 실시하였다. The method of measuring the content of amlodipine and rozatan was carried out in the same manner as described in Test Example 1.
표 14
분류 성분 실시예 3(이중정) 실시예 4(단일정)
함량(mg) 함량비(%) 함량(mg) 함량비(%)
약리학적 유효성분 암로디핀 베실레이트 암로디핀 층 6.94 1.74 6.94 1.74
충진제 미결정셀룰로오스 (101) 130.00 32.57 130.00 32.57
부형제 D-만니톨 40.00 10.02 40.00 10.02
붕해제 글리콘산전분 나트륨 17.00 4.26 17.00 4.26
결합제 포비돈 5.00 1.25 5.00 1.25
활택제 스테아린산마그네슘 1.50 0.38
항산화제 갈산프로필 0.06 0.02 0.06 0.02
약리학적 유효성분 로잘탄 칼륨 로잘탄 층 50.00 12.53 50.00 12.53
충진제 미결정셀룰로오스 (102) 135.10 33.85 135.10 33.85
붕해제 크로스포비돈 12.00 3.01 12.00 3.01
활택제 스테아린산마그네슘 1.50 0.38 3.00 0.75
총중량 399.10 100.00 399.10 100.00
Table 14
Classification ingredient 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
Filler Microcrystalline Cellulose (101) 130.00 32.57 130.00 32.57
Excipient D-mannitol 40.00 10.02 40.00 10.02
Disintegrant Starch sodium glyconate 17.00 4.26 17.00 4.26
Binder Povidone 5.00 1.25 5.00 1.25
Lubricant Magnesium stearate 1.50 0.38
Antioxidant Gallic acid profile 0.06 0.02 0.06 0.02
Pharmacologically active ingredient Rosaltan Potassium Rosaltan floor 50.00 12.53 50.00 12.53
Filler Microcrystalline Cellulose (102) 135.10 33.85 135.10 33.85
Disintegrant Crospovidone 12.00 3.01 12.00 3.01
Lubricant Magnesium stearate 1.50 0.38 3.00 0.75
Gross weight 399.10 100.00 399.10 100.00
(2) 시험 결과(2) test result
상기 시험에 따른 결과를 표 15에 기재하였다.The results according to the test are shown in Table 15.
표 15
함량 실시예 3 실시예 4
암로디핀 초기함량 99.6% 96.7%
2주 98.4% 95.0%
4주 95.6% 91.2%
8주 94.4% 88.5%
로잘탄 초기함량 100.3% 96.8%
2주 99.6% 96.9%
4주 99.5% 96.6%
8주 98.4% 96%
Table 15
content Example 3 Example 4
Amlodipine Initial content 99.6% 96.7%
2 weeks 98.4% 95.0%
4 Weeks 95.6% 91.2%
8 Weeks 94.4% 88.5%
Rosaltan Initial content 100.3% 96.8%
2 weeks 99.6% 96.9%
4 Weeks 99.5% 96.6%
8 Weeks 98.4% 96%
상기 표 15에 나타난 것과 같이, 실시예 3 및 실시예 4에서 모두 8주 후에도 비교적 안정성을 가지는 복합제를 형성하는 것으로 나타났으나, 시간이 지남에 따라 이중정으로 제제화된 실시예 3의 함량이 적게 떨어졌다. 따라서 단일정보다 이중정으로 제제화할 경우 향상된 안정성을 나타낸다는 것을 알 수 있었으며, 이것은 두 약물사이의 접촉면을 최소화시킴으로써 약물 상호 작용을 방지하는 것으로부터 기인하는 것으로 고찰된다.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.
4.2 코팅 시험4.2 Coating Test
본 발명의 복합제의 장기적인 안정성 확인을 위해 3종의 코팅기제를 이용하여 코팅에 따른 안정성의 변화를 측정하였다. In order to confirm the long-term stability of the composite of the present invention, three kinds of coating bases were used to measure the change in stability according to the coating.
(1) 제조방법(1) manufacturing method
암로디핀과 로잘탄을 하기 표 16에 나타난 처방과 같이 암로디핀 층과 로잘탄 층으로 나누지는 이중정으로 정제화 하였으며, 각각의 정제는 3종의 코팅기제(KollicoatProtect (BASF), Opadry, 히드록시프로필메틸셀룰로오스(HPMC, Hydroxypropyl methylcellulose))를 이용하여 코팅한 후 각각 표 2의 조건으로 가속챔버에 노출 시켜 제조직후, 2주 후, 4주 후, 8주 후 함량을 측정하였다.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.
① 암로디핀의 함량 측정① Determination of Amlodipine Content
각 샘플 3정 또는 동일 분량을 취해 무게를 정밀히 달고 가루로 한다. 암로디핀으로서 약 5 mg 해당량을 달아 100mL 갈색용량플라스크에 넣고 이동상을 넣어 정확히 100mL가 되게 한다. 이 액 25mL를 취해 50mL 갈색용량플라스크에 넣어 이동상으로 표선까지 맞춘 후 0.45㎛ 멤브레인 필터로 여과하여 표 3과 같은 조건으로 HPLC를 이용하여 함량을 측정한다. Take 3 tablets or the same amount of each sample, weigh it precisely, and powder it. Weigh about 5 mg of amlodipine in a 100 mL brown volumetric flask and add mobile phase to exactly 100 mL. Take 25 mL of this solution, place it in a 50 mL brown volumetric flask, adjust the mark to the mobile phase, and filter with 0.45 μm membrane filter. Measure the content using HPLC under the same conditions as in Table 3.
② 로잘탄의 함량 측정② Determination of the content of lozatan
각 샘플 3정 또는 동일 분량을 취해 무게를 정밀히 달고 가루로 한다. 로자탄칼륨으로서 약 50mg 해당량을 정밀히 달아 200mL 용량플라스크에 넣고, 이동상 A로 약 100mL을 채운 후 약 10분간 초음파 추출한 뒤 이동상 A를 가해 정확히 200mL로 맞춘 후 0.45㎛ 멤브레인 필터로 여과하여 표 3과 같은 조건으로 HPLC를 이용하여 함량을 측정한다.Take 3 tablets or the same amount of each sample, weigh it precisely, and powder it. About 50mg of 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㎛ membrane filter. The content is measured using HPLC under the same conditions.
표 16
분류 성분 실시예 5 실시예 6 실시예 7
함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%)
암로디핀 층 약리학적 유효성분 암로디핀 베실레이트 6.94 1.70 6.94 1.70 6.94 1.70
충진제 미결정셀룰로오스 (101) 130.00 31.78 130.00 31.78 130.00 31.78
부형제 D-만니톨 40.00 9.78 40.00 9.78 40.00 9.78
붕해제 글리콘산전분 나트륨 17.00 4.16 17.00 4.16 17.00 4.16
결합제 포비돈 5.00 1.22 5.00 1.22 5.00 1.22
활택제 스테아린산마그네슘 3.00 0.73 3.00 0.73 3.00 0.73
항산화제 Propyl gallate 0.06 0.01 0.06 0.01 0.06 0.01
로잘탄 층 약리학적 유효성분 로잘탄 칼륨 50.00 12.22 50.00 12.22 50.00 12.22
충진제 미결정셀룰로오스 (102) 135.10 33.02 135.10 33.02 135.10 33.02
붕해제 크로스포비돈 12.00 2.93 12.00 2.93 12.00 2.93
활택제 스테아린산마그네슘 3.00 0.73 3.00 0.73 3.00 0.73
코팅기제 kollicoat protect 7.00 1.71 - - - -
Opadry - - 7.00 1.71 - -
HPMC - - - - 7.00 1.71
총중량 409.10 100.00 409.10 100.00 409.10 100.00
Table 16
Classification ingredient Example 5 Example 6 Example 7
Content (mg) Content ratio (%) Content (mg) Content ratio (%) Content (mg) Content ratio (%)
Amlodipine layer Pharmacologically active ingredient Amlodipine Besylate 6.94 1.70 6.94 1.70 6.94 1.70
Filler Microcrystalline Cellulose (101) 130.00 31.78 130.00 31.78 130.00 31.78
Excipient D-mannitol 40.00 9.78 40.00 9.78 40.00 9.78
Disintegrant Starch sodium glyconate 17.00 4.16 17.00 4.16 17.00 4.16
Binder Povidone 5.00 1.22 5.00 1.22 5.00 1.22
Lubricant Magnesium stearate 3.00 0.73 3.00 0.73 3.00 0.73
Antioxidant Propyl gallate 0.06 0.01 0.06 0.01 0.06 0.01
Rosaltan floor Pharmacologically active ingredient Rosaltan Potassium 50.00 12.22 50.00 12.22 50.00 12.22
Filler Microcrystalline Cellulose (102) 135.10 33.02 135.10 33.02 135.10 33.02
Disintegrant Crospovidone 12.00 2.93 12.00 2.93 12.00 2.93
Lubricant Magnesium stearate 3.00 0.73 3.00 0.73 3.00 0.73
Coating base kollicoat  protect 7.00 1.71  -  -  -  -
Opadry  -  - 7.00 1.71  -  -
HPMC  -  -  -  - 7.00 1.71
Gross weight 409.10 100.00 409.10 100.00 409.10 100.00
            
(2) 시험 결과(2) test result
상기 시험 결과를 하기 표 17에 기재하였다.The test results are shown in Table 17 below.
표 17
함량 실시예 5 실시예 6 실시예 7
암로디핀 초기함량 100.2% 97.7% 101.6%
2주 100.4% 95.6% 99.4%
4주 99.6% 94.1% 98.8%
8주 98.9% 93.5% 95.2%
로잘탄 초기함량 99.5% 99.5% 100.3%
2주 99.3% 97.6% 98.4%
4주 99.9% 96.9% 96.5%
8주 99.5% 96.0% 95.3%
Table 17
content 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%
상기 표 17에 나타난 것과 같이 각각의 처방으로 초기함량, 2주, 4주 8주의 함량을 측정한 결과 kollicoat protect를 이용하여 코팅한 제제인 실시예 5가 가장 우수한 안정성을 나타내는 것으로 확인되었다. kollicoat protect는 약물의 수분과의 접촉을 차단함으로써 약물이 가수분해되는 것을 효과적으로 차단할 수 있기 때문인 것으로 생각된다. 그 외 HPMC와 Opadry 을 사용하여 코팅된 실시예 6 및 실시에 7도 약물의 안정성을 향상시키는 역할을 하나 kollicoat protect가 가장 효과적으로 차단되는 것으로 관찰되었다.As shown in Table 17, the results of measuring the contents of the initial content, 2 weeks, 4 weeks and 8 weeks with each prescription  It was found that Example 5, the formulation coated with protect, 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.
시험예 5. 용출 시험Test Example 5 Dissolution Test
5.1 용출 시험5.1 Dissolution Test
안정성이 확보된 암로디핀 및 로잘탄을 포함하는 복합제의 이상적인 용출곡선을 찾기 위해 아래와 같이 부형제의 양을 조절하여 다양한 처방으로 실험을 실시하였다.In order to find the ideal dissolution curve of the composite containing amlodipine and rozatan with stability, experiments were carried out with various prescriptions by adjusting the amount of excipients as follows.
(1) 제조방법(1) manufacturing method
암로디핀과 로잘탄을 하기 표 18 및 표 19에 나타난 처방과 같이 암로디핀 층과 로잘탄 층으로 나누지는 이층정으로 정제화 및 코팅을 하여 제조하였다.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.
표 18
분류 성분 실시예 8 실시예 9 실시예 10 실시예 11 실시예 12
함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%)
암로디핀 층 약리학적유효성분 암로디핀 베실레이트 6.94 1.72 6.94 1.70 6.94 1.72 6.94 1.72 6.94 1.72
충진제 미결정셀룰로오스 (101) 130.00 32.17 130.00 31.78 130.00 32.17 130.00 32.17 130.00 32.17
부형제 D-만니톨 40.00 9.90 40.00 9.78 40.00 9.90 40.00 9.90 40.00 9.90
붕해제 글리콘산전분나트륨 12.00 2.97 17.00 4.16 20.00 4.95 12.00 2.97 17.00 4.21
결합제 포비돈 5.00 1.24 5.00 1.22 5.00 1.24 5.00 1.24 5.00 1.24
활택제 스테아린산마그네슘 3.00 0.74 3.00 0.73 3.00 0.74 3.00 0.74 3.00 0.74
항산화제 Propyl gallate 0.06 0.01 0.06 0.01 0.06 0.01 0.06 0.01 0.06 0.01
로잘탄 층 약리학적유효성분 로잘탄칼륨 50.00 12.37 50.00 12.22 50.00 12.37 50.00 12.37 50.00 12.37
충진제 미결정셀룰로오스 (102) 135.10 33.43 135.10 33.02 135.10 33.43 135.10 33.43 135.10 33.43
붕해제 크로스포비돈 12.00 2.97 12.00 2.93 12.00 2.97 10.00 2.47 10.00 2.47
활택제 스테아린산마그네슘 3.00 0.74 3.00 0.73 3.00 0.74 3.00 0.74 3.00 0.74
코팅기제 kolcoat protect 7.00 1.73 7.00 1.73 7.00 1.73 7.00 1.73 7.00 1.73
총중량 404.10 100.00 409.10 100.02 412.10 101.98 402.10 99.51 407.10 100.74
Table 18
Classification ingredient Example 8 Example 9 Example 10 Example 11 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 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
Antioxidant Propyl gallate 0.06 0.01 0.06 0.01 0.06 0.01 0.06 0.01 0.06 0.01
Rosaltan floor Pharmacologically active ingredient Rosaltan Potassium 50.00 12.37 50.00 12.22 50.00 12.37 50.00 12.37 50.00 12.37
Filler Microcrystalline Cellulose (102) 135.10 33.43 135.10 33.02 135.10 33.43 135.10 33.43 135.10 33.43
Disintegrant Crospovidone 12.00 2.97 12.00 2.93 12.00 2.97 10.00 2.47 10.00 2.47
Lubricant Magnesium stearate 3.00 0.74 3.00 0.73 3.00 0.74 3.00 0.74 3.00 0.74
Coating base kolcoat protect 7.00 1.73 7.00 1.73 7.00 1.73 7.00 1.73 7.00 1.73
Gross weight 404.10 100.00 409.10 100.02 412.10 101.98 402.10 99.51 407.10 100.74
표 19
분류 성분 실시예 13 실시예 14 실시예 15 실시예 16 실시예 17
함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%) 함량(mg) 함량비(%)
암로디핀 층 약리학적 유효성분 암로디핀 베실레이트 6.94 1.72 6.94 1.70 6.94 1.72 6.94 1.72 6.94 1.72
충진제 미결정셀룰로오스 (101) 130.00 32.17 130.00 31.78 130.00 32.17 130.00 32.17 130.00 32.17
부형제 D-만니톨 40.00 9.90 40.00 9.78 40.00 9.90 50.00 12.37 50.00 12.37
붕해제 글리콘산전분 나트륨 12.00 2.97 17.00 4.16 20.00 4.95 12.00 2.97 17.00 4.21
결합제 포비돈 7.00 1.73 7.00 1.71 7.00 1.73 7.00 1.73 5.00 1.24
활택제 스테아린산마그네슘 3.00 0.74 3.00 0.73 3.00 0.74 3.00 0.74 3.00 0.74
항산화제 Propyl gallate 0.06 0.01 0.06 0.01 0.06 0.01 0.06 0.01 0.06 0.01
로잘탄 층 약리학적 유효성분 로잘탄 칼륨 50.00 12.37 50.00 12.22 50.00 12.37 50.00 12.37 50.00 12.37
충진제 미결정셀룰로오스 (102) 135.10 33.43 135.10 33.02 135.10 33.43 135.10 33.43 135.10 33.43
붕해제 크로스포비돈 10.00 2.47 10.00 2.44 10.00 2.47 10.00 2.47 10.00 2.47
활택제 스테아린산마그네슘 3.00 0.74 3.00 0.73 3.00 0.74 3.00 0.74 3.00 0.74
코팅기제 kolcoat protect 7.00 1.73 7.00 1.73 7.00 1.73 7.00 1.73 7.00 1.73
총중량 404.10 100.00 409.10 100.02 412.10 101.98 414.10 102.47 417.10 103.22
Table 19
Classification ingredient Example 13 Example 14 Example 15 Example 16 Example 17
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 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 50.00 12.37 50.00 12.37
Disintegrant Starch sodium glyconate 12.00 2.97 17.00 4.16 20.00 4.95 12.00 2.97 17.00 4.21
Binder Povidone 7.00 1.73 7.00 1.71 7.00 1.73 7.00 1.73 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
Antioxidant Propyl gallate 0.06 0.01 0.06 0.01 0.06 0.01 0.06 0.01 0.06 0.01
Rosaltan floor Pharmacologically active ingredient Rosaltan Potassium 50.00 12.37 50.00 12.22 50.00 12.37 50.00 12.37 50.00 12.37
Filler Microcrystalline Cellulose (102) 135.10 33.43 135.10 33.02 135.10 33.43 135.10 33.43 135.10 33.43
Disintegrant Crospovidone 10.00 2.47 10.00 2.44 10.00 2.47 10.00 2.47 10.00 2.47
Lubricant Magnesium stearate 3.00 0.74 3.00 0.73 3.00 0.74 3.00 0.74 3.00 0.74
Coating base kolcoat protect 7.00 1.73 7.00 1.73 7.00 1.73 7.00 1.73 7.00 1.73
Gross weight 404.10 100.00 409.10 100.02 412.10 101.98 414.10 102.47 417.10 103.22
상기 제조된 실시예 8 내지 실시예 17의 제제를 각각 아래와 같은 조건으로 용출시험을 수행하였다.Each of the formulations of Examples 8 to 17 prepared above was subjected to dissolution test under the following conditions.
① 암로디핀① Amlodipine
암로디핀 베실레이트 표준품 약 34.7 mg을 정밀히 달아 250 mL 갈색용량플라스크에 넣고 0.001mol/L 염산액으로 정확히 250 mL가 되도록 한다. 이 액 10 mL를 정확히 취해 100 mL 갈색용량 플라스크에 넣고, 0.01 mol/L 염산액을 가하여 표선까지 혼화한 뒤, 0.45㎛ 멤브레인 필터로 여과한 액을 표준액으로 한다. Approximately 34.7 mg of 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 µm membrane filter as standard solution.
또한 샘플 3정을 취해 무게를 정밀히 달고 표 20과 같은 조건으로 용출시험 후 용출 개시 5, 10, 15, 30, 45 분후 용출액 10mL을 취하여 0.45 um 멤브레인 필터로 여과한 액을 검액으로 한다. In addition, take 3 tablets, weigh them accurately, and after dissolution test under the conditions shown in Table 20, take 10 mL of the elution solution after 5, 10, 15, 30, and 45 minutes of elution, and filter the solution with a 0.45 um membrane filter.
검액 및 표준액은 상기 표 3과 같은 조건으로 HPLC를 이용하여 분석한다.The sample solution and the standard solution are analyzed using HPLC under the same conditions as in Table 3.
표 20
장치 대한약전 일반시험법의 용출 시험법 제2법의 장치
시험액 0.01 mol/L, 염산액 500mL
용출 온도 37±0.5℃
회전수 100±5 rpm
Table 20
Device Apparatus of Dissolution Test Method 2 of the Korean Pharmacopoeia General Test Method
Test solution 0.01 mol / L, hydrochloric acid solution 500mL
Elution temperature 37 ± 0.5 ℃
Revolutions
100 ± 5 rpm
② 로잘탄② Rosaltan
로잘탄 칼륨 표준품 50 mg을 정밀히 달아 100 mL 용량 플라스크에 넣고 이동상 A를 가하여 녹인 후 표선까지 채운 후 혼화한 액 10 mL를 100mL 용량플라스크에 넣고, 정제수를 가하여 표선까지 혼화한 후 0.45㎛ 멤브레인 필터로 여과한 액을 표준액으로 한다. Precisely weigh 50 mg of Rozatan potassium standard and dissolve it in a 100 mL volumetric flask, add mobile phase A, dissolve it, fill it to the mark, add 10 mL of the mixed solution to a 100 mL volumetric flask, mix with purified water, and filter to 0.45 ㎛ membrane filter. One solution is used as the standard solution.
또한 샘플 3정을 취해 무게를 정밀히 달고 표 21과 같은 조건으로 용출시험 후 용출 개시 5, 10, 15, 30, 45 분후 용출액 10mL을 취하여 0.45㎛ 멤브레인 필터로 여과한 액을 검액으로 한다. In addition, take 3 tablets, weigh them accurately, and after dissolution test under the conditions shown in Table 21, take 10 mL of the elution solution after 5, 10, 15, 30, and 45 minutes of elution, and filter the solution with a 0.45 μm membrane filter.
검액 및 표준액은 상기 표 3과 같은 조건으로 HPLC를 이용하여 분석한다.The sample solution and the standard solution are analyzed using HPLC under the same conditions as in Table 3.
표 21
장치 대한약전 일반시험법의 용출 시험법 제 2법의 장치
시험액 정제수, 900mL
용출 온도 37±0.5℃
회전수 75±5 rpm
Table 21
Device Apparatus of Dissolution Test Method 2 of the Korean Pharmacopoeia General Test Method
Test solution Purified water, 900mL
Elution temperature 37 ± 0.5 ℃
Revolutions 75 ± 5 rpm
(2) 용출시험 결과(2) Dissolution test result
상기 용출시험 결과를 도 1 및 도 2에 나타내었다.The dissolution test results are shown in FIGS. 1 and 2.
도 1은 실시예 8 내지 실시예 17에 대한 암로디핀의 용출 시험의 결과를 나타낸 그래프이며, 도 2는 실시예 8 내지 실시예 17에 대한 로잘탄의 용출 시험의 결과를 나타낸 그래프이다.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.
도 1에 나타난 암로디핀에 대한 용출 시험의 결과에서 나타난 것과 같이, 모든 처방이 초기에 높은 용출율을 나타내었으나 기준인 5분에 85%이상을 만족시킨 처방은 실시예 9와 실시예 10이었다. 도 2에 나타낸 로잘탄의 경우 역시 실시예 8 및 실시예 9가 5분 간 85%이상의 기준을 만족시켰다. 따라서 안정성을 향상된 암로디핀 및 로잘탄을 함유하는 복합제의 최적 처방은 실시예 9인 것으로 나타났다.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.

Claims (11)

  1. 암로디핀 또는 이의 약제학적 허용가능한 염, 로잘탄 또는 이의 약제학적 허용가능한 염, 및 갈산프로필을 포함하는 심혈관계 질환의 예방 및 치료용 복합제 조성물.A combination composition for preventing and treating cardiovascular diseases, including amlodipine or a pharmaceutically acceptable salt thereof, lozatan or a pharmaceutically acceptable salt thereof, and propyl gallate.
  2. 청구항 1에 있어서, 상기 암로디핀 또는 이의 약제학적 허용가능한 염을 포함하는 암로디핀 층 및 로잘탄 또는 이의 약제학적 허용가능한 염을 포함하는 로잘탄 층으로 분리된 상태인, 이중층 구조를 이루는 이중정인 것을 특징으로 하는 복합제 조성물.The double agent of claim 1, wherein the double-layered double tablet is separated into an amlodipine layer comprising amlodipine or a pharmaceutically acceptable salt thereof and a rozatantan layer comprising rozatan or a pharmaceutically acceptable salt thereof. Composition.
  3. 청구항 2에 있어서, 상기 갈산프로필은 암로디핀 또는 이의 약제학적 허용가능한 염을 포함하는 암로디핀 층에 포함되는 것을 특징으로 하는 복합제 조성물.The combination composition of claim 2, wherein the propyl gallate is included in an amlodipine layer comprising amlodipine or a pharmaceutically acceptable salt thereof.
  4. 청구항 1에 있어서, 상기 갈산프로필은 조성물 총 중량에 대하여 0.001 내지 1중량%로 포함되는 것을 특징으로 하는 복합제 조성물.The composite composition of claim 1, wherein the propyl gallate is included in an amount of 0.001 to 1% by weight based on the total weight of the composition.
  5. 청구항 1에 있어서, 조성물 총 중량에 대하여 상기 암로디핀 또는 이의 약제학적 허용가능한 염은 1 내지 6 중량% 및 상기 로잘탄 또는 이의 약제학적 허용가능한 염은 5 내지 30 중량%로 포함되는 것을 특징으로 하는 복합제 조성물.The combination composition according to claim 1, wherein the amlodipine or the pharmaceutically acceptable salt thereof is 1 to 6% by weight and the rozatan or the pharmaceutically acceptable salt thereof is 5 to 30% by weight based on the total weight of the composition. .
  6. 청구항 1에 있어서, 상기 조성물은 코팅기제를 더 포함하는 것을 특징으로 하는 복합제 조성물.The composite composition of claim 1, wherein the composition further comprises a coating base.
  7. 청구항 6에 있어서, 상기 코팅기제는 수용성 코팅기제 중 폴리비닐 알코올유도체, 메타크릴산 유도체 및 폴리아크릴산 유도체를 포함한 코팅기제, Kollicoat Protect, Opadry 및 히드록시프로필메틸셀룰로오스(HPMC)로 이루어지는 군에서 선택되는 일종 이상인 것을 특징으로 하는 복합제 조성물.The coating base of claim 6, wherein the coating base includes a polyvinyl alcohol derivative, a methacrylic acid derivative, and a polyacrylic acid derivative in a water-soluble coating base, Kollicoat.  It is at least one kind selected from the group consisting of Protect, Opadry and hydroxypropylmethylcellulose (HPMC).
  8. 청구항 1에 있어서, 상기 암로디핀의 약제학적 허용가능한 염은 암로디핀 베실레이트이고, 상기 로잘탄의 약제학적 허용가능한 염은 로잘탄 칼륨인 것을 특징으로 하는 복합제 조성물.2. The combination composition of claim 1, wherein the pharmaceutically acceptable salt of amlodipine is amlodipine besylate and the pharmaceutically acceptable salt of rozatan is rozatan potassium.
  9. 청구항 1에 있어서, 상기 조성물에 약제학적으로 허용가능한 첨가제를 추가로 더 포함하는 것을 특징으로 하는 복합제 조성물.The combination composition of claim 1, further comprising a pharmaceutically acceptable additive in the composition.
  10. 청구항 9에 있어서, 상기 첨가제는 조성물 총 중량에 대하여 5 내지 90 중량%로 포함되는 것을 특징으로 하는 복합제 조성물.The composite composition of claim 9, wherein the additive is included in an amount of 5 to 90 wt% based on the total weight of the composition.
  11. 청구항 1에 있어서, 상기 심혈관계 질환은 협심증, 고혈압, 동맥연축, 심부정맥, 뇌경색, 심비대, 울혈심부전 및 심근경색으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 복합제 조성물.The combination composition of claim 1, wherein the cardiovascular disease is selected from the group consisting of angina pectoris, hypertension, arterial spasm, deep vein, cerebral infarction, cardiac hypertrophy, congestive heart failure and myocardial infarction.
PCT/KR2013/003231 2012-04-17 2013-04-17 Composite composition having improved stability and containing amlodipine and rozaltan WO2013157840A1 (en)

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