TW201639563A - Pharmaceutical complex formulation comprising AMLODIPINE, LOSARTAN and CHLORTHALIDONE - Google Patents

Abstract

The present invention provides a pharmaceutical complex formulation comprising a first mixture including amlodipine and chlorthalidone and a second mixture including losartan, which has an improved dissolution and stability. The complex formulation according to the present invention may achieve improved preventive or therapeutic effects for cardiovascular diseases by actuating different mechanism of amlodipine, losartan and chlorthalidone, and exhibits high dissolution rates of amlodipine, losartan and chlorthalidone and improved storage stability, due to the minimized drug interactions, and therefore, it is useful in the fields of pharmaceuticals and medicine.

Description

Pharmaceutical complex formulation comprising AMLODIPINE, Losartan (LOSARTAN) and losalidone (CHLORTHALIDONE) Field of invention

The present invention relates to a pharmaceutical compound formulation comprising amlodipine, losartan and chlorthalidone, and more particularly to a pharmaceutical compound formulation comprising A first mixture comprising anisopine and losalone and a second mixture comprising losartan, the pharmaceutical composite formulation having improved dissolution and stability.

Background of the invention

Approximately 90 to 95% of hypertensive patients have underlying (primary) hypertension that is not found. Although the underlying cause of essential hypertension is unclear, it is known that the increase in cardiac output (the volume of blood pumped by the heart as it contracts) or the increase in peripheral vascular resistance can cause this state. hypertension. Risk factors for high blood pressure are psychological and environmental factors such as drinking, smoking, aging, lack of exercise, obesity, eating habits of salty foods, stress, and so on. Furthermore, because there is a family of high blood pressure The tendency of history, when parents have high blood pressure, 80% of their children may later be high blood pressure, and when one of the parents is high blood pressure, the other 25-50% of the children may be high blood pressure .

The main goal in the treatment of hypertension is to prevent internal organ damage caused by high blood pressure by maintaining blood pressure within the normal range. Therefore, improving lifestyle is as important as taking medication. The goal of patients with high blood pressure is to control blood pressure to less than 140/90 mmHg. If the patient has diabetes or kidney disease, the target for blood pressure should be less than 130/80mmHg.

Treatment of high blood pressure can reduce mortality caused by stroke or cardiovascular disease. Controlling blood pressure in hypertensive patients can reduce the incidence of stroke by 35-40%, myocardial infarction by 20-25%, and heart failure by about 50% or higher. Reducing systolic blood pressure to 5 mmHg can reduce stroke mortality by 14%, coronary artery disease mortality by 9%, and total mortality by 7%. Furthermore, because blood pressure control is related to dementia, it is possible to reduce the occurrence of dementia by appropriately controlling the blood pressure of hypertensive patients.

Therefore, continuous control of blood pressure is important for the prevention of cardiovascular complications in hypertensive patients. Antihypertensive agents require long-term administration, and advanced therapies using a combination of two or more drugs with different pharmacological effects can lead to improved prophylactic or therapeutic efficacy, while reducing the dose by a single drug Side effects caused by long-term administration.

Well-known antihypertensive drugs are classified into diuretics, sympatholytic agents, and vasodilators based on their pharmacological effects. Vasodilators are the most widely prescribed antihypertensive drug prescriptions, and their differentiation into groups according to their pharmacological effects. Etc. include ACE (angiotensin-converting enzyme) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers.

Amlodipine is 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-6-methyl-1. The scientific name of 4-dihydro-3,5-pyridinedicarboxylate. Anloprol besylate is currently marketed on the market under Norvasc ^® (trademark). Amlodipine camsylate has been disclosed in Korean Patent Registration No. 452 491, which has superior physical properties such as solubility and stability, and is currently superior to anisoprofen benzene sulfonate. to Anmo horizon ^{® (Amodipin ®)} (trademark) sold on the market. Anlopoxine is a calcium channel blocker for the treatment of cardiovascular diseases such as angina pectoris, hypertension and septic heart failure.

Losartan is 2-butyl-4-chloro-1-[[2'-(1 H -tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1 H - imidazole-5-methanol scientific name, which has been disclosed in U.S. Pat. No. 5,608,075; No. 5,138,069; No. 5,153,197 in the second. Losartan potassium is commercially available, such as Cozaar ^® (trademark). Losartan blocks the interaction of the vasoconstrictor angiotensin II with its receptor and is primarily used to treat hypertension and heart failure. It is also used to treat ischemic peripheral circulatory disorders, myocardial ischemia (angina), diabetic neuropathy, and glaucoma, as well as to prevent progression of heart failure after myocardial infarction.

The advantages of a combination formulation containing anisoprofen and losartan having different pharmacological activities are more effective than a single drug in preventing and treating hypertension and cardiovascular diseases, and reducing side effects caused by a single drug. Improve patient compliance. Korean Patent Registration No. 1232296 and second No. 1,160,151 has disclosed compositions of the formulations, and the currently Anmo losartan ^{® (Amosartan ®)} (trademark) sold on the market.

Chlorthalidone is the scientific name of phenylsulfonamide-2-chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol-1-yl) It is currently marketed on the market under the Hygroton ^® (trademark). Chlorsalone, a thiazide diuretic, blocks the Na ⁺ /Cl ^- co-transported protein in the distal tubules of the kidney, thereby inhibiting the re-recovery of Na ⁺ and Cl ^- and increasing the excretion of K ⁺ , This causes water to stay in the urine. Recently, in addition to hydrochlorothiazide, which is already a representative thiazide diuretic, chlorsalone has recently been noted and recommended by the National Institute of Health and Care Excellence (NICE) for hypertension treatment guidelines. It is recommended to replace hydrochlorochlorosis.

The half-life of chlorsalone is 50 to 60 hours and the reaction time is 48 to 72 hours, and it is more useful to control blood pressure at night because it has a half-life of 9 to 10 hours and a reaction time of 16 to 24 hours. Compared to hydrochlorochlorosis, chlorsalone has a longer duration of action and reaction time.

Even though there is a growing need in the clinical field for a combination of anisopine, losartan and chlorthalidone containing different pharmacological activities for more effective treatment of cardiovascular disease, it is very It is difficult to commercialize, because the interaction of drugs may reduce the dissolution rate and stability, and it is highly difficult to develop a combination formulation.

Although research has been conducted to solve the problems of the above combination formulations, the inventors have found that the dissolution and stability are greatly different depending on the form and manufacturing method of the composite bilayer tablet, and one has been developed. A complex formulation containing anisopine, losartan, and rosuvastatin having improved dissolution and stability.

Summary of invention 【reveal】

It is an object of the present invention to provide a pharmaceutical compound formulation comprising anisopine, losartan and chlorsalone which is highly effective in the treatment of cardiovascular diseases by stimulating different mechanisms and has a high degree of safety. Lofap, losartan and chlorsalone dissolution rates and improved storage stability.

The present invention provides a pharmaceutical compound formulation for preventing or treating cardiovascular diseases, the formulation comprising: a first mixture comprising acyclovir or a pharmaceutically acceptable salt thereof, polsalone or a pharmaceutically acceptable salt, and a pharmaceutically acceptable additive; and a second mixture comprising losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, wherein the first A mixture and the second mixture are present in physically separate form from one another.

The pharmaceutical composite formulation comprising anisopine, losartan and losalidone according to the invention can be improved by stimulating different mechanisms The efficacy of preventing or treating cardiovascular disease, and exhibiting a high degree of dissolution of anisopine, losartan, and losalizin, as well as improved storage stability due to minimal drug interactions, and thus in medicine and medicine It is useful in the field.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic illustration of a two-layer tablet in accordance with one embodiment of the present invention.

2 is a graph showing the dissolution rate of anisoprofen observed in the tablets prepared in Example 1 and Comparative Example 1.

Fig. 3 is a graph showing the dissolution rate of losalizal observed in the tablets prepared in Example 1 and Comparative Example 1.

4 is a graph showing the dissolution rate of losartan observed in the tablets prepared in Example 1 and Comparative Example 1.

Fig. 5 is a graph showing the dissolution rate of anisoprofen observed in the tablets prepared in Examples 1 to 3 and Comparative Examples 3 to 6.

Fig. 6 is a graph showing the dissolution rate of losaliztone observed in the tablets prepared in Examples 1 to 3 and Comparative Examples 3 to 6.

Fig. 7 is a graph showing the dissolution rate of losartan observed in the tablets prepared in Examples 1 to 3 and Comparative Examples 3 to 6.

Fig. 8 is a graph showing the dissolution rate of anisoprofen observed in the tablets prepared in Example 1 and Comparative Examples 7 and 8.

Fig. 9 is a graph showing the dissolution rate of losalizide observed in the tablets prepared in Example 1 and Comparative Examples 7 and 8.

Figure 10 is a view showing the results produced in Example 1 and Comparative Examples 7 and 8. A plot of the losartan dissolution rate observed for the prepared tablets.

Fig. 11 is a graph showing the dissolution rate of anisoprofen observed in the tablets prepared in Examples 4 to 6 and Comparative Examples 9 to 12.

Fig. 12 is a graph showing the dissolution rate of losalizide observed in the tablets prepared in Examples 4 to 6 and Comparative Examples 9 to 12.

Fig. 13 is a graph showing the dissolution rate of losartan observed in the tablets prepared in Examples 4 to 6 and Comparative Examples 9 to 12.

Detailed description of the preferred embodiment [Best mode]

The present invention provides a pharmaceutical compound formulation for preventing or treating cardiovascular diseases, the formulation comprising a first mixture comprising anisoprofen or a pharmaceutically acceptable salt thereof, polsalone or a medicament thereof An acceptable salt, and a pharmaceutically acceptable additive; and a second mixture comprising losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, wherein the first The mixture and the second mixture are present in physically separate form from one another.

In the composite formulation of the present invention, the first mixture and the second mixture are physically separated from one another. Since the complex formulation contains azepam and losartan, respectively, the interaction between anisopine and losartan can be prevented, which achieves a high degree of stability.

In a specific embodiment of the invention, the composite formulation may be a two-layer tablet comprising a first layer comprising anisoprofen or a pharmaceutically acceptable salt thereof, losalone or Its pharmaceutically acceptable salts, And a pharmaceutically acceptable additive; and a second layer comprising losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive (see Figure 1). In addition to the bilayer tablet, the formulation according to the invention can be prepared in a variety of different forms (e.g., a core-shell structure) wherein the first mixture and the second mixture are physically separated open.

The complex formulation of the present invention comprises an acyclovir or a pharmaceutically acceptable salt thereof in the first mixture (or the first layer). The pharmaceutically acceptable salts of erlotine are those prepared from an acid containing a pharmaceutically acceptable anion which forms a non-toxic acid addition salt and includes, for example, hydrochloric acid Salt, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, besylate and camphor Sulfonate, but is not limited thereto. Among these salts, acyclovir benzene sulfonate and camphor sulfonate are preferred, and alum is also known as camphor sulfonate. Also, the erlotine used in the present invention may include an acyclovir racemate and (S)-anloline. Even though the dose of anisoprofen or its pharmaceutically acceptable salt varies with age, the sex or weight of the patient, the severity of the disease, the route of administration, etc., typical doses for adults (weight: 60 kg) It can fall within the range of about 5 to 10 mg/day.

The complex formulation of the present invention comprises losalone or a pharmaceutically acceptable salt thereof in the first mixture. Even though the dose of losalone or its pharmaceutically acceptable salt varies with age, the sex or weight of the patient, the severity of the disease, the route of administration, etc., but in adulthood Weight: 60 kg) A typical dose can fall within the range of about 12.5 to 25 mg/day.

The complex formulation of the present invention comprises losartan or a pharmaceutically acceptable salt thereof in the second mixture (or the second layer). An example of a pharmaceutically acceptable salt of losartan is losartan potassium, but is not limited thereto. Even though the dose of losartan or its pharmaceutically acceptable salts varies with age, the sex or weight of the patient, the severity of the disease, the route of administration, etc., typical doses for adults (weight: 60 kg) can be It falls within the range of about 50 to 100 mg/day.

In the complex formulation of the present invention, acyclovir or a pharmaceutically acceptable salt thereof, polsalone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof It is possible to use an amount corresponding to a weight ratio in the range of 1:1.25 to 5:5 to 20, preferably 1:2.5 to 5:10 to 20.

In the complex formulations of the present invention, the pharmaceutically acceptable additives which may be used in the first mixture and the second mixture may be, for example, pharmaceutically acceptable carriers or excipients. Pharmaceutically acceptable carriers or excipients can include, for example, lactose hydrate, microcrystalline cellulose, mannitol, sodium citrate, calcium phosphate, glycine, starch, disintegrant [ For example, crospovidone, copovidone, sodium starch glycolate, croscarmellose sodium, and specific complex citrates, as well as binders [eg , polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl averaverin (HPC), sucrose, gelatin and gum arabic (acacia gum)].

In a specific embodiment, the composite formulation of the present invention may comprise an additive selected from the group consisting of lactose hydrate, microcrystalline cellulose, mannitol, starch, and the like, in a first mixture. . Preferred additives comprise lactose hydrate and/or microcrystalline cellulose. The lactose hydrate may be included in an amount of from 20 to 60% by weight based on the total amount of the first mixture. In another embodiment of the present invention, the weight ratio of the lactose hydrate to the microcrystalline cellulose may be from 1:0.5 to 1:2 in the above range.

When the above range of amounts of lactose hydrate is used as a water-soluble excipient, it accelerates the dissolution of the active substance by forming a diffusion-promoting passageway in the formulation, thereby causing rapid dissolution. However, an amount smaller than the above range cannot achieve rapid dissolution, but an amount exceeding the above range prolongs the time during which the lactose hydrate is completely dissolved, thereby delaying the dissolution of the active material. When the above range of amounts of microcrystalline cellulose is used, smooth formulation molding can be achieved in the tableting process. However, an amount smaller than the above range causes some difficulties in the tableting process, but an amount exceeding the above range results in the production of an excessively large formulation.

Thus, the dissolution rate of anisopine, losalidone and losartan can be considerably improved by using the above range of amounts of lactose hydrate and microcrystalline cellulose.

In a particular embodiment of the invention, the first mixture and the second mixture of the complex formulation can be granulated by conventional granulation methods, for example compression granulation, followed by tableting. In another embodiment, the first mixture and the second mixture may be by a roll compression method (roller Particle form prepared by compression process). The results of the test examples of the present invention show that the bilayer tablet comprising the first mixture and the second mixture prepared by the compression granulation method exhibits an increased dissolution rate of anisopine, losalizate and losartan. , and the excellent dissolution of azolidine and chlorsalone.

Gelation of losartan occurs disadvantageously when a combination of anisoprofen, losalizide and losartan is prepared by simply mixing the drugs. Losartan shows a very good dissolution pattern in purified water or at a relatively high pH (eg pH 4.0 or pH 6.8), but at low pH (eg pH 1.2 or pH 2.0) because Gelation and release is very slow. Considering that the oral formulation is first decomposed and dissolved in the stomach exposed to a digestive juice having a low pH value, the gelation of losartan has a decisive effect on the dissolution rate of the formulation, as well as the intake of the drug. It also has a decisive role. Furthermore, in combination with the formulation, the combination of anisoprofen and losalidone and losartan may be trapped in the gel due to gelation of the losartan, and its dissolution is reduced. This reduction in dissolution can be demonstrated in Comparative Example 1 of the present specification, and a single-layer tablet prepared by dry direct compression using a simple mixture of three components in Comparative Example 1 shows that apoloxine and chlorine are present. The dissolution rate of salitonone is much lower than the general dissolution standard (80% or more dissolution rate in artificial gastric juice at pH 1.2 for 30 minutes).

Meanwhile, in the complex formulation of the present invention, the first mixture comprising anisoprofen and losalizone and the second mixture including losartan can be physically separated, and the contact area of losartan can be lowered. To prevent the gelation of losartan, thereby achieving the treatment of anisopine, losalidone and losartan Good dissolution and stability.

Further, the present invention provides a fixed-dose combination formulation for preventing or treating cardiovascular diseases, the formulation comprising a first mixture comprising erlotine or a pharmaceutically acceptable salt thereof, chlorsali a ketone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and a second mixture comprising losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, Wherein the first mixture and the second mixture are present in physically separate form from one another.

In a fixed-dose combination formulation, anisoprofen or a pharmaceutically acceptable salt thereof can be included in the form of an albendix free acid in an amount of 5 to 10 milligrams (mg), chlorsarilone or The pharmaceutically acceptable salts can be included in the free acid form of the losalone in an amount of 12.5 to 25 mg, and the losartan or a pharmaceutically acceptable salt thereof can be contained in the amount of 50 to 100 mg in the amount of losar. Within the free acid form.

The invention also provides a method for preparing a pharmaceutical compound formulation for preventing or treating cardiovascular diseases, the method comprising the steps of: a) mixing an acyclovir or a pharmaceutically acceptable salt thereof; a ketone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and b) a mixed losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

Furthermore, the present invention also provides a method for preparing a bilayer tablet for preventing or treating cardiovascular diseases, the method comprising the steps of: a) mixing an acyclovir or a pharmaceutically acceptable salt thereof, Chlorsalone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive to obtain a mixture and granulating the mixture; b) mixing losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive to obtain a mixture and then granulating the mixture; and c) step a The granules obtained in b) and b) are pressed into a bilayer tablet.

In a specific embodiment of the present invention, the cardiovascular disease is selected from the group consisting of angina pectoris, hypertension, arterial spasm, arrhythmia, cardiac hypertrophy, cerebral infarction, septic heart failure, and myocardial infarction, but not Limited to this.

[invention mode]

In the following, the invention is illustrated in more detail by way of examples. The following examples are intended to further illustrate the invention without limiting its scope.

Examples 1 to 3: Preparation of composite bilayer tablets by compression granulation

As shown in Table 1, amoxicillin camphorsulfonate, losalidone, lactose hydrate, microcrystalline cellulose, and crospovidone were mixed, and the mixture was screened through a 30 mesh sieve. The screened portion was extruded to form a sheet type by using a roller compactor (roller compactor WP200, Alexanderwerk) at a minimum pressure of 20 kN and a roll speed of 2 to 10 rpm. Part of the particle. The obtained granules were sheared by using a grinder (Fitz Mill; BAS 06, Fitzpatrick, USA) and passed through a 20 mesh screen, magnesium stearate was added thereto and the mixture was finally used as a mixer. To mix to obtain a portion of the granules containing anisoprofen and chlorsalione.

Mixing losartan potassium, microcrystalline cellulose and crospovidone to And screening the mixture via a 30 mesh screen. The screened portion was extruded to form a flake-type particle portion by using a roll compactor (roll compactor WP200, Alexanderwerk) at a minimum pressure of 20 kN and a roll speed of 2 to 10 rpm. The obtained granules were sheared by using a grinder (Fitz Mill; BAS 06, Fitzpatrick, USA) and passed through a 20 mesh screen, magnesium stearate was added thereto and the mixture was finally used as a mixer. To mix to obtain a portion of the granules containing losartan.

Subsequently, a composite bilayer tablet was prepared by using a tablet press (pressing machine; Kilian Synthesis 700, Germany), which was composed of erlotine and chlorsalone granules (first layer, upper layer) and Luo The composition of the sartan granules (second layer, lower layer).

Comparative Example 1: Single layer tablet prepared by dry direct compression method

As shown in Table 2, anisomycin camphor sulfonate, chlorsalone, losartan potassium, lactose hydrate, microcrystalline cellulose and crospovidone were mixed and screened through a 30 mesh sieve. The mixture. Magnesium stearate was added to the screened portion, and the mixture was finally mixed as a mixer. The mixed portion is pressed to obtain a single layer tablet.

Comparative Example 2: Bilayer tablet prepared by dry direct compression method

As shown in Table 3, anisomycin camphorsulfonate, losalidone, lactose hydrate, microcrystalline cellulose, and crospovidone were mixed, and the mixture was screened through a 30 mesh sieve. Magnesium stearate is added thereto and the mixture is finally mixed by a mixer to obtain an alopine and a chloride Part of the mixture of ketones.

The losartan potassium, microcrystalline cellulose and crospovidone were mixed and the mixture was screened through a 30 mesh screen. Magnesium stearate was added thereto and the mixture was finally mixed in a mixer to obtain a mixture portion of losartan.

Subsequently, a composite bilayer tablet was prepared by using a tablet press, which consisted of a mixture of erlotine and chlorsalone (first layer; upper layer) and part of losartan mixture (second layer; lower layer) )composition.

Comparative Examples 3 to 6: Preparation of composite bilayer tablets by compression granulation method

As shown in Table 4, according to the same procedure as in Embodiment 1 A composite bilayer tablet of lactose to cellulose in various proportions is produced.

Comparative Example 7: Preparation of a composite bilayer tablet having layers of various compositions

As shown in Table 5, according to the same procedure as in Embodiment 1 A composite bilayer tablet having a first layer of erlotin and losartan granules and a second layer of losalidone granules is formed.

Comparative Example 8: Preparation of a composite bilayer tablet having layers of various compositions

As shown in Table 6, a composite bilayer tablet having the first layer of the ergozapine granule portion and the losartan and losalidone granule portion was produced according to the same procedure as in Example 1. Second floor.

Examples 4 to 6: Preparation of composite bilayer tablets having various amounts of active ingredients

As shown in Table 7, composite bilayer tablets having varying amounts of the active component in Examples 1 to 3 were produced.

Comparative Examples 9 to 12: Composite bilayer tablets having various amounts of active ingredients Preparation

As shown in Table 8, a composite bilayer tablet was produced in accordance with the same procedure as in Example 1.

Test Example 1: Dissolution test of double-layer tablets and single-layer tablets

The tablet prepared in Example 1 and the tablet prepared in Comparative Example 1 were subjected to a drug dissolution test under the following conditions to measure the dissolution of anisopine, losalidone and losartan during the time period. rate.

- Dissolution test conditions -

Effluent: artificial gastric juice 900 ml (pH 1.2)

Dissolution test system: USP paddle method, 50 rpm

Temperature: 37 ° C

Dissolution time: After measuring the dissolution rate at 5, 10, 15, 30, 45, 60, 90 and 120 minutes, the paddle speed was changed from 50 rpm to 150 rpm, and then at 150 minutes, the final dissolution rate was measured.

- Analysis conditions -

Column: stainless steel column for 3 μm liquid chromatography, filled with 18-mercaptopurine ruthenium gel (inner diameter: 4.6 mm, length: 15 cm)

Mobile phase: *6mM sodium 1-hexanesulfonate / 0.05% (v / v) phosphoric acid: acetonitrile (60:40, v / v)

(*6 mM sodium 1-hexanosulfonate/0.05% (v/v) phosphoric acid: 1.24 g of sodium 1-hexanesulfonate monohydrate was placed in a 1 L flask, and 0.5 mL of phosphoric acid was carefully added to the flask. Inside, then by adding pure water to dissolve and dilute the mixture)

Detector: UV spectrophotometer (254nm)

Flow rate: 1.3 mL/min

Injection volume: 10μL

Column temperature: 45 ° C

- criteria for dissolution rate -

80% or higher at 30 minutes (for anisopine and losalone)

The results of the measured dissolution tests are shown in Figures 2 to 4. As shown in Figures 2 and 3, the bimodal tablet separated from the losartan layer according to Example 1 and the losartan layer was used as compared to Comparative Example 1. Single-layer tablets prepared by dry direct compression method exhibit higher Dissolution rate. Unlike the single-layer tablet prepared in Comparative Example 1, the double-layer tablet of Example 1 showed satisfactory characteristics and good dissolution characteristics and dissolution rate of oxaprozil.

Further, as shown in Fig. 4, the losartan dissolution rate of the single-layer tablet of Comparative Example 1 at 60 minutes was 20% or less, and the double-layer tablet of Example 1 exhibited very High losartan dissolution rate.

The above results show that gelation of losartan slows the solubility of anisoprofen or losalizate when losartan is present in the same layer as acyclovir or chlorsalone.

Test Example 2: Double-layer tablet prepared by compression granulation method and uniformity of dosage unit in double-layer tablet prepared by dry direct compression method

For the bilayer tablet prepared by the compression granulation method in Example 1 and the double-layer tablet prepared by the dry direct compression method of the simple mixture in Comparative Example 2, the test of anisopine, losalidone and Luo The quality change of satan and the content uniformity. The results are shown in Tables 9 and 10.

As shown in Table 9, the double-layer tablet of Comparative Example 2 prepared by the dry direct compression method of a simple mixture was not used in the double-layer tablet prepared in Example 1, without using a roll compactor. Shows a relatively degraded quality change. As shown in Table 10, the double-layer tablet of Comparative Example 2 did not satisfy the criteria for the uniformity of the content of anisopine and closalone (acceptance value of 15 or lower). Further, the bilayer tablet of Comparative Example 2, which was prepared without processing by compression and screening, showed low productivity due to capping during the tableting process. On the other hand, the double-layer tablet prepared by using a roller compactor in Example 1 exhibits excellent uniformity of anisoprofen and chlorsalone, and satisfies the uniformity of the dosage unit. Guidelines.

The above results demonstrate that the roller compaction method of ancyclovir-closlone granules and losartan granules affects the uniformity of the dosage units of the three active components and affects the productivity of the tableting process.

Test Example 3: Dissolution change depending on the proportion of excipients in the ancyclovir-clozarone layer

With regard to the bilayer tablets prepared in Examples 1 to 3 and the bilayer tablets prepared in Comparative Examples 3 to 6, the dissolution rates of anisopine, losalidone and losartan were carried out as in the test experiment. Example 1 was measured in the same manner. The results are shown in Figures 5 to 7.

As shown in Figure 7, the double layer tablets of Examples 1 to 3 The losartan dissolution rate did not differ much from the dissolution rates of Comparative Examples 3 to 6.

However, as shown in Figures 5 and 6, the bilayer tablets of Examples 1 to 3 exhibited satisfactory and rapid dissolution in terms of the dissolution rate of anisoprofen and closalone. The double layer tablets of Comparative Examples 3 to 6 did not satisfy the criteria for the dissolution test (80% or more in 30 minutes of artificial gastric juice at pH 1.2).

The above results show that the lactose hydrate in the anisopine-closalone layer is 20 to 60% by weight and the weight ratio of lactose hydrate to microcrystalline cellulose is 1:0.5 to 1:2, which results in Good dissolution rate.

Test Example 4: A tablet prepared in Comparative Example 7 (composed of an acyclovir-loxartan layer and a losalidone layer) and a tablet prepared in Comparative Example 8 (from Anzao Ping and Luo Dissolution rate of the composition of the sartan-closlone layer

In the bilayer tablet prepared in Example 1 and the bilayer tablet prepared in Comparative Examples 7 and 8, the dissolution rates of anisopine, losalidone and losartan were as in the test example. 1 The same method to measure. The results are shown in Figures 8 to 10.

As shown in Figures 8 to 10, the double-layer ingot of Example 1 consisting of the anisopine-closlone layer and the losartan layer in terms of the dissolution rate of anisoprofen and losalizate The agent exhibits a fast and good dissolution that meets the solubility rate criteria. On the other hand, the bilayer tablet of Comparative Example 7 consisting of the aloprofen-loxatan layer and the losalidone layer did not satisfy the dissolution rate criterion of anisoprodine, and the apollo layer And the double-layer tablet of Comparative Example 8 having the composition of the losartan-closlone layer did not satisfy the dissolution rate criterion of chlorsalone.

The above results show that since the gelation of losartan reduces the tablet consisting of the ancyclovir-losartan layer and the losalidone layer, or by the ampoules and losartan- The dissolution of the tablet of the losalone layer, the bivalent tablet consisting of the anzapine-clozarone layer and the losartan layer is preferred, and it is also shown that the separation of the three drugs is good. The solubility rate is the most important.

Test Example 5: Change in content according to stability test under accelerated storage conditions

With respect to the tablets prepared in Examples 1 to 3, the changes in the contents of anisopine, losalidone and losartan were measured under the following accelerated storage conditions to evaluate the stability of the tablet. The results are shown in Table 11.

- Accelerated storage conditions -

Storage conditions: packaged in HDPE (high density polyethylene) bottles at 40 ° C, 75% relative humidity

Test time: 0 (initial), 1, 2, 4 and 6 months

Test subjects: anisopine, losalidone and losartan

- Analysis conditions -

Column: stainless steel column for 3 μm liquid chromatography, filled with 18-mercaptopurine ruthenium gel (inner diameter: 4.6 mm, length: 15 cm)

Mobile phase: 6 mM sodium 1-hexanosulfonate / 0.05% (v / v) phosphoric acid: acetonitrile (6: 4, v / v)

Detector: UV spectrophotometer (254nm)

Flow rate: 1.3 mL/min

Injection volume: 10μL

Column temperature: 45 ° C

As shown in Table 11, this demonstrates that the bilayer tablet prepared in Examples 1 to 3 has excellent stability, and the content of anisoprofen, losalidone and losartan is accelerated at 6 months. The reduction after the condition is very small.

Test Example 6: Storage test under light and thermal stress conditions

With respect to the tablets prepared in Examples 1 to 3 and Comparative Examples 1 to 8, the changes in the contents of related compounds derived from anisopine, losalidone and losartan were carried out under conditions of light and thermal stress. Measurement to assess stability. The results are shown in Table 12.

- Conditions for light stability test chamber (light stress conditions) -

(1) Device: Xe-3-HC (Q-Lab)

(2) Temperature and humidity: 25 °C ± 2 °C / 60% ± 5% RH

(3) Illumination 0.80W/m ² /nm, 18.44 hours

(1,200,000 lux, light stability test conditions recommended in accordance with ICH guidelines)

(4) Sample: stored in a Petri dish

(5) Test time: start of the test and after light exposure (after exposure to 1,200,000 lux)

- Conditions for thermal stability test chamber (thermal stress conditions) -

(1) Temperature and humidity: 50 °C ± 2 °C

(2) Sample: packed in HDPE bottle

(3) Test time: 28 days after the start and storage of the test

- Analysis conditions -

Column: stainless steel column for 5 μm liquid chromatography, filled with 18-mercaptopurine ruthenium gel (inner diameter: 4.6 mm, length: 25 cm)

Mobile phase: 6 mM sodium 1-hexanosulfonate / 0.05% (v / v) phosphoric acid: acetonitrile (6: 4, v / v)

Detector: UV spectrophotometer (239nm)

Flow rate: 1.0 mL/min

Injection volume: 10μL

Column temperature: 45 ° C

[Table 12] Changes in the content of related compounds derived from anisopine, losalidone and losartan

As shown in Table 12, this proves that the tablets prepared in Examples 1 to 3 are under light or thermal stress conditions, and have few related compounds derived from loftin, chlorsalone and losartan. It is highly stable. However, can The tablet prepared by comparing the simple mixture of the three components in Comparative Example 1 proved that the related compound had been increased by 3 to 10 times as compared with the examples of Examples 1 to 3. These results show that tablets prepared by simple mixtures are difficult to ensure sufficient stability due to changes over time under light or thermal stress conditions.

Further, the related compounds produced by the tablets of Comparative Examples 7 and 8 were as high as the tablets of Comparative Example 1. The results of Comparative Example 7 show that a bilayer tablet consisting of an acyclovir-losartan layer and a losalidone layer is difficult to ensure sufficient stability due to changes over time under light or thermal stress conditions. Sex. The results of Comparative Example 8 show that the bilayer tablet consisting of the ampoules and the losartan-closlone layer is also difficult to ensure sufficient time due to changes under light or thermal stress conditions over time. Stability.

The above results demonstrate that the bilayer tablets prepared from Examples 1 to 3 consisting of the ancyclovir-closlone layer and the losartan layer are stable.

Test Example 7: Dissolution change in the bilayer tablet having various amounts of the active ingredient, depending on the proportion of the excipient in the ancyclovir-clozarone layer

With respect to the tablets prepared in Examples 4 to 6 and Comparative Examples 9 to 12 having various amounts of the active ingredient, the dissolution rates of anisopine, losalone, and losartan were as in the test experiment example. 1 The same method to measure. The results are shown in Figures 11 to 13.

As shown in Figures 11 to 13, the tablets of Examples 4 to 6 exhibited a dissolution pattern similar to that of the tablets of Examples 1 to 3, satisfying the criteria, although the amount of losartan and losalone Change to 50mg and 12.5mg respectively.

On the other hand, the tablets of Comparative Examples 9 to 12 were not satisfied. Guidelines for the dissolution rate of ampoules and chlorsalone.

The above results show that, in terms of good dissolution rate, the content of lactose hydrate in the ancyclovir-clostrione layer is 20 to 60% by weight and the weight ratio of lactose hydrate to microcrystalline cellulose is 1. : 0.5 to 1:2 is preferred and is not related to the content of the active ingredient.

Claims (12)

A pharmaceutical composite formulation for preventing or treating cardiovascular diseases, the formulation comprising: a first mixture comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone Or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and a second mixture comprising losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt An additive, wherein the first mixture and the second mixture are present in physically separated form from one another. The formulation of claim 1, wherein the composite formulation is a bilayer tablet comprising: a first layer comprising anisofloxacin or a pharmaceutically acceptable salt thereof, a chlorin a ketone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and a second layer comprising losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive . The formulation of claim 1, wherein the additive of the first mixture is selected from the group consisting of lactose hydrate, microcrystalline cellulose, mannitol, starch, and the like. The formulation of claim 3, wherein the lactose hydrate is included in an amount of from 20 to 60% by weight based on the total of the first mixture. The formulation of claim 3, wherein the additive is lactose hydrate and micro The weight ratio of crystalline cellulose, and the like, is from 1:0.5 to 1:2. The formulation of claim 1, wherein the first mixture and the second mixture are in the form of granules prepared by a roll compression process. A fixed-dose combination formulation for preventing or treating a cardiovascular disease, the formulation comprising: a first mixture comprising anisopine or a pharmaceutically acceptable salt thereof, polsalone or a medicinal thereof An acceptable salt, and a pharmaceutically acceptable additive; and a second mixture comprising losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, wherein the first mixture And the second mixture is present in a physically separated form from each other. The formulation of claim 7, wherein the anisoprofen or a pharmaceutically acceptable salt thereof is included in the form of acyclovir free acid in an amount of from 5 to 10 milligrams (mg). The formulation of claim 7, wherein the losalone or a pharmaceutically acceptable salt thereof is included in the free acid form of the losalidone in an amount of from 12.5 to 25 mg. The formulation of claim 7, wherein the losartan or a pharmaceutically acceptable salt thereof is included in the losartan free acid form in an amount of from 50 to 100 mg. A method for the preparation of a pharmaceutical compound formulation for preventing or treating cardiovascular diseases, the method comprising the steps of: a) mixing an acyclovir or a pharmaceutically acceptable salt thereof, chlorsali a ketone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and b) a mixed losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive. A method for preparing a bilayer tablet for preventing or treating cardiovascular diseases, the method comprising the steps of: a) mixing an acyclovir or a pharmaceutically acceptable salt thereof, polsalone or a medicament thereof An acceptable salt, and a pharmaceutically acceptable additive to obtain a mixture and granulate the mixture; b) a mixture of losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive Obtaining a mixture and granulating the mixture; and c) pressing the granules obtained in the preparation of steps a) and b) into a bilayer tablet.