KR101907881B1 - Fixed dose combination formulation comprising losartan, amlodipine and hydrochlorothiazide - Google Patents

Abstract

The present invention relates to fixed-dose combination formulations for the prevention or treatment of cardiovascular diseases, including losartan, amlodipine and hydrochlorothiazide, which are excellent in dissolution rate and stability, It is possible to minimize the side effects as compared with the combination agent, and it is excellent in dissolution rate, biologically equivalent to or better than each single product, and excellent in stability of the product due to aging change, thus being useful for prevention or treatment of cardiovascular diseases.

Description

FIXED DOSE COMBINATION FORMULATION COMPRISING LOSARTAN, AMLODIPINE AND HYDROCHLOROTHIAZIDE, LOSATANE, AMRODIPIN, AND HYDROCHLOROTHIAZIDE.

The present invention relates to fixed dose combination formulations for the prevention or treatment of cardiovascular diseases, including losartan, amlodipine and hydrochlorothiazide, which are excellent in dissolution rate and stability.

Hypertension is classified into essential hypertension and secondary hypertension. Most of hypertension, ie, 90 to 95%, is an essential hypertension whose exact cause is unknown. In the treatment of hypertension, secondary hypertension can be treated by eliminating its cause, but in the case of essential hypertension, stabilization, diet, and exercise therapy are performed because the exact cause of hypertension is unknown. However, If the effect is not significant, drug therapy is performed.

The most commonly used drugs for the treatment of hypertension are vasodilators, diuretics and sympathomimetics depending on the mechanism of action of the drug. The vasodilators that are currently used are the angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers and calcium channel blockers.

It is important to keep blood pressure in the normal range rather than to treat blood pressure itself, so it is important to prevent cardiovascular complications such as life-threatening stroke, heart failure such as heart failure, myocardial infarction and renal failure, It is important to control your blood pressure. As such, blood pressure medication is required to be taken for a long period of time, so care should be taken in choosing therapeutic drugs. Therefore, rather than choosing one drug for continuous treatment, the combination of drugs with different mechanisms will give better prophylactic and therapeutic effects and can be caused by long-term use of medication by reducing the use of a single drug with concomitant use. There is a need to reduce side effects. In the Hypertension Guideline (JNC7), if sufficient blood pressure control can not be achieved with single-dose administration, it is recommended that patients should be treated with drugs of different mechanisms.

However, in the case of the co-administration, drug prescriptions administered in two or more individual dosage units may lower the patient's compliance with the medication, which may lead to a great inconvenience to hypertensive patients who need constant blood pressure management. In addition, when taking a single dose, several individual drugs should be taken, and the necessity of carrying several individual drugs is also a major inconvenience for patients with hypertension who need to continue their social life.

In order to improve these disadvantages, development and research on FDC (fixed dose combination drug) have been variously carried out in recent years. The term " fixed dose combination " drug or formulation refers to a combination of two or more drugs or active ingredients present in a single dosage unit such as a tablet or capsule. In contrast, the term " free dose combination " drug or formulation refers to a combination of two or more drugs or active ingredients administered simultaneously, but as two or more dosage units. However, such fixed-dose combination formulations of certain active ingredients are not easy to develop due to the following reasons.

First, when formulating a fixed dose combination administration composition, the fixed dose combination dosage form composition will provide a biologically equivalent effect with the respective individual free dose combination of the same active ingredient or provide a pharmacological effect that is superior to the individual ingredient Hard. This is because the development of fixed dose combination dosage forms can cause unexpected problems due to the pharmacokinetic and pharmaceutical properties of the drug to be formulated.

For example, rosemary has low absolute oral bioavailability in the range of about 25-35%. This indicates that when the rosemary is eluted at a relatively high pH such as purified water and pH 6.8, it exhibits a very good dissolution pattern, but at a low pH (for example, pH 1.2, pH 2.0) corresponding to the gastrointestinal tract (Cozaar), which is a commercial losartan preparation, also has a problem that the dissolution rate of the initial 30 minutes is less than 30% at pH 1.2 to 2.0. When the fixed dose combination formulations with amlodipine or hydrochlorothiazide are developed due to the characteristics of this losartan, gelatinization of losartan causes the problem that amlodipine or hydrochlorothiazide is entrapped in the gel and the elution is lowered.

In addition, since hydrochlorothiazide has a low solubility and low in vivo absorbability (BCS Class IV, low solubility, low biotransmission), it has a very large change in bioavailability even when administered in individual units, It is difficult to develop a fixed-dose combination formulation.

Another problem is that the stability tends to deteriorate due to the mutual reactivity between the different active ingredients. In particular, when combining difficult-to-handle compounds, it is more difficult to develop fixed-dose combination dosage forms in a physiologically stable form.

For example, amlodipine preparations are made by combining amlodipine, an ingredient that generally exhibits pharmaceutical efficacy, and a salt that assists in the activation and formulation of the drug efficacy. The salt is a part that helps stabilize amlodipine as an active ingredient. Although amlodipine is in a free base form, it is preferably administered in the form of a salt with a pharmaceutically acceptable acid because of its low solubility in water.

It has been known that acid addition salts of amlodipine such as amlodipine malate salt can be decomposed into amlodipine aspartate of the following formula (1) or amino-pyridine of the following formula (2) over time when formulated Patent No. 6,919,087). The pharmaceutical composition containing amlodipine maleate salt has a problem of poor stability due to the decomposition reaction and the like.

[Chemical Formula 1]

(2)

Because of the problems of such stability deterioration, amlodipine besylate salt disclosed in EP 244 944 (corresponding US Patent No. 4,879,303) is mainly used for tablets currently on the market. However, the amlodipine besylate salt is also smaller than the amlodipine malate salt, but the decomposition reaction is caused to various decomposition products. In the case of the pharmaceutical composition containing the amlodipine besylate salt, the stability is poor and the drug efficacy is deteriorated with time .

Accordingly, the present inventors developed a camsylate salt which is superior to the amlodipine besylate salt in physical properties such as solubility and stability, and then formulated and marketed as a product called Amodipin. However, surprisingly, even when the amlodipine camsylate salt having the best stability is mixed with rosatane, it is found that amlodipine is decomposed into various products, unlike in a single preparation of amlodipine. This is because the physical properties of amlodipine itself are unstable to light and humidity, and it may be very difficult to ensure the stability of amlodipine when combined with other pharmacologically active substances, for example, a fixed dose combination formulation with rosigadam and hydrochlorothiazide. In addition, it is already known that potassium salt of rosigadam which is generally known to be good in stability also forms a polymeric substance named decomposition products E and F when heat is applied under acidic conditions (Z. Zhao et al., J. Pharm . Biomed . Anal , 20: 129-136, 1999). Also, in the case of hydrochlorothiazide, it is easily decomposed into benzothiadiazine type A and the like over time.

Therefore, the inventors of the present invention have studied to prepare a fixed dose combination formulation of losartan, amlodipine and hydrochlorothiazide for the prevention and treatment of cardiovascular diseases, and prepared all the three components as independent separation layers, Thereby confirming that bioequivalence with a single product can be secured and stability and compliance with medicines can be improved, thereby completing the present invention.

Accordingly, it is an object of the present invention to provide fixed-dose combination formulations for the prevention or treatment of cardiovascular diseases with excellent dissolution rate and stability, containing roza tan, amlodipine and hydrochlorothiazide having different action mechanisms.

To achieve the above object, the present invention provides a pharmaceutical composition comprising, as an active ingredient, losartan or a pharmaceutically acceptable salt thereof; Amlodipine or a pharmaceutically acceptable salt thereof; And hydrochlorothiazide, wherein the active ingredients are each in a separate layer and are packed in capsules. The present invention provides fixed dose combination formulations for the prevention or treatment of cardiovascular diseases.

The fixed-dose combination formulation according to the present invention can minimize adverse effects compared to existing single agents and complex agents, and is excellent in dissolution rate, biologically equivalent to or better than each single product, And can be usefully used for the prevention or treatment of a related disease.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic diagram of a fixed dose combination formulation of roza tan, amlodipine and hydrochlorothiazide according to the present invention.
2 is a graph showing the dissolution rate of hydrochlorothiazide as a result of Test Example 1. Fig.
3 is a graph showing dissolution rate of amlodipine as a result of Test Example 1. Fig.

The present invention relates to a pharmaceutical composition comprising, as an active ingredient, losartan or a pharmaceutically acceptable salt thereof; Amlodipine or a pharmaceutically acceptable salt thereof; And hydrochlorothiazide, wherein the active ingredients are each packed in capsules with separate separation layers, in a fixed dose combination formulation for the prevention or treatment of cardiovascular diseases.

4-yl] methyl] -1H-imidazol-1-yl] - [ 5-Methanol, U. S. Patent No. 5,608, 075; 5,138,069; 5,153,197, and the like. In particular, losartan potassium is currently marketed under the trade name Cozaar. Accordingly, the preferred pharmaceutically acceptable salt of the losartan of the present invention is potassium losartan. Rozatan treats hypertension and heart failure by blocking the binding of angiotensin II, a vasoconstrictor, to the receptor, treats ischemic peripheral circulatory disorder, myocardial ischemia (angina pectoris), prevents the progression of heart failure after myocardial infarction, Neuropathy, glaucoma, and the like. The daily dose of roza tan or a pharmaceutically acceptable salt thereof is 0.1 to 500 mg, preferably 1 to 200 mg, more preferably 25 to 200 mg as a rosemary lotion.

Amlodipine can be obtained from 3-ethyl-5-methyl-2- (2-aminoethoxy-methyl) -4- (2- chlorophenyl) -6- And pharmaceutically acceptable salts of amlodipine used in the present invention are formed from acids which form non-toxic acid addition salts containing a pharmaceutically acceptable anion, for example, hydrochloride, hydrobromide, sulfate But are not limited to, phosphate, acetate, malate, fumarate, lactate, tartrate, citrate, gluconate, besylate and camsylate. Of these, the amlodipine besylate salt is sold under the trade name Novasc, and the camsylate salt having excellent physical properties such as solubility and stability as compared with the besylate salt is described in Korean Patent No. 452491. Thus, amlodipine camsylate is most preferred as the pharmaceutically acceptable salt of amlodipine of the present invention. Amlodipine is a long-acting calcium channel blocker in the human body and is useful for the treatment of cardiovascular diseases such as angina, hypertension and congestive heart failure. The daily dosage of amlodipine or a pharmaceutically acceptable salt thereof is 0.5 to 20 mg, preferably 1 to 10 mg, more preferably 2.5 to 10 mg as amlodipine.

Hydrochlorothiazide is a generic name for 6-chloro-1,1-dioxy-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide, . Hydrochlorothiazide is a thiazide diuretic that acts mainly in the distal tubules and reduces sodium reabsorption by inhibiting the sodium / chlorine cavitation in the tubular smooth muscle. As a result, increasing the concentration of sodium and chlorine in the tubular fluid causes diuretic action with increased excretion of sodium and chlorine. Therefore, it is clinically used for the treatment of hypertension, heart failure, hypercalciuria and diabetes insipidus. The daily dose of hydrochlorothiazide is 1 to 100 mg, preferably 3 to 50 mg, more preferably 6.25 to 25 mg.

Fixed dose combination formulations comprising a roza tan or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof, and hydrochlorothiazide of the present invention may be used for the prevention or treatment of cardiovascular diseases. Cardiovascular diseases include, but are not limited to, angina, hypertension, arterial spasm, cardiac arrhythmia, cardiomyopathy, cerebral infarction, congestive heart failure, myocardial infarction and the like. The fixed dose combination formulation of the present invention comprising losartan or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof and hydrochlorothiazide is more effective for the prevention or treatment of cardiovascular diseases than the existing single agent And has the advantage of decreasing the side effects of the drugs used and increasing the compliance of the patients. However, due to the differences in the physical properties inherent to losartan, amlodipine and hydrochlorothiazide, the following problems arise in the case of simple combination of them and making a fixed-dose combination formulation.

The first problem is the gelation of rosaceae. The losartan exhibits a very good dissolution pattern when eluted at a relatively high pH such as purified water, pH 6.8, but is slowly gelated at low pH (for example, pH 2.0, pH 1.2, etc.). This phenomenon has a great effect on the dissolution rate of the preparation in that the organs in which the first disintegration and dissolution occurs when the oral preparation is administered have a low pH, and may also affect in vivo absorption. In addition, as the rosin is gelled in the composition, amlodipine and hydrochlorothiazide contained together are entrapped in the gel to lower the elution. This phenomenon can also be confirmed in the dissolution rate graphs of Figs. 2 and 3 obtained in Test Example 1. [ That is, in the case of a tablet obtained by simply mixing the two components, the results are far less than the "quick dissolution rate at 30 minutes, 80% dissolution rate", which is the rapid release elution standard of single amlodipine formulation and single hydrochlorothiazide formulation. These results demonstrate that fixed dose combination formulations of rosaceous, amlodipine and hydrochlorothiazide prepared by simple mixing methods may not be able to achieve bioequivalence with the free-dose combination formulations. Therefore, it is necessary to develop a fixed-dose combination formulation of three active ingredients without lowering of elution due to gelation of rosadan under low pH conditions.

The second problem is that the combination formulation of losartan, amlodipine and hydrochlorothiazide in simple formulations results in an increased production of impurities under accelerated conditions, resulting in a significant reduction in formulation stability. This is because the physicochemical reaction between rosato, amlodipine and hydrochlorothiazide interferes with the stability of each active ingredient.

In order to solve such a problem, a method of stabilizing an effective ingredient by adding an acid or an alkalizing agent to optimize the pH of the composition may be considered. In this case, however, amlodipine having an ester bond in a molecule is easily hydrolyzed, There is a problem that the rosacea is likely to be converted into degradation products under the conditions. Substantially, even when the pH of a composition containing an excipient is adjusted to 5.5 to 7.0 as disclosed in U.S. Patent No. 6,919,087, the amlodipine-rozatan combination preparation does not exhibit sufficient stability.

To improve this, it is possible to attempt separation between drugs by using a two-layer tablet machine or a three-layer tablet machine, but it requires special production equipment such as two-layer tablet or three-layer tablet machine, , It is mechanically impossible to separate 100% of the active component from each layer.

In order to minimize the deterioration of the dissolution rate of amlodipine and hydrochlorothiazide due to gelation of rosemary so as to ensure the inherent efflux and stability of each drug to maximize its clinical usefulness, A fixed dose combination form of a pharmaceutically acceptable salt, amlodipine or a pharmaceutically acceptable salt thereof, and a hydrochlorothiazide in the form of a separate layer separated from each other and filled in a capsule. Since the pharmaceutical compositions of the present invention are physically separated from each other, bioequivalence is easily ensured and the stability is excellent. Since the respective components are separately produced, the reactivity between the respective active ingredients can be completely eliminated , Minimizing the mass of the excipient used in the production of each independent layer, thereby reducing the size of the dosage form, and thus it is advantageous in that the compliance with the medicament is much superior to that of the conventional complex. In addition, it is possible to alleviate the side effects of the existing single agent and the combined agent, and at the same time, to exhibit the improved prevention and therapeutic effect of cardiovascular diseases.

In one embodiment, the losartan, amlodipine, and hydrochlorothiazide in the fixed-dose combination formulations of the present invention each comprise a separate separation layer and are packed within the capsule, and the separation layer may have a tablet form. In a specific embodiment, the fixed-dose combination formulations of the present invention comprise a tablet comprising a losartan or a pharmaceutically acceptable salt thereof, a tablet comprising amlodipine or a pharmaceutically acceptable salt thereof and a tablet comprising a hydrochlorothiazide It can be a capsule.

The losartan, amlodipine and hydrochlorothiazide tablets may each be compressed in a tablet press in the form of a mixture with a pharmaceutically acceptable excipient or in the form of granules, with various hardnesses depending on the tableting pressure of the tablet. Depending on the tableting pressure at the time of tabletting, even a composition having the same mass may exhibit various densities. In general, tablets having a density of 0.8 g / ml or more can be obtained. Generally, tablets of circular, rectangular, and elliptical types can be selected as the tablets obtained in this way, but circular tablets are preferable in consideration of the filling property into capsules. The diameter of the tablet showing the circular shape is preferably 1 mm to 7 mm, more preferably 2 mm to 6 mm. When the diameter of the tablet is increased, the size of the capsule used for filling the tablet becomes large, which may cause inconvenience of the medication. When the diameter of the tablet is small, the tabletable mass can not only be limited, There is a drawback that the operation speed is lowered.

In the fixed dose combination formulations of the present invention, one or more of the tablets present as separate, separate layers may be coated with the polymeric film coating layer. Examples of the pharmaceutically acceptable polymer used in the film coating layer include methyl cellulose, ethyl cellulose, polyvinyl alcohol, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and polyvinyl pyrrolidone. However, Any conventional polymer can be used. The amount of the polymer to be used is preferably kept at a minimum to provide an optimal preparation size and effective production, and about 1 to about 20% by weight, preferably about 2 to about 10% by weight, based on the total weight of the preparation, Do.

In the fixed-dose combination formulations of the present invention, separate separation layers, each containing the active ingredient losartan or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof and hydrochlorothiazide, Or excipients. Such pharmaceutically acceptable excipients include, but are not limited to, pharmaceutically acceptable diluents, pharmaceutically acceptable disintegrants, pharmaceutically acceptable binders, pharmaceutically acceptable stabilizers, pharmaceutically acceptable lubricants and pharmaceutically acceptable pigments and the like . In the fixed-dose combination formulations of the present invention, the active ingredient and the pharmaceutically acceptable excipients may be used in a weight ratio of 1: 0.25 to 1:20.

Examples of pharmaceutically acceptable diluents include microcrystalline cellulose, lactose, ruddy press, mannitol, calcium dihydrogen phosphate, starch, low substituted hydroxypropyl cellulose and mixtures thereof. The diluent may be used in an amount ranging from about 5 to about 95 weight percent, preferably from about 10 to about 85 weight percent, based on the total weight of the formulation. On the other hand, the diluent may preferably be a water-soluble diluent. When the diluent is used, the ratio of the active ingredient to the diluent contained in the individual separation layer is very important. The water-soluble diluent may be dissolved in water, such as lactose, excipients with Ludipress (BASF): lactose, crospovidone, povidone (93: 3.5: 3.5, w / w (%)), mannitol, sorbitol, Excipient, for example, when mixed with rosin as an active ingredient, the dissolution rate can be maximized when mixed at a constant weight ratio. This is because of the physical properties of rosetons gelled at low pH, the rosetta coats can exhibit fast disintegration rates when the weight ratio of rosatan and aqueous diluent is optimized. The weight ratio of rosin to water-soluble diluent is preferably from 1: 0.1 to 1:40, more preferably from 1: 0.25 to 1:20.

On the other hand, as a method for producing granules used for tableting rosaceous layer, it is advantageous in terms of stability of rosacea to be made by simple mixing or dry granule production method without using water and organic solvent. Surprisingly, when the water content of the rosetta layer was too high, it was confirmed that the stability of the rosette was drastically degraded because of the high water solubility of the rosette, causing hydrolysis of the rosette and changes in the properties thereof. In the present invention, the number of the excipients used in the rosaceous layer is preferably 5% or less, more preferably 3% or less.

Specific examples of the disintegrant that can be used in the fixed-dose combination formulations of the present invention include crospovidone, sodium starch glycolate, sodium croscarmellose sodium, low-substituted hydroxypropylcellulose, starch, alginic acid or its sodium salt, and And mixtures thereof. Preferably, crospovidone, sodium starch glyconate, croscarmellose sodium, low-substituted hydroxypropylcellulose or a mixture thereof may be used, more preferably, crospovidone and sodium starch glycolate may be used. The disintegrant may be used in an amount ranging from about 1 to about 30 weight percent, preferably from about 2 to about 15 weight percent, based on the total weight of the composition.

Specific examples of binders that can be used in the fixed-dose combination formulations of the present invention include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, copovidone, macrogol, light silicic anhydride, synthetic aluminum silicate, silicic acid Silicate derivatives such as calcium or magnesium metasilicate aluminate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, and mixtures thereof.

In addition, specific examples of stabilizers that can be used in the fixed-dose combination formulations of the present invention include antioxidants. The use of an antioxidant may increase the stability of the active ingredient, especially amlodipine, and reduce the deformation of the active ingredient by temperature and moisture, thereby increasing stability to changes over time. Specific examples of the antioxidant include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid, ascorbyl palmitic acid, ethylenediamine tetraacetic acid (EDTA), sodium pyrosulfite And mixtures thereof. In particular, butylated hydroxytoluene is preferred.

Also, specific examples of lubricants that may be used in the fixed-dose combination formulations of the present invention include stearic acid metal salts such as stearic acid, calcium stearate or magnesium stearate, talc, colloidal silica, sucrose fatty acid esters, hydrogenated vegetable oils , A wax having a high melting point, glyceryl fatty acid esters, glycerol dibehenate, and mixtures thereof.

The capsules used in the fixed-dose combination formulations of the present invention can be any of ordinary hard capsules used in medicines. Hard capsules (such as NP caps ^TM, Capsugel, Inc.) type gelatin capsule, marshmallow agarose capsules, pullulan capsules in the hip in accordance with the mechanisms that make up, poly there is vinyl alcohol and the like, losartan of the present invention, amlodipine and hydrochlorothiazide thiazole Gelatin capsules are preferred when the initial dissolution rate is important, such as in a fixed dose combination formulation of Zoids.

The capsule size of the hard capsule used in the fixed-dose combination formulation of the present invention may be any standard capsule size used in medicine. The capsule size has various internal volumes depending on the lake of the capsule, and it is more preferable that the size of the capsule is small considering the convenience of medication of the patient taking the complex formulation of the present invention. However, it is desirable to select an appropriate capsule size because of the mass limit of the contents to be filled in the capsule. The size of the hard capsule that can be used in the formulation of the present invention is preferably 0, 1, 2, 3 or 4 capsules. A schematic diagram of the fixed-dose combination formulation described above is shown in FIG.

The fixed dose combination formulations of the present invention reach a dissolution rate of greater than 80% with amlodipine or a pharmaceutically acceptable salt thereof and hydrochlorothiazide within 30 minutes after the start of the dissolution test, as seen in Figures 2 and 3.

The present invention also provides a method for preparing a losartan tablet comprising the steps of: a) mixing or granulating losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient and then tableting to obtain a losartan tablet; b) admixing or granulating amlodipine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and then tableting to obtain an amlodipine tablet; c) mixing or granulating the hydrochlorothiazide with a pharmaceutically acceptable excipient and then tableting to obtain a hydrochlorothiazide tablet; And d) filling the same hard capsules with the losartan tablet, the amlodipine tablet and the hydrochlorothiazide tablet, in a fixed dose combination formulation for the prevention or treatment of cardiovascular diseases. One or more of the steps a) to c) above may further comprise coating the resulting tablet with a pharmaceutically acceptable polymer.

The fixed-dose combination formulations of the present invention are excellent in solubility of rosatan, amlodipine and hydrochlorothiazide in the same level as the commercially available single agent, and exhibit a very stable change with time due to a small change in the amount of the flexible substance during the severe test. Therefore, the formulation of the present invention can be used for cardiovascular diseases such as angina pectoris, hypertension, arterial spasm, cardiac arrhythmia, cardiomyopathy, cerebral infarction, congestive heart failure, myocardial infarction and the like.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

Example 1: Preparation of Fixed-Capacity Combination Formulations I

- Rozan carbon containing layer -

Potassium rosinate 50.0 mg

Rudi Press 15.7 mg

Co-opvidone 3.0 mg

Light anhydrous silicic acid 0.5 mg

Microcrystalline cellulose 10.0 mg

Magnesium stearate 0.8 mg

Opadry Y-1-7000 2.4 mg

Purified water (12.0 mg)

- Amlodipine-containing layer -

7.84 mg amlodipine camsylate (5 mg as amlodipine)

Microcrystalline cellulose 43.76 mg

D-mannitol 14.0 mg

Sodium starch glycolate 1.7 mg

Hydroxypropylcellulose 2.0 mg

Magnesium stearate 0.7 mg

Purified water (35.0 mg)

Opadry Y-1-7000 2.1 mg

Purified water (11.0 mg)

- Hydrochlorothiazide-containing layer -

Hydrochlorothiazide 12.5 mg

38.80 mg of microcrystalline cellulose

Mannitol 13.0 mg

Starch sodium gluconate 3.0 mg

Hydroxypropylcellulose 2.0 mg

Magnesium stearate 0.7 mg

Purified water (35.0 mg)

Opadry Y-1-7000 2.1 mg

Purified water (11.0 mg)

The powder corresponding to the rosin carbon-containing layer was mixed. The lozenge mixture was compressed using a circular punch having a die diameter of 5 mm and the opaque dry Y-1-7000 (color cone) was dissolved in purified water.

Further, in the composition corresponding to the amlodipine-containing layer, the mixture of the remaining excipients was wet-granulated using a binding solution in which 2.0 mg of hydroxypropylcellulose was dissolved in 35.0 mg of purified water per unit tablet, and the mixture was dried with 20 mesh and dried to obtain granules . After granulating the above granules, Opadry Y-1-7000 was dissolved in purified water to prepare a coating solution, which was coated with amlodipine 5 mg tablets.

In addition, tablets were prepared by tableting in the same manner as in amlodipine tablets, followed by coating with 12.5 mg hydrochlorothiazide.

The cleanser was filled into Hard Capsule No. 2 to complete a fixed dose combination formulation of 50 mg rozatan, 5 mg amlodipine and 12.5 mg hydrochlorothiazide. The mass sum of the cleaning agent filled in the hard capsule was 226.6 mg, which was very small.

Example  2: Preparation of fixed-dose combination formulations II

- Rozan carbon containing layer -

Potassium rosinate 50.0 mg

Rudi Press 15.7 mg

Co-opvidone 3.0 mg

Light anhydrous silicic acid 0.5 mg

Microcrystalline cellulose 10.0 mg

Magnesium stearate 0.8 mg

Hephromelose 1.6 mg

0.4 mg of hydroxypropylcellulose

0.36 mg of titanium oxide

Talc 0.04 mg

Purified water (28.0 mg)

- Amlodipine-containing layer -

7.84 mg amlodipine camsylate (5 mg as amlodipine)

Microcrystalline cellulose 22.5 mg

D-mannitol 7.26 mg

Sodium starch glycolate 0.85 mg

Hydroxypropylcellulose 1.15 mg

Magnesium stearate 0.4 mg

Purified water (20.0 mg)

Hephromelose 0.8 mg

0.2 mg of hydroxypropylcellulose

0.18 mg of titanium oxide

Yellow iron oxide 0.01 mg

Talc 0.01 mg

Purified water (14.0 mg)

- Hydrochlorothiazide-containing layer -

Hydrochlorothiazide 12.5 mg

Microcrystalline cellulose 18.5 mg

Mannitol 5.95 mg

Starch sodium glyconate 1.5 mg

Hydroxypropylcellulose 1.15 mg

Magnesium stearate 0.4 mg

Purified water (20.0 mg)

Hephromelose 0.8 mg

0.2 mg of hydroxypropylcellulose

0.18 mg of titanium oxide

Red iron oxide 0.01 mg

Talc 0.01 mg

Purified water (14.0 mg)

Coated tablets of rosadan, amlodipine and hydrochlorothiazide were prepared according to the same procedure as described in Example 1, and then filled in Rigid Capsules No. 2 to obtain 50 mg of rosatane, 5 mg of amlodipine, and hydrochlorothiazide A fixed dose combination formulation of 12.5 mg was completed. The mass sum of the cleaning agent filled in the hard capsule was 164.8 mg, which was very small.

Example  3: Preparation of fixed-dose combination formulations III

- Rozan carbon containing layer -

Potassium rosinate 50.0 mg

Rudi Press 15.7 mg

Co-opvidone 3.0 mg

Light anhydrous silicic acid 0.5 mg

Microcrystalline cellulose 10.0 mg

Magnesium stearate 0.8 mg

Hephromelose 1.6 mg

0.4 mg of hydroxypropylcellulose

0.36 mg of titanium oxide

Talc 0.04 mg

Purified water (28.0 mg)

- Amlodipine-containing layer -

7.84 mg amlodipine camsylate (5 mg as amlodipine)

Microcrystalline cellulose 22.5 mg

D-mannitol 7.26 mg

Sodium starch glycolate 0.85 mg

Hydroxypropylcellulose 1.15 mg

Magnesium stearate 0.4 mg

Purified water (20.0 mg)

Hephromelose 0.8 mg

0.2 mg of hydroxypropylcellulose

0.18 mg of titanium oxide

Yellow iron oxide 0.01 mg

Talc 0.01 mg

Purified water (14.0 mg)

- Hydrochlorothiazide-containing layer -

Hydrochlorothiazide 25.0 mg

Microcrystalline cellulose 37.0 mg

Mannitol 11.9 mg

Starch sodium gluconate 3.0 mg

Hydroxypropylcellulose 2.3 mg

Magnesium stearate 0.8 mg

Purified water (40.0 mg)

Hephromelose 1.6 mg

0.4 mg of hydroxypropylcellulose

0.36 mg of titanium oxide

0.02 mg of red iron oxide

Talc 0.02 mg

Purified water (28.0 mg)

Coated tablets of rosadan, amlodipine and hydrochlorothiazide were prepared according to the same procedure as described in Example 1, and then filled in Rigid Capsules No. 2 to obtain 50 mg of rosatane, 5 mg of amlodipine, and hydrochlorothiazide A fixed dose combination formulation of 25 mg was completed. The mass sum of the cleaning agent filled in the hard capsule was 206 mg, which was very small.

Example  4: Preparation of fixed-dose combination formulations IV

- Rozan carbon containing layer -

Potassium rosinate 50.0 mg

Rudi Press 15.7 mg

Co-opvidone 3.0 mg

Light anhydrous silicic acid 0.5 mg

Microcrystalline cellulose 10.0 mg

Magnesium stearate 0.8 mg

Hephromelose 1.6 mg

0.4 mg of hydroxypropylcellulose

0.36 mg of titanium oxide

Talc 0.04 mg

Purified water (28.0 mg)

- Amlodipine-containing layer -

15.68 mg amlodipine camsylate (10 mg as amlodipine)

Microcrystalline cellulose 15.0 mg

D-mannitol 14.52 mg

Sodium starch glycolate 1.7 mg

Hydroxypropylcellulose 2.3 mg

Magnesium stearate 0.8 mg

Purified water (40.0 mg)

Hephromelose 1.6 mg

0.4 mg of hydroxypropylcellulose

0.36 mg of titanium oxide

Yellow iron oxide 0.02 mg

Talc 0.02 mg

Purified water (28.0 mg)

- Hydrochlorothiazide-containing layer -

Hydrochlorothiazide 12.5 mg

Microcrystalline cellulose 18.5 mg

Mannitol 5.95 mg

Starch sodium glyconate 1.5 mg

Hydroxypropylcellulose 1.15 mg

Magnesium stearate 0.4 mg

Purified water (20.0 mg)

Hephromelose 0.8 mg

0.2 mg of hydroxypropylcellulose

0.18 mg of titanium oxide

Red iron oxide 0.01 mg

Talc 0.01 mg

Purified water (14.0 mg)

Coated tablets of rosatan, amlodipine and hydrochlorothiazide were prepared according to the same procedure as described in Example 1, and then filled in Rigid Capsules No. 2 to obtain 50 mg of rosatan, 10 mg of amlodipine, and hydrochlorothiazide A fixed dose combination formulation of 12.5 mg was completed. The mass sum of the cleaning agent filled in the hard capsule was 206 mg, which was very small.

Comparative Example  1: Preparation of fixed dose combination formulation V (simple mixed tablet)

Potassium rosinate 50.0 mg

7.84 mg amlodipine camsylate (5 mg as amlodipine)

Hydrochlorothiazide 12.5 mg

Rudi Press 15.7 mg

Co-opvidone 3.0 mg

Light anhydrous silicic acid 0.5 mg

Microcrystalline cellulose 92.56 mg

Mannitol 27.0 mg

Sodium starch glycolate 4.7 mg

4.0 mg of hydroxypropylcellulose

Magnesium stearate 2.2 mg

In the composition of Comparative Example 1, losartan, amlodipine, hydrochlorothiazide and excipients were mixed together and triturated to give a fixed dose combination formulation of 50 mg losartan, 5 mg amlodipine and 12.5 mg hydrochlorothiazide.

Comparative Example  2: Preparation of fixed-dose combination formulations VI  (Simple mixed capsule)

Potassium rosinate 50.0 mg

7.84 mg amlodipine camsylate (5 mg as amlodipine)

Hydrochlorothiazide 12.5 mg

Rudi Press 15.7 mg

Co-opvidone 3.0 mg

Light anhydrous silicic acid 0.5 mg

Microcrystalline cellulose 92.56 mg

Mannitol 27.0 mg

Sodium starch glycolate 4.7 mg

4.0 mg of hydroxypropylcellulose

Magnesium stearate 2.2 mg

In the composition of Comparative Example 1, losartan, amlodipine, hydrochlorothiazide and excipients were mixed together and filled in hard capsule No. 1 to obtain a fixed dose combination formulation of 50 mg of rosatan, 5 mg of amlodipine and 12.5 mg of hydrochlorothiazide ≪ / RTI >

Test Example  One: Amlodipine  And Of hydrochlorothiazide  Dissolution test

Using the fixed-dose combination formulations prepared in Example 1 and Example 2 and the fixed-dose combination formulation prepared in Comparative Example 1 and Comparative Example 2, Dichlorojung (Yuhan) and 5 mg of Nobasuk tablets, elution was carried out under the following conditions Tests were conducted and compared.

- elution condition -

Elution: 900 mL of 0.01 N HCl (pH 2.0)

Apparatus: USP paddle method, 75 rpm

Temperature: 37 ° C

- Analysis conditions -

Column: A column packed with octadecylsilylated silica gel for a liquid chromatograph of 5 mu m in a stainless steel tube having an inner diameter of about 4.6 mm and a length of 25 cm

Mobile phase: 0.015 M potassium dihydrogen phosphate: acetonitrile: methanol

        (47: 32: 23, v / v)

Detector: Ultraviolet absorptiometer (measuring wavelength 238 nm)

Flow rate: 1.2 mL / min

Injection volume: 20 uL

Column temperature: 40 ° C

- Criteria -

The dissolution rate at 30 minutes is 80% or more.

- result -

As shown in FIGS. 2 and 3, in the case of the fixed dose combination form in which all of the rosatan, amlodipine and hydrochlorothiazide of Example 1 and Example 2 were separated, Comparative Example 1 and Comparative Example 2 . Both hydrochlorothiazide and amlodipine showed satisfactory dissolution profiles satisfying the criteria. On the other hand, in the case of Comparative Example 1 and Comparative Example 2 which were simply blended, both hydrochlorothiazide and amlodipine did not satisfy the criteria.

Test Example   2: Stiff storage stability test

The fixed-dose combination formulations obtained in Example 1 and Example 2 and the fixed-dose combination formulations prepared in Comparative Example 1 and Comparative Example 2 were subjected to a harsh storage test for light and heat under the following conditions to obtain losartan, amlodipine and hydrochlorothiophen The degree of change of the flexible substance due to thiazide was evaluated and the stability was compared. The results are shown in Table 3 below.

- Light stability chamber conditions (light harsh conditions) -

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

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

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

          (1.2 million lux, optical stability test conditions presented in the ICH Guidelines)

(4) Sample: Petri dish storage

Test point - after initial and light exposure (after 1.2 million lux exposure)

- Severe stability chamber conditions (thermal harsh conditions) -

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

(2) Sample: HDPE bottle packing

Test point - after initial and 28 days storage

- Analysis conditions (rosaceans and amlodipine)

Column: A column filled with octadecylsilylated silica gel for a liquid chromatograph having a particle diameter of 5 mu m and having a diameter of about 4.6 mm and a length of 5 cm (for example, Symmetry C18, Waters)

Mobile:

    Mobile phase A: 6 nM sodium hexacyano sulfonate monohydrate solution containing 0.05% phosphoric acid

    Mobile phase B: methanol

    Concentration gradient system Time (minutes) Mobile phase A% Mobile phase B% 0 56 44 5 56 44 13 20 80 13.1 56 44 15 56 44

Detector: Ultraviolet absorptiometer (measuring wavelength 239 nm)

Flow rate: 1.5 mL / min

Injection volume: 10 uL

Column temperature: 45 ° C

- Analysis conditions (flexible material with hydrochlorothiazide groups) -

Column: A column filled with octasilylated silica gel for a liquid chromatograph having a particle diameter of 5 um and having a diameter of about 4.6 mm and a length of 5 cm (for example, Symmetry C18, Waters)

Mobile:

    Mobile phase A: acetonitrile: methanol = 3: 1 (v / v)

    Mobile phase B: formic acid: water = 5: 995 (v / v)

    Concentration gradient system Time (minutes) Mobile phase A% Mobile phase B% 0 3 97 5 3 97 14 36 64 20 90 10 25 3 97 28 3 97

Detector: Ultraviolet absorptiometer (measuring wavelength: 275 nm)

Flow rate: 1.0 mL / min

Injection volume: 10 uL

Column temperature: 35 ° C

Rosatan, amlodipine, and hydrochlorothiazide groups. sample Early Light exposure, 1.2 million lux 50 ℃, HDPE bottle packing
Keep 28 days Rozan tan
cause
Flexible material
(%) Amlodipine
Flexible material
(%) Hydrochlorothiazide
Flexible Substance (%) Roza tanjin
Flexible Substance (%) Amlodipine
Flexible Substance (%) Hydrochlorothiazide
Flexible Substance (%) Rozan tan
cause
Flexible Substance (%) Amlodipine
Flexible Substance (%) Hydrochlorothiazide
cause
Flexible Substance (%) Example 1 0.01 0.01 0.04 0.02 0.10 0.09 0.05 0.09 0.11 Example 2 0.02 0.01 0.06 0.03 0.12 0.08 0.05 0.07 0.12 Comparative Example 1 0.01 0.03 0.04 0.03 0.86 0.34 0.04 1.12 1,45 Comparative Example 2 0.04 0.05 0.11 0.09 0.78 0.43 0.55 1.36 1.98

As can be seen from the above table, the fixed dose combination formulations of rosatan, amlodipine and hydrochlorothiazide prepared by the methods of Example 1 and Example 2 were used in combination with losartan, amlodipine and hydrochlorothiophene in harsh conditions by light or heat All three components of the thiazide were found to be very stable without significant changes in the flux. However, in the case of the formulations of Comparative Example 1 and Comparative Example 2 prepared by simple mixing of the three components, it was confirmed that the amounts of generation of the flexible substances were increased by at least 10 times as compared with Examples 1 and 2 in all three components. This shows that the fixed-dose combination formulations of the present invention are significantly more stable over time than the fixed-dose combination formulations prepared by simple mixing methods.

Claims (16)

As active ingredients,
Losartan or a pharmaceutically acceptable salt thereof;
Amlodipine or a pharmaceutically acceptable salt thereof; And
Which comprises hydrochlorothiazide,
Wherein the active ingredients are each independently separated into a capsule,
Wherein the separation layer is in the form of a tablet,
Wherein said tablet is coated with a pharmaceutically acceptable polymer.
delete delete 2. The fixed dose combination formulation of claim 1, wherein the pharmaceutically acceptable salt of losartan is potassium losartan.
2. The fixed dose combination formulation of claim 1, wherein the pharmaceutically acceptable salt of amlodipine is amlodipine camsylate.
The fixed dose combination formulation of claim 1, wherein the pharmaceutically acceptable salt of amlodipine is amlodipine besylate.
2. The fixed dose combination formulation of claim 1, wherein the losartan or a pharmaceutically acceptable salt thereof is contained in an amount ranging from 25 mg to 200 mg.
2. The fixed dose combination formulation of claim 1, wherein the amlodipine or a pharmaceutically acceptable salt thereof is included in an amount ranging from 2.5 mg to 10 mg.
The fixed dose combination formulation of claim 1, wherein said hydrochlorothiazide is included in an amount ranging from 6.25 mg to 25 mg.
2. The fixed dose combination formulation of claim 1, wherein said separation layer comprises a pharmaceutically acceptable excipient and wherein the active ingredient and excipient are used in a weight ratio of 1: 0.25 to 1:20.
11. The composition of claim 10 wherein said pharmaceutically acceptable excipient is selected from the group consisting of crospovidone, sodium starch glycolate, croscarmellose sodium, low substituted hydroxypropyl cellulose, starch, alginic acid or its sodium salt, ≪ / RTI > wherein said disintegrant comprises a disintegrant selected from the group consisting of: < RTI ID = 0.0 >
The fixed dose combination formulation of claim 1, wherein the amlodipine or a pharmaceutically acceptable salt thereof has a dissolution rate of greater than 80% within 30 minutes after the start of the dissolution test.
The fixed dose combination formulation of claim 1, wherein the hydrochlorothiazide reaches a dissolution rate of greater than 80% within 30 minutes after the start of the dissolution test.
The method according to claim 1, wherein the formulation is used for cardiovascular disease and the disease is selected from the group consisting of angina pectoris, hypertension, arterial spasm, cardiac arrhythmia, cardiomyopathy, cerebral infarction, congestive heart failure and myocardial infarction. Formulation.
a) mixing or granulating losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient and then tableting to obtain a losartan tablet;
b) admixing or granulating amlodipine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and then tableting to obtain an amlodipine tablet;
c) mixing or granulating the hydrochlorothiazide with a pharmaceutically acceptable excipient and then tableting to obtain a hydrochlorothiazide tablet; And
d) filling the same hard capsules with the losartan tablet, the amlodipine tablet and the hydrochlorothiazide tablet,
Further comprising coating the tablet obtained in one or more of steps a), b) and c) with a pharmaceutically acceptable polymer.
A method for the manufacture of a fixed dose combination formulation for the prevention or treatment of cardiovascular diseases. delete

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