KR20180049510A - Pharmaceutical complex formulation comprising amlodipine, losartan and chlorthalidone - Google Patents

Abstract

The present invention relates to a pharmaceutical complex formulation comprising amlodipine, losartan and chlorthalidone as active ingredients. The pharmaceutical complex formulation comprising amlodipine, losartan and chlorthalidone as active ingredients according to the present invention has excellent elution characteristics of the active ingredients and exhibits high content uniformity and thermal stability. Therefore, the complex formulation of the present invention can be utilized as a preventive or therapeutic agent having excellent quality and thermal stability for cardiovascular diseases.

Description

[0001] PHARMACEUTICAL COMPLEX FORMULATION COMPRISING AMLODIPINE, LOSARTAN AND CHLORTHALIDONE [0002]

The present invention relates to a pharmaceutical combination comprising amlodipine, losartan and chlorthalidone as active ingredients.

Hypertension is defined as an adult over 18 years of age with a systolic blood pressure greater than 140 mmHg or a diastolic blood pressure greater than 90 mmHg. Hypertension is the most common cause of chronic cardiovascular disease and is relatively uncomplicated. However, it requires more aggressive management and treatment because it can cause fatal complications such as stroke, heart failure and coronary artery disease.

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

Amlodipine is a 3-ethyl-5-methyl-2- (2-aminoethoxy-methyl) -4 - (- 2- chlorophenyl) -6- Pyridinedicarboxylate and is a dihydropyridine calcium channel blocker and is used in the treatment of cardiovascular diseases such as angina pectoris, hypertension and congestive heart failure by blocking the calcium channel.

Losartan is a 2-butyl-4-chloro-1- [2 '- (1H-tetrazol-5-yl) [1,1'-biphenyl] It is a common name for azathioprine-5-methanol. It inhibits angiotensin II binding to the receptor to treat hypertension and heart failure, treats ischemic peripheral circulatory disorder, myocardial ischemia (angina pectoris) Prevent progression, and treat diabetic neuropathy, glaucoma, and the like.

The combination of amlodipine and rosatan, which have different mechanisms of action, is more effective in the prevention or treatment of hypertension and cardiovascular diseases than the conventional monotherapy, reduces the adverse effects of each drug used, and improves patient compliance . The combination preparation is disclosed in Korean Patent Nos. 1160151 and 1232296, and is currently marketed under the trade name Amosartan ( ^R ).

Chlorthalidone is a generic name for benzenesulfonamide-2-chloro-5- (2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol- Hygroton < ( ^R ) >. Chlortalidone is a thiazide - based diuretic that blocks the Na ⁺ / Cl ^- transporter in the kidney distal tubule, inhibits reabsorption of Na ⁺ and Cl ^- , increases excretion of K ⁺ .

In order to effectively treat cardiovascular diseases, a combination of amlodipine, rozatan and chloretallidone using different mechanisms is being studied. For example, Korean Patent Laid-Open Publication No. 2016-0117055 discloses a combined preparation wherein a first mixing portion containing amlodipine and chlorertalidone and a second mixing portion containing rosin are separated. The combined preparation can be implemented in a two-layer tablet, minimizing the interactions between the drugs and improving the stability of the active ingredient against the dissolution rate, light and heat of the drug.

However, in order to further improve the quality and bioavailability of the combination product of amlodipine, rosatan, and chlortalidone, it is necessary to study a pharmaceutical combination having improved dissolution rate, uniformity of content, and stability.

Korean Patent Publication No. 2016-0117055, amlodipine, rozatan, and chlortalidone

The present inventors have studied a method for improving the dissolution rate, content uniformity, and stability of a pharmaceutical combination comprising amlodipine, rozatan and chlortalidone, and as a result, the present invention has been completed.

Accordingly, an object of the present invention is to provide a pharmaceutical combination comprising amlodipine, rozatan and chlorertalidone which exhibits excellent dissolution characteristics, content uniformity and stability.

Another object of the present invention is to provide a process for preparing the pharmaceutical combination.

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising a first mixture comprising amlodipine or a pharmaceutically acceptable salt thereof and chlortalidone or a pharmaceutically acceptable salt thereof; And

Or a pharmaceutically acceptable salt thereof; and a second mixing portion comprising losartan or a pharmaceutically acceptable salt thereof,

Wherein the first mixing portion and the second mixing portion are physically separated from each other,

And the particle size (D90) of the chlortalidone or a pharmaceutically acceptable salt thereof is 0.5 to 50 mu m.

Preferably, the particle size (D90) of the chlortalidone or a pharmaceutically acceptable salt thereof may be 0.5 to 25 [mu] m.

More preferably, the particle size (D90) of the chlortalidone or a pharmaceutically acceptable salt thereof may be between 0.5 and 10 mu m.

Wherein the pharmaceutical combination comprises a first layer comprising amlodipine or a pharmaceutically acceptable salt thereof and chlortalidone or a pharmaceutically acceptable salt thereof; And

Or a second layer comprising a losartan or a pharmaceutically acceptable salt thereof.

At this time, according to the paddle method of the dissolution test item of the United States Pharmacopoeia clotalidon tablet tablet, the combination preparation may have a dissolution rate of chlortalidone of not less than 85% within a period of not more than 30 minutes in the elution test in purified water, The dissolution rate of the talidone may be 85% or more.

At this time, the first mixing portion may further include a disintegrant as an additive.

The disintegrant may be crospovidone, croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch, or a combination thereof.

At this time, the disintegrant may be contained in an amount of 2 to 7.5% by weight based on the total weight of the first mixing portion.

At this time, the first mixing part may further include lactose hydrate and microcrystalline cellulose as additives.

At this time, the first mixing portion and the second mixing portion may be in the form of granules which have undergone a roller compaction process.

The present invention also relates to a pharmaceutical composition comprising: a) admixing amlodipine or a pharmaceutically acceptable salt thereof, chlortalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; And

b) mixing roszatan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive,

Wherein the clathalidone or pharmaceutically acceptable salt thereof has a particle size (D90) of 0.5 to 50 占 퐉.

The combination preparation may also comprise a) granulating after admixing amlodipine or a pharmaceutically acceptable salt thereof, chlortalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive;

b) granulating after mixing roszatan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; And

c) titrating the mixture of step a) and the mixture of step b)

Wherein the clathalidone or a pharmaceutically acceptable salt thereof has a particle size (D90) of 0.5 to 50 占 퐉.

In this case, the pharmaceutical combination preparation may be a composition or a combination preparation for prevention or treatment of cardiovascular diseases.

The combined pharmaceutical preparation containing amlodipine, rosatan and chloretallidone as an active ingredient according to the present invention has excellent dissolution characteristics of the active ingredient and exhibits high content uniformity and thermal stability. Therefore, the combination preparation of the present invention can be utilized as a preventive or therapeutic agent for cardiovascular diseases having excellent quality and thermal stability.

Fig. 1 is a graph showing dissolution rates of chlortalidone in Examples 1 to 3 and Comparative Examples 1 and 2. Fig.
Fig. 2 is a graph of amlodipine dissolution rates of Examples 1 to 3 and Comparative Examples 1 and 2. Fig.
Fig. 3 is a graph of solubility in losartan of Examples 1 to 3 and Comparative Examples 1 and 2. Fig.
Fig. 4 is a graph showing dissolution rates of chlortalidone in Examples 1 and 4 to 7; Fig.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, exemplary embodiments of the present invention will be described in detail with reference to the accompanying drawings. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

The present invention provides a pharmaceutical composition comprising a first mixture comprising amlodipine or a pharmaceutically acceptable salt thereof and chlortalidone or a pharmaceutically acceptable salt thereof; And

Or a pharmaceutically acceptable salt thereof; and a second mixing portion comprising losartan or a pharmaceutically acceptable salt thereof,

Wherein the first mixing portion and the second mixing portion are physically separated from each other,

And the particle size (D90) of the chlortalidone or a pharmaceutically acceptable salt thereof is 0.5 to 50 mu m.

In the present invention, the particle size of the drug is expressed based on the particle size distribution. D90 is the cumulative distribution of the particle size distribution of the drug obtained by measuring the particle diameter of the drug, 90% of the diameter of the particle.

In the present invention, the particle size of chlortalidone or a pharmaceutically acceptable salt thereof (hereinafter referred to as chlortalidone) can be carried out using a commercially available apparatus based on the laser diffraction / scattering method based on the Mie theory. For example, it can be measured using a commercially available apparatus such as HELOS (Helium-neon Laser for Optical Spectrometry, Sympatec) laser diffraction apparatus. In this device, when a helium-neon laser beam is irradiated on a particle, scattering occurs, a light scattering pattern appears on the detector, and the light scattering pattern is analyzed according to the Mie theory to obtain the particle diameter distribution. The measurement method can be either a dry method or a wet method, but in the following examples, measurement results using a dry method are shown.

In the pharmaceutical combination preparation of the present invention, the particle size of the chlortalidone is 0.5 to 50 탆, preferably 0.5 to 25 탆, more preferably 0.5 to 10 탆.

As a result of the studies conducted by the present inventors, it has been found that when the particles of chlortalidone are micronized in a pharmaceutical combination comprising amlodipine, rozatan and chlortalidone as active ingredients, the dissolution rate, content uniformity and thermal stability of the active ingredient are improved It was found that

This effect is better as the particle size of chlortalidone is smaller. However, when the particle size (D90) is less than 0.5 μm, it is difficult to collect the active ingredient in the undifferentiated process and the preparation process of the complex preparation. There is a falling problem. Therefore, in the present invention, the particle size of chlortalidone preferably satisfies the above-mentioned range.

In the present invention, the method for controlling the particle size of the chlortalidone is not particularly limited, and any method known in the art can be appropriately selected. Specifically, the chlortalidone is produced by using a conventional mill capable of pulverizing particles such as a jet mill, a hammer mill, a ball mill, a fluid energy mill, and the like It can be pulverized. In addition, the particle size of the drug can be subdivided by using a sieve method or a size classification method such as air current classification. In one embodiment of the present invention, the particle size of chloretallidone was controlled using an air jet mill.

The combined preparation of the present invention may be prepared in various forms such as a core-shell structure in which the first mixing part and the second mixing part can be physically separated, and may be formulated into a formulation such as tablets or capsules. According to a preferred embodiment of the present invention, the combination preparation comprises a first layer comprising amlodipine or a pharmaceutically acceptable salt thereof and chlortalidone or a pharmaceutically acceptable salt thereof; And a second layer comprising losartan or a pharmaceutically acceptable salt thereof.

Since the combination preparation contains amlodipine, chlortalidone and rosacean separately, it can prevent interaction between the active ingredients and exhibits high stability and excellent dissolution characteristics.

The combination preparation of the present invention comprises amlodipine or a pharmaceutically acceptable salt thereof in the first mixing part (or the first layer).

The pharmaceutically acceptable salt of amlodipine is formed from an acid which forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, a hydrochloride, a bromide salt, a sulfate, a phosphate, an acetate, , Fumarate, lactate, tartrate, citrate, gluconate, besylate salt and camsylate salt, but are not limited thereto. Of these, amlodipine besylate salt and camsylate salt are preferable, and camsylate salt is more preferable. In addition, the amlodipine of the present invention includes amlodipine racemate and (S) -amlodipine. The dosage of the amlodipine or a pharmaceutically acceptable salt thereof varies depending on the age, sex, weight, degree of pathology, and route of administration of the patient, but is generally 5 mg / day as amlodipine (adult weight: 60 kg) To 10 mg per day.

The combination preparation of the present invention comprises chlortalidone or a pharmaceutically acceptable salt thereof in the first mixing part. The dose of the chlortalidone or a pharmaceutically acceptable salt thereof may vary depending on the age, sex, weight, degree of pathology, and route of administration of the patient, but is generally determined based on the adult (body weight: 60 kg) In an amount of 12.5 to 25 mg per day.

The combination preparation of the present invention comprises losartan or a pharmaceutically acceptable salt thereof in the second mixing part (or the second layer). Examples of the pharmacologically acceptable salt of the losartan include, but are not limited to, losartan potassium salt. The dose of the losartan or a pharmaceutically acceptable salt thereof may vary depending on the age, sex, weight, degree of pathology, and route of administration of the patient but is generally 1 The dose of 40 to 100 mg per day may be administered.

The weight ratio of amlodipine or a pharmaceutically acceptable salt thereof, chlortalidone or a pharmaceutically acceptable salt thereof, and losartan or a pharmaceutically acceptable salt thereof contained in the combination preparation according to the present invention is preferably amlodipine: chlortalidone: And may be in the range of 1: 1.25 to 5: 5 to 20, preferably 1: 2.5 to 5:10 to 20,

The combined preparation of the present invention comprises a first mixing part (or first layer) containing chlortalidone satisfying the particle size (D90) range and containing amlodipine and chlortalidone, and a second mixing part (Or the second layer) was physically separated to ensure improved dissolution characteristics and content uniformity.

Gelation of rosaceae is problematic when a combination preparation is prepared by simple mixing of amlodipine, chlortalidone and rosatan. The losartan exhibits a very good dissolution pattern when eluted at a relatively high pH such as purified water, pH 4.0, pH 6.8. However, losartan is gelled at low pH (for example, pH 1.2, pH 2.0, etc.) and slowly elutes. This phenomenon has a great influence on the dissolution rate of the preparation in that the place where the first disintegration and dissolution occurs when the oral preparation is taken is in a state in which the digestive juice is secreted at a low pH and may further affect the in vivo absorption of the drug . Further, as described above, as the rosaceous gel is gelled, amlodipine and chlortalidone mixed with rosaceous powder are also entrapped in the gel, resulting in deterioration of dissolution.

On the contrary, the combination preparation of the present invention reduces the contact area with the losartan by separating the first mixed portion containing amlodipine and chlortalidone and the second mixed portion containing losartan, It is possible to prevent the elution of amlodipine and chlortalidone from being delayed due to gelation, and thus it is possible to achieve excellent dissolution rate and stability of amlodipine, chlortalidone and rosantan. Further, by controlling the particle size of the chlorotridon, the uniformity of the content in the combination preparation and the dissolution characteristics of the chlorotallidone can be further improved.

Specifically, the combination preparation of the present invention has a dissolution rate of chlortalidone of not less than 85% within a period of not more than 30 minutes in a dissolution test in purified water according to the paddle method of the dissolution test item of the United States Pharmacopoeia chlortalidone tablet term, preferably within 15 minutes The dissolution rate of chlortalidone is 85% or more.

Meanwhile, the pharmaceutical combination preparation of the present invention may further include pharmaceutically acceptable additives such as excipients, disintegrants, binders, lubricants and the like.

Examples of the excipient include lactose (lactose hydrate), microcrystalline cellulose, mannitol, sodium citrate, calcium phosphate, glycine, starch, or a combination thereof.

As the disintegrant, for example, crospovidone, croscarmellose sodium, sodium starch glyconate, starch, pregelatinized starch, or a combination thereof may be used.

As the binder, for example, polyvinyl pyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin, acacia or combinations thereof may be used.

As the lubricant, for example, palmitic acid, talc (talc), magnesium stearate, zinc stearate, calcium stearate, or a combination thereof may be used.

Preferably, the combined preparation of the present invention comprises a disintegrant as an additive in the first mixing portion.

The disintegrant is a substance added to promote the disintegration of a preparation in a digestive juice. It improves the elution properties of the active ingredient so that the drug to be absorbed can be released more effectively.

The kind of the disintegrant which can be used in the present invention is not particularly limited, and for example, the disintegrant as described above can be used, and preferably crospovidone can be used.

In this case, the disintegrant is preferably contained in an amount of 2 to 7.5% by weight, more preferably 5 to 7.5% by weight, based on the total weight of the first mixing portion. If the disintegrant content of the first mixed portion is less than 2% by weight, there is a problem that the initial elution of the active ingredient is delayed. If the disintegrant content exceeds 7.5% by weight, the occurrence of the flexible substance due to the active ingredient increases during storage There is a problem in that the stability of the film is deteriorated.

In addition, the combination preparation of the present invention may preferably include a disintegrant as an additive in the first mixing portion, and specifically, the disintegrant may be lactose hydrate and microcrystalline cellulose.

The lactose hydrate may be contained in an amount of 20 to 60% by weight based on the total amount of the first mixing portion. In another embodiment of the present invention, the weight ratio of lactose hydrate to microcrystalline cellulose may be in the range of 1: 0.5 to 1: 2.

When the lactose hydrate is used as the water-soluble excipient in the above-mentioned content range, the lactose hydrate forms a wetting channel in the preparation to accelerate the dissolution of the active ingredient to exhibit a fast dissolution pattern. If the lactose hydrate is less than the above content range, If the content is higher than the above range, the time required for completely dissolving the lactose hydrate is prolonged, so that the dissolution of the active ingredient is rather slowed. In the case of the microcrystalline cellulose, when the tablet is used in the above-mentioned content range, tablet formation is smoothly performed during tableting work, whereas if it is less than the above-mentioned content, tableting trouble occurs during tableting work, Lt; / RTI >

In addition, the pharmaceutical combination preparation of the present invention may further comprise a pH adjusting agent, a suspending agent, a preservative, a flavoring agent, a coloring agent, a sweetening agent, an adsorbent, and a solubilizing agent, if necessary. The content of the additive is not particularly limited in the present invention and can be appropriately adjusted as needed.

In the combination preparation of the present invention, the first mixing portion and the second mixing portion can be tableted after granulation by a conventional granulation method, for example, a compression granulation method. In another embodiment, the first mixer and the second mixer may be in the form of granules which have undergone a roller compaction process. When the compression granulated first mixing part and the second mixing part are tableted in a two-layer tablet, amlodipine, chlortalidone and rosantan show excellent dissolution patterns.

The pharmaceutical combination preparation of the present invention described above comprises a) mixing amlodipine or a pharmaceutically acceptable salt thereof, chlortalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; And b) mixing the rosatarts or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

In addition, the pharmaceutical combination preparation of the present invention comprises a) granulating after mixing amlodipine or a pharmaceutically acceptable salt thereof, chlortalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; b) granulating after mixing roszatan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; And c) granulating the granules of step a) and granules of step b) into a bi-layer tablet.

When preparing the pharmaceutical combination preparation and the two-layered tablet of the present invention according to the above method, it may further include adjusting the particle size of the active ingredient before each step a). At this time, the particle size adjustment step may be performed by the particle size adjustment method described above.

The pharmaceutical combination preparation of the present invention can be used for prevention or treatment of cardiovascular diseases such as angina pectoris, hypertension, arterial spasm, cardiac arrhythmia, cardiomyopathy, cerebral infarction, congestive heart failure and myocardial infarction.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope and spirit of the invention as disclosed in the accompanying claims. Changes and modifications may fall within the scope of the appended claims.

[Example]

Example 1: Preparation of a two-layered composition containing micronised chloraltidal

The powder of chlortalidone was pulverized with an air jet mill (AS50, Hosokawa Micron) at a grinding pressure of 1.5 bar to prepare a raw material having a particle size (D90) of 10.4 μm. Thereafter, amlodipine camsylate, micronized chlortalidone, lactose hydrate, microcrystalline cellulose and crospovidone were mixed according to the composition shown in Table 1 below, and the mixture was stirred at a roller speed of 5 rpm and a hydraulic pressure of about 6.5 MPa at a roller speed of 1 rpm. The granules on the flakes formed using a compressor (TF-1-A60, Freund vector) were passed through a 1.0 mm sieve. Magnesium stearate sieved with a 24 mesh sieve was added to the above granules and finally mixed in a mixer to prepare amlodipine and chlortalidone granules.

In addition, flakes of rhodozoite, microcrystalline cellulose and crospovidone were mixed and dried using a roller compressor (TF-1-A60, Freund vector) under a hydraulic pressure of about 6.0 MPa and a hopper speed of 5 rpm and a roller speed of 1 rpm The granules on the top were passed through a 0.8 mm sieve size sieve. Magnesium stearate sieved with a 24-mesh sieve was added to the obtained granules, followed by final mixing in a mixer to prepare a granulated losartan granule.

Then, using a tabletting machine (Autotab-200TR, ichihashi seiki co., LTD), a composite two-layer tablet composed of amlodipine and chlortalidone granule part (first layer; upper layer) and rosato granule part (second layer: .

division ingredient Content (mg) Amlodipine and chlortalidone
Containing layer (upper layer) Amlodipine camsylate 7.84 Chlortalidone 25.0 Lactose baggage 100.96 Microcrystalline cellulose 54.0 Crospovidone 10 Magnesium stearate 2.2 Total weight of upper layer 200.0 Rozan carbon-containing layer (lower layer portion) Potassium rosinate 100.0 Microcrystalline cellulose 206.0 Crospovidone 12.0 Magnesium stearate 2.0 Gross Weight 320.0 Total refined weight 520.0

Example  2 to 3 and Comparative Example  1 to 2: chlortalidone Grain size  Different two layer definition manufacturing

Composite twinning tablets were prepared in the same manner as in Example 1 using chlortalidone having different particle sizes according to the composition shown in Table 2 below.

Chlortalidone particle size (D90, μm) Example 2 20.5 Example 3 31.6 Comparative Example 1 50.4 Comparative Example 2 72.4

Example  4 to 7: Upper layer Disintegration  Manufacture of two layers with different ratios

According to the following Table 3, the composite two-layered tablets were prepared in the same manner as in Example 1, except that the disintegration ratio of the upper layer was varied based on the total weight of the upper layer. At this time, chlortalidone having a particle size (D90) of 10.4 [mu] m was used, and the content of lactose hydrate was adjusted according to the content of the disintegrant to make the total weight of the upper layer equal to 200 mg.

ingredient Example 4 Example 5 Example 6 Example 7 Crospovidone (mg)
(Ratio based on total weight of upper layer) 0
(0.0%) 5
(2.5%) 15
(7.5%) 20
(10%)

Test Example  1: chlortalidone In particle size (D90)  Determination of the dissolution rate of oral combination preparations

The dissolution rates of amlodipine, chlortalidone and rosatan were measured over time according to the following conditions using the tablets of Examples 1 to 3 and the composite two-layered tablets of Comparative Examples 1 to 2.

- elution condition -

Apparatus: United States Pharmacopeia (USP) Chlorotridone Tablet Termination Dissolution test item Test Method Method 2 (paddle method)

Test Solution: Purified water, 900 mL

Elution temperature: 37 캜

Revolutions: 75 rpm

- Analysis conditions -

Detector: Ultraviolet absorptiometer (measuring wavelength 254 nm)

Column: Column (150 x 4, 6 nm, 3 μm) packed with octadecylsilylated silica gel for liquid chromatography

Mobile phase: buffer: acetonitrile = 60: 40

(Preparation of Buffer Solution: 6 mM Sodium Hexanesulfonate Sodium Hydroxide / 0.05% (v / v) Phosphoric Acid 1.24 g of 1-hexanesulfonic acid sodium salt monohydrate was placed in a 1 L flask, mL diluted with distilled water, and mixed well.)

Column temperature: 45 ° C

Flow rate: 1.3 mL / min

Injection amount: 10 μm

Criteria: At 15 minutes, the dissolution rate was 85% or more

The dissolution rate measurement results are shown in Figs.

As shown in Figs. 2 and 3, both of the amlodipine and losartan in Examples 1 to 3 and Comparative Examples 1 and 2 showed a dissolution rate suitable for the criteria.

On the other hand, as shown in Fig. 1, the dissolution rate of chlortalidone showed a significant difference depending on the particle size of chlortalidone. The tablets of Examples 1 to 3 containing micronized chlortalidone exhibited a fast dissolution rate from the early stage and showed a dissolution rate suitable for the criteria. However, the tablets of Comparative Examples 1 and 2 containing chlortalidone having a particle size of 50 占 퐉 or more were not suitable for the criteria because of the relatively low initial dissolution rate.

From the above experimental results, it can be confirmed that the effective ingredient dissolution rate of the combination preparation containing amlodipine, rozatan, and chlortalidone can be improved by controlling the particle size of chlortalidone to a specific range.

Test Example 2: Determination of the content uniformity of the oral preparation

In order to investigate the uniformity of the content of the combination preparation depending on the particle size of the chlortalidone, an experiment was conducted according to the content uniformity test method of the Korean Pharmacopoeia general test method.

The tablets prepared in Examples 1 to 3 and Comparative Examples 1 and 2 were tested according to the formulation uniformity test method described in the Korean Pharmacopoeia. The content was analyzed by HPLC using the assay method described in Test Example 1, and the results are shown in Table 4 below.

Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Chlortalidone 2.9 3.0 6.6 10.6 14.1 Amlodipine 3.4 2.8 3.2 2.5 2.7 Rozan tan 2.3 2.7 2.4 2.4 2.6

As shown in Table 4, when Examples 1 to 3, in which the particle size (D90) of chlortalidone was about 50 m or less, were compared with Comparative Examples 1 and 2 in which the particle size of chlortalidone was larger than about 50 m, Significantly improved sexuality.

Through this, it can be confirmed that by using chlortalidone having a specific range of particle size, it is possible to improve the mixing uniformity and the uniformity of the contents of the combination preparation containing amlodipine, rozatan, and chlortalidone.

Test Example 3: Determination of the dissolution rate of the oral preparation according to the disintegration ratio of the upper layer

The tablets of Examples 1 and 4 to 7 were used to measure the dissolution rate of chlortalidone over time under the same conditions as in Test Example 1, and the measurement results are shown in FIG.

As shown in Figure 4, the tablets of Example 5 containing 2.5% by weight of the disintegrant in the first layer weights were relatively slow or acceptable for acceptance criteria, and did not contain a disintegrant in the first layer The tablets of Example 4 exhibited even lower elution properties.

On the other hand, the tablets of Examples 1, 6 and 7 containing 5 to 10% by weight of the disintegrant in the weight of the first layer showed a fast dissolution rate in the early stage and were found to meet the criteria.

Test Example  4: Upper layer Disintegration  Stability test of combination oral formulations according to ratios

The tablets of Examples 1 and 4 to 7 were stored for 14 days under harsh conditions (60 ° C) after packaging of the HDPE bottle, and the stability was evaluated by measuring changes in the content of the flexible substances. The results are shown in Table 5 below.

sample Early 60 ° C, HDPE bottles 14 days storage (%) Amlodipine group (%) Of chlortalidone group Flexible Substance (%) (%) Amlodipine group (%) Of chlortalidone group Flexible Substance (%) Example 1 0.00 0.76 0.02 0.04 0.92 0.02 Example 4 0.00 0.79 0.01 0.04 0.94 0.04 Example 5 0.01 0.78 0.04 0.05 0.92 0.03 Example 6 0.00 0.79 0.01 0.07 0.97 0.04 Example 7 0.01 0.76 0.02 0.21 1.63 0.03

As shown in Table 5, it was confirmed that the tablets of Examples 1 and 4 to 6 were stable because of less generation of amlodipine, chlortalidone and rosatan suppository in a severe condition by heat. However, the tablets of Example 7 showed an increase of about two times as compared with the tablets of Example 1, in which the production of a flexible substance, which is amlodipine and chlortalidone group, was increased.

From this, it can be seen that it is difficult to obtain sufficient stability according to changes over time under severe conditions caused by heat, in which the content of the disintegrant exceeds 10% by weight based on the total weight of the first mixing portion.

From the results of Test Examples 1 and 2, it can be confirmed that the combination preparation of the present invention exhibits improved elution properties and content uniformity of the active ingredient, which is further improved by using chlortalidone with controlled particle size.

Furthermore, from the results of Test Examples 3 and 4, it can be seen that the combination preparation of the present invention can exhibit better dissolution characteristics than those containing a disintegrant in the first mixing portion, and in order to secure thermal stability together with dissolution characteristics, Based on the total weight of the first mixed part of the combination preparation, is preferably in the range of 2 to 7.5 wt%.

Claims (14)

A first mixing portion comprising amlodipine or a pharmaceutically acceptable salt thereof, and chlortalidone or a pharmaceutically acceptable salt thereof; And
Or a pharmaceutically acceptable salt thereof; and a second mixing portion comprising losartan or a pharmaceutically acceptable salt thereof,
Wherein the first mixing portion and the second mixing portion are physically separated from each other,
Wherein the chloraltidal or pharmaceutically acceptable salt thereof has a particle size (D90) of 0.5 to 50 占 퐉. The method according to claim 1,
Wherein the chloraltidalin or a pharmaceutically acceptable salt thereof has a particle size (D90) of 0.5 to 25 占 퐉. 3. The method of claim 2,
Wherein the chloraltidalin or a pharmaceutically acceptable salt thereof has a particle size (D90) of 0.5 to 10 占 퐉. The method according to claim 1,
Said pharmaceutical combination comprising a first layer comprising amlodipine or a pharmaceutically acceptable salt thereof and chlortalidone or a pharmaceutically acceptable salt thereof; And
Wherein the second layer is composed of a second layer comprising losartan or a pharmaceutically acceptable salt thereof. 5. The method of claim 4,
Wherein the combined preparation has a dissolution rate of chlortalidone of not less than 85% within 30 minutes in a dissolution test in purified water according to the paddle method of the dissolution test item of USP Chloralidon tablet. 5. The method of claim 4,
Wherein the combined preparation has a dissolution rate of chlortalidone of not less than 85% within 15 minutes in the dissolution test in purified water according to the paddle method of the dissolution test item of the USP Chloratidal tablet. The method according to claim 1,
Wherein the first mixing part further comprises a disintegrant as an additive. 8. The method of claim 7,
Wherein the disintegrant is crospovidone, croscarmellose sodium, sodium starch glyconate, starch, pregelatinized starch, or a combination thereof. 8. The method of claim 7,
Wherein the disintegrant is contained in an amount of 2 to 7.5% by weight based on the total weight of the first mixing portion. The method according to claim 1,
Wherein the first mixing part comprises lactose hydrate and microcrystalline cellulose as additives. The method according to claim 1,
Wherein the first mixing part and the second mixing part are in the form of granules which have undergone a roller compaction process. a) mixing amlodipine or a pharmaceutically acceptable salt thereof, chlortalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; And
b) mixing roszatan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive,
Wherein the chloraltidalin or a pharmaceutically acceptable salt thereof has a particle size (D90) of 0.5 to 50 占 퐉. a) granulating after mixing amlodipine or a pharmaceutically acceptable salt thereof, chlortalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive;
b) granulating after mixing roszatan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; And
c) titrating the mixture of step a) and the mixture of step b)
Wherein the chloraltidalin or a pharmaceutically acceptable salt thereof has a particle size (D90) of 0.5 to 50 占 퐉. The method according to claim 1,
Wherein said pharmaceutical combination preparation is for prevention or treatment of cardiovascular diseases.

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