KR20210074428A - Pharmaceutical complex formulation comprising amlodipine, losartan and chlorthalidone - Google Patents

Abstract

The present invention discloses a pharmaceutical complex formulation for preventing or treating cardiovascular diseases which contains low doses of amlodipine, losartan, and chlorthalidone, uses low-substituted hydroxypropyl cellulose to improve a dissolution rate of chlorthalidone, improves flowability to reduce variations during tableting, and at the same time has good tableting properties.

Description

Pharmaceutical combination formulation comprising amlodipine, losartan and chlorthalidone {PHARMACEUTICAL COMPLEX FORMULATION COMPRISING AMLODIPINE, LOSARTAN AND CHLORTHALIDONE}

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

About 90-95% of hypertension is essential (primary) hypertension with no known cause. The root cause of essential hypertension is not clear, but it is known to be caused by an increase in cardiac output (the amount of blood pumped out every time the heart contracts) or an increase in peripheral vascular resistance. Risk factors related to hypertension include psychological and environmental factors such as drinking, smoking, old age, lack of exercise, obesity, salty eating habits, and stress. If there is a familial tendency, if both parents are hypertensive, 80% of the children can become hypertensive in the future, and if one parent is hypertensive, 25-50% of the children can become hypertensive.

The main goal of hypertension treatment is to prevent damage to organs caused by hypertension by maintaining an optimal blood pressure. Therefore, lifestyle changes are as important as taking medications. Hypertensive patients aim to control blood pressure below 140/90 mmHg. If you have diabetes or kidney disease, your target blood pressure should be less than 130/80 mmHg.

Treating high blood pressure can reduce mortality from stroke and cardiovascular disease. Controlling blood pressure in hypertensive patients can reduce stroke by 35-40%, myocardial infarction by 20-25%, and heart failure by more than 50%. Reducing systolic blood pressure by just 5 mmHg can reduce stroke mortality by 14%, coronary artery disease mortality by 9%, and total mortality by 7%. In addition, blood pressure control is also related to dementia, so good control of blood pressure in hypertensive patients can reduce the risk of dementia.

As such, it is important to prevent cardiovascular complications in hypertensive patients, so it is important to constantly control blood pressure. Since blood pressure drugs are required to be taken for a long period of time, rather than selecting one drug for treatment, co-administration of drugs with different mechanisms can achieve better preventive and therapeutic effects. In addition, by reducing the amount of a single drug used in combination administration, side effects that may occur due to long-term administration of the drug can be reduced.

Drugs commonly used for the treatment of hypertension are broadly classified into diuretics, sympathomimetic agents, and vasodilators depending on the mechanism of action of the drug. The vasodilators currently widely used are ACE (Angiotension converting enzyme) inhibitors, angiotensin, and angiotensin according to their mechanism of action. It is divided into II receptor blockers and calcium channel blockers.

Amlodipine is 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(-2-chlorophenyl)-6-methyl-1,4-dihydro-3,5- Common name of pyridine dicarboxylate, of which amlodipine besylate salt is currently marketed under the trade name of Novasc®. A camsylate salt, which has superior physical properties, such as solubility and stability, compared to the besylate salt, is currently being marketed under the trade name of Amodipine®. Amlodipine blocks calcium channels and is used in the treatment of cardiovascular diseases such as angina, hypertension and congestive heart attack.

losartan is 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imi The generic name for dazole-5-methanol, specifically losartan calcium, is currently marketed under the trade name Cozaar®. Losartan is used to treat hypertension and heart failure by blocking the binding of angiotensin II, a vasoconstrictor, to receptors. In addition, it is used to treat ischemic peripheral circulation disorder, myocardial ischemia (angina pectoris), prevent the progression of heart failure after myocardial infarction, and treat diabetic neuropathy, glaucoma, and the like.

The combination of amlodipine and losartan, which have different mechanisms of action, has a superior effect in the prevention or treatment of hypertension and cardiovascular disease than the existing single agent, reduces the side effects of each drug, and improves patient compliance. There is this. The combination formulation is disclosed in Korean Patent Nos. 1160151 and 1232296, etc., and is currently sold under the trade name of Amosartan®.

Chlorthalidone is a common name for benzenesulfonamide-2-chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol-1-yl), hygro It is currently sold under the trade name Hygroton®.

Chlorthalidone is a thiazide diuretic that blocks the ^{Na +} /Cl ^- transporter in the distal renal tubule, inhibits the reabsorption of ^{Na +} and Cl ^{- and increases the excretion of K +} to retain water in the urine. acts to

In order to effectively treat cardiovascular diseases, research is being conducted on a combination preparation of amlodipine, losartan and chlorthalidone using different mechanisms. For example, Korean Patent Registration Nos. 1914930 and 1910902 propose a combination formulation in which a first mixed part containing amlodipine and chlorthalidone and a second mixed part containing losartan are separated. The combination formulation can be implemented as a two-layer tablet, and the interaction between drugs is minimized, thereby exhibiting the effect of improving the dissolution rate of the drug, and the stability of the active ingredient against light and heat.

In order to effectively treat cardiovascular diseases including high blood pressure, Korean Patent Registration No. 1914930 proposes a combination drug containing amlodipine, losartan and chlorthalidone including a single dosage. For example, a commercially available Amosartan Plus ^TM tablet contains 5/50/12.5 mg, 5/100/12.5 mg, or 5/100/25 mg of amlodipine, losartan potassium and chlorthalidone, respectively. However, when a combination drug containing the usual dose of a single agent is administered to a patient with early hypertension, there is a risk of excessive blood pressure lowering and side effects thereof, and may not be suitable for the purpose of blood pressure control in patients with early hypertension. Therefore, it is necessary to develop a low-dose combination formulation that can be safely administered even in early hypertensive patients and can improve blood pressure control.

However, in the case of a combination formulation containing low doses of amlodipine, losartan and chlorthalidone, there is a problem that the dissolution rate is low or slow even if the tablet disintegrates quickly due to the low solubility and permeability properties of chlorthalidone itself. In addition, the flowability is reduced during the tableting process, and a high tableting pressure is required, so that the content uniformity of the formulation is reduced, and a large difference occurs in the disintegration rate of the active ingredient in the upper and lower layers.

Therefore, in order to manufacture high-quality tablets, it is necessary to control the dissolution rate of chlorthalidone and to improve flowability and tabletting properties during the tableting process.

Korean Patent Registration No. 1160151 Korean Patent Registration No. 1232296 Korean Patent Registration No. 1914930 Korean Patent Registration No. 1910902

Accordingly, the present inventors introduced a new composition in a complex two-layer tablet containing low doses of amlodipine, chlorthalidone and losartan while researching to supplement the problems of the formulation to improve flowability and tabletting properties during the tableting process. The effect of improving the dissolution rate of chlorthalidone was confirmed.

Accordingly, an object of the present invention is to provide a pharmaceutical combination preparation comprising amlodipine, losartan and chlorthalidone, and a method for preparing the same.

In addition, another object of the present invention is to provide a low-dose fixed-dose combination formulation as the pharmaceutical combination formulation.

The present invention relates to a first mixture comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and

Provided is a pharmaceutical combination preparation for the prevention or treatment of cardiovascular diseases, comprising a second mixture comprising losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

In this case, the low-substituted hydroxypropyl cellulose as a pharmaceutically acceptable additive in the first mixed part is included in an amount of more than 30% by weight and less than 70% by weight based on the total amount of the first mixed part.

The first mixing unit and the second mixing unit exist in a state physically separated from each other.

Specifically, the pharmaceutical combination preparation comprises: a first layer comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and

It is a bilayer tablet composed of a second layer comprising losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

In particular, the pharmaceutical combination preparation is characterized in that it is a low-dose, fixed-dose combination preparation.

Also, the present invention

a) mixing amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and

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

c) tabletting the mixture obtained in steps a) and b),

It provides a method for preparing a pharmaceutical combination preparation for the prevention or treatment of cardiovascular diseases, in which a low-substituted hydroxypropyl cellulose is added as a pharmaceutically acceptable additive in the first mixing part in step a).

The pharmaceutical combination formulation comprising low doses of amlodipine, chlorthalidone and losartan as active ingredients according to the present invention has excellent flowability and tabletting properties, and has excellent dissolution properties of the active ingredient, particularly chlorthalidone, , showing 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 with excellent quality.

1 is a graph showing the dissolution of chlorthalidone by (a) paddle method and (b) basket method.
2 is a graph showing the dissolution of amlodipine by (a) paddle method, (b) basket method.
3 is a graph showing the dissolution of losartan by (a) the paddle method and (b) the basket method.
4 is a graph showing a change in the dissolution pattern of chlorthalidone according to the content of low-substituted hydroxypropyl cellulose.
5 is a graph showing the change in the dissolution pattern of amlodipine according to the content of low-substituted hydroxypropyl cellulose.
6 is a graph showing a change in the dissolution pattern of losartan according to the content of low-substituted hydroxypropyl cellulose.

The combination preparation according to the present invention comprises: 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 additive, for preventing or treating cardiovascular diseases.

In the composite formulation according to the present invention, the first mixing part and the second mixing part are physically separated from each other. That is, by including amlodipine and losartan separately from each other, the mutual reaction between amlodipine and losartan can be prevented, thereby exhibiting high stability.

In one embodiment of the present invention, the combination preparation comprises a first layer comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone 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. In addition, the formulation according to the present invention may be prepared in various forms (eg, core-shell structure) in which the first mixed part and the second mixed part can be physically separated in addition to the double-layered tablet.

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

Pharmaceutically acceptable salts of amlodipine are those formed from acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, hydrochloride, hydrobromide, sulfate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, besylate salt, and camsylate salt, and the like, but are not limited thereto. Among them, amlodipine besylate salt and camsylate salt are preferable, and besylate salt is more preferable. In addition, amlodipine of the present invention includes amlodipine racemate and (S)-amlodipine.

Meanwhile, the pharmaceutical combination preparation of the present invention may be selected from the group consisting of pharmaceutically acceptable additives, for example, excipients (diluents), binders, disintegrants, lubricants, and any combination thereof. .

The excipient is used to extend the weight, and includes lactose or its hydrate, microcrystalline cellulose, mannitol, starch, sucrose, sorbitol, xylitol, glucose, calcium dihydrogen phosphate, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, and It may be selected from the group consisting of any combination thereof, but is not limited thereto.

The binder is hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose, macrogol, pregelatinized starch, polyvinylacetic acid, polyvinylpyrrolidone, copovidone, macrogol, sodium lauryl sulfate, light anhydrous silicic acid, Synthetic aluminum silicate, silicate derivatives such as calcium silicate or magnesium metasilicate aluminate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, gums such as acacia gum, gelatin, cellulose derivatives such as ethylcellulose, and mixtures thereof It may be selected from the group consisting of combinations, but is not limited thereto.

The disintegrant is crospovidone, croscarmellose sodium, sodium starch glycolate, starch, alginic acid or sodium salt thereof, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, pregelatinized starch, and any combination thereof. It may be selected from the group, but is not limited thereto.

The lubricant is stearic acid, stearic acid metal salts (eg, calcium stearate, magnesium stearate, etc.), talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, wax, glyceryl fatty acid ester, glycerol dibehenate, And it may be selected from the group consisting of any combination thereof, but is not limited thereto.

In one embodiment, the excipient is microcrystalline cellulose and/or low-substituted hydroxypropyl cellulose, the binder is crospovidone, and the lubricant is magnesium stearate.

In a preferred embodiment, the additive in the first mixing part is that the excipient is microcrystalline cellulose and low-substituted hydroxypropyl cellulose, the disintegrant is crospovidone, the lubricant is magnesium stearate, and the additive in the second mixing part is the excipient is microcrystalline cellulose , the disintegrant is crospovidone, and the lubricant is magnesium stearate.

In particular, in the present invention, by using a specific additive in a predetermined amount in the first mixing portion, the flowability is improved to reduce the deviation during tableting, and at the same time, good tableting property is secured, so that the dissolution rate of the active ingredient is improved. It enables the manufacture of tablets with

In the present invention, by using the low-substituted hydroxypropyl cellulose having these characteristics, the quality of the pharmaceutical combination preparation, that is, the tablet is improved.

Specifically, the pharmaceutical combination formulation of the present invention is mixed with a large deviation in the process of filling in a tableting machine when the tablet mass is small and the flowability during tableting is not good, so that the uniformity and content of the formulation is relatively high compared to tablets with a large mass. affect. In addition, the tableting process must be performed with a high compression pressure. In this case, since the tableting has an unreasonable effect on the lower punch made of a thin column, it should be possible to achieve a desired hardness even with a low compression pressure.

To this, additives may be added to improve flowability and tabletting properties. Selection of additives for improving the flowability and tabletting properties should not affect or increase the dissolution rate of the active ingredient, and should not affect the disintegration rate.

In the present invention, low-substituted hydroxypropyl cellulose is selected as the additive, and by introducing it to the first mixing part, specifically, the upper layer of the double-layer tablet, flowability is improved during tablet tableting of a small mass, and chlor, an active active ingredient in the upper layer, is improved. In addition to improving the dissolution rate of thalidon, it was possible to ensure that tableting was possible with a desired level of hardness (target hardness of 10 kp) even with a low tableting pressure.

In the present invention, as low-substituted hydroxypropyl cellulose is used in the first mixing part, it has the best compression pressure compared to other excipients at a target hardness of 10 kp, and the flowability is improved to ensure uniformity of the formulation.

In particular, with respect to the active active ingredients amlodipine, chlorthalidone and losartan, the dissolution rate of chlorthalidone is improved, and the dissolution rate reduction does not occur for amlodipine and losartan. That is, the chlorthalidone is a BCS Class IV drug, characterized by low solubility and low permeability, and the wettability of chlorthalidone by using low-substituted hydroxypropyl cellulose in the first mixture in which the chlorthalidone is present. property), it can be expected to improve the bioavailability by improving the dissolution rate.

This effect can be further maximized by controlling the content of low-substituted hydroxypropyl cellulose.

Based on the total weight of the first mixture, the low-substituted hydroxypropyl cellulose is 30% by weight or more, 70% by weight or less, specifically more than 30% by weight and less than 70% by weight, 32 to 68% by weight, 35 to 65% by weight, It is used in an amount of 37 to 62% by weight, 40 to 60% by weight, 40 to 50% by weight, and 40 to 45% by weight. When the content exceeds the above range, the stability of the tablet is reduced, such as cracking occurs after accelerated exposure, and when the content is less than the above range, the amount of other excipients is relatively increased and the dissolution rate of chlorthalidone is likely to decrease. properly used within

In addition, the content of the low-substituted hydroxypropyl cellulose and other excipients in the first mixing part should be adjusted. Based on the total weight of the first mixed part, 85 wt% or less, 84 wt% or less, 83 wt% or less is used. In this case, the other excipient is one selected from the group consisting of lactose or its hydrate, microcrystalline cellulose, mannitol, starch, sucrose, sorbitol, xylitol, glucose, calcium dihydrogen phosphate, starch, pregelatinized starch, and any combination thereof. , preferably microcrystalline cellulose.

More preferably, the content of microcrystalline cellulose as an excipient: low-substituted hydroxypropyl cellulose is 1:0.6 to 1:5.0, 1:0.7 to 1:4.5, 1:0.9 to 1:2.6, 1:0.9 to 1: It is used in a weight ratio of 1.5. When the low-substituted hydroxypropyl cellulose is used in the above content range, the flowability and tabletting property of the tablet can be improved, and the dissolution rate of chlorthalidone can be improved. On the other hand, when the content of microcrystalline cellulose is less than the above range, a tableting disorder occurs during the tableting operation when the content is less than the above range, and when the content of microcrystalline cellulose is greater than the content, a problem occurs in that a formulation larger than necessary is made. Accordingly, by using the low-substituted hydroxypropyl cellulose and microcrystalline cellulose in the above-described content range, it is possible to prepare a tablet with improved quality.

The disintegrant of the first mixture is used in the range of 1 to 10% by weight, 2 to 8% by weight, and 3 to 7% by weight based on the total weight of the first mixture, and the lubricant of the first mixture is used in the first mixture It is used in the range of 0.1 to 5% by weight, 0.5 to 4% by weight, and 0.7 to 3% by weight based on the total weight.

Meanwhile, the second mixing unit includes losartan, an excipient, a binder, a lubricant, and other additives. The content of each composition is not particularly limited in the present invention, and follows a known content range.

The other additives may be any additives known in the pharmaceutical arts as useful for improving processability, flowability, stability or moldability of a unit dosage form, if necessary. For example, it may further include a pH adjusting agent, a suspending agent, a preservative, a flavoring agent, a coloring agent, a sweetening agent, an adsorbent, a solubilizing agent, and the like. The content of the additive is not particularly limited in the present invention and may be appropriately adjusted as necessary.

The pharmaceutical combination preparation for the prevention or treatment of cardiovascular diseases according to the present invention having the above composition can effectively reduce the cardiovascular risk by using drugs of different mechanisms, including amlodipine, chlorthalidone, and losartan. have. However, since cardiovascular diseases such as high blood pressure are caused by various factors, when two or more drugs are used in combination for efficacy and effectiveness, there is an advantage in that side effects can be reduced through complementary action, but side effects still remain and drugs The increase in number leads to reduced compliance and increased cost. This problem can be addressed with a low-dose, fixed-dose combination.

That is, the pharmaceutical combination preparation of the present invention can prevent side effects caused by drugs as a low-dose combination therapy, and by using the fixed-dose combination preparation, it is a low-dose fixed-dose combination preparation that can improve the patient's medication compliance due to the convenience of taking the drug. .

As used herein, the term “low dose” refers to a dose that is lower than the usual daily dose of a drug. In one embodiment, the low dose may be about 1/6 to about 1/2 of the daily normal dose. In one embodiment, the low dose may be about 1/5 to about 1/2 of the daily normal dose. In one embodiment, the low dose may be about 1/4 to about 1/2 of the daily normal dose.

In the low-dose fixed-dose combination preparation according to one embodiment, amlodipine or a pharmaceutically acceptable salt thereof may be included in an amount of about 0.5 to 5 mg when converted into amlodipine free base form, or in a range setting the numerical value as the upper or lower limit. have.

In the low-dose, fixed-dose combination preparation according to one embodiment, it may be included in an amount of about 1 to 7 mg when converted into chlorthalidone free base form, or in a range setting the numerical value as the upper or lower limit.

In the low-dose, fixed-dose combination preparation according to one embodiment, losartan or a pharmaceutically acceptable salt thereof is in an amount of about 5 to 30 mg when converted into losartan free base form, or in a range setting the numerical value as the upper or lower limit. may be included.

The weight ratio of amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof included in the low-dose, fixed-dose combination preparation according to the present invention is amlodipine:chloride, respectively. As thalidon:losartan, it may be in the range of 1:1.25-5:5-20, preferably 1:2.5-5:10-20.

In the pharmaceutical combination preparation of the present invention as described above, the first mixed part and the second mixed part may be tableted after granulation by a conventional granulation method, for example, a compression granulation method. In another embodiment, the first mixing unit and the second mixing unit may be in the form of granules subjected to a roller compression process. When the compression-granulated first mixed part and the second mixed part are compressed as a double-layer tablet, amlodipine, chlorthalidone and losartan exhibit excellent dissolution characteristics.

The pharmaceutical combination preparation of the present invention described above may include: a) mixing amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and b) mixing losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

In addition, the pharmaceutical combination preparation of the present invention comprises: a) mixing amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and b) mixing losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and c) tabletting the mixture obtained in steps a) and b).

At this time, the tableting can be prepared as a double-layer tablet by granulating the mixture of steps a) and step b), respectively, and tableting the mixture into a double-layer tablet.

In addition, in step a), low-substituted hydroxypropyl cellulose is added as a pharmaceutically acceptable additive in the first mixing part.

At this time, the pulverizer used in the manufacturing process may include, for example, a hammer mill, a ball mill, a jet pulverizer, a colloid mill, an electric mesh, an oscillator, a co-mill, etc., but if it is a method that can be pulverized in general pharmaceuticals, it is an apparatus, means All are not particularly limited.

As a mixing device for each component continuously used for pulverization, for example, a V-type mixer, a ribbon-type mixer, a container mixer, a high-speed stirring mixer, etc. can be mentioned, but usually each component can be uniformly mixed pharmaceuticalally. If it is a method, an apparatus and a means are not particularly limited.

Examples of the tableting device include a rotary tableting machine and a single-shot tableting machine, but as long as it is a method for producing a compression-molded product (suitably a tablet) in a pharmaceutical manner, both the device and the means are not particularly limited.

According to the present invention, it is possible to quickly prepare a pharmaceutical combination preparation through the simplified manufacturing process of direct tableting, and the stability of the combination preparation is also excellent. In addition, even if the mass of the tablet is small, the flowability is excellent, so that tableting is possible with a small tableting pressure, and the dissolution rate of chlorthalidone can be improved.

According to one embodiment, the pharmaceutical combination formulation of the present invention has a dissolution rate of chlorthalidone of 90% or more within 15 minutes in a dissolution test in purified water according to the paddle method of the dissolution test item of the US Pharmacopoeia chlorthalidone tablet section, and a basket According to the law, when dissolution test in purified water, the dissolution rate of chlorthalidone within 15 minutes has a value of 85% or more.

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

[Example]

Hereinafter, preferred examples are presented to help the understanding of the present invention, but the following examples are merely illustrative of the present invention, and it will be apparent to those skilled in the art that various changes and modifications are possible within the scope and spirit of the present invention, It goes without saying that changes and modifications fall within the scope of the appended claims.

Example 1, Comparative Examples 1 to 4: Preparation of composite bilayer tablets

According to the composition of Table 1 below, amlodipine besylate, chlorthalidone, microcrystalline cellulose, low-substituted hydroxypropyl cellulose (11% substitution) or D-mannitol or pregelatinized starch or calcium hydrogen phosphate hydrate, crospovidone 240 After mixing and compacting to prepare granules, granules were established using a 1 mm sieve. The granules were mixed with magnesium stearate 180 times to prepare an upper mixing part.

On the other hand, after mixing losartan potassium, microcrystalline cellulose, and crospovidone 240 times, compacting was performed to prepare granules, and then granules were established using a 1 mm sieve. The granules were mixed 180 times with magnesium stearate and red iron oxide to prepare a lower mixing part.

Then, using a tablet press (Kilian Synthesis 700, Germany), 95.0 mg of the upper mixing part and 82.2 mg of the lower mixing part were compressed into two-layer tablets to prepare a composite formulation.

Ingredients (mg/T) Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 upper part Amlodipine Besylate 3.47 3.47 3.47 3.47 3.47 chlorthalidone 6.25 6.25 6.25 6.25 6.25 Microcrystalline Cellulose 39.79 39.79 39.79 39.79 39.79 Low-substituted hydroxypropyl cellulose 39.79 - - - - D-mannitol - 39.79 - - - pregelatinized starch - - 39.79 - - Calcium Hydrogen Phosphate Hydrate - - - 39.79 - lactose hydrate 39.79 crospovidone 4.75 4.75 4.75 4.75 4.75 Magnesium Stearate 0.95 0.95 0.95 0.95 0.95 Whole upper supernatant (mg/T) 95 95 95 95 95 lower part losartan potassium 25 25 25 25 25 Microcrystalline Cellulose 54 54 54 54 54 crospovidone 2.2 2.2 2.2 2.2 2.2 Magnesium Stearate 0.5 0.5 0.5 0.5 0.5 red iron oxide 0.5 0.5 0.5 0.5 0.5 Lower subdivision (mg/T) 82.2 82.2 82.2 82.2 82.2

Test Example 1: Comparison of tabletting properties and flow properties

In the final mixture obtained in Examples and Comparative Examples, the tableting pressure and density were measured at the time of production with a hardness of 10 kp target hardness, and the Hausner ratio (tap density/bulk density) was obtained. The results obtained are shown in the table below.

Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 (low-substituted hydroxypropyl cellulose) (D-mannitol) (pregelatinized starch) (Calcium hydrogen phosphate hydrate) (lactose hydrate) Compression pressure (kgf/cm ² )
(Target hardness: 10kp) 280 310 340 400 350 Bluk density 0.46 0.52 0.55 0.6 0.64 Tap density 0.61 0.72 0.72 0.83 0.85 Hausner ratio 1.33 1.39 1.32 1.37 1.33

Referring to Table 2 above, when the target hardness was set to 10 kp and the tableting pressure during production was measured with a hardness of 10 kp, 280, which is the lowest tableting pressure when manufacturing the tablet containing the low-substituted hydroxypropyl cellulose of Example 1 kgf/cm ² , and tablets containing D-mannitol, pregelatinized powdered starch, calcium hydrogen phosphate hydrate and lactose hydrate, respectively, exhibited higher compression pressure.

The low tableting pressure means that the target hardness can be obtained even by applying a relatively small force to produce a tablet of the target hardness. Although similar, it can be seen that the tabletting property is low.

Test Example 2: Comparison of disintegration time

Disintegration time was measured for the tablets obtained in Examples and Comparative Examples, and the results obtained are shown in the table below.

Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 (low-substituted hydroxy
propyl cellulose) (D-mannitol) (pregelatinized starch) (Calcium hydrogen phosphate hydrate) (lactose hydrate) disintegration time
(Upper part) 7 minutes 15 seconds 7 minutes 26 seconds 8 minutes 3 seconds 7 minutes 11 seconds 7 minutes 20 seconds disintegration time
(lower level) 13 minutes and 8 seconds 14 minutes and 11 seconds 17 minutes 46 seconds 21 minutes 25 seconds 18 minutes 02 seconds

Referring to Table 3, in the case of the upper layer of the tablet containing the low-substituted hydroxypropyl cellulose, the disintegration time of amlodipine and chlorthalidone was about 7 to 8 minutes, showing similar results. However, in the case of the lower layer containing losartan, in the case of the tablet of Example 1 containing the low-substituted hydroxypropyl cellulose, it can be seen that the time is significantly reduced compared to the tablets of other Comparative Examples 1 to 4.

These results can be interpreted as bringing about a difference in disintegration time as different levels of tableting pressure confirmed in Test Example 1 are applied depending on the type of excipient used in the upper layer.

Test Example 3: Comparison of dissolution patterns

The dissolution rate of the tablets obtained in Examples and Comparative Examples was measured.

end. Paddle method dissolution analysis

[Elution conditions]

- Apparatus: Apparatus of dissolution test method 2 (paddle method) of the dissolution test item of the US Pharmacopoeia (USP) chlorthalidone tablet

- Test solution: purified water, 900 mL

- Elution temperature: 37 ℃

- RPM: 75 rpm

- Sample collection time: 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes

[Analysis Conditions]

- Detector: Ultraviolet absorbance spectrometer (measurement wavelength 254 nm)

- Column: Column filled with octadecyl silylated silica gel for liquid chromatography (150 x 4,6 nm, 3 μm)

- Mobile Phase: Buffer: Acetonitrile = 61: 39

(Method for preparing buffer: 10 mM sodium hexanesulfonate hydrate/0.05% (v/v) phosphoric acid: 2.06 g of 1-hexansulfonic acid sodium salt monohydrate was put into a 1L flask, and phosphoric acid 0.5 mL was carefully added, and purified water was added to dissolve and dilute, and then mix well.)

- Column temperature: 45 ℃

- Flow: 1.3 mL/min

- Injection volume: 10 μm

I. Basket method dissolution analysis

[Elution conditions]

- Apparatus according to the first method of dissolution test of the Korean Pharmacopoeia (basket method)

- Test solution: purified water, 900 mL

- Elution temperature: 37.5℃

- Rotational speed: 75 rpm

- Sample collection time: 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes

[Analysis Conditions]

- Detector: Ultraviolet absorbance spectrometer (measurement wavelength: 254nm)

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

- Flow rate: 1.3 ml/min

- Column temperature: 45℃

- Injection volume : 10 ul

- Mobile phase: Mobile phase: Buffer: Acetonitrile = 61: 39

(Method for preparing buffer: 10 mM sodium hexanesulfonate hydrate/0.05% (v/v) phosphoric acid: 2.06 g of 1-hexansulfonic acid sodium salt monohydrate was put into a 1L flask, and phosphoric acid 0.5 mL was carefully added, then added purified water to dissolve and dilute, and then mix well.)

1 is a graph showing the dissolution of chlorthalidone, (a) the paddle method, (b) the basket method, and FIG. 2 is the dissolution graph of amlodipine. (a) the paddle method, (b) the basket method. 3 is a graph showing the dissolution of losartan, and is a numerical value measured by (a) paddle method and (b) basket method.

Referring to FIG. 1(a), in the case of chlorthalidone, the dissolution pattern measured by the paddle method did not show a significant difference depending on the type of excipient. It can be seen that the dissolution of money is affected by the type of excipient.

In the case of the paddle method, there is no difference in dissolution rate because it is continuously affected by the paddle, but in the case of the basket test, only a short time before coming out of the basket is affected. is judged as Referring to Figure 1 (b), it can be seen that the low-substituted hydroxypropyl cellulose is advantageous in securing a fast and high dissolution rate of chlorthalidone. Since the chlorthalidone is a BCS Class IV drug, it has low solubility and low permeability, so it is possible to improve the bioavailability of chlorthalidone by improving its problems with low-substituted hydroxypropyl cellulose.

Looking at the dissolution graph of amlodipine in FIG. 2 and losartan in FIG. 3, both the paddle method and the basket method showed similar trends, and it was found that the use of low-substituted hydroxypropyl cellulose did not significantly affect the dissolution characteristics. can

Examples 2 to 6: Preparation of Composite Bilayer Tablets

Composite bilayer tablets were prepared with the composition shown in Table 4 below.

After mixing amlodipine besylate, chlorthalidone, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and crospovidone 240 times in each ratio composition, compacting was performed to prepare granules, and then granules were established using a 1 mm sieve. The granules were mixed with magnesium stearate 180 times to prepare an upper mixing part.

In addition, after mixing losartan potassium, microcrystalline cellulose, and crospovidone 240 times, compacting was performed to prepare granules, and then granules were established using a 1 mm sieve. The granules were mixed 180 times with magnesium stearate and red iron oxide to prepare a lower mixing part.

Then, using a tablet press (Kilian Synthesis 700, Germany), 95.0 mg of the upper mixing part and 82.2 mg of the lower mixing part were compressed into two-layer tablets to prepare a composite formulation.

Ingredients (mg/T) Example 2 Example 3 Example 4 Example 5 Example 6 (L-HPC 30%) (L-HPC 40%) (L-HPC 50%) (L-HPC 60%) (L-HPC 70%) upper part Amlodipine Besylate 3.47 3.47 3.47 3.47 3.47 chlorthalidone 6.25 6.25 6.25 6.25 6.25 Microcrystalline Cellulose 51.08 41.58 32.08 22.58 13.08 Low-substituted hydroxypropyl cellulose 28.5 38 47.5 57 66.5 crospovidone 4.75 4.75 4.75 4.75 4.75 Magnesium Stearate 0.95 0.95 0.95 0.95 0.95 Whole upper supernatant (mg/T) 95 95 95 95 95 lower part losartan potassium 25 25 25 25 25 Microcrystalline Cellulose 54 54 54 54 54 crospovidone 2.2 2.2 2.2 2.2 2.2 Magnesium Stearate 0.5 0.5 0.5 0.5 0.5 red iron oxide 0.5 0.5 0.5 0.5 0.5 Lower subdivision (mg/T) 82.2 82.2 82.2 82.2 82.2

Test Example 4: Comparison of dissolution patterns according to the content of low-substituted hydroxypropyl cellulose

The dissolution patterns of the composite bilayer tablets prepared in Examples 2 to 6 were measured by the basket method, and the results are shown in FIGS. 4 to 6 below.

4 is a graph showing the change in the dissolution pattern of chlorthalidone according to the content of low-substituted hydroxypropyl cellulose, FIG. 5 is amlodipine, and FIG. 6 is losartan.

Referring to FIG. 4 , it can be seen that the dissolution rate of chlorthalidone varies according to the content of the low-substituted hydroxypropyl cellulose. Specifically, as in Examples 3 to 6, when the content was 40 wt% or more, the dissolution rate after 15 minutes was 85% or more. Example 2 In the case of the dissolution rate of the tablet, about 51 wt% of microcrystalline cellulose used together with low-substituted hydroxypropyl cellulose was used in a higher content than in other Examples, and the ratio was higher than that of the tablets of other Examples, the main component of which It can be seen that it affects the dissolution rate of money. From these results, it can be seen that the dissolution rate of chlorthalidone is simultaneously affected by the content of low-substituted hydroxypropyl cellulose as well as the content of microcrystalline cellulose.

In comparison, in the case of amlodipine and losartan of FIGS. 5 and 6, it was confirmed that the dissolution rate was not significantly affected by the content of low-substituted hydroxypropyl cellulose.

Test Example 5: Comparison of properties according to the content of low-substituted hydroxypropyl cellulose

In the case of low-substituted hydroxypropyl cellulose, there is a possibility of a change in properties during accelerated exposure due to its disintegration power. Therefore, the stability of the tablet was evaluated by measuring the change in the thickness of the tablet after storage for 1 day compared to the initial under accelerated storage conditions (high density polyethylene (HDPE) bottle packaging at 40° C. and 75% relative humidity).

Example 2 Example 3 Example 4 Example 5 Example 6 (L-HPC 30%) (L-HPC 40%) (L-HPC 50%) (L-HPC 60%) (L-HPC 70%) Tablet thickness (mm) Initial 4.4 4.41 3.39 4.4 4.42 1 day of accelerated exposure 4.7 4.72 4.77 4.83 delamination

Referring to Table 5, as the content of the low-substituted hydroxypropyl cellulose increased, the thickness of the tablet increased during accelerated exposure, and when the content was 70% by weight, between the upper and lower layers on the first day of accelerated exposure. It was confirmed that the layers were split.

When looking at the results of Test Examples 4 and 5, when the low-substituted hydroxypropyl cellulose was 40 to 60 wt% of the upper layer, tablets having excellent quality and productivity could be prepared.

Claims (13)

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 excipient;
A pharmaceutical combination preparation for the prevention or treatment of cardiovascular diseases, comprising a low-substituted hydroxypropyl cellulose as a pharmaceutically acceptable additive in the first mixture.
According to claim 1,
The first mixed part and the second mixed part exist in a state physically separated from each other, a pharmaceutical combination formulation.
According to claim 1,
The low-substituted hydroxypropyl cellulose is included in an amount of 30% by weight or more based on the total amount of the first mixed part, a pharmaceutical combination preparation.
According to claim 1,
The first mixing part is an excipient selected from the group consisting of lactose or a hydrate thereof, microcrystalline cellulose, mannitol, starch, sucrose, sorbitol, xylitol, glucose, calcium dihydrogen phosphate, starch, pregelatinized starch, and any combination thereof. A pharmaceutical combination formulation further comprising one type.
5. The method of claim 4,
The excipient is a low-substituted hydroxypropyl cellulose and 1:0.6 to 1:5.0, a pharmaceutical combination formulation included in a content ratio.
According to claim 1,
The pharmaceutical combination preparation comprises: a first layer comprising amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and
A double-layered tablet comprising a second layer comprising losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, a pharmaceutical combination preparation.
According to claim 1,
The combination formulation is a pharmaceutical combination formulation, characterized in that the dissolution rate of chlorthalidone is 90% or more within 15 minutes when the dissolution test in purified water according to the paddle method of the dissolution test item of the US Pharmacopoeia chlorthalidone tablet section.
According to claim 1,
The combination preparation is a pharmaceutical combination preparation, characterized in that the dissolution rate of chlorthalidone is 85% or more within 15 minutes when the dissolution test in purified water according to the first method (basket method) of the dissolution test of the Korean Pharmacopoeia.
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 excipient;
A low-dose fixed-dose combination agent for the prevention or treatment of cardiovascular diseases, comprising a low-substituted hydroxypropyl cellulose as a pharmaceutically acceptable additive in the first mixture.
10. The method of claim 9,
A low-dose fixed-dose combination agent, wherein the amlodipine or a pharmaceutically acceptable salt thereof is included in an amount of 0.5 to 5 mg in terms of amlodipine free base form.
10. The method of claim 9,
A low-dose fixed-dose combination agent, wherein the chlorthalidone or a pharmaceutically acceptable salt thereof is included in an amount of 1 to 7 mg in terms of chlorthalidone free base form.
10. The method of claim 9,
A low-dose fixed-dose combination agent, wherein the losartan or a pharmaceutically acceptable salt thereof is included in an amount of 5 to 30 mg in terms of losartan free base form.
a) mixing amlodipine or a pharmaceutically acceptable salt thereof, chlorthalidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and
b) mixing losartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive; and
c) tabletting the mixture obtained in steps a) and b),
In the step a), a method for preparing a pharmaceutical combination for the prevention or treatment of cardiovascular diseases, wherein a low-substituted hydroxypropyl cellulose is added as a pharmaceutically acceptable additive in the first mixing part.

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