HK1181685B - Pharmaceutical formulation in the form of bilayered tablets comprising hmg-coa reductase inhibitor and irbesartan - Google Patents

Description

Pharmaceutical formulation in the form of a bilayer tablet comprising an HMG-CoA reductase inhibitor and irbesartan

Technical Field

The present invention relates to a pharmaceutical formulation in the form of a bilayer tablet comprising HMG-CoA reductase inhibitor and irbesartan as active ingredients, which has improved stability and dissolution rate.

Background

Hyperlipidemia is a condition in which the level of lipids (e.g., cholesterol, triglycerides, etc.) in plasma is abnormally elevated. Hyperlipidemia (especially hypercholesterolemia) induces arterial thrombosis, leading to arteriosclerosis in which the arterial wall is thickened due to lipid accumulation. Arteriosclerosis is clinically important because it can cause cardiovascular diseases such as ischemic heart disease, angina pectoris, and myocardial infarction. Prevention of arteriosclerosis can be achieved by treating hypercholesterolemia highly associated therewith.

Hyperlipidemia or elevated plasma lipid levels are associated with increased frequency of occurrence of cardiovascular diseases and arteriosclerosis. More specific types of hyperlipidemia may include hypercholesterolemia, familial dysbetalipoproteinemia, diabetic dyslipidemia (diabetic dyslipemia), dyslipidemia associated with renal disease, familial combined hyperlipidemia, and the like. Hypercholesterolemia results in increased plasma levels of LDL-cholesterol and total cholesterol. LDL transports cholesterol in the blood. In addition, familial dysbetalipoproteinemia (also known as type III hyperlipidemia) is characterized by the accumulation of beta VLDL (very low density lipoprotein) in the plasma. In addition, the symptom is involved in the replacement of the normal apolipoprotein E3 with the abnormal isoform, apolipoprotein E2. Diabetic dyslipidemia results in a variety of lipoprotein disorders including overproduction of VLDL-cholesterol, abnormal lipolysis of VLDL triglycerides, decreased LDL-cholesterol receptor activity, frequent occurrence of type III hyperlipidemia, etc. Dyslipidemia associated with kidney disease is difficult to treat, and frequently occurring examples are hypercholesterolemia and hypertriglyceridemia. Familial combined hyperlipidemia is classified into multiple hyperlipidemia phenotypes, i.e., IIa, IIb, IV, V or apolipoprotein β -lipoproteinemia (hyperpapetalipoprotienemia).

HMG-CoA reductase inhibitors have been used for many decades to treat hyperlipidemia. These compounds are known to lower total and LDL-cholesterol in humans and to raise HDL-cholesterol in some individuals. The conversion of HMG-CoA to mevalonate (mevalonate) is an early and rate-limiting step in the biosynthesis of cholesterol. Inhibition of HMG-CoA reductase, which blocks the production of mevalonate, is achieved based on HMG-CoA reductase inhibitors exhibiting a lowering effect on total cholesterol as well as on LDL-cholesterol (Grundy s.m., n.engl.j.med., 319 (1): 24-32, 25-26, 31 (1988)).

Examples of HMG-CoA reductase inhibitors include mevastatin (U.S. Pat. No.3,983,140), lovastatin (also known as mevinolin (mevinolin); U.S. Pat. No.4,231,938), pravastatin (U.S. Pat. Nos. 4,346,227 and 4,410,629), pravastatin lactone (U.S. Pat. No.4,448,979), velostatin (also known as synvinolin); U.S. Pat. Nos. 4,448,784 and 4,450,171), simvastatin (simvastatin), rivastatin (rivastatin), fluvastatin, atorvastatin, rosuvastatin (rosuvastatin), cerivastatin, and the like.

Lipitor of Warner-Lambert according to the U.S. Food and Drug Administration (FDA)^TM(Lipitor^TM) The Summary of Approval references (SBA), atorvastatin exists in a variety of amorphous and crystalline forms. Originally, atorvastatin was synthesized in an amorphous form, but this form has been reported to be hygroscopic and unstable when exposed to oxygen. On the other hand, the crystalline forms of atorvastatin developed later showed improved in vivo yield (i.e., an increase in Cmax of about 50%), but were highly sensitive to heat, moisture, low pH environment and light, which required careful selection of excipients or additives in product development.

Irbesartan (chemically known as 3-butyl-3- ((4- (2- (2-tetrazol-5-yl) phenyl) methyl) -1, 3-diazaspiro (4, 4) non-1-en-4-one) is an angiotensin II receptor antagonist which blocks binding of angiotensin II, a vasoconstrictor, to AT1, and thus exhibits an antihypertensive effect. It selectively blocks the AT1receptor, but allows angiotensin II to bind to the AT2 receptor, thereby inhibiting endothelial proliferation, vasoconstriction and tissue repair while maintaining vasodilation.

Over the past several years, these commercially available angiotensin II receptor antagonists have been widely used as hypertension treatment drugs. Their effects have been demonstrated by clinical trials [ pharmacological, and therapeutic differentiation, amplifying iotentisin-II-receptor antagonists: pharmacotherapy 20 (2): 130-139, 2000].

These angiotensin II receptor antagonists are known to be effective for the prevention or treatment of heart failure associated with various hypertension symptoms, arrhythmia and heart failure after myocardial infarction, diabetic complications, renal failure and stroke. In addition, they are known to have other Effects, such as antiplatelet Effects, prevention of arteriosclerosis, inhibition of adverse Effects of aldosterone, alleviation of symptoms of metabolic syndrome, and prevention of worsening of circulatory disease [ j.wagner et al, Effects of AT1 receiver block on block compression and the recovery in systems in plasma hypertension of Clin, exp.hypertens, vol.20(1998), p.205-221; m. bohm et al, Angiotensin-II-receptor blockade inTGR (mREN2) 27: effects of fresh-angiotensins-system gene expressions and cardiovascular functions, J.Hypertens, vol.13(8) (1995), p.891-899 ].

Irbesartan is a fluffy material with a relatively low bulk and tap density (tap density). Furthermore, irbesartan is sticky and can adhere to surfaces (e.g., tablet punches and dies), causing problems in tableting. In addition, since irbesartan has low water solubility (i.e., solubility in water), it is important to use a surfactant to enhance wetting or solubility of tablets (korean patent No. 0442719).

When an angiotensin II receptor antagonist is used in combination with an HMG-CoA reductase inhibitor, not only hypertension and hyperlipidemia are more effectively treated than each single formulation, but also diabetes can be treated as a result of enhancement of vascular endothelial cells (protective membrane) and increase of insulin sensitivity.

In addition, it has been demonstrated that about 60% of patients with hypertension also suffer from hyperlipidemia, and hypertension and hyperlipidemia are closely related to each other. Co-administration of these two drugs to patients with cardiovascular disease is highly effective in reducing the occurrence of complications (e.g., death from stroke and stroke) and preventing diabetes [ Circulation, May 2005; 111: 2518-2524, Circulation, Dec 2004; 110: 3687-3692].

Korean patent publication nos. 2009-0114328 and 2009-0114190 disclose complex formulations of irbesartan and atorvastatin. The complex formulation allows for delayed release of one of the two drugs over a period of 2 hours for the purpose of preventing the interaction of ARBs (including irbesartan) with HMG-CoA reductase inhibitors. However, this delayed release formulation is designed only for in vitro tests (e.g., dissolution tester), and it is difficult to prepare a product having a constant delayed release rate by using the formulation. Furthermore, due to differences in the individual gastrointestinal tract movements, it is also difficult to accurately predict the delayed release time. Furthermore, it is known that irbesartan is mainly metabolized by 2C9 (a liver metabolizing enzyme) of cytochrome P450, while HMG-CoA reductase inhibitors (e.g., losuvastatin, pitavastatin and pravastatin) are rarely metabolized by the liver, and HMG-CoA reductase inhibitors (e.g., atorvastatin, lovastatin and simvastatin) are mainly metabolized by 3a4 of cytochrome P450, which indicates that there is little or no possibility of correlation between irbesartan and HMG-CoA reductase inhibitors [ pharmacogology & Therapeutics, vol.112, Issue1, October 2006; 71-105, FDA Avapro label ].

Therefore, when there is no correlation between the two drugs in the complex formulation with each other, an immediate release formulation, which shows the therapeutic effects of the two drugs in a short time, is considered to be ideal, and the inventors of the present invention have thus completed the present invention by developing an immediate release formulation containing an HMG-CoA reductase inhibitor and irbesartan as active ingredients, which has improved stability and dissolution rate.

Brief description of the invention

Accordingly, it is an object of the present invention to provide a complex formulation of an HMG-CoA reductase inhibitor and irbesartan, which has improved stability due to minimized physical and chemical interactions of irbesartan with an HMG-CoA reductase inhibitor and exhibits immediate release characteristics for both drugs, as well as improved solubility and bioavailability of irbesartan.

According to another aspect of the present invention, there is provided a pharmaceutical formulation in the form of a bilayer tablet comprising: a) a first layer comprising irbesartan or a pharmaceutically acceptable salt thereof; and b) a second layer comprising an HMG-CoA reductase inhibitor and a basic additive.

The complex formulation of the present invention can improve the dissolution rate and stability of irbesartan and HMG-CoA reductase inhibitors, thereby improving the bioavailability of the drug and minimizing the production of related compounds, compared to conventional complex formulations, thereby being effectively used as a stable and excellent therapeutic agent for hypertension and hypercholesterolemia.

Brief Description of Drawings

The above and other objects and features of the present invention will become apparent from the following description of the invention when taken in conjunction with the accompanying drawings, in which:

FIG. 1 is a graph showing the change in the amount of atorvastatin lactone, related compounds after storage of the formulations prepared in examples and comparative examples under accelerated conditions (40 ℃, 75% RH);

fig. 2 is a graph showing the change in the amount of irbesartan degradation product (RRT0.8) after storage of the formulations prepared in examples and comparative examples under accelerated conditions (40 ℃, 75% RH);

FIG. 3 is a graph showing the change in the amount of the related compound after storage of a single tablet (single tablet) prepared in comparative example under accelerated conditions (40 ℃, 75% RH);

fig. 4 is a graph showing the dissolution rate of irbesartan of the formulations prepared in examples and comparative examples and a commercially available formulation (ambowel);

fig. 5 is a graph showing the atorvastatin dissolution rates of the formulations prepared in examples and comparative examples and a commercially available formulation (Lipitor);

fig. 6 is a graph showing irbesartan saturated solubility of formulations prepared in examples and comparative examples;

fig. 7 is a graph showing changes in bioavailability of irbesartan formulations prepared in examples and comparative examples; and

fig. 8 is a schematic illustration of an exemplary pharmaceutical formulation in the form of a bilayer tablet according to the present invention.

Detailed Description

The complex formulation according to the present invention is characterized by a bilayer tablet consisting of a first layer comprising irbesartan or a pharmaceutically acceptable salt thereof and a second layer comprising an HMG-CoA reductase inhibitor and a basic additive. An example of a pharmaceutical formulation in the form of a bilayer tablet is depicted in figure 8. The characteristics and types of the components contained in the complex formulation of the present invention are described in detail hereinafter.

(i) First layer

In the complex formulation in the form of a bilayer tablet according to the present invention, the first layer may comprise irbesartan or a pharmaceutically acceptable salt thereof.

Irbesartan, 2-n-butyl-4-spirocyclopentane-1- [ (2' - (tetrazol-5-yl) biphenyl-4-yl) methyl ] -2-imidazolin-5-one, is a potential long-acting angiotensin II receptor antagonist that binds with high affinity to angiotensin receptors to inhibit vasoconstriction, aldosterone secretion, and moisture and sodium absorption, and thus exhibits antihypertensive effects. It is therefore particularly useful for the treatment of cardiovascular diseases, such as hypertension and heart failure. Formula (I) shows irbesartan as described in us patent No.5,270,317.

Pharmaceutically acceptable salts of irbesartan are well known in the art.

The complex formulation according to the present invention may preferably contain irbesartan or a pharmaceutically acceptable salt thereof in an amount of 8mg to 600mg per unit dosage form.

The first layer may further comprise a surfactant for improving the hydrophobicity of irbesartan. The surfactant improves the water granulation of irbesartan, makes the release of tablets after compression easier, and accelerates the dissolution of the irbesartan active ingredient. Representative examples of surfactants used include, but are not limited to, sodium lauryl sulfate, poloxamers (poloxamers), polyethylene glycols and mixtures thereof, especially poloxamers. In one embodiment of the present invention, the surfactant is preferably present only in the first layer to improve solubility, but is not limited thereto.

In addition, the first layer may further comprise a binder, a disintegrant, a lubricant, or a mixture thereof, and any other excipients and adjuvants. The binder may be at least one selected from the group consisting of: alginic acid, sodium alginate, sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gelatin, povidone, starch, pregelatinized starch, and mixtures thereof. The disintegrant may be at least one selected from the group consisting of: alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, pregelatinized starch, sodium carboxymethyl starch, and mixtures thereof. The lubricant may be at least one selected from the group consisting of: calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate (sodium stearyl fumarate), zinc stearate or stearic acid, hydrogenated vegetable oils, polyethylene glycols, sodium benzoate, talc and mixtures thereof, but are not limited thereto.

In addition, the other excipients and adjuvants may be diluents, colorants, anti-adherents or mixtures thereof, but are not limited thereto.

In a preferred embodiment, the first layer comprising irbesartan may comprise (a) irbesartan in an amount of about 20% to about 70% by weight, more preferably 40% to about 60% by weight, (b) diluent in an amount of about 1% to about 70% by weight, (c) binder in an amount of about 2% to about 20% by weight, (d) disintegrant in an amount of about 1% to about 10% by weight, (e) detackifier in an amount of about 0.1% to about 5% by weight, (f) lubricant in an amount of about 0.2% to about 5% by weight, and (g) colorant in an amount of 2% by weight or less, preferably about 0.1% to 1% by weight, all based on the weight of the first layer.

(ii) Second layer

The second layer of the two-layer complex formulation according to the present invention comprises an HMG-CoA reductase inhibitor and a basic additive.

The HMG-CoA reductase inhibitor is a drug capable of preventing or treating hyperlipidemia and arteriosclerosis by lowering a lipoprotein or lipid level in blood, and specific examples thereof are rosuvastatin, lovastatin, atorvastatin, pravastatin, fluvastatin, pitavastatin, simvastatin, rivastatin, cerivastatin, velostatin, mevastatin and pharmaceutically acceptable salts, precursors or mixtures thereof, more preferably atorvastatin, but not limited thereto.

The complex formulation according to the present invention may contain HMG-CoA reductase inhibitor preferably in an amount of 0.5mg to 100mg, more preferably 2.5mg to 80mg, most preferably 5mg to 80mg per unit dosage form, but is not limited thereto.

In the complex formulation of the present invention, examples of the basic additive include NaHCO₃、CaCO₃、MgCO₃、KH₂PO₄、K₂HPO₃Calcium phosphate (tribasic calcium phosphate), arginine, lysine, histidine, meglumine, magnesium aluminum silicate (magnesium aluminum silicate), magnesium aluminum metasilicate (magnesium aluminum silicate), salts and mixtures thereof, and preferably includes NaHCO₃、CaCO₃、MgCO₃And mixtures thereof, but are not limited thereto. The basic additive should be present in the same layer as the HMG-CoA reductase inhibitor to improve the stability of the HMG-CoA reductase inhibitor and provide basic microenvironment conditions that improve the solubility of irbesartan, ultimately improving the bioavailability of irbesartan.

The basic additive may be used in an amount of 2 to 10 parts by weight based on 1 part of HMG-CoA reductase inhibitor and in an amount of 0.2 to 10 parts by weight based on 1 part of irbesartan.

In addition, the second layer may further comprise a water-soluble diluent and optionally other excipients and adjuvants. The water-soluble diluent may be at least one selected from the group consisting of: mannitol, sucrose, lactose, sorbitol, xylitol, glucose and mixtures thereof, but is not limited thereto. In addition, the excipient and adjuvant may be a disintegrant, a binder, a carrier (carrier), a filler, a lubricant, a rheology modifier, a crystallization retarder, a solubilizer, a colorant, a pH adjuster, a surfactant, an emulsifier, a coating agent (coating agent), or a mixture thereof, but is not limited thereto.

Examples of the disintegrant include hydroxypropyl cellulose, crospovidone, sodium starch glycolate (sodium starch glycolate), croscarmellose sodium and the like, and may be suitably selected from conventionally available disintegrants. Examples of binders are povidone, copovidone, cellulose, and the like. Further, examples of the lubricant are magnesium stearate, sodium stearyl fumarate, talc, glycerin fatty acid ester, glycerin behenate (glycerol dibehnate), and the like, and may be suitably selected from conventionally available lubricants. Further, examples of the coating agent are polyvinyl alcohol, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose and the like, and may be suitably selected from conventionally available coating agents.

In a preferred embodiment, the second layer may comprise HMG-CoA reductase inhibitor in an amount of about 5% to about 20% by weight, more preferably about 6% to about 9% by weight, components (e.g., diluent, disintegrant and binder) for preparing the granule in an amount of about 2% to about 70% by weight, more preferably 2% to 20% by weight, lubricant or coating agent in an amount of about 0.5% to 2% by weight, more preferably 0.7% to 1.5% by weight, and additives in an amount of about 10% to 92.5% by weight, more preferably 15 to 80% by weight, all based on the weight of the second layer.

(iii) Bilayer tablet

The complex formulation according to the present invention is a bilayer tablet consisting of a first layer containing irbesartan or a pharmaceutically acceptable salt thereof and a second layer containing an HMG-CoA reductase inhibitor and a basic additive, thereby minimizing contact between drugs to improve stability and dissolution rate of each drug.

In particular, the pharmaceutical formulation in the form of a tablet according to the present invention includes a basic additive in the second layer, and the additive used can improve not only the stability of HMG-CoA reductase inhibitor but also the stability of irbesartan by minimizing the contact between irbesartan and the basic additive.

In addition, the additive can increase the dissolution rate of both drugs, thereby improving the disadvantages of the composite tablet, such as lower stability and dissolution rate. For example, a pharmaceutical formulation in the form of a bilayer tablet according to the invention may exhibit such a dissolution profile: 80% or more, preferably 80% or more, of each of irbesartan and HMG-CoA reductase inhibitor is released within 30 minutes, preferably within 15 minutes.

The pharmaceutical formulation in the form of a bilayer tablet comprising an HMG-CoA reductase inhibitor and irbesartan may be prepared by a process comprising the steps of:

(i) granulating irbesartan or a pharmaceutically acceptable salt thereof to obtain granules for the first layer;

(ii) granulating a mixture of an HMG-CoA reductase inhibitor and a basic additive to obtain granules for the second layer; and

(iii) compressing the granules for the first layer and the second layer into a bilayer tablet.

Various methods involved in the preparation of the complex formulation of the present invention can be performed based on conventional methods.

In one embodiment of the present invention, the granulation process may comprise the steps of:

(a) mixing irbesartan or atorvastatin with a preferred disintegrant and optionally with some or all of the excipients required for the final composition;

(b) adding a granulating solvent to the mixture obtained in step (a) under shear conditions;

(c) optionally, the product obtained in step (b) is crushed, milled or sieved, followed by drying of the moist material by air drying, fluidized bed drying, oven drying or microwave drying;

(d) optionally, pulverizing or sieving the material obtained in step (c);

(e) mixing the composition thus obtained with one or more disintegrants and optionally further excipients (preferably including lubricants); and

(f) the final composition was molded into pellets.

In step (a), the excipients may comprise diluents, binders and other materials necessary for enhancing flowability and stability or for processing and forming unit dosage forms. In step (b), preferred granulating solvents include water, ethanol, isopropanol, and mixtures thereof. Other components known in the art (e.g., binders, wetting agents, buffers, etc.) may be added to the granulation solvent. In step (b), various methods known in the art based on high shear granulation, low shear granulation, fluidized bed granulation, compression granulation, and the like may be used. In step (c), drying may preferably be carried out at a temperature of not more than about 60 ℃, more preferably at a temperature of not more than about 50 ℃, most preferably at a temperature of not more than about 40 ℃.

The complex formulation of the present invention can improve the dissolution rate and stability of irbesartan and HMG-CoA reductase inhibitors to improve the bioavailability of the drug and minimize the production of related compounds, compared to conventional complex formulations, thereby being effectively used as a stable and excellent therapeutic agent for hypertension and hypercholesterolemia.

The following examples are provided to illustrate preferred embodiments of the present invention and are not intended to limit the scope of the invention.

Preparation example 1-1: preparation of granules comprising irbesartan

Irbesartan (Hanmi Fine Chemical co., ltd., Korea), mannitol, pregelatinized starch, and croscarmellose sodium (DMV international) were mixed according to the composition described in table 1, followed by kneading the mixture with a binding solution (binddissolution) of povidone (BASF, Germany) dissolved in water, drying and passing through a 30-mesh screen to obtain wet granules, followed by adding magnesium stearate and mixing to prepare irbesartan granules.

Preparation examples 1 to 2: preparation of granules comprising irbesartan

Irbesartan (Hanmi Fine chemical co., ltd., Korea), mannitol, pregelatinized starch, and croscarmellose sodium (DMV international) were mixed according to the composition described in table 1, followed by kneading the mixture with a binding solution of povidone (BASF, Germany) and poloxamer 188(BASF, Germany) dissolved in water, drying and passing through a 30-mesh screen to obtain wet granules, followed by adding magnesium stearate and mixing to prepare irbesartan granules.

< Table 1>

Granules comprising irbesartan (unit: mg)

Composition (I)	Preparation of examples 1 to 1	Preparation examples 1 to 2
			Irbesartan	150	150
Mannitol	47	47
			Pregelatinized starch	23	23
Croscarmellose sodium	12	12
			Povidone	8	8
Poloxamer 188		9
			<Water (W)>	<80>	<80>
Magnesium stearate	4	4
			Total of	244	253

Preparation example 2-1: preparation of atorvastatin-containing granules

Atorvastatin calcium (TEVA, India), mannitol, microcrystalline cellulose and crospovidone (BASF, Germany) were mixed with NaHCO according to the composition described in Table 2₃(Pendrice Soda, Australia), followed by kneading the mixture with a binding solution of HPC (hydroxypropylcellulose) and polysorbate 80(Croda, USA) dissolved in water, drying and passing through a 30-mesh sieve to obtain wet granules, followed by adding magnesium stearate and mixing to prepare HMG-CoA reductase inhibitor granules.

Preparation examples 2 to 2: preparation of atorvastatin-containing granules

Atorvastatin calcium (TEVA, India), mannitol, microcrystalline cellulose and crospovidone (BASF, Germany) were mixed with magnesium carbonate (Tomita, Japan) according to the composition described in table 2, followed by kneading the mixture with a binding solution of HPC and polysorbate 80(Croda, USA) dissolved in water, drying and passing through a 30-mesh screen to obtain wet granules, followed by adding magnesium stearate and mixing to prepare HMG-CoA reductase inhibitor granules.

Preparation examples 2 to 3: preparation of atorvastatin-containing granules

Atorvastatin calcium (TEVA, India), mannitol, microcrystalline cellulose and crospovidone (BASF, Germany) were mixed according to the composition described in table 2, followed by kneading the mixture with a binding solution of polysorbate 80(Croda, USA) dissolved in water, drying and passing through a 30-mesh sieve to obtain wet granules, followed by adding magnesium stearate and mixing to prepare HMG-CoA reductase inhibitor granules.

< Table 2>

Granules comprising atorvastatin (unit: mg)

Examples 1 to 4: preparation of irbesartan-atorvastatin bilayer tablet according to the present invention

A complex formulation in the form of a tablet comprising HMG-CoA reductase inhibitor and irbesartan was prepared by combining the granules of the preparation examples as described in table 3.

Irbesartan granules as a first layer and HMG-CoA reductase inhibitor granules as a second layer were laminated into a bilayer tablet using a tabletting apparatus to obtain a composite formulation having an equivalent of irbesartan 150mg and HMG-CoA reductase inhibitor 10 mg.

Comparative examples 1 to 13

Comparative examples 1 and 2: preparation of bilayered tablets of irbesartan-atorvastatin not containing a basic additive

The granules of the preparation examples were combined and compressed into a bilayer tablet comprising irbesartan as a first layer and HMG-CoA reductase inhibitor as a second layer as listed in table 3.

Comparative examples 3 to 8: preparation of a monolayer tablet of irbesartan-atorvastatin

The granules of the preparation examples were simply mixed and compressed into a mono-layer tablet as listed in table 3.

Comparative examples 9 to 13: preparing a single tablet

Each of the granules of preparation examples 9 to 13 was compressed into a single tablet as listed in table 3.

As described above, the formulations of comparative examples 1 to 13 having an equivalent of irbesartan 150mg and/or HMG-CoA reductase inhibitor 10mg were prepared.

< Table 3>

Preparation comprising irbesartan and/or atorvastatin

	Type of tablet	Irbesartan	Atorvastatin
				Example 1	Double layer	Preparation of examples 1 to 1	Preparation example 2-1
Example 2	Double layer	Preparation of examples 1 to 1	Preparation examples 2 to 2
				Example 3	Double layer	Preparation examples 1 to 2	Preparation example 2-1
Example 4	Double layer	Preparation examples 1 to 2	Preparation examples 2 to 2
				Comparative example 1	Double layer	Preparation of examples 1 to 1	Preparation examples 2 to 3
Comparative example 2	Double layer	Preparation examples 1 to 2	Preparation examples 2 to 3
				Comparative example 3	Single layer	Preparation of examples 1 to 1	Preparation example 2-1
Comparative example 4	Single layer	Preparation of examples 1 to 1	Preparation examples 2 to 2
				Comparative example 5	Single layer	Preparation of examples 1 to 1	Preparation examples 2 to 3
Comparative example 6	Single layer	Preparation examples 1 to 2	Preparation example 2-1
				Comparative example 7	Single layer	Preparation examples 1 to 2	Preparation examples 2 to 2
Comparative example 8	Single layer	Preparation examples 1 to 2	Preparation examples 2 to 3
				Comparative example 9	Is single	Preparation of examples 1 to 1
Comparative example 10	Is single	Preparation examples 1 to 2
				Comparative example 11	Is single		Preparation example 2-1
Comparative example 12	Is single		Preparation examples 2 to 2
				Comparative example 13	Is single		Preparation examples 2 to 3

Experimental example 1: stability test

The complex formulations prepared in examples 1 to 4 and comparative examples 1 to 8 and the single formulations prepared in comparative examples 9 to 13 were each packaged in HDPE bottles together with 1g of silica gel and stored under accelerated conditions (40 ℃, 75% RH), and their stability was measured after three and six months. The amount of irbesartan degradation product (RRT0.8) and the amount of atorvastatin lactone (representative acid degradation product) as a related compound were measured. The results are shown in tables 4 to 6 and fig. 1 to 3.

< Table 4>

Atorvastatin lactone after storage under accelerated conditions (40 ℃, 75% RH)

< Table 5>

Degradation products of irbesartan after storage under accelerated conditions (40 ℃, 75% RH) (RRT0.8)

< Table 6>

Single tablet related compounds after storage under accelerated conditions (40 ℃, 75% RH)

Under accelerated conditions, as shown in tables 4 to 6 and fig. 1 to 3, the amount of atorvastatin lactone and irbesartan degradation product (RRT0.8) increased with time. Especially the stability of the drug after 6 months under accelerated conditions is a key factor in determining the shelf life of the drug. According to the ICH guidelines, the relevant compounds should not exceed 0.2% for irbesartan and 0.25% for atorvastatin by 6 months of acceleration.

When the bilayered composite formulations of examples 1 to 4 and comparative examples 1 and 2 were compared as shown in table 4 and fig. 1, the basic additive (e.g., NaHCO) was contained as compared to the experimental group without the basic additive (comparative example 1) in terms of the amount of atorvastatin lactone generated₃Or magnesium carbonate) (examples 1 and 2) showed more improved stability. Furthermore, the bilayer complex formulations (examples 1 and 2) showed more improved stability with respect to the amount of atorvastatin lactone produced, compared to the monolayer complex formulations (comparative examples 3 to 8).

In addition, table 5 and fig. 2 demonstrate that the configuration of the bilayer tablet can improve the stability of the formulation by inhibiting the interaction of the basic additive (e.g., carbonate) with irbesartan. More specifically, the basic additive (e.g., NaHCO) was included in the formulation, as compared with the case where the basic additive was not included in the formulation (comparative examples 1-2)₃Or magnesium carbonate) (comparative examples 3-4), but examples 1-4 in the form of a bilayer complex formulation showed a decrease in the amount of the relevant compound despite the inclusion of a basic additive, thereby satisfying the ICH guidelines.

In summary, the basic additive, although improving the stability of atorvastatin, has a problem of decreasing the stability of irbesartan. However, the formulation of the present invention can minimize contact between drugs or between drugs and substances having adverse effects on the drugs, resulting in improved preparation and storage stability of the irbesartan-atorvastatin complex formulation.

Experimental example 2: dissolution test

Comparative example 3, example 1, comparative example 9 and ambervol 150mg (control drug, Sanofi-aventis) were tested using the USP "irbesartan tablets" dissolution test. Samples were taken 5, 10, 15, 20 and 30 minutes after the start of the test and the dissolution rate was measured. The results are shown in FIG. 4.

In addition, comparative example 3, example 1, comparative example 9 and lipitor 20mg (control drug, Pfizer) were tested using USP apparatus 2 in 900mL of water at a paddle speed of 50 rpm. Samples were taken at 5, 10, 15, 30 and 45 minutes and the dissolution rate was measured. The results are shown in FIG. 5.

From the results of fig. 4 and 5, it was found that the monolayer formulation caused a decrease in the dissolution of irbesartan and atorvastatin, while the bilayer formulation did not affect the above compounds, showing a dissolution rate comparable to that of the control drug. Therefore, a bilayer preparation in which two drugs are separated from each other may be preferable in preparing the irbesartan-atorvastatin complex formulation to improve dissolution rate.

Example 3: evaluation of saturated solubility of irbesartan

The irbesartan saturation stability of comparative example 1, comparative example 9 and example 1 was measured. The test was carried out using ten (10) tablets in 1000mL of water and 1000mL of pH6.8 solution at a paddle speed of 50rpm using USP apparatus 2. After 12 hours of testing, a sample of the solution was taken and its saturated solubility was measured, and the results are shown in fig. 6.

The results of fig. 6 reveal that a single tablet of irbesartan (comparative example 9) shows very low saturation solubility in water and ph6.8 solution due to the hydrophobicity of irbesartan, and a complex formulation of atorvastatin and irbesartan not containing a basic additive (comparative example 1) also shows lower saturation stability comparable to that of the single tablet of irbesartan, whereas the complex formulation containing a basic additive (example 1) shows a great improvement in water and ph6.8 solution. Thus, it was found that the basic additive increases the solubility of the water-insoluble irbesartan.

Experimental example 4: evaluation of bioavailability of irbesartan

The bioavailability of example 1 and comparative example 9 was evaluated using beagle dog (beagle dog). Six beagle dogs were randomly crossed and the results are shown in table 7 and figure 7. Figure 7 shows mean plasma concentrations (mg/mL) of irbesartan calculated on a linear scale versus time (hr).

< Table 7>

As shown in table 7 and fig. 7, the irbesartan-atorvastatin complex formulation comprising a basic additive (example 1) showed higher bioavailability of irbesartan than irbesartan single formulation (comparative example 9), which is believed to be related to increased solubility. Thus, it was found that the basic additive increases the solubility of irbesartan and ultimately its bioavailability.

While the invention has been described with respect to the above specific embodiments, it will be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims (16)

1. Use of a basic additive for improving the dissolution rate and bioavailability of irbesartan in an immediate release pharmaceutical formulation in the form of a tablet comprising:

a) a first layer comprising irbesartan or a pharmaceutically acceptable salt thereof; and

b) a second layer comprising atorvastatin or a pharmaceutically acceptable salt thereof and an alkaline additive,

wherein the basic additive is present only in the second layer;

wherein the basic additive is included in an amount of 2 to 10 parts by weight per 1 part of atorvastatin; and is

Wherein the basic additive is included in an amount of 0.2 to 10 parts by weight per 1 part of irbesartan.

2. The use of claim 1, said pharmaceutical formulation exhibiting a dissolution profile which is: 80% or more of each of irbesartan and atorvastatin is released within 30 minutes.

3. The use according to claim 2, said pharmaceutical formulation exhibiting a dissolution profile which is: 80% or more of each of irbesartan and atorvastatin is released within 15 minutes.

4. Use according to claim 1, wherein the alkaline additive is selected from: NaHCO 2₃、CaCO₃、MgCO₃、KH₂PO₄、K₂HPO₃Calcium phosphate, arginine, lysine, histidine, meglumine, magnesium aluminum silicate, magnesium aluminum metasilicate, and salts and mixtures thereof.

5. Use according to claim 4, wherein the basic additive is NaHCO₃、MgCO₃Or mixtures thereof.

6. The use of claim 1, wherein the second layer of the formulation further comprises a water soluble diluent selected from the group consisting of: mannitol, sucrose, lactose, sorbitol, xylitol, glucose and mixtures thereof.

7. The use of claim 1, wherein the second layer of the formulation further comprises a disintegrant, binder, carrier, filler, lubricant, rheology modifier, crystallization retarder, solubilizer, colorant, pH adjuster, surfactant, emulsifier, coating agent, or mixture thereof.

8. The use of claim 1, wherein the first layer of the formulation further comprises a binder, a disintegrant, a lubricant, or a mixture thereof.

9. The use of claim 8, wherein the binder is selected from the group consisting of: alginic acid, sodium alginate, sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gelatin, povidone, starch, pregelatinized starch, and mixtures thereof.

10. The use of claim 8, wherein the disintegrant is selected from the group consisting of: alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, pregelatinized starch, sodium carboxymethyl starch, and mixtures thereof.

11. The use of claim 8, wherein the lubricant is selected from the group consisting of: calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate or stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc and mixtures thereof.

12. The use according to claim 1, wherein the formulation comprises irbesartan or a pharmaceutically acceptable salt thereof in an amount of 8 to 600mg per unit dosage form.

13. The use of claim 1, wherein the formulation comprises atorvastatin in an amount of from 0.5mg to 100mg per unit dosage form.

14. The use of claim 1, wherein the formulation further comprises a surfactant in the first layer.

15. The use of claim 14, wherein the surfactant is selected from the group consisting of: sodium lauryl sulfate, poloxamer, polyethylene glycol, and mixtures thereof.

16. The use according to any one of claims 1 to 15, wherein the process for preparing the immediate release pharmaceutical formulation in the form of a tablet comprises the steps of:

(i) granulating irbesartan or a pharmaceutically acceptable salt thereof to obtain granules for the first layer;

(ii) granulating a mixture of atorvastatin and an alkaline additive to obtain granules for the second layer; and

(iii) compressing the granules for the first layer and the second layer into a bi-layer tablet,

wherein the basic additive is present only in the second layer,

wherein the basic additive is included in an amount of 2 to 10 parts by weight per 1 part of atorvastatin; and is

Wherein the basic additive is included in an amount of 0.2 to 10 parts by weight per 1 part of irbesartan.