KR102545274B1 - Sustained-release formulation comprising sacubitril and valsartan for treating heart failure, and multiple-release composite formulation comprising the same and method for preparation thereof - Google Patents

Abstract

The present invention includes sacubitril and valsartan, or a pharmaceutically acceptable salt thereof, and a sustained-release formulation for the treatment of heart failure comprising at least one of a nonionic hydrophobic polymer and a lipid as a sustained-release agent, and the sustained-release formulation It relates to a multiple-release combination preparation that is administered once a day, exhibits the same therapeutic effect as a preparation administered twice a day, and can greatly improve patient compliance.

Description

Sustained-release formulation comprising sacubitril and valsartan for treating heart failure, and multiple-release composite formulation comprising the same and method for preparation thereof}

The present invention relates to a sustained-release formulation containing sacubitril and valsartan, a multiple-release combination formulation containing the sustained-release formulation, and a method for preparing the same.

Heart failure refers to a condition that occurs when the heart fails to supply necessary blood to body tissues due to a decrease in the diastolic function of receiving blood or the contractile function of pumping blood due to structural or functional abnormalities of the heart. It is not a specific disease but a complex pathophysiology syndrome you have Heart failure is a disease in which patients complain of severe panting, difficulty breathing, and extreme fatigue due to insufficient blood supply, and a feeling of being submerged in water and unable to breathe. When heart function declines, compensatory mechanisms to maintain blood flow to major organs are activated, but if these compensatory mechanisms continue inappropriately, heart failure gradually worsens. is needed

Myocardial ischemia due to ischemic heart disease (angina pectoris, myocardial infarction, etc.) is the biggest cause of heart failure, and arrhythmias caused by chronic diseases such as hypertension that can cause abnormal tension in the heart muscle for a long time appear as the second leading cause. In addition, it can be seen that there is a patient's noncompliance with medications as a factor that worsens heart failure. In the management of chronic heart failure patients, it is required to develop a treatment that can increase patient's medication compliance by reducing the number of doses. there is.

As a treatment for heart failure, tablets containing sacubitril, which inhibits neprilysin, and valsartan, an angiotensin receptor antagonist (ARB), are marketed under the product name Entresto. The indication for Entresto tablet is to reduce the risk of death due to cardiovascular disease and hospitalization due to heart failure in patients with chronic heart failure, specifically, chronic heart failure patients with reduced systolic function of the left ventricle (NYHA class II-IV). It is intended to be administered twice a day, and in relation to this, Korean Patent Registration No. 10-1589317, a prior patent, is a tablet form of sacubitril and valsartan that releases an average of 40% (by weight) or more of valsartan free acid after 10 minutes. An immediate release formulation exhibiting an in vitro dissolution profile is disclosed.

International Patent Publication No. 2017/012600 discloses a tablet containing sacubitril and valsartan in the form of free acid, sodium, calcium salt, etc., respectively, together with fillers, binders, lubricants, surfactants and/or glidants as pharmaceutical additives. is disclosed, but is described as having the same release characteristics as Entresto tablets.

In the case of such an immediate-release formulation, since it must be administered twice or more a day, there has been a demand for a sustained-release formulation capable of reducing the number of doses.

Chinese Registered Patent No. 105748420 and Chinese Patent Publication No. 105935358 disclose sustained-release formulations using hydroxypropylmethylcellulose, a hydrophilic sustained-release polymer, for oral administration once a day. However, in the case of the sustained-release formulation to which the hydrophilic sustained-release polymer is applied, it can be confirmed that the dissolution tendencies of sacubitril and valsartan are different from each other, as disclosed in Chinese Patent Publication No. 105935358. Looking at this in more detail, as a result of the dissolution test, it can be seen that the dissolution rate of Sacubitril is up to about 21% lower than that of Valsartan at 8 hours, and about 18% lower even at 12 hours. This difference in dissolution rate may appear as a difference in pharmacokinetics, and as a result, it is likely to act toward reducing the synergistic effect of sacubitril and valsartan.

Z. Kobalava et al . According to the thesis, Entresto tablet is dissociated into sacubitril and valsartan when administered orally, and sacubitril is quickly absorbed and metabolized into its active metabolite, sacubitril. In this process, sacubitril and valsartan are mutually absorbed. And it can be seen that it does not affect metabolism. In addition, it can be seen that the pharmacokinetic characteristics (blood concentration curve over time) of valsartan and sacubitril, which have pharmacological activity, are very similar, especially T _max of 2 to 2.5 hours. In order to obtain the maximum effect, it is considered very important to match the pharmacokinetic properties of the active ingredients, valsartan and sacubitrilat.

From this point of view, since the dissolution rate of sacubitril is lower than that of valsartan in the case of the sustained-release formulation disclosed in Chinese Patent Publication No. 105935358, unlike the above paper, the pharmacokinetic properties of valsartan and sacubitrlat, which are active ingredients, are not mutually exclusive. It is highly likely that it will appear differently, which is not desirable.

In addition, according to the USFDA approval data (NDA#207620, reference ID 375689), the blood half-lives of valsartan and sacubitrillat are long at 9.9 hours and 11.5 hours, respectively. As the degree of exposure to the body increases over a longer period of time, unintended side effects may occur.

Accordingly, the inventors of the present invention developed an optimal dosage form capable of reducing the number of doses of sacubitril and valsartan twice a day to once a day, and at the same time exhibiting a consistent dissolution tendency between sacubitril and valsartan, thereby reducing drug use. The present invention was completed after confirming that the therapeutic effect could be maximized by not only maintaining the blood concentration for one day but also improving the convenience of taking the patient.

KR 10-1589317 B1 CN 105935358 A CN 105748420 B WO 2017/012600 A1

Z. Kobalava et al., Cardiovascular Therapeutics, 34 (2016), 191-198. Pharmacodynamic and pharmacokinetics profiles of sacubitril/valsartan (LCZ696) in patients with heart failure and reduced ejection fraction. AXEL U. DIGNASS et al., Clinical Castroenterology and Hepatology, 7 (2009) 762-769, Mesalamine once daily is more effective than twice daily in patients with quiescent ulcerative colitis.

An object of the present invention is to provide a sustained-release formulation containing sacubitril and valsartan, which can exert a useful therapeutic effect even when taken in a once-daily regimen.

In addition, an object of the present invention is to provide a multi-release combination preparation containing sacubitril and valsartan, which can exert a useful therapeutic effect even when taken in a once-a-day regimen.

Another object of the present invention is to provide a method for preparing a multi-release combination preparation containing sacubitril and valsartan.

In order to achieve the above object, the present invention provides a treatment for heart failure comprising sacubitril and valsartan, or pharmaceutically acceptable salts thereof, as active ingredients, and at least one of nonionic hydrophobic polymers and lipids as sustained-release agents. It relates to a sustained-release formulation for use.

The sustained-release formulation can release active ingredients, sacubitril and valsartan, over a long period of time, and can be administered as a once-a-day regimen.

According to another aspect, the present invention includes sacubitril and valsartan, or pharmaceutically acceptable salts thereof, as active ingredients, and at least one of a nonionic hydrophobic polymer and a lipid as a sustained-release agent, and has an apparent density of 0.30. ~ 0.45 g / mL, tap density 0.40 ~ 0.60 g / mL, and particle size (D ₉₀ ) of 100 ~ 1000㎛ granules, or may be a sustained-release formulation formulated with the granules into tablets or capsules.

The nonionic hydrophobic polymer is at least one of cellulose acetate and ethyl cellulose as a cellulose derivative, and the lipid is glyceryl dibehenate, glyceryl stearate, glyceryl monooleate, and glyceryl palmitostearate as fatty acid esters ; The fatty alcohol may be at least one selected from the group consisting of stearyl alcohol, cetostearyl alcohol, and myristyl alcohol.

According to another aspect, the present invention includes a first release part containing sacubitril and valsartan, or a pharmaceutically acceptable salt thereof as active ingredients, and further comprising the sustained-release formulation as a second release part. , It relates to multiple release combination preparations for the treatment of heart failure.

In the multiple-release combination preparation, the first release unit may be an immediate release type or a sustained release type, preferably an immediate release type. That is, according to one preferred embodiment, an immediate release type first release part containing sacubitril and valsartan, or a pharmaceutically acceptable salt thereof, as active ingredients; and a sustained-release second-release portion comprising at least one of sacubitril and valsartan, or pharmaceutically acceptable salts thereof, as active ingredients, and at least one of nonionic hydrophobic polymers and lipids as a sustained-release agent. It's about combination drugs.

The weight ratio of the active ingredient between the first release part and the second release part may be 1:3 to 1:9.

The multi-release combination preparation includes a first release part containing an active ingredient, an excipient, a disintegrant, and a lubricant; And at least one selected from the group consisting of ethyl cellulose, glyceryl dibehenate, glyceryl distearate, stearyl alcohol, cetostearyl alcohol, and myristyl alcohol as an active ingredient and a sustained release agent, excipients and lubricants It may include a second release part including one or more types.

In the first and second release parts, the excipient is at least one selected from the group consisting of lactose hydrate, corn starch, anhydrous calcium hydrogen phosphate, and microcrystalline cellulose, and the lubricant is magnesium stearate, talc, stearic acid , Sodium stearyl fumarate, and at least one selected from the group consisting of colloidal silicon dioxide, and in the first release part, the disintegrant is croscarmellose sodium, sodium starch glycolate, and low-substituted hydroxypropyl It may be at least one selected from the group consisting of cellulose, carboxymethyl cellulose calcium, and crospovidone.

The first release part contains 10 to 70% by weight of an active ingredient, 5 to 70% by weight of an excipient, 15 to 35% by weight of a disintegrant, and 0.5 to 3.5% by weight of a lubricant, based on the total weight of the first release part. The second release part may include 40 to 70% by weight of an active ingredient, 15 to 50% by weight of a sustained release agent, and 1 to 25% by weight of one or more of excipients and lubricants based on the total weight of the second release part. .

The multi-release combination preparation can release the active ingredients, sacubitril and valsartan, over a long period of time, so it can be administered in a once-a-day regimen, and can also be administered in a once-a-day regimen to achieve the following pharmacokinetic parameters: It can be satisfied:

(i) the relative proportions of AUC _{0 -24} are 75-130% for sacubitril, 75-130% for sacubitril, and 75-130% for valsartan, compared to an immediate release formulation administered in a twice daily regimen; ,

(ii) the relative proportions of Cmax are 50-100% for sacubitril, 50-100% for sacubitril, and 50-100% for valsartan, as compared to immediate release formulations administered in a twice daily regimen; Preferably, the relative proportions of Cmax are 50-90% for sacubitril, 50-90% for sacubitril, and 50-90% for valsartan.

The second release part of the multi-release combination preparation is a granulate having an apparent density of 0.30 to 0.45 g/mL, a tap density of 0.40 to 0.60 g/mL, and a particle size (D ₉₀ ) of 100 to 1000 μm, or the granule is purified or It may be formulated as a capsule.

The multi-release combination preparation may be in the form of tablets or capsules.

The multi-release combination preparation may be in the form of a double-layer tablet, a multi-layer tablet, or a core tablet, or a hard capsule filled with granules, pellets, or mini-tablets.

According to the dissolution test method 2 (paddle method) of the Korean Pharmacopoeia, the multi-release combination preparation, when dissolution test was performed under the conditions of 37 ± 0.5 ℃, pH 6.8, each active ingredient after 30 minutes based on the weight of the active ingredient 40 %, 40-70% after 2 hours, and 80% or more after 12 hours.

According to another aspect, the present invention provides a method for preparing a multi-release combination preparation comprising the steps of (a) preparing a first release portion containing sacubitril and valsartan as active ingredients; (b) preparing a second release part comprising sacubitril and valsartan as active ingredients, and at least one of nonionic hydrophobic polymer and lipid as a sustained release agent; and (c) compressing the first release portion and the second release portion together into a double-layered tablet or a core tablet, or forming into granules, pellets, or mini-tablets, and then filling the hard capsule.

In the step (a) of preparing the first release part, (a-1) adding a solvent containing water, alcohol or an aqueous alcohol solution to a mixture containing an active ingredient, an excipient, and a disintegrant, and combining them to prepare a union step; (a-2) drying and sizing the kneaded material to prepare granules; (a-3) mixing an excipient and a disintegrant with the granules; and (a-4) adding a lubricant.

The step (b) of preparing the second release part may include (b1-1) preparing a binding solution by dispersing the sustained-release agent in a solvent containing alcohol or an aqueous alcohol solution; (b1-2) mixing an active ingredient, a sustained-release agent, and an excipient, and then adding a binding solution and combining them to prepare a compound; (b1-3) preparing granules by drying and curing the kneaded material or by drying and curing the kneaded material; and (b1-4) adding a lubricant to the granules.

In addition, the step (b) of preparing the second release part may include (b2-1) hot-melting and extruding after mixing the active ingredient and the sustained-release agent; (b2-2) sizing the extrudate to prepare granules; and (b2-3) adding a lubricant to the granules.

Hereinafter, the present invention will be described in more detail.

'Sacubitril', which is one component used in the sustained-release preparation or multiple-release combination preparation of the present invention, is 4-{[(2 S ,4 R )-1-(4-biphenylyl)-5- A compound named ethoxy-4-methyl-5-oxo-2-pentanyl] amino} -4-oxobutanoic acid has a structure represented by Chemical Formula 1 below. Sacubitril is a neprilysin (NEP) inhibitor, which is activated by deethylation of esterase to form sacubitrilat, an atrial and brain natriuretic peptide, a blood pressure lowering peptide that acts to reduce blood flow. acts to decompose.

In addition, 'Valsartan', which is one component used in the sustained-release preparation or multiple-release combination preparation of the present invention, is (S)-N-(1-carboxy-2-methyl-pro-1-pil)-N- It is a compound named pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl-methyl]amine and has a structure represented by Chemical Formula 2 below. Valsartan is an angiotensin-II receptor blocker, which blocks the action of angiotensin-II, thereby relaxing blood vessels and lowering blood pressure, and is also used for the treatment of heart failure, ischemic heart disease, and the like.

In the present invention, 'pharmaceutically acceptable salt' refers to a salt commonly used in the art, and includes salts prepared from inorganic ions, inorganic acids, or organic acids, as well as hydrates or solvates of the salts. It refers to including. Sacubitril and valsartan or their pharmaceutically acceptable salts suitable for the present invention include free acids or salts of 1 to 3 inorganic ions such as sodium, calcium, potassium and magnesium, or monohydrates to trihydrates thereof, and the like. , As specific examples, a co-crystal form such as the 2.5 hydrate of sacubitril/valsartan trisodium salt conventionally known as LCZ696 or a mixture form of free acids or salts of each active ingredient may be cited, but is not limited thereto.

In addition, in the sustained-release preparation or multiple-release combination preparation of the present invention, the two active ingredients, sacubitril and valsartan, may be included in a molar ratio of 1:5 to 5:1, preferably in a molar ratio of 1:1. .

The sustained-release formulation of the present invention includes at least one of a nonionic hydrophobic polymer and a lipid as a sustained-release agent, and can release active ingredients, sacubitril and valsartan, over a long period of time, and can be administered in a once-a-day regimen. can

The nonionic hydrophobic polymer or lipid is a material that is immiscible with water molecules and is generally non-polar, so it is well soluble in non-polar solvents and does not have anionic or cationic functional groups.

The nonionic hydrophobic polymer is a cellulose derivative such as cellulose acetate or ethyl cellulose, and the lipid is a fatty acid ester such as glyceryl dibehenate, glyceryl distearate, glyceryl monooleate or glyceryl palmitostearate, or stearyl Fatty acid alcohols, such as alcohol, cetostearyl alcohol, and myristyl alcohol. At least one selected from the group consisting of such nonionic hydrophobic polymers and lipids may be used as a sustained-release mechanism. As the sustained-release agent, preferably at least one selected from the group consisting of ethyl cellulose, glyceryl dibehenate, glyceryl distearate, stearyl alcohol, cetostearyl alcohol, and myristyl alcohol is used, more preferably uses at least one selected from the group consisting of ethyl cellulose, glyceryl dibehenate, and stearyl alcohol, and most preferably ethyl cellulose and glyceryl dibehenate.

The sustained-release preparation is a granulate having an apparent density of 0.30 to 0.45 g/mL, a tap density of 0.40 to 0.60 g/mL, and a particle size (D ₉₀ ) of 100 to 1000 μm, preferably an apparent density of 0.30 to 0.45 g/mL, tab Density of 0.40 to 0.60 g/mL, and particle size (D ₉₀ ) of 500 to 1000 μm, or granules, or the granules may be formulated into tablets or capsules. By being composed of granules having a density and particle size in the above numerical range, the sustained-release formulation has the effect of enabling sustained release and delayed release of the active ingredient while showing a dissolution profile consistent with sacubitril and valsartan.

The multi-release combination preparation according to one aspect of the present invention includes a first release part and a second release part, and as the second release part, the same ingredient composition as the sustained-release preparation, that is, as active ingredients, sacubitril and valsartan; or a pharmaceutically acceptable salt thereof, and at least one of a nonionic hydrophobic polymer and a lipid as a sustained release agent, and as the first release part, sacubitril and valsartan, or a pharmaceutically acceptable salt thereof are effective It is included as a component and may be one of an immediate release type and a sustained release type.

By including the active ingredients sacubitril and valsartan at the same time as the immediate-release first release part and the sustained-release second release part, the multiple-release combination preparation enables immediate release of the active ingredients after administration, while maintaining a sustained release time of 12 hours or more. By enabling sustained release, it has the advantage of being able to show both rapid and sustained effects in the expression of drug effects.

The weight ratio of the active ingredient between the first release part and the second release part is preferably 1:3 to 1:9, more preferably 1:4 to 1:9. When the weight ratio of the active ingredient is within the range of more than 1:9, it is preferable to reduce the time delay until the onset of the drug compared to the case where the ratio of the second release portion is increased, and the ratio of the second release portion is less than 1:3. This is preferable because it can achieve a sustained release effect over 12 hours or more compared to the case where the amount is reduced.

According to one embodiment of the present invention, a first release portion containing an active ingredient, an excipient, a disintegrant, and a lubricant; And at least one selected from the group consisting of ethyl cellulose, glyceryl dibehenate, glyceryl distearate, stearyl alcohol, cetostearyl alcohol, and myristyl alcohol as an active ingredient and a sustained-release agent, and one of an excipient and a lubricant It may include a second release portion comprising more than one species.

The disintegrant used in the multi-release combination preparation of the present invention is 1 selected from crospovidone, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, polysorbate and sodium lauryl sulfate Paper can be used.

As the excipient used in the multi-release combination preparation of the present invention, substances commonly used pharmaceutically may be used within the range that does not affect the medicinal effect, and is selected from lactose hydrate, corn starch, anhydrous calcium hydrogen phosphate, and microcrystalline cellulose. One or more types may be used.

The lubricant used in the multi-release combination preparation of the present invention can prevent the surface of the tablet from adhering to a tableting punch during tableting and increase the flowability of the granules. As a specific example, at least one selected from among magnesium stearate, talc, stearic acid, sodium stearyl fumarate, and colloidal silicon dioxide may be used.

In the multi-release combination preparation, the excipient used in the first release part is at least one of lactose hydrate, corn starch, anhydrous calcium hydrogen phosphate, and microcrystalline cellulose, preferably at least one of microcrystalline cellulose and lactose hydrate, The disintegrant is at least one of crospovidone, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, polysorbate and sodium lauryl sulfate, preferably crospovidone and croscarmellose At least one of sodium, and the lubricant is at least one of magnesium stearate, talc, stearic acid, sodium stearyl fumarate, and colloidal silicon dioxide, preferably magnesium stearate, talc, and colloidal silicon dioxide It may be one or more of them.

In the multi-release combination preparation, the excipient used in the second release part is at least one of lactose hydrate, corn starch, anhydrous calcium hydrogen phosphate, and microcrystalline cellulose, preferably at least one of microcrystalline cellulose and lactose hydrate. , The lubricant is at least one of magnesium stearate, talc, stearic acid, sodium stearyl fumarate, and colloidal silicon dioxide, preferably at least one of magnesium stearate, talc, and colloidal silicon dioxide. The types and contents of excipients and lubricants used in the second release part herein may be equally applied to the sustained-release preparation according to one embodiment of the present invention.

The first release part contains 10 to 70% by weight of an active ingredient, 5 to 70% by weight of an excipient, 15 to 35% by weight of a disintegrant, and 0.5 to 3.5% by weight of a lubricant, based on the total weight of the first release part. The second release part may contain 40 to 70% by weight of an active ingredient, 15 to 50% by weight of a sustained-release base, and 1 to 25% by weight of one or more of excipients and lubricants based on the total weight of the second release part. Here, when both the excipient and the lubricant are used, 0.5 to 22% by weight of the excipient and 0.5 to 3% by weight of the lubricant may be included.

According to another embodiment, the multi-release combination preparation of the present invention includes a first release portion comprising an active ingredient, an excipient, and a binder; and at least one selected from the group consisting of ethyl cellulose, glyceryl dibehenate, glyceryl distearate, stearyl alcohol, cetostearyl alcohol, and myristyl alcohol as an active ingredient, a sustained release agent, an excipient and a binder. A second discharge unit; may be included. In this case, the first release portion includes 25 to 70% by weight of active ingredients, 25 to 70% by weight of excipients, and 0.5 to 5% by weight of a binder, based on the total weight of the first release portion, and the second release portion is Based on the total weight of the release part, it may include 40 to 70% by weight of active ingredient, 15 to 40% by weight of sustained-release substrate, 5 to 30% by weight of excipient, and 0.5 to 5% by weight of binder, which can be used here. The initiating agent is also as described above, and the binding agent may be used without limitation as long as it is a material capable of increasing the binding force of the formulation, but polyvinylpyrrolidone (common name povidone) may be preferably used.

The multi-release combination preparation of the present invention is in an orally administrable form, and may be in the form of, but not limited to, tablets and capsules. Preferably, the first release portion and the second release portion may be in the form of tablets or capsules prepared by separate granules and compressed into tablets. Tablets may be in the form of two-layer tablets, core tablets, and multi-layer tablets, and capsules may be in the form of hard capsules including granules, pellets, and mini-tablets. A schematic diagram of the multiple release combination preparation according to this embodiment is shown in FIG. 1 .

According to one specific aspect, the multi-release combination preparation of the present invention comprises the steps of (a) preparing a first release portion containing sacubitril and valsartan as active ingredients; (b) preparing a second release part comprising sacubitril and valsartan as active ingredients, and at least one of nonionic hydrophobic polymer and lipid as a sustained release agent; and (c) compressing the first release portion and the second release portion together into a double-layered tablet or a core tablet, or by preparing them into granules, pellets, or mini-tablets and then filling them into hard capsules.

The first release part or the second release part of step (a) or (b) may be prepared through wet granulation.

Specifically, step (a) of preparing the first release part is, (a-1) adding water, alcohol or an aqueous alcohol solvent to a mixture containing an active ingredient, an excipient, and a disintegrant, and preparing a union by combining ; (a-2) drying and sizing the kneaded material to prepare granules; (a-3) mixing an excipient and a disintegrant with the granules; and (a-4) adding a lubricant.

In the step (a-1), coalescence is performed by adding water, alcohol or an aqueous alcohol solution solvent. Alcohol includes at least one of methanol, ethanol, and isopropanol.

In the above (a-2), drying is performed at 35 to 60 ° C using a tray dryer, LOD (Loss on Drying, loss on drying) is checked, and 20 mesh is used to establish.

Specifically, the step (b) of preparing the second release part includes (b1-1) dispersing the sustained-release agent in alcohol or an aqueous alcohol solvent to prepare a binding solution; (b1-2) mixing an active ingredient, a sustained-release agent, and an excipient, and then adding a binding solution and combining them to prepare a compound; (b1-3) preparing granules by drying, curing and sizing the kneaded material or drying, sizing and curing the kneaded material; and (b1-4) adding a lubricant to the granules.

It is preferable to prepare a binding solution by dispersing the above (b1-1) in an alcohol or an aqueous alcohol solvent in which a sustained-release agent is dispersed. Alcohol includes at least one of methanol, ethanol, and isopropanol.

The wet granulation process of (b1-2) to (b1-3) is not particularly limited, but is, for example, a high speed mixer (HSM) or a fluid bed granulator (FBG). This can be done using equipment used in the industry.

The sustained-release mechanism in step (b1-2) may be the same as or different from the sustained-release mechanism used in (b1-1).

In the above (b1-3), drying is performed at 35 to 60 ° C using a tray dryer or a fluidized bed granulator, and the LOD value is checked. Sizing is carried out using a 20mesh, and curing is performed for 20 minutes to 3 hours, preferably 25 minutes to 2 hours by heating to a temperature of 60 ~ 80 ℃ before and after sizing. As described above, by performing curing before or after sizing, the effect of maximizing the drug release delay of sacubitril and valsartan can be obtained.

The multi-release combination preparation may further include a pharmaceutically acceptable film coating as a final outer layer. As an example of the film coating agent, trade names Opadry (Colorcon), specifically, Opadry I, Opadry II, Opadry fx, Opadry AMB, and the like can be used.

The first-release portion and the second-release portion prepared as above may be in the form of a mini-tablet, a double-layer tablet, or a multi-layer tablet including a core tablet.

In addition, the first discharge unit and the second discharge unit may be prepared using a hot melt extruder (HME) or a pellet manufacturing method using an extruder and a spheronizer.

Pellets using the hot melt extrusion (HME) method are mixed with the active ingredient, sustained release agent and excipient, put into a heated hot melt extruder, and rotated two screws in opposite directions to extrude granules. By continuously driving the conveyor belt, the sequentially extruded extrudates are cooled to room temperature and set. Subsequently, an excipient and a lubricant are added to the sized granules and mixed.

Alternatively, the pellets using an extruder and a spheronizer are kneaded by adding active ingredients and binders to a binder solution, extruded into a mesh body using an extruder, spheronized using a spheronizer, dried, and then slowly released. Pellets are prepared by spraying and drying the fire agent.

The first release portion and the second release portion prepared as above may be in the form of capsules filled with pellets. The contents filled in the capsules are not limited to pellets, but may include granules, mini-tablets, and the like.

The multi-release combination preparation of the present invention, according to the dissolution test method 2 (paddle method) of the Korean Pharmacopoeia, in the dissolution test at 37 ± 0.5 ° C, pH 6.8, each active ingredient is 30 minutes based on the weight of the active ingredient less than 40% after 2 hours, 40-70% after 2 hours, and 80% or more after 12 hours.

The combination preparation of the present invention, through an in vitro dissolution test, is slowly and continuously released for more than 12 hours, enabling once-a-day administration, and sacubitril and valsartan have a consistent dissolution tendency, resulting in a synergistic effect according to the combination of ingredients. It was found to be maximal.

The combination preparation of the present invention is the type of disease of the patient, the severity of the disease, the type of dosage form, the patient's age, sex, weight, health condition, diet, administration time and method of administration of the composition for pharmaceutical treatment, administration route, excretion rate and It can be variously prescribed by factors such as response sensitivity.

The sustained-release formulation of the present invention has the effect of maximizing the efficacy according to the combination of active ingredients by showing a consistent dissolution tendency of sacubitril and valsartan.

In addition, the multi-release combination preparation of the present invention shows consistent dissolution tendency of sacubitril and valsartan, so that it has the effect of maximizing the efficacy according to the combination of active ingredients, while enabling drug release from the beginning of drug administration. By allowing the active ingredient to be continuously absorbed in the body, the medicinal effect can be continuously maintained and side effects can be minimized.

In a thesis (AXEL U. DIGNASS et al ., 2009) evaluating the efficacy and safety of the twice-daily administration group and once-a-day administration group, the test results for 12 months, the complete cure rate of the once-daily administration group (70.9 %) can be significantly improved compared to the complete cure rate (58.9%) of the group administered twice a day, improving the dosing regimen from twice a day administration to once a day administration Through this, the present invention can improve the treatment effect as well as improve the patient's medication compliance.

1 is a schematic diagram of a multiple-release combination formulation according to various embodiments of the present invention.
2 is a graph evaluating the dissolution patterns of valsartan and sacubitril of formulations prepared according to Examples 1-2.
FIG. 3 is a graph evaluating the dissolution pattern of valsartan in multiple-release combination preparations containing granules of Examples 1-2 and Comparative Examples 1-2 and 1-3 as a second release part.
Figure 4 is a graph evaluating the dissolution pattern of the commercially available Entresto tablet 100mg and the preparation prepared according to Examples 2-3.
5 is a graph evaluating the dissolution patterns of valsartan and sacubitril of the multiple-release combination preparation prepared in Example 3-3.
6 is a graph evaluating valsartan dissolution patterns of multiple-release combination preparations prepared according to Examples 3-1 and 3-4 and Comparative Examples 2-1 and 2-2.
7 is a graph showing the evaluation of valsartan dissolution patterns of the multiple-release combination preparations prepared in Examples 4-1, 5-2, and 5-3.
8 schematically shows an experiment execution schedule of Experimental Example 7.
9 is a graph showing the results of the biomarker (BNP) of Experimental Example 7.
10 is a graph showing ejection fraction (EF) among echocardiographic results of Experimental Example 7;

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the disclosure herein is provided so that it will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.

< Example 1. Preparation of sustained-release tablet according to the present invention>

After preparing sustained-release granules using the wet granulation method according to the composition shown in Table 1 below, they were compressed into tablets. That is, a binder solution is prepared by partially dispersing a sustained-release agent in an ethanol solvent, and sacubitril/valsartan, a sustained-release agent, and microcrystalline cellulose are mixed in a high speed mixer (HSM), and then the binder solution is added and stirred. While mixing for 5 minutes, a union was prepared. The above compound was dried using a tray dryer, sized in a sizing machine, and then cured for 25 minutes to 2 hours by raising the temperature to 60 ~ 80 ℃ in a tray dryer again. Thereafter, magnesium stearate was added to the granules, followed by lubricating and mixing to form final sustained-release granules. Then, tablets were prepared by compressing the granules with a rotary tablet press (XENA-I-rotary, Raon Xena).

Ingredients weight(%) Example 1-1 1-2 1-3 1-4 1-5 1-6 active ingredient Sacubitril/Valsartan 55.0 39.4 39.4 39.4 39.4 39.4 westernization
mechanism ethyl cellulose 42.0 - - - - - glyceryl dibehenate - 57.6 - - - - Glyceryl Distearate - - 57.6 - - - Stearyl Alcohol - - - 57.6 - - myristyl alcohol - - - - 57.6 - Cetostearyl Alcohol - - - - - 57.6 excipient microcrystalline cellulose 1.5 1.5 1.5 1.5 1.5 1.5 glidant Magnesium Stearate 1.5 1.5 1.5 1.5 1.5 1.5 Sum 100.0 100.0 100.0 100.0 100.0 100.0

As sacubitril/valsartan in the above table, trisodium salt 2.5 hydrate having a 1:1 molar ratio of sacubitril and valsartan was used, and the same material was used in the Examples and Comparative Examples below unless otherwise noted.

< comparative example 1-1. Manufacture of sustained-release tablets>

Sustained-release tablets were prepared using the dry granulation method described in Chinese Patent Publication No. 105935358 with the composition shown in Table 2 below. That is, according to the composition of the ingredients in Table 2 below, sacubitril valsartan, HPMC K100M as a hydrophilic sustained-release base material, and colloidal silicon dioxide and magnesium stearate as pharmaceutically acceptable additives were mixed and dried in a dry granulator (RC-60, Seoul). Hi-Tech) into the final granules formed by compression and pulverization, into which colloidal silicon dioxide and magnesium stearate were added, mixed, and tableted. Tablets that were tableted were obtained film-coated tablets using Opadry AMB™ in a film coating machine (Auto Tablet Coating Machine, KC50F, Keumseong Industrial Co., Ltd.).

Ingredients weight(%) Comparative Example 1-1 Sacubitril/Valsartan 54.3 HPMC K100M 36.1 colloidal silicon dioxide 2.9 Magnesium Stearate 2.9 OpadryAMB™ 3.8 Sum 100.0

< Example 2. Multiple-release combination preparation according to the present invention to the first release Preparation of Corresponding Tablets>

Example In 2, tablets were prepared using sacubitril/valsartan mono-trisodium salt hydrate in which sacubitril and valsartan were in a 1:1 molar ratio, and the components listed in the table below. That is, sacubitril/valsartan, microcrystalline cellulose, and crospovidone were mixed in a high-speed mixer (High Speed Mixer, HSM: KMLC, Geumseongsangi), and then the binding solution was added and stirred for 5 minutes to prepare a kneaded product. The above combination was dried using a tray dryer (MOV-212F, SANYO) and sized in a sizing machine (UMA, Pharmaters), and then crospovidone, colloidal silicon dioxide, and magnesium stearate were added to the granules, and then mixed and tableted. .

Ingredients weight(%) Example 2-1 Example 2-2 Example 2-3 monosodium disodium trisodium Sacubitril/Valsartan 56.6 56.6 56.6 microcrystalline cellulose 12.4 12.4 12.4 crospovidone 29 29 29 colloidal silicon dioxide 0.5 0.5 0.5 Magnesium Stearate 1.5 1.5 1.5 Sum 100.0 100.0 100.0

< Example 3 and comparative example 2. Manufacture of Multiple Release Combination Formulation>

The manufacturing steps of each example according to the component content of Table 4 are as follows.

One) of the first release manufacturing

After putting sacubitril/valsartan, microcrystalline cellulose, and crospovidone in a high speed mixer (HSM) and mixing them, an ethanol solvent was added and united while stirring to prepare a kneaded product. The mixture was dried using a tray dryer. Thereafter, after sizing in a sizing machine, colloidal silicon dioxide and crospovidone were added and post-mixing was performed. Thereafter, magnesium stearate was added to the granulated material to form the final first-release granulated material.

2) of the second release manufacturing

After mixing sacubitril/valsartan and glyceryl dibehenate, the mixture was put into a heated hot melt extruder (HME: HTGD-16, Hartek), and the granules were extruded by rotating two screws in opposite directions. By continuously driving the conveyor belt, the sequentially extruded extrudates were cooled to room temperature and regulated. Subsequently, talc was added to the sized granules, mixed, magnesium stearate was added, and lubricating was performed to form final second-release granules.

3) Manufacture of double-layer tablets

The granules of the first release part and the granules of the second release part prepared above are tableted using a multi-layer tableting machine so that the weight ratio of the first release portion and the second release portion is 1:2 to 1:10 in a two-layer tablet. was manufactured.

Ingredients weight(%) comparative example
2-1 Example
3-1 Example
3-2 Example
3-3 Example
3-4 comparative example
2-2 1st discharge unit: 2nd release unit
Active ingredient weight ratio 1:2 1:3 1:4 1:6 1:9 1:10 first discharge unit
active ingredient Sacubitril/Valsartan 40.9 40.9 40.9 40.9 40.9 40.9 excipient microcrystalline cellulose 28.1 28.1 28.1 28.1 28.1 28.1 disintegrant crospovidone 29.0 29.0 29.0 29.0 29.0 29.0 glidant colloidal silicon dioxide 0.5 0.5 0.5 0.5 0.5 0.5 Magnesium Stearate 1.5 1.5 1.5 1.5 1.5 1.5 Sum 100.0 100.0 100.0 100.0 100.0 100.0 2nd discharge unit active ingredient Sacubitril/Valsartan 56.6 56.6 56.6 56.6 56.6 56.6 westernization
mechanism glyceryl dibehenate 41.4 41.4 41.4 41.4 41.4 41.4 glidant Talc 0.8 0.8 0.8 0.8 0.8 0.8 glidant Magnesium Stearate 1.2 1.2 1.2 1.2 1.2 1.2 Sum 100.0 100.0 100.0 100.0 100.0 100.0

< Example 4. Manufacture-Purification of Multiple Release Combination Formulations>

Example 4-1. Manufacture of multi-release combination formulation- double decker

The manufacturing steps of Example 4-1 according to the component contents in Table 5 are as follows.

One) of the first release manufacturing

Sacubitril/Valsartan, microcrystalline cellulose, and crospovidone were mixed in a high-speed mixer, and ethanol solvent was added thereto while stirring to prepare a kneaded product. The mixture was dried using a tray dryer. Thereafter, after sizing in a sizing machine, colloidal silicon dioxide and crospovidone were added and post-mixed, and then magnesium stearate was added to the granules to form final first-release granules.

2) of the second release manufacturing

A binding solution was prepared by dispersing ethyl cellulose in an ethanol solvent. After mixing sacubitril/valsartan, glyceryl dibehenate, and microcrystalline cellulose in a fluid bed granulator (FBG: FBG-1, Enger), the binder was sprayed to prepare a kneaded product. The kneaded material was dried, and the temperature was raised to 60 to 80° C. and cured for 25 minutes to 2 hours. Thereafter, after sizing in a sizing machine, magnesium stearate was added to the granules and then lubricated to form the final second-release granules.

3) Manufacture of double-layer tablets

The granules of the first release portion and the granules of the second release portion prepared above were compressed into tablets using a multi-layer tablet press (Autotab 200RT, Ichihashiceiki) such that the active ingredient weight ratio was 1:6 to prepare a double-layer tablet.

Ingredients weight(%) Example 4-1
first discharge unit active ingredient Sacubitril/Valsartan 40.9 excipient microcrystalline cellulose 28.1 disintegrant crospovidone 29.0 glidant colloidal silicon dioxide 0.5 Magnesium Stearate 1.5 Sum 100.0 2nd discharge unit active ingredient Sacubitril/Valsartan 50.3 sustained-release agent glyceryl dibehenate 31.2 ethyl cellulose 4.4 excipient microcrystalline cellulose 12.6 glidant Magnesium Stearate 1.5 Sum 100.0

Example 4-2. Manufacture of multi-release combination formulation- nuclear crystal

The manufacturing steps of Example 4-2 according to the component content in Table 6 below were the same as 1) and 2) of Example 4-1, but the first and second release parts were prepared, but Example 4-1 3 ) Unlike the step, it was prepared by tableting with a core tablet in the tableting step.

That is, after tableting the granules of the second release part prepared above into circular tablets having a diameter of 6 to 10 mm to prepare a core tablet, putting the granules of the first release part into the first layer using a multi-layer tablet press and tableting with a preload , The core tablet was placed in the second layer, and the granules of the first release portion were again put into the third layer and compressed into tablets to prepare core tablets such that the weight ratio of the active ingredients of the first release portion and the second release portion was 1:6.

Ingredients weight(%) Example 4-2
first discharge unit active ingredient Sacubitril/Valsartan 11.7 excipient microcrystalline cellulose 70.0 disintegrant crospovidone 16.7 glidant colloidal silicon dioxide 0.6 Magnesium Stearate 1.1 Sum 100.0 2nd discharge unit active ingredient Sacubitril/Valsartan 46.8 sustained-release agent glyceryl dibehenate 39.8 ethyl cellulose 4.4 excipient microcrystalline cellulose 7.5 glidant Magnesium Stearate 1.5 Sum 100.0

< Example 5. Manufacture of multi-release combination formulation- capsules >

Example 5-1. Manufacture of multi-release combination formulation- capsules ( pellet )

With the component composition shown in Table 7, capsules were prepared by preparing the first release portion and the second release portion as pellets, respectively, and filling them into capsules as described below.

One) first discharge unit of pellets manufacturing

A binding solution was prepared by dissolving povidone in an ethanol solvent. After putting sacubitril/valsartan and microcrystalline cellulose in a high speed mixer (HSM) and mixing them, the binder solution was added and kneaded for 5 minutes while stirring to prepare a kneaded product. The kneaded material was extruded using an extruder (TDG-70, Dalton) and a spheronizer (QJ-230T, Dalton) and spheronized for 5 minutes. Thereafter, drying was performed using a dryer to prepare pellets of the first discharge unit.

2) 2nd discharge unit of pellets manufacturing

A binding solution was prepared by dissolving povidone in an ethanol solvent. After putting sacubitril/valsartan and microcrystalline cellulose in a high speed mixer (HSM) and mixing them, the binder solution was added and kneaded for 5 minutes while stirring to prepare a kneaded product. The kneaded material was extruded using an extruder (TDG-70, Dalton) and a spheronizer (QJ-230T, Dalton) and spheronized for 5 minutes, and then sprayed with a sustained release agent (Surelease®) using a fluidized bed granulator. After drying, the pellets of the second discharge unit were prepared.

3) Capsule filling

The first release portion pellets and the second release portion pellets prepared above were filled into capsules such that the active ingredient weight ratio was 1:6.

Ingredients weight(%) Example 5-1 first discharge unit active ingredient Sacubitril/Valsartan 64.6 binder povidone 2.9 excipient microcrystalline cellulose 32.5 Sum 100.0 2nd discharge unit active ingredient Sacubitril/Valsartan 53.9 binder povidone 2.4 excipient microcrystalline cellulose 27.1 slow-release mechanism Surelease® 16.7 Sum 100.0

Example 5-2. Manufacture of multi-release combination formulation- capsules (granular)

With the component composition shown in Table 8 below, the first release part and the second release part were prepared in the same manner as 1) and 2) of Example 4-1, but unlike step 3) of Example 4-1, the prepared The granules of the first release portion and the granules of the second release portion were filled into capsules such that the active ingredient weight ratio was 1:6.

Ingredients weight(%) Example 5-2
first discharge unit active ingredient Sacubitril/Valsartan 63.9 excipient microcrystalline cellulose 13.6 disintegrant crospovidone 21.0 glidant colloidal silicon dioxide 0.5 Magnesium Stearate 1.0 Sum 100.0 2nd discharge unit active ingredient Sacubitril/Valsartan 46.8 sustained-release agent glyceryl dibehenate 39.8 ethyl cellulose 4.4 excipient microcrystalline cellulose 7.5 glidant Magnesium Stearate 1.5 Sum 100.0

Example 5-3. Manufacture of multi-release combination formulation- capsules (mini tablets)

With the component composition shown in Table 9, the first release part and the second release part were prepared in the same manner as in 1) and 2) of Example 4-1, but unlike step 3) of Example 4-1, the prepared The granules of the first release part and the second release part were compressed into tablets using a rotary tablet press, respectively, to prepare circular mini-tablets having a diameter of 1 to 6 mm. Thereafter, the mini-tablets of the first release part and the second release part were filled into capsules so that the active ingredient weight ratio was 1:6.

Ingredients weight(%) Example 5-3
first discharge unit active ingredient Sacubitril/Valsartan 63.9 excipient microcrystalline cellulose 13.6 disintegrant crospovidone 21.0 glidant colloidal silicon dioxide 0.5 Magnesium Stearate 1.0 Sum 100.0 2nd discharge unit active ingredient Sacubitril/Valsartan 46.8 sustained-release agent glyceryl dibehenate 39.8 ethyl cellulose 4.4 excipient microcrystalline cellulose 7.5 glidant Magnesium Stearate 1.5 Sum 100.0

< Experimental example One. Example 1 and comparative example Dissolution test of sustained-release tablet of 1-1>

A dissolution test was conducted to evaluate the dissolution pattern of the tablets prepared in Example 1 and Comparative Example 1-1, and more specific dissolution test conditions and HPLC analysis conditions are as follows.

Dissolution test conditions

- Test method: Method 2 (paddle method) of the general test methods of the Korean Pharmacopoeia

- Eluent: pH6.8

- Elution amount: 900mL

- Elution temperature: 37±0.5℃

- Rotation speed: 50rpm

HPLC analysis condition

- Column: Zorbax SB-C18, 5 μm, 4.6 mm x 150 mm or equivalent column

- Mobile phase: potassium dihydrogen phosphate aqueous solution: 90% methanol solution = 350 : 650 (v/v)

- Injection amount: 10 μl

- Flow rate: 1.5mL/min

- Detector: UV absorbance photometer (281nm)

- Column temperature: 35 ℃

Dissolution test result

The dissolution test results of Comparative Example 1-1 are shown in Table 10 below.

Dissolution rate (%) pH6.8 Comparative Example 1-1 Elution time (h) Valsartan Sacubitril 0.25 8.2 4.6 0.5 14.5 8.9 One 23.9 14.5 1.5 32.2 20.3 2 39.0 25.3 3 50.4 33.9 5 67.2 47.4 6 74.2 53.4 8 84.4 63.4 10 91.4 71.5 12 96.0 78.4

In the sustained-release tablet of Comparative Example 1-1, the dissolution of the active ingredient lasted for 12 hours, but the dissolution within 2 hours was less than 40%, confirming that the drug effect expression time was delayed. In addition, it was confirmed that the dissolution rates of valsartan and sacubitril were 14.5% and 8.9% after 30 minutes, 39.0% and 25.3% after 2 hours, and 96.0% and 78.4% after 12 hours, respectively.

On the other hand, when ethyl cellulose, glyceryl dibehenate, glyceryl distearate, stearyl alcohol, myristyl alcohol, and cetostearyl alcohol were used as sustained-release agents as in Examples 1-1 to 1-6, respectively, It was confirmed that Sacubitril and Valsartan showed consistent dissolution profiles. Representatively, the dissolution profile for glyceryl dibehenate is shown in FIG. 2 .

< Experimental example 2. Example 1's granular characteristics and to the granularity Evaluation of dissolution rate according to

In the tablet of Example 1, apparent density, tap density, Carr's index and particle size were evaluated in order to examine the properties of the granulated material immediately before mixing after lubricant. That is, the apparent density was determined by measuring the weight using a 100mL cylinder, and the tap density was determined by measuring the volume by tapping 1250 times with a tap density meter (SVM122, ERWEKA) after filling the 100mL cylinder, Flowability was determined by obtaining the Carr's Index using the apparent density and tap density values.

division Example comparative example 1-1 1-2 1-3 1-4 1-5 1-6 1-2 1-3 Apparent density (g/mL) 0.30 0.38 0.33 0.31 0.45 0.41 0.48 0.36 Tap Density (g/mL) 0.40 0.49 0.42 0.42 0.60 0.52 0.61 0.44 Carr's Index 25.0 22.4 21.4 26.2 25.0 21.2 21.3 18.2 Particle size (D ₉₀ ) 593㎛ 930㎛ 915㎛ 992㎛ 929㎛ 972㎛ 1254㎛ 90㎛

As shown in the table above, the granules prepared according to the methods of Examples 1-1 to 1-6 showed uniform distribution in particle size (D ₉₀ ) in the range of 100 to 1000 μm, and also had an apparent density of 0.30 to 0.45 g/mL, and the tap density was 0.40 to 0.60 g/mL.

Meanwhile, the granules of Comparative Example 1-2 were prepared in the same manner as in Example 1-2, but the particle size was adjusted by changing the sieve during sizing. At this time, the apparent density was 0.48 g/mL and the tap density was 0.61 g/mL, and the particle size (D ₉₀ ) was 1254 μm, exceeding 1000 μm. The granules of Comparative Example 1-3 were prepared in the same manner as in Example 1-2, but without performing a curing process. At this time, the apparent density was 0.36 g/mL, the tap density was 0.44 g/mL, and the particle size (D ₉₀ ) was 90 μm.

The granules of Example 1-2 and Comparative Examples 1-2 and 1-3 are used as the second release portion, and the granules of the first release portion of Example 4-1 are used as the first release portion. When a two-layer tablet was prepared using the active ingredient weight ratio of the two release parts to be 1:6, and the dissolution pattern was evaluated according to Experimental Example 1, as shown in FIG. 3, the tablet using the granules of Comparative Example 1-2 In this case, the dissolution rate at 12 hours was less than 80%, and it was confirmed that the drug release delay time was excessively increased. In addition, in the case of the tablet using the granules of Comparative Example 1-3, the dissolution rate at 30 minutes was 40% or more and the dissolution rate at 2 hours was 70% or more, so proper delayed release was not achieved. It was confirmed that the tablets used had a dissolution rate of about 50% at 2 hours and a dissolution rate at 12 hours of 80% or more, achieving continuous and appropriate delayed release.

Through the above experimental results, as in the granules of Examples 1-1 to 1-6 according to the present invention, specific density and particle size, that is, apparent density of 0.30 to 0.45 g / mL, tap density of 0.40 to 0.60 g / mL, And in the case of having a particle size (D ₉₀ ) of 100 to 1000 μm, it was confirmed that valsartan and sacubitril have an effect on enabling sustained release and appropriate delayed release of these active ingredients while showing consistent dissolution profiles.

< Experimental example 3. Example 2 and of the reference preparation Dissolution test>

Commercially available Entresto Tab. 100mg (Sacubitril 48.6mg/Valsartan 51.4mg, Sacubitril/Valsartan 100mg) (Lot No. TU149, expiration date: 2021.08.20) was used as a control formulation, and the control formulation and The dissolution test of the sacubitril valsartan component was conducted in comparison with the tablet of Example 2 prepared to have the same active ingredient content, and the specific test method was as follows, and the HPLC analysis conditions were as in Experimental Example 1.

Dissolution test conditions

- Test method: Method 2 (paddle method) of the general test methods of the Korean Pharmacopoeia

- Eluent: water, pH4.0, pH6.8, pH1.2

- Elution amount: 900mL

- Elution temperature: 37±0.5℃

- Rotation speed: 50rpm

Dissolution test result

The dissolution test results are shown in Figure 4. It was confirmed that Example 2-3 and Entresto tablet 100mg, a control preparation, showed dissolution profiles consistent with those of Valsartan and Sacubitril, and that more than 90% of the active ingredient was released within 30 minutes in water, pH4.0, and pH6.8. . In addition, in the case of the tablets of Examples 2-1 and 2-2, as in Example 2-3, valsartan and sacubitril showed a dissolution profile consistent with active ingredients within 30 minutes in water, pH4.0, pH6.8. It has been found to release more than 90%.

< Experimental example 4. Example 3 and comparative example Dissolution test of the tablet of 2>

In order to evaluate the dissolution pattern for the tablet prepared in Example 3-3, a dissolution test was conducted under the same conditions as in Experimental Example 1, and the HPLC analysis conditions were the same as in Experimental Example 1.

Dissolution test result

The dissolution test results of Example 3 and Comparative Example 2 are shown in FIGS. 5 and 6. In the tablet of Example 3-3, it was confirmed that the active ingredient was continuously released for 12 hours after reaching about 30% or less at 30 minutes of the dissolution test, and that sacubitril and valsartan were released in a very similar form. In addition, as shown in FIG. 6, compared to the tablets of Comparative Examples 2-1 and 2-2, the tablets of Examples 3-1 and 3-4 were less than about 40% by weight of valsartan after 30 minutes and 40-70% after 2 hours. And 80% or more was released after 12 hours, so it was confirmed that it had fast-acting and long-lasting effects.

< Experimental example 5. Example Dissolution test of multiple release combination preparations of 4 and 5>

In order to evaluate the dissolution pattern of the two-layer tablet prepared in Example 4-1 and the capsules prepared in Examples 5-2 and 5-3, a dissolution test was conducted under the same conditions as in Experimental Example 1, and HPLC analysis conditions is the same as Experimental Example 1.

Dissolution test result

As shown in FIG. 7, the double-layer tablet of Example 4-1, the capsule formulation (granule) of Example 5-2, and the capsule formulation (mini tablet) of Example 5-3 were about 40% by weight of valsartan after 30 minutes. %, 40 to 70% after 2 hours and 80% or more after 12 hours were released, so it was confirmed to have fast-acting and long-lasting effects.

< Experimental example 6. pharmacokinetic evaluation>

1) Test method

In order to evaluate the pharmacokinetics of the multi-release combined preparation according to the present invention in an animal test model, Entresto tablets were administered twice a day (at 12-hour intervals), 1 tablet each, and the tablet of Example 4-1 was administered once a day. After oral administration to each of three cynomolgus monkeys, blood was collected (about 1.5 mL) from the femoral vein, and the blood collection time was performed at the following intervals.

- Entresto Tab. 100mg: Before administration (0 hour), 0.5, 1, 1.5, 2, 4, 8, 12 hours after administration (2nd administration) 12.5, 13, 13.5, 14, 16, 20, 24 hours.

- Example 4-1: Before administration (0 hour), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24 hours after administration

The collected blood was centrifuged to separate plasma and stored frozen until analysis. After a sufficient withdrawal period of 14 days, a 2x2 crossover design was tested, and the drug concentration in plasma was analyzed by LC-MS/MS.

<LC-MS/MS analysis conditions>

- Column: Imtakt UNISON C18 (2.0×50mm, 3㎛)

- Mobile phase: 10mM Ammonium formate (0.1% formic acid) : Methanol = 30 : 70 (v/v)

- Injection amount: 2 μl

- Flow rate: 0.25 μl/min

- Equipment: LC/MS (Agilent 1200 series)

- Detector: 4000 Qtrap MRM mode (positive)

2) Pharmacokinetic parameter measurement results

Blood concentration of 100mg of commercially available Entresto tablets (100mg as Sacubitril/Valsartan) taken twice at 12-hour intervals for monkeys and 200mg of tablets of Example 4-1 according to the present invention (Sacubitril/Valsartan 100mg) 200 mg as valsartan) was taken once, the blood concentrations of sacubitril, sacubitril and valsartan were compared, and the results of the comparative experiment are shown in the table below.

Pharmacokinetic parameters
(Sacubitril) Mean±SD control group
(Entresto Tab: 100mg*2ea) experimental group
(Example 4-1: 200mg*1ea) C _max (ng/mL) 4182.33±3072.61 2877.45±1738.91 AUC _{0 -24} (hr·ng/mL) 12956.84±8252.43 9851.05±3794.31 Pharmacokinetic parameters
(Valsartan) Mean±SD control group
(Entresto Tab: 100mg*2ea) experimental group
(Example 4-1: 200mg*1ea) C _max (ng/mL) 3154.87±1565.83 2305.84±1150.41 AUC _{0 -24} (hr·ng/mL) 23044.59±10508.02 23545.47±9527.38 Pharmacokinetic parameters
(Sacubitrillat) Mean±SD control group
(Entresto Tab: 100mg*2ea) experimental group
(Example 4-1: 200mg*1ea) C _max (ng/mL) 17291.31±6851.97 15544.88±4766.31 AUC _{0 -24} (hr·ng/mL) 72187.27±12735.01 70632.23±14278.40

Calculating the AUC _{0 -24} ratio (T/R ratio) of the experimental group to the control group, the inactive sacubitril showed a slightly lower value at 76.03%, but the active forms sacubitril and valsartan showed 97.85% and 102.17, respectively. It is judged to be similar to Entresto tablet in terms of therapeutic effectiveness. In addition, looking at the T/R ratio of C _max , Sacubitril 68.80%, Sacubitrillat 89.90%, and Valsartan 73.09%, showing lower values than Entresto tablets, which was expected to be advantageous in terms of side effects. It was confirmed that the effect of reducing the clinical symptoms related to side effects was confirmed.

< Experimental example 7. Effect confirmation test>

1) Experimental animal model

A heart failure model was constructed by performing the transverse aortic constriction (TAC) method in 7-week-old male Sprague Dawley ^® ™ SD ^® ™ rats (200 g). That is, after anesthetizing the animal, hair removal is performed on the left 2-3 intercostal area of the animal, and disinfection is performed using povidone and 70% alcohol. After securing the airway using an endotracheal tube, it is connected to a ventilator. After performing a thoracotomy, check the aortic arch between the innominate artery and the left common carotid artery, and then ligate it using a 4-0 suture with a 22 gauge needle applied. After ligation, the 22 gauge needle is removed and the chest cavity and skin are sutured. After the TAC was maintained for a period of 2 weeks, the experiment was conducted by dividing into each test group (n = 5). The test group was a normal control group (Nomal), a negative control group (TAC), a positive control group (Example 2-3; SV bid, twice a day administration group), an experimental group (Example 5-2; SV qd, once a day) Administration group) It was divided into 4 groups, and only the normal control group was not subjected to TAC. All rats were allowed free access to a standard diet and water. The room temperature was 23 ± 3 ° C, the humidity was 55 ± 1.5%, the number of ventilation was 10-20 times / hr, and the lighting time was 12 hours (8:00 am on - 8:00 pm off) ) and the illuminance was set to 150 to 300 Lux.

Based on the active ingredient, the positive control group is administered twice a day to a dose of 25mg/kg/day, and the experimental group is administered once a day to a dose of 50mg/kg/day. administered twice. It was administered repeatedly for a total of 2 weeks according to the experimental schedule as shown in FIG. 8, and after the test was completed, the rats were anesthetized and euthanized for evaluation.

2) heart failure Therapeutic effect - biomarkers measurement

In order to evaluate the therapeutic effect on heart failure, preferably to evaluate the effect on ejection-sparing heart failure (HFpEF), the test substance was administered to the test animals for 2 weeks, followed by RT-PCR, Western blot, and ELISA. , Immunohistochemistry was used to measure changes in biomarkers according to known methods. In particular, natriuretic peptides (BNP, NT-proBNP), troponin (Troponin I, Troponin T), galectin-3, sST2 (Soluble suppression of tumorigenicity 2), Changes in biomarkers known to be related to cardiac function and structural changes, such as cardiac fibrosis, cardiac remodeling, and myocardial hypertrophy, including growth differentiation factor 15 (GDF-15) and circulating microRNAs, were measured.

As a result of biomarker measurement for the BNP, NT-proBNP, Troponine, Galectin-3, etc., it was confirmed that the experimental group according to the present invention had equal or better treatment effects for heart failure than the positive control group. Representative BNP results are shown in FIG. 9 .

3) Heart failure treatment effect - Echocardiography results

Echocardiography was performed 2 weeks after TAC was administered and test drug administration was terminated (2 weeks), and left ventricular internal dimension diastole (LVIDD) and left ventricular interanl dimension in systole (LVIDS) were evaluated. and the fractional shortening (FS), end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) were obtained.

army LVIDd (mm) LVIDs (mm) FS ( % ) EDV ( μl ) ESV ( μl ) EF ( % ) normal
control group
(Normal) MEAN 2.97 1.49 49.57 34.35 6.01 82.09 SD 0.22 0.11 4.90 5.88 1.09 3.93 voice
control group
(TAC) MEAN 2.79 1.78 35.92 30.05 9.63 67.26 SD 0.41 0.21 3.61 10.38 2.68 4.47 experimental group
(S/V qd ) MEAN 2.75 1.59 42.18 26.09 7.10 72.74 SD 0.19 0.11 0.58 4.76 1.20 0.50 positivity
control group
(S/V bid) MEAN 2.79 1.67 40.28 29.51 8.06 70.15 SD 0.18 0.13 2.22 4.70 1.65 1.02

As shown in Table 13 and FIG. 10, when looking at the heart failure treatment effect through echocardiography, it was confirmed that the ejection fraction (EF) result of the experimental group (once a day) was significantly improved compared to the negative control group and the positive control group It became.

4) Effect of reducing side effects

After 2 weeks of TAC, blood pressure was measured in rats before test drug administration (week 0) and after drug administration was terminated (week 2), and average blood pressure was confirmed. It was confirmed that the side effects caused by hypotension can be lowered.

In addition, to confirm the effect of reducing side effects such as renal damage or hyperkalemia, serum creatinine (SCr), Cystatin C, blood urea nitrogen (BUN), and potassium were measured 1 day and 2 weeks after drug administration. , and glucose contained in urine, lactate dehydrogenase (LDH), aspartate aminotransferase (AST), glomerular filtration rate (eGFR), and total protein were measured according to conventional methods.

As a result, in the experimental group according to the present invention, compared to the negative control group or the positive control group, it was found that the increase in the amount of potassium and the level of kidney toxicity diagnostic markers such as serum crenitine and C-cystatin was low. Therefore, it was confirmed that there is an effect capable of reducing side effects such as hyperkalemia, renal impairment such as renal inflammation or renal failure.

Claims (18)

delete delete delete delete A first release part containing sacubitril and valsartan, or pharmaceutically acceptable salts thereof, as active ingredients; and
A second release comprising sacubitril and valsartan, or a pharmaceutically acceptable salt thereof, as active ingredients, and a sustained-release agent selected from the group consisting of a combination of glyceryldibehenate and ethylcellulose or ethylcellulose alone as a sustained-release agent. wealth;
Containing, a multi-release combination preparation for the treatment of heart failure. According to claim 5,
A multi-release combination preparation for the treatment of heart failure, characterized in that the weight ratio of the active ingredient of the first release part and the second release part is 1:3 to 1:9. According to claim 5,
A first release part containing an active ingredient, an excipient, a disintegrant, and a lubricant; and
A second release part containing at least one of an active ingredient, a sustained-release agent selected from the group consisting of a combination of glyceryl dibehenate and ethyl cellulose or ethyl cellulose as a sustained-release agent, an excipient, and a lubricant;
Multiple-release combination preparation for the treatment of heart failure, characterized in that it comprises a. According to claim 7,
In the first and second release parts, the excipient is at least one selected from the group consisting of lactose hydrate, corn starch, anhydrous calcium hydrogen phosphate, and microcrystalline cellulose, and the lubricant is magnesium stearate, talc, and stearic acid , Sodium stearyl fumarate, and at least one member selected from the group consisting of colloidal silicon dioxide,
In the first release part, the disintegrant is characterized in that at least one selected from the group consisting of croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, and crospovidone Multi-release combination formulation for the treatment of heart failure. According to claim 7,
The first release part contains 10 to 70% by weight of an active ingredient, 5 to 70% by weight of an excipient, 15 to 35% by weight of a disintegrant, and 0.5 to 3.5% by weight of a lubricant, based on the total weight of the first release part.
The second release part contains 40 to 70% by weight of an active ingredient, 15 to 50% by weight of a sustained-release base, and 1 to 25% by weight of one or more excipients and lubricants based on the total weight of the second release part. A multi-release combination preparation for the treatment of heart failure. According to claim 5,
The multiple-release combination preparation for the treatment of heart failure, characterized in that administered in a once-a-day regimen. According to claim 10,
The multiple-release combination preparation for the treatment of heart failure, characterized in that the multiple-release combination preparation is administered in a once-a-day regimen and satisfies the following pharmacokinetic parameters:
(i) the relative proportions of AUC _{0 -24} are 75-130% for sacubitril, 75-130% for sacubitril, and 75-130% for valsartan, compared to an immediate release formulation administered in a twice daily regimen; ,
(ii) Compared to an immediate release formulation administered in a twice-daily regimen, the relative proportions of Cmax are 50-90% for Sacubitril, 50-90% for Sacubitrilat, and 50-90% for Valsartan. According to claim 5,
The second release part is granules having an apparent density of 0.30 to 0.45 g/mL, a tap density of 0.40 to 0.60 g/mL, and a particle size (D ₉₀ ) of 100 to 1000 μm, or the granules formulated into tablets or capsules. A multi-release combination preparation for the treatment of heart failure, characterized in that. According to claim 5,
The multi-release combination preparation for the treatment of heart failure, characterized in that in the form of a double-layer tablet, multi-layer tablet, or core tablet, or in the form of a hard capsule filled with granules, pellets, or mini-tablets. According to claim 5,
According to the dissolution test method 2 (paddle method) of the Korean Pharmacopoeia, the multiple-release complexes, when dissolution test was carried out under the conditions of 37 ± 0.5 ℃, pH 6.8, each active ingredient 40% after 30 minutes based on the weight of the active ingredient A multi-release combination preparation for the treatment of heart failure, characterized by dissolution of 40 to 70% after less than 2 hours and 80% or more after 12 hours. (a) preparing a first release portion containing sacubitril and valsartan as active ingredients;
(b) preparing a second release part comprising sacubitril and valsartan as active ingredients, and at least one of nonionic hydrophobic polymer and lipid as a sustained release agent; and
(c) compressing the first release portion and the second release portion together into a double-layer tablet or a core tablet, or preparing a granule, pellet, or mini-tablet, and then filling the hard capsule into a multi-release combination preparation for the treatment of heart failure manufacturing method. According to claim 15,
Step (a) of preparing the first discharge unit,
(a-1) adding a solvent containing water, alcohol, or an aqueous alcohol solution to a mixture containing an active ingredient, an excipient, and a disintegrant to prepare a union;
(a-2) drying and sizing the kneaded material to prepare granules;
(a-3) mixing an excipient and a disintegrant with the granules; and
(a-4) adding a lubricant; method for producing a multi-release combination preparation for the treatment of heart failure, comprising the. According to claim 15,
In the step (b) of preparing the second release part,
(b1-1) preparing a binding solution by dispersing the sustained-release agent in a solvent containing alcohol or an aqueous alcohol solution;
(b1-2) mixing an active ingredient, a sustained-release agent, and an excipient, and then adding a binding solution and combining them to prepare a compound;
(b1-3) preparing granules by drying, curing and sizing the kneaded material or drying, sizing and curing the kneaded material; and
(b1-4) adding a lubricant to the granules; method for producing a multi-release combination preparation for the treatment of heart failure, characterized in that it comprises. According to claim 15,
In the step (b) of preparing the second release part,
(b2-1) hot-melting and extruding after mixing the active ingredient and the sustained-release agent;
(b2-2) sizing the extrudate to prepare granules; and
(b2-3) adding a lubricant to the granules; method for producing a multi-release combination preparation for the treatment of heart failure, characterized in that it comprises.

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