RU2773029C2 - Galenic compositions of organic compounds - Google Patents

Abstract

''FIELD: pharmaceutics.

SUBSTANCE: group of inventions relates to a solid standard oral dosage form, including sacubitril and valsartan, suitable for use in sick children or other patients who need for the administration of low and individual doses or who have swallowing problems. The proposed minitablet contains a core and outer coating, where the core includes as an active ingredient therapeutically effective amount of sacubitril and valsartan in a molar ratio of 1:1; wherein the specified effective amount of the active ingredient is 3.534 mg of trisodium [3-((1S,3R)-1-biphenyl-4-ilmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-methyl-2'-(pentanoyl{2''-(tetrazole-5-ylate)biphenyl-4'-ilmethyl}amino)butyrate] hemipentahydrate (LCZ696) per minitablet. The core includes the active ingredient in a concentration from 30 to 70 wt.% of the core weight before coating and pharmaceutically acceptable excipients, in % by the core weight before coating: from 35 to 45% of microcrystalline cellulose, from 3.5 to 5.5% of hydroxypropyl cellulose, from 1.5 to 3.5% of magnesium stearate, from 1.0 to 2.0% by weight of colloidal silicon dioxide, from 0.5 to 1.0% of talc. Outer coating is presented in the form of controlled release coating and/or protective film coating, where coating contains, in % by weight: from 55 to 60% of main butylated copolymer based on methacrylate, from 25 to 30% of talc, from 7.5 to 9% of stearic acid or Mg stearate, from 4 to 8% of sodium lauryl sulfate. In this case, the specified butylated copolymer is 1:2:1 copolymer formed from butyl methacrylate, (2-dimethylaminoethyl)methacrylate and methyl methacrylate. The minitablet has a size from 1 to 3 mm. An oral capsule containing a certain number of minitablets is also proposed. The minitablet is characterized by the size, acceptability and taste properties desirable for use in the pediatric group of patients, while maintaining bioavailability comparable to the currently available medicinal product, and it is intended, in particular, for the treatment of heart failure in such patients.

EFFECT: use of a minitablet ensures the flexibility of dosing.

9 cl, 3 tbl, 5 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to a solid oral dosage unit form comprising sacubitril and valsartan in a 1:1 molar ratio, preferably in the form of the so-called neprilysin angiotensin receptor inhibitor (ARNI) LCZ696, which is a complex salt of the hydrate of sacubitril ions, valsartan and sodium, suitable for use in pediatrics or for the treatment of other patients where individual and low doses are required, or when there are problems with swallowing, for example, as a result of illness or due to age, to obtain said solid dosage form and to those embodiments of the present invention that relate to the use of said dosage form.

BACKGROUND OF THE INVENTION

LCZ696: Sacubitrile prodrug as NEP inhibitor (AHU377, (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, also known as ethyl ester N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenmylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ester, IUPAC name 4-{[(1S,3R)- 1-([1,1-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoic acid), in combination with valsartan, a known angiotensin receptor blocker (ARB), forms a sodium salt hydrate complex known as LCZ696, comprising the anionic forms of sacubitrile and valsartan, sodium cations and water molecules in a molar ratio of 1:1:3:2.5, respectively (6:6:18:15 ratio in the asymmetric standard cell of the solid crystal form ), which is schematically described by the following formula:

(formula on page 1)

This complex is also known by the following chemical names: trisodium hemipentahydrate-[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-methyl-2 '-(pentanoyl{2''-(tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate] or octadecanoylhexakis(4-{[(1S,3R)-1-([1,1' -biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-hexakis(N-pentanoyl-N-{[2'-(1H-tetrazol-1-ide -5-yl)[1,1'-biphenyl]-4-yl]methyl}-L-valinate)-water (1/15) (IUPAC nomenclature).

Administration of LCZ696 results in systemic exposure to the prodrug sacubitril, the inhibitor of neprilysin (neutral endopeptidase 24.11, NEP) (NEPi), where said prodrug is converted to the active form LBQ657 (2R,4S)-5-biphenyl-4-yl-4-(3-carboxypropionylamino )-2-methylpentanoic acid) and valsartan, in a 1:1 molar ratio, which have an inhibitory effect on the angiotensin II receptor, type 1 (AT1).

Combinations of sacubitrile and valsartan, in particular LCZ696 and compositions based on it, were previously described in WO 2003/059345, WO 2007/056546 and WO 2009/061713, where these patents are incorporated into the present description by reference.

Mode of action: Inhibition of neprilysin leads to the formation of elevated levels of physiologically active natriuretic peptides (NP), including atrial natriuretic peptide (ANP). NPs exert their cardiovascular effects through activation of the natriuretic peptide receptor A (NPR-A) and the second messenger cyclic GMP (cGMP), which results in potent vasodilation, natriuresis, diuresis, and inhibition of the renin-angiotensin-aldosterone system (RAAS) by reducing release renin and aldosterone, reducing sympathetic tone and antiproliferative and antihypertrophic effects on vascular endothelium and smooth muscle cells. The angiotensin receptor blocker (ARB) component antagonizes the AT1 receptor, which prevents the harmful effects of angiotensin II and therefore reduces peripheral vascular resistance. Due to its dual and potentially complementary beneficial effects, LCZ696 may provide clinical benefit to patients with CVD and kidney disease.

Various applications of combinations of sacubitril and valsartan, and in particular LCZ696, for the treatment of patients with various cardiovascular and/or kidney diseases are described, for example, in WO 2003/059345, WO 2007/056546, WO 2012/027237, WO 2014 /029848, WO 2015/030711 and WO 2015/028941.

In particular, inhibition of neprilysin (NEP) by chronic oral administration of LCZ696 may enhance the body's endogenous ability to compensate for complications arising from heart failure (HF) by potentiating the activity of natriuretic peptides secreted by the heart in response to cardiac stress and increased intravascular volume. LCZ696, unlike other agents used to treat HF heart failure, provides concomitant inhibition of NEP and angiotensin receptor type 1 (AT1). The resulting increase in natriuretic peptide (NP) activity, determined by NEP inhibition and blockade of the AT1 receptor through inhibition of the renin-angiotensin-aldosterone system (RAAS), has complementary effects on the cardiovascular system (CV) that is beneficial for patients with cardiac insufficiency.

In the PARADIGM-HF trial (CLCZ696B2314; N=8442), a phase 3 pivotal clinical study in adult patients with heart failure (HF) with reduced ejection fraction (HFrEF), LCZ696 was more effective than enalapril (the standard drug used in therapy). ), in terms of delaying the first manifestation of a combined endpoint such as CV death or hospitalization for heart failure (HF), with a 20% relative risk reduction (RRR) rate (p=0.0000002). In addition, LCZ696 was more effective than enalapril in delaying time to death from cardiovascular events (CV) (at 20% RRR p=0.00004) and delaying time to first hospitalization for heart failure (HF), at 21% RRR (p=0.00004). The PARADIGM-HF trial also showed that LCZ696 was generally safe and well tolerated when administered to adult patients with cardiovascular insufficiency (HF) (McMurray et al, 2014).

LCZ696 is currently being considered for use in children as an alternative to currently available treatments for cardiovascular diseases such as heart failure (HF).

Congenital heart disease and cardiomyopathy are the two most common causes of heart failure in children. A 10.4% incidence of heart failure (HF) has been reported in patients younger than 16 years of age with congenital or acquired heart disease, and a heart failure rate of 2 to 7.7/100,000 people (HF) in the general pediatric population. The highest incidence of heart failure (HF) occurs in infants and children aged 0 to 4 years. The second peak in the manifestation of heart failure (HF) in the child population, associated mainly with cardiomyopathy and causes determined by the presence of non-recoverable or palliatively treatable congenital heart diseases, appears between 10 and 18 years of age. Each year in the US, between 12,000 and 35,000 children under the age of 19 are diagnosed with pediatric heart failure (HF). The highest proportion of cases of heart failure in children is determined by the presence of congenital disorders. Congenital heart disease occurs in about 8 cases per 1000 live births, with 1-2 per 1000 developing heart failure (HF). A wide variety of congenital anomalies may be present. Most of these children are diagnosed before 1 year of age, and many have surgery, usually before 2 years of age.

Another important cause of heart failure (HF) in children is cardiomyopathy. At any given point in time, cardiomyopathy affects at least 100,000 children worldwide. Recent studies have shown that the annual incidence of cardiomyopathy in the United States, Australia, the United Kingdom and Ireland is similar at about 1 in 100,000 children aged 18 years or younger. The highest frequency of occurrence is observed in children under the age of 1 year. The most common type is dilated cardiomyopathy Dilated cardiomyopathy (which is usually diagnosed as idiopathic cardiomyopathy, familial cardiomyopathy, or myocarditis). In the United States, the annual incidence of dilated cardiomyopathy in children under 18 years of age is approximately 0.57 cases per 100,000 person-years. Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy due to familial isolated cardiomyopathy, congenital metabolic disorder, or malformation syndrome is the next most common type. Cardiomyopathy may also be associated with muscular dystrophy such as Duchenne and myotonic dystrophy. Other types of cardiomyopathy, including restrictive and arrhythmic cardiomyopathy, are less common. In 41-63% of cases of cardiomyopathy, the diagnosis is made in the first year of life, usually in association with symptoms of heart failure (HF). Morbidity and mortality rates due to these diseases are very high, and these diseases are the most common cause of heart transplants in children older than 1 year. Approximately 40% of children with symptomatic cardiomyopathy either undergo heart transplant surgery or die within the first 2 years of life.

It should be noted that no trials of other drugs conducted to date have found a beneficial effect of pharmacotherapy in children with heart failure (HF). To study the efficacy and safety of using LCZ696 in the treatment of children, it is necessary to have appropriate compositions suitable for research in children and further for the treatment of children. Such compositions, suitable for pediatric patients, may also be applicable to other patients who have problems with swallowing, either as a result of a disease, or due to age, or for psychological reasons,

Liquid dosage forms would be acceptable for such individualized delivery to patients due to ease of swallowing, however, the chemical and physical stability and thus the storage and transport of LCZ696, as noted above, in particular the stability of the complex, and in particular the prodrug form of sacubitril, may be impaired in liquids, may also create certain limitations on excipient tolerance, and, in addition, palatability may make it difficult to accept and deliver drugs in dissolved or dispersed form in liquid compositions.

On the other hand, conventional solid oral dosage forms such as tablets and capsules for adult patients and/or for patients administered a standard adult dosage can reduce the problem of difficulty swallowing and provide some flexibility in dosing.

Solid dosage forms comprising small particles such as powders, granules, agglomerates or spherules (e.g. obtained from a fluidized bed or other manufacturing processes), small capsules or uncoated tablets could, in principle, meet the requirements for dosing flexibility, however , most of these options use flavor improvers and may be difficult to use when administered with food, making the administration of such agents more enjoyable and palatable to children and other patients.

LCZ696, currently marketed under the trade name ENTRESTO™, is available in oral dosage form as 200 mg, 100 mg and 50 mg fast release film-coated tablets. This formulation does not meet the requirements for formulations for pediatric use in terms of potency, dosing flexibility, patient acceptability (eg, swallowability) and size.

In addition, the physicochemical properties, in particular the stability of the sucubitrile prodrug, and to a lesser extent the taste properties of the prodrug substance, hinder the development of an oral liquid formulation that meets the standard formulation requirements for pediatric use.

One dosage form sometimes considered for pediatric use includes mini-tablet formulations to which a small amount of soft food (or no such additive) may be added, such as pudding or apple juice. However, due to the small size of these tablets, in the region of a few mg, the production of tablets, while maintaining the uniformity of the composition for each individual mini-tablet, as described in WO 2010/086312, can be very difficult. In addition, not all pharmacopoeial methods established for pharmaceuticals are applicable to minitablets. In this regard, mini-tablets are not described in any pharmacopoeial manual.

In addition, due to the chemical nature of LCZ696, presented as a complex salt, premature release and dissolution of the drug should be prevented when mixed with food, so that the rapid release profile when taken orally is maintained.

In particular, the release profile of the pediatric formulation, at the appropriate total dosage, should also show bioequivalence with respect to the 50 mg, 100 mg and 200 mg film-coated tablets already available on the market for LCZ696.

In this regard, there is still an unresolved problem associated with the need to develop and obtain a composition of LCZ696, which could solve the difficulties found in commercially available coated tablets intended for pediatric use, where the specified composition will be characterized by size, dosing flexibility , acceptability and palatability desirable for use in the pediatric patient population and the other patients mentioned above, while maintaining a bioavailability comparable to currently available drug product.

BRIEF DESCRIPTIONS OF THE INVENTION

Despite the technical difficulties and limitations inherent in the composition of LCZ696, an approach already known in the art can be used, in particular determined by the appropriate adaptation process, and it was developed in the present invention, in relation to the production of minitablets, which made it possible to overcome these difficulties and limitations and obtain a solid standard dosage form of sacubitril and valsartan, in a 1:1 molar ratio, for oral administration in the form of a mini-tablet containing a core and an outer coating shell, where:

the core of said tablet contains as active ingredient a therapeutically effective amount of sacubitril and valsartan, in a 1:1 molar ratio, preferably in the form of LCZ696; and at least one pharmaceutically acceptable excipient, and

- the outer shell has the form of a film coating with a controlled release and/or with a protective effect, and which optionally also performs the function of improving the taste, in particular, said film shell has the ability to controlled release in relation to the food that was added to the composition before its introduction.

In one embodiment of the present invention, the effective amount of the active ingredient is from about 2 mg to about 5 mg per mini-tablet, corresponding to a specific combined amount of valsartan (free acid) and sacubitril (free acid), in a 1:1 molar ratio.

In another embodiment of the present invention, said mini-tablet is 1 mm to 4 mm in size.

Accordingly, the present invention, in one aspect, relates to a solid oral dosage unit form, in the form of a mini-tablet, having a core and an outer shell, where:

- the core of said tablet contains as active ingredient a therapeutically effective amount of sacubitril and valsartan, in a 1:1 molar ratio, preferably in the form of LCZ696; and at least one pharmaceutically acceptable excipient,

where the effective amount of said active ingredient is from about 2 mg to about 5 mg per mini-tablet, corresponding to the specific combined amount of valsartan (free acid) and sacubitril (free acid), in a 1:1 molar ratio,

- the outer shell is presented in the form of a film coating with a controlled release or with a protective effect, and

said mini-tablet has a size of 1 mm to 4 mm.

In one embodiment of the present invention, said active ingredient is trisodium-[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3' hemipentahydrate -methyl-2'-(pentanoyl{2''-(tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate] (LCZ696) as described in more detail above in the introduction section.

In one aspect, said mini-tablets are supplied with a dispenser to facilitate dosing and administration.

In one aspect, said minitablets are supplied in a container such as a capsule. Such a capsule contains a certain number of mini-tablets of the present invention. The specified number can be selected from the following options: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20; wherein, preferably, the container, preferably in the form of a capsule, contains 4 or 10 min-tablets.

In one aspect, the present invention also relates to a method for preparing the solid oral dosage form described above.

In another aspect, the present invention relates to a solid unit dosage form of sacubitril and valsartan, in a 1:1 molar ratio, in particular as LCZ696, for oral administration, in the form of coated minitablets, used as a composition adjusted for a pediatric patient group, which meet the technical requirements, comply with the norms of administration and possess the required pharmacokinetic properties.

In another aspect, the present invention relates to a solid unit dosage form of sacubitril and valsartan, in a 1:1 molar ratio, for oral administration in the form of a mini-tablet, as described herein, for use in the treatment of pediatric patients, in particular for use in the treatment of heart failure. in patients in the pediatric population.

However, the use of the solid dosage unit form of the present invention is not limited to children, but may find use, for example, in the treatment of patients who have difficulty in swallowing as a result of the patient's disease, or because of age, or due to psychological reasons that limit the patient's ability to take orally available on the pharmaceutical market preparations LCZ696. Accordingly, in another aspect, the present invention relates to the use of the solid oral dosage form described herein in angina pectoris, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal failure, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction and stroke, in in particular in the case of patients for whom it is necessary to administer low individual doses or who have difficulty in swallowing.

Other features and advantages of the present invention will become apparent from the following detailed description of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:

In the text of the entire description and in the following claims, the following terms have the meanings described below, unless expressly stated otherwise. The following definitions may be used independently to represent more specific variations of one or more or all (of those listed in the description, below or above) generic terms, thus explaining more specific embodiments of the present invention:

The term "prophylaxis" refers to prophylactic administration to a healthy subject for the purpose of preventing the development of the above conditions. In addition, the term "prophylaxis" means prophylactic administration to all patients at a stage that precedes the condition to be treated.

The term "treatment" refers to the management of patients and the care of patients for the purpose of combating a disease, condition or disorder.

The terms "effective amount" or "therapeutically effective amount" refer to that amount of a drug or therapeutic agent that will elicit the desired biological and/or medical response in a tissue, system, or animal (including human) that a researcher or clinician is trying to achieve. In particular, the terms "effective amount" or "therapeutically effective amount" refer to that amount of the active ingredient or agent which stops or attenuates the progression of the condition being treated, or which in any other way, in whole or in part, cures the condition in question or acts palliatively on a condition such as, for example, chronic heart failure.

The term "patient" includes, without limitation, humans, dogs, cats, horses, pigs, cows, monkeys, rabbits, and mice. In this case, humans are the preferred patients.

The terms "administration" and/or its various grammatical forms should be construed as referring to the administration of a compound of the present invention, or a pharmaceutically acceptable salt or ester form thereof, or a prodrug thereof, to a subject in need of treatment. Administration of a composition of the present invention for the implementation of the methods of treatment of the present invention is by administering a therapeutically effective amount of the compounds in the composition to a subject in need of such treatment or such prophylaxis. The need for prophylactic treatment using the methods of the present invention is determined based on well-known risk factors. The effective amount of an individual compound is determined by the results of the analysis recommended by the attending physician, and it depends on a number of factors, such as the specific disease being treated, the severity of the disease and other comorbid diseases or conditions that the patient has, as well as the chosen route of administration, the presence other medicines and treatments that the patient may additionally require, as well as other factors, as determined by the physician.

The term "about" in the context of the present description refers to +/- 20%, +/- 10%, +/- 5% or +/- 2% relative to the given value.

The term "pharmaceutically acceptable" in the context of the present description refers to such compounds, materials, compositions and/or dosage forms, which, according to information currently known in the art, are suitable for contact with tissues of mammals, in particular humans, and do not cause when this excessive toxicity, irritation, allergic reaction and other problems complicating the benefit/risk ratio.

The term "release" as used herein refers to the method by which a pharmaceutical oral dosage form is contacted with a liquid and the liquid releases the drug (one or more) from the dosage form into the liquid that surrounds the dosage form. The combination of delivery rate and duration of delivery exhibited by a given dosage form in a patient's body can be described as its in vivo release profile. Dosage form release profiles may exhibit different release rates and durations and may be continuous. Continuous release profiles include those release profiles in which one or more active ingredients are released continuously, either at a constant or varying rate.

In the context of the present description, an immediate release composition is one that demonstrates the release of active substances, one or more, and such release is not specifically created or modified by the development of the composition itself or methods for its production.

In the context of the present description, the phrase "composition with controlled release" is a composition that demonstrates the release of active substances, one or more, which is specifically controlled (modified) by a specific form of the composition or a specific production method. Typically, such controlled release can be achieved by delaying the release time of the active ingredient. In a typical case, according to the present invention, controlled release refers to the release, delayed by 30-60 minutes.

The term "disintegration" in the context of the present description refers to the method by which a pharmaceutical oral dosage form, typically with the help of a liquid, is divided into individual particles and dispersed. Degradation is achieved when the solid oral dosage form is in a state where any residue of the solid oral dosage form, except for fragments of the insoluble coating or capsule shell, if any, viewed on the screen of the assay apparatus, appears as a soft mass , in which no hard core is detected on palpation, according to the USP <701> method. The liquid used to determine the degradability is water, such as tap water or deionized water. The decomposition time is determined in the framework of standard techniques known to specialists in this field, see the Harmonizing procedure described in the USP <701> and Eur.Pharm. 2.9.1 and Yap.Pharm.

The term "dissolution" or its various grammatical forms, as used herein, refers to a process in which a solid, in particular an active ingredient, is dispersed in its molecular form throughout a medium, resulting in the formation of a clear solution, in the absence of other opaque material. The rate of dissolution of an active ingredient in a pharmaceutical oral dosage form of the present invention is determined by the amount of drug substance (defined as sacubitril and/or valsartan, alone or in combination of the present invention) that is present in solution per unit time under standard conditions, at the boundary liquid/solid, at appropriate temperature and solvent composition. The dissolution rate is determined using standard procedures known to those skilled in the art, see the Harmonizing Procedure section of USP <711> and Eur.Pharm EP 2.9.3 and Yap.Pharm. According to the present invention, the evaluation of the degree of dissolution of an individual active ingredient is carried out according to the method given in USP <711>, at pH 6.8 using paddle mixing at a speed of 50 rpm (revolutions per minute). The dissolving medium is preferably a buffer, usually a phosphate buffer pH 6.8, for example 900 ml of 0.05M phosphate buffer pH 6.8 is used for this purpose. Alternatively, said individual active ingredient dissolution assay is carried out according to the method of USP <711> at pH 2.0 using the 50 rpm (rpm) paddle method. The dissolving medium is usually 900 ml of 0.01 N HCl at pH 2.0 and at 37±0.5°C, but a buffer can also be used, usually a phosphate buffer, in particular with a molarity of 0.1 M at pH 2.0 and temperature 37±0.5°C. Alternatively, the assay to determine the level of dissolution of an individual active ingredient is performed according to the method given in USP, USP <711> at pH 4.5 using paddle mixing at 50 rpm or 75 rpm as indicated. A buffer is usually used as the dissolving medium, usually a phosphate buffer (eg 900 ml or 1000 ml of phosphate buffer at pH 4.5). All tests to determine the degree of dissolution are carried out at the appropriate specified temperature, in particular at 37±0.5°C.

The term "mini-tablet" in the context of this definition refers to small tablets with a total weight of from about 2 to 30, for example, about 4 to 9 mg, for example, about 7 mg, in uncoated form, and from about 2.2 to 32 mg eg about 4.1 to 10 mg, eg about 7.1 to 7.5 mg in a coated form.

Minitablets are a specific form of the minitablets described herein. Get minitablets according to the procedure described in the present description, including their production from other, smaller forms, consisting of many particles, such as particles, granules or beads. These mini-tablets may have a variety of shapes known to those skilled in the art, for example, they may be round, in particular, with a diameter of from about 1.25 to 3 mm or others, as defined here; they may have a cylindrical shape, for example, have a convex upper part and a convex lower part, and, in particular, have a shape where the diameter and height of the cylinder, independently of each other, are from 1 to 3 mm, or another size, as defined here ; or it may be biconvex minitablets, such as minitablets in which the height and diameter are approximately equal and range from 1.25 to 3 mm, or others, as defined here.

The term "sacubitril and valsartan in a 1:1 molar ratio" of the present invention refers to a combination comprising a therapeutically effective amount in a 1:1 molar ratio

(i) valsartan or a pharmaceutically acceptable salt thereof; and

(ii) sacubitrile or a pharmaceutically acceptable salt thereof,

in the form of a combined sodium salt complex 2''-(tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate]hemipentahydrate (LCZ696), and as will be described in more detail below. The term "sacubitrile and valsartan in a 1:1 molar ratio" may also refer to alternative complexes or compounds comprising valsartan and sacubitrile, where they are joined together via a non-covalent or covalent bond, optionally with a linker.

Embodiments of the present invention

Size and Shape: The present invention, in one embodiment, relates to a mini-tablet dosage unit form as described herein, wherein said mini-tablet has a diameter of 1 mm to 3 mm, in particular 1.25 mm to 2.75 mm, and even more specifically, from 1.5 mm to 2.5 mm. Preferably, the mini-tablet is in the form of a curved circle. In one embodiment of the present invention, said mini-tablet has a diameter of 1.9 to 2.1 mm, in particular about 2 mm.

The thickness of the mini-tablet may be, for example, from 1 to 3 mm, in particular from 1.5 to 2.6 mm, for example from 1.9 to 2.3 mm, in particular from 2 to 2.2 mm.

Active Ingredient: The term "sacubitril and valsartan in a 1:1 molar ratio" of the present invention refers to a combination comprising a therapeutically effective amount in a 1:1 molar ratio

(i) valsartan or a pharmaceutically acceptable salt thereof; and

(ii) sacubitril or a pharmaceutically acceptable salt thereof.

Sacubtril is the short name (INN) for N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-2R-methylbutanoic acid ethyl ester. This compound is a prodrug of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methylpetanoic acid. Sacubitril can be prepared according to known methods, such as those described in US Patent No. 5217996, which is included in the present description by reference.

Valsartan is S-N-valeryl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}valine. Valsartan or (S)-N-valeryl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}valine) or a pharmaceutically acceptable salt thereof may be obtained from commercial sources or may be manufactured according to known methods, which are described, in particular, in US patent No. 5399578 and in European patent EP 0443983, where the preparative procedures described therein are incorporated into the present description by reference. Valsartan can be used, in some embodiments of the present invention, in the form of a free acid, as well as in the form of any acceptable salt. Depending on the conditions, esters or other derivatives based on the carboxylic acid group, as well as salts and derivatives of the tetrazole group, can be used.

In one embodiment of the present invention, said combination comprises in a 1:1 molar ratio

(i) valsartan; and

(ii) sacubitril or a pharmaceutically acceptable salt thereof such as sodium or calcium salt.

In another embodiment of the present invention, said combination is provided as a compound of formula (I)

[(A ₁ )(A ₂ )](Na ⁺ ) _y ⋅ x H ₂ O (I)

where

A ₁ is valsartan in anionic form; A ₂ is sacubitrile in anionic form; Na ⁺ denotes a sodium ion; y is from 1 to 3, preferably 1, 2 or 3; and x is between 0 and 3, preferably 0, 0.5, 1, 1.5, 2, 2.5, or 3.

In one embodiment of the present invention, y is 3 and x is 2.5.

In particular, said compound is trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-methyl-2'-(pentanoyl {2''-(tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate]hemipentahydrate (LCZ696).

In a preferred embodiment of the present invention, said compound trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-methyl-2'- (Pentanoyl{2''-(tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate]hemipentahydrate is present in crystalline form.

The corresponding active ingredient, or a pharmaceutically acceptable salt thereof, may also be used in the form of a hydrate, or may include other solvents used in crystallization.

Preferably, the compounds sacubitril or a salt thereof, valsartan or a salt thereof, or LCZ696 are substantially pure compounds or are present in substantially pure form. As used herein, the term "substantially pure" refers to an embodiment that is at least about 90% pure, more preferably at least about 95% pure, and most preferably at least about 98% pure.

Also preferred are embodiments where such compounds are solid or are in solid form or in solid state. Said solid, solid form or solid state may be crystalline, partially crystalline, amorphous or semi-amorphous, preferably in crystalline form.

Amount of Active Ingredient: One embodiment of the present invention relates to the minitablet solid dosage unit form described above, wherein said minitablet contains an effective amount of the active ingredient in an amount of from about 2 mg to about 5 mg per minitablet, in particular from about 2. 5 mg to 4.0 mg per mini-tablet, depending on the respective combined amount of valsartan (as the free acid) and sacubitril (as the free acid) in a 1:1 molar ratio. In one preferred embodiment of the present invention, each mini-tablet contains the active ingredient in an amount of 3.125 mg per mini-tablet as described above.

The present invention, in one embodiment, relates to the active ingredient in the form of LCZ696. The effective amount of LCZ696 is determined by the weight of the two active ingredients: sacubitril and valsartan, excluding the weight of sodium and bound water included in the complex; those. the effective amount of LCZ696 in minitablets ranges from about 2 mg to about 5 mg of LCZ696 per unit dosage form, in particular from about 2.5 mg to 4.0 mg per unit dosage form. In one embodiment of the present invention, each mini-tablet contains LCZ696 in an amount of 3.125 mg, as described above. Considering sodium and water of hydration, said minitablets will contain from about 3 mg to about 4 mg, preferably about 3.534 mg, trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl- 1-butylcarbamoyl)propionate-(S)-3'-methyl-2'-(pentanoyl{2''-(tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate] hemipentahydrate per tablet.

Core: The core of the minitablet of the present invention comprises at least one pharmaceutically acceptable excipient. Such excipients (or additives) include those suitable for the preparation of the solid oral dosage form of the present invention. Tabletting aids commonly used in the manufacture of tablets may be used and information on such agents is well documented in the scientific literature, see in particular Fiedler's "Lexikon der Hilfstoffe," 4th Edition, ECV Aulendorf 1996, which is incorporated herein by links. Such agents include, without limitation, fillers or diluents, binders, lubricants, glidants, stabilizers, surfactants, emollients, pigments, and the like.

The present invention, in one embodiment, relates to a solid oral dosage form comprising a therapeutically effective amount of sacubitril and valsartan in a 1:1 molar ratio, in particular in the form of LCZ696, and at least one excipient (diluent), as an additive . Other additives include, without limitation, one or more additives selected from the group consisting of binders, lubricants, glidants (anti-tack agents), stabilizers, surfactants, pigments, emollients, and others. ingredient and other additives is given below.

In another embodiment, the present invention relates to a solid oral dosage form comprising a therapeutically effective amount of sacubitril and valsartan in a 1:1 molar ratio, in particular in the form of LCZ696, and a filler (diluent) and a binder, as additives. Other optional additives include, without limitation, a lubricant, one or more, for example, two glidants, and optionally, one or more stabilizers, surfactants, pigments and emollients, etc. Preferred amounts of the active ingredient and other additives are described below.

The present invention, in another embodiment, relates to a solid oral dosage form comprising a therapeutically effective amount of sacubitril and valsartan in a 1:1 molar ratio, in particular in the form of LCZ696, and a filler (diluent), a binder, a lubricant and one or several glidants, for example two, as additives. Other optional additives include, without limitation, one or more stabilizers, surfactants, pigments and emollients, and others. Preferred amounts of the active ingredient and other additives are listed below.

One or more of the additives listed below may be selected and then used by one of ordinary skill in the art, taking into account the specific properties of the solid oral dosage form required, these procedures being performed as part of a routine selection that does not require undue effort and time.

The filler or diluent may be selected from conventional additives known, such as, for example, microcrystalline cellulose (MK GR cellulose), confectionery sugar, compressed sugar, dextrates, dextrin, dextrose, lactose, in particular lactose anhydrous, mannitol, starches, for example , potato starch, wheat starch and corn starch; powdered cellulose, sorbitol, sucrose and microcrystalline cellulose; preferably, the specified filler is microcrystalline cellulose, for example, products available under the trademarks Avicel (AVICEL), Filtrak (FILTRAK), Hyuten (HEWETEN) or Pharmacel (PHARMACEL). The most preferred filler is microcrystalline cellulose, in particular microcrystalline cellulose with a density of about 0.45 g/cm ³ eg Avicel (AVICEL). The filler, in particular microcrystalline cellulose, may be present at a concentration of from about 20 wt.% to about 60 wt.%; for example, from about 30 wt.% to about 50 wt.% of the weight of the minitablet core (before coating), preferably 40 wt.% relative to the weight of the minitablet core.

The binder may be selected from conventional additives known in the art, such as, for example, cellulose derivatives, in particular hydroxypropyl cellulose (HPC), in particular hydroxypropyl methyl cellulose, having a Brookfield viscosity in the range of 100 to 5000 cps. , for example, hydroxypropyl cellulose (HP-cellulose) with a viscosity in the range of 300 to 600 cps. The binder, in particular HP-cellulose, may be present at a concentration of from 1 to about 40 wt.%, from about 2 wt.% to about 20 wt.%, from 3 wt.% to about 10 wt.%, in particular , from about 3.5 wt.% to about 5.5 wt.%, in particular, from 4 wt.% to about 5 wt.% relative to the weight of the minitablet core (before coating). While some of these excipients may be considered as disintegrants, they are considered as binders in the context of the present invention.

As lubricants, mention may be made of stearic acid and its salts, in particular magnesium (Mg), magnesium, aluminum (Al), aluminum or calcium (Ca) stearate, calcium stearate; esters of glycerol, in particular PEG from 4000 to 8000; hydrogenated castor oil, Na-stearyl fumarate, hydrogenated cottonseed oil, etc. The most preferred lubricant is Mg stearate and/or stearic acid. The amount of lubricant present in the composition may vary in the range of values from 0.2 to 6 wt.%, in particular, for Mg sterate, from 1.0 wt.% to 5.0 wt.%, for example, from 1.5 wt. % to 3.5 wt.%, in particular from 2.0 wt.% to 3.0 wt.% relative to the weight of the mini-tablet core (before coating).

Glidants include, in particular, colloidal silica, such as colloidal silicon dioxide, for example, Aerosil (AEROSIL), magnesium trisilicate (Mg), powdered cellulose, starch, talc, and tribasic calcium phosphate, or combinations thereof. In particular, glidants may be present as combinations of said glidants with fillers or binders, such as siliconized microcrystalline cellulose (PROSOLV). The most preferred glidant is colloidal silicon dioxide (eg Aerosil 200 (AEROSIL 200)) and/or talc. AEROSIL® is a trademark of Evonik Industries AG, Darmstadt, Germany. The amount of glidants present in the composition, one or more, may vary in the range of values from 0.1 to 5 wt.%, for example, from 1.5 to 3.5 wt.%, in particular, in the case of talc, from 0.5 wt.% to 1.0 wt.%, and in the case of colloidal silicon dioxide, from 0.2 wt.% to 4.0 wt.%, in particular from 1.0 wt.% to 2.0 wt.% relative to the weight of the minitablet core (before coating).

Accordingly, in one embodiment of the present invention, the solid oral dosage form of the present invention includes, as an additive, a filler, in particular microcrystalline cellulose, and a binder, in particular hydroxypropyl cellulose (HP-cellulose).

In one embodiment of the present invention, said solid oral dosage form of the present invention comprises as an additive, in addition to a filler, a binder and a lubricant, in particular microcrystalline cellulose, hydroxypropyl cellulose and magnesium stearate.

In one embodiment of the present invention, said solid oral dosage form of the present invention comprises as an additive, in addition to a filler, a binder and a lubricant, at least one glidant, in particular microcrystalline cellulose, hydroxypropyl cellulose, magnesium stearate, colloidal silicon dioxide and/or talc.

A characteristic property of the solid oral dosage forms of the present invention is that they contain relatively low amounts of excipients for a given high amount of active ingredient. This in turn leads to the need to create physically small unit dosage forms. The total amount of additives in each uncoated unit dosage form (i.e., its cores only) may be about 70% by weight or less, based on the weight of the core, prior to coating, more specifically, about 60% by weight or less. Preferably, the content of the excipient ranges from 40 wt.% to 59 wt.%, more specifically, from about 45 wt.% to about 54 wt.% relative to the weight of the core before coating. Relative to the total weight of the considered solid oral dosage form (comprising core and coating), the total amount of additives in the core may be about 65 wt.% or less, relative to the total weight of the solid oral dosage form, more specifically, about 60 wt.% or less. Preferably, the content of additives ranges from about 40 wt.% to 55 wt.%, more specifically, the content of additives ranges from about 55 wt.% to about 50 wt.% relative to the total weight of the entire unit dosage form.

Accordingly, the active ingredient is present at a concentration of from 30 wt.% to 70 wt.%, preferably from 40 wt.% to 60 wt.%, more preferably about 50 wt.% relative to the weight of the core before coating.

The preferred amount of filler in the tablet core, in particular microcrystalline cellulose, ranges from about 35 wt.% to 45 wt.%, for example, from 39 wt.% to 41 wt.%, relative to the weight of the core, before coating, respectively.

The preferred amount of binder in the tablet core, in particular hydroxypropyl cellulose, ranges from 2 wt.% to 8 wt.%, for example, from 3.5 wt.% to 5.5 wt.%, for example, from 4 wt. .% to 5 wt.%, relative to the weight of the core before coating, respectively.

The preferred amount of lubricant in the tablet core, in particular Mg stearate, ranges from 0.2 wt.% to 6.0 wt.%, for example, from 1.0 wt.% to 5.0 wt.%, for example , from 1.5 wt.% to 3.5 wt.%, in particular, from 2.0 wt.% to 3.0 wt.%, relative to the weight of the core before coating, respectively.

The preferred amount of glidant in the tablet core, in particular colloidal silicon dioxide and/or talc, ranges from 0.1 wt.% to 5.0 wt.%, from a total content of glidant, for example, from 1.5 wt. % to 3.5 wt.%, for example, from 1.5 wt.% to 2.5 wt.%, relative to the weight of the core before coating, respectively. In particular, the amount of individual glidant present in the composition varies, for talc - from 0.5 wt.% to 1.0 wt.%, and for colloidal silicon dioxide - from 0.2 wt.% to 4.0 wt.%, for example, from 1.0 wt.% to 2.0 wt.% of the weight of the core (before coating).

In one embodiment of the present invention, the solid oral dosage of the present invention comprises, as excipients, microcrystalline cellulose in an amount of from 35 wt.% to 45 wt.%, hydroxypropyl cellulose in an amount of from 2 wt.% to 8 wt.%, for example, from 3 .5 wt.% to 5.5 wt.%, Mg stearate in an amount from 1.0 wt.% to 5.0 wt.%, for example, from 1.5 wt.% to 3.5 wt.%, colloidal silicon dioxide in an amount of from 0.2 wt.% to 4.0 wt.%, for example, from 1.0 wt.% to 2.0 wt.%, and talc in an amount of from 0.5 wt.% to 1, 0 wt.%, where wt.% means wt.% relative to the weight of the core before coating.

In one embodiment of the present invention, the solid oral dosage of the present invention comprises, as excipients, microcrystalline cellulose in an amount of from 35 wt.% to 45 wt.%, hydroxypropyl cellulose in an amount of from 2 wt.% to 8 wt.%, Mg stearate in an amount of from 1.0 wt.% to 5.0 wt.%, colloidal silicon dioxide in the amount of from 0.2 wt.% to 4.0 wt.%, and talc in the amount of from 0.5 wt.% to 1.0 wt.%, where wt.% means wt.% relative to the weight of the core before coating.

In another embodiment of the present invention, the solid oral dosage of the present invention comprises, as excipients, microcrystalline cellulose in an amount of from 35 wt.% to 45 wt.%, hydroxypropyl cellulose in an amount of from 3.5 wt.% to 5.5 wt.%, Mg stearate - in an amount of from 1.5 wt.% to 3.5 wt.%, colloidal silicon dioxide - in an amount of from 1.0 wt.% to 2.0 wt.%, and talc - in an amount of from 0.5 wt.% up to 1.0 wt.%, where wt.% denotes wt.% relative to the weight of the core before coating.

Other preferred amounts of LCZ696 and additives are shown in the illustrative examples.

The absolute amounts of each of the additives and their amounts relative to other additives depend on what properties are desired for the solid oral dosage form in question, and they can be selected by one of skill in the art without time-consuming selection procedures. Thus, for example, said solid oral dosage form may be chosen to achieve a delay in the release of the active agent, with or without quantitative control of the release of the active agent, especially in the case of pre-administration meals.

Film Coating: The cores of the minitablets of the present invention described herein are coated with a film coating that has a controlled release and/or protective function, where said coating may also serve to mask/improve the taste of the drug substance and, accordingly, to improve drug compliance. In particular, the film coating serves to control the release of the active ingredient, for example, LCZ696, in vitro and in vivo, and in particular, prevents its dissolution by food taken before administration, which is done so that the administration of the drug is more comfortable.

In another embodiment of the present invention, the dissolution behavior of minitablets is adjusted to that of commercially available monotablets by modifying release by film coating.

Accordingly, in one embodiment of the present invention, said film coating prevents premature release of the drug when mixed with food.

In one embodiment of the present invention, the specified film coating, which performs the function of maintaining a controlled release, has a pH-dependent release profile, which, in particular, allows you to mix with food known to the child (for example, having a good taste) before administration; in particular, the coating preferably only dissolves at a pH of 5 or lower, so that, for example, dissolution in the food and thus, for example, loss of masking flavors is avoided. Or, in other words, the film coating has acid-soluble properties at pH values up to 5.0.

In one embodiment, the solid dosage form of the present invention comprises a film coating with a pH dependent release profile that results in a similar or even reduced in vitro dissolution rate of the active ingredient at or below pH 5.0 compared to the in vitro dissolution rate of the active ingredient. at pH 6.5 or higher.

Accordingly, the present invention, in one embodiment, relates to a solid dosage unit form as described herein, wherein said film coating is suitable to lead or result in such a level of dissolution in vitro of the active ingredient, in particular in the form of LCZ696, such that , when measured according to the USP method, including paddle stirring at a speed of approximately 50 rpm in 900 ml of 0.05 M phosphate buffer at pH 6.8 and at a temperature of 37 ± 0.5 ° C - after 10 minutes, is released an amount corresponding to about 30 wt.% or more, for valsartan and about 25 wt.% sacubitril, after 20 minutes, an amount corresponding to about 35 wt.% or more, for valsartan and about 30 wt.% or more, sacubitril, is released, and after 30 minutes, an amount corresponding to about 40 wt.% or more is released for valsartan and about 35 wt.% or more, sacubitril, where the specified wt.% denotes wt.% sacubitry la and valsartan, separately, relative to the total weight of the effective amount of the active ingredient sacubitril and valsartan, in a 1:1 molar ratio.

In another embodiment, the present invention relates to a solid standard dosage form as described herein, wherein said film coating is suitable to lead or lead to such a level of dissolution in vitro of the active ingredient, in particular in the form of LCZ696, such that, when carried out measurements according to the USP method, including paddle stirring at a speed of approximately 50 rpm in 900 ml of 0.05 M phosphate buffer at pH 6.8 and at a temperature of 37 ± 0.5 ° C - after 10 minutes, an amount corresponding to about 35 wt.% or more, for valsartan and about 30 wt.% sacubitril, after 20 minutes, an amount corresponding to about 40 wt.% or more is released for valsartan and about 35 wt.% sacubitril, and after 30 minutes, is released an amount corresponding to about 45 wt.% or more for valsartan and about 40 wt.% sacubitril, where the specified wt.% denotes the wt.% of sacubitril and valsartan, separately, relative to about the total weight of the effective amount of the active ingredient sacubitril and valsartan, in a molar ratio of 1:1.

In another embodiment, the present invention relates to a solid dosage unit form as described herein, wherein said film coating is suitable to lead or result in a level of in vitro dissolution of valsartan such that

- at a pH of about 2 to 4.5, in particular at a pH of 4.5, after 10 minutes about 35 wt.% or more is released, after 20 minutes about 40 wt.% or more, and after 30 minutes - about 45 wt% or more of valsartan and/or

- at a pH of from about 6 to about 7, in particular at pH 6.8, after 10 minutes about 40 wt.% or less is released, after 20 minutes - about 45 wt.% or more, and after 30 minutes - about 50 wt. % or less of valsartan,

where the specified wt.% means wt.% valsartan, individually, relative to the total weight of the effective amount of the active ingredient sacubitril and valsartan, in a molar ratio of 1:1.

In one embodiment of the present invention, the assessment of the level of dissolution of an individual active ingredient is carried out at neutral pH, according to the method described in United States Pharmacopeia, USP <711>, at pH 6.8 using a paddle mixing method at a speed of 50 rpm, where in as a dissolving medium, 900 ml of 0.05 M phosphate buffer at pH 6.8 and at a temperature of 37±0.5°C are used.

In one embodiment of the present invention, the determination of the level of dissolution of an individual active ingredient is carried out at neutral pH, according to the method described in United States Pharmacopeia, USP <711>, at pH 4.5 using a paddle mixing method at a speed of 50 rpm, where in 900 ml of 0.05 M phosphate buffer at pH 6.8 and at a temperature of 37 ± 0.5°C are used as dissolving medium.

In one embodiment of the present invention, the determination of the level of dissolution of an individual active ingredient is carried out at neutral pH, according to the method described in United States Pharmacopeia, USP <711>, at pH 2.0 using a paddle mixing method at a speed of 50 rpm, where in 900 ml of 0.01 N HCl at pH 2.0 and at a temperature of 37 ± 0.5°C are used as dissolving medium.

In one embodiment of the present invention, said solid dosage unit form exhibits in vitro dissolution profile of the active ingredient such that, when measured by the USP method with paddle mixing at about 50 rpm in 900 ml of 0.05 M phosphate buffer at pH 6, 8 and a temperature of 37 ± 0.5°C, the dissolution profile achieved for a combined amount of mini-tablets equivalent to a 200 mg effective amount of active ingredient corresponds to the dissolution profile of the composition of commercially available 200 mg LCZ696 tablets. Said release profile is described in WO 2009/061713. In particular, an oral dosage form containing a 200 mg dose of the therapeutic agent (sacubitril and valsartan in a 1:1 m molar ratio) exhibits this dissolution profile in vitro when measured by the USP method with paddle mixing at about 50 rpm in 900 ml of 0.05 M phosphate buffer at pH 6.8 and at a temperature of 37 ± 0.5°C, after 10 minutes, about 50 wt.% or more of valsartan is released, after 20 minutes, about 85 wt.% or more of valsartan is released , after 30 min, about 95 wt.% or more of valsartan is released, where the weight. % means % by weight of valsartan alone relative to an effective amount of only a portion of valsartan in the active ingredient as sacubitril and valsartan in a 1:1 molar ratio. In other words, since the 200 mg dose includes 103 mg of valsartan and 97 mg of sacubitril, this corresponds to an in vitro dissolution profile such that when measured by the USP method with paddle mixing at approximately 50 rpm in 900 ml of 0.05 M phosphate buffer at pH 6.8 and a temperature of 37 ± 0.5°C, after 10 minutes, about 26 wt.% or more of valsartan is released, after 20 minutes, about 44 wt.% or more of valsartan is released, after 30 minutes, about 49 wt. wt.% or more of valsartan, where wt. % denotes the weight % of sacubitrile and valsartan, individually, relative to the total weight of an effective amount of the active ingredient in the form of sacubitrile and valsartan in a 1:1 molar ratio.

In the solid oral dosage forms of the film-coated minitablets of the present invention, said coating typically comprises a polymer such as HPMC, PVP, or the like, sugar, shellac, or other material suitable for film-coating and commonly used in the art, and most preferably, such material is polyacrylate. There are many techniques in the art for the purpose of coating, e.g. by spraying in a fluidized bed, e.g. coating pan, according to known methods using apparatus from Accela Cota, Glatt, Driam or other companies, or using other standard methods known in this field. Such methods may use additives commonly used in the manufacture of confectionery products.

In one embodiment, the present invention relates to a solid unit dosage form of the present invention, described here, where the specified film coating includes at least one polyacrylate as a film-forming agent.

In a preferred embodiment of the present invention, said film coating comprises a basic butylated methacrylate copolymer (optionally a variant as defined in EurPharm.) as a film forming agent.

In one embodiment, the present invention relates to a solid unit dosage form of the present invention, described herein, where the specified film coating comprises an ammonium methacrylate copolymer, in particular type A ammonium methacrylate copolymer (optionally, a variant defined in Eur.Pharm.) and / or a copolymer of ammonium methacrylate type B (optionally, a variant defined in Eur.Pharm.) as a film-forming agent. In one embodiment of the present invention, said polyacrylate is selected from:

a) a methacrylate-based butylated base copolymer formed from monomers selected from butyl methacrylate, (2-dimethylaminoethyl)methacrylate and methyl methacrylate, preferably a copolymer consisting of butyl methacrylate, (2-dimethylaminoethyl)methacrylate and methyl methacrylate,

b) a copolymer formed from monomers selected from methacrylic acid and lower alkyl esters of methacrylic acid; and

c) an ammoniomethacrylate copolymer formed from monomers selected from ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride.

In one specific embodiment of the present invention, the minitablets are coated using a polyacrylate, preferably EudragitR, such as EudragitR-E or Eudragit®-RD100 or -RS/RL (see Handbook of Pharmaceutical Excipients, loc. cit. hereafter, p 362), in particular Eudragit®-E PO (Eudragit® is a trademark of Evonik Industries AG Kirschenallee, Darmstadt, Germany).

Accordingly, suitable materials for coating the compositions of the present invention include polyacrylic polymers such as:

a) a copolymer formed from butyl methacrylate, (2-dimethylaminoethyl)-methacrylate and methyl methacrylate, in a ratio of 1:2:1, available under the trademark Eudragit® E, especially Eudragit® E PO (chemical name: poly(butyl methacrylate-co- (2-dimethylaminoethyl)methacrylate-co-methylmethacryate, CAS no.: 24938-16-7) 1:2:1);

b) copolymers formed from methacrylic acid and methacrylic acid alkyl esters in a 1:1 ratio, such as copolymers containing a 1:1 ratio of methacrylic acid and methyl methacrylate, available under the trademark Eudragit® L, for example, Eudragit® L100 and copolymer containing a 1:1 ratio of methacrylic acid and acrylic acid ethyl ester, available under the trademark Eudragit® L100-55;

c) a copolymer formed from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride in a ratio of 1:2:0.2, available under the trademark Eudragit® RL; or the corresponding 1:2:0.1 copolymer available under the trademark Eudragit® RS; or the corresponding copolymer formed from ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride in a ratio of 1:2:0.2, in combination with carboxymethyl cellulose and available under the trademark Eudragit® RD;

more preferably, the materials specified in point a).

The above polyacrylates preferably have an average molecular weight of from about 30,000 to about 500,000, for example about 30,000 g/mol, respectively.

Polyacrylates, in particular Eudragit® E PO, have been shown to be well suited for coating solid dosage forms including LCZ696, in part because a coating made from Eudragit® E PO does not exhibit rapid dissolution at neutral pH, in the oral cavity or in the ingested food, but dissolves mainly at pH values below 5, and, in this regard, prevents premature dissolution of LCZ696, so that the ingested complex remains intact until it enters the stomach.

The above coating materials can be used in admixture with other excipients commonly used in coating applications such as e.g. talc, magnesium stearate or stearic acid or silica e.g. synthetic amorphous silicic acid e.g. from SyloidR (Grace) , in particular SyloidR 244 FP, or colloidal silicon dioxide, such as AerosilR, such as, for example, AerosilR 200, and/or humectants, such as sodium dodecyl sulfate (sodium lauryl sulfate), such as Duponol (DuponolR), or polyethylene glycols or polysorbates .

Particularly preferred compositions of the present invention include suitably coated LCZ696 containing particles, e.g. tablets, such as mini-tablets or pellets in particular, wherein said coating comprises a (taste-masking) polyacrylate coating, preferably EudragitR E or Eudragit RD100®, in specifically, Eudragit® E PO, and where in said coating, magnesium stearate or stearic acid is used as a release agent, a basic butylated methacrylate copolymer as a film-forming agent, sodium lauryl sulfate (Duponol) as a solubilizer, and purified water - as a solvent for the coating material (which is then removed).

In one embodiment of the present invention, the solid dosage form of the present invention comprises a film coating which comprises, in addition to polyacrylate, also a basic butylated methacrylate copolymer, which is preferably a copolymer formed from butyl methacrylate, (2-dimethylaminoethyl)methacrylate and methyl methacrylate in a ratio of 1 :2:1 and also includes sodium lauryl sulfate, steric acid and talc.

In one embodiment of the present invention, said film coating comprises a basic butylated methacrylate copolymer in an amount of 50 wt% to 70 wt%, preferably 55 wt% to 60 wt%, talc in an amount of 20 wt% to 40 wt%, preferably from 25 wt% to 30 wt%, stearic acid or Mg stearate in an amount of from 5 wt% to 10 wt%, preferably from 7.5 wt% to 9 wt%, sodium lauryl sulfate - in an amount of from 1 wt% to 10 wt%, preferably from 4 wt% to 8 wt%.

In another aspect, said solid dosage forms may include an additional coating, for example, a layer of anti-adhesive material applied over the above coatings, for example, including a product based on colloidal silicon dioxide, such as, in particular, AerosilR, which prevents adhesion of solid dosage forms to each other. to a friend or to the wall materials of a container such as, for example, a capsule.

In one embodiment of the present invention, the amount of film-forming coating in solid dosage form may vary in the range of values from 0.1 wt.% to 10 wt.%, for example, from 2.0 wt.% to 8.5 wt.%, relative to the total weight of the dosage form, including core and coating. The preferred amount of film-forming coatings ranges from about 4 wt.% to about 8 wt.%, for example, about 0.2 mg to 0.4 mg per standard 7 mg mini-tablet.

In another embodiment of the present invention, the amount of film-forming coating may vary in the range of values from 0.1 to 5 mg/cm2, for example, from 0.4 mg/cm2 to 0.7 mg/cm2.

Production method: To obtain a tablet core comprising a therapeutically effective amount of sacubitril and valsartan in a 1:1 molar ratio, in particular as LCZ696, dry granulation, in particular rolling, can preferably be used. Wet granulation can change the drug substance and cause stability problems.

Dry granulation of LCZ696 using a dry mixture of drugs and excipients has been shown to be the best way to obtain suitable solid oral dosage forms of LCZ696 of the present invention, especially minitablets, as it has the following advantages:

- the influence of a possible change in the quality of the medicinal substance is minimized;

- a stable method for the production of a medicinal product is achieved;

- achieved scaling the process of obtaining the composition and the reproducibility of the method of production of the medicinal substance; and

- process stability is achieved, which affects the maintenance of an appropriate shelf life.

The excipients can be distributed partly in the internal (granular) phase and partly in the external phase of the core, and this option is characteristic of the present invention. Preferably, the filler, in particular microcrystalline cellulose, the glidant, in particular colloidal silicon dioxide and the lubricant, in particular Mg stearate, are distributed partly in the internal environment and partly in the external phase; a binder, in particular hydroxypropyl cellulose used as a binder in granulation, as well as a glidant, in particular talc, are present only in the internal phase; and only the filler, especially microcrystalline cellulose, the glidant, especially colloidal silicon dioxide, and the lubricant, especially Mg stearate, are present in the external phase.

Internal phase excipients, for example, filler, glidant(s), binder and lubricant, and drug substance are subjected to mixing and granulation using rolling. Next, the granulate is sieved. The outer phase, containing, for example, filler, glidant and lubricant, is sorted relative to the granulate and mixed. Next, the mixture is compressed into tablets. The cores are preferably coated with a film-forming coating.

The granulate phase is considered as the internal phase, the excipients added to the granulate are considered as the external phase in the tabletting mix.

The present invention also relates to a method for obtaining solid oral dosage forms described herein above and below. Such a solid oral dosage form can be prepared by adding the components described above in appropriate amounts to form unit dosage forms of the present invention, in particular minitablets.

Accordingly, the present invention relates to a process for preparing a solid oral dosage form of the present invention, comprising:

a) mixing the active ingredient and additives in the internal phase and dry granulation (in particular rolling) of these components; optionally, using sorting steps built into the process;

b) mixing the granulate with external phase excipients;

c) compressing the resulting mixture into a solid oral dosage core (particularly a mini-tablet core), preferably using a multi-tipped instrument; and

d) coating the resulting tablet core to form a film-coated tablet, in particular a mini-tablet.

Preferably, the additives for step (a) are selected from a filler, at least one glidant, a lubricant, and a binder; and excipients for the outer phase used in step (b) are selected from filler, lubricant and glidant.

The production of granulate can be carried out on standard equipment suitable for performing granulation processes. The production of the finished mixture and its pressing into tablets can be performed on standard equipment.

Thus, for example, in step (a), mixing can be done with a diffusion mixer (drum) or a bin mixer, for example using a Bohle container blender or Turbula T10B, the first sorting can be done with a sieve mill, for example using round wire 0.8 mm/rocking grate, such as for example from Frewitt, granulation can be achieved using a roller press, such as for example Bepex 200/50, to obtain granular material, followed by another sorting step, for example , as described above, but replacing the 0.8 mm round wire with a 1.0 mm round wire. Step (b) can then be carried out by mixing the filler and glidant with a diffusion mixer (drum) or a bin mixer, for example using a Turbula T10B or a Bohle container blender, followed by sorting, for example manually, using a 0 pore size sieve. .8 mm, with the addition (after sorting, for example, through a hand sieve with a pore size of 0.8 mm) of more lubricant and subsequent mixing with a diffusion mixer (drum) or bin mixer, for example, using a Turbula T10B or a Bohle container blender. Further, step (c) can be performed using a compression method, for example a tablet press such as Korsch PH250, Korsch XL400 or Fette P1200i. All this leads to the production of nuclei.

Minitablets are produced by compression on a standard rotary tablet press using a special multi-tip tool. Said multi-tip tool may include, for example, up to 19 nibs per punch. These mini-tablet punches have a wider contact area in the bore than a standard tablet punch. Therefore, the particle size distribution and flow properties of the powder are important to obtain a uniform tablet mass. The lubrication of the composition and/or other processing (eg, splash lubrication) perform an important function in this manufacturing process.

As noted above, the cores of the resulting tablets are then film-coated in step (d) to form a tablet (in particular a mini-tablet) according to the present disclosure. The coating mixture can be made, for example, by mixing the ingredients, including water, using a mixer, for example, a screw mixer from IKA, followed by sorting, for example, through a hand sieve with a pore size of 0.5 mm, and then coating the cores obtained in step (c), e.g. using a fluidized bed dryer, in particular using direct heat, e.g. in the Aeromatic-Fielder MP1 variant using a peristaltic pump with Wurster fixation (such as Watson Marlow) and connecting tubing of a suitable diameter.

Due to the high water solubility of LCZ696, it is preferable to keep it out of contact with water for a long time in order to prevent degradation of the drug. Typically, water is removed immediately during coating, preventing prolonged contact of LCZ696 with water. Alternatively, the organic film deposition process may be useful as protection against adverse effects on said complex.

In order to circumvent the unfavorable combination of high minitablet surface area and LCZ696's low hygroscopicity, and the potential consequences of this combination, the kettle drying conditions can be modified to reduce the high water content of the film coated minitablets. This can be achieved by using a coater with improved drying performance, such as, for example, in the application of a fluidized bed coater.

The coating layer considered here can also contain pigments, for example, pigments based on iron oxide, titanium dioxide, used as dyes, one or more, or one or more dyes can be used to give the composition an improved appearance, as well as for greater ease of identification. compositions. Dyes suitable for such use typically include, but are not limited to, carotenoids, chlorophyll, and lacs.

Use: The solid oral dosage form of the present invention can be used in pediatrics for the treatment or prevention (in combination with "treatment") of cardiovascular or kidney diseases, in particular heart failure, or in the manufacture of a medicament for the treatment or prevention (in combination with "treatment") of cardiovascular or kidney disease, in particular heart failure.

Accordingly, the present invention relates to the treatment (including prophylactic treatment) of cardiovascular diseases or kidney diseases, in particular heart failure, comprising the administration to children, in particular children aged 0.5-17 years, in need of such treatment, a therapeutically effective amount of the solid oral dosage form of the present invention.

The present invention also relates to the use of the solid oral dosage form of the present invention in the manufacture of a medicament for the treatment in children (the term "treatment" also includes prophylactic treatment) of cardiovascular or renal diseases, in particular heart failure.

The present invention also relates to a pharmaceutical composition for use in the treatment in children (the term "treatment" also includes prophylactic treatment) of cardiovascular or renal diseases, in particular heart failure, comprising a solid oral dosage form of the present invention.

Finally, the precise dosage of the active agent and particular composition may be determined and administered in consideration of a variety of factors such as, for example, the condition being treated, the desired duration of treatment, and the rate of release of the active agent. For example, the required amount of the active agent and its release rate can be determined based on known in vitro or in vivo methods of such assessment, which allow one to estimate how long the blood plasma concentration of a particular active agent remains at an acceptable level to provide a therapeutic effect. The mini-tablets make it easy to tailor a particular dosage by simply varying the number of mini-tablets used in administration according to the needs (in particular the individual needs) of the patient.

The above description fully discloses the present invention, including preferred options for its implementation. Modifications and improvements may be made to the options specifically described herein as the following claims fall within the scope of the present claims. In this case, any person skilled in the art will be able to fully apply the present invention, without lengthy training and development, using the present description. In this regard, the examples given here are given only for the purpose of further explanation, but not for the purpose of limiting the scope and scope of the present invention.

Examples

Drug study: LCZ696:

LCZ696 denotes the supramolecular complex trisodium[3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylkaarbamoyl)propionate-(S)-3'-methyl-2'-(pentanoyl{2ʺ- (tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate]hemipentahydrate. This compound and pharmaceutical compositions based on it have been described previously in WO2007/056546 and WO 2009/061713, and the relevant sections of these documents relating to the method of preparation are incorporated herein by reference.

Example 1: Obtaining mini-tablets

Batches were made comprising from 200,000 to 1,303,142 unit dosage forms (2.0 mm film-coated mini-tablets in the form of a curved circle), where each unit dosage form had the following composition and contained an effective amount equal to 3.125 mg of sacubitril and valsartan in a 1:1 molar ratio (corresponding to 3.534 mg of LCZ696 or an estimated amount of 3.368 mg of LCZ696 in the form of anhydrous acid, i.e. containing sacubitrile, valsartan and sodium, but without water):

Excipients:

- Cellulose MK GR is a microcrystalline cellulose available for example from JRS Pharama, Germany (Vivapur 102)

- HP-cellulose 300-600 cP is hydroxypropyl cellulose, available for example from Ashland Specialty, South Park, US

- Aerosil® 200 is colloidal silica (pyrogenic silica) available from Evonik, Germany.

- Duponol (Duponol®) is sodium lauryl sulfate, available, for example, from tensa Chem, Belgium.

- Basic methacrylate E PO refers to Eudragit® E PO available from Evonik Germany

The composition of the mini-tablet is shown below in Table 1:

Table 1

Component Ingredient Composition per standard unit [mg/unit] External phase (granulate) LCZ696 3.534 ¹ Cellulose MK GR ³ 2.121 GP-cellulose 300-600 cP 0.312 Aerosil 200 (Aerosil 200) 0.031 Talc 0.047 magnesium stearate 0.094 Total weight of granulate 6.139 Internal phase Cellulose MK GR 0.686 Aerosil 200 (Aerosil 200) 0.070 magnesium stearate 0.105 The weight of the resulting core 7,000 Coating Duponol (Duponol) 0.0171 Basic Polymethacrylate EPO 0.1713 Stearic acid 0.0258 Talc 0.0856 Purified water ² - Finished coated tablet weight 7.2998

¹ Salt formation and hydration factor 1.131 (the ratio of the sum of valsartan, sacubitril plus sodium and crystalline water to the molecular weight of valsartan plus sacubitril without sodium and without crystalline water); which is 3.534 mg and corresponds to 3.125 mg of pure valsartan plus pure sacubitril;

² is removed during processing;

³ excipient used to compensate for the corrected weight of the drug substance if the content is < 99.5 wt.%.

Production process:

Stage 1: LCZ696, Cellulose MK-GR, Aerosil (Aerosil), HP-cellulose 300-600 cP, Mg stearate and talc are mixed at a speed of 150 revolutions, to obtain the desired mixture.

Step 2: The resulting mixture is screened to obtain a PREMIX I premix.

Step 3: The PREMIX I premix is processed by agitation at 100 revolutions to obtain a second PREMIX II premix.

Stage 4: The second PREMIX II premix is subjected to dry granulation (compaction between press rollers).

Step 5: The resulting granules are screened through a sieve with a pore size of 1.0 mm.

Stage 6: Cellulose MK GR and Aerosil (Aerosil) for the outer phase are screened through a sieve with a pore size of 0.8 mm and contribute to stage 7 to the granules and then everything is mixed at a speed of 100 revolutions.

Step 8: Mg stearate for the outer phase is screened through a sieve with a pore size of 0.8 mm and added to the mixture obtained after carrying out step 7.

Step 9: The blend obtained in Step 8 is subjected to a 60 rpm agitation treatment to obtain a Finished Blend (for the tablet core).

Step 10: The finished mixture is subjected to tableting to obtain the bulk density of the material for the core.

For tableting use the following tools:

Punch Punch shape Upper Curved circle, with 19 individual punch tips, per punch (EPMO/Elisabeth* punches) Lower Curved circle, with 19 individual punch tips, per punch (EPMO/Elisabeth* punches)

*) Elizabeth, McKeesport, Pennsylvania, US

Stage 11: The basic polymethacrylate E PO, stearic acid, Duponol (Duponol) and purified water are stirred at a speed of 700 revolutions.

Step 12: To the mixture obtained in step 11, talc is added and the resulting material is stirred.

Step 13: The mixture obtained in step 12 is screened to obtain a film coating slurry, which is applied by spraying the coating material onto the bulk core material obtained in step 10 in a fluidized bed with direct heating (for example, the temperature of the product during application coating can be 28-35°C, this spraying is carried out using a nozzle size of 1.2 mm, achieving a spraying rate of 4-8 g/min, while maintaining the pressure during spraying at 1.5 bar for a batch size of 500 g) .

"Revolutions" refers in the context of the present description to revolutions per minute.

Equipment used in production:

Production process stage Type of equipment Manufacturer, model, size 1. Stirring Diffusion mixer (drum),
hopper mixer Bohle container blender or Turbula 2. Screening Sieve mill, round wire with a diameter of 0.8 mm, oscillating grate Frewitt 3. Stirring Diffusion mixer (drum),
hopper mixer Turbula T10B or Bohle container blender 4. Dry granulation roller press Bepex 200/50; Bepex 200/30 5. Screening Sieve mill, round wire with a diameter of 1.0 mm, oscillating grate Frewitt 6. Screening Manual sieve, 0.8 mm Manual sieve, 0.8 mm 7. Stirring Diffusion mixer (drum),
hopper mixer Turbula T10B or Bohle container blender 6. Screening Manual sieve, 0.8 mm Manual sieve, 0.8 mm 9. Final mixing Diffusion mixer (drum),
hopper mixer Turbula T10B or Bohle container blender 10. Tableting Tablet press, with booster Korsch PH250 or Fette P1200i 11, 12. Obtaining a mixture for the overlay Mixer IKA with screw agitator 13. Screening and Manual sieve, 0.5 mm Manual sieve, 0.5 mm Coating application Direct heating, fluidized material (fluid bed dryer)
peristaltic pump
Connecting tubes Aeromatic-Fielder MP1 with Wurster Watson Marlow
ID: 1.6 mm, OD: 4.8 mm ID: 3.2 mm; OD: 6.4 mm

The resulting tablets are packaged in sublots in PETP/Al/PE flat bags.

Example 2: Mini-tablet in dosage form

The mini-tablets are provided in a 64 unit vial (200 mg total) or they can be presented as capsules each containing either 4 mini-tablets (total 12.5 mg) or 10 min-tablets (total 31.25 mg). These forms have been designed to facilitate the administration process for subjects/parents/caregivers, as well as to make it easier for caregivers to select the correct dose.

Example 3: Dissolution Level Analysis

The tablets described in the examples above were analyzed to determine their degree of dissolution, in 900 ml of phosphate buffer, pH 6.8, using paddle mixing at a speed of 50 rpm.

The complex consisted of the following components: a closable vessel made of glass or other inert transparent material; a motor and a blade including a blade and a rod and acting as a mixing element. The vessel was partially immersed in a suitable water bath of any suitable size or placed in a heating jacket. The water bath or heating jacket helps to maintain the temperature in the vessel at 37 ± 0.5°C during the entire testing process, as well as to keep the liquid in the water bath in constant and even motion. None of the parts of the complex, including the environment in which the complex is placed, did not exert a significant motor impulse, mixing effect or vibration, in excess of the even level of rotation that the mixing element performed. The apparatus, which allows the observation of the sample and the stirring element during testing, is characterized by the following dimensions and capacity: the height is from 160 mm to 210 mm and the inner diameter is from 98 mm to 106 mm. Its sides are flanked at the top. The casing attached to the apparatus is used to delay the evaporation process. The rod is positioned so that its axis at any point does not deviate by more than 2 mm from the vertical axis of the vessel and maintains smooth rotation without noticeable wobble. The vertical center line of the blade passes through the shaft axis so that the bottom of the blade is flush with the bottom of the shaft. The shape and structure of the vane correspond to those specified in the United States Pharmacopeia, USP <711>, FIG. 2. During the entire testing process, a distance of 25 ± 2 mm is maintained between the blade and the inner bottom of the vessel. Made of metal or a suitable inert material, a rigid blade and rod form a single complex. A suitable split version of the device, consisting of two parts, can be used, provided that the specified complex is firmly fixed during testing. The blade and blade shaft may be coated with a suitable inert material. The use of a standard dosage form or a combined number of standard units makes it possible to immerse them in the bottom of the vessel before the blade rotates. A small loose piece of non-reactive material may be attached to the dosage units so that no more than a few turns of the wire coil take place, otherwise it will float on the surface. Other validated capsule weights may also be used.

900 ml buffered aqueous solution adjusted to pH 6.8 ± 0.05 (0.05 M phosphate buffer prepared by dissolving 6.805 g potassium dihydrogen phosphate and 0.896 g sodium hydroxide, then diluting with water to 1000 ml and adjusting the value pH to 6.80 ± 0.05 using 0.2 M sodium hydroxide or 1 M phosphoric acid; hereinafter referred to as "Dissolution medium") is placed in a vessel in the apparatus, the apparatus is assembled, the temperature of the dissolution medium is adjusted to 37 ± 0.5 ° and then remove the thermometer. 1 dosage form (eg tablet or capsule) is placed in the apparatus, avoiding the formation of air bubbles on the surface of the standard dosage form, and immediately the apparatus is put into operation at a speed of 50+2 rpm. Within a specified period of time (e.g. 10, 20, 30, 45, 60, 90 and 120 min) or at each of the specified time points, a sample (> 1 ml) is taken from the area between the surface of the dissolving medium and the top of the rotating blade, at distance of at least 1 cm from the vessel wall. [Note: Aliquots taken for analysis are replaced with equal volumes of dissolving fresh medium at 37°C or, if it is seen that it is not necessary to replace the withdrawn medium, a change in the volume of medium should be made in the calculation. During the whole test, the vessel is kept closed, and the temperature of the test mixture is confirmed at the appropriate time points]. The sample is filtered through an appropriate filter, for example a 0.45 µm PVDF filter (Millipore) and the first volume (2 to 3 ml) of the filtrate is discarded. The analysis is carried out by the HPLC method or by UV detection. The assay is repeated at least 6 times using additional dosage standard forms.

The tablets described in the above examples can also be analyzed by the above method at pH 4.5, according to the procedure described above, with the optional modification of the following: the preparation of a phosphate buffer pH 4.5 is carried out by dissolving 13.61 g potassium dihydrogen phosphate in 750 ml of water, followed by pH adjustment, if necessary, using 0.1 M sodium hydroxide or 0.1 M hydrochloric acid and further diluting with water to 1000.0 ml.

Alternative condition for dissolution analysis at pH 4.5: rotation speed: 75±3 rpm; assay medium: 900 ml phosphate buffer solution, pH 4.5.

Reference Example: LCZ696 200mg Tablets

Table 2 below shows a composition containing 100, 200 and 400 mg of an effective amount of the active agent (according to WO 2009/061713, page 18 ff and with appropriate adaptation of the material).

table 2

Ingredients 100 mg 200 mg 400 mg mg/tablet mg/tablet mg/tablet INTRAGRANULAR LCZ696 113.1 226.2 452.4 Complies with LCZ696 (anhydrous free acid) 107.8 215.6 431.2 Microcrystalline cellulose (cellulose MK GR) 34.9 69.8 139.6 L-HPC (low substitution) 25.0 50.0 100.0 Crospovidone 10.0 20.0 40.0 colloidal silicon dioxide 1.0 2.0 4.0 Talc 1.5 3.0 6.0 magnesium stearate 3.0 6.0 12.0 EXTRAGRANULAR Talc 0.5 1.0 2.0 Crospovidone 8.0 16.0 32.0 magnesium stearate 3.0 6.0 12.0 Covering sheath White opadra 4.43 6.63 9.95 yellow opadrai 2.86 4.30 6.44 Red opadrai 0.65 0.98 1.47 Black opadrai 0.06 0.09 0.14 Weight gain per tablet (mg) eight 12 eighteen Total tablet weight (mg) 208 412 818

The manufacturing process is described in WO 2009/061713, page 20.

Example 5 Bioavailability Comparison

Objective: This study was conducted to determine the relative bioavailability of 200mg LCZ696 minitablets versus the final LCZ696 200mg minitablets when taken on an empty stomach, and to assess the effect of food intake on the bioavailability of LCZ696 minitablets. weighing 200 mg. To evaluate the effect of food intake on LCZ696, the mini-tablets were administered with a tablespoon of pudding or with pudding and a high-fat meal.

Study design: Conducted a randomized crossover study in healthy subjects with an open label and a single dose. The study included: 40 subjects; completed the study: 39 subjects.

Treatment A: Single oral dose of LCZ696 200mg FMI (final to be marketed)

Treatment B: Single oral dose of 200 mg LCZ696 minitablets

Treatment C: Single oral dose of 200mg LCZ696 minitablets added to a tablespoon of pudding

Treatment D: Single oral dose of 200mg LCZ696 minitablets added to a tablespoon of pudding and administered with a high fat meal

Pharmacokinetics: Statistical analysis of the relative bioavailability of the minitablets compared to the final marketed tablet (FMI), the effect of adding pudding, and the effect of a high-fat meal is described in Table 4. After a single oral dose of 200 mg on an empty stomach, the primary variables The PK parameters for macubitril, LBQ657, and valsartan were similar for minitablets and final marketed tablets (FMI), with the geometric mean ratio and corresponding 90% CI for Cmax and AUC within the 80-125% range. The Tmax values were also similar for the two compositions, suggesting that the composition had no effect on the rate of absorption.

Similarly, when the 200 mini-tablets were administered with a tablespoon of pudding, the GMR and 90% CI for AUClast, AUCinf, and Cmax for LCZ696 were also in the range of 0.80-1.25, indicating no significant effect of a small amount of vanilla pudding on the bioavailability of minitablets. The Tmax values were also similar for the two treatments, indicating no effect of vanilla pudding on the rate of absorption of LCZ696 analytes.

When a single dose of 200mg LCZ696 minitablets was added to pudding and then administered with a high fat meal, Cmax for sacubitril and LBQ657 were reduced by 60% and 19%, respectively. However, AUCinf and AUClast for sacubitril and LBQ657 did not change to the same extent with a high fat meal, with GMR and 90% CI within the 80-125% range. Food delayed the absorption of sacubitril and LBQ657 from minitablets by 2.5 hours and 2 hours, respectively. When LCZ696 minitablets were administered with a high fat meal, Cmax and AUC for valsartan were reduced by 57% and 41%, respectively. The absorption rate of valsartan was reduced by 2 hours when LCZ696 mini-tablets were administered with food.

The relative bioavailability of LCZ696 analytes after administration of 200 mg minitablets was compared with that of the final 200 mg tablet for sale (FMI), data obtained, and data on the effect of added pudding and high-fat food on PK values minitablets are shown in Table 3.

Table 3: Evaluation of the relative bioavailability of LCZ696 analytes following administration of 200 mg minitablets compared to final 200mg tablet versions (FMI)

FK parameter Mini-tablets vs. FMI tablets a
(on an empty stomach) Adding pudding to minitablets b
(on an empty stomach) Pudding + high fat food c
(mini-tablets) Sacubitril AUCinf (ng⋅h/mL) 0.96
(0.92-1.00) 1.04
(1.00-1.08) 1.01
(0.97-1.05) AUClast (ng⋅h/mL) 0.96
(0.92-1.00) 1.04
(1.00-1.08) 1.00
(0.96-1.04) Cmax (ng⋅h/ml) 0.94
(0.8-1.11) 1.00
(0.85-1.18) 0.4
(0.34-0.46) LBQ657 AUCinf (ng⋅h/mL) 0.98
(0.96-0.99) 1.01
(0.99-1.03) 1.02
(1.00-1.04) AUClast (ng⋅h/mL) 0.98
(0.96-0.99) 1.01
(0.99-1.03) 1.02
(1.00-1.04) Cmax (ng/ml) 0.95
(0.91-0.99) 0.99
(0.95-1.03) 0.81
(0.77-0.85) Valsartan AUCinf (ng⋅h/mL) 1.11
(1.00-1.24) 1.02
(0.93-1.11) 0.6
(0.54-0.66) AUClast (ng⋅h/mL) 1.11
(1.00-1.22) 1.04
(0.94-1.14) 0.59
(0.54-0.65) Cmax (ng/ml) 1.09
(0.98-1.21) 1.02
(0.92-1.13) 0.43
(0.38-0.48)

Data are presented as a ratio of geometric mean values (90% CI) for:

test sample (mini-tablets)/reference variant (FMI tablets)

test sample (mini-tablets with pudding) / reference variant (mini-tablets)

test sample (mini-tablets on pudding + high-fat food) / reference variant (mini-tablets on pudding)

Conclusions and conclusion

- The rate (Cmax) and level (AUC) of absorption of analytes from LCZ696 are comparable for LCZ696 200-mg mini-tablets and 200 mg final LCZ696 tablets for sale (FMI) in healthy subjects when taken on an empty stomach.

- The rate (Cmax) and level (AUC) of absorption of analytes from LCZ696 were comparable when LCZ696 200 mini-tablets were administered with or without a small amount of vanilla pudding.

- When LCZ696 from LCZ696 200mg minitablets added to pudding was administered with a high fat meal, Cmax values for AHU377, LBQ657 and valsartan were reduced by 60%, 19% and 57%, respectively. However, the absorption rates (AUC) for AHU377 and LBQ657 were comparable, while the absorption rate (AUC) of valsartan was reduced by ~40%.

Claims (24)

1. Minitablet for oral administration containing a core and an outer coating, where - the core includes as an active ingredient a therapeutically effective amount of sacubitril and valsartan in a molar ratio of 1:1; and at least one pharmaceutically acceptable excipient, where the specified effective amount of the active ingredient is 3.534 mg (pentanoyl{2''-(tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate]hemipentahydrate per mini-tablet, and where the core includes the active ingredient in a concentration of from 30 wt.% to 70 wt.% from the weight of the core before coating, where the core contains as pharmaceutically acceptable excipients microcrystalline cellulose in an amount of from 35% to 45% by weight, hydroxypropylcellulose in an amount of from 3.5% to 5.5% by weight, magnesium stearate in an amount of from 1.5 to 3.5% by weight, colloidal silicon dioxide in the amount of from 1.0% to 2.0% by weight and talc in the amount of from 0.5 to 1.0% by weight, where % by weight refers to % by weight of the core before coating, - the outer coating is presented in the form of a coating with controlled release and / or a protective film coating, where the film coating contains a basic butylated copolymer, based on methacrylate in an amount of from 55% to 60% by weight, talc in an amount from 25% to 30% by weight , stearic acid or Mg stearate in an amount of 7.5% to 9% by weight and sodium lauryl sulfate in an amount of 4% to 8% by weight, where the main butylated methacrylate copolymer is a 1:2:1 copolymer formed from butyl methacrylate, (2-dimethylaminoethyl)methacrylate and methyl methacrylate, and said mini-tablet has a size of 1 mm to 3 mm. 2. Mini-tablet according to claim 1, characterized in that said mini-tablet has a diameter of 1.9 mm to 2.1 mm. 3. A mini-tablet according to claim 1 or 2, characterized in that said mini-tablet has a diameter of approximately 2 mm. 4. Minitablet according to any one of paragraphs. 1-3, characterized in that the specified film coating has a weight of 4 wt.% to 8 wt.% of the total weight of the dosage form, including the core and the coating. 5. Capsule for oral administration, containing a certain number of mini-tablets according to any one of paragraphs. 1-4, where said number is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. 6. Capsule for oral administration according to claim 5, containing 4 or 10 mini-tablets. 7. Mini-tablet for the treatment of heart failure in a patient belonging to the pediatric group, where the mini-tablet is intended for oral administration and has a core and an outer coating, where - the core contains as an active ingredient a therapeutically effective amount of sacubitril and valsartan in a molar ratio of 1:1; and at least one pharmaceutically acceptable excipient, where the effective amount of the active ingredient is 3.534 mg trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionate-(S)-3'-methyl-2'-( pentanoyl{2''-(tetrazol-5-ylate)biphenyl-4'-ylmethyl}amino)butyrate]hemipentahydrate per mini-tablet, and where the core contains the active ingredient in a concentration of from 30% to 70% by weight of the core before coating, where the core contains as pharmaceutically acceptable excipients microcrystalline cellulose in an amount of from 35% to 45% by weight, hydroxypropylcellulose in an amount of from 3.5% to 5.5% by weight, magnesium stearate in an amount of from 1.5 to 3.5% by weight, colloidal silicon dioxide in the amount of from 1.0% to 2.0% by weight and talc in the amount of from 0.5 to 1.0% by weight, where % by weight refers to the % by weight of the core before coating, - the outer coating is presented in the form of a coating with controlled release and / or a protective film coating, where the film coating contains a basic butylated copolymer based on methacrylate in an amount of from 55% to 60% by weight, talc in an amount of 25% to 30% by weight, stearic acid or Mg stearate in an amount of 7.5% to 9% by weight and sodium lauryl sulfate in an amount of 4% to 8% by weight, where the main butylated methacrylate copolymer is a 1:2:1 copolymer formed from butyl methacrylate, (2-dimethylaminoethyl)methacrylate and methyl methacrylate, and said mini-tablet has a size of 1 mm to 3 mm. 8. Minitablet according to any one of paragraphs. 1-4 used in the treatment or prevention of chronic heart failure, hypertension, angina pectoris, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiomyopathy, renal failure, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, and stroke. 9. Mini-tablet according to claim 8, for patients who require a low and individualized dose, or for patients who have problems with swallowing.