SI21400A - Stable pharmaceutical form with hmg-coa reductase inhibitor - Google Patents

Abstract

The present invention relates to stable pharmaceutical forms comprising active ingredients resistant to environmental effects and auxiliary pharmaceutical substances which enable stability of one or several active ingredients to pH of environment and do not contain alkalifying or buffer substances or their combinations. Stable pharmaceutical forms are described also, comprising active ingredients sensitive to pH of environment, oxidation and/or moisture of environment, auxiliary pharmaceutical substances providing resistance of active ingredient to pH of environment and a lining which enables protection of active ingredient from environmental effects, first of all from oxidation and/or moisture in environment. Procedures of preparation of stable pharmaceutical forms are described also as well as applications of such active ingredients for preparation of pharmaceutical forms for treatment of dislipidemias, cardiovascular diseases and other diseases.

Description

Lek pharmaceutical company d.d.

Verovskova 57

Sl-1526 Ljubljana, Slovenia

Stable dosage form with HMG-CoA reductase inhibitor

FIELD OF THE INVENTION

The present invention relates to the field of the pharmaceutical industry and more specifically to stable pharmaceutical forms comprising active ingredients that are sensitive to environmental influences. Preferably, the active ingredient is sensitive to environmental pH, oxidation and / or moisture in the environment and is selected from the group of HMG-CoA reductase inhibitors. Most preferably, the active ingredient is atorvastatin.

The stable pharmaceutical formulation of the present invention comprises one or more active ingredients sensitive to the pH of the environment and one or more auxiliary pharmaceuticals which allow the stability of one or more active ingredients to the pH of the environment, said pharmaceutical form having a water content of less than 3.5%, preferably less than 3% by weight by weight of the total pharmaceutical formulation and does not contain base or buffering agents or combinations thereof. In such pharmaceutical form, one or more excipients are selected from the group consisting of various types of microcrystalline cellulose and modified forms of microcrystalline cellulose.

Further, the stable pharmaceutical formulation may contain uncoated or coated particles comprising an active ingredient that is sensitive to environmental influences and is preferably sensitive to environmental pH, oxidation and / or environmental moisture and is selected from the group of HMGCoA reductase inhibitors.

Coated particles of the present invention are active substance coated particles that protect the active ingredient from environmental influences and especially from oxidation and / or moisture in the environment. Such coated particles are either in uncoated pharmaceutical form or in coated pharmaceutical form, the coating of such form providing protection of the active ingredient and auxiliary pharmaceutical substances against environmental influences and especially against oxidation and / or moisture in the environment.

Other pharmaceutical forms of the present invention comprise uncoated active ingredient particles, one or more auxiliary pharmaceutical substances which allow the active ingredient to be stable at ambient pH, said pharmaceutical form having a water content of less than 3.5%, preferably less than 3%, by weight by weight of the total dosage forms and free of base or buffering substances or combinations thereof, and a coating which allows the active substance and the excipients to be protected from environmental influences and, in particular, from oxidation and / or moisture in the environment.

The coated pharmaceutical forms of the present invention are stable with respect to environmental influences or provide stability of the active ingredient as well as pharmaceutical auxiliaries with respect to environmental influences by protecting the active ingredient and pharmaceutical auxiliaries from environmental influences.

The present invention also relates to methods and processes for the manufacture of stable pharmaceutical forms of the present invention. At the same time, the present invention relates to the use of an active ingredient for the preparation of stable pharmaceutical forms of the present invention for treatment and to methods of treating various diseases by the application of coated particles and / or pharmaceutical forms of the present invention, the diseases being selected from the group consisting of dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, arteriosclerosis, cardiovascular disease, coronary artery disease, coronary heart disease, circulatory disorders, inflammatory diseases, allergic diseases, neurodegenerative diseases, cancer, viral diseases (WO 0158443), 01 disorders of processing the protein of the amyloid beta precursor as Alzheimer's disease or Down syndrome (VVO0132161).

Demonstration of the problem that the invention solves

Many active substances are sensitive to environmental influences and, as a result of these effects, their active forms are converted into disintegration products, which are often less effective than active forms. In addition to lower efficacy, decomposition products can also cause side effects and thus affect the safety of use. Even a very small proportion of impurities or degradation products of the active substance can significantly impair the safety of the product. Therefore, it is important that the active substance is as pure as possible in the application, which means that the proportion of the active substance's decomposition products as well as impurities is minimized. The fraction of degradation products and impurities in the active substance and in the pharmaceutical form is affected by the manufacturing processes of the active substance itself (eg isolation and purification processes) as well as the intermediate storage steps of the active substance and / or its intermediates in the manufacturing process and the storage phase of the active ingredient up to the pharmaceutical form production process and in the process of its production. At the same time, the fraction of active substance degradation products and impurities in the active substance in the pharmaceutical form are also influenced by the auxiliary pharmaceutical substances covered by the pharmaceutical form. These pharmaceutical excipients are selected from the group consisting of fillers or diluents, binders, lubricants, glidants, decomposers, colorants, flavors, adsorbents, plasticizers and other similar excipients.

Not only the active substance decomposes under the influence of the environment, but also the pharmaceutical excipients in pharmaceutical form can be decomposed. Decomposition products of these may act as reactive sites, triggering the decomposition of the active substance in pharmaceutical form.

Among the environmental influences that affect the substance are, for example. temperature, humidity, light (eg UV rays) and gases present in the environment, such as oxygen or carbon dioxide. An important factor is the pH of the environment or the presence of substances that affect the acidity or basicity of the environment (eg acids, bases, salts, metal oxides) and the reactivity of the medium or active substances (free radicals, heavy metals), etc.

Most active substances are temperature sensitive, especially high. As the temperature rises, the chemical reactions proceed more quickly, resulting in more decomposition products in a shorter time. In certain cases, at elevated temperatures, reactions that otherwise would not have expired at normal temperature. Thus, temperature influences the kinetic and thermodynamic parameters of chemical reactions of the formation of decomposition products.

Many ingredients are sensitive to moisture. In case of high humidity, water is bound to the active substance only and / or to the excipients in the surrounding of the active substance, which, in combination with one or more other environmental influences, may trigger the degradation reactions of the active substance. It is known from the prior art that moisture-sensitive HGM-CoA reductase inhibitors, e.g. pravastatin and atorvastatin.

Compounds containing structural elements that undergo a lactone form at low pH are generally sensitive to the acidic environment. Among them, the most well-known are HGM-CoA reductase inhibitors (statins) and similar compounds comprising 7-substituted-3,5-dihydroxyheptanoic and / or 7-substituted-3,5-dihydroxyheptenoic acid groups. In addition to the transition to the lactone form, other mechanisms of degradation of these substances may take place in acidic, e.g. isomerization at pravastatin. (Serrajuddin, A. T. M. et al., Biopharm. Sci. 80, 830-834, 1991; Kearney, A. S. et al., Pharm. Res. 10, 1993, 1461-1465).

Statins and similar compounds, which are in the form of cyclic ester - lactone, are, among other things, sensitive to the basic medium, or the environment, where they transition to acid form.

Compounds in the environment that increase the acidity or alkalinity of the environment trigger the degradation reactions of the substance, sensitive to acidic or basic environments. Carbon dioxide, in the presence of moisture or water in which it is well soluble, forms carbonic acid, which increases the acidity of the environment.

Light, and especially UV rays, cause decaying reactions of active substances, especially organic ones. Atorvastatin is known to be sensitive to light among others (Hurley, T. R. et al., Tetrahedron 49, 1993, 1979-1984).

Oxygen causes oxidation or oxidative decomposition reactions of the active substance and / or excipients, resulting in reactive sites and / or disintegration products, which lead to further oxidation or further oxidative decomposition reactions of the active ingredient and / or excipients. It is known from the prior art that HGM-CoA reductase inhibitors, e.g. pravastatin, atorvastatin, simvastatin and lovastatin (Javernik, S., et al., Pharmazie 56, 2001,738-740; Smith, G. B., et al., Tetrahedron 49, 1993, 4447-4462; Application P-200200244).

HMG-CoA reductase inhibitors (statins) are among the substances that are sensitive to environmental pH, moisture, light, temperature, carbon dioxide and oxygen. These are known to be the therapeutically most effective agents for the treatment of dyslipidemias and cardiovascular diseases, selected from the group consisting of dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, arteriosclerosis, cardiovascular disease, coronary artery disease, coronary heart disease, coronary heart disease, coronary heart disease, lipid and cholesterol metabolism. Statins have a mechanism of inhibiting the biosynthesis of cholesterol and other sterols in the liver of humans or animals, acting on the principle of competitive inhibition of the enzyme HMG-CoA reductase or 3-hydroxy-3-methyl-glutanl-coenzyme A reductase, which catalyzes the conversion of HMG-CoA to mevalonate human or animal liver, which is an important step in the cholesterol biosynthesis of the liver. Recent studies show that statins have, in addition to these therapeutic effects, other therapeutic effects and are therefore useful for the treatment of diseases, conditions and disorders selected from the group consisting of circulatory disorders, inflammatory diseases, allergic diseases, neurodegenerative diseases , cancers, viral diseases (WO 0158443), bone disease (WO 0137876), disorders of the processing of the amyloid beta precursor protein such as Alzheimer's disease or Down syndrome (VVO0132161).

Among statins are known e.g. pravastatin, atorvastatin, simvastatin, lovastatin, mevastatin or compactin, fluvastatin or fluindostatin, cer (i) vastatin rivastatin, rosuvastatin or visastatin, and itavastatin or pitavastatin or nisvastatin.

Pravastatin is chemical (betaR *, deltaR, 1S, 2S, 6S, 8S, 8aR) -1,2,6,8,8a-hexahydro-beta, delta, 6-trihydroxy-2-methyl-8 - ((2S) -2-Methyl-1-oxobutoxy) -1-naphthalenheptanoic acid. The sodium salt of this acid is pravastatin sodium. It was first described in US patent 4346227.

Atorvastatin is a chemical-chemical salt of (R- (R *, R *)) - 2- (4-fluorophenyl-beta, deltadihydroxy-5- (1-methylethyl) -3-phenyl-4 - ((phenylamino) carbonyl)) - 1 H-pyrrol-1-heptanoic acid. It was first described in U.S. Pat. No. 5,273,995.

Rosuvastatin is a chemical calcium salt (2: 1) (3R, 5S, 6E) -7- (4- (4-fluorophenyl) -6- (1-methylethyl) 2- (methyl (methylsulfonyl) amino) -5-pyrimidinyl) -3,5-Dihydroxy-6-heptenoic acid. It was first described in U.S. Pat. No. 5,260,440.

Fluvastatin is chemically R *, S * - (E) - (+ -) - 7- (3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl) -3,5-dihydroxy -6-Heptenoic acid. Fluvastatin sodium is the sodium salt of the specified acid. It was first described in EP 114027.

Simvastatin is chemical (1S- (1alpha, 3alpha, 7beta, 8beta (2S *, 4S *) 8a beta)) - 1,2,3,7,8,8ahexahydro-3,7-dimethyl-8- (2- ( tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl) -1-naphthalenyl-2,2dimethylbutanoate. It was first described in US patent 4444784.

Lovastatin is chemical (1S- (1alpha, 3alpha, 7beta, 8beta (2S *. 4S *) 8a beta)) - 1,2,3,7,8,8 ahexahydro-3,7-dimethyl-8- (2- ( tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl) -1-naphthalenyl-2methylbutanoate It was first described in patents US 4231938 and JP 8425599.

Itavastatin is a chemical (S- (R *, S * - (E))) - 7 (2-cyclopropyl-4 ~ (4-fluorophenyl) -3-quinolinyl) -3,5-dihydroxy-6-heptenoic acid. Pitavastatin is a lactone form of itavastatin. They were first described in EP 304063 or Pat. US 5011930.

Mevastatin is a chemical (3R, 5R) -3,5-dihydroxy-7 - ((1S, 2S, 6S, 8S, 8aR) -2-methyl-8 - ((2S) · 2-methylbutanoyl) oxy) -1. 2,6,7,8,8a-Hexahydronaphthalen-1-yl) heptanoic acid.It was first described in US patent 3983140.

Cerivastatin is chemically (S- (R *, S * - (E))) - 7- (4- (4-fluorophenyl) -5- (methoxymethyl) -2,6-bis (1methylethyl) -3-pyridinyl) - 3,5-Dihydroxy-6-heptanoic acid. It was first described in EP 491226.

Many of these statins are particularly sensitive to environmental influences, such as atmospheric influences and environmental pH. It is known in the art that some statins are sensitive e.g. to an acidic or low pH environment in which it decomposes into its lactone forms and various isomers. Thus, e.g. in the acidic environment, pravastatin, atorvastatin, itavastatin, and fluvastatin are converted to lactone forms.

Kearney, A.S., et al. In The Interconversion Kinetics, Equilibrium, and Solubilities of the Lactone and Hydroxyacid Forms of the HMG-CoA Reductase Inhibitor, CI-981, Pharmaceutical Research Vol. 10, No. 1 No. 10,1993,1461-1465, describe the passage of atorvastatin in the form of hydroxy acid into a lactone form at a low pH starting at an ambient pH of about 4, and with increasing acidity of the medium, the equilibrium transition reaction moves towards the formation of lactone.

The effect of moisture and pharmaceutical lactose filler on the formation of atorvastatin lactone in amorphous and four polymorphic forms of atorvastatin was investigated. Samples of amorphous and polymorphic forms I to IV of atorvastatin and binary mixtures with lactose in a ratio of 1: 2 were exposed to 80 ° C for 3 days in an air atmosphere with a relative humidity of 5% and 100%. The content of atorvastatin lactone was determined by the analytical method of liquid chromatography. As reference samples, all of the selected forms of atorvastatin stored at 4 ° C were analyzed.

Table 1. Increase in atorvastatin lactone content in amorphous atorvastatin and various atorvastatin crystalline forms and lactose binary mixtures stored for 3 days at 80 ° C in a 5% and 100% relative humidity relative to the respective reference samples.

Increment atorvastatin lactone% Amorphous atorvastatin Crystal Form I Crystal Form II Crystal Form III Crystal Form IV Relative moisture 5% 0.21 0.43 0.40 0.32 0.15 Relative 100% moisture 0.62 0.49 1.15 1.00 0.88 Relative moisture 5% Mixture with lactose 1: 2 0.37 0.58 0.70 I 0.48 0.27 Relative 100% moisture Mixture with lactose 1: 2 8.60 1.43 3.29 5.43 9.27

This study has shown that different forms of atorvastatin are relatively similarly sensitive to the influence of moisture on the formation of atorvastatin lactone. At higher relative humidity, lactone increment is significantly higher in all forms except crystalline Form I.

At low relative humidity, lactose does not significantly affect the formation of atorvastatin lactone, while this effect is very strong at high humidity. This phenomenon is explained by the fact that lactose acts acidic in the presence of water, which affects the formation of atorvastatin lactone.

It is also known in the art that statins that are in lactone form, e.g. lovastatin and simvastatin are sensitive to the alkaline environment in which they pass into acidic form.

The sensitivity of various pharmaceutical agents to oxidative degradation is described by Waterman, KC, et al. In “Stabilization of Pharmaceuticals to Oxidative Degradation”, Pharmaceutical Development and Techno? Ogy, 7 (1), 2002, 1-32, and also indicates possible ways of stabilizing the pharmaceutical ingredients before oxidative decomposition. This article states that the study of oxidation mechanisms in solid pharmaceutical forms is difficult and demanding, as shown by the few articles in this field. It can oxidize the compound itself, which is the active substance, and more often the active ingredient in pharmaceutical form. In the preparation of a solid pharmaceutical form, mechanical processing may also result in an amorphous form, even if the active substance is itself a crystalline form. The resulting amorphous form is usually small and less than 1%. Parts of the amorphous form of the active substance have greater mobility (lack of stabilization energy of the crystal lattice) and are therefore more permeable to oxygen and dissolve oxygen therein, while greater mobility and higher concentrations of oxygen in the amorphous active substance accelerate electron transfer to oxygen (Vaterman, KC, et al., Stabilization of Pharmaceuticals to Oxidative Degradation, Pharmaceutical Development and Technology, 7 (1), 2002, 1-32).

Byrn, SR, et al (Solid-State Chemistry of Drugs, 2 ^nd Ed., SSCI, Vest West Lafayette,

1999) describe that molecular oxygen from the atmosphere reacts with organic crystals and that this reactivity depends on the crystalline form or morphology, which determines the permeability to oxygen and its solubility in the crystal network. In some cases, the reactivity decreases with increasing melting point, indicating that higher energy of the crystal lattice inhibits oxygen diffusion.

In general, the sensitivity of the active substance to oxidation is higher at higher pH and lower at lower pH, but this also depends on the pharmaceutical form itself and the excipients therein. The oxidation of the active substance in the pharmaceutical form is also affected by the excipients. These can cause oxidation directly through the wetting of the active substance or indirectly by the transfer of moisture to the active substance. Excipients themselves may be the origin of oxidizers or metals (eg impurities present) and may be involved in the formation of mobile oxidizing compounds such as peroxide radicals, superoxides and hydroxyl radicals. Peroxide impurities are often present due to polymer auxiliaries. This depends on the strength of the hydrogen bonds and the presence of the electron donor groups in the excipient (eg amino groups) (Waterman, KC, et al., Stabilization of Pharmaceuticals to Oxidative Degradation, Pharmaceutical Development and Technology, 7 (1), 2002, 1-32 ).

Research has found that some of these statins are particularly sensitive to oxidation. Some of the polymorphic or amorphous forms of atorvastatin, pravastatin, lovastatin, simvastatin and rosuvastatin are particularly sensitive.

The effect of oxygen on the formation of the decomposition products of amorphous and four polymorphic forms of atorvastatin was investigated. Samples of amorphous and polymorphic forms I to IV of atorvastatin were exposed to 80 ° C for 3 days in air and oxygen atmosphere. The content of oxidation products was determined by the analytical method of liquid chromatography. As reference samples, all of the selected forms of atorvastatin stored at 4 ° C were analyzed.

Table 2. Increase of content of decomposition products of amorphous atorvastatin and different crystalline forms of atorvastatin stored for 80 days at 80 ° C in air and oxygen atmosphere, according to the corresponding reference samples

Increment decay % of products Amorphous ATV Crystal Form I Crystal Form II Crystal the shape of a lil Crystal Form IV AIR 1.04 0.04 0.25 0.11 1.14 Oxygen 3.4 0.07 0.71 0.47 3.67

This study showed that different forms of atorvastatin are differently sensitive to the influence of oxygen on the formation of breakdown products. In amorphous atorvastatin and in crystalline form IV, the proportion of oxidative decay products significantly increased in the oxygen atmosphere and in the air atmosphere. For crystalline Forms I, II and lil, the proportion of these decay products is low in the air atmosphere during this study, and increased for oxygen Forms II and lil in the oxygen atmosphere. This indicates that crystalline Form I is resistant to oxygen and oxidation, that crystalline Forms II and III are slightly sensitive to oxidation and that crystalline Form IV and the amorphous form of atorvastatin are highly sensitive to oxidation.

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Background information

Patent documents that address the problem of ensuring the stability of some of these statins at low pH are:

- for atorvastatin with basic compounds US 5686104, US 6126971, WO 9416693 and EP 680320 and with basic and / or buffer compounds WO 02072073;

- for pravastatin with basic compounds EP 336298, US 5030447 and US 5180589, with basic and / or buffer compounds and other excipients WO 02076376, with buffer compounds WO 03000239 and WO 03000177,

- for fluvastatin with alkaline medium EP 547000 and US 5356896;

- for itavastatin with basic compound WO 9723200 and EP 814782;

for atorvastatin, pravastatin and other statins with polymers containing amino groups or amido groups, WO 0176566 and US 20020035142;

- for atorvastatin, pravastatin, fluvastatin, cerivastatin, mevastatin, pitavastatin, rosuvastatin, lovastatin and simvastatin with amino sugars WO 02089788;

- for atorvastatin, pravastatin, fluvastatin and cerivastatin with buffer compounds WO 0035425;

- for atorvastatin, pravastatin, fluvastatin and cerivastatin with basic and / or buffer compounds WO 0193860.

WO 02/076376 describes stabilization of pravastatin with carriers comprising at least one diluent and at least one lubricant, the diluent being further specified as water soluble and selected from the group consisting of e.g. calcium carbonate, calcium phosphate, calcium hydrogen phosphate, tribasic calcium phosphate, calcium sulfate, compressible sugar, lactose, sucrose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin and mixtures thereof, or as dispersible in water and it consists of e.g. cellulose and its derivatives, starch and its derivatives, clay and clay minerals and mixtures thereof, and the lubricant is selected from the group consisting of sodium stearyl fumarate, palmitic xl, calcium stearate, magnesium stearate, zinc stearate, talc, carnuba wax, silicon dioxide, hydrogenated vegetable oil and mixtures thereof.

WO 0176566 and US 20020035142 describe stable pharmaceutical formulations for

-1111 treatment of dyslipidemias comprising as an active ingredient at least one open-ring 7-substituted-3,5-dihydroxyheptanoic acid or open-ring 7-substituted-3,5-dihydroxyheptenoic acid and a polymer compound containing at least one amide group (e.g. PVP, transverse -connected PVPs, copolymers of vinylpyrrolidone and vinyl acetate, polynoxylin), or a polymer compound containing at least one amino group (a polymer with a quaternary ammonium group such as cholestyramine), or a combination of the two, with other stabilizers as buffers and bases excluded. These polymers are present in an amount that allows effective stabilization.

WO 02089788 describes stabilization of statins, including pravastatin, atorvastatin, fluvastatin, mevastatin, rivastatin, pitavastatin, rosuvastatin, lovastatin and simvastatin with amino sugars such as e.g. meglumine oz. N-methyl-glucamine.

EP 336298 oz. US 5030447 and US 5180589 describe the stabilization of pravastatin by base substances, which include, in particular, strong bases such as alkali metal and alkali metal hydroxides and ammonium hydroxide, and preferably specified substances such as magnesium oxide, magnesium hydroxide, calcium hydroxide, sodium hydroxide, calcium hydroxide, lithium hydroxide and ammonium hydroxide and magaldrate.

WO 9416693 oz. US 5686104 oz. EP0680320 describes the stabilization of atorvastatin with a metal salt as an additive which is an alkaline earth metal salt, for example, calcium or magnesium carbonate, calcium or magnesium hydroxide, magnesium silicate, magnesium aluminate and aluminum magnesium hydroxide.

WO 0035425 describes the stabilization of statins by buffers, among which e.g. sodium and potassium citrate, sodium phosphate, disodium phosphate, calcium carbonate, calcium hydrogen phosphate, calcium phosphate, calcium sulphate, sodium or magnesium carbonate, sodium ascorbate, benzoate, sodium or potassium hydrogen carbonate, sodium or potassium lauryl.

WO 0193860 describes the stabilization of statins by cocrystallization and / or co-precipitation of a statin and a buffer substance or base substance in a homogeneous mixture of statins and said buffer or base substance. Among the buffering agents, e.g. sodium and potassium citrate, sodium and potassium phosphate or hydrogen phosphate, dibasic sodium phosphate, sodium, potassium magnesium or calcium carbonate or hydrogen carbonate, sulfates, aminoguanidine carbonate or hydrogen

-1212 carbonate, guanidine carbonate or hydrogen carbonate, succinimide carbonate or hydrogen carbonate, 1-adamantyl amine carbonate or hydrogen carbonate, etc. Among the baseing agents, e.g. metal oxides such as magnesium oxide, aluminum oxide, alkali metal and alkaline earth metal hydroxides, and organic bases such as succinimide, 1-adamantyl amine, Ν, Ν'-bis (2-hydroxyethyl) ethylenediamine, tris (hydroxymethyl) aminomethane, D (-) - N-methylglucamine and also organic acids with basic character as 3- (N-morpholino) propanesulfonic acid, 4- (cyclohexylamino) -1-butanesulfonic acid, 4- (cyclohexylamino) -1-ethanesulfonic acid and alkali and alkaline earth metal salts with these acids or with arginine, ornithine, lysine, etc.

WO 9723200 oz. EP0814782 describes the stabilization of NK-104 or itavastatin (pitavastatin) with a basic compound, e.g. antacids in the group consisting of magnesium metasilicate aluminate, magnesium silicate aluminate, magnesium aluminate, aluminum hydroxide, synthetic hydrotalcite, synthetic aluminum silicate, magnesium carbonate, calcium carbonate, magnesium oxide, aluminum hydroxide, sodium hydrogen carbonate, e.g. pH regulators in the group consisting of L-arginine, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dicalium hydrogen phosphate, potassium dihydrogen phosphate, disodium citrate, sodium succinate, ammonium chloride and sodium benzoate.

EP 547000 oz. US 5356896 describes the stabilization of fluvastatin with an alkaline medium that is either a base or a buffer and specifies water-soluble alkaline substances from the group consisting of inorganic carbonate salts such as sodium or potassium carbonate, sodium bicarbonate, potassium hydrogen carbonate, phosphate salts as anhydrous sodium, potassium calcium dibasic phosphate, trisodium phosphate and alkali metal hydroxides such as sodium, potassium or lithium hydroxide and mixtures thereof. It also specifies non-soluble or poorly soluble alkaline substances such as magnesium oxide, hydroxide or carbonate, magnesium hydrogen carbonate, aluminum or calcium hydroxide and carbonate, compound compounds of aluminum and magnesium as magnesium aluminum hydroxide, as well as salts of phosphoric acids such as tribasic calcium phosphate and mixtures thereof .

WO 03000239 describes stabilization of pravastatin by buffers such as e.g. TRIS - tromethamine and disodium hydrogen phosphate.

Among the patent documents that solve the problem of ensuring the stability of some of

-1313 of said statins at high humidity and temperature is WO 9949896, which describes stabilization of pravastatin by beta-cyclodextrin.

An overview of known methods (antioxidants, packaging) for stabilizing active ingredients prior to oxidation is generally found e.g. in Waterman, K. C., et al., Pharm. Dev. and Technol. 7,2002,1-32.

Various approaches are used to prevent or reduce the oxidation of active ingredients in the pharmaceutical form, such as:

increasing the concentration of the active substance in the pharmaceutical form when the oxidation is caused by peroxide and metal impurities in the excipients;

- adding chelators (such as citric acid, EDTA, fumaric and maleic acid) to the preparation for the removal of metal impurities;

- use of high purity excipients;

the use of alternative excipients or the reduction of their amount in pharmaceutical form, especially when peroxide impurities are the cause of oxidation; the use of antioxidants that can prevent or reduce the production of peroxides in the pharmaceutical form but cannot reduce the levels of peroxides already present,

However, optimal methods cannot be predicted for individual substances, and there are few publications (Waterman, K.C., et al., Stabilization of Pharmaceuticals to Oxidative Degradation, Pharmaceutical Development and Technology, 7 (1), 2002, 1-32).

Suitable antioxidants include:

chain terminators (e.g., thiols and phenols);

reducing agents which are more oxidized than the active substance and therefore remove the oxygen present (eg sulfites and ascorbic acid), and their combination may have a synergistic effect (eg combination of ascorbic palmitate and tocopherol); Peroxide "silencers" that degrade peroxides (eg Fe2 +) by the Fenton process, but their use is restricted because this process produces a free hydroxyl radical which can further cause free radical reactions and thereby breakdown of the active substance; cyclodextrins that cover the site of the active substance undergoing oxidation (Vaterman, K.C., et al., Stabilization of Pharmaceuticals to Oxidative Degradation, Pharmaceutical Development and Technology, 7 (1), 2002, 1-32).

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In addition, the described methods describe the prevention of oxidation by packaging and packaging elements, which regulate the amount of oxygen in the packaging space around the active substance and the permeability of oxygen through the walls and the stopper of the packaging. Nitrogen packing is possible to reduce the amount of oxygen in the packing compartment. However, in the case of the medicinal product, the packaging is most suitable. Covers that are less permeable or impermeable to oxygen (eg, foil) are usually more expensive. Despite the described methods of stabilization in various ways, for example by adding antioxidants to the pharmaceutical form or by packing the pharmaceutical forms in suitable packaging, these solutions have not proven to be suitable for all active substances or for all markets (Waterman, KC, et al., Stabilization of Pharmaceuticals to Oxidative Degradation, Pharmaceutical Development and Technology, 7 (1), 2002, 1-32).

A variety of patent documents describe various types of packaging for protecting pharmaceutical ingredients and pharmaceutical forms from oxidation.

WO 0076879 describes packagings that are air-tight and comprising an overlay connected to a base part, where the cover portion has at least one recess (compartment) in which the product is located, and where the cover and / or base part has an absorbent (e.g. . desiccant).

EP 370755 discloses a drug packaging specifically designed with a foil comprising an inner polypropylene layer, a middle olefin layer and an outer polypropylene layer. Further, such packaging may further comprise aluminum foil.

EP 595800 describes a package containing an oxygen removal layer from the enzyme reaction package, the packaging having an outer gas-tight layer and water vapor (e.g. laminate as polyamide and polyethylene), an inner gas-permeable layer and is impermeable to liquids (e.g., lethal and its copolymers), and a middle layer that removes oxygen and comprises a liquid phase with an oxygen removal enzyme (oxidase as glucose oxidase), with the insoluble filler suspended in the liquid phase.

The prior art also knows methods of coating oxidizing-sensitive substances or products with a coating that protect such substances or products from oxidation. Milk protein coatings, including carboxymethylcellulose, have been described to protect apples and potatoes from oxidation (Le Tien, C., et al.

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Milk Protein Coatings Prevent Oxidative Browning of Apples and Potatoes, Journal of Food Science Vol. 66, No. 3 4, 2001, 512-516).

In the field of pharmacy, the use of ethylcellulose for coating ascorbic acid granules for protection against oxidation is known (Wade, A., et al., Handbook of Pharmaceutical Excipients, 2nd Ed, American Pharmaceutical Association, Washington, and The Pharmaceutical Press, London, 1994, 186- 190).

The sensitivity of lovastatin to oxidation and its stabilization and protection against oxidation by natural antioxidants is described by Javernik, S., et al., In Pharmazie 56 (9), September 2001, 738-740.

The sensitivity of lovastatin and simvastatin and other active substances (eg, basic substances with pKa 1 to 10 and 5 to 9, respectively, which have a redox potential of about 1300 mV and about 1000 mV, respectively) to oxidation is described in US patent application 20020132359 and EP 1241110, which solves the problem oxidation with a special form of packaging consisting of several units of oxygen-sensitive drug, a stopper and a wrap, each unit of drug being inserted separately between the stopper and the wrap by means of a sealing surface on said stopper, and in which there is a surface in that wrap , an oxygen absorber is embedded in this stopper or in the layer between the surface and the stopper so that said absorbent removes at least a portion of the oxygen from the surroundings of the drug. Oxygen absorbent is selected from the group consisting of absorbers that are either self-activated or moisture-activated (eg copper dust, zinc dust), UV rays, electron beams, irradiation, microwaves or a combination thereof.

Prevention of atorvastatin oxidation by suitable packing (into nitrogen atmosphere) is also described in patent application P-200200244.

No patent documents and other state of the art documents were found relating to other methods of addressing the problem of protecting the pharmaceutical ingredients from environmental pH, oxidation and / or moisture in the environment, and pharmaceutical forms from oxidation and / or moisture in the environment. The problem of the conversion of HMG-CoA reductase inhibitors in the form of hydroxy acids, such as atorvastatin, pravastatin, mevastatin, cerivastatin, rosuvastatin, fluvastatin and itavastatin to the lactone form and various isomers at low pH, has so far been solved by the addition of alkaline and basifying agents, respectively. respectively

-1616 Alkalizing substances (alkalizers) and / or buffering agents in pharmaceutical form.

Therefore, the present invention seeks to stabilize an active ingredient that is sensitive to environmental influences and to stabilize a pharmaceutical form comprising such active ingredient and excipients. Further, the present invention is intended to stabilize an active ingredient that is sensitive to environmental pH, oxidation and / or moisture in the environment, and to stabilize a pharmaceutical form comprising such active ingredient and excipients. It is advantageous for the present invention to stabilize the active ingredient, which is statin and most preferably atorvastatin, from environmental influences and preferably from environmental pH, oxidation and / or moisture in the environment.

Description of new solutions

The subject of the invention is a stable pharmaceutical formulation containing the active ingredient inhibitor of HMG CoA reductase and providing protection of the active substance against environmental influences and preferably against environmental pH, oxidation and / or moisture in the environment. The active ingredient is atorvastatin, preferably.

Furthermore, the invention provides a pharmaceutical formulation which, surprisingly, under low humidity conditions, that is, at 3.5% loss in drying (IPS below 3.5%) and preferably IPS below 3%, prevents the HMG CoA reductase inhibitor from passing from the hydroxy form acids to the lactone form, without the addition of base substances or alkalizers or buffers to the pharmaceutical form. The stable pharmaceutical formulation of the present invention comprises one or more active ingredients sensitive to the pH of the environment and one or more auxiliary pharmaceuticals which allow the stability of one or more active ingredients to the pH of the environment, said pharmaceutical form having a water content of less than 3.5% by weight based on the weight of the total pharmaceutical formulation, and preferably less than 3%, and does not contain base or buffering agents or combinations thereof.

The auxiliary pharmaceutical substance of the stable pharmaceutical forms of the present invention is selected from the group consisting of various types of microcrystalline cellulose and modified forms of microcrystalline cellulose. It is preferably selected from the group of physical mixtures of microcrystalline cellulose and colloidal SiO2 and is most preferably selected from various types of microcrystalline cellulose such as e.g. ProSolv ™ SMCC® 90, ProSolv ™ HD 90 and Avicel® PH 200.

-1717

It is also an object of the present invention to provide a stable pharmaceutical formulation comprising:

a) one or more uncoated particles of one or more active substances that are sensitive to environmental pH, to environmental moisture and / or to oxidation;

b) one or more auxiliary pharmaceutical substances which enable the active substance to be resistant to the pH of the environment, said pharmaceutical form having a water content of less than 3.5% by weight and preferably less than 3% by weight of the total pharmaceutical formulation and free of base or buffering agents or combinations thereof; and

c) a coating, around a pharmaceutical form, which enables the protection of one or more active ingredients, one or more auxiliary pharmaceuticals and pharmaceutical form from oxidation and / or moisture in the environment, and wherein the coating comprises one or more film-makers selected from the group to be selected; consists of sodium carboxymethyl cellulose, hydroxyethyl cellulose and polyvinyl alcohol.

In such formulation, the active ingredient is preferably an inhibitor of HMG-CoA reductase.

Furthermore, the present invention also provides a stable pharmaceutical formulation comprising:

a) one or more coated particles of one or more active ingredients that are sensitive to the pH of the environment, to oxidation and / or moisture in the environment, the active ingredient particle being coated to allow the active substance to be resistant to oxidation and / or moisture, and which comprising one or more film formers selected from the group consisting of sodium carboxymethyl cellulose, hydroxyethyl cellulose and polyvinyl alcohol; and

b) one or more auxiliary pharmaceutical substances which enable the active substance to be resistant to the pH of the environment, said pharmaceutical form having a water content of less than 3.5% by weight and preferably less than 3% by weight of the total pharmaceutical formulation and free of base or buffering agents or combinations thereof.

Such pharmaceutical form may also be coated to protect one or more active ingredients, one or more auxiliary pharmaceuticals and pharmaceutical forms from oxidation and / or moisture in the environment, wherein the coating of the coated particle and pharmaceutical form comprises one or more filmmakers selected from the group consisting of sodium carboxymethyl cellulose, hydroxyethyl cellulose and polyvinyl alcohol.

-1818

Buffer components that are excluded from the stable pharmaceutical formulation of the present invention include salts of weak acids and strong bases or salts of strong acids and weak bases or other similar substances that maintain a pH in a particular range. Preferably, these buffer components are selected from the group consisting of:

a) alkali metal salts, alkaline earth metal salts and ammonium salts of citric acid, ascorbic acid, maleic acid, sorbic acid, succinic acid, benzoic acid, phosphoric acid, carbonic acid, sulfuric acid, nitric acid, boric acid and silicic acid;

b) amines in combination with strong or weak acid (eg tromethamine, EDTA);

c) ion exchangers; and

d) combinations thereof.

Organic or inorganic compounds containing basic acting groups and selected from the group consisting of:

a) alkali and / or alkaline earth metal oxides and hydroxides, oxides 4, 5 and / or 6 of the group of the periodic system, such as e.g. MgO, MgOH, NaOH, Ca (OH) 2;

b) amines such as TRIS (tromethamine), ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, glucosamine, ethylenediamine, diethylamine, triethylamine, isopropylamine, diisopropylamine;

c) alkaline amino acids such as e.g. arginine, histidine and lysine.

The active substance itself or the active ingredient with one or more excipients may be in the form of particles, which may be of the correct or irregular shape. The formed particles may be, for example, microcapsules, microspheres, granules, pellets. These particles may be uncoated or coated. Several of these particles, which may be uncoated or coated, may consist of larger shaped or unformed units (pharmaceutical forms) which may be coated.

The pharmaceutical formulation of the present invention is preferably a solid pharmaceutical formulation and may be in the form of particles of regular or irregular forms and is selected from the groups of pharmaceutical forms, such as powders, powders for suspensions, granules, tablets and capsules.

-1919

The pharmaceutical formulation of the present invention comprises, in addition to one or more coated active ingredients and / or one or more uncoated active ingredients, and a selected excipient, one or more excipients, selected from the group consisting of:

a) one or more binders;

b) one or more decomposers;

c) one or more gliders;

d) one or more surfactants;

e) and other components for solid pharmaceutical forms known in the art and selected from the group consisting of dyes, flavors and adsorption substances.

The binder of the pharmaceutical formulation of the present invention is selected from the group consisting of various types of starch, modified starch forms, microcrystalline cellulose (MCC), hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethylcellulose, hydroxyethyl cellulose, methylcellulomethyl carbose, carboxymethylcellulose, carboxymethylcellulose carbose.

The diluent of the pharmaceutical forms of the present invention is selected from the group consisting of cross-linked sodium carboxymethylcellulose, cross-linked carboxymethyl starch, various types of starch and microcrystalline cellulose, and combinations thereof.

The pharmaceutical form slider of the present invention is selected from the group consisting of magnesium, calcium and zinc stearate, calcium behenate, talc, carnauba wax, silica and combinations thereof.

The surfactant of the pharmaceutical form according to this invention is selected from the group consisting of ionic surfactants, such as sodium lauryl sulfate, non-ionic surfactants, such as different types of poloxamers (copolymers of polyoxyethylene and polyoxypropylene), natural or synthetic lecithin and esters of lecithin and esters with lecithobits acids (such as Atlas Chemie), polyoxyethylene sorbitan and fatty acid esters (eg polyoxyethylene (20) sorbitan monooleate such as Polysorbate 80 and Twain (Atlas Chemie)), polyoxyethylated hydrogenated castor oil (such as Cremophor) (BAS) polyoxyethylene

-2020 stearates (such as Myrj® (Atlas Chemie)) or cationic surfactants such as cetylpyridinium chloride or any combination of said surfactants.

Other components for solid pharmaceutical forms are components that are known and common in the art and are used in the art for solid pharmaceutical forms. They are selected from the group consisting of dyes, flavors and substances for adsorption.

The pharmaceutical forms of the present invention can be prepared in the following ways:

a) a mixture of one or more coated and / or one or more uncoated active ingredients, fillers, binders, decomposers and, if necessary, other surfactants and other conventional components for solid pharmaceutical forms, are homogeneously mixed on suitable mixers, compacted on suitable compactors or briquetted on the briquetting machines or conventional tablets, the compacts or briquettes are crushed and / or sieved, the fillers, disintegrants, sliders, lubricators and other conventional excipients for the tablets or capsules added and mixed homogeneously again. The resulting mixture is tableted or filled into capsules;

b) a mixture of one or more coated and / or one or more uncoated active ingredients, fillers, binders, decomposers and, where appropriate, surfactants and other conventional components for solid pharmaceutical forms, are homogeneously mixed on suitable mixers, glidants and lubricators are added and homogeneous again mix. The resulting mixture is tableted or filled into capsules;

c) a mixture of one or more coated and / or one or more uncoated active ingredients, fillers, binders, decomposers and, where appropriate, surfactants and other conventional components for solid pharmaceutical forms, is homogeneously mixed on suitable mixers, granulated with a suitable solvent such as water, ethanol, methanol, isopropyl alcohol, n-butyl alcohol,

-2121 acetone, diethyl ether, ethyl acetate, isopropyl acetate, methyl acetate, dichloromethane, chloroform, mixtures of these solvents such as ethanol and acetone, methanol and acetone, dichloromethane and methanol, and mixtures thereof. The obtained granulate is dried in suitable dryers, such as conventional tray dryers, vortex dryers, vacuum and microwave dryers, at temperatures up to 60 ° C. To the dried granulate, fillers, decomposers, sliders and lubricators are added, as well as other conventional components for solid pharmaceutical forms, if necessary. The resulting mixture was again stirred homogeneously and tableted or filled into capsules.

Particles of regular or irregular shapes (microcapsules, microspheres, granules, pellets) can be prepared by one of the known technological procedures.

Active substance, particles of regular or irregular shapes such as e.g. microcapsules, microspheres, granules, pellets and the like, and larger shaped or unformed units such as e.g. tablets, capsules and other similar forms may, if necessary, be coated with a film coating of the present invention providing protection of the active ingredient against environmental factors, or may be coated with any other film coating known in the art.

Within the scope of the present invention, the term coating means a coating or layer applied directly to the nucleus, which is either the active substance itself or the active ingredient with one or more excipients in the form of particles of regular or irregular shapes selected from the group consisting of microcapsules, microspheres, granules, pellets and other similar forms known in the art, or a pharmaceutical form selected from the group consisting of tablets, capsules and other similar pharmaceutical forms known in the art. Such coating may be a coating that provides protection of the active ingredient (s) and excipients and pharmaceutical forms from oxidation and / or moisture in the environment. Within the scope of the present invention, such coating may be any other known film or lacquer coating applied directly to the tablet, a capsule or other similar form comprising a coated active ingredient within the scope of the present invention.

A coating within the scope of the present invention is a coating or layer around an active ingredient particle or around a core of a pharmaceutical form comprising one or more filmmakers. A suitable film maker is any film maker applied in the form of a coating to an active ingredient particle or to a pharmaceutical form core comprising an active ingredient sensitive to said environmental influences to provide protection

-2222 of the active substance against the indicated environmental effects and the preferred protection of the active substance against oxidation and / or moisture in the environment. Most preferably, such a film maker is any film maker that allows the active ingredient to be protected from oxidation. Such a film maker is selected from the group consisting of polyvinyl alcohol (PVA) and cellulose derivatives. Among the cellulose derivatives, the film-maker is preferably sodium carboxymethyl cellulose (Na CMC) or hydroxyethyl cellulose (HEC) and most preferably sodium carboxymethyl cellulose (Na CMC). At the same time, a filmmaker can also be a combination of one or more such filmmakers, in all possible proportions.

The coating of the present invention may further comprise one or more pharmaceutically acceptable excipients (excipients) selected from the group consisting of:

d) one or more plasticizers;

e) one or more viscosity enhancing substances for the coating dispersion;

f) one or more gliders;

g) one or more colorants;

h) one or more surfactants; and

i) other auxiliary pharmaceutical substances used in the art for film coatings.

The coating softener may be selected from the group consisting of glycerol, diglycerol, ethanolamines, ethylene glycol, polyethylene glycols, glycerol alpha-monomethyl ether, glycerol monochloridine, 2,3-butylene glycol, 1,2,6-hexantriol, 2-nitro -2-methyl-1,3-propanediol, propylene glycol, glyceryl triacetate, polyoxyethylene / polyoxypropylene copolymers, triethyl citrate, oleic acid, fractionated coconut oil and combinations thereof. The plasticizer is added in concentrations of 1-50%, preferably in concentrations of 5-40%, depending on the amount of film builder in the coating, and more preferably in concentrations of 10-30%.

The viscosity of the coating dispersion viscosity may be selected from the group consisting of carboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, xanthan, alginates, chitosan and combinations thereof. Viscosity enhancers are added in concentrations of 0-50%, preferably in concentrations of 0.1-20%.

The coating slider may be selected from the group consisting of talc, magnesium stearate, calcium stearate and combinations thereof.

-2323

The coating colorant may be selected from the group consisting of aluminum lacquers, insoluble pigments, water-soluble paints, titanium dioxide, talc and combinations thereof.

The surfactant of the coating may be selected from the group consisting of ionic surfactants such as sodium lauryl sulfate, non-ionic surfactants, such as different types of poloxamers (copolymers of polyoxyethylene and polyoxypropylene), natural or synthetic lecithins, and sorbitan and fatty acid esters such as Span® (Atlas Chemie)), esters of polyoxyethylene sorbitan and fatty acids (eg polyoxyethylene (20) sorbitan monooleate such as Polysorbate 80 and Tween® (Atlas Chemie)), polyoxyethylated hydrogenated castor oil (such as Cremophor® (BASFiet)) (such as Myrj® (Atlas Chemie)) or cationic surfactants such as cetylpyridinium chloride or any combination of said surfactants.

Other pharmaceutical auxiliary coatings are those which are used in the art for film coatings and are known in the art.

Water, various combinations of organic solvents, and combinations of organic solvents and water may be used as the coating dispersion solvent.

The amount of film coating applied to the active substance, particles of regular or irregular shapes (microcapsules, microspheres, granules, pellets) and larger shaped or unformed units (tablets, capsules) is in the range of 2-20% by weight, preferably 4-12%.

It is also an object of the present invention to use an active ingredient within the scope of this invention for the preparation of coated particles and / or pharmaceutical forms of the present invention for the treatment and treatment of various diseases by the application of coated particles and / or pharmaceutical forms of the present invention, wherein the diseases are selected from the group Consisting of dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, arteriosclerosis, cardiovascular disease, coronary artery disease, coronary heart disease, circulatory disorders, inflammatory diseases, allergic diseases, neurodegenerative diseases, cancers3One diseases44 (WO 0137876), amyloid beta precursor protein processing disorders such as Alzheimer's disease or Down syndrome

-2424 (VVO0132161).

Implementation examples

Example 1

Composition of one film-coated tablet

1.1. Tablet core

Table 3. Kernel composition

Ingredient Weight (mg) Atorvastatin (as atorvastatin Ca) 40,00 Sodium lauryl sulfate 5,00 ProSolv SMCC 90 139.00 Pregelatinized corn starch 3.00 Cross-linked carboxymethyl cellulose 10,00 Magnesium stearate 1.00 Talc and 2.00

Making the tablet core

A solution of sodium lauryl sulfate is sprayed in warm air to atorvastatin Ca. The obtained granulate is dried and sieved. Add ProSolv SMCC 90, pregelatinized corn starch and crosslinked carboxymethyl cellulose and mix homogeneously. Magnesium stearate and talc are added, homogeneously mixed, and tablets are coated with 200 mg tablets.

1.2. Tablet coating

Table 4. Lining composition

Lining component Weight fraction of lining by kernel mass (%) and

-2525

weight of ingredient in coating (mg) 8% Sodium carboxymethyl cellulose 14,90 mg Glycerol 1,50 mg

Preparation of dispersion for coating and coating the tablet core

Sodium carboxymethyl cellulose (Blanose CMC 7LF PH, Aqualon) (109.00 g) with a viscosity of 25 - 50 mPas and glycerol (11.00 g) were dissolved in water (2513.60 g) while stirring. The prepared dispersion was sprayed onto the cores to give an 8% application by weight relative to the weight of the core. During the coating process, the mass of the tablets was checked and the coating applied.

1.3. Determination of pH of the tablet

The potency of the tablet of Example 1, determined potentiometrically, is 6.7. The pH of a mixture of atorvastatin Ca and ProSolv SMCC 90 (a mixture in a ratio equal to their tablet weight ratio) was 7.93 using the same procedure.

The pH of the tablet and ProSolv SMCC 90 active ingredient and filler mixture were determined in 20 ml aqueous dispersion of 1 tablet containing 40 mg of atorvastain Ca or dispersion of the ProSolv SMCC 90 active ingredient and filler mixture in the amount present in such a tablet. The pH was determined on 720 KFS Titrino Methrom analytical equipment using a combined micro pH electrode Methrom 6.0204.100 pH 14/0 70 ° C.

1.4. Analysis of the stability of the active ingredient in the pharmaceutical form according to Example 1 in different atmospheres

The influence of water / moisture and excipients on the formation of decomposition products (lactone and oxidation decomposition products) was determined by testing film-coated tablets in packages (HDPE bottles) with different desiccants (excluding, silica gel, molecular sieves). The film-coated tablets were stored for 1 month at 40/75 conditions (40 ° C ± 2 ° C, 75% rel. ± 5%). The liquid chromatography method of analysis determined the content of the breakdown products of atorvastatin (lactone and oxidative degradation) in tablets. As

-2626 reference sample The tablets that were refrigerated (2 to 8 ° C) were analyzed. The moisture content of the tablets was evaluated by gravimetric determination of drying loss (IPS).

Table 5. Growth content of atorvastatin (lactone) decomposition products in film-coated tablets of the present invention stored for 1 month at 40/75 conditions (40 ^c C ± 2 ° C, 75% rel. ± 5%)

Drying agent IPS * (%) Storage conditions Increment content Reference sample 5.08 Refrigerator, 1 month (reference) lactone in% according to the reference sample without a desiccant 5.17 40/75, 1 month 0.21 2 g of silica gel 3.49 40/75, 1 month 0.05 4 g of silica gel 2.73 40/75, 1 month 0.04 2 g molecular sieves 1.99 40/75, 1 month 0.03 4 g molecular sieves 1.55 40/75, 1 month 0.03 2 g silica gel + 2 g molecular sieves 1,73 40/75, 1 month 0.03

IPS * - Drying loss

After one month of accelerated stability testing, we find that due to the lower moisture content of the tablets where the desiccant has been added, the lactone in these tablets is formed to a much smaller extent (0.05% level) than in the non-desiccant tablets ( level 0.22%). There is no significant difference in the percentage of lactone produced below a certain level of moisture in the tablets, i.e. below 3.50% moisture, evaluated as loss on drying.

Table 6. Increase content of atorvastatin degradation products (oxidation degradation products) in film-coated tablets of the present invention stored for 1 month at 40/75 conditions (40 ° C ± 2 ° C, 75% rel. ± 5%)

-2727

Drying agent IPS * (%) Storage conditions Content increment oxidation decomposition products in% by% reference sample Unlined Coated Reference sample 5.08 Refrigerator, 1 month (reference) pills tablets by case 1 without a desiccant 5.17 40 / 75.1 months 0.20 0.14 2 g of silica gel 3.49 40/75, 1 month 0.42 0.12 4 g of silica gel 2.73 40/75, 1 month 0.34 0.12 2 g molecular sieves 1.99 40/75, 1 month 0.43 0.15 4 g molecular sieves 1.55 40/75, 1 month 0.38 0.13 2 g silica gel + 2 g molecular sieves 173 i 40/75, 1 month 0.36 0.11

IPS * - Drying loss

After one month of accelerated stability testing, it is found that the increment of atorvastatin degradation products (oxidation degradation products) in the coated tablet of the present invention is significantly smaller than in the uncoated tablet.

Example 2

Composition of one film-coated tablet

2.1. Tablet core

Table 7. Sail composition

Ingredient Weight (mg) Atorvastatin (as atorvastatin Ca) 40,00 Sodium lauryl sulfate 30,00 ProSolv HD 90 160,00 Pregelatinized corn starch 3.75 Cross-linked carboxymethyl cellulose 12.50

-2828

Magnesium stearate 1,25 Talc 2.50

Making the tablet core

Atorvastatin Ca, ProSolv H D 90, sodium lauryl sulfate, pregelatinized corn starch and cross-linked carboxymethyl cellulose are mixed homogeneously, Magnesium stearate and talc are added, homogeneously mixed and tableted in a controlled low relative humidity 250 mg tablet mass.

2.2. Tablet coating

Table 8. Lining composition

Lining component Weight ratio of core by weight of core (%) and weight of ingredient in coating (mg) 6% 8% Sodium carboxymethyl cellulose 12,275 mg 16,363 mg Glycerol 1,225 mg 1,637 mg Titanium dioxide 1,406 mg 1,875 mg The pigment is yellow 0.094 mg 0,125 mg

Preparation of dispersion for coating and coating the tablet core

Sodium carboxymethyl cellulose (Blanose CMC 7LF PH, Aqualon), (98.178 g) with a viscosity of 25-50 mPas and glycerol (9.822 g) was dissolved in water (2230 g) while stirring and then a dispersion of the colored concentrate was added while stirring. The color concentrate was prepared by grinding aqueous dispersion of titanium dioxide (11,250 g) and pigment yellow (Sicopharm 10, BASF) (0.750 g). The dispersion was sprayed onto the cores to obtain two different coatings of 6% and 8% by weight relative to the weight of the core. During the coating process, the mass of the tablets was checked and the coating applied. 6% film-coated tablets were thus removed from the coating drum during the coating process at an appropriate mass.

For the purposes of this description of the invention, it is believed that the invention may be implemented within a wide and equivalent range of parameters, technical characteristics and conditions as understood by one of skill in the art.

-2929 to the prior art, wherein the embodiments and features, parameters, and conditions described herein should not be construed as limiting the scope of the invention or any object thereof. All references cited herein are incorporated herein by reference to the entire scope and content of the reference.

Claims (27)

A stable pharmaceutical formulation comprising one or more active ingredients sensitive to the pH of the environment and one or more auxiliary pharmaceuticals which allow the stability of one or more active ingredients to the pH of the environment, said pharmaceutical form having a water content of less than 3.5% by weight based on the weight of the total pharmaceutical formulation and does not contain base or buffering agents or combinations thereof. 2. A stable pharmaceutical formulation comprising one or more active ingredients sensitive to the pH of the environment and one or more auxiliary pharmaceuticals which allow the stability of one or more active ingredients to the pH of the environment and selected from the group consisting of different types of microcrystalline cellulose and modified forms of microcrystalline cellulose, wherein said pharmaceutical form has a water content of less than 3.5% by weight by weight of the total pharmaceutical form and does not contain base or buffering agents or combinations thereof. 3. A stable pharmaceutical formulation comprising one or more active ingredients sensitive to the pH of the environment and one or more auxiliary pharmaceuticals which enable the stability of one or more active ingredients to the pH of the environment and selected from the group of physical mixtures of microcrystalline cellulose and colloidal SiO2, wherein said pharmaceutical form has a water content of less than 3.5% by weight by weight of the total pharmaceutical form and does not contain basifying or buffering agents or combinations thereof. A stable pharmaceutical formulation according to any one of the preceding claims 1 to 3, wherein the active ingredient is selected from the group of HMG-CoA reductase inhibitors. A stable pharmaceutical formulation according to any one of the preceding claims 1 to 4, wherein the active ingredient is preferably atorvastatin. 6. A stable pharmaceutical form comprising: a) one or more uncoated particles of one or more active substances that are sensitive to environmental pH, to environmental moisture and / or to oxidation; b) one or more auxiliary pharmaceutical substances which allow the active substance to be stable at ambient pH, wherein said pharmaceutical form is -3131 a water content of less than 3.5% by weight by weight of the total pharmaceutical formulation and does not contain base or buffering agents or combinations thereof; and c) a coating, around a pharmaceutical form, which enables the protection of one alt more active ingredients, one or more auxiliary pharmaceutical substances and pharmaceutical form from oxidation and / or moisture in the environment, and wherein the coating comprises one or more film-makers selected from the group to be selected; consists of sodium carboxymethyl cellulose, hydroxyethyl cellulose and polyvinyl alcohol. 7. A stable pharmaceutical form comprising: a) one or more uncoated particles of one or more active ingredients sensitive to environmental pH, environmental moisture and / or oxidation, and selected from the group of HMG-CoA reductase inhibitors; b) one or more auxiliary pharmaceutical substances which allow the active substance to be stable at ambient pH, said pharmaceutical form having a water content of less than 3.5% by weight by weight of the total pharmaceutical formulation and not containing any base or buffering agent or a combination thereof; and c) a coating, around a pharmaceutical form, which enables the protection of one or more active ingredients, one or more auxiliary pharmaceutical substances and pharmaceutical form from oxidation and / or moisture in the environment, and wherein the coating comprises one or more film-makers selected from the group consisting of it consists of sodium carboxymethyl cellulose, hydroxyethyl cellulose and polyvinyl alcohol. 8. A stable pharmaceutical form comprising: a) one or more uncoated particles of one or more active substances that are sensitive to environmental pH, to environmental moisture and / or to oxidation; b) one or more auxiliary pharmaceutical substances which enable the active substance to be resistant to the pH of the environment and selected from the group consisting of different types of microcrystalline cellulose and modified forms of microcrystalline cellulose, said pharmaceutical form having a water content of less than 3.5% by weight by weight of the total pharmaceutical formulation and does not contain any base or buffering agent or a combination thereof; and c) a coating, around a pharmaceutical form, which enables the protection of one or more active ingredients, one or more auxiliary pharmaceutical substances and pharmaceutical form from oxidation and / or moisture in the environment and wherein the coating comprises one or more -3232 film-makers selected from the group consisting of sodium carboxymethyl cellulose, hydroxyethyl cellulose and polyvinyl alcohol. 9. A stable pharmaceutical form comprising: a) one or more uncoated particles of one or more active ingredients sensitive to environmental pH, environmental moisture and / or oxidation, and selected from the group of HMG-CoA reductase inhibitors; b) one or more auxiliary pharmaceutical substances which enable the active substance to be resistant to the pH of the environment and selected from the group consisting of different types of microcrystalline cellulose and modified forms of microcrystalline cellulose, said pharmaceutical form having a water content of less than 3.5% by weight by weight of the total pharmaceutical formulation and does not contain any base or buffering agent or a combination thereof; and c) a coating, around a pharmaceutical form, which enables the protection of one or more active ingredients, one or more auxiliary pharmaceuticals and pharmaceutical form from oxidation and / or moisture in the environment, and wherein the coating comprises one or more film-makers selected from the group to be selected; consists of sodium carboxymethyl cellulose, hydroxyethyl cellulose and polyvinyl alcohol. 10. A stable pharmaceutical form comprising: a) one or more uncoated particles of one or more active substances that are sensitive to environmental pH, to environmental moisture and / or to oxidation; b) one or more auxiliary pharmaceutical substances which enable the active substance to be resistant to the pH of the environment and selected from the group of physical mixtures of microcrystalline cellulose and colloidal SiO2, said pharmaceutical form having a water content of less than 3.5% by weight by weight of the total pharmaceutical form and does not contain any baseifying or buffering agents or a combination thereof; and c) a coating, around a pharmaceutical form, which enables the protection of one or more active ingredients, one or more auxiliary pharmaceutical substances and pharmaceutical form from oxidation and / or moisture in the environment, and wherein the coating comprises one or more film-makers selected from the group consisting of it consists of sodium carboxymethyl cellulose, hydroxyethyl cellulose and polyvinyl alcohol. -3333 11. A stable pharmaceutical form comprising: a) one or more uncoated particles of one or more active ingredients sensitive to environmental pH, environmental moisture and / or oxidation, and selected from the group of HMG-CoA reductase inhibitors; b) one or more auxiliary pharmaceutical substances which enable the active substance to be resistant to the pH of the environment and selected from the group of physical mixtures of microcrystalline cellulose and colloidal SiO2, said pharmaceutical form having a water content of less than 3.5% by weight by weight of the total pharmaceutical form and does not contain any baseifying or buffering agents or a combination thereof; and c) a coating, around a pharmaceutical form, which enables the protection of one or more active ingredients, one or more auxiliary pharmaceutical substances and pharmaceutical form from oxidation and / or moisture in the environment, and wherein the coating comprises one or more film-makers selected from the group consisting of it consists of sodium carboxymethyl cellulose, hydroxyethyl cellulose and polyvinyl alcohol. 12. A stable pharmaceutical form comprising: a) one or more coated particles of one or more active ingredients that are sensitive to environmental pH, to oxidation and / or moisture in the environment, the active ingredient particle being coated to allow the active substance to be resistant to oxidation and / or moisture in the environment and comprising one or more film formers selected from the group consisting of sodium carboxymethyl cellulose, hydroxyethyl cellulose and polyvinyl alcohol; and b) one or more auxiliary pharmaceuticals which allow the active ingredient to remain at ambient pH, said pharmaceutical form having a water content of less than 3.5% by weight by weight of the total pharmaceutical formulation and not containing any base or buffering agent or a combination thereof. 13. A stable pharmaceutical form comprising: a) one or more coated particles of one or more active ingredients that are sensitive to environmental pH, to oxidation and / or moisture in the environment, the active ingredient particle being coated to allow the active ingredient to resist oxidation and / or moisture; environment; and -3434 b) one or more auxiliary pharmaceutical substances which allow the active substance to be stable at ambient pH, said pharmaceutical form having a water content of less than 3.5% by weight by weight of the total pharmaceutical formulation and not containing any base or buffering agent or a combination thereof; and c) a coating, around a pharmaceutical form, which enables the protection of one or more active ingredients, one or more auxiliary pharmaceutical substances and pharmaceutical form from oxidation and / or moisture in the environment, wherein the coating of the coated particle and pharmaceutical form comprises one or more film formers, which is selected from the group consisting of sodium carboxymethyl cellulose, hydroxyethyl cellulose and polyvinyl alcohol. A stable pharmaceutical formulation according to any one of the preceding claims 6 to 13, wherein the active substance is preferably atorvastatin. A stable pharmaceutical formulation according to any one of the preceding claims 6 to 11 and 12, wherein the pharmaceutical dosage form further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of one or more plasticizers, one or more substances for increasing the viscosity of the coating dispersion, one or more slides, one or more colorants, one or more surfactants and other auxiliary pharmaceutical substances used for film coatings. 16. A stable pharmaceutical formulation as claimed in claim 13, wherein the pharmaceutical formulation and / or coated pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of one or more plasticizers, one or more substances for increasing the viscosity of the coating dispersion, one or more slides, one or more colorants, one or more surfactants and other auxiliary pharmaceuticals used in film coatings. A stable pharmaceutical form according to any preceding claim 15 or 16, wherein the coating softener is selected from the group consisting of glycerol, diglycerol, ethanolamines, ethylene glycol, polyethylene glycols, glycerol alpha-monomethyl ether, glycerol monochloridine, 2,3- butylene glycol, 1,2,6-hexanetriol, 2-nitro-2-methyl-1,3-propanediol, -3535 Propylene glycol, glyceryl triacetate, polyoxyethylene / polyoxypropylene copolymers, triethyl citrate, oleic acid, fractionated coconut oil and combinations thereof. A stable pharmaceutical formulation according to any preceding claim 15 to 17, wherein the viscosity enhancer is selected from the group consisting of carboxymethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, xanthan, alginates, chitosan and combinations thereof. A stable pharmaceutical formulation according to any one of the preceding claims 15 to 18, wherein the coating slider is selected from the group consisting of talc, magnesium stearate, calcium stearate and combinations thereof. A stable pharmaceutical formulation according to any preceding claim 15 to 19, wherein the coating colorant is selected from the group consisting of aluminum lacquers, insoluble pigments, water-soluble paints, titanium dioxide and talc. A stable pharmaceutical formulation according to any preceding claim 15 to 20, wherein the surfactant of the coating is selected from the group consisting of ionic surfactants, non-ionic surfactants or cationic surfactants, or any combination of said surfactants. A stable dosage form according to any one of the preceding claims 1 to 21, further comprising one or more auxiliary pharmaceuticals selected from the group consisting of one or more binders, one or more disintegrators, one or more different glides, one or more surfactants and other similar substances. A stable pharmaceutical form according to any one of the preceding claims 1 to 22, characterized in that it is a solid pharmaceutical form. A stable pharmaceutical formulation according to claim 23, selected from the group consisting of powders, powders for suspensions, granules, tablets, capsules and other similar forms. -3636 A method of preparing a pharmaceutical formulation according to any one of the preceding claims 1 to 24. Use of an environmental pH sensitive agent, oxidation and / or moisture in the environment for the preparation of the pharmaceutical form according to any one of the preceding claims 1 to 24 for the treatment of diseases selected from the group consisting of dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, arteriosclerosis , cardiovascular disease, coronary artery disease, coronary heart disease, circulatory disorders, inflammatory diseases, allergic diseases, neurodegenerative diseases, cancers, viral diseases, bone disorders, disorders of amyloid beta precursor protein processing such as Alzheimer's disease or Down syndrome. Use of an environmentally sensitive agent for the preparation of the pharmaceutical formulation according to any one of the preceding claims 1 to 24 for the treatment of diseases selected from the group consisting of dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, arteriosclerosis, cardiovascular disease, coronary artery disease, coronary heart disease, circulatory disorders, inflammatory diseases, allergic diseases, neurodegenerative diseases, cancers, viral diseases, bone diseases, disorders of amyloid beta precursor protein processing such as Alzheimer's disease or Down syndrome.