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WO2010057449A2 - A solid pharmaceutical composition with atorvastatin and telmisartan as the active substances - Google Patents

A solid pharmaceutical composition with atorvastatin and telmisartan as the active substances Download PDF

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Publication number
WO2010057449A2
WO2010057449A2 PCT/CZ2009/000138 CZ2009000138W WO2010057449A2 WO 2010057449 A2 WO2010057449 A2 WO 2010057449A2 CZ 2009000138 W CZ2009000138 W CZ 2009000138W WO 2010057449 A2 WO2010057449 A2 WO 2010057449A2
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WO
WIPO (PCT)
Prior art keywords
telmisartan
atorvastatin
pharmaceutical composition
composition according
mixture
Prior art date
Application number
PCT/CZ2009/000138
Other languages
French (fr)
Other versions
WO2010057449A3 (en
Inventor
Alena Prokopova
Eva Gryczova
Original Assignee
Zentiva, K.S.
Linek Jan
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zentiva, K.S., Linek Jan filed Critical Zentiva, K.S.
Publication of WO2010057449A2 publication Critical patent/WO2010057449A2/en
Publication of WO2010057449A3 publication Critical patent/WO2010057449A3/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • the invention solves the problem of a pharmaceutical composition containing at the same time two substances, namely atorvastatin, an efficient inhibitor of HMG Co A reductase, and telmisartan, a blocker of ATII receptors. Both these substances exhibit a number of positive effects for treatment and prevention of cardiovascular problems.
  • atorvastatin is primarily used for treatment of hypercholesterolemia while telmisartan is effective against hypertension. It is obvious that a combination of treatment of these two best-known risk factors will significantly improve the development prognosis of various cardiovascular diseases. Pharmaceutical compositions containing both these substances in one dose will improve compliance compared to administration of each dose separately.
  • EP1514543 further describes combinations of atorvastatin with various ATII blockers. The effect of this combination is again focused on treatment and prevention of cardiovascular diseases and reduction of the two risk factors.
  • WO 2004/62557 deals with the use of atorvastatin in combination with telmisartan for treatment of cardiovascular, cardiopulmonary and cardiorenal disorders. According to the application this composition is especially useful for metabolic disorders related to disorders of sugar management of the body. But this application does not mention any composition that would contain both the substances together.
  • Several patent applications are known that deal with the problem of combining telmisartan with another substance. Namely it is the case of hydrochlorothiazide (WO03059327A1 and WO07060170A2) or amlodipine (WO06048208A1). In all the cases the substances are contained in a layered tablet.
  • WO04096215A1 describes a composition of telmisartan with hydrochlorothiazide together in one layer.
  • Atorvastatin is known to be quite an unstable substance and its composition must always be designed from this point of view.
  • a composition of two different active substances must be not only stable, but it also must manifest a corresponding rate of releasing of both the substances. For this reason it is not possible to simply apply the knowledge of behaviour of one composition to another one.
  • the invention provides a solid pharmaceutical composition of telmisartan and atorvastatin in the form of their alkali or alkaline earth salts, containing a basically reacting substance, together either: a) with a mono- or oligosaccharide, soluble in water, or with an alcoholic sugar; or b) with an insoluble polysaccharide
  • Solid particles of the saccharide may appear separately or in granules. In any case, virtually all particles of saccharides are smaller than 0.355 mm.
  • sorbitol is selected as the soluble saccharide. In this case selecting 50 to 80% of the total number of particles smaller than 160 ⁇ m has proved to the beneficial.
  • microcrystalline cellulose was selected as the insoluble saccharide the size of which is, in a preferable embodiment, limited by max. 30% by weight of all particles larger than 75 ⁇ m and at least 50% of the total number of all particles larger than 32 ⁇ m.
  • the particles of microcrystalline cellulose are agglomerated in granules, then advantageously about 75% by weight of all the granules are smaller than 0.5 mm and the size of about 40% by weight of all the granules is in the range of 0.1 to 0.25 mm.
  • the pharmaceutical composition consists of two mixtures, usually produced separately while one of them is a telmisartan mixture and the other one is an atorvastatin mixture.
  • the weight of both the mixtures varies between 50 and 600 mg/tablet in the case of the telmisartan layer and between 140 and 1000 mg/tablet in the case of the atorvastatin layer.
  • these mixtures can only be homogenized and compressed in tablets.
  • a more preferable, but more laborious solution consists in forming a two-layer tablet where each layer will contain one of the mixtures.
  • the invention also provides preferable technical parameters of the product. They include sizes of particles of the active substances, sizes of granules where the active substances may be incorporated, as well as of other pharmaceutical additives.
  • composition stability and the required releasing of both the active substances can be best solved by means of tablets composed of two layers one of which contains an atorvastatin mixture and the other contains a telmisartan mixture. If for technical reasons the problem must be solved by means of a tablet that contains both the active substances in one layer, using an alkali salt of telmisartan in the form of particles obtained by spray drying appears to be convenient.
  • Spray drying is preferably carried out in the following manner: Telmisartan is dissolved in water, preferably in a water/ethanol mixture, in the presence of basic substances, such as NaOH, KOH, meglumine, and the like, conveniently only NaOH, and a binder, e.g. povidone, which does not only serve as a binder, but also a stabilizer of the solution. This solution is spray dried.
  • basic substances such as NaOH, KOH, meglumine, and the like, conveniently only NaOH, and a binder, e.g. povidone, which does not only serve as a binder, but also a stabilizer of the solution.
  • a binder e.g. povidone
  • the spray mixture After drying the spray mixture is mixed with a soluble filler selected from saccharides or sugar alcohols, with an atorvastatin salt, which can be in a granulate form, and other auxiliary substances.
  • a soluble filler selected from saccharides or sugar alcohols
  • an atorvastatin salt which can be in a granulate form
  • other auxiliary substances auxiliary substances.
  • the selection of auxiliary substances is in principle equal to the substances for the atorvastatin layer described below.
  • atorvastatin which would not be in the form of granules additives for direct tabletting of atorvastatin are selected. If atorvastatin has the granulate form, the intergranular additives mentioned below are used.
  • the rate of releasing is controlled by the size of particles of the telmisartan spray dried mixture and the auxiliary substance.
  • the first layer contains telmisartan, which is slowly dissolved from the matrix, and the other layer contains atorvastatin; unlike the first one this layer is quickly disintegrated and so atorvastatin is released quickly. With different disintegration rates or washing of individual layers different dissolution profiles can be achieved, which are important for optimum absorption of both the active substances.
  • a filler that is soluble in water on the basis of carbohydrates is used, such as glucose, sucrose, anhydrous lactose or lactose monohydrate and alcoholic sugars such as sorbitol, mannitol, xylitol, or insoluble saccharides such as microcrystalline cellulose and the like.
  • a filler that is soluble in water on the basis of carbohydrates such as glucose, sucrose, anhydrous lactose or lactose monohydrate and alcoholic sugars such as sorbitol, mannitol, xylitol, or insoluble saccharides such as microcrystalline cellulose and the like.
  • sorbitol or microcrystalline cellulose were preferred.
  • an organic or inorganic base may be used as the basic constituent, such as sodium or potassium hydroxide, meglumine, arginine, and the like. Conveniently, a combination of sodium hydroxide and meglumine in a suitable proportion was used.
  • Substances from the group of polyvinyl pyrrolidones can be used as the binders, such as various types of povidones, povidone 25, povidone 30, or povidone 90, copolymers of vinylpyrrolidones with other vinyl derivatives, e.g. povidone VA 64, microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose and pregelatinized starch. Out of this group of substances the use of povidone and hydroxypropyl cellulose is preferred.
  • Substances such as sodium stearyl fumarate, stearic acid, calcium stearate, magnesium stearate or talc can be used as lubricants. Out of this group of substances mainly magnesium stearate is preferred.
  • the other layer which contains a calcium salt of atorvastatin, gets quickly disintegrated, which means that it quickly releases the active substance.
  • fillers from the group of substances such as pregelatinized starch, microcrystalline cellulose, cellulose, mannitol, sorbitol, xylitol, anhydrous lactose, lactose monohydrate, calcium phosphate, hydrogen or dihydrogen calcium phosphate, and the like can be used. Out of this group a mixture of lactose monohydrate and microcrystalline cellulose is preferred for the second layer.
  • excipients that can be used as the basic constituent include an organic or inorganic base such as sodium or potassium hydroxide, meglumine, arginine, calcium, magnesium, sodium or potassium hydroxide, oxide, carbonate or hydrogen carbonate, etc.
  • an organic or inorganic base such as sodium or potassium hydroxide, meglumine, arginine, calcium, magnesium, sodium or potassium hydroxide, oxide, carbonate or hydrogen carbonate, etc.
  • meglumine or magnesium oxide can be used.
  • Substances from the group of polyvinyl pyrrolidones are used as the binders, such as various types of povidones, povidone 25, povidone 30, or povidone 90, copolymers of vinylpyrrolidones with other vinyl derivatives, e.g. povidone VA 64, microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose and pregelatinized starch. Out of this group of substances the use of hydroxypropyl cellulose is preferred.
  • disintegrants from the group of substances such as maize starch, pregelatinized starch, low substituted hydroxypropyl methylcellulose, microcrystalline cellulose, and further substances from the group of super disintegrants such as sodium salt of crosscarmellose, sodium salt of carboxymethyl starch of type A, B or C, or crosspovidone are used.
  • a mixture of low substituted hydroxypropyl cellulose and sodium salt of crosscarmellose is preferred.
  • colloidal silicon dioxide Colloidal silicon dioxide is conveniently used
  • a substance such as sodium stearyl fumarate, stearic acid, calcium stearate, magnesium stearate, talc, cutin, can be used as the lubricant Out of this group of substances mainly magnesium stearate is preferred
  • Purified water or a mixture of water and ethanol, or possibly methanol in various proportions is used as the solvents
  • Preferred solvents are pu ⁇ fied water and ethanol These solvents are lemoved from the tablet mass in the course of the production process by drying For coating of tablets film-forming substances, lubricants, pigments, softeners are used
  • Two-layered tablets in accordance with the invention may contain 10 - 80 mg of telmisartan and 10 - 80 mg of atorvastatin in the calcium salt form Preferably 20, 40 and 80 mg of telmisartan and 10, 20, 40 and 80 mg of atorvastatin in the calcium salt form
  • the telmisartan layer can be prepared by the following procedures:
  • telmisartan in the tablet mass is in the amorphous form
  • Spray drying - Telmisartan is dissolved in water, conveniently in a water/ethanol mixture, in the presence of basic substances such as NaOH, KOH, meglumine, and the like, preferably only NaOH, and a binder, e g povidone, which serves not only as a binder, but also as stabilizer of the solution
  • a binder e g povidone
  • This solution is spray dried After drying the spray mixture is mixed with a soluble filler, such as sorbitol, or an insoluble filler, microcrystalline cellulose with a suitable particle size, and other excipients such as meglumine or magnesium stearate
  • Fluid gianulation - Telmisartan is dissolved in water, conveniently in a water/ethanol mixture in the presence of basic substances such as NaOH, KOH, meglumine, and the like, preferably only NaOH, and a binder, e g povidone, which serves not only as a binder, but also as stabilizer of the solution.
  • a soluble filler such as sorbitol or monosaccharides, or an insoluble filler, e.g. microcrystalline cellulose, is fluid granulated with this solution.
  • the dried and sieved granulate is mixed with a portion of the soluble or insoluble filler with a suitable particle size and with other excipients such as meglumine or magnesium stearate.
  • the particle size of the soluble filler can be in the range of 0 - 355 microns, preferably 100 microns.
  • the particle size of the insoluble filler can be in the range of 0 - 250 microns, preferably 50 microns.
  • An example of using a soluble saccharide as the filler can include sorbitol with the particle size of at most 7% of all particles greater than 315 ⁇ m; 20 to 50% greater than 160 ⁇ m; and at least 80% greater than 40 ⁇ m.
  • Another method of characterization is by means of percentiles, e.g. D50 greater than 125 ⁇ m.
  • an insoluble saccharide as the filler microcrystalline cellulose can by conveniently used with at most 1% by weight of particles greater than 250 ⁇ m; at most 30% greater than 75 ⁇ m and at least 50% greater than 32 ⁇ m.
  • the size of used particles can be characterized by means of percentiles, namely DlO smaller than 30 ⁇ m; D50 in the range of 40-60 ⁇ m and D90 larger than 80 ⁇ m.
  • meglumine as the basic constituent of the telmisartan solution may cause hardening of the granulate after drying, so that it is difficult to process afterwards. This hardening is manifested even after additional mixing with tabletting additives, e.g. magnesium stearate. It has been surprisingly found out that if meglumine is only added in the extragranulation stage, this effect does not appear and the granulate or tablet mass are much easier to process. Description of preparation of the atorvastatin layer:
  • Atorvastatin calcium salt is in the tablets in the amorphous form, or a crystalline modification can be used
  • a/ Granulation by mastication - Atorvastatin in the calcium salt form is mixed with the other ingredients such as microcrystalline cellulose, lactose, hydroxypropyl cellulose and possibly a poition of crosscarmellose, or magnesium oxide or calcium carbonate
  • This mixture is granulated with an aqueous or spirituous-aqueous solution of meglumine, or with only water oi a water/ethanol mixture
  • the resulting granulate is dned in a fluid way or on metal sheets
  • the dried granulate is sieved to a suitable size of granules, which are subsequently mixed with additional extragranular excipients such as magnesium stearate and colloidal silicon dioxide, or a portion of crosscarmellose
  • b/ Dry granulation - Atorvastatin in the calcium salt form is mixed with the other ingredients such as microcrystalline cellulose, lactose, hydroxypropyl cellulose and possibly a portion of crosscarmellose, or magnesium oxide or meglumine
  • the resulting mixture is compacted in a suitable compactor or compressed in a tabletting press using large dies
  • the resulting compactates are sieved to a suitable size of granules, which are subsequently mixed with additional extragranular excipients such as magnesium stearate and colloidal silicon dioxide, oi a portion of crosscarmellose
  • c/ Direct mixing - Atorvastatin in the calcium salt form is mixed with the other ingredients such as microcrystalline cellulose, lactose, hydroxypropyl cellulose, and possibly a portion of crosscarmellose, or magnesium oxide or meglumine Extragranular excipients such as magnesium stearate and colloidal silicon dioxide, or a portion of crosscarmellose are admixed to the iesulting mixture
  • compositions are compressed to two-layer tablets, which are coated with a coat of a film-forming substance containing softeners, pigments and other fillers
  • the coated tablets are conveniently adjusted into Al/Al blister packs, optionally under an inert atmosphere.
  • the speed of releasing of individual constituents was monitored in a dissolution device with the use of the paddle method in a phosphate buffer with pH 7.5.
  • composition A7 Under these conditions e.g. in the case of composition A7 the following percentages of active constituents were released:
  • T he speed of releasing of individual constituents was monitored in a dissolution device with the use of the paddle method in a phosphate buffer with pH 7.5. Under these conditions e.g. in the case of composition A9 the following percentages of active constituents were released:

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Abstract

A solid pharmaceutical composition with the active substances telmisartan and atorvastatin, characterized by in that both the substances are in the form of alkali or alkaline earth salts and the composition further contains an organic or inorganic base selected from the substances meglumine, sodium or potassium hydroxide, calcium or magnesium or sodium or potassium hydroxide, oxide or carbonate, and further polyvinyl pyrrolidone and a filler selected either from: a) a mono- or oligosaccharide soluble in water, or an alcoholic sugar, the size of 95% by weight of all particles of the filler, which may be present in the composition either individually or combined in larger granules, 99% by weight of which are smaller than 1.0 mm, being in the range of 0.025 to 0.355 mm; b) or a polysaccharide insoluble in water, 95% by weight of all particles of the filler, which may be present in the composition either individually or combined in large granules, 75% by weight of which are smaller than 0.50 mm, being smaller than 0.25 mm.

Description

A SOLID PHARMACEUTICAL COMPOSITION WITH ATORVASTATIN AND TELMISARTAN AS THE ACTIVE SUBSTANCES
Technical Field
The invention solves the problem of a pharmaceutical composition containing at the same time two substances, namely atorvastatin, an efficient inhibitor of HMG Co A reductase, and telmisartan, a blocker of ATII receptors. Both these substances exhibit a number of positive effects for treatment and prevention of cardiovascular problems. However, atorvastatin is primarily used for treatment of hypercholesterolemia while telmisartan is effective against hypertension. It is obvious that a combination of treatment of these two best-known risk factors will significantly improve the development prognosis of various cardiovascular diseases. Pharmaceutical compositions containing both these substances in one dose will improve compliance compared to administration of each dose separately.
Background Art
Possibilities of combined administration of inhibitors of HMG Co A reductase and blockers of ATII receptors have been known for some time. For example, publication no. WO 95/26188 suggests treatment of atherosclerosis, reduction of the cholesterol level and possibly blood pressure reduction by the effect of this combination.
The application no. EP1514543 further describes combinations of atorvastatin with various ATII blockers. The effect of this combination is again focused on treatment and prevention of cardiovascular diseases and reduction of the two risk factors.
The application no. WO 2004/62557 deals with the use of atorvastatin in combination with telmisartan for treatment of cardiovascular, cardiopulmonary and cardiorenal disorders. According to the application this composition is especially useful for metabolic disorders related to disorders of sugar management of the body. But this application does not mention any composition that would contain both the substances together. Several patent applications are known that deal with the problem of combining telmisartan with another substance. Namely it is the case of hydrochlorothiazide (WO03059327A1 and WO07060170A2) or amlodipine (WO06048208A1). In all the cases the substances are contained in a layered tablet.
WO04096215A1 describes a composition of telmisartan with hydrochlorothiazide together in one layer.
Atorvastatin is known to be quite an unstable substance and its composition must always be designed from this point of view.
A composition of two different active substances must be not only stable, but it also must manifest a corresponding rate of releasing of both the substances. For this reason it is not possible to simply apply the knowledge of behaviour of one composition to another one.
So the task was to develop such a composition of telmisartan and atorvastatin that would meet all the relevant requirements to improve satisfaction of patients as well as physicians with the combined therapy.
Disclosure of Invention
The invention provides a solid pharmaceutical composition of telmisartan and atorvastatin in the form of their alkali or alkaline earth salts, containing a basically reacting substance, together either: a) with a mono- or oligosaccharide, soluble in water, or with an alcoholic sugar; or b) with an insoluble polysaccharide
(generally a saccharide).
Solid particles of the saccharide may appear separately or in granules. In any case, virtually all particles of saccharides are smaller than 0.355 mm.
If they are cumulated in granules, virtually all granules must be smaller than 1 mm and in the case of an insoluble polysaccharide even smaller than 0.5 mm. In a preferable embodiment sorbitol is selected as the soluble saccharide. In this case selecting 50 to 80% of the total number of particles smaller than 160 μm has proved to the beneficial.
In a preferable embodiment microcrystalline cellulose was selected as the insoluble saccharide the size of which is, in a preferable embodiment, limited by max. 30% by weight of all particles larger than 75 μm and at least 50% of the total number of all particles larger than 32 μm.
If the particles of microcrystalline cellulose are agglomerated in granules, then advantageously about 75% by weight of all the granules are smaller than 0.5 mm and the size of about 40% by weight of all the granules is in the range of 0.1 to 0.25 mm.
The pharmaceutical composition consists of two mixtures, usually produced separately while one of them is a telmisartan mixture and the other one is an atorvastatin mixture.
The weight of both the mixtures varies between 50 and 600 mg/tablet in the case of the telmisartan layer and between 140 and 1000 mg/tablet in the case of the atorvastatin layer.
In the simplest embodiment according to the invention these mixtures can only be homogenized and compressed in tablets.
A more preferable, but more laborious solution consists in forming a two-layer tablet where each layer will contain one of the mixtures.
The invention also provides preferable technical parameters of the product. They include sizes of particles of the active substances, sizes of granules where the active substances may be incorporated, as well as of other pharmaceutical additives.
Detailed description of the invention
The problem of composition stability and the required releasing of both the active substances can be best solved by means of tablets composed of two layers one of which contains an atorvastatin mixture and the other contains a telmisartan mixture. If for technical reasons the problem must be solved by means of a tablet that contains both the active substances in one layer, using an alkali salt of telmisartan in the form of particles obtained by spray drying appears to be convenient.
Spray drying is preferably carried out in the following manner: Telmisartan is dissolved in water, preferably in a water/ethanol mixture, in the presence of basic substances, such as NaOH, KOH, meglumine, and the like, conveniently only NaOH, and a binder, e.g. povidone, which does not only serve as a binder, but also a stabilizer of the solution. This solution is spray dried.
After drying the spray mixture is mixed with a soluble filler selected from saccharides or sugar alcohols, with an atorvastatin salt, which can be in a granulate form, and other auxiliary substances. The selection of auxiliary substances is in principle equal to the substances for the atorvastatin layer described below. In the case of addition of atorvastatin which would not be in the form of granules additives for direct tabletting of atorvastatin are selected. If atorvastatin has the granulate form, the intergranular additives mentioned below are used.
In this case the rate of releasing is controlled by the size of particles of the telmisartan spray dried mixture and the auxiliary substance.
If a two-layer tablet is selected, it is considerably easier to adjust the required profiles of releasing of the active substances, but the production is more demanding from the technological point of view as it requires less usual tabletting equipment.
The first layer contains telmisartan, which is slowly dissolved from the matrix, and the other layer contains atorvastatin; unlike the first one this layer is quickly disintegrated and so atorvastatin is released quickly. With different disintegration rates or washing of individual layers different dissolution profiles can be achieved, which are important for optimum absorption of both the active substances.
It has been found out that in order to achieve the required effect such composition must be produced that would, at the conditions described in Pharm.Eur., with the use of the paddle method at the rotational speed of 75 min" , achieve the following values of releasing the active ingredients in the phosphate buffer environment at pH 7.5:
for atorvastatin:
Figure imgf000006_0001
for telmisartan:
Figure imgf000006_0002
For preparation of the first layer containing telmisartan, to produce a soluble layer either a filler that is soluble in water on the basis of carbohydrates is used, such as glucose, sucrose, anhydrous lactose or lactose monohydrate and alcoholic sugars such as sorbitol, mannitol, xylitol, or insoluble saccharides such as microcrystalline cellulose and the like. For the composition of the telmisartan layer sorbitol or microcrystalline cellulose were preferred.
Out of other excipients, an organic or inorganic base may be used as the basic constituent, such as sodium or potassium hydroxide, meglumine, arginine, and the like. Conveniently, a combination of sodium hydroxide and meglumine in a suitable proportion was used.
Substances from the group of polyvinyl pyrrolidones can be used as the binders, such as various types of povidones, povidone 25, povidone 30, or povidone 90, copolymers of vinylpyrrolidones with other vinyl derivatives, e.g. povidone VA 64, microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose and pregelatinized starch. Out of this group of substances the use of povidone and hydroxypropyl cellulose is preferred.
Substances such as sodium stearyl fumarate, stearic acid, calcium stearate, magnesium stearate or talc can be used as lubricants. Out of this group of substances mainly magnesium stearate is preferred.
The other layer, which contains a calcium salt of atorvastatin, gets quickly disintegrated, which means that it quickly releases the active substance. For this layer fillers from the group of substances such as pregelatinized starch, microcrystalline cellulose, cellulose, mannitol, sorbitol, xylitol, anhydrous lactose, lactose monohydrate, calcium phosphate, hydrogen or dihydrogen calcium phosphate, and the like can be used. Out of this group a mixture of lactose monohydrate and microcrystalline cellulose is preferred for the second layer.
Other excipients that can be used as the basic constituent include an organic or inorganic base such as sodium or potassium hydroxide, meglumine, arginine, calcium, magnesium, sodium or potassium hydroxide, oxide, carbonate or hydrogen carbonate, etc. Preferably, meglumine or magnesium oxide can be used.
Substances from the group of polyvinyl pyrrolidones are used as the binders, such as various types of povidones, povidone 25, povidone 30, or povidone 90, copolymers of vinylpyrrolidones with other vinyl derivatives, e.g. povidone VA 64, microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose and pregelatinized starch. Out of this group of substances the use of hydroxypropyl cellulose is preferred.
For quick disintegration disintegrants from the group of substances such as maize starch, pregelatinized starch, low substituted hydroxypropyl methylcellulose, microcrystalline cellulose, and further substances from the group of super disintegrants such as sodium salt of crosscarmellose, sodium salt of carboxymethyl starch of type A, B or C, or crosspovidone are used. For this layer a mixture of low substituted hydroxypropyl cellulose and sodium salt of crosscarmellose is preferred. For improvement of flow characteπstics substances from the group of substances such as colloidal silicon dioxide, talc, and the like are used Colloidal silicon dioxide is conveniently used
A substance such as sodium stearyl fumarate, stearic acid, calcium stearate, magnesium stearate, talc, cutin, can be used as the lubricant Out of this group of substances mainly magnesium stearate is preferred
Purified water or a mixture of water and ethanol, or possibly methanol in various proportions is used as the solvents Preferred solvents are puπfied water and ethanol These solvents are lemoved from the tablet mass in the course of the production process by drying For coating of tablets film-forming substances, lubricants, pigments, softeners are used
Two-layered tablets in accordance with the invention may contain 10 - 80 mg of telmisartan and 10 - 80 mg of atorvastatin in the calcium salt form Preferably 20, 40 and 80 mg of telmisartan and 10, 20, 40 and 80 mg of atorvastatin in the calcium salt form
The telmisartan layer can be prepared by the following procedures:
Several different methods of preparation of telmisartan tablet mass can be used Telmisartan in the tablet mass is in the amorphous form
Spray drying - Telmisartan is dissolved in water, conveniently in a water/ethanol mixture, in the presence of basic substances such as NaOH, KOH, meglumine, and the like, preferably only NaOH, and a binder, e g povidone, which serves not only as a binder, but also as stabilizer of the solution This solution is spray dried After drying the spray mixture is mixed with a soluble filler, such as sorbitol, or an insoluble filler, microcrystalline cellulose with a suitable particle size, and other excipients such as meglumine or magnesium stearate
Fluid gianulation - Telmisartan is dissolved in water, conveniently in a water/ethanol mixture in the presence of basic substances such as NaOH, KOH, meglumine, and the like, preferably only NaOH, and a binder, e g povidone, which serves not only as a binder, but also as stabilizer of the solution. A soluble filler, such as sorbitol or monosaccharides, or an insoluble filler, e.g. microcrystalline cellulose, is fluid granulated with this solution. The dried and sieved granulate is mixed with a portion of the soluble or insoluble filler with a suitable particle size and with other excipients such as meglumine or magnesium stearate.
The particle size of the soluble filler can be in the range of 0 - 355 microns, preferably 100 microns. The particle size of the insoluble filler can be in the range of 0 - 250 microns, preferably 50 microns. The use of a fine filler in the case of fluid granulation results in the formation of fine granules with even distribution of the active substance telmisartan. If a large size of filler particles is used, telmisartan is applied on the surface of the filler particles and the homogeneity of the granulate is lower.
An example of using a soluble saccharide as the filler can include sorbitol with the particle size of at most 7% of all particles greater than 315 μm; 20 to 50% greater than 160 μm; and at least 80% greater than 40 μm.
Another method of characterization is by means of percentiles, e.g. D50 greater than 125 μm.
In the case of an insoluble saccharide as the filler microcrystalline cellulose can by conveniently used with at most 1% by weight of particles greater than 250 μm; at most 30% greater than 75 μm and at least 50% greater than 32 μm.
Otherwise, the size of used particles can be characterized by means of percentiles, namely DlO smaller than 30 μm; D50 in the range of 40-60 μm and D90 larger than 80 μm.
Using meglumine as the basic constituent of the telmisartan solution may cause hardening of the granulate after drying, so that it is difficult to process afterwards. This hardening is manifested even after additional mixing with tabletting additives, e.g. magnesium stearate. It has been surprisingly found out that if meglumine is only added in the extragranulation stage, this effect does not appear and the granulate or tablet mass are much easier to process. Description of preparation of the atorvastatin layer:
Several different procedures of preparation of the tablet mass of atorvastatin can be used Atorvastatin calcium salt is in the tablets in the amorphous form, or a crystalline modification can be used
a/ Granulation by mastication - Atorvastatin in the calcium salt form is mixed with the other ingredients such as microcrystalline cellulose, lactose, hydroxypropyl cellulose and possibly a poition of crosscarmellose, or magnesium oxide or calcium carbonate This mixture is granulated with an aqueous or spirituous-aqueous solution of meglumine, or with only water oi a water/ethanol mixture The resulting granulate is dned in a fluid way or on metal sheets The dried granulate is sieved to a suitable size of granules, which are subsequently mixed with additional extragranular excipients such as magnesium stearate and colloidal silicon dioxide, or a portion of crosscarmellose
b/ Dry granulation - Atorvastatin in the calcium salt form is mixed with the other ingredients such as microcrystalline cellulose, lactose, hydroxypropyl cellulose and possibly a portion of crosscarmellose, or magnesium oxide or meglumine The resulting mixture is compacted in a suitable compactor or compressed in a tabletting press using large dies The resulting compactates are sieved to a suitable size of granules, which are subsequently mixed with additional extragranular excipients such as magnesium stearate and colloidal silicon dioxide, oi a portion of crosscarmellose
c/ Direct mixing - Atorvastatin in the calcium salt form is mixed with the other ingredients such as microcrystalline cellulose, lactose, hydroxypropyl cellulose, and possibly a portion of crosscarmellose, or magnesium oxide or meglumine Extragranular excipients such as magnesium stearate and colloidal silicon dioxide, or a portion of crosscarmellose are admixed to the iesulting mixture
Compression, coating and packing of tablets
Thus prepared tablet masses are compressed to two-layer tablets, which are coated with a coat of a film-forming substance containing softeners, pigments and other fillers The coated tablets are conveniently adjusted into Al/Al blister packs, optionally under an inert atmosphere. Examples of compositions:
Telmisartan 80 mg / Atorvastatin 10 mg - 2-layer cores
Figure imgf000011_0001
Telmisartan 80 mg / Atorvastatin 10 mg - 2-layer cores
Figure imgf000012_0001
Examples of compositions:
Telmisartan 80 mg / Atorvastatin 10 mg - 2-layer cores
Figure imgf000013_0001
The speed of releasing of individual constituents was monitored in a dissolution device with the use of the paddle method in a phosphate buffer with pH 7.5.
Under these conditions e.g. in the case of composition A7 the following percentages of active constituents were released:
Figure imgf000014_0001
Examples of compositions:
Telmisartan 80 mg / Atorvastatin 20 mg - 2-layer cores
Figure imgf000014_0002
Figure imgf000015_0001
Tclmisartan 80 mg / Atorvastatin 20 mg - 2-layer cores
Figure imgf000016_0001
T he speed of releasing of individual constituents was monitored in a dissolution device with the use of the paddle method in a phosphate buffer with pH 7.5. Under these conditions e.g. in the case of composition A9 the following percentages of active constituents were released:
Figure imgf000017_0001

Claims

C LAIM S
A solid phaimaceutical composition with the active substances telmisartan and atoivastatin, characterized in that both the substances are in the form of alkali or alkaline earth salts and the composition further contains an organic or inorganic base selected from the substances meglumine, sodium or potassium hydroxide, calcium or magnesium or sodium or potassium hydroxide, oxide or carbonate, and further polyvinyl pyrolidone PVP and a filler selected either from a) a mono- oi oligosaccharide soluble in water, or an alcoholic sugar, the size of 95% by weight of all particles of the filler, which can be present in the composition eithei individually or combined in larger granules 99% by weight of which are smaller than 1 0 mm, being in the range of 0 025 to 0 355 mm, b) oi a polysaccharide insoluble in water, 95% by weight of all particles of the filler, which can be present in the composition either individually or combined in large gi anules 75% by weight of which are smaller than 0 50 mm, being smaller than
0 25 mm
The phaimaceutical composition according to claim 1, characterized in that a soluble filler is selected, 70 to 80% by weight of possible granules of the filler being in the size iange of 0 1 to 0 8 mm and 60 to 70% of all particles of the filler being in the size iange of 0 025 to 0 125 mm
The pharmaceutical composition according to claim 1 , characterized in that an insoluble filler is selected, 50 to 70% by weight of possible granules of the filler being in the size iange of 0 1 to 0 8 mm and 80% being smaller than 0 25 mm and the size of all free particles of the filler being in the size interval at most 1 % > 250 μm (60 mesh), at most 30 % > 75 μm (200 mesh), at least 50 % > 32 μm (469 mesh), or DlO < 30 μm, D50 = 40-60 μm, D90 < 80 μm
The pharmaceutical composition according to claims 1 or 2, characterized in that the soluble fillei sorbitol is selected The pharmaceutical composition according to claims 1 or 3, characterized in that the insoluble filler microcrystalline cellulose is selected
The pharmaceutical composition according to claims 1 to 5, characterized in that it is composed of two mixtures, the first one of which contains telmisartan sodium or potassium salt, a) a water-soluble filler according to claims 1, 2 or 4 or b) a water- insoluble filler according to claims 1, 3 or 5, PVP and sodium or potassium hydroxide, meglumine, sodium crosscarmellose, optionally other pharmaceutically acceptable substances, and the other one of which contains atorvastatin calcium or magnesium salt, magnesium or calcium hydroxide, oxide or carbonate, or meglumine and optionally other pharmaceutically acceptable substances
The pharmaceutical composition according to claim 6, characterized in that both the mixtures are either compressed together in a single layer of the tablet, or are separated in two different layers
The pharmaceutical composition according to any one of the preceding claims, characterized in that the telmisartan mixture consists of a granulate that is bound with a solution of the telmisartan salt and PVP and a base consisting of sodium or potassium hydroxide, optionally in a mixture with meglumine
The pharmaceutical composition according to claim 8, characterized in that PVP of type 25, 30 oi 90 is used for the function of a binder in an amount of 5 to 10% by weight, based on the telmisartan mixture
The pharmaceutical composition according to claim 9, characterized in that the amount of PVP of type 25 is selected as 8 3 ±0 5% by weight, based on the telmisartan mixture
The pharmaceutical composition according to claims 1 to 10, characterized in that it contains a telmisartan salt with the particle size of 0 5 to 5 μm, which does not form clusters laiger than 50 μm
12. The pharmaceutical composition according to claim 11, characterized in that it contains a telmisartan salt with the particle size of 2 to 3 μm.
13. The pharmaceutical composition according to claims 6 to 12, characterized in that the telmisartan mixture contains sodium or potassium hydroxide inside granules while meglumine outside granules.
14. The pharmaceutical composition according to claims 6 to 13, characterized in that it contains 0.5 to 3% of sodium or potassium hydroxide, 1 to 10% of meglumine, 10 to 20% of telmisartan and 0.5 to 3% of magnesium stearate, based on the weight of the telmisartan mixture.
15. The pharmaceutical composition according to claim 14, characterized in that it contains 1 to 2% of sodium or potassium hydroxide, 4 to 8% of meglumine, 10 to 20% of telmisartan and 0.8 to 2.5% of magnesium stearate, based on the telmisartan mixture.
16. The pharmaceutical composition according to any one of the preceding claims, characterized in that it contains atorvastatin calcium salt in the amorphous form with the size of 95% of particles smaller than 50 μm.
17. The pharmaceutical composition according to any one of the preceding claims, characterized in that it contains atorvastatin calcium salt in the crystalline form with the particle size of 0 to 40 μm.
18. The pharmaceutical composition according to any one of the preceding claims, characterized in that the atorvastatin component consists of a granulate that contains 50 to 80% by weight of granules with the size of 0.1 to 1.5 mm and 20 to 50% of powder fractions smaller than 0.1 mm, the substance atorvastatin being inside these granules.
19. The pharmaceutical composition according to any one claims 1 to 17, characterized in that the atorvastatin mixture contains a filler with the size of particles or granules of 0.025 to 3 mm , the atorvastatin salt being outside said particles or granules.
20. The pharmaceutical composition according to any one of the preceding claims, characterized in that the atorvastatin mixture contains a base selected from calcium or magnesium or sodium carbonate or calcium or magnesium or sodium oxide, or meglumine.
21. The pharmaceutical composition according to claim 20, characterized in that the base is selected from the substances magnesium oxide, calcium carbonate or meglumine, or their combination.
22. The pharmaceutical composition according to any one of the preceding claims, characterized in that it contains tween (polysorbate) in an amount of 0.5 to 10% by weight, based on the atorvastatin mixture.
23. The pharmaceutical composition according to claim 22, characterized in that it contains tween in an amount of 1 to 4% by weight, based on the atorvastatin mixture.
24. The pharmaceutical composition according to claims 20 to 23, characterized in that the atorvastatin mixture further contains a filler selected from microcrystalline cellulose, lactose or sorbitol, or their mixture, a binder selected from PVP, hydroxypropyl cellulose, hydroxypropyl methylcellulose or starch, a disintegrant selected from crosscarmellose, crosspovidone, carboxymethyl cellulose or its salt and a lubricant selected from stearic acid or its salts.
25. The pharmaceutical composition according to claim 24, characterized in that the atorvastatin mixture contains a mixture of microcrystalline cellulose and lactose as a filler, hydroxypropyl cellulose as a binder, crosscarmellose as a disintegrant and the magnesium salt of stearic acid as a lubricant.
26. The pharmaceutical composition according to claim 25, characterized in that the atorvastatin mixture contains 5 to 15% of atorvastatin, based on the free acid, 10 to 40% of lactose, 30 to 60% of microcrystalline cellulose, 2.5 to 10% of crosscarmellose and 5 to 20% of hydroxypropyl cellulose, each based on the atorvastatin mixture.
27. The pharmaceutical composition according to any one of the preceding claims, characterized in that the weight proportion of the atorvastatin and telmisartan mixtures is in the range of 2 : 1 to 1 : 10.
28. The pharmaceutical composition according to claim 27, characterized in that the weight proportion of the atorvastatin and telmisartan mixtures is in the range of 1 : 1 to
1 : 5.
29. A method for the manufacture of the composition according to any one of the preceding claims, characterized in that first the atorvastatin and telmisartan mixtures are prepared separately, the mixtures are mixed in a homogenization device and finally compressed in a tabletting machine, and optionally the tablet is provided with a coating.
30. A method for the manufacture of the composition according to claims 1 to 28, characterized in that the atorvastatin and telmisartan mixtures are prepared and separately fed to the tabletting machine where the telmisartan layer is compressed first and the second atorvastatin layer is compressed afterwards.
31. The method according to claims 29 or 30, characterized in that the method comprises preparation of the telmisartan mixture consisting in spraying of a solution of telmisartan in water, or in a mixture of water and ethanol, sodium hydroxide, PVP and optionally meglumine onto a fluidized layer of a filler selected from a soluble mono- or oligosaccharide or sugar alcohol according to claims 1 or 2 or an insoluble polysaccharide according to claims 1 or 3, whereafter the dried granulate is mixed with another fraction of the saccharide, a lubricant and optionally with meglumine.
32. The method according to claim 31, characterized in that meglumine is only admixed to the prepared granulate.
33. The method according to claims 29 or 30, characterized in that the method comprises preparation of the telmisartan mixture consisting in spray drying of a solution of telmisartan, sodium hydroxide and optionally meglumine and mixing of the resulting solid mixture with a filler selected from a soluble mono-' or oligosaccharide or sugar alcohol, or an insoluble polysaccharide and with other auxiliary substances and optionally meglumine.
34. The method according to claim 33, characterized in that meglumine is only admixed to the prepared spray dried mixture.
35. The method according to claims 29 or 30, characterized in that the method comprises preparation of the atorvastatin mixture by mastication of the active substance, filler, binder, optionally a portion of the disintegrant and optionally calcium or magnesium carbonate or oxide with water, a mixture of water and ethanol or a solution of meglumine in water or in said mixture, whereafter the resulting mixture is granulated, dried and further processed by grinding or sieving and mixed with the disintegrant or its remaining portion, the lubricant and a substance for improving flow characteristics.
36. The method according to claims 29 or 30, characterized in that for the preparation of the atorvastatin mixture the active substance in the salt form is mixed with the filler, binder, optionally a portion of the disintegrant and optionally with the corresponding base and compacted in a special compactor or tabletting press with large dies, whereafter the resulting compactate is sieved to granules of the required size, which are further mixed with the disintegrant or its remaining portion and the lubricant.
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