Patent Application
20060110450
This application claims priority to European Application No. EP 04 026 234.7, filed Nov. 5, 2004, which is hereby incorporated by reference in its entirety.
The present invention relates to a pharmaceutical tablet comprising a first layer of the angiotensin II receptor antagonist telmisartan in a dissolving tablet matrix and a second layer of the calcium channel blocker amlodipine in a disintegrating or eroding tablet matrix.
Telmisartan is an angiotensin II receptor antagonist developed for the treatment of hypertension and other medical indications as disclosed in EP-A-502314. Its chemical name is 4′-[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid having the following structure:
Telmisartan is manufactured and supplied in the free acid form. It is characterized by its very poor solubility in aqueous systems at the physiological pH range of the gastrointestinal tract between pH 1 to 7. As disclosed in WO 00/43370, crystalline telmisartan exists in two polymorphic forms having different melting points. Under the influence of heat and humidity, the lower melting polymorph B transforms irreversibly into the higher melting polymorph A.
Amlodipine was first disclosed in EP-A-89167. It belongs to the group of calcium channel blockers and its chemical name is 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate (C20H25ClN2O5; MR 408.88), having the following structure:
Pharmaceutically amlodipine is used as maleate (C24H29ClN2O9; MR 524.96), benzenesulfonate or besylate (C26H31ClN2O8S; MR 567.10; EP-A-244,944), and mesylate (C21H26ClN2O8S; MR 502.01) salts.
“Calcium channel blockers” are also called “calcium antagonists” or “calcium blockers”. They are medications that decrease the heart's pumping strength and relax blood vessels. They are used to treat high blood pressure, angina (chest pain or discomfort caused by reduced blood supply to the heart muscle), and some arrhythmias.
The mechanisms of action of telmisartan and amlodipine are considered to cooperate favorably in the treatment of hypertension particularly in patients where the target blood pressure cannot be achieved with one of the medications only. There is an increasing desire for a fixed dose combination product comprising the active ingredients telmisartan and amlodipine. However, both telmisartan and amlodipine are chemical compounds difficult to handle. Therefore, an oral fixed dose combination dosage form which combines the features of pharmacologic efficacy, adequate drug stability, and a reliable and robust method of manufacture has to overcome a number of technical problems. It is an object of the present invention to provide such a fixed dose combination dosage form.
There are various types of fixed dose combination dosage forms conceivable but it cannot be predicted which of these dosage forms best combines product stability, pharmacological efficacy, and reliable manufacture. Generally, combinations of two active pharmaceutical ingredients could be formulated as oral solid or oral liquid dosage forms such as tablets, capsules, coated or sugar-coated tablets, granules, oral solutions, emulsions or suspensions, syrups, and lozenges. In view of experiences with liquid dosage forms of telmisartan, oral liquid dosage forms are not considered a preferred embodiment according to the present invention. An instant release oral solid dosage form containing two drugs could be prepared by either making a powder mixture or a co-granulate of the two active ingredients with the necessary excipients. However, for a combination of telmisartan and amlodipine, this approach turns out not to result in a dosage form with sufficient product stability. A telmisartan formulation with acceptable in vivo performance has to comprise basic components like, for example, sodium hydroxide or meglumine, whereas amlodipine is surprisingly not stable enough when it gets in direct contact with excipients to be used in a telmisartan formulation. The ester bonds in the amlodipine molecule appear to be subject to hydrolysis when exposed to an alkaline milieu. Therefore, the standard approach of directly mixing the active components with the necessary excipients cannot be applied to a fixed dose combination of telmisartan and amlodipine and more sophisticated techniques are needed to separate the basic telmisartan formulation from the amlodipine drug substance. Under these circumstances, perlonget, coating, or bilayer tablet technology could be used.
The perlonget approach is to produce separate film-coated tablets for telmisartan and amlodipine in such a size and shape that these can be filled into capsules. It turns out that large capsule sizes like 0 or bigger would be required for the high dose combinations, which is not preferable with regard to patients' compliance.
Another approach is to apply a film coat to the pure amlodipine drug substance or to granules/pellets containing amlodipine. Surprisingly, these coated particles are not stable in the alkaline and hygroscopic milieu of the telmisartan formulation.
The present invention is based on the recognition, that the dosage form, which best combines adequate drug stability, optimum drug release of both active ingredients, pharmacological efficacy, and reliable manufacture for a combination of telmisartan and amlodipine, is a bilayer tablet.
In accordance with the present invention, problems associated with the preparation of a fixed dose combination drug comprising telmisartan and amlodipine can best be handled by means of a bilayer pharmaceutical tablet comprising a first layer of telmisartan, preferably in substantially amorphous form, in a dissolving tablet matrix, and a second layer of amlodipine in a disintegrating or eroding tablet matrix.
The tablet according to the present invention provides a largely pH-independent dissolution of the poorly water-soluble telmisartan, thereby facilitating dissolution of the drug at a physiological pH level, and adequate stability and drug release of amlodipine. The tablet structure also overcomes the stability problem caused by the incompatibility of amlodipine with basic constituents of the telmisartan formulation.
As used herein, the term “substantially amorphous” refers to a product comprising amorphous constituents in a proportion of at least 90%, preferably at least 95%, as determined by X-ray powder diffraction measurement.
The term “dissolving tablet matrix” refers to a pharmaceutical tablet base formulation having instant release (fast dissolution) characteristics that readily dissolves in a physiological aqueous medium.
The term “disintegrating or eroding tablet matrix” refers to a pharmaceutical tablet base formulation having instant release characteristics that readily disintegrates or erodes in a physiological aqueous medium.
A fixed dose combination according to the present invention represents a pharmaceutical bilayer tablet comprising a first layer of telmisartan in substantially amorphous form and a second layer of amlodipine in a disintegrating or eroding tablet matrix.
The active ingredient telmisartan is generally supplied in its free acid form, although pharmaceutically acceptable salts such as the sodium salt may also be used. Since during subsequent processing telmisartan is normally dissolved and transformed into a substantially amorphous form, its initial crystal morphology and particle size are of little importance for the physical and biopharmaceutical properties of the bilayer tablet formulation obtained. It is, however, preferred to remove agglomerates from the starting material, e.g., by sieving, in order to facilitate wetting and dissolution during further processing.
Substantially amorphous telmisartan may be produced by any suitable method known to those skilled in the art, for instance, by freeze drying of aqueous solutions, coating of carrier particles in a fluidized bed, and solvent deposition on sugar pellets or other carriers. Preferably, however, the substantially amorphous telmisartan is prepared by the specific spray-drying method described in WO 03/059327 (corresponding to U.S. Patent Application Pub. No. 2005/0089575, which is hereby incorporated by reference).
A bilayer tablet according to the present invention generally contains 10 to 160 mg, preferably 20 to 80 mg or 40 to 80 mg, of telmisartan; and 1 to 20 mg, preferably 2.5 to 10 mg, of amlodipine. Preferred dose strengths of telmisartan are 20 mg, 40 mg, and 80 mg; preferred dose strengths of amlodipine are 2.5 mg, 5 mg, and 10 mg. Presently preferred forms are bilayer tablets comprising 20/10 mg, 40/10 mg, 80/10 mg, 20/5 mg, 40/5 mg, 80/5 mg, 20/2.5 mg, 40/2.5 mg, and 80/2.5 mg of telmisartan and amlodipine, respectively.
The first tablet layer contains telmisartan in substantially amorphous form dispersed in a dissolving tablet matrix having instant release (fast dissolution) characteristics. The dissolving tablet matrix may have neutral or basic properties, although a basic tablet matrix is preferred.
In such a preferred embodiment, the dissolving matrix of the telmisartan layer comprises a basic agent, a water-soluble diluent and, optionally, other excipients and adjuvants.
Specific examples of suitable basic agents are alkali metal hydroxides such as NaOH and KOH; basic amino acids such as arginine and lysine; and meglumine (N-methyl-D-glucamine), NaOH and meglumine being preferred.
Specific examples of suitable water-soluble diluents are carbohydrates such as monosaccharides like glucose; oligosaccharides like sucrose, anhydrous lactose, and lactose monohydrate; and sugar alcohols like sorbitol, mannitol, erythrol, and xylitol. Sorbitol is a preferred diluent.
The other excipients and/or adjuvants are, for instance, selected from binders, carriers, fillers, lubricants, flow control agents, crystallization retarders, solubilizers, coloring agents, pH control agents, surfactants, and emulsifiers, specific examples of which are given below in connection with the second tablet layer composition. The excipients and/or adjuvants for the first tablet layer composition are preferably chosen such that a non-acidic, fast dissolving tablet matrix is obtained.
The first tablet layer composition generally comprises 3 to 50 wt. %, preferably 5 to 35 wt. %, of active ingredient; 0.25 to 20 wt. %, preferably 0.40 to 15 wt. %, of basic agent; and 30 to 95 wt. %, preferably 60 to 80 wt. % of water-soluble diluent (filler).
Other (optional) constituents may, for instance, be chosen from one or more of the following excipients and/or adjuvants in the amounts indicated:
The second tablet layer composition comprises amlodipine dispersed in a disintegrating or eroding tablet matrix having instant release (fast dissolution) characteristics. The disintegrating or eroding tablet matrix may have weakly acidic, neutral, or weakly basic properties, a neutral tablet matrix being preferred.
In a preferred embodiment, the disintegrating or eroding matrix comprises one or more fillers, a disintegrant, a lubricant and, optionally flow control agents, binders or polymers, other excipients and adjuvants.
Preferred fillers for the second layer are selected from the group consisting of pregelatinized starch, microcrystalline cellulose, cellulose, mannitol, erythritol, lactose monohydrate, dibasic calcium phosphate anhydrous, sorbitol, and xylitol. Particularly preferred are pregelatinized starch, microcrystalline cellulose, dibasic calcium phosphate anhydrous, and lactose monohydrate.
Preferred lubricants are sodium stearyl fumarate and magnesium stearate. Particularly preferred is magnesium stearate.
Preferred disintegrants are selected from the group consisting of croscarmellose sodium (crosslinked carboxymethylcellulose sodium), sodium starch glycolate, crospovidone (crosslinked polyvinylpyrrolidone), corn starch, pregelatinized starch, low-substituted hydroxypropylcellulose, and microcrystalline cellulose. Particularly preferred are sodium starch glycolate and crospovidone.
Preferred binders are selected from the group consisting of polyvinylpyrrolidone (Povidone), copolymers of vinyl pyrrolidone with other vinyl derivatives (Copovidone), microcrystalline cellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, and pregelatinized starch. Particularly preferred are hydroxypropylmethylcellulose and povidone.
Particularly preferred fillers of the second tablet layer composition are pregelatinized starch and/or microcrystalline cellulose as these fillers can additionally serve the purpose of a binder or disintegrant.
Preferred flow control agents are colloidal silicon dioxide and talc. Particularly preferred is colloidal silicon dioxide.
The other excipients and adjuvants, if used, are for example coloring agents including dyes and pigments such as iron oxides.
The second tablet layer composition generally comprises 0.5 to 20 wt. %, preferably 1 to 10 wt. % of amlodipine and 50 to 99.5 wt. %, preferably 80 to 99 wt. % of fillers.
The other excipients and/or adjuvants are, for instance, selected from binders (0 to 7 wt. %, preferably 1 to 5 wt. %), disintegrants (0 to 10 wt. %, preferably 1 to 5 wt. %), lubricants (0.25 to 3 wt. %, preferably 0.5 to 2 wt. %), flow control agents (0.25 to 3 wt. %, preferably 0.5 to 2 wt. %), and coloring agents (0.05 to 3 wt. %, preferably 0.1 to 1 wt. %), specific examples of which are also given below. The excipients and/or adjuvants for the second tablet layer composition are preferably chosen such that a neutral, disintegrating or eroding tablet matrix is obtained.
As solvent for the granulation liquid, which, as a volatile component, does not remain in the final product, methanol, ethanol, isopropyl alcohol, or purified water can be used; preferred solvents are ethanol and purified water.
The layers can be differentiated by using different colors.
For preparing a bilayer tablet according to the present invention, the first and second tablet layer compositions may be compressed in the usual manner in a bilayer tablet press, e.g., a high-speed rotary press in a bilayer tabletting mode. However, care should be taken not to employ an excessive compression force for the first tablet layer. Preferably, the ratio of the compression force applied during compression of the first tablet layer to the compression force applied during compression of both the first and second tablet layers is in the range of from 1:10 to 1:2. For instance, the first tablet layer may be compressed at moderate force of 4 to 8 kN, whereas the main compression of first plus second layer is performed at a force of 10 to 20 kN. During bilayer tablet compression, adequate bond formation between the two layers is achieved by virtue of distance attraction forces (intermolecular forces) and mechanical interlocking between the particles.
The bilayer tablets obtained release the active ingredients rapidly and in a largely pH-independent fashion, with complete release occurring within less than 60 minutes and release of the major fraction occurring within less than 15 minutes.
In accordance with the present invention, a substantially increased dissolution rate of the active ingredients and, in particular, of telmisartan is achieved. Normally, at least 70% and typically at least 90% of the drug load are dissolved after 30 minutes.
The bilayer tablets of the present invention tend to be slightly hygroscopic and are therefore preferably packaged using a moisture-proof packaging material such as aluminum foil blister packs, or polypropylene tubes and HDPE bottles which preferably contain a desiccant.
A preferred method of producing the bilayer tablet according to the present invention comprises:
To provide a first tablet layer composition, an aqueous alkaline solution of telmisartan is prepared by dissolving the active ingredient in purified water with the help of one or more basic agents like sodium hydroxide and meglumine. Optionally, a solubilizer and/or a recrystallization retarder may be added. The dry matter content of the starting aqueous solution is generally 10 to 40 wt. %, preferably 20 to 30 wt. %.
The aqueous solution is then spray-dried at room temperature or preferably at increased temperatures of, for instance, between 50° C. and 100° C. in a co-current or countercurrent spray-drier at a spray pressure of, for instance, 1 to 4 bar. Generally speaking, the spray-drying conditions are preferably chosen in such a manner that a spray-dried granulate having a residual humidity of ≦5 wt. %, preferably ≦3.5 wt. %, is obtained in the separation cyclone. To that end, the outlet air temperature of the spray-drier is preferably kept at a value between about 80° C. and 90° C. while the other process parameters such as spray pressure, spraying rate, inlet air temperature, etc., are adjusted accordingly.
The spray-dried granulate obtained is preferably a fine powder having the following particle size distribution:
After spray-drying, the active ingredient telmisartan as well as the excipients contained in the spray-dried granulate are in a substantially amorphous state with no crystallinity being detectable. From a physical point of view, the spray-dried granulate is a solidified solution or glass having a glass transition temperature Tg of preferably >50° C., more preferably >80° C.
Based on 100 parts by weight of active ingredient telmisartan, the spray-dried granulate preferably contains 5 to 200 parts by weight of basic agent and, optionally, solubilizer and/or crystallization retarder.
The water-soluble diluent is generally employed in an amount of 30 to 95 wt. %, preferably 60 to 80 wt. %, based on the weight of the first tablet layer composition.
The lubricant is generally added to the premix in an amount of 0.1 to 5 wt. %, preferably 0.3 to 2 wt. %, based on the weight of the first tablet layer composition.
Mixing is carried out in two stages, i.e., in a first mixing step the spray-dried granulate and the diluent are admixed using, e.g., a high shear mixer or a free fall blender, and in a second mixing step the lubricant is blended with the premix, preferably also under conditions of high shear. The method of the invention is however not limited to these mixing procedures and, generally, alternative mixing procedures may be employed in steps c), d), and also in the subsequent steps f) and g), such as, e.g., container mixing with intermediate screening.
To provide a second tablet layer composition comprising amlodipine, several different manufacturing methods can be used, for example, the direct compression, wet granulation, or roller compaction processes.
The present invention is preferably directed to a method of manufacturing the second tablet layer composition of amlodipine by a direct compression process comprising the steps of:
In case of wet granulation, amlodipine or a pharmaceutically acceptable salt thereof is premixed in a high shear granulator with suitable fillers such as microcrystalline cellulose, lactose monohydrate, or dibasic calcium phosphate anhydrous, and wet binding agents such as hydroxypropylmethylcellulose or povidone, disintegrants such as crospovidone and optionally other suitable excipients. Agglomeration of the powder is promoted through the addition of the granulation liquid (for example, purified water or ethanol). After high shear granulation, the granulate is wet screened through an appropriate sieve and subsequently dried using a fluid bed dryer or a vacuum tray dryer. The dried granules are optionally dry screened through an appropriate sieve. After addition of the lubricant (for example, magnesium stearate), and/or other excipients, the mixture is blended in a free fall blender or a high shear mixer.
Alternative methods for wet granulation of active ingredient and excipients with the granulation liquid are fluid bed granulation or one pot granulation.
In case of roller compaction, or in other words, dry granulation, either a mixture of amlodipine or a pharmaceutically acceptable salt thereof with a part of the excipients used in the direct compression process, or the complete mixture containing all excipients, is processed through a conventional roller compactor to form ribbons, which are thereafter screened down to granules which are optionally mixed with other excipients, like glidants, lubricants, and antiadherents.
First and second tablet layer compositions as described above can be compressed into bilayer tablets of the target tablet weight with appropriate size and crushing strength, using an appropriate tablet press. Optionally an appropriate external lubricant spray system for the dies and punches can be used during manufacturing of tablets in order to improve lubrication.
For the production of bilayer tablets according to the present invention, the separate tablet layer compositions can be compressed in a bilayer tablet press, e.g., a rotary press in the bilayer tabletting mode, in the manner described above. In order to avoid any cross-contamination between the tablet layers (which could lead to decomposition of amlodipine), any granulate residues have to be carefully removed during tabletting by intense suction of the die table within the tabletting chamber.
A method described above can be used for the manufacture of a tablet according to the present invention to treat hypertension either alone or in combination with the treatment or prevention of a condition selected from the group consisting of chronic stable angina, vasospastic angina, stroke, myocardial infarction, transient ischemic attack, congestive heart failure, cardiovascular disease, diabetes, insulin resistance, impaired glucose tolerance, pre-diabetes, type 2 diabetes mellitus, diabetic nephropathy, metabolic syndrome (syndrome X), obesity, dyslipidemia, hypertriglyceridemia, elevated serum concentrations of C-reactive protein, elevated serum concentrations of lipoprotein(a), elevated serum concentration of homocysteine, elevated serum concentration of low-density lipoprotein (LDL)-cholesterol, elevated serum concentration of lipoprotein-associated phospholipase (A2), reduced serum concentration of high density lipoprotein (HDL)-cholesterol, reduced serum concentration of HDL(2b)-cholesterol, reduced serum concentration of adiponectin, cognitive decline, and dementia.
Particularly preferred is the additional treatment or prevention of chronic stable angina, vasospastic angina, stroke, myocardial infarction, congestive heart failure, diabetes, dyslipidemia, or dementia.
In order to further illustrate the present invention, the following non-limiting examples are given.
* Volatile component, does not remain in final product
* Volatile component, does not remain in final product
* Volatile component, does not remain in final product
* Volatile component, does not remain in final product
* Volatile component, does not remain in final product
* Volatile component, does not remain in final product
* Volatile component, does not remain in final product
* Volatile component, does not remain in final product
* Volatile component, does not remain in final product
* Volatile component, does not remain in final product
*Volatile component, does not remain in final product
*Volatile component, does not remain in final product
*Volatile component, does not remain in final product
| Number | Date | Country | Kind |
|---|---|---|---|
| 04 026 234.7 | Nov 2004 | EP | regional |
