Technical Field

The present invention relates to a pharmaceutical composition which is a bilayer tablet comprising a layer composition comprising telmisartan and a layer composition comprising amlodipine or a salt thereof.

Background Art

Telmisartan is an angiotensin-ll-antagonist which is useful for treating hypertension and cardiac insufficiency and for treating other cardiovascular disorders including ischemic peripheral circulation disorders, myocardial ischemia (angina). Its chemical name is 4'-[4- Methyl-6-(1 -methyl-1 FI-benzimidazol-2-yl)-2-propyl-1 FI-benzimidazol-1 -ylmethyl]biphenyl- 2-carboxylic acid and has the following structure:

Amlodipine is a calcium channel blocker or calcium antagonist useful for treating high blood pressure (hypertension) or chest pain (angina) and other conditions caused by coronary artery disease. Its chemical name is 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)- 4-(2-chlorophenyl)-1 ,4-dihydro-6-methyl-3,5-pyridinedicarboxylate and has the following structure:

Pharmaceutically amlodipine is used as maleate, besylate (or benzenesulfonate) and mesylate salt.

Fixed dose formulations of telmisartan and amlodipine have been described. For example, W02006048208 discloses a bilayer pharmaceutical tablet comprising a first layer of telmisartan in a dissolving tablet matrix, and a second layer of amlodipine in a disintegrating or eroding tablet matrix. Typically, the excipients of the telmisartan dissolving matrix are sodium hydroxide, meglumine, povidone, sorbitol and magnesium stearate. The preparation of the telmisartan layer composition as disclosed in this patent application involves spray-drying, which is a costly processing step. Furthermore, the mass of the obtained bilayer tablets is relatively high, in particular for the tablets having a strength of 80/5 mg and 80/10 mg (telmisartan/amlodipine) the total mas is 680 mg: 480 mg of the telmisartan layer and 200 mg of the amlodipine layer. This may be disadvantageous for patient compliance.

W02006048208 discloses the reference product Twynsta®. The tablet dimensions for the 80/5 and 80/10 mg tablets are 16.3 mm (length) x 8.0 mm (width) x 6.2 mm (thickness). The tablets are to be administered every day. As it has been described in the document issued by the Food and Drug Administration (FDA): “Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules Guidance for Industry”, difficulty swallowing tablets and capsules can be a problem for many individuals and can lead to a variety of adverse events and patient noncompliance with treatment regimens. Individuals who find it difficult to swallow tablets and capsules frequently cite the size as the main reason for the difficulty in swallowing.

Studies in adults evaluating the effect of tablet and capsule size on ease of swallowing suggest that increases in size are associated with increases in patient complaints related to swallowing difficulties at tablet sizes greater than approximately 8 mm in diameter. The size of the tablet or capsule influences esophageal transit, irrespective of patient factors and administration techniques (i.e., use of fluids, patient position). Smaller tablets generally have been shown to have significantly faster transit times in these studies.

Lee et al (“ Quality by Design (QbD) approach to optimize the formulation of a bilayer combination tablet (Telmiduo) manufactured via high shear wet granulation", International Journal of Pharmaceutics 2017, 534(1-2), 144-158) disclose a bilayer tablet (Telmiduo®) containing telmisartan and amlodipine. Among other excipients the telmisartan layer contains mannitol (in an amount from 28.3 to 40.8% w/w relative to the telmisartan layer), microcrystalline cellulose (in an amount from 1.9 to 14.4% w/w relative to the telmisartan layer) and crospovidone (in an amount from 18.3 to 30.8% w/w relative to the telmisartan layer). The telmisartan layer of Telmiduo® is prepared by high shear wet granulation. Bilayer tablets are formed by compressing two layers together. Formulation of bilayer tablets is basically the same as monolayers. However, there are some additional aspects that need to be considered, such as for example having a granulate with adequate flowability that can be measured by Carr index, optimally lower than 10. In Lee et al, the authors disclose that the Carr’s index values of the telmisartan granulate in the disclosed composition range from 15.5 to 18.9, which just corresponds to fair or passable flowability and can be a problem as indicated above.

Finally, the mass of the Telmiduo® bilayer tablets, although lower than the one disclosed in W02006048208, it is still relatively high, in particular for the mass for the tablets having a strength of 80/5 mg (telmisartan/amlodipine) is approximately 580 mg: approximately 480 mg of the telmisartan layer and 100 mg of the amlodipine layer.

In summary, the pharmaceutical compositions of the prior art as disclosed above involve either complex and costly processing steps, and/or the weights of the tablets obtained are high, and therefore the resulting tablets are difficult to swallow.

Consequently, there is still the need of providing stable pharmaceutical compositions comprising telmisartan and amlodipine obtained through simpler manufacturing process and having efficacy, stability, and lower tablet sizes.

Summary of Invention

The inventors have found that when in a bilayer tablet containing amlodipine and telmisartan, specific proportions of mannitol, cellulose microcrystalline, and crospovidone are used as excipients in the telmisartan layer composition, a bilayer tablet is obtained which shows good efficacy and stability, an appropriate dissolution profile, and good physical parameters such as adequate hardness, friability, and disintegration time.

An advantage of the bilayer tablets of the invention is that they show better flowability of the telmisartan granulate in comparison of the prior art tablets disclosed in Lee et al. Thus, granulates manufactured according to the invention show Carr’ index values from about 8 to about 12, which correspond to excellent flowability properties, and leads to better producibility and higher yields. Besides, the bilayer tablets of the invention can be prepared by a cost effective process in comparison to the reference product.

Additionally, as illustrated in the examples herein, the bilayer tablets of the invention show low hygroscopicity or moisture intake and improved stability during storage. In particular, it was seen that the telmisartan tablets according to the invention showed the lowest hygroscopicity (7.2%), while the hygroscopicity of the telmisartan tablets according to Lee et al, and of the telmisartan layer separated from reference product Twynsta® was 11.3% and 19.4%, respectively. Further, the appearance of bilayer tablets according to the invention did not change after 24 hours at 40 °C/75% RH while the amlodipine layer of the bilayer tablets of the comparative example separated from the telmisartan layer (FIG. 4).

Besides, the examples also demonstrate that the dissolution profiles of the bilayer tablets according to the invention showed much less variability than the ones of Twynsta®.

Furthermore, the bilayer tablets of the invention have lower tablet weight in comparison with the bilayer tablets of the prior art. Typically, the mass of the bilayer tablets having a strength of 80/5 mg (telmisartan/amlodipine) is 460 mg: 360 mg of the telmisartan layer and 100 mg of the amlodipine layer. This represents a reduction of tablet mass of 120 mg or 220 mg with respect of the prior art tablets (Telmiduo®/Twynsta® respectively). Accordingly, the bilayer tablets of the present invention are much easier to swallow and give rise to significantly better patients' compliance.

Therefore, a first aspect of the invention relates to a pharmaceutical composition which is a bilayer tablet comprising: a) a layer composition comprising: i) telmisartan, ii) one or more basic agents selected from an alkali metal hydroxide and meglumine; iii) from 40 to 70% w/w mannitol, iv) from 5 to 15% w/w cellulose microcrystalline, and v) from 1 to 6% w/w crospovidone, where the % w/w are expressed with respect to the total weight of the telmisartan layer composition; and b) a layer composition comprising amlodipine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients or carriers.

The bilayer tablets of the present invention may be prepared by a convenient and simple process which does not include any complex or costly spray-drying. Rather, telmisartan layer is produced by fluid bed granulation. Besides, fluid bed granulation has the advantage over high shear granulation that granulation and drying can be performed in the same one equipment.

Thus, a second aspect of the invention relates to a process for the preparation of the pharmaceutical composition, which is a bilayer tablet as previously disclosed, the process comprising the following steps: a) providing a granulating fluid by suspending telmisartan and the basic agent in an appropriate solvent or mixture of solvents, b) granulating mannitol, cellulose microcrystalline and the granulating fluid of step a) in a fluid bed to obtain a granulate, c) blend crospovidone with the granulate of step b), d) providing a granulate of amlodipine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients or carriers, e) compressing the telmisartan granulate of step c) with the amlodipine granulate of step d) to obtain a bilayer tablet.

A further aspect of the invention relates to the pharmaceutical composition which is a bilayer tablet as defined above for use in the treatment of hypertension. Therefore, this aspect relates to the use of telmisartan, and amlodipine or a pharmaceutically acceptable salt thereof for the manufacture of the bilayer tablet as defined above for the treatment of hypertension. Alternatively, this aspect may also be formulated as a method for the treatment of hypertension in a mammal, including a human, the method comprising administering to said mammal an effective amount of the previously defined pharmaceutical composition which is a bilayer tablet.

Brief Description of Drawings

FIG. 1 shows the appearance of the separated telmisartan layer of the reference product Twynsta® (80/5 mg) after storage under 40 °C and 75% RH for 24 h.

FIG. 2 shows the appearance of telmisartan tablets according to Lee et al (80 mg) after storage under 40 °C and 75% RH for 24 h.

FIG. 3 shows the appearance of telmisartan tablets according to the invention (80 mg) after storage under 40 °C and 75% RH for 24 h.

FIG. 4 shows the appearance of the bilayer tablets of the comparative example (80/5 mg) after storage under 40 °C and 75% RH for 24 h.

FIG. 5 shows the appearance of bilayer tablets according to the invention (80/5 mg) after storage under 40 °C and 75% RH for 24 h.

Detailed description of the invention

All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly through-out the specification and claims.

The term "about" or “around” as used herein refers to a range of values ± 10% of a specified value. For example, the expression "about 10" or “around 10” includes ± 10% of 10, i.e. from 9 to 11. Unless otherwise stated, all percentages referred herein are by weight. The term “percentage (%) by weight or % w/w” refers to the percentage of each ingredient in relation to the total weight of the layer composition, or to the pharmaceutical composition which is a bilayer tablet as herein indicated. The weight of the components must be understood as dry weight.

The term “bilayer tablet” refers to a layered tablet consisting of two layers of granulate compressed together to form a single tablet. This dosage form has the advantage of separating two incompatible substances. Each layer is fed from distinct feed frame with individual weight control. For the purposes of the invention the expressions “layer” and “layer composition” have the same meaning.

The bilayer tablets of the invention comprise a layer composition comprising telmisartan, and a layer comprising amlodipine or a pharmaceutically acceptable salt thereof as defined above.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the bilayer tablets of the invention consist of the layer composition comprising telmisartan, and the layer comprising amlodipine or a pharmaceutically acceptable salt thereof, wherein the layers are as defined above.

For the purposes of the present invention, there is no limitation on the layer order in which the different individual layers of telmisartan and amlodipine are tableted.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, in the bilayer tablets of the invention the layer composition comprising telmisartan is the first layer, and the layer comprising amlodipine or a pharmaceutically acceptable salt thereof is the second layer. This means that when the bilayer tablet is prepared, the telmisartan layer is first compressed and then the amlodipine layer is compressed onto the telmisartan layer.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the bilayer tablets of the invention the layer composition comprising amlodipine or a pharmaceutically acceptable salt thereof is the first layer, and the layer comprising telmisartan is the second layer. In this case, when the bilayer tablet is prepared, the amlodipine layer is first compressed and then the telmisartan layer is compressed onto the amlodipine layer. There is no limitation on the type of salt of amlodipine that can be used, provided that it is pharmaceutically acceptable when used for therapeutic purposes. The term "pharmaceutically acceptable salts", embraces salts commonly used to form alkali metal salts and to form addition salts of free bases. For example, acid addition salts include, without limitation, hydrochloride, hydrobromide, hydrogensulfate, tosylate, fumarate, maleate, tartrate, or benzenesulfonate (besylate) and methanesulfonate (mesylate) salts.

The preparation of pharmaceutically acceptable salts may be carried out by methods known in the art. Generally, such salts may be prepared by reacting the free base form with a stoichiometric amount of the appropriate pharmaceutically acceptable acid in an appropriate solvent such as water, an organic solvent, or a mixture thereof. The obtained salts may differ in some properties with respect to amlodipine in free base form, but they are equivalent to them for the purposes of the present invention.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the amlodipine layer composition comprises amlodipine mesylate or amlodipine besylate, more particularly amlodipine besylate.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan layer composition comprises telmisartan in an amount which is equivalent to an amount from 10 to 160 mg, more particularly from 20 to 80 mg, and even more particularly from 40 to 80 mg.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan layer composition comprises telmisartan in an amount of about 40 or about 80 mg.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the amlodipine layer composition comprises amlodipine or a pharmaceutically acceptable salt thereof in an amount which is equivalent to an amount from 1 to 20 mg, more particularly from 5 to 10 mg, amlodipine in free base form.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the amlodipine layer composition comprises amlodipine or a pharmaceutically acceptable salt thereof in an amount which is equivalent to an amount of about 5 or about 10 mg amlodipine in free base form. More particularly, the amlodipine layer comprises amlodipine besylate or amlodipine mesylate in an amount which is equivalent to about 5 or about 10 mg amlodipine in free base form. In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan layer composition comprises telmisartan in an amount of about 40 mg, and the amlodipine layer composition comprises amlodipine or a pharmaceutically acceptable salt thereof in an amount which is equivalent to an amount of about 5 mg amlodipine in free base form. More particularly, the telmisartan layer composition comprises about 40 mg telmisartan, and the amlodipine layer composition comprises amlodipine besylate or amlodipine mesylate in an amount which is equivalent to about 5 mg amlodipine in free base form. The tablets of this strength are also referred herein to as 40/5 mg bilayer tablets.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan layer composition comprises telmisartan in an amount of about 40 mg, and the amlodipine layer composition comprises amlodipine or a pharmaceutically acceptable salt thereof in an amount which is equivalent to an amount of about 10 mg amlodipine in free base form. More particularly, the telmisartan layer comprises about 40 mg telmisartan, and the amlodipine layer comprises amlodipine besylate or mesylate in an amount which is equivalent to about 10 mg amlodipine in free base form. The tablets of this strength are also referred herein to as 40/10 mg bilayer tablets.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan layer composition comprises telmisartan in an amount of about 80 mg, and the amlodipine layer composition comprises amlodipine or a pharmaceutically acceptable salt thereof in an amount which is equivalent to an amount of about 5 mg amlodipine in free base form. More particularly, the telmisartan layer comprises about 80 mg telmisartan, and the amlodipine layer comprises amlodipine besylate or mesylate in an amount which is equivalent to about 5 mg amlodipine in free base form. The tablets of this strength are also referred herein to as 80/5 mg bilayer tablets.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan layer composition comprises telmisartan in an amount of about 80 mg, and the amlodipine layer composition comprises amlodipine or a pharmaceutically acceptable salt thereof in an amount which is equivalent to an amount of about 10 mg amlodipine in free base form. More particularly, the telmisartan layer comprises about 80 mg telmisartan, and the amlodipine layer comprises amlodipine besylate or mesylate in an amount which is equivalent to about 10 mg amlodipine in free base form. The tablets of this strength are also referred herein to as 80/10 mg bilayer tablets.

The telmisartan layer composition of the bilayer tablet of the invention comprises one or more basic agents selected from an alkali metal hydroxide and meglumine (N-methyl-D- glucamine), or a combination thereof. Non-limiting examples of alkali metal hydroxides include sodium hydroxide and potassium hydroxide.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the basic agent comprises an alkali metal hydroxide, particularly sodium hydroxide, and meglumine. More particularly, the basic agent is present in an amount from 1 .5 to 10% w/w, even more particularly about 4.9% w/w, with respect to the total weight of the telmisartan layer composition.

The telmisartan layer composition of the bilayer tablet of the invention further comprises from 40 to 70% w/w mannitol, from 5 to 15% w/w cellulose microcrystalline, and from 1 to 6% w/w crospovidone, where these % w/w are expressed with respect to the total weight of the telmisartan layer composition. This layer may optionally comprise a binder, and/or a lubricant. Alternatively or additionally, this layer composition may also comprise other pharmaceutically acceptable excipients.

The expression "pharmaceutically acceptable excipients or carriers" as used herein refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio.

Examples of further pharmaceutically acceptable excipients or carriers that may be contained in the telmisartan layer composition include, without limitation, binders, lubricants, colorants, glidants and solubilizers.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan layer composition comprises from 45 to 60% w/w, more particularly from 50 to 60% w/w, and even more particularly about 55% w/w, mannitol with respect to the total weight of the layer composition. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan layer composition comprises from 5 to 10% w/w, more particularly about 8% w/w, cellulose microcrystalline with respect to the total weight of the layer composition.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan layer composition comprises from 1 to 4% w/w, more particularly about 2% w/w, crospovidone with respect to the total weight of the layer composition.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the weight ratio of mannitol and cellulose microcrystalline in the telmisartan layer composition is from 40:15 (2.67) to 70:5 (14), more particularly from 50:10 (5) to 60:5 (12), even more particularly about 6.8.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the weight ratio of cellulose microcrystalline and crospovidone in the telmisartan layer composition is from 15:1 (15) to 5:6 (0.83), more particularly from 10:1 (10) to 5:4 (1.25), even more particularly about 4.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the weight ratio of mannitol and crospovidone in the telmisartan layer composition is from 70:1 (70) to 40:6 (6.67), more particularly from 60:1 (60) to 50:4 (12.5) , even more particularly about 27.5.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan layer composition further comprises a binder, more particularly polyvinylpyrrolidone (povidone), in an amount from 2 to 9% w/w, more particularly about 6.7% w/w with respect to the total weight of the layer composition.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan layer composition further comprises a lubricant, more particularly magnesium stearate, in an amount from 0.5 to 3% w/w, more particularly about 1.5% w/w with respect to the total weight of the layer composition. In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan layer composition comprises a binder, more particularly povidone, and a lubricant, more particularly magnesium stearate.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan layer composition further comprises colorants, more particularly iron oxides, in an amount from 0.01 to 0.3% w/w, more particularly about 0.02% or about 0.1% w/w with respect to the total weight of the layer composition.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan layer composition comprises telmisartan, one or more basic agents, mannitol, cellulose microcrystalline, crospovidone, povidone, colorants, and magnesium stearate.

More particularly, the telmisartan layer comprises or consists of telmisartan, particularly in an amount from 19 to 24% w/w, particularly about 22.2% w/w (referred to telmisartan acid); one or more basic agents, particularly sodium hydroxide and meglumine, in an amount from 1 .5 to 10% w/w, particularly about 4.9% w/w; mannitol in an amount from 40 to 70% w/w, particularly from 45 to 60% w/w, and even more particularly about 55% w/w; cellulose microcrystalline in an amount from 5 to 15% w/w, particularly from 5 to 10% w/w, and even more particularly about 8% w/w; crospovidone in an amount from 1 to 6% w/w, particularly from 1 to 4% w/w, and even more particularly about 2% w/w; a binder, particularly povidone, in an amount from 2 to 9% w/w, particularly about 6.7% w/w; and a lubricant, particularly magnesium stearate, in an amount from 0.5 to 3% w/w, particularly about 1.5% w/w; and optionally colorants, particularly iron oxides, in an amount from 0.01 to 0.3% w/w, particularly about 0.02% or about 0.1% w/w; wherein the % w/w are given with respect to the total weight of the telmisartan layer composition.

The amlodipine layer composition of the bilayer tablet of the invention comprises amlodipine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients or carriers.

Examples of pharmaceutically acceptable excipients or carriers that may be contained in the amlodipine layer composition include, without limitation, fillers, binders, disintegrants, lubricants, and glidants. For the purposes of the invention, non-limiting examples of fillers include pregelatinized starch, microcrystalline cellulose, cellulose, mannitol, erythritol, lactose, dibasic calcium phosphate, sorbitol, xylitol, maltose, fructose, magnesium hydroxide.

Non-limiting examples of lubricants include magnesium stearate, calcium stearate, zinc stearate, high molecular weight polyethylene glycol, stearic acid, and sodium stearyl fumarate.

Non-limiting examples of disintegrants include low-substituted hydroxypropylcellulose, croscarmellose sodium (crosslinked carboxymethylcellulose sodium), sodium starch glycolate, crospovidone (crosslinked polyvinylpyrrolidone), maize starch, and pregelatinized starch.

Non-limiting examples of binders include starch, pregelatinized starch, sodium carboxymethylcellulose, polyvinylpyrrolidone (povidone), copolymers of vinylpyrrolidone with other vinylderivatives (copovidone), hydroxypropylmethylcellulose, methylcellulose, and hydroxypropylcellulose, polyethylene glycol, hydrolyzed gelatin, and natural gums.

Non-limiting examples of glidants are colloidal silicon dioxide and talc. Particularly preferred is colloidal silicon dioxide.

Non-limiting examples of colorants include dyes, an aluminum lake and iron oxides.

Non-limiting examples of solubilizers include poloxamer and meglumine.

Non-limiting examples of disintegrants include, without limitation, natural, modified or maize starch, pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, or combinations thereof.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the amlodipine layer comprises amlodipine or a salt thereof, fillers, disintegrants, lubricants, and glidants.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the amlodipine layer comprises amlodipine or a salt thereof, cellulose microcrystalline, pregelatinized starch, maize starch, magnesium stearate and colloidal silicon dioxide. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the amlodipine layer comprises or consists of amlodipine or a salt thereof in an amount from 2.5 to 7.5% w/w, particularly about 5% w/w (referred to amlodipine base); cellulose microcrystalline in an amount from 40 to 70% w/w, particularly about 59.4%; pregelatinized starch in an amount from 15 to 30% w/w, particularly about 26.5%; maize starch in an amount from 1 to 10% w/w, particularly about 5.0% w/w; magnesium stearate in an amount from 0.25 to 3% w/w, particularly about 1.2% w/w; colloidal silicon dioxide in an amount from 0.25 to 2 w/w, particularly about 1.0% w/w; wherein the % w/w are given with respect to the total weight of the amlodipine layer composition.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the excipients or carriers for the telmisartan layer composition are chosen such that a disintegrating or eroding tablet matrix is obtained.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the excipients or carriers for the amlodipine layer composition are chosen such that a disintegrating or eroding tablet matrix is obtained.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the excipients or carriers for both layer compositions are chosen such that a disintegrating or eroding tablet matrix is obtained.

The layer compositions of the present invention can be prepared according to methods well known in the state of the art. The appropriate excipients and/or carriers, and their amounts, can readily be determined by those skilled in the art according to the type of composition being prepared.

The term "disintegrating or eroding tablet matrix" as used herein refers to a pharmaceutical tablet base formulation having instant release characteristics that readily disintegrates or erodes in a physiological aqueous medium.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan layer composition is capable of providing an instant release (fast dissolution) characteristics.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the amlodipine layer composition is capable of providing an instant release (fast dissolution) characteristics. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan and the amlodipine layer compositions are capable of providing an instant release (fast dissolution) characteristics.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the bilayer tablets obtained are capable of releasing the active ingredients in a period of time which is equal to or lower than 60 min.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the bilayer tablets obtained are capable of releasing at least 70%, more particularly at least 90% of the active ingredients in a period of time which is equal to or lower than 30 min.

As mentioned above, an advantage of the bilayer tablets of the invention is that they show improved flowability of the telmisartan granulate. Thus, in one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the granulate of the telmisartan layer has a Carr’ index value from 5 to 15, more particularly from about 8 to about 10.

The Carr’s index may be calculated from the following equation:

Carr’s index = (V _t -V _b )/V _t x 100

Typically, the bulk (V _b ) and tapped (V _t ) densities may be measured using an Erweka type SVM22 (European Pharmacopoeia 10: sections 2.9.34 (bulk density and tapped density of powders) and 2.9.36 (powder flow)).

Additionally, the bilayer tablets of the invention show low hygroscopicity or moisture intake after storage. Thus, in one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the bilayer tablet of the invention is capable of showing intact appearance after being stored in bulk (unpackaged) under 40 °C and 75% relative humidity (RH) for 24 hours (FIG.1 ). The appearance may be assessed by visual inspection.

The bilayer tablets of the invention also show reduced tablet size. Thus, in one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the mass of the telmisartan layer composition is from 320 to 400 mg, more particularly is about 360 mg when this layer composition comprises about 80 mg telmisartan.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the mass of the telmisartan layer composition is from 160 to 200 mg, more particularly is about 180 mg, when this layer composition comprises about 40 mg telmisartan.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the mass of the amlodipine layer composition is from 160 to 240 mg, more particularly is about 200 mg, when this layer composition comprises amlodipine or a salt thereof in an amount which is equivalent to an amount of about 10 mg amlodipine in free base form.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the mass of the amlodipine layer composition is from 80 to 120 mg, more particularly is about 100 mg, when this layer composition comprises amlodipine or a salt thereof in an amount which is equivalent to an amount of about 5 mg amlodipine in free base form.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the mass of the bilayer tablet is about 560 mg, when the telmisartan layer composition comprises about 80 mg telmisartan and the amlodipine layer composition comprises amlodipine or a salt thereof in an amount which is equivalent to an amount of about 10 mg amlodipine in free base form.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the mass of the bilayer tablet is about 460 mg, when the telmisartan layer composition comprises about 80 mg telmisartan and the amlodipine layer composition comprises amlodipine or a salt thereof in an amount which is equivalent to an amount of about 5 mg amlodipine in free base form.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the mass of the bilayer tablet is about 380 mg, when the telmisartan layer composition comprises about 40 mg telmisartan and the amlodipine layer composition comprises amlodipine or a salt thereof in an amount which is equivalent to an amount of about 10 mg amlodipine in free base form.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the mass of the bilayer tablet is about 280 mg, when the telmisartan layer composition comprises about 40 mg telmisartan and the amlodipine layer composition comprises amlodipine or a salt thereof in an amount which is equivalent to an amount of about 5 mg amlodipine in free base form.

As mentioned above, the pharmaceutical composition of the invention in the form of a bilayer tablet may be prepared by an appropriate process, wherein the telmisartan layer composition is produced by fluid bed granulation with granulation fluid comprising telmisartan and a basic agent and/or basic agents.

More particularly, the process for the preparation of the bilayer tablets as previously disclosed comprises the following steps: a) providing a granulating fluid by suspending telmisartan and the basic agent in an appropriate solvent or mixture of solvents, b) granulating mannitol, cellulose microcrystalline and the granulating fluid of step a) in a fluid bed to obtain a granulate, c) blend crospovidone with the granulate of step b), d) providing a granulate of amlodipine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients or carriers, e) compressing the telmisartan granulate with the amlodipine granulate of step d) to obtain a bilayer tablet.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, when the telmisartan layer composition comprises a binder and/or colorants, the granulation fluid of step a) further comprises the binder and/or colorants.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, when the telmisartan layer composition comprises a lubricant, the process further comprises a step c’) after step c) of blending the lubricant with the blend of step c). In this embodiment, step e) comprises compressing the telmisartan granulate obtained in step c’) with the amlodipine granulate of step d) to obtain a bilayer tablet.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the solvent of step a) is water or an alcoholic solvent such as methanol, ethanol, isopropanol, or a mixture thereof. More particularly, in step a) a solvent mixture of water and ethanol is used. If the telmisartan layer comprises colorants, these are also added in step a). In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step b) is performed at an atomising pressure of 250 - 400 KPa.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step b) is performed at spray rate of 650-1300 mL/min.

The granulate obtained in step b) may be optionally dried and sieved.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process as described above comprises a further step after step b) and before step c), of drying the granulate of step b).

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process as described above comprises a further step after step b) or after the drying step as defined above, and before step c), of sieving the granulate by using a sieve from 0.5 to 1 .0 mm.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step c) is performed for a period of time from 10 to 20 min, particularly for about 15 min.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step c) is performed under mixing at 8 to 20 rpm, particularly at about 12 rpm.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process as described above comprises step d) of blending the lubricant with the blend of step c). In a more particular embodiment, step d) is performed for a period of time from 3 to 10, particularly for about 7 min. In another more particular embodiment, step d) is performed under stirring at 8 to 20 rpm, particularly at about 12 rpm.

Step d) of the process above comprises providing a granulate of amlodipine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients or carriers. This granulate may be prepared by different processes such as a direct compression process, a wet granulation process or a dry granulation process (roller compaction).

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step d) comprises the steps of: i) providing a blend of amlodipine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients or carriers, and ii) compacting the blend in a roller compactor to form ribbons which are screened down to granules.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step i) is performed by using a premix, i.e., by mixing first amlodipine with part of the excipients (e.g. part of the filler) and then with the rest of excipients or carriers (e.g. rest of fillers and filler/disintegrants), or alternatively, by mixing amlodipine with all the excipients or carriers. In a particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, a premix is formed by mixing first amlodipine or a salt thereof with part of cellulose crystalline, and this premix is blended with the remaining cellulose microcrystalline, pregelatinized starch and maize starch.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the blend obtained in step i) is mixed with a lubricant before step ii).

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step ii) is performed at a roller pressure of about 3-7 klM.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the granules obtained after step ii) are mixed with further excipients or carriers such as e.g. glidants and/or lubricants.

Finally, in step e) the telmisartan granulate of step c), or alternatively step c’) (if a lubricant is used), and the amlodipine granulate of step d) are compressed by methods well known in the art, for example using a bilayer tablet press such a high-speed rotary press in a bilayer tableting mode, to obtain a bilayer tablet.

As mentioned above, the granulates may be compressed in any order. In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the telmisartan layer is first compressed and then the amlodipine layer is compressed onto the telmisartan layer.

In another embodiment, optionally in combination with one or more features of the various embodiments described above or below, the amlodipine layer is first compressed and then the telmisartan layer is compressed onto the amlodipine layer.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, step e) is carried out at an appropriate compression force. Generally, the compression used for the first layer will depend on the strength used.

The appropriate compression force used can readily be determined by those skilled in the art according to the type of composition being prepared.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the first tablet layer is compressed at compression force from 200 to 2000 N, and the main compression force of both layers is from 10 to 30 klM.

The bilayer tablets of the present invention may be packaged in an appropriate package material such as aluminium foil blister packs, or polypropylene tubes and HDPE bottles.

The pharmaceutical composition of the present invention can also be defined by its preparation process. Thus, it is also part of the invention a bilayer tablet as defined above "obtainable” by the process comprising steps a) to e) as previously described.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the invention relates to the pharmaceutical composition which is a bilayer tablet as previously defined, wherein the telmisartan layer is obtainable by wet granulation, more particularly by fluid bed granulation.

In one embodiment, optionally in combination with one or more features of the various embodiments described above or below, the invention relates to the pharmaceutical composition which is a bilayer tablet as previously defined, wherein the amlodipine layer is obtainable by roller compaction.

The term "obtainable by the process” is used herein for defining the pharmaceutical composition of the invention by its preparation process and refers to the pharmaceutical composition that can be obtained through the preparation process which comprises the steps a) to e) as previously defined. For the purposes of the invention, the expressions “obtainable”, “obtained” and similar equivalent expressions are used interchangeably and, in any case, the expression “obtainable” encompasses the expression “obtained”.

Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word “comprise” encompasses the case of “consisting of”. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.

Examples

Example 1 .- Preparation of bilaver tablets according to the invention

Bilayer tablets of Telmisartan/Amlodipine in strengths 40/5 mg, 40/10 mg, 80/5 mg, and

80/10 mg tablets were prepared.

1.1 .- Preparation of the telmisartan granulate

• Telmisartan, sodium hydroxide, meglumine, povidone, iron oxide yellow/iron oxide red, mannitol, cellulose microcrystalline, ethanol anhydrous and water purified were weighed.

• Mannitol and cellulose microcrystalline were screened.

• Preparation of granulating fluid: telmisartan, sodium hydroxide, meglumine, iron oxide yellow/iron oxide red and povidone were suspended in ethanol anhydrous and water purified.

• Fluid bed granulation of components: mannitol and cellulose microcrystalline with granulation fluid was conducted. During fluid bed granulation, 250-400 KPa of atomising pressure and 650 - 1300 mL/min of spray rate were used.

• The granulate was dried in a fluid bed drier until loss on drying was maximum 2%.

• The dry granulate was sieved (sieve: 0.5 - 1.0 mm).

• Crospovidone was weighed, screened and added to granulate and the whole mass was mixed for 15 min by 12 rpm.

• Magnesium stearate was weighed, screened and added to granulate and the whole mass was mixed for 7 min by 12 rpm.

1.2.- Preparation of the amlodipine granulate • Amlodipine besylate, cellulose microcrystalline, starch pregelatinized (maize), starch maize and magnesium stearate were weighed.

• Premix: Amlodipine besylate and part of cellulose microcrystalline (approximately 11%) were screened alternately.

• Blend 1 : Starch pregelatinized (maize), starch maize, premix of amlodipine with cellulose microcrystalline and rest part of cellulose microcrystalline were screened and mixed for 30 min by 12 rpm.

• Blend for roller compaction: Magnesium stearate was mixed with blend 1 for 5 min by 12 rpm.

• The blend was compacted using 3 - 7 klM of roller pressure on a roller compactor.

• Silica colloidal anhydrous was screened and mixed with granulate after roller compaction for 15 min by 12 rpm.

• Magnesium stearate was screened and added to granulate and the whole mass was mixed for 5 min by 12 rpm.

1.3.- Bilaver tabletinq

Telmisartan and amlodipine granulates were compressed on bilayer tableting machine using the following punches:

- oblong, 12.5 x 6 mm (40/5 mg and 40/10 mg strength);

- oblong, 15 x 7.25 mm (80/5 mg and 80/10 mg strength).

During tableting process telmisartan layer was obtained as first layer and amlodipine was compressed on to the compressed telmisartan layer. During bilayer tableting, compression forces were controlled:

1 4 Packing

Telmisartan/amlodipine 40/5 mg, 40/10 mg, 80/5 mg, 80/10 mg tablets were packed in AI/OPA/AI/PVC foil blisters.

The quantitative composition of the obtained bilayer tablets is the following:

Table 1 :

Comparative example - Preparation of bilaver tablets (strength 80/5 mg)

The telmisartan granulate was prepared in similar way as disclosed in Lee et al. (Telmiduo®). Sodium hydroxide, meglumine, telmisartan and povidone K-25 were added in a 50% (v/v) ethanol at ambient temperature and mixed (preparation of suspension); the granulation of D-mannitol, dicalcium phosphate, crospovidone and cellulose microcrystalline (previously screened through 0.8 mm sieve) was performed in a high shear granulator with prepared suspension. The impeller and chopper speed were set at 840 rpm and 1000 rpm, respectively. The granulation time was 2 min. The granulate was dried in a fluid bed drier. The dry granulate was milled and mixed with magnesium stearate for 5 min by 12 rpm. Final granulate was compressed on tableting machine into mono tablets or bilayer tablets using the following punches: 15 x 7.25 mm. The preparation of the amlodipine granulate, and bilayer tableting was performed as disclosed in example 1. The quantitative composition of the obtained bilayer tablets is the following: Table 2:

Measurement of the Carr’s index of the telmisartan layer

The bulk and tap densities of the telmisartan granules of the bilayer tablets according to the invention (prepared as in example 1) were measured using an Erweka type SVM22 (according to European Pharmacopoeia 10: sections 2.9.34 (bulk density and tapped density of powders) and 2.9.36 (powder flow)). Several batches were tested. The Carr’s index was calculated from the following equation:

Carr’s index = (V _t -V _b )/V _t x 100

Table 3 below shows the Carr’ index values for telmisartan granulates of different batches:

Table 3:

As can be seen the telmisartan granulates showed in all cases Carr’s index values from about 8 to about 12, which corresponds to a good or excellent flowability.

Hyqroscopicitv/moisture intake after storage

First Test: 24 h, 40 °C/75% RH - hardness, weight, appearance of telmisartan tablets The hygroscopicity or moisture intake of the telmisartan tablets (80 mg) according to the invention (prepared as in example 1) was compared to the one of telmisartan tablets (80 mg) according to Lee et al (prepared as in comparative example), and the separated telmisartan layer from the marketed tablets sold under the name Twynsta® (80/5 mg, excipients: agnesium stearate, Meglumine, Povidone K25, Pregelatinised starch, Sodium hydroxide, Sorbitol).

The unpacked tablets were stored in stability chamber at conditions 40 °C and 75% RH (relative humidity) for 24 hours. The appearance, weight and hardness of telmisartan tablets were investigated.

Initially, the hardness of telmisartan tablets according to Lee et al was approximately 182 N, but decreased to 52 N (about 3.5 times) after 24 hours at 40 °C and 75% RH. In the case of telmisartan tablets according to invention the hardness increased (initially: 136 N and after 24 hours at 40 °C and 75% RH: 170 N). The weight of the telmisartan tablets according to Lee et al and according to invention increased by 6.8% and 5.2%, respectively.

The separated telmisartan layer of the reference product Twynsta® absorbed water and liquefied in these conditions (FIG. 1). In case of telmisartan tablets according to Lee et al the surface of tablets became rough, but it did not liquefy. Colour of the tablets was slightly changed (tablets became slightly yellowish after storage, at the initial point tablets had white colour) (FIG. 2). The appearance of the telmisartan tablets of the composition according to invention visually did not change apart from the colour. Yellow colour (caused by iron oxide) of the tablets became more intensive in comparison with initial sample (FIG. 3)

Second Test: 24 h, 25 °C/80% RH - hygroscopicity test of telmisartan tablets The same samples as for the first test were put into stability chamber at 25 °C and 80% RH for 24 h and hygroscopicity test according to European Pharmacopoeia 10, section 5.11 was performed. The highest hygroscopicity was observed for telmisartan layer separated from reference product (19.4%; due to high content of hygroscopic sorbitol in composition). Result for telmisartan tablets according to Lee et al was 11.3%. The lowest hygroscopicity was observed in case of the telmisartan tablets according to invention - 7.2%. The telmisartan layer separated from reference product can be described as very hygroscopic according to the European Pharmacopoeia definition. The other two samples - telmisartan tablets according to Lee et al and telmisartan tablets according to invention can be described as hygroscopic according to the European Pharmacopoeia definition. Third Test: 24 h, 40 °C 75% RH - hardness, weight, appearance of telmisartan/ amlodipine biiaver tablets

The hygroscopicity or moisture intake of the bilayer tablets (80/5 mg) according to the invention (example 1) was compared to the one of the bilayer tablets (80/5 mg) of the comparative example.

The unpackaged bilayer tablets were stored in stability chamber at conditions 40 °C and 75% RH (relative humidity) for 24 hours and the changes of appearance, weight and hardness were evaluated. Telmisartan layer of Twynsta® tablets was liquefied after 24 hours at 40°C/75% RH and it was not possible to assess the physical parameters.

The appearance of the bilayer tablets of the comparative example changed after 24 hours at 40 °C/75% RH: the amlodipine layer separated from telmisartan layer (FIG. 4). The hardness of the remaining tablet after separation of layers (i.e. telmisartan layer) was tested. Hardness decreased by 3.5 times after 24 hours at 40 °C/75% RH: from 113 N to 32 N (it confirmed results obtained for telmisartan tablets). Physical changes in telmisartan layer during stability caused problems with bilayer tablets (bilayer tablet delamination and significant hardness decrease).

In the case of bilayer tablets according to invention, the appearance of bilayer tablets did not change after 24 hours at 40 °C/75% RH (no delamination occurred, FIG. 5). The hardness of those tablets increased (initially 179 N up to 196 N).

Physical parameters

Physical parameters of the bilayer tablets according to the invention such as hardness, friability, and tablet disintegration time were measured according to European Pharmacopoeia 10: sections 2.9.1 Disintegration time, 2.9.8 Hardness, and 2.9.7 Friability). The results are shown in the tables below:

Table 4: average mass was tested

Table 5: time [min:sl; max., Av. average mass was tested

Comparative in vitro dissolution study of telmisartan

The dissolution profile of telmisartan in the bilayer tablets according to the invention as disclosed in example 1 was measured and was compared to the dissolution profile of the marketed tablets Twynsta® at different strengths. For each strength several batches of bilayer tablets were measured.

The test was carried out in phosphate buffer pH 7.5, 900 ml. (paddle apparatus, 75 rpm). The results are shown in the tables below:

Table 6:

Table 7:

Table 8:

Table 9:

Batch Twynsta 80/10 mg tablets

As can be seen, the dissolution profiles of the bilayer tablets according to the invention showed much less variability than the ones of the marketed tablets.

Citation List

- W02006048208

- Lee, Ah Ram et al; “Quality by Design (QbD) approach to optimize the formulation of a bilayer combination tablet (Telmiduo) manufactured via high shear wet granulation", International Journal of Pharmaceutics 2017, 534(1-2), 144-158

- Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules Guidance for Industry June 2015, Issued by Center for Drug Evaluation and Research, FDA

- European Pharmacopoeia 10: sections 2.9.34 (bulk density and tapped density of powders), 2.9.36 (powder flow), 2.9.1 (Disintegration time), 2.9.8 (Hardness), and 2.9.7 (Friability), 5.11 (Hygroscopicity test).