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EP4093381A1 - Comprimé bicouche comprenant du telmisartan et de l'amlodipine - Google Patents

Comprimé bicouche comprenant du telmisartan et de l'amlodipine

Info

Publication number
EP4093381A1
EP4093381A1 EP21703147.5A EP21703147A EP4093381A1 EP 4093381 A1 EP4093381 A1 EP 4093381A1 EP 21703147 A EP21703147 A EP 21703147A EP 4093381 A1 EP4093381 A1 EP 4093381A1
Authority
EP
European Patent Office
Prior art keywords
telmisartan
amlodipine
layer composition
layer
pharmaceutical composition
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
EP21703147.5A
Other languages
German (de)
English (en)
Inventor
Anna Madanecka
Agne KUCINSKAITE-PISZCZEK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zaklady Farmaceutyczne Polpharma SA
Original Assignee
Zaklady Farmaceutyczne Polpharma SA
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 Zaklady Farmaceutyczne Polpharma SA filed Critical Zaklady Farmaceutyczne Polpharma SA
Publication of EP4093381A1 publication Critical patent/EP4093381A1/fr
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine

Definitions

  • Bilayer tablet comprising telmisartan and amlodipine
  • 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.
  • 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:
  • amlodipine is used as maleate, besylate (or benzenesulfonate) and mesylate salt.
  • telmisartan and amlodipine have been described.
  • 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.
  • 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.
  • 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.
  • FDA Food and Drug Administration
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • bilayer tablets of the invention show better flowability of the telmisartan granulate in comparison of the prior art tablets disclosed in Lee et al.
  • 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.
  • the bilayer tablets of the invention can be prepared by a cost effective process in comparison to the reference product.
  • the bilayer tablets of the invention show low hygroscopicity or moisture intake and improved stability during storage.
  • 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.
  • 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).
  • the bilayer tablets of the invention have lower tablet weight in comparison with the bilayer tablets of the prior art.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • telmisartan and amlodipine are tableted.
  • 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.
  • 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.
  • the amlodipine layer is first compressed and then the telmisartan layer is compressed onto the amlodipine layer.
  • pharmaceutically acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free bases.
  • acid addition salts include, without limitation, hydrochloride, hydrobromide, hydrogensulfate, tosylate, fumarate, maleate, tartrate, or benzenesulfonate (besylate) and methanesulfonate (mesylate) salts.
  • 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.
  • 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.
  • the amlodipine layer composition comprises amlodipine mesylate or amlodipine besylate, more particularly amlodipine besylate.
  • 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.
  • the telmisartan layer composition comprises telmisartan in an amount of about 40 or about 80 mg.
  • 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.
  • 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.
  • the telmisartan layer composition comprises telmisartan in an amount of about 40 mg
  • 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.
  • the telmisartan layer composition comprises about 40 mg telmisartan
  • 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.
  • the telmisartan layer composition comprises telmisartan in an amount of about 40 mg
  • 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.
  • the telmisartan layer comprises about 40 mg telmisartan
  • 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.
  • the telmisartan layer composition comprises telmisartan in an amount of about 80 mg
  • 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.
  • the telmisartan layer comprises about 80 mg telmisartan
  • 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.
  • the telmisartan layer composition comprises telmisartan in an amount of about 80 mg
  • 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.
  • the telmisartan layer comprises about 80 mg telmisartan
  • 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.
  • alkali metal hydroxides include sodium hydroxide and potassium hydroxide.
  • 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.
  • pharmaceutically acceptable excipients or carriers 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.
  • telmisartan layer composition examples include, without limitation, binders, lubricants, colorants, glidants and solubilizers.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a binder more particularly polyvinylpyrrolidone (povidone)
  • povidone polyvinylpyrrolidone
  • 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.
  • the telmisartan layer composition comprises a binder, more particularly povidone, and a lubricant, more particularly magnesium stearate.
  • 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.
  • the telmisartan layer composition comprises telmisartan, one or more basic agents, mannitol, cellulose microcrystalline, crospovidone, povidone, colorants, and magnesium stearate.
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • the amlodipine layer comprises amlodipine or a salt thereof, fillers, disintegrants, lubricants, and glidants.
  • the amlodipine layer comprises amlodipine or a salt thereof, cellulose microcrystalline, pregelatinized starch, maize starch, magnesium stearate and colloidal silicon dioxide.
  • 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.
  • the excipients or carriers for the telmisartan layer composition are chosen such that a disintegrating or eroding tablet matrix is obtained.
  • the excipients or carriers for the amlodipine layer composition are chosen such that a disintegrating or eroding tablet matrix is obtained.
  • 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.
  • 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.
  • the telmisartan layer composition is capable of providing an instant release (fast dissolution) characteristics.
  • the amlodipine layer composition is capable of providing an instant release (fast dissolution) characteristics.
  • the telmisartan and the amlodipine layer compositions are capable of providing an instant release (fast dissolution) characteristics.
  • 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.
  • 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.
  • the bilayer tablets of the invention show improved flowability of the telmisartan granulate.
  • 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:
  • 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)).
  • the bilayer tablets of the invention show low hygroscopicity or moisture intake after storage.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the granulation fluid of step a) further comprises the binder and/or colorants.
  • step e) comprises compressing the telmisartan granulate obtained in step c’) with the amlodipine granulate of step d) to obtain a bilayer tablet.
  • 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.
  • step b) is performed at spray rate of 650-1300 mL/min.
  • the granulate obtained in step b) may be optionally dried and sieved.
  • the process as described above comprises a further step after step b) and before step c), of drying the granulate of step b).
  • 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.
  • step c) is performed for a period of time from 10 to 20 min, particularly for about 15 min.
  • step c) is performed under mixing at 8 to 20 rpm, particularly at about 12 rpm.
  • step d) of blending the lubricant with the blend of step c).
  • step d) is performed for a period of time from 3 to 10, particularly for about 7 min.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • the blend obtained in step i) is mixed with a lubricant before step ii).
  • step ii) is performed at a roller pressure of about 3-7 klM.
  • the granules obtained after step ii) are mixed with further excipients or carriers such as e.g. glidants and/or lubricants.
  • 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.
  • the granulates may be compressed in any order.
  • the telmisartan layer is first compressed and then the amlodipine layer is compressed onto the telmisartan layer.
  • the amlodipine layer is first compressed and then the telmisartan layer is compressed onto the amlodipine layer.
  • step e) is carried out at an appropriate compression force.
  • the compression used for the first layer will depend on the strength used.
  • 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.
  • composition of the present invention can also be defined by its preparation process.
  • 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.
  • 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.
  • the expressions “obtainable”, “obtained” and similar equivalent expressions are used interchangeably and, in any case, the expression “obtainable” encompasses the expression “obtained”.
  • telmisartan 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.
  • Crospovidone was weighed, screened and added to granulate and the whole mass was mixed for 15 min by 12 rpm.
  • amlodipine granulate • Amlodipine besylate, cellulose microcrystalline, starch pregelatinized (maize), starch maize and magnesium stearate were weighed.
  • 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.
  • Magnesium stearate was screened and added to granulate and the whole mass was mixed for 5 min by 12 rpm.
  • Telmisartan and amlodipine granulates were compressed on bilayer tableting machine using the following punches:
  • telmisartan layer was obtained as first layer and amlodipine was compressed on to the compressed telmisartan layer.
  • compression forces were controlled:
  • 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:
  • 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:
  • the bulk and tap densities of the telmisartan granules of the bilayer tablets according to the invention 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:
  • telmisartan granulates showed in all cases Carr’s index values from about 8 to about 12, which corresponds to a good or excellent flowability.
  • telmisartan tablets 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.
  • telmisartan tablets according to Lee et al were approximately 182 N, but decreased to 52 N (about 3.5 times) after 24 hours at 40 °C and 75% RH.
  • 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.
  • telmisartan tablets according to Lee et al The separated telmisartan layer of the reference product Twynsta® absorbed water and liquefied in these conditions (FIG. 1).
  • 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%.
  • 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 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.
  • 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).
  • 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 dissolution profiles of the bilayer tablets according to the invention showed much less variability than the ones of the marketed tablets.

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Abstract

La présente invention concerne une composition pharmaceutique qui est un comprimé bicouche comprenant a) une composition de couche comprenant : i) du telmisartan, ii) un ou plusieurs agents basiques choisis parmi un hydroxyde de métal alcalin et la méglumine, iii) de (40) à (70) % p/p de mannitol, iv) de (5) à (15) % p/p de cellulose microcristalline, et v) de (1) à (6) % p/p de crospovidone, les % en poids étant exprimés par rapport au poids total de la couche ; et b) une composition de couche comprenant de l'amlodipine ou un sel pharmaceutiquement acceptable de celle-ci et un ou plusieurs excipients ou véhicules pharmaceutiquement acceptables. L'invention concerne également un procédé de préparation de cette composition pharmaceutique et son utilisation dans le traitement de l'hypertension.
EP21703147.5A 2020-01-20 2021-01-18 Comprimé bicouche comprenant du telmisartan et de l'amlodipine Pending EP4093381A1 (fr)

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