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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
  • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• • 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
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
• • 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
• • 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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • 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
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

• the present invention relates to the pharmaceutical filed, and particularly to stable pharmaceutical compositions and processes for preparing such compositions, which are suitable for industrial scale.
• the present invention relates to oral pharmaceutical compositions containing a surfactant-free granulate comprising amorphous telmisartan or a salt thereof, at least one filler and optionally, hydrochlorothiazide.
• Telmisartan is a benzimidazole derivative antagonist of subtype 1 angiotensin Il receptors (AT1) intended for the treatment of essential arterial hypertension. Its structural formula is:
• Telmisartan is chemically described as 4'-[(1,4'-dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'- biphenyl]-2-carboxylic acid. Its empirical formula is C33H30N4O2 and its molecular weight is 514.63. Telmisartan was first disclosed in EP502314 A1. Telmisartan is generally manufactured and supplied as an API in the free acid form and it is marketed under the trade name Micardis ® in doses of 20 mg, 40 mg and 80 mg.
• telmisartan The main physicochemical properties of telmisartan are high lipophilicity and polymorphism. As disclosed in WO00/43370 A1, crystalline telmisartan exists in two polymorphic forms having different melting points. Under the influence of heat and humidity, the lower melting polymorph B transforms irreversibly into the higher melting polymorph A.
• Telmisartan is a white to off-white, odourless crystalline powder. It is practically insoluble in water or an aqueous solution in the pH range of 3 to 9, and sparingly soluble in a strong acid, with the exception of hydrochloric acid in which it is insoluble. Telmisartan is soluble in a strong base.
• WO00/272397 A1 discloses the preparation of a pharmaceutical dosage form containing lacidipine and telmisartan.
• a telmisartan "granulate" is obtained by a spray drying technique and then mixed with other excipients and lacidipine.
• EP1467712 A1 discloses the preparation of bilayer tablets comprising a first layer containing telmisartan in substantially amorphous form in a dissolving tablet matrix, and a second layer containing a diuretic in a disintegrating tablet matrix.
• Amorphous telmisartan is obtained by spray drying a telmisartan aqueous solution with a basic agent and povidone. This product is then blended with a water-soluble filler and a lubricant in a high shear mixer.
• EP1545467 A1 discloses pharmaceutical compositions comprising 3 to 50 wt. % of telmisartan dispersed in a dissolving matrix comprising: a) a basic agent in a molar ratio of basic agent: telmisartan of 1:1 to 10:1, b) a surfactant or emulsifier in an amount of about 1 to 20 % of the final composition, c) 25 to 70 wt. % of a water- soluble filler, and d) optionally, 0 to 20 wt. % of further excipients and/or adjuvants.
• the process for preparing the pharmaceutical compositions includes the use of a fluid bed granulator instead of spray drying equipment; however the use of surfactants or emulsifiers is required to achieve a suitable drug dissolution profile.
• EP1797872 A1 discloses pharmaceutical compositions comprising telmisartan, a basic agent, a surfactant and at least one filler selected from water-soluble and water-insoluble fillers, wherein the amount of water soluble fillers in the pharmaceutical composition is less than 25 % by weight of the pharmaceutical composition. These compositions are prepared by using a high shear mixer.
• the method comprises the steps of mixing a disintegrant and one or more fillers in the high shear mixer to form a homogeneous mixture; preparing a granulation suspension of purified water, alcohol, a basic agent, a surfactant, and telmisartan; combining the homogeneous mixture and the granulation suspension to form a combined mixture; preparing a granulation solution of water and a binder; adding the granulation solution to the combined mixture to form a granulate; drying the formed granules; sizing the dried granules; mixing the dried granulate with a filler and a disintegrant; and adding a lubricant to form a final mixture.
• WO2007/060170 A1 discloses bilayer pharmaceutical tablets comprising a first layer containing 3 to 50 wt. % of telmisartan dispersed in a dissolving matrix comprising: a) a basic agent in a molar ratio of basic agent: telmisartan of 1:1 to 10:1, b) a surfactant or emulsifier in an amount of about 1 to 20 % of the final composition, c) 25 to 70 wt. % of a water-soluble filler, and d) optionally 0 to 20 wt. % of further excipients and/or adjuvants and a second layer containing a diuretic in a disintegrating tablet matrix.
• the process for preparing the pharmaceutical composition includes the use of a fluid bed granulator instead of spray drying equipment. However, the use of surfactants or emulsifiers to achieve a suitable drug dissolution profile is required.
• telmisartan is manufactured in two steps. Starting from the free acid form, telmisartan is processed into a spray dried granulate, which is then mixed with sorbitol and magnesium stearate to give a final mixture that is ready to compress.
• EP1970053 A1 discloses tablets or tablet layers comprising telmisartan in amorphous form, a basic agent and sorbitol, characterized in that the sorbitol has a specific surface area.
• the problem to be solved by the present invention is to provide alternative, efficient, cost-effective and stable pharmaceutical compositions comprising amorphous telmisartan or a salt thereof.
• the first aspect of the present invention is a surfactant-free granulate comprising amorphous telmisartan or a salt thereof, at least one filler and optionally, hydrochlorothiazide, wherein telmisartan or a salt thereof has not been spray-dried.
• the present inventors have surprisingly discovered that the use of such granulate to develop a solid pharmaceutical composition such as tablets overcome the problems associated with the formulations described in the prior art.
• the present inventors have noticed that it is possible to use conventional granulation methods instead of spray-drying techniques to obtain bioavailable telmisartan pharmaceutical compositions with suitable dissolution profiles.
• telmisartan was spray-dried in order to obtain a fine powder and, consequently, increase its bioavailability limited by its hydrophobicity.
• this method is time consuming and costly as it adds another step to the process, also it is not industrially feasible and scale up is difficult.
• the use of telmisartan processed by spray drying results in products which are very fine, with many static charges and lacking in suitable flow characteristics, all of which makes the handling of these products difficult on an industrial scale.
• the granulate of the invention has a more homogeneous particle size and good flowability, which makes it more suitable for the manufacture of tablets.
• the granulates of the invention do not require a particle size reduction of telmisartan by spray drying or even the use of surfactants or emulsifiers to achieve a suitable dissolution profile. It is well known that these substances can increase the permeability and dissolution rate of active ingredients. Generally, if the permeability is increased the active ingredient bioavailability is altered and T max is reduced. This could cause a rapid decrease in blood pressure and such pharmacokinetic change could induce sudden hypotension. In view of the fact that surfactants increase the dissolution rate the differences between dissolution profiles performed at different pH's are masked, and batch to batch reproducibility as regards dissolution rate cannot easily be determined.
• surfactants or emulsifiers leads to technological problems such as the production of foam and scum which can obturate tubes or nozzles and lead to an incorrect transfer of the product between different equipment, consequently the yield of the process is reduced.
• surfactants and emulsifiers are reactive substances which may be incompatible with the active ingredients, other excipients or even manufacturing equipment or instruments. Using the granulates according to the first aspect of the present invention overcome these problems.
• the invention in a second aspect, relates to a solid pharmaceutical composition
• a solid pharmaceutical composition comprising the surfactant-free granulate of the first aspect of the present invention, preferably in the form of tablets.
• the present invention overcomes the technological problems associated with the use of telmisartan processed by spray drying which leads to product which is very fine, with a many static charges and lacking suitable flow properties. This leads to difficulty in handling on a larger scale.
• manufacturing of tablets or other solid pharmaceutical compositions is feasible, due to the homogeneous particle size distribution and the suitable flowability of the granulate.
• the invention in a third aspect, relates to a method for the manufacture of the said solid pharmaceutical composition, wherein the method comprises at least the granulation of telmisartan or a salt thereof by wet or dry granulation, preferably by wet granulation.
• the present invention discloses a method wherein amorphous telmisartan is granulated at least with a filler to form a granulate. Once the granulated is obtained, the handling of the product is easier because the particle size and the sphericity increase. Wet granulation is preferred because it transforms the hydrophobic surface of telmisartan particles into a more hydrophilic surface.
• the invention relates to a method for preparing a telmisartan pharmaceutical composition
• a method for preparing a telmisartan pharmaceutical composition comprising at least the steps of: a) placing a filler or a mixture of it with other pharmaceutical acceptable excipients in a fluid bed processor, b) preparing a binding solution comprising telmisartan or a salt thereof, at least one base and at least one binder in an aqueous solvent, c) spraying the binding solution into the filler or the mixture of it with other pharmaceutical acceptable excipients forming a granulate, preferably by top spray technique, d) drying the granulate, e) optionally, mixing the dried granulate with lubricants and, optionally, with other pharmaceutical acceptable excipients, and f) compressing the resulting granulate of the previous steps into tablets.
• the dry starting product is placed in the product container.
• it is mixed vigorously in the heated gas stream, held in suspension and agglomerated/granulated by spraying with a suitable binding material.
• the product is then dried to the required end moisture content with high heat and material transition coefficients.
• the present process is simplified and shortened because this step is avoided and spray drying equipment is not required.
• both the mixing process in the presence of a liquid that causes the powder to clump into granules and the drying process are performed in the same equipment, a fluid bed processor. Consequently, the granulation process is less time consuming because it is not necessary to transfer the product from the mixer to the granulator and then to a drier. Reducing the number of transfers increases the yield of the process because this avoids any loss of product that otherwise would remain in the equipment. Furthermore, time is not lost in cleaning extra equipment. Another important aspect is the scale-up feasibility of the present invention and the possibility of automation.
• the present inventors have realized that it is preferable to use a top spray technique, wherein the binding solution is sprayed crosscurrent to the heated gas stream, because the nozzles clog less frequently than with the bottom spray technique.
• the homogeneity of the particle size distribution of the granules obtained is also better with the top spray technique.
• the specific surface area of the filler in this case sorbitol
• sorbitol has no influence on the manufacture of telmisartan pharmaceutical compositions according to this aspect of the present invention.
• Different trials have been performed using sorbitol with a specific surface area ranging from 0.5 to 3.5 nf/g without encountering the problems mentioned in EP1970053 A1 : finding a wide range of bulk densities in the product to be compressed, possible segregation of mixtures, excessive pressure needed which leads to tablets with too high resistance to breakage which results in slow dissolution profile of certain batches, and therefore in a less robust process lacking uniformity.
• telmisartan interacts with the rest of the excipients during granulation.
• the granulate obtained has a homogenous particle size and constant density, thus the granules of the invention do not segregate in the compression machine hopper. Consequently, the tablets obtained meet the specifications for uniformity of mass and content.
• the invention in a fifth aspect, relates to surfactant-free loaded cores comprising: a) amorphous telmisartan or a salt thereof, b) optionally, hydrochlorothiazide, and c) inert cores, wherein telmisartan or a salt thereof has not been spray-dried.
• the present invention includes the use of inert cores which are coated with a surfactant- free telmisartan or a salt thereof solution.
• the loaded cores obtained are totally spherical from which a homogeneous distribution of telmisartan or a salt thereof is achieved. Consequently, these cores suitably release the active ingredient.
• the invention relates to a solid pharmaceutical composition
• a solid pharmaceutical composition comprising said loaded cores, preferably in the form of tablets.
• the telmisartan cores obtained, from which different pharmaceutical dosage forms can be derived such as capsules they also show good tabletting properties. For this reason, tablets are preferred in the present invention.
• the invention relates to a method for the manufacture of a tablet according to sixth aspect, comprising at least the steps of: a) preparing a seal coating solution containing a coating agent, b) placing the inert cores in a fluid bed processor and coating them with the seal coating solution, c) preparing a solution comprising telmisartan or salts thereof, at least one base and at least one binder in an aqueous solvent, d) performing the drug loading of the sealed cores with the solution prepared in the previous step, preferably using a bottom spray coating technique, e) optionally, performing a top coating of the drug loaded cores with a solution containing a coating agent, preferably using a bottom spray coating technique, f) optionally, mixing the coated drug loaded cores with lubricants and, optionally, with other pharmaceutical acceptable excipients, g) compressing the result of the previous step into tablets.
• the invention relates to a method for preparing a telmisartan pharmaceutical composition
• telmisartan cores using a fluid bed processor.
• This method has suitable scale-up feasibility and a high process yield.
• the starting material is based on inert cores which do not have a tendency to stick and are in motion in the fluid bed chamber while they are coated with a telmisartan or a salt thereof solution.
• bottom spray technique the inert cores do not tend to clog the nozzle because they have a higher particle size than normal powder mixture.
• a bottom spray technique there is a better distribution of active ingredient around the cores.
• Surfactant-free as used herein is intended to mean that the amount of surfactant or emulsifier, present, if any, in the dosage form or pharmaceutical composition of telmisartan is insufficient to act as surfactant or emulsifier.
• Granulate is considered a mixture of agglomerated powders obtained by a conventional process of granulation using a mixer and a granulator, a high shear mixer or a fluid bed granulator. Telmisartan comes into contact with at least one filler during the granulation so that particle size of the initial powders increases.
• Aqueous solvent includes water and mixtures of water-miscible organic solvents such as alcohols (for ex. ethanol or isopropyl alcohol) or acetone with water.
• water-miscible organic solvents such as alcohols (for ex. ethanol or isopropyl alcohol) or acetone with water.
• a fluid bed processor is a bed of solid particles with a stream of air or gas passing upward through the particles at a rate great enough to set them in motion. As the air travels through the particle bed, it imparts unique properties to the bed. For example, the bed behaves as a liquid. It is possible to propagate wave motion, which creates the potential for improved mixing. In a bubbling fluidized bed, no temperature gradient exists within the mass of the fluidized particles. This isothermal property results from the intense particle activity in the system. Thus, the fluid bed can be used to dry the wet product, agglomerate particles, improve flow properties or produce coated particles for controlled release or taste masking.
• Top spray technique is understood as being a kind of granulation performed in a fluid bed processor by spraying solvent or a solvent/binder solution onto a fluidized powder bed.
• Bottom spray technique is understood as a kind of granulation by concurrently spraying solvent or a solvent/binder solution into a segregated dilute phase powder stream.
• Suitable dissolution profile is understood as yielding a profile similar to the innovator pharmaceutical composition comprising telmisartan sold as Micardis®.
• Carr's index and the Hausner ratio are both based on the decrease in powder volume during tapping, and their usefulness lies in their ability to predict flowability. The lower the number the more free-flowing the powder.
• An increase in the value is proportional to the adhesion and friction properties of a powder, including (attractive) electric charge and compressibility. The mathematical expression of each one is:
• the present invention is directed to surfactant-free granulates comprising amorphous telmisartan and at least one filler, wherein telmisartan or a salt thereof has not been spray-dried.
• telmisartan or a salt thereof has not been spray-dried.
• the filler is a sugar.
• the sugar is selected from the group consisting of sucrose, lactose, mannitol, xylitol, maltitol, sorbitol, lactitol, erythritol, isomalt and mixtures thereof.
• the sugar is sorbitol.
• sorbitol is the preferred filler in a surfactant-free granulate because the yield of the present processes increases when sorbitol is used in the formulation. During granulation no lumps were formed, the granules were uniform and not much material was collected from the finger bags. During the drying step granulate comprising sorbitol was less friable than those comprising mannitol, sucrose or lactose. The granulate with sorbitol is more suitable for compression and provide non friable tablets (see table 3).
• the amount of sugar ranges from 70 % to 90 % by weight of the tablet. Using more than 70 % by weight of sugar, surprisingly, improves the dissolution rate of telmisartan. Furthermore, besides being a more economical alternative to surfactants or emulsifiers, sugars do not show the afore-mentioned technological problems, such as formation of foam and scum or the risk of adverse effects due to a change of permeability and the consequent altered bioavailability.
• the wet granulation is carried out using a conventional mixer or a fluid bed processor.
• the present formulation is so consistent that it can be performed by these two different methods of granulation.
• wet granulation is performed using a fluid bed processor comprising at least the steps of: a) placing a filler or a mixture of it with other pharmaceutical acceptable excipients in the fluid bed processor, b) preparing a binding solution comprising telmisartan or a salt thereof, at least one base and at least one binder in an aqueous solvent, c) spraying the binding solution into the filler or a mixture of it with other pharmaceutical acceptable excipients forming a granulate, preferably by a top spray technique. d) drying the granulate, e) optionally, mixing the dried granulate with lubricants and, optionally, with other pharmaceutical acceptable excipients, f) compressing the result of the previous steps into tablets.
• the present inventors have realized that when wet granulation is performed, the use of fluid bed equipment reduces the process time. The reason for this is that the binding solution which contains telmisartan or a salt thereof has to be incorporated into the filler or mixture of it with other pharmaceutical acceptable excipients.
• the solvent evaporates during the granulation process.
• a simple mixer is used, the mixture needs to be transferred to a granulator and then to a drier.
• this due to the high volume of binding solution needed this has to be incorporated in more than one step.
• the pharmaceutical acceptable excipients may be selected from the group consisting of binders (e.g. hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, gelatine, arabic gum, ethylcellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, solutions of sorbitol and mixtures thereof ), disintegrants (e.g. calcium carboxymethylcellulose, colloidal silicon dioxide, starch, croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof) and lubricants (e.g.
• binders e.g. hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, gelatine, arabic gum, ethylcellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, solutions of
• magnesium stearate colloidal anhydrous silica, stearic acid, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and mixtures thereof).
• the inert cores comprise sucrose, mannitol, sorbitol, lactose, microcrystalline cellulose, starch and mixtures thereof.
• Inert cores of different compositions are suitable to be coated by a solution of telmisartan or a salt thereof.
• the tablet compositions containing surfactant-free granulate comprising amorphous telmisartan or a salt thereof obtained by top spray fluid bed processing are shown in table 1.
• the optimal set process parameters are in table 2.
• Examples T1-T6 disclosed correspond to a batch sizes of 2000 tablets with a unit weight of 480 mg for the 80 mg strength.
• the optimal length, breadth and thickness are 16 mm, 8 mm and 4.3-4.5 mm, respectively.
• the examples T1 , T2 and T3 are reproduced with two different kinds of sorbitol (A: Neosorb P60W and B: C*PharmSorbidexP16616 (in the past sold as Sorbidex P6)).
• the specific surface areas are 1.2 m2/g and 0.56 m2/g respectively determined according to the USP monograph ⁇ 846>, using a suitable, calibrated BET instrument, at 77 0 K with nitrogen.
• step 2 Place the sifted material from step 2 into a fluid bed processor bowl and pre-heat for 10 min.
• step 2 Place the sifted material from step 2 into a fluid bed processor bowl and pre-heat for 10 min.
• telmisartan Place telmisartan in a vessel. 4. Prepare the binding solution: a) Dissolve sodium hydroxide in 50 g of water in a vessel (A). Allow to cool. b) Place 200 g of water in a mixing vessel (B) and under constant stirring add the povidone. Continue stirring for 5 min. Under constant stirring add the meglumine and continue stirring for 5 min. c) Add the solution of sodium hydroxide to mixing vessel (B), rinse vessel (A) with 41 g of water and add the liquid to the mixing vessel (B) under stirring. d) Under constant stirring, add the solution in mixing vessel (B) to the vessel containing telmisartan. Rinse vessel B with 27 g of water and add the liquid to the solution of telmisartan. Continue stirring to form a clear solution. Set aside for deaeration.
• step 2 Place the sifted material from step 2 into a fluid bed processor bowl and pre-heat for 10 min.
• step 2 Place the sifted material from step 2 into a fluid bed processor bowl and pre-heat for 10 min.
• step 2 Place the sifted material from step 2 into a fluid bed processor bowl and pre-heat for 10 min.
• T1-T6 are reproduced using telmisartan and hydrochlorothiazide in the strengths of 40 /12.5 mg, 80/12.5 mg and 80/25 mg, respectively.
• the formula is exactly the same for all strengths and the weight of the tablet determines the strength of the drug substance.
• the weight of the tablet is 600 mg from which 480 mg corresponds to telmisartan granulate and 120 mg to hydrochlorothiazide granulate, approximately.
• the manufacturing process has an additional step which consists in the granulation of hydrochlorothiazide (20.83 %) in a suitable granulation equipment, such as a high shear granulator using a filler, such as sorbitol (75.16 %), a disintegrant, such as sodium starch glycolate (2.5 %) and a binder solution comprising a binder, such as povidone (dry povidone 1.5 %).
• a suitable equipment such as a high shear granulator using a filler, such as sorbitol (75.16 %), a disintegrant, such as sodium starch glycolate (2.5 %) and a binder solution comprising a binder, such as povidone (dry povidone 1.5 %).
• a suitable equipment such as a high shear granulator using a filler, such as sorbitol (75.16 %), a disintegrant, such as sodium starch glycolate (2.5 %) and a binder solution
• hydrochlorothiazide is incompatible with basic agents which are present in the telmisartan granulate
• the hydrochlorothiazide containing granules are protected with a film-coating polymer by using for instance a solution, such as one comprising hydroxypropyl methylcellulose (1 %), polyethylene glycol 400 (1 %), yellow ferric oxide (0.05 %) and titanium dioxide (0.05 %) in suitable equipment, such as fluid bed equipment.
• a solution such as one comprising hydroxypropyl methylcellulose (1 %), polyethylene glycol 400 (1 %), yellow ferric oxide (0.05 %) and titanium dioxide (0.05 %) in suitable equipment, such as fluid bed equipment.
• both active granulates are mixed in suitable equipment, such as a tumbling mixer with a lubricant, such as magnesium stearate (1.5 % of the total weight). Then, the previous mixture is compressed into tablets.
• examples T1 -T3 correspond to those tablets containing sorbitol B. Similar values are obtained when sorbitol A is used.
• the tablet compositions containing surfactant-free cores comprising amorphous telmisartan or a salt thereof obtained by a bottom spray coating technique are shown in the table 4.
• the optimal set process parameters are given in table 5.
• T7-T10 correspond to batch sizes of 1525 tablets with a unit weight of 600 mg for the strength of 80 mg of telmisartan.
• the optimal length, breadth and thickness are 16 mm, 8 mm and 5.5-5.7 mm, respectively.
• the core sizes are between 150 ⁇ m to 300 ⁇ m.
• mannitol beads Peariitol 200 SD
• FBP fluid bed processor
• This example differs from example T9 in the use of the excipients which are mixed with the drug loaded beds before compression.
• the excipients are lactose, crospovidone and colloidal anhydrous silica and magnesium stearate.
• telmisartan and hydrochlorothiazide in the strengths of 40 /12.5 mg, 80/12.5 mg and 80/25 mg, respectively.
• the formula is exactly the same for all strengths and the weight of the tablet determines the strength of the drug substance.
• the weight of the tablet is 746 mg from which 628 mg corresponds to telmisartan loaded cores and 150 mg to hydrochlorothiazide loaded cores, approximately.
• the rest of the weight is completed with the other pharmaceutical acceptable excipients (povidone 18 mg, croscarmellose sodium 12 mg, sorbitol 85.5 mg and magnesium stearate 3 mg).
• the manufacturing process has an additional step which consists in the same process of coating inert cores but using hydrochlorothiazide as active ingredient.
• hydrochlorothiazide is incompatible with basic agents which is a component of the telmisartan granulate
• the hydrochlorothiazide loaded cores are protected with a film-coating polymer, which can be applied by using a solution comprising for instance hydroxypropyl methylcellulose (1 %), polyethylene glycol 400 (1 %), yellow ferric oxide (0.05 %) and titanium dioxide (0.05 %) in fluid bed equipment.
• both active loaded cores are mixed, for instance in a tumbling mixer, optionally with a binder, such as povidone, optionally with a disintegrant, such as croscarmellose sodium, optionally with a filler, such as sorbitol and with a lubricant, such a magnesium stearate); preferably including all the optional ingredients, and more preferably including the exemplified excipients.
• a binder such as povidone
• a disintegrant such as croscarmellose sodium
• a filler such as sorbitol and with a lubricant, such a magnesium stearate
• the present invention relates to oral pharmaceutical compositions comprising valsartan, optionally in combination with a diuretic, and preferably in the form of tablets.
• Valsartan is a specific angiotensin Il receptor antagonist which acts selectively on the AT1 receptor subtype. Its formula is:
• Valsartan is absorbed from the small intestine where its solubility is low, the oral administration of this drug in the form of tablets or capsules has certain advantages over parenteral administration such as i.v. or i.m.
• Valsartan is of low density and therefore rather bulky, which makes it more difficult to develop oral formulations in the form of tablets in a reliable and robust way.
• due to its hydrophobic character it is difficult to achieve good oral bioavailability, especially in the form of immediate release tablets.
• Valsartan may be administered in doses containing a substantial quantity of the active agent (e.g., 40, 80, 160 and 320 mg).
• Valsartan is a fluffy material and has certain undesirable flow characteristics, for example, it is sticky and can adhere to surfaces such as tablet punch faces and dies, causing tabletting problems, especially on a high speed tablet press.
• the low aqueous solubility of valsartan also presents a challenge, since, to keep the tablet mass small, only limited amounts of excipients may be added to facilitate wetting, disintegration, and ultimately, rapid and complete control of drug release.
• valsartan or a pharmaceutically acceptable salt thereof, combined in a dose range from about 10 to 350 mg/day with hydrochlorothiazide in a dose range from about 6 to 60 mg/day, is suitable for more efficient treatment of hypertension.
• these dose ranges of the combined active agents valsartan is found to have a greater efficacy in reducing elevated blood pressure to normal levels than it would have if used at the same dose range in monotherapy.
• hydrochlorothiazide is being administered in combination with valsartan, the diuretic agent is more effective as compared to monotherapy at the daily dose range indicated.
• a daily dose range from about 50 to 350 mg of valsartan or an equivalent amount of a pharmaceutically acceptable salt thereof and from about 10 to 30 mg hydrochlorothiazide. More preferred are unit doses of about 80 mg valsartan and 12.5 mg or 25 mg of hydrochlorothiazide, 160 mg valsartan and 12.5 mg or 25 mg of hydrochlorothiazide and 320 mg valsartan and 12.5 mg or 25 mg of hydrochlorothiazide to be taken once daily.
• hydrochlorothiazide is also a fluffy material exhibiting poor flow and low aqueous solubility, which further contribute to tabletting problems.
• One of the aims of the present invention is to provide an alternative single tablet formulation of both active ingredients.
• the first documents describing solid oral pharmaceutical compositions comprising valsartan used the well- known wet granulation technique using either organic solvents or water (US5399578 and WO 95/24901 A1).
• the wet granulation technique enhances the contact between the components and the homogenization of the mixtures.
• the prior art suggests that the presence of water in the formulation and coating of valsartan containing solid oral pharmaceutical compositions has to be avoided.
• the use of water may arise problems from in any step of the tablet preparation process as losses in process efficiency, stability, bioavailability, etc.
• the active agent e.g. valsartan
• pharmaceutically acceptable additives the description clearly states that to obtain a well reproducible tablet at least 90 % of the crystals of both the active agent and the additives have to be present in particle sizes from about 0.1 micrometers to 200 micrometers, preferably from 1.0 to 100 micrometers
• the method of dry granulation described in the prior art requires the step of grinding all the components before granulate the mixture, which is a stress-involving process step and time consuming. This step is normally performed to guarantee the homogeneity of the mixture avoiding the segregation of particles with different size.
• WO 2005041941 discloses a method of direct compression to produce valsartan tablets.
• no example of wet or dry granulation technique is disclosed.
• Mannitol as, a typical direct compression excipient, is disclosed in examples, but the use of mannitol for dry or wet granulation is not suggested.
• the present invention provides some alternatives to produce reproducible valsartan pharmaceutical compositions which are either suitable for dry or wet granulation.
• the WO 2006066961 A1 application discloses the non suitability of crospovidone in wet granulation processes. Moreover, this application does not disclose the use of solid sugar alcohols as an alternative to reduce the amount of disintegrant used and improve the bioavailability of valsartan. However, the present inventors have also found the possibility to improve the dry granulation technique shortening the manufacturing process by avoiding the process step of grinding, while guarantying the homogeneity of the mixture during all the process.
• the problem to be solved by the present invention is to provide alternative, efficient, safe, cost-effective, stable pharmaceutical compositions comprising valsartan, optionally in combination with a diuretic, and methods for the manufacture thereof.
• the first aspect of the present invention is a pharmaceutical composition in the form of a tablet comprising an effective amount of valsartan and at least one solid sugar alcohol wherein the tablet is obtained by wet or dry granulation techniques.
• the inventors have surprisingly found that using solid sugar alcohols in dry and wet granulation techniques solves the technological problems which are associated with some of the properties of the active ingredient. For example, once the active ingredients are mixed with the solid sugar alcohol they become more flowing and then more easily compressible. At the same time sticking problems also disappear.
• the tablets produced with a solid sugar alcohol as filler have low disintegration times even if low quantities of a disintegrant are used. Moreover, it is not necessary that this low quantity of disintegrant be incorporated both inside and outside the granulate.
• solid sugar alcohols are not metabolized by oral bacteria, and so they do not contribute to tooth decay. Moreover, they do not brown and caramelize when heated so that they are useful as pharmaceutical excipients which have to be brought to high temperatures, for example, during the drying process after a wet granulation.
• solid sugar alcohols are usually incompletely absorbed into the blood stream from the small intestines which generally results in a smaller change in blood glucose than "normal" sugar (sucrose). This property makes them useful among diabetics and people on low-carbohydrate diets. Moreover, they do not tend to produce as many cases of intolerance as lactose, which is typically used as filler in pharmaceutical compositions. Lactose intolerance is the inability to metabolize lactose because the required enzyme lactase is absent or its availability is lowered. It is estimated that 70% of adult humans are lactose intolerant.
• the present inventors have surprisingly found that both of the manufacturing processes using wet granulation, described above, are suitable for the preparation of the present pharmaceutical compositions. Including the active ingredient intra or extragranularly prior to the compression step has been found to be suitable.
• the present process enables the manufacture of highly reproducible compositions. Also such process is easy to scale up, cost effective and less time consuming.
• the third aspect of the present invention is a granulate prepared by wet granulation, process described in the previous aspect of the present invention, wherein at least one filler is a solid sugar alcohol, and the granulate comprises valsartan and optionally hydrochlorothiazide.
• This granulate has a suitable Hausner ratio to be compressed.
• the inventors have surprisingly found that even when adding the diuretic hydrochlorothiazide, the process of wet granulation using solid sugar alcohols achieves a granulate with ideal properties for tabletting. It is noteworthy that hydrochlorothiazide is also a fluffy material which may involve sticking and dosage problems.
• the fourth aspect of present invention of the invention is a method for the manufacture of pharmaceutical compositions in the form of tablets comprising an effective amount of valsartan and at least one solid sugar alcohol by using dry granulation techniques.
• the present inventors have surprisingly found that replacing the wet granulation by dry granulation, but also using a solid sugar alcohol, the pharmaceutical compositions comprising valsartan also show good stability and dissolution performance.
• the present process enables the manufacture of highly reproducible compositions. Also, such process is easy to scale up, cost effective and less time consuming.
• the fifth aspect of the present invention is a granulate wherein the granulate has been prepared by the dry granulation process described in the previous aspect of present invention. Although this granulate is obtained by a simpler method, without solvents, it is still suitable for tabletting, due to the presence of the solid sugar alcohol, which provides suitable compression properties to the mixture of components.
• a solid sugar alcohol is a hydrogenated form of carbohydrate, whose carbonyl group (aldehyde or ketone, reducing sugar) has been reduced to a primary or secondary hydroxyl group.
• Some solid solid sugar alcohols are erythritol, arabitol, xylitol, ribitol, mannitol, sorbitol, isomalt, maltitol and lactitol.
• Carfs index and the Hausner ratio are both based on the decrease in powder volume during tapping, and their usefulness lies in their ability to predict flowability. The lower the number, the more free-flowing the powder. An increase in the value is proportional to adhesion and friction properties of a powder, including (attractive) triboelectric charge.
• the mathematical expression of each one is:
• An immediate release dosage form has to be understood as a dosage form having a dissolution performance such that about 80 % or more of the valsartan or salt thereof contained in said tablet dissolves within 60 minutes.
• An aqueous solvent is defined as water or a mixture of water with a pharmaceutically acceptable water miscible solvent such as ethanol, isopropanol or acetone.
• tablettes also include coated tablets.
• One embodiment of the first aspect of the present invention is a pharmaceutical composition wherein at least one filler is selected from the group of solid sugar alcohol consisting of mannitol, xylitol, maltitol, sorbitol, lactitol, erythritol, isomalt and mixtures thereof.
• at least one filler is selected from the group of solid sugar alcohol consisting of mannitol, xylitol, maltitol, sorbitol, lactitol, erythritol, isomalt and mixtures thereof.
• such alcohols are preferred because they are readily available, not-expensive and non-toxic.
• These components are suitable fillers in pharmaceutical compositions comprising valsartan prepared by wet or dry granulation.
• sugar alcohols can be used either in low or high proportions, but preferably the sugar alcohol is present in a range from 20 % to 70 % w/w. In this range, sugar alcohols not only avoid the technological challenges to formulate valsartan, but also enhance valsartan's solubility, thus improving bioavailability. Best results are obtained when the sugar alcohol ranges from 40% to 65 % w/w.
• the inventors have surprisingly found that it is possible to use solid sugar alcohol as the only filler in the pharmaceutical composition. This reduces the number of compatibility studies to be carried out between excipients and active substances. Moreover, it increases the solubility, thus improving the dissolution performance of the solid dosage forms.
• the pharmaceutical composition contains mannitol as solid sugar alcohol. It has been found that mannitol is a useful excipient in either wet or dry granulations, although it is a typical direct compression excipient. Once mannitol is mixed with valsartan, the bulk and tap densities increase thus avoiding the technological problems associated with the low density or fluffiness and making the granulation step easier. Moreover, it has been found that impurities of pharmaceutical compositions are in a low level, they do not increase over the time and the final tablet obtained in not hygroscopic at all. Then solid sugar alcohols, and especially mannitol, enable to shorten the drying time when using wet granulation techniques.
• the pharmaceutical composition comprises:
• the pharmaceutical compositions obtained are reproducible showing uniformity of mass and content, good disintegration and dissolution profiles and low friability. It is worth mentioning that, contrary to what is disclosed in EP1275391 A1 that povidone increases the degradation of hydrochlorothiazide, the present inventors have realized that the use of povidone, when a solid sugar alcohol is present, surprisingly does not destabilize at all the final pharmaceutical composition.
• Valsartan has low solubility, which suggests using solubilising agents, among them disintegrant agents, in certain amounts.
• the use of solid sugar alcohols reduces the amount of disintegrant needed, if desired, to a very low levels, and it is even enough to incorporate it in the extragranular phase, to form the compression mixture.
• the disintegrant is selected from the group consisting of calcium carboxymethylcellulose, colloidal silicon dioxide, starch, croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof.
• the disintegrant used is craspovidone. Some examples are shown in the table 1 (V5 and V6) and table 3 (all cases).
• crospovidone is not recommended in wet granulation processes because is an insoluble substance, the presence of a sugar alcohol has enabled crospovidone to be used, either in wet or dry granulation, and to obtain reproducible and suitable pharmaceutical compositions.
• the lubricants are calcium stearate and talc.
• the sugar alcohol's effect on solubility allows to use two lipophilic lubricants without affecting the dissolution profile.
• the pharmaceutical composition contains a surfactant, and especially sodium lauryl sulphate, this improves the dissolution of the active ingredient by acting synergistically with the solid sugar alcohol.
• the granulate is prepared by fluidised air bed technology. Wet granulation performed in a fluid bed granulator enables the granulate to be formed and dried in the same place, thus reducing process time and increasing yield. Moreover, this kind of technology enhances the contact between valsartan and solid sugar alcohol thus improving the solubilising effect.
• the method comprises at least the steps of:
• binder solution Preparation of binder solution, preferably with an aqueous solvent, preferably water.
• a solid sugar alcohol such as mannitol
• shortens the wet granulation process because less drying time is needed to achieve a residual humidity suitable for tabletting.
• the impurity profile is better due to the fact that tablets are less time under stressful conditions.
• the obtained pharmaceutical compositions are stable over the time.
• the fluidised air bed technology is based on a top spray system, with a spray and air flow rate ranging from 1g/min to 500 g/min and 10 CFM to 600 CFM, respectively; and an atomizing air pressure ranging from 1 to 4 Bar. Using these conditions, increase the homogeneity of the granulate and avoid the sticking of particles to the fluid bed equipment.
• the method used to obtain the pharmaceutical composition of valsartan is dry granulation comprising at least the following steps of: a. Providing the active substance and optionally mixing it with at least one pharmaceutically acceptable excipient until a homogenous mixture is formed. b.
• the initial grinding step can be avoided when the compositions contain the solid sugar alcohol.
• the pharmaceutical components in spite of having different particle sizes are able to form a homogenous mixture and then be tabletted without difficulty.
• the option of avoiding the grinding of valsartan and excipients is a particularly preferred embodiment which shortens and simplifies the process by avoiding one step which is considered essential in the prior art.
• sugar alcohols with mean particle sizes greater than 300 microns such as Pearfitol DC400®, it is possible to avoid the first grinding step contrary to what is stated in WO 97/49394A1.
• the compression step b) is carried out using roller compactation or a slugging technique, preferably using a compactation force between 80 and 200 bar and a roller speed between 1.3 and 7.5 ⁇ m.
• the mixture obtained without a previous grinding step can be pre- compacted perfectly under these conditions.
• step c) is carried out by screening or milling the comprimate, preferably through a 1 mm mesh sieve. Both of these two methods obtain a dry granulate suitable for compression to form the final tablet.
• Examples V1 -V6 Valsartan tablets obtained by wet granulation.
• compositions of the tablets comprising valsartan obtained by wet granulation are shown in the table V1.
• AII the strengths (40, 80, 160 and 320 mg) are dose proportional, the formula is exactly the same for all strengths and the weight of the tablet determines the strength of the drug substance.
• hydrochlorothiazide in the strengths of 80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg, 320/25 mg the quantity of this additional active ingredient replacing that of the sugar alcohol acting as filler.
• Valsartan, mannitol and monohydrated lactose were blended in a fluidized air bed (FAB).
• the com starch was dissolved into 74 ml of water for the 160 mg dose and a proportional amount for the other doses for 5 min at 500 rpm by magnetic stirring.
• the FAB chamber was heated for 10 min at 50 0 C 434.2 g of the binding solution comprising corn starch was sprayed onto the mixture for 11 min at 60 0 C/ 0.5 bar by a top spray system with a nozzle size of 1.8 mm. After that, the granulate was dried for 18 min and 30 s at 60 0 C.
• the granulate was mixed with pregelatinized starch, talc and calcium stearate, blended for 10 minutes and the mixture was compressed to form tablets using a rotary trabletting machine, equipped with 15.5 mm x 8 mm oblong punches.
• Valsartan and mannitol were blended in a FAB for 10 minutes at 25 rpm.
• the povidone was dissolved in 200 ml of water for the 160 mg dose and a proportional amount for the other doses for 5 min at 250 rpm by magnetic stirring.
• the FAB chamber was heated for 10 min at 60 0 C and 215.9 g binding solution was sprayed onto the mixture for 15 min at 60 0 C/ 0.5 bar by a top spray system with a nozzle size of 1.8 mm. After that the granulate was dried for 5 min at 60 0 C.
• the granulate was mixed with pregelatinized starch, talc and calcium stearate, blended for 10 minutes and the mixture was compressed to form tablets using a rotary trabletting machine, equipped with 15.5 mm x 8 mm oblong punches.
• Valsartan, isomalt and povidone were blended in a FAB.
• the FAB chamber was heated for 10 min at 50 0 C and then 199.9 g of water was sprayed onto the mixture for 9 min and 18 s at 60 0 C/ 0.5 bar by a top spray system with a nozzle size of 1.8 mm. After that the granulate was dried for 3 min at 60 0 C. Then the granulate was mixed with pregelatinized starch, talc and calcium stearate and blended for 10 minutes. Then the mixture was compressed to form tablets using a rotary trabletting machine, equipped with 15.5 mm x 8 mm oblong punches.
• Example V4 Example V4:
• Valsartan and isomalt were blended in a FAB.
• Povidone was dissolved in 200 ml of water for the 160 mg dose and a proportional amount for the other doses for 5 min at 250 rpm by magnetic stirring.
• the FAB chamber was heated for 6 min at 55 0 C and then 218.6 g of binder solution was sprayed for 19 min at 55 0 C/ 0.5 bar by a top spray system with a nozzle size of 1.8 mm. After that, the granulate was dried for 36 min at 55 0 C.
• the granulate was mixed with pregelatinized starch, talc and calcium stearate, blended for 10 minutes and the mixture was compressed to form tablets using a rotary trabletting machine, equipped with 15.5 mm x 8 mm oblong punches.
• Valsartan and mannitol were blended for 10 minutes at 25 rpm in a blender.
• Granulation was carried out in a FAB spraying 483.2 of an aqueous solution of povidone and sodium dodecyl sulfate by a top spray system with a nozzle size of 1.8 mm. After that, the granulate was dried in the FAB until a loss on drying of 1.7%. Then the granulate was mixed with crospovidone, talc and calcium stearate, blended for 10 minutes and the mixture was compressed to form tablets using a rotary trabletting machine, equipped with 15.5 mm x 8 mm oblong punches.
• Valsartan, isomalt and monohydrate lactose and corn starch were blended for 10 minutes.
• Granulation was carried out in a FAB spraying an aqueous solution of corn starch and sodium dodecyl sulfate in 245 ml of warm water by a top spray system with a nozzle size of 1.8 mm. After that, the granulate was dried in the FAB until a loss on drying of 1.7%. Then, the granulate was mixed with crospovidone, talc and calcium stearate, blended for 10 minutes and the mixture obtained was compressed to form tablets using a rotary trabletting machine, equipped with 15.5 mm x 8 mm oblong punches.
• the granulating parameters of the FAB that are common to all the examples are as follows: spray rate ranging from 1g/min to 500 g/min, air flow rate ranging from 10 CFM to 600 CFM, and an atomizing air pressure ranging from 1 to 4 Bar
• the main control tests on the granulate and tablets are shown in table V2.
• the Hausner ratios from the granulates obtained by wet granulation are from 1 to 1.50 and compressibility indexes lower than 20 %. These parameters indicate that these granulates are suitable to be compressed without problems.
• all the tablets obtained have a dissolution performance such that about 80 % or more of the valsartan or salt thereof contained in said tablet dissolves within 30 minutes.
• Table V1 Valsartan tablet compositions prepared by wet granulation
• Table V2 Control tests on valsartan tablets produced by wet granulation corresponding to the 160 mg dose.
• compositions of the tablets, comprising valsartan, obtained by dry granulation are shown in the table 3. All the strengths (40, 80, 160 and 320 mg) are dose proportional, the formula is exactly the same for all strengths and the weight of the tablet determines the strength of the drug substance.
• hydrochlorothiazide in the strengths of 80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg, 320/25 mg the quantity of this additional active ingredient replacing that of the solid sugar alcohol.
• Valsartan and mannitol were blended for 10 minutes in a blender at 25 ⁇ m.
• Granulation was carried out in a roller compactor granulator using a compaction force of 20 bar, a feeder speed of 25 rpm and a roller speed of 2 rpm.
• the compact mixture was screened through 1 mm mesh sieve. After that, the remaining excipients were added and blended for 10 minutes. Then the mixture was compressed to form tablets using a rotary trabletting machine, equipped with 15.5 mm x 8 mm oblong punches.
• Valsartan and isomalt were blended for 10 minutes at 25 rpm in a blender.
• Granulation was carried out in a roller compactor granulator using a compaction force of 35 bar, a feeder speed of 10 rpm and a roller speed of 4.5 rpm.
• the compact mixture was screened through a 1 mm mesh sieve. After that, the remaining excipients were added and blended for 10 minutes. Then the mixture was compressed to form tablets using a rotary trabletting machine, equipped with 15.5 mm x 8 mm oblong punches.
• Valsartan and mannitol were blended for 10 minutes at 25 rpm in a blender. Granulation was carried out in a roller compactor granulator using a compaction force of 30 bar, a feeder speed of 16.2 rpm and a roller speed of 2.7 rpm. The compact mixture was screened through 1 mm mesh sieve. After that, the remaining excipients were added and blended for 10 minutes. Then the mixture was compressed to form tablets using a rotary trabletting machine, equipped with 15.5 mm x 8 mm oblong punches.
• Valsartan and isomalt were blended for 10 minutes at 25 rpm in a blender. Granulation was carried out in a roller compactor granulator using a compaction force of 85 bar, a feeder speed of 5.4 rpm and a roller speed of 2 rpm. The compact mixture was calibrated through 1 mm mesh sieve. After that, the remaining excipients were added and blended for 10 minutes. Then, the mixture was compressed to form tablets using a rotary trabletting machine, equipped with 15.5 mm x 8 mm oblong punches.
• Example V11 Example V11
• Valsartan alone was granulated out in a roller compactor granulator using a compaction force between l 80 and 200 bar, a feeder speed between 2 to 10 ⁇ m and a roller speed between 1.3 and 7.5 rpm.
• the compact mixture was calibrated through 1 mm mesh sieve. After that, the excipients were added and blended for 10 minutes. Then, the mixture was compressed to form tablets using a rotary trabletting machine, equipped with 15.5 mm x 8 mm oblong punches.
• Table V3 Valsartan tablet compositions prepared by dry granulation
• Table V4 Control tests on valsartan tablets produced by dry granulation corresponding to the 160 mg dose.
• the Hausner ratios from the granulates obtained by wet granulation are from 1 to 1.50 but not all compressibility indexs are lower than 20 %. Moreover, all the tablets obtained have a dissolution performance such that about 80 % or more of the valsartan or salt thereof contained in said tablet dissolves within 30 minutes.
• the tablets compositions, comprising valsartan, obtained by direct compression are shown in the table V5. All the strengths (40, 80, 160 and 320 mg) are dose proportional, the formula is exactly the same for all strengths and the weight of the tablet determines the strength of the drug substance. The same examples are reproduced with hydrochlorothiazide in the strengths of 80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg, 320/25 mg the quantity of this additional active ingredient replacing that of the filler.
• Valsartan, isomalt and sodium dodecyl sulfate were blended for 10 minutes at 25 rpm in a blender.
• Magnesium stearate and calcium stearate were added to the mixture and blended for 5 minutes. Then the mixture was compressed to form tablets using a rotary trabletting machine, equipped with 15.5 mm x 8 mm oblong punches.
• Valsartan, and mannitol were blended for 10 minutes at 25 rpm in a blender.
• Magnesium stearate and calcium stearate were added to the mixture and blended for 5 minutes. Then the mixture was compressed to form tablets using a rotary trabletting machine, equipped with 15.5 mm x 8 mm oblong punches.
• Table V5 Valsartan tablet compositions prepared by direct compression
• Table V7 Stability data at 2 time points (40°C/75%RH) of Valsartan tablets (example V5)
• Tablets comprising 2-butyl-3-[p-(o-1 H-tetrazol-5-ylphenyl)benzyl]-1.3-diazaspiro[4.4]non-1-en-4-one (described in Bemhart et al., U.S. patent N 0 . 5270317) hereafter active substance I 1 without poloxamer 188 according to table 11 were prepared as follows. Firstly, sieve through 1 mm mesh size and mix the active substance I 1 and the rest of the intra-granulate excipients (microcrystalline cellulose, monohydrate lactose, sodium croscarmellose, pregelatinized starch) for 5 minutes.
• excipients microcrystalline cellulose, monohydrate lactose, sodium croscarmellose, pregelatinized starch
• a granulation suspension was prepared dissolving the povidone in purified water and mixing well in a low-shear mixer. Then, this solution is sieved through 3 mm mesh screen. In a blender, blend the screened starting materials with the solution until a homogeneous mixture with a suitable consistency for granulation is obtained. The wet mass is granulated a) in a oscillating granulator or b) in a wet rotary granulator. Then dry the granulate in a fluid-bed drier, approximately for 90 min at 40 0 C.
• Table 11 Compositions of active substance I tablets used in the examples
• Tablets comprising active substance I and hydrochlorothiazide with povidone and without poloxamer 188 according to table I2 were prepared as follows. Firstly, sieve and mix both active substances and the rest of the intra-granular excipients (microcrystalline cellulose, monohydrate lactose, sodium croscarmellose, pregelatinized starch) for 5 minutes. Secondly, a granulation suspension was prepared dissolving the povidone in purified water and mixing well in a low-shear mixer. Then, this solution is sieved through 3 mm mesh screen. In a blender, blend the screened starting materials with the solution until a homogeneous mixture with a suitable consistency for granulation is obtained.
• the intra-granular excipients microcrystalline cellulose, monohydrate lactose, sodium croscarmellose, pregelatinized starch
• the wet mass is granulated in an oscillating granulator. Then dry the granulate in a fluid-bed drier, approximately for 90 min at 40 0 C. Then, it was milled with a mesh size of 1mm and mixed with croscarmellose and silica colloidal anhydrous in a biconic drum or similar for 10 min. After that, magnesium stearate and talc was added and mixed for a further 5 min. Finally, the final product was tabletted on a rotary press. Optionally, the tablets are coated with Opadry Il white until cores have increased by 2 % of the original weight. The tablets thus prepared were stored at 40°C/75 % RH and subjected to stability tests. The results are shown in table I3. The dissolution tests of the tablets were also performed.
• Table I2 Compositions of active substance I and hydrochlorothiazide tablets used in the examples
• Table I3 Stability data at 3 time points (40°C/75%RH) of active substance I and hydrochlorothiazide (example CI7)
• a pharmaceutical composition in the form of tablets comprising an effective amount of valsartan and at least one solid sugar alcohol, wherein the tablet is obtained by wet or dry granulation techniques.
• composition of clause 1 comprising at least a solid sugar alcohol selected from the group consisting of mannitol, xylitol, maltitol, sorbitol, lactitol, erythritol, isomalt and mixtures thereof.
• valsartan or a pharmaceutically salt thereof in an amount ranging from 10 % to 35 % w/w.
• (g) optionally, at least one surfactant ranging from 0.1 % to 5% w/w.
• composition according to any one of the clauses 6 to 8 comprising at least sodium lauryl sulfate as surfactant.
• a method for the manufacture of the pharmaceutical composition as defined in any one of the clauses 1 to 10 in the form of tablets comprising at least the steps of: a) granulating a mixture of at least one pharmaceutical acceptable excipient using an aqueous solvent as granulation liquid to obtain a granulate. b) adding valsartan. and optionally hydrochlorothiazide to said granulate, or, alternatively, adding valsartan, and optionally hydrochlorothiazide, initially to the mixture to be granulated in step (a).
• step (b) if needed, adding further pharmaceutical acceptable excipients to the product obtained in step (b) to obtain a compression mixture, and d) compressing the compression mixture to obtain tablets, and optionally, applying a coating.
• the granulate is prepared by fluidised air bed technology.
• the method according to any one of the clauses 11 or 12 comprising at least the steps of: a) Preparation of binder solution, preferably with an aqueous solvent, preferably water. b) Spraying the binder solution onto the mixture to form a granulate. c) Drying the granulate at inlet temperature equal to or below 7O 0 C, preferably below 6O 0 C. d) Sizing the dried granules, preferably through a 1 mm mesh screen. e) Mixing the granules with the rest of the pharmaceutical acceptable excipients. f) Compressing the granulate to form a tablet, and optionally coating.
• a granulate prepared comprising valsartan wherein the granulate has been prepared as defined in clauses 11 to 14.
• a method to prepare a pharmaceutical composition in the form of tablet as defined in any one of the clauses 1 to 10 comprising dry granulation techniques.
• step c) is carried out by screening or milling the comprimate, preferably through a 1 mm mesh sieve.
• the present invention relates to formulations comprising escitalopram oxalate with a mean particle size of less than 20 micrometers or escitalopram hydrobromide with a mean particle size ranging from 1 to 250 micrometers and methods for the manufacture thereof.
• Escitalopram is a selective serotonin reuptake inhibitor (SSRI) used to treat depression. It is approved for the treatment of major depressive disorder and generalized anxiety disorder; other indications include social anxiety disorder, panic disorder and obsessive-compulsive disorder.
• Escitalopram is the S-stereoisomer (enantiomer) of the earlier drug citalopram. Escitalopram is noted for its high selectivity of serotonin reuptake inhibition and, as a result it has fewer side effects that are not related to its serotonergic activity.
• Escitalopram has the following structure:
• Escitalopram the pharmaceutical activity thereof and crystalline escitalopram oxalate are disclosed in US Patent No 4,943, 590. Methods to produce pharmaceutical preparations of escitalopram are outlined.
• active substances with a small particle size mixed with excipients having a larger particle size will typically segregate or de-mix during the tabletting process.
• escitalopram has significantly different solubility and salt formation properties from the citalopram racemate.
• the only pharmaceutically crystalline salt known so far is the oxalate
• the citalopram racemate forms crystalline hydrobromide and hydrochloride salts.
• Crystalline escitalopram hydrobromide has recently been disclosed in W02004/056791A1.
• the escitalopram oxalate product prepared by crystallisation from acetone as outlined in US Patent No 4,943,590 has, like the citalopram hydrobromide product described above, a very small mean particle size of around 2-20 micrometers, resulting in very poor flow properties. s
• W003/011278 discloses crystalline particles of escitalopram oxalate with a particle size of at least 40 ⁇ m, which are suitable for direct compression.
• the method proposed to manufacture said crystalline particles comprises gradual cooling a solution of escitalopram oxalate in a suitable solvent system from a first temperature to a second temperature while maintaining a controlled cooling profile and seeding said solution of escitalopram oxalate by the addition of escitalopram oxalate crystals during said cooling followed by a holding time at said second temperature.
• the yield of such process is about 58 %.
• Escitalopram is a very expensive drug and therefore it would be of great interest to obtain a pharmaceutical composition in the form of tablets and methods for the manufacture thereof using the small particles sizes. This would avoid a further step of enlarging the particles by recrystallisation, which involves a 42 % of the product lost. Moreover this step increases the process length.
• W02004/056791A1 discloses crystalline particles of escitalopram hydrobromide. Such application discloses that the physicochemical properties of crystalline escitalopram hydrobromide are very different from those of the citalopram hydrobromide, and moreover it is silent about how to obtain pharmaceutical compositions comprising escitalopram hydrobromide.
• Polymorph in the meaning of the present invention, comprises the different crystal packing, different conformers of the same molecule in conformational polymorphism, and the different pseudopolymorphism (different crystal types are the result of hydration or solvation).
• the problem to be solved by the present invention is to provide an alternative, efficient, safer, cost-effective and stable pharmaceutical compositions comprising escitalopram oxalate with a mean particle size preferably ranging from 1 to 20 micrometers or escitalopram hydrobromide with a mean particle size ranging from 1 to 250 micrometers and methods for the manufacture thereof.
• the first aspect of the present invention is a pharmaceutical composition in the form of tablets comprising escitalopram oxalate having a mean particle size ranging from 1 to 20 micrometers, wherein the tablet is prepared by direct compression of escitalopram oxalate and at least one pharmaceutically acceptable excipient selected from stearic acid, wax, hydrogenated vegetable oil, talc and colloidal silica.
• escitalopram oxalate having a mean particle size ranging from 1 to 20 micrometers
• at least one pharmaceutically acceptable excipient selected from stearic acid, wax, hydrogenated vegetable oil, talc and colloidal silica.
• the second aspect of the present invention is a manufacturing process of said pharmaceutical composition comprising at least the steps of:
• the present process enables the manufacturing of highly reproducible compositions. Also such process is easy to scale up, cost effective and less time consuming, because neither recrystallization nor granulation is required.
• the third aspect of the present invention is a granulate for the preparation of a stable oral dosage form prepared by wet granulation comprising escitalopram oxalate wherein the mean particle size of the escitalopram oxalate ranges from 0.1 to 200 micrometers and which has a water content below 4% after drying.
• Such granulate enables oral solid dosage forms to be obtained that are stable enough to be used as pharmaceuticals.
• a higher water content in these types of granulates leads to unstable compositions, sticking problems and low reproducibility among others problems.
• the mean particle size ranges from 1 to 20 micrometers to avoid the step of increasing the mean particle size of the escitalopram oxalate by recrystallization.
• the fourth aspect of the present invention is a manufacturing process of the pharmaceutical composition comprising the granulate of the third aspect of the present invention and at least one lubricant.
• the method is a wet granulation which comprises at least the steps of: i) Mixing of the escitalopram oxalate and at least one pharmaceutically acceptable excipient. ii) Preparing a binder solution, preferably with water and blending with the mixture of step i) to form a wet mass iii) Screening of the wet mass iv) Drying the granules at a temperature equal to or below 4O 0 C, preferably below 3O 0 C, until a final water content of below 4 % is obtained. v) Screening the dry granules vi) Mixing the sieved granules with at least one lubricant and at least one disintegrant vii) Tablet compression, and optionally coating
• the fifth aspect of the present invention is an oral solid dosage form comprising escitalopram hydrobromide with a mean particle size ranging from 1 to 250 micrometers prepared by dry methods, such as dry granulation and melt granulation followed by compression or direct compression comprising at least one lubricant and pharmaceutically acceptable additives suitable for the preparation of oral solid dosage forms for such dry compression methods.
• escitalopram hydrobromide with a mean particle size ranging from 1 to 250 micrometers prepared by dry methods, such as dry granulation and melt granulation followed by compression or direct compression comprising at least one lubricant and pharmaceutically acceptable additives suitable for the preparation of oral solid dosage forms for such dry compression methods.
• the use of a mean particle size of smaller than 1 micrometer leads to poor flowability and segregation problems of the mixture during the compression.
• the use of active ingredient particles with a mean particle size greater than 250 micrometers increases the drug release time and reduces the reproducibility of the release profile.
• the sixth aspect of the present invention is a stable oral solid dosage form comprising escitalopram hydrobromide with a mean particle size ranging from 1 to 250 micrometers prepared by wet granulation.
• a stable pharmaceutical composition comprising this compound has been prepared for the first time.
• the seventh aspect of the present invention is a granulate for the preparation of a stable oral solid dosage form as defined in the sixth aspect of the present invention, wherein the content of escitalopram hydrobromide in the granulate is below 35% and the water content is below 4% after drying.
• a granulate with a higher concentration of escitalopram hydrobromide and a higher water content leads to different kinds of problems, such as more has poorer compressibility properties plus more drying time is required with the consequent increase in impurities and a poor stability of the final oral solid dosage form comprising such granulate.
• the granule of the present invention has optimal properties for the manufacture of oral solid dosage forms, preferably in the form of tablets.
• the eighth and ninth aspects of the present invention are stable oral solid dosage forms comprising the granulate as defined in the seventh aspect of the present invention and at least one lubricant, preferably magnesium stearate, and a method of preparing such pharmaceutical composition comprising:
• step (i) Mixing the active ingredient with at least one or more pharmaceutically acceptable excipients ii) adding a binding solution comprising a solvent, preferably water, and at least one pharmaceutically acceptable excipient to the blend formed in step (i) to form a wet mass; iii) granulating the wet mass and iv) drying the wet granulate
• One embodiment of the first aspect of the present invention is the pharmaceutical composition wherein the total amount of said pharmaceutically acceptable excipients is at least 4.5% w/w, preferably between 6 to 9 %.
• the pharmaceutical composition comprises additionally at least one stearate selected from magnesium, calcium or sodium, preferably in an amount of less than 5%, and more preferably ranging from 1.5 % to 4%. This has a synergic effect with said pharmaceutically acceptable excipients.
• the pharmaceutical composition comprises a filler selected from lactose anhydrous, lactose monohydrate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, compressible sugar, white sugar, sucrose, sugar confectionery, dextrates, dextrose, dextrin, fructose, glucose, kaolin, lactitol, mannitol, sorbitol, microcrystalline sorbitol, and mixtures thereof.
• a filler selected from lactose anhydrous, lactose monohydrate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, compressible sugar, white sugar, sucrose, sugar confectionery, dextrates, dextrose, de
• the pharmaceutical composition the filler is a microcrystalline cellulose, as for example Avicel PH 200 or ProSolve SMCC 90.
• One embodiment of the second aspect of the present invention is a method wherein the mixing step i) is about 15 to 25 minutes. This period of time provides good mixtures and avoids the separation of the excipients.
• step ii) of the mixing process is about 3 to 7 minutes.
• the granulate obtained comprises additionally a filler.
• the filler is selected from lactose anhydrous, lactose monohydrate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, compressible sugar, white sugar, sucrose, sugar confectionery, dextrates, dextrose, dextrin, fructose, glucose, kaolin, lactitol, mannitol, sorbitol, microcrystalline sorbitol, and mixtures thereof.
• the granulate comprises additionally a lubricant.
• the granulates are used in the manufacture of an oral solid dosage form, preferably tablets, comprising additionally and at least one lubricant, preferably magnesium stearate.
• the temperature of the air stream during the drying steps is below 5O 0 C.
• the humidity of the air stream is below 5%.
• the oral solid dosage form contains less than 30 % by weight of active substance and at least one lubricant in an amount below 5% w/w, preferably in the range of 0.4 % to 3%.
• These oral dosage forms have very good properties, such as excellent stability. Moreover during the manufacturing process the mixture showed good flowability and no sticking problems were observed during tabletting.
• the active ingredient is present in an amount ranging from about 5% to 25%.
• the mean particle size ranges from 40 to 200 micrometers, and preferably from 50 to 125 micrometers.
• the oral solid form comprises at least one filler. More preferably the filler is microcrystalline cellulose. Even more preferably microcrystalline cellulose is present in an amount of 60 to 90 % by weight.
• the oral solid dosage form comprises at least one disintegrant, preferably crosslinked polyvinylpyrrolidone (PVP) as a pharmaceutically acceptable additive.
• PVP polyvinylpyrrolidone
• the crosslinked PVP is present in an amount of 2 to 7 % by weight.
• the oral solid dosage form is prepared by direct compression, and preferably in the form of tablets.
• the granulate comprises additionally a filler.
• the filler is selected from lactose anhydrous, lactose monohydrate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, compressible sugar, white sugar, sucrose, sugar confectionery, dextrates, dextrose, dextrin, fructose, glucose, kaolin, lactitol, mannitol, sorbitol, microcrystalline sorbitol, and mixtures thereof.
• the granulate comprises additionally at least one lubricant.
• Such granulate is very useful to prepare a stable oral solid dosage form comprising additionally at least one lubricant, preferably magnesium stearate.
• Direct compression comprising escitalopram oxalate with a mean particle size of less than 20 micrometers.
• the escitalopram oxalate was prepared by crystallisation from acetone as outlined in US Patent No 4,943, 590. When a smaller mean particle size was desired the product was micronized.
• Escitalopram oxalate crystals, microcrystalline cellulose, croscamnellose sodium, colloidal anhydrous silica and talc were blended at 20 rpm for 20 min in a mixer. Magnesium stearate was added and blending continued for 5 min at the same speed.
• the resulting mixture was tabletted (125,000 tablets/hour) on a 30 station
• Fette P 1200/IC tablet press fitted with oval 12.5 x 6.5 mm punches. Tablet core weight was set to 250 mg.
• the tablet press was run until the mixture level was just above the forced feeder, i. e. the tabletting was continued as long as possible in order to identify possible segregation tendencies in the last quantities of mixture.
• the tablets were coated with white Sepifilm 752.
• the increase of weight was around 2% (around 5 mg).
• the coated tablets were dried for 10 min at 4O 0 C.
• Tablets comprising escitalopram oxalate, with a mean particle size of 13 micrometers, according to example 9 are prepared as follows. First, all components of the formulation are weighed and then sieved.
• a binding solution is prepared dissolving Plasdone S-630 in purified water and mixing well in a low- shear mixer.
• the sieved components are mixed with the binding solution and afterwards the wet mass is granulated.
• the granulate is dried in a fluid bed drier, at a temperature of below 4O 0 C until the final water content is below 4 %, and sieved.
• the dry granulate is mixed with the extra-granulate excipients. After that, the granulate is compressed using a rotary tablet press and the tablets coated in a coating pan.
• example E9 The granulation of example E9 was repeated but and an additional drying step was carried out before mixing the granulate with the extra-granulate excipient. After sieving the granulate, it was dried again in a fluid bed drier, at a temperature of below 4O 0 C, for an 30 additional minutes. The final water content of the granulate was 1.0%.
• the examples E9 and E10 was repeated using crystals of escitalopram oxalate with a mean particle size of 0.1, 5.0, 7.0, 27.2, 105, 178 micrometers. Excellent results were obtained with mean particle sizes ranging from 1 to 20 micrometers.
• Escitalopram hydrobromide (12.0 kg) was dissolved in a mixture of methanol (12.5 kg) and water (1.2 kg) at reflux. The solution was cooled down to 30° C 1 seeded with escitalopram hydrobromide crystals (27 g) and kept at 30° C for 16 hours, whereupon it was cooled down to 10° C within 1 hour. The crystals were isolated by filtration, washed with cold (10° C) methanol (3.5 kg) and dried.
• Escitalopram hydrobromide 200 kg was dissolved in a mixture of methanol (170 L) and acetone (680 L) at 56° C. The solution was cooled down to15 0 C, seeded with escitalopram hydrobromide crystals (50 g), hexane (1600 L) was gradually added within 60 minutes, whereupon the suspension was left to stand with moderate stirring and cooling for 8 hours. The crystals were isolated by filtration, washed first with a cold (10° C) mixture of acetone (50 L) and hexane then with cold (10° C) hexane (220 L) and dried.
• Tablets prepared by direct compression of escitalopram hydrobromide crystals are prepared by direct compression of escitalopram hydrobromide crystals.
• Tablet ingredients Escitalopram, HBr 580Og (20 % w/w) ProSolv SMCC90 23055 g (79.5 % w/w) Magnesium stearate 145g (0.5 % w/w)
• Escitalopram hydrobromide crystals from example E11 and ProSolv SMCC90 were blended at 7 rpm for 10 min in a 100 litre Bohle PTM 200 mixer. Magnesium stearate was added and blending continued for 3 min.
• 25 kg of the resulting mixture was tabletted (125,000 tablets/hour) on a 30 station Fette P 1200/IC tablet press fitted with oblong, embossed, scored 5.5 x 8 mm punches. Tablet core weight was set to 125 mg. The nominal yield was 200,000 tablets. The tablet press was run until the mixture level was just above the forced feeder, i. e. the tabletting was continued as long as possible in order to identify possible segregation tendencies in the last quantities of mixture.
• Sampling was performed 50 times at regular intervals during tabletting, corresponding to sampling of every 4000 tablets produced. Two tablets were withdrawn for each sample.
• the tablets were assayed by a validated method using UV-absorption in an aqueous solution. A total of 100 tablets were tested. The relative standard deviation in escitalopram content was less than 0.6%.
• the pharmaceutical composition was repeated with the crystal of escitalopram hydrobromide obtained in the example E12 and E13. In all cases the tablets showed a low friability and low variability. In addition the mixture showed good flowability.
• Tablet prepared by direct compression of escitalopram hydrobromide crystals Tablet prepared by direct compression of escitalopram hydrobromide crystals.
• ProSolv SMCC90 (77.1 % w/w) crosslinked PVP (5.2 % w/w)
• Magnesium stearate (0.7 % w/w) Escitalopram hydrobromide crystals from example E11 , ProSolv SMCC90 and PVP were blended. Magnesium stearate was added and blending continued. Tablets (125 mg nominal weight) were produced.
• the tablets had satisfactory technical properties.
• the examples E14 and E15 was repeated using crystals of escitalopram hydrobromide with a mean particle size of 0.04, 0.1 , 3.0, 7.0, 25.0, 45, 80, 120, 195, 235, 304, 450 micrometers. Best results were obtained with mean particle sizes ranging from 50 to 125 micrometers, followed by those ranging from 40 to 200. With a mean particle size of less than 1 micrometer or bigger than 250 micrometers the tablet properties were not satisfactory.
• the tablets containing N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine were prepared using wet granulation (composition of tablets is shown in table 1).
• Escitalopram hydrobromide (example E11), microcrystalline cellulose, lactose monohydrate and maize starch were homogenized in high shear mixer. Copovidone dissolved in water was sprayed onto the mixture, the granulate obtained was dried in a fluid-bed dryer. The optimum loss on drying of the dried granulate is between 0.2% and 2.5%. Additional excipients (maize starch, colloidal silicon dioxide and magnesium stearate) were added to the dried granulate and mixed.
• Loss on drying of the tabletting mixture is preferably between 1.5% and 3.5%.
• Flowability of the tabletting mixture should be between 10 and 40 seconds and angle of repose between 25° and 50°.
• Optimum bulk volume is between 1.3 mL/g and 2.0 mL/g and tapped volume between 1.0 mL/g and 1.8 mL/g.
• the mixture was then pressed into tablets.
• Optimal tablet hardness is between 3ON and 150N.
• the tabletting mixture is preferably mixed in a high shear mixer, but can also be mixed in conventional blenders.
• Lactose monohydrate 18.0 10.0 - 28%
• the pharmaceutical composition was repeated with the crystals of escitalopram hydrobromide obtained in the example E12 and E13 and was also repeated using crystals of escitalopram hydrobromide with a mean particle size of 0.04, 0.1, 3.0, 7.0, 25.0, 45, 80, 120, 195, 235, 304, 450 micrometers.
• the pharmaceutical compositions comprising particle sizes ranging from 1 to 250 micrometers had satisfactory technical properties.
• a pharmaceutical composition in the form of tablets comprising escitalopram oxalate having a mean particle size ranging from 1 to 20 micrometers, wherein the tablet is prepared by direct compression of escitalopram oxalate, at least one filler and at least one pharmaceutically acceptable excipient selected from stearic acid, wax, hydrogenated vegetable oil, talc and colloidal silica.
• composition according to any one of the proceeding clauses comprising additionally at least one stearate selected from magnesium, calcium or sodium, preferably in an amount of less than 5%, and more preferably ranging from 1.5 % to 4%.
• composition comprising a filler selected from lactose anhydrous, lactose monohydrate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, compressible sugar, white sugar, sucrose, sugar confectionery, dextrates, dextrose, dextrin, fructose, glucose, kaolin, lactitol, mannitol, sorbitol, microcrystalline sorbitol, and mixtures thereof.
• a filler selected from lactose anhydrous, lactose monohydrate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, compressible sugar, white sugar, sucrose, sugar confectionery, dextrates, dextrose, dex
• composition according to clause 4 wherein the filler is a microcrystalline cellulose, as for example Avicel PH 200 or ProSolve SMCC 90.
• step i) is carried out substantially free of unbound water.
• a direct compression method comprising escitalopram oxalate having a mean particle size ranging from 1 to 20 micrometers suitable of being industrially scaled up.
• a wet granulate for the preparation of a stable oral dosage form comprising escitalopram oxalate prepared by wet granulation methods, wherein the mean particle size of the escitalopram oxalate ranges from 0.1 to 200 micrometers, preferably ranges from 1 to 20 micrometers, and the granulate has a water content of below 4% after drying.
• the granulate according to any one of the clauses 11 or 12 comprising a filler selected from lactose anhydrous, lactose monohydrate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, compressible sugar, white sugar, sucrose, sugar confectionery, dextrates, dextrose, dextrin, fructose, glucose, kaolin, lactitol, mannitol, sorbitol, microcrystalline sorbitol, and mixtures thereof.
• a filler selected from lactose anhydrous, lactose monohydrate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, compressible sugar, white sugar, sucrose, sugar confection
• a stable oral solid dosage form preferably in the form of tablets, comprising the granulate as defined in any one of the clauses 11 to 14 and at least one lubricant, preferably magnesium stearate.
• a process for the manufacture of the pharmaceutical composition as defined in the clause 15 by wet granulation comprising at least the step of:
• An oral solid dosage form comprising escitalopram hydrobromide with a mean particle size ranging from 1 to 250 micrometer prepared by dry methods, such as dry granulation and melt granulation followed by compression or direct compression comprising at least one lubricant and pharmaceutically acceptable additives suitable for the preparation of oral solid dosage forms for such dry compression methods.
• the oral solid dosage form according to any one of the clauses 21 to 27 which comprises at least one disintegrant, preferably crosslinked polyvinylpyrrolidone (PVP) as a pharmaceutically acceptable additive.
• PVP polyvinylpyrrolidone
• the oral solid dosage form according to any one of the clauses 21 to 29 which is prepared by direct compression, and preferably in the form of tablets.
• a stable oral solid dosage form comprising escitalopram hydrobromide with a mean particle size ranging from 1 to 250 micrometers prepared by wet granulation, comprising at least one filler and at least one binder.
• the granulate according to any one of the clauses 32 or 33 comprising a filler selected from lactose anhydrous, lactose monohydrate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, compressible sugar, white sugar, sucrose, sugar confectionery, dextrates, dextrose, dextrin, fructose, glucose, kaolin, lactitol, mannitol, sorbitol, microcrystalline sorbitol, and mixtures thereof.
• a filler selected from lactose anhydrous, lactose monohydrate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, compressible sugar, white sugar, sucrose, sugar confection
• a stable oral solid dosage form comprising the granulate as defined in any one of the clauses 31 to 35 and at least one lubricant, preferably magnesium stearate.
• 37. A method of preparing a pharmaceutical composition according to clauses 36 comprising at least the steps of:
• step (i) Mixing the active ingredient with at least one or more pharmaceutically acceptable excipients ii) adding a binding solution comprising a solvent, preferably water, and at least one pharmaceutically acceptable excipient to the blend formed in step (i) to form a wet mass; iii) granulating the wet mass and iv) drying the wet granulate
• the present invention relates to formulations comprising moxifloxacin hydrochloride and methods for the manufacture thereof.
• the quinolones are a family of broad-spectrum antibiotics.
• the parent of the group is nalidixic acid.
• the majority of quinolones in clinical use belong to the subset of fluoroquinolones, which have a fluoro group attached to the central ring system, typically at the 6-position.
• Examples of quinolones are levofloxacin, ciinafloxacin, gemifloxacin mesylate, moxifloxacin hydrochloride, sitafloxacin, ecinofloxacin and prulifloxacin.
• Moxifloxacin was developed by Bayer AG and it is marketed worldwide (as the hydrochloride) under the brand name Avelox® for oral treatment. Each tablet contains 400 mg. In most countries the drug is also available in parenteral form for intravenous infusion. Moxifloxacin is also sold in an ophthalmic solution (eye drops) under the name Vigamox® for the treatment of conjunctivitis.
• Moxifloxacin can be used to treat respiratory infections including acute sinusitis, acute exacerbations of chronic bronchitis and community-acquired pneumonia as well as skin and skin structure infections. It is also known that it can treat ear infections. Moxifloxacin is also used for the treatment of complicated intra- abdominal infections, as seen in hospitals.
• Moxifloxacin is used as a Second-line agent in tuberculosis and may potentially have benefits in reducing treatment duration from its current six month to four months.
• moxifloxacin is available the form of eye drops, marketed by Alcon as Vigamox®, to treat conjunctival infections caused by susceptible bacteria and to prevent infection following eye surgeries such as LASIK. It has been disclosed in the literature that moxifloxacin hydrochloride can be found in different crystalline forms.
• EP1128831 discloses pharmaceutical preparations for oral administration that includes moxifloxacin or a salt or sol vate/hyd rate thereof, at least one dry binder, at least one disintegrant and at least one lubricant, characterized in that the preparation contains 2.5 % to 25% of lactose, but the it is silent about the water content of the excipients and the effect that in the polymorph stability.
• Polymorphism is important in the development of pharmaceutical ingredients. Many drugs receive regulatory approval for only a single crystal form or polymorph. Polymorphism in drugs can also have direct medical implications. Medicine is often administered orally as a crystalline solid and dissolution rates depend on the exact crystal form of a polymorph.
• the problem to be solved by the present invention is to provide an efficient alternative, safer and cost-effective stable formulations comprising moxifloxacin hydrochloride and methods to manufacture thereof, which would be susceptible of use on an industrial scale.
• the first aspect of the present invention is a pharmaceutical composition in the form of tablets comprising moxifloxacin hydrochloride, at least one diluent, and total amount of the diluent or diluents is lower than 45% (by weight), and the water content of the diluents or diluents is lower than 3%, preferably 2% and even more preferably lower than 1 %.
• the total amount of diluent or diliuents the lower than 35%, and more preferable ranges from 33% to 20%.
• the present inventors have surprisingly discovered that when the diluent contains water, the polymorph form is no longer stable and several polymorphs are detected in the final pharmaceutical composition.
• the present formulations may be manufactured under water free conditions, as direct compression or dry granulation.
• the manufacture process is double compression or dry granulation.
• This dry granulation has allowed to the present inventor to reduce the amount of diluent, providing smaller and stabler pharmaceutical compositions.
• the moxifloxacin HCI is even more important because the big amount of API in the final dosage form.
• a second aspect of the present invention is a granulate comprising moxifloxacin hydrochloride, an amount of colloidal silicon dioxide ranging from 0.1% to 1.0 % and an amount of lubricant ranging from 0.3% to 1.5%. This relationship of colloidal silicon dioxide and lubricant helps to the polymorph stability of the formulation, but having the then blended product the goods glidant/lubricant properties.
• a third aspect of the present invention is a pharmaceutical composition in the form of tablet, comprising a basic anhydrous salt and a granulate of moxifloxacin hydrochloride.
• the four aspect of the invention is a manufacture process.
• the inventor has surprisingly found the good stability, particularly polymorph stability, of the pharmaceutical compositions obtained by a dry granulation processes, comprising moxifloxacin hydrochloride.
• An anhydrous basic salt in the meaning of the present invention, is an anhydrous salt selected form the group of a carbonate, phosphate, silicate or sulphate of calcium, magnesium or aluminium or mixtures thereof. Preferabbly it is anhydrous dibasic calcium phosphate.
• Polymorph in the meaning of the present invention, comprises the different crystal packing, different conformers of the same molecule in conformational polymorphism, and the different pseudopolymorphism (different crystal types are the result of hydration or salvation)
• Non-aqueous granulation in the meaning of the present invention, is a dry granulation or wet granulation where water is not present during the blend in a significant amount.
• the problem to be solved by the present invention is to provide an efficient alternative, safer and cost-effective stable formulations comprising moxifloxacin hydrochloride and methods to manufacture thereof, which would be susceptible of use on an industrial scale.
• the first aspect of the present invention is a pharmaceutical composition in the form of tablets comprising moxifloxacin hydrochloride, at least one diluent, and total amount of the diluent or diluents is lower than 45% (by weight), and the water content of the diluents or diluents is lower than 3%, preferably 2% and even more preferably lower than 1%.
• the total amount of diluent or diliuents the lower than 35%, and more preferable ranges from 33% to 20%.
• the present inventors have surprisingly discovered that when the diluent contains water, the polymorph form is no longer stable and several polymorphs are detected in the final pharmaceutical composition.
• Process Mix all the above ingredients in a suitable blender. Prepare compacts /slugs of sutable hardness. Screen the compacts or slugs using 0.8-1.Omm screens.
• formulations comprise lactose monohydrate as a binder and moxifloxacin anhydrous a portion of moxifloxacin anhydrous reverts to the monohydrate form.
• formulation 1 was manufactured by the wet granulation using water. This amount of conversion was reduced when lactose anhydrous or dry granulation processes were used.
• a pharmaceutical composition in the form of tablets of comprising moxifloxacin hydrochloride and at least one diluent, wherein total amount of the diluent or diluents is lower than 45%, and the water content of the diluents which are present in proportion higher than 5% is lower than 3%, preferably lower than 2%.
• composition comprising an anhydrous basic salt, preferably anhydrous dibasic calcium phosphate.
• composition according to any of the preceding clauses comprising amount colloidal silicon dioxide ranges from 0.1% to 1.0 % and an amount of lubricant ranges from 0.3% to 1.5%.
• a granulate comprising moxifloxacin hydrochloride, colloidal silicon dioxide and at least one lubricant, wherein the amount of colloidal silicon dioxide ranges from 0.1% to 1.0 % and the amount of lubricant ranges from 0.3% to 1.5%.
• the lubricant is magnesium stearate.
• a pharmaceutical composition comprising the granulate of clauses 10 or 11.
• composition according to clauses 10 to 15 comprising an anhydrous basic salt, preferably anhydrous dibasic calcium phosphate.
• composition according to clauses 10 to 17 comprising an amount of colloidal silicon dioxide ranging from 0.1% to 1.0 % and a amount of lubricant ranging from 0.3% to 1.5%, and preferably the lubricant is magnesium stearate.
• a granulate comprising moxifloxacin hydrochloride and a basic anhydrous salt.
• a pharmaceutical composition comprising the granulate of clauses 20 or 21.
• the present invention relates to stable orally disintegrating tablets comprising rizatriptan benzoate, wherein such tablets are stable and have low tendency to provoke vomiting or nausea and methods for the manufacture thereof.
• Migraine is a neurological syndrome characterized by altered bodily experiences, painful headaches, and nausea. It is a common condition which affects women more frequently than men.
• migraine headache is one-sided and pulsating, lasting 4 to 72 hours.
• Accompanying complaints are nausea and vomiting, and a heightened sensitivity to bright lights (photophobia) and noise (hyperacusis).
• photophobia photophobia
• noise hypereracusis
• Conventional treatment focuses on three areas: trigger avoidance, symptomatic control, and preventive drugs. Patients who experience migraines often find that the recommended migraine treatments are not 100% effective at preventing migraines, and sometimes may not be effective at all.
• the first line of treatment is over-the-counter abortive medication, such as paracetamol (known as acetaminophen in the USA), aspirin, ibuprofen, or other simple analgesics that are useful for tension headaches.
• abortive medication such as paracetamol (known as acetaminophen in the USA), aspirin, ibuprofen, or other simple analgesics that are useful for tension headaches.
• triptans are a family of tryptamine based drugs used as abortive medication in the treatment of migraine and cluster headaches. While effective at treating individual headaches, they are neither a preventative treatment nor a cure.
• Triptans include sumatriptan, rizatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, and frovatriptan.
• Triptans are excellent for severe migraines or those that do not respond to NSAIDs or other over-the-counter drugs.
• Triptans are a mid-line treatment suitable for many migraineurs with typical migraines.
• triptans The action of the triptans is attributed to their binding to serotonin 5-HT1 B and 5-HT1 D receptors in cranial blood vessels (causing their constriction) and subsequent inhibition of pro-inflammatory neuropeptide release. Evidence is accumulating that these drugs are effective because they act on serotonin receptors in nerve endings as well as the blood vessels. This leads to a decrease in the release of several peptides, including CGRP and substance P.
• triptans There are two aspects that affect the design of pharmaceutical forms comprising triptans. The first one is the accompanying complaints to migraine attacks (i.e. nausea, vomiting or unpleasant smell). The second one is that the rizatriptan is not indicated as a prophylactic medication. For these two reasons it is very recommendable the use of orally disintegrating tablets (ODT). These kinds of tablets disintegrate rapidly, usually within a matter of seconds, when placed upon the tongue, being easy to take in any moment/place, even without water, independently when the migraine attack occurs.
• ODT orally disintegrating tablets
• a triptan ODT means that the pharmaceutical form is swallowed in the form of granulate, having a small size, decreasing the possibilities to provoke nausea and vomiting when it is compared with normal immediately release tablets.
• rizatriptan One of the most common triptans is rizatriptan.
• Rizatriptan is described chemically as: N,N-dimethyl-5-(1 H- 1,2,4-triazol-1-ylmethyl)-1 H- indole-3-ethanamine and its structural formula is:
• the prior art discloses several salts comprising rizatriptan, in turn having each salt different crystalline forms (i.e. polymorphs or pseudomorphs).
• EP0497512 A2 discloses rizatriptan in the form of free base, the oxalate hemihydrate salt, the succinate salt and the benzoate salt. Also EP0497512 discloses an immediate release tablet comprising rizatriptan benzoate. However, nowhere in EP0497512 is there a specific disclosure of which particular salt or polymorph is more suitable to be used in an ODT. Moreover, EP0497512 does not disclose any ODT formulation comprising any triptan derivate.
• EP0573221 discloses the sulphate salt of the rizatriptan. According to EP0573221 , this salt has been found to possess advantageous properties in several respects which make it particularly suitable for use as a pharmaceutical agent. For example it is relatively free from flavour and very soluble.
• the patent discloses some buffered sublingual tablets comprising the sulphate salt, being silent about the use of the benzoate salt. From the disclosure of EP0573221 a skilled in the art would be encouraged to use the sulphate salt in ODTs, instead of the other known salts, such as the benzoate.
• WO97/03068 discloses the bisulphate salt.
• the patent is focused on providing a high soluble salt with low tonicity in order to reduce the local irritancy in those regions of the body to which such solutions are administered, in particular in those regions possessing especially sensitive membranes, such as the intranasal cavity.
• WO2005/068453A1 disclosed two polymorphic forms, form A and form B, of the rizatriptan benzoate and processes for the synthesis thereof.
• WO2006/082598A2 discloses three additional polymorphs, namely Form I 1 Il and III.
• US2007/105927 discloses the amorphous form. Although the prior art discloses at least these six crystalline forms, the prior art is silent about the specific properties of each polymorphs and about the suitability of each of the solid forms to be used in ODT formulations.
• ODT orally dissolving or orally disintegrating tablet
• An ODT refers to an uncoated tablet intended to be placed in the mouth where it can disperse rapidly before being swallowed, as described in Eur. Ph. 5.0 .
• An ODT disintegrates within three minutes when tested according to the disintegration testing described herein (2.9.1).
• the disintegration time is less than 1 minute, and more preferably it is less than 30 seconds.
• disintegration does not imply complete dissolution of the unit or even of its constituent.
• Complete disintegration is defined as that state in which any residue of the unit, remaining on the screen of the test apparatus or adhering to the lower surface of the discs, if used, is a soft mass having no palpably firm core.
• any residue from an ODT shouldn't remain in the mouth.
• the procedure consists on placing one dosage unit in each of the six tubes of a basket- rack assembly and, if prescribed, adding a disc. Operate the apparatus using the specified medium, maintained at 37 ⁇ 2 0 C, as the immersion fluid.
• the apparatus contains a device for raising and lowering the basket in the immersion fluid at a constant frequency rate between 29 and 32 cycles per minute, through a distance of 55 ⁇ 2 mm. At the end of the specified time, lift the basket from the fluid and observe the dosage units: all of the dosage units have disintegrated completely. If 1 or 2 dosage units fail to disintegrate, repeat the test on 12 additional dosage units. The requirements of the test are met if not less than 16 of the 18 dosage units tested have disintegrated.
• disintegrant means a substance or a mixture of substances added to a tablet to facilitate its breakup or disintegration after administration.
• Other miscellaneous disintegrants include surfactants, natural sponge, resins, effervescent mixtures, and hydrous aluminum silicate.
• Suitable disintegrants include one or more of water-soluble disintegrants, such as pregelatinized starch, sodium carboxymethyl cellulose and sodium alginate, and water- insoluble cross-linked polymers, such as cross-linked carboxymethylcellulose, croscarmellose sodium also known as crosslinked sodium carboxymethylcellulose, sodium starch glycolate and cross-linked povidone also known as crosslinked polyvinylpyrrolidone.
• water-soluble disintegrants such as pregelatinized starch, sodium carboxymethyl cellulose and sodium alginate
• water- insoluble cross-linked polymers such as cross-linked carboxymethylcellulose, croscarmellose sodium also known as crosslinked sodium carboxymethylcellulose, sodium starch glycolate and cross-linked povidone also known as crosslinked polyvinylpyrrolidone.
• super disintegrants are completely effective when used at low relative amounts (2 to 4% w/w of the tablet). It is postulated that the rate, force, and extent of swelling play an important role in these disintegrants that work by swelling.
• filler means one or more inert substances, organic or inorganic, that dilutes the active ingredient in the immediate release portion, provides additional bulk to the immediate release portion allowing the rapid intrusion of water and release of the active ingredient, and aids in providing the desired flow properties and compression characteristics.
• water soluble filler refers to a filler having a cold water (25 0 C) solubility of at least 10 grams per 100 cubic centimeters (g/100 cc) of water, more preferably at least 50 g/100 cc of water.
• Such fillers include, for example, sugars such as glucose, maltose, sucrose, and lactose; polyalcohols such as sorbitol, mannitol or xylitol; amino acids such as glycine; polymers such as polyvinylpyrrolidone; polysaccharides such as dextran; certain inorganic salts, such as sodium or potassium phosphates, or sodium chloride.
• the filler is sorbitol.
• lubricant means a substance that reduces friction between the composition of the present invention and the surfaces of the apparatus used to compact the composition into a compressed form.
• Suitable lubricants for the present invention include, for example, fatty acids, such as palmitic acid, stearic acid, oleic acid, hydrogenated vegetable oils, triglycerides of fatty acids, metal salts of fatty acids, such as for example, zinc stearate and magnesium stearate, glycols, such as polyethylene glycol, and talc, as well as mixtures thereof.
• lubricants are sodium benzoate, adipic acid, fumaric acid, glyceryl monostearate, gyceryl behenate, glyceryl palmitostearate.
• the lubricant component of the composition of the present invention comprises magnesium stearate.
• direct compression refers to a process, wherein the various components of a tablet are blended, optionally milled and/or sieved, and then compressed into tablets.
• the blending of the compounds may be achieved in one or more steps.
• the active ingredient may first be mixed with a binder and then this mixture can be combined with a mixture of other ingredients.
• the whole process is preferably performed in the absence of a solvent.
• wet granulation refers to the general process of using a granulation liquid in the granulation process to subsequently form granules, as discussed in Remington: The Science and Practice of Pharmacy, 20th Edition (2000), Chapter 45, which is hereby incorporated by reference.
• “Dry granulation” refers to a granulation process where no external fluid is added during processing.
• the therapeutic compounds being granulated contain a total of at least about 4 wt % moisture, more preferably from about 5 wt % to about 15 wt % moisture, and most preferably from about 6 wt % to about 10 wt % moisture, based on the total weight of the therapeutic compounds.
• Such moisture is preferably inherently present in the therapeutic compounds as supplied.
• the moisture present is water. It is believed that having some moisture in the therapeutic compounds aids in achieving an intimate admixture during dry granulation
• This invention relates to pharmaceutical compositions having antimigraine activity, and more particularly, to compositions comprising a triptan derivate.
• the aim of the present invention is to overcome or at least reduce the problems associated to the treatment of the migraine with a triptan, and especially with rizatriptan.
• the first aspect of the present invention provides an orally disintegrating tablet comprising rizatriptan benzoate crystalline form A and at least one pharmaceutical acceptable excipient.
• the present inventors have found that such pharmaceutical compositions have many advantages versus the already known composition.
• the first one is that the ODTs comprising form A have lower unpleasant taste when they are compared with the same ODTs comprising any one of the other known solid forms, crystalline or amorphous, of the benzoate salt (i.e. form B, form II, form III and amorphous form).
• the reduction of the unpleasant taste and the use of ODTs improve the tolerability and compliance of the patient to the migraine treatment, mainly reducing the tendency to vomit or to have nausea.
• the second advantage is that the present inventors have discovered that ODTs comprising form A are more stable in several facets than the ODTs comprising the other crystalline forms. Surprisingly the crystalline form A is more stable, from the crystalline point of view, during the ODT manufacturing process and also once the tablet is already manufactured. When the other crystalline forms are used, mixtures of polymorphs are present in the final tablets. This phenomenon, polymorph mixtures, has been observed in the tablets just after manufacturing them or some time later, during the storage at room temperature. Such phenomenon could lead to the manufacture of ODTs comprising unpredictable variable mixtures of several polymorphs, having variable physical properties, a situation unacceptable in view of stringent GMP requirements.
• the impurity profile and the chemical stability of the ODTs comprising form A are better than the same ODTs comprising the other crystalline forms.
• the better stability observed in the ODTs comprising the form A is not so remarkably observed, or even negligible, when standard immediately release tablet are manufactured instead of the ODTs.
• the intrinsic characteristics of the ODT affect the stability of the tablet, being the form A the less affected. It should be kept in mind that an ODT must absorb water very quick in order to disintegrate in the mouth in a short period of time. Obviously the ODTs also absorb water during and after the manufacture from the environment, which could be the reason for stability differences being observed, and for the fact that rizatriptan benzoate in form A is less affected by environmental water.
• One additional advantage due to the above mentioned good stability, is that the present ODTs can be manufactured in less restrictive conditions, and therefore be more cost-effective.
• the second aspect of the present invention relates to a tablet comprising: rizatriptan benzoate in an amount ranging from 3 to 15 % w/w, at least one water soluble filler in an amount ranging from 25 to 95 % w/w, at least one lubricant in an amount ranging from 0.2 to 2% w/w, and optionally, a disintegrant in an amount ranging from 0.5 to 5 % w/w.
• the present inventors have found that the above proportions make it possible to achieve a tablet with an ODT behavior, and in turn the tablet is stable and suitable to be manufactured on an industrial scale.
• the third aspect of the present invention relates to processes for the manufacture of the ODT as disclosed in the first and second aspects.
• the present ODTs are suitable for being manufactured by direct compression and dry granulation, as the roller compaction. Wet granulation processes can also be used, where desired.
• the blends can be processed in the form of powder or granulate on standard tabletting machines.
• the blends comprising form A offer good flowability, exceptionally high cohesion, and no segregation of the active ingredient. As a result, they can be easily processed.
• Direct compression offers clear advantages because of its simplicity: the components are weighed, mixed and directly compressed. It has been found that the direct compression is very gentle on the active ingredient giving stable compositions. Therefore the tablet can be manufactured in high quality at low cost and with short time-to-production.
• the last aspect of the present invention relates to the use of the rizatriptan form A for the manufacture of an orally disintegrating tablet. After many attempts the inventor has discovered the extreme suitability of form A to be used in pharmaceutical compositions in the form of ODTs.
• the mean particle size of the crystalline rizatriptan benzoate form A ranges from 1 to 200 microns, preferably from 50 to 150 microns.
• This mean particle size distribution is suitable for any manufacturing process, but it is preferred for direct compression as it has been observed that the flowability is excellent. Also this mean particle size distribution allows the use of standard tableting processes, yielding excellent content uniformity, even at high tableting speed.
• the tablet comprises form A polymorph that is essentially free of other polymorphic forms, i.e. greater than 70, 80, 90, 95, 98 or even 99% pure.
• Form A can be evaluated by X-ray diffraction as described more particularly in example R16
• the ODT comprises at least one water soluble filler, preferably in an amount ranging from 25 to 95 % w/w, and optionally a disintegrant in an amount ranging from 0 to 20 % w/w.
• a disintegrant in an amount ranging from 0 to 20 % w/w.
• the water soluble filler is selected from the group consisting of mannitol, sorbitol, erytrhol, xylitiol, lactose, modified lactose, maltodextrin, dextrate, dextrose, sucrose and mixtures thereof.
• said disintegrant is selected from the group consisting of starches, clays, celluloses, alginates, gums, cross-linked polymers, surfactants, natural sponge, resins, effervescents mixtures, and hydrous aluminum silicate and mixtures thereof, preferably croscarmellose, sodium starch glycolate and crospovidone.
• magnesium stearate All the ingredients except magnesium stearate were mixed together in a suitable blender. The resulting mixture was then lubricated with magnesium stearate and compressed on a tablet press.
• the mixture is molded at 60 kg/cm2 with the aid of a punch and dye having a diameter of 1 cm.
• the thus obtained molded body was heated for 10 minutes at 5O 0 C with the aid of a ventilating dryer and then dried for one night in a closed container with a desiccant to obtain an ODT.
• Mannitol, polyvinylpyrrolidone and polysorbate 80 were dissolved in water and the solution was subjected to spray drying to obtain a particulate material.
• the particulate was mixed with the remaining ingredients and the resulting mixture was tableted.
• the resulting tablet was dried at 45 0 C for 24 hours to sublime menthol until the content of residual menthol became 1 mg or less, to obtain a rapidly disintegrating tablet.
• example R4 Using the above ingredients, the procedure of example R4 was repeated except that mannitol and polyvinylpyrrolidone were used in the preparation of the particulate, to obtain a rapidly disintegrating tablet.
• Microcrystalline cellulose (Avicel PJ 112) 10.00 7.72%
• Tableting was performed using the above composition.
• the blend was compressed into tablets.
• Blended rizatriptan benzoate from example R8 is granulated using wet granulation procedures known in the art.
• the solvent is aqueous.
• solvents such as isopropanol or ethanol may be used. These materials may be incorporated via spray granulation system whereby the solvent is removed. These granules are blended with magnesium stearate and compressed into tablets.
• Titanium dioxide 0.30 0.32%
• magnesium stearate All the ingredients except magnesium stearate were mixed together in a suitable blender. The resulting mixture was then lubricated with magnesium stearate and compressed on a tablet press.
• Ludiflash ® (90% mannitol + 5 % Crospovidone + 5% polyvinyl acetate) The ingredients are blended in a free-fall mixer for 10 minutes, passed through an 0.8 mm sieved and compressed at a force of 3.7 kN.
• Aerosil ® 200 1.00 0.50% 0-5
• the ingredients are blended in a free-fall mixer for 10 minutes, passed through an 0.8 mm sieved and compressed at a force of 4 kN at 40 rpm.
• PharmaburstTM C1 ® made up of 120.60 66.44% 50-95
• Crospovidone type B 1.76 0.97% 0-5
• Rizatriptan benzoate, Avicel PH 200, Ludiflash ®, sodium bicarbonate, saccarine sodium, peppermint and magnesium stearate were blended in a mixer for approximately 3 minutes.
• the mixture was wet granulated in a mixer granulator using Polyvinylpyrrolidone (PVP) dissolved in water.
• PVP Polyvinylpyrrolidone
• the wet mass was then gradually fed into a small scale extruder (1.5 mm, 50 rpm) and the extrudate collected.
• the extrudate was spheronised at about 600 rpm for 5-10 minutes.
• the resulting pellets were transferred to a tray and dried in an oven at 50 0 C overnight. After that, these pellets were mixed with a second portion of magnesium stearate.
• pellets were compressed into tablets using a conventional rotary tablet press.
• Immediate release (IR) beads Rizatriptan benzoate (210.0 g) was slowly added to an aqueous solution of 32.6 g polyvinylpyrrolidone (binder) and 978 g of purified water and mixed well. 60-80 mesh (177-250 micron) sugar spheres (1470 g) were coated with the drug-layering formulation in a Glatt fluid-bed coater equipped with a bottom-spray Wurster insert. The drug containing pellets were dried, and a seal coat of Opadry Clear for a weight gain of 2% was applied on the drug-layered beads.
• Rapidly-dispersing Microgranules The rapidly-dispersible microgranules comprising a sugar alcohol such as mannitol and a disintegrant such as crospovidone are prepared. Currently, D-mannitol (147 kg) with an average particle size of approximately 20 microns or less (Pearlitol 25 from Roquette, France) is blended with 8 kg of cross-linked 11
• -85- povidone (Crospovidone XL-10 from ISP) in a high shear granulator (GMX 600 from Vector) and granulated with an aqueous solution of 5 kg mannitol dissolved in 37 kg purified water.
• Two such high shear granulation batches are vacuum-transferred into a fluid-bed drier, Glatt GPCG 200 through a Comil from Quadra and dried in the Glatt.
• the rapidly-dispersible microgranules thus obtained typically have an average particle size in the range of approximately 125-200 microns.
• ODT Rizatriptan benzoate Beads at 15% and 25% coating and the mix (93.38%, rapidly-dispersing microgranules, 5.91% crospovidone, 0.35% orange flavor, and 0.35% Aspartame) at a ratio of 1/3, were blended together and compressed into 441 mg (15% coating) or 500 mg (25% coating) tablets containing 14.53 mg of rizatriptan benzoate. Almost complete release of the active in about 5 minutes was observed when dissolution tested in 0.1 N HCI.
• Instrumentation - X-ray diffraction patterns can be obtained on a Miniflex X-ray diffractometer (Rigayu), by laying the sample on a static sample holder.
• the goniometer radius is 150 mm.
• the X-ray tube has a copper target, with a current intensity of 15 mA and a voltage of 30 kV: the radiation generated by the Cockcroft- Walton method, is constituted by K01(1.540562 A) and K02(1.544398 A); nickel filter is used for the suppression of K[beta] radiation (1.392218 A).
• the detector is a NaI scintillator with a beryllium window. Continuous scanning occurred using a sampling width of 0.01 deg and a scanning rate of 2 deg/minute; 2 [theta] range of 2 / 50 deg.
• the sample holder was amorphous glass, and the sample was pressed with a glass plate.
• the in vitro dissolution profile is not affected by the solid form used of rizatriptan benzoate (Form A, B, I, II, III or amorphous).
• An orally disintegrating tablet comprising rizatriptan benzoate crystalline form A and at least one pharmaceutical acceptable excipient.
• the orally disintegrating tablet according to any one of the preceding clauses comprising at least one water soluble filler, preferably in an amount ranging from 25 to 95 % w/w, and optionally a disintegrant in an amount ranging from 0 to 20 % w/w
• water soluble filler is selected from the group consisting of mannitol, sorbitol, erythritol, xylitiol, lactose, modified lactose, maltodextrin, dextrate, dextrose, sucrose and mixtures thereof.
• disintegrating tablet according to clauses 3 or 4, wherein the disintegrant is selected from the group consisting of starches, clays, celluloses, alginates, gums, cross-linked polymers, surfactants, natural sponge, resins, effervescents mixtures, and hydrous aluminum silicate and mixtures thereof, preferably croscarmellose, sodium starch glycolate, crospovidone and mixtures thereof.
• a tablet comprising: a) rizatriptan benzoate in an amount ranging from 3 to 15 % w/w, b) at least one water soluble filler in an amount ranging from 25 to 95 % w/w, c) at least one lubricant in an amount ranging from 0.2 to 2% w/w, and d) optionally, a disintegrant in an amount ranging from 0.5 to 5 % w/w which disintegrates in less than 3 minutes.
• SIXTH INVENTION BACKGROUND OF THE SIXTH INVENTION
• Clopidogrel is a platelet aggregation inhibitor indicated in the prevention of cerebrovascular accidents and heart attacks in persons at risk of developing these problems. Clopidogrel helps to prevent the formation of clots.
• Clopidogrel is the international non-proprietary name (INN) of the methyl ester of (+)-(S)- ⁇ -(2-chlorophenyl)- 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid.
• Clopidogrel is marketed in the form of tablets as one of its acid addition salts, namely the hydrogen sulfate salt, under the brand name Plavix.
• EP 281459 disclosed for the first time clopidogrel and several acid addition salts thereof such as hydrogen sulfate, hydrobromide, hydrochloride and taurocholate.
• Example 1f discloses the process for the preparation of hydrobromide, which yields crystalline clopidogrel hydrobromide monohydrate.
• the product sold under the Plavix brand name in the USA which includes the bisulfate salt (hydrogen sulfate), contains anhydrous lactose and microcrystalline cellulose as fillers and hydrogenated castor oil and polyethylene glycol 6000 as lubricants.
• the product sold in Europe includes mannitol and microcrystalline cellulose as fillers and the same lubricants as in the USA.
• WO 2005/048992 describes pharmaceutical compositions comprising clopidogrel and its salts of monobasic acids such as clopidogrel mesylate, hydrochloride, hydrobromide, hydroiodide.
• Clopidogrel base and salts of monobasic acids are described as difficult to formulate because of its high hygroscopicity and low stability.
• hydrophobic excipients such as stearic acid, cetyl alcohol, cetostearyl alcohol, hydrogenated vegetable oils, cellulose acetate, polymethacrylates, polyvinyl acetate, polyvinyl alcohol, cyclodextrins, etc. All the excipients are used in anhydrous form.
• hydrogenated vegetable oil which is a hydrophobic compound, is used as a lubricant in all the examples. Fillers used in these compositions include lactose, microcrystalline cellulose, mannitol and mixtures thereof.
• European patent application EP 1310245 discloses clopidogrel bisulfate tablets. Tablets prepared using zinc stearate, stearic acid or sodium stearyl fumarate as lubricants are found to be much more stable than those using magnesium stearate and calcium stearate
• compositions of "salts of monobasic acids" such as clopidogrel hydrochloride, hydrobromide, mesylate, besylate, benzoate, salycilate, lactate or gluconate are less stable than clopidogrel bisulfate due to the presence of the second proton with confers acidity to the bisulfate anion. Therefore many common excipients cannot be used with these salts such as magnesium stearate, zinc stearate, magnesium stearyl fumarate, polyethylene glycol, croscarmellose or others.
• Polyethylene glycol is suggested to produce transesterification reactions with clopidogrel (a methyl ester) and therefore it is said to be incompatible with clopidogrel besylate, a fact not disclosed with clopidogrel bisulfate.
• Stearic acid and fumaric acid are said to be suitable lubricants while lactoses, celluloses, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyols and starches are said to be suitable fillers and binders.
• This patent application discloses that the use of non-ionic and non-basic excipients increases the stability of pharmaceutical compositions comprising salts of monobasic acids. Stable clopidogrel besylate compositions are disclosed.
• WO 2005070464 discloses clopidogrel bisulphate tablets which contain hydrogenated vegetable oils as a lubricant and lactose monohydrate and microcrystalline cellulose as fillers. According to this patent application, composition containing clopidogrel derivatives (clopidogrel bisulfate is the only compound mentioned) exhibited unacceptable rapid decomposition as a result of the inclusion of certain excipients such as magnesium stearate, povidone or gelatine. Clopidogrel bisulfate compositions not containing magnesium stearate are specifically claimed.
• WO 2004072084 and WO 2004072085 disclose general formulations comprising various sulfonic acid salts of clopidogrel. Specific lubricants or fillers have not been mentioned.
• WO 2004074215 describes oral formulations, inter alia containing clopidogrel mesylate and clopidogrel hydroiodide.
• Several examples include tablet compositions comprising clopidogrel mesylate and polyethylene glycol 6000, hydrogenated vegetable oil and magnesium stearate as lubicants. No information is provided regarding the stability of these compositions.
• Formulations containing magnesium stearate as lubricant are said to be less stable than formulations containing sodium stearyl fumarate as lubricant in amounts of about 0.5 to 1.5%.
• Stable tablet formulations further included lactose monohydrate, 15 to 35%, as filler, low substituted hydroxypropylcellulose, 2 to 8%, as disintegrant, hydroxypropylmethyl-cellulose, 1 to 6%, as binder, and silicon dioxide, 0.5 to 1.5%, as glidant.
• the tablets were manufactured by wet granulation and then coated. The amounts of excipients are described as ranges and, what is more important, no solvent nor the amount of said solvent is specified for the wet granulation process, providing an incomplete account of the process to reproduce the experiments.
• CZ297481 discloses pharmaceutical compositions obtained through direct compression including clopidogrel hydrobromide crystalline form II. Hydrogenated castor oil is used as lubricant and lactose and microcrystalline cellulose as fillers. Dissolution profiles of the tablets are provided.
• WO2007049868 discloses stabilized tablets comprising clopidogrel bisulfate and starch. The stability of different composition was tested, the worst results being obtained in comparative test 2 and 5 which included magnesium stearate as lubricant. Glycerol dibehenate was the lubricant included in the formulations having better stability profiles. The choice of lubricant could be the cause of it.
• compositions comprising clopidogrel salts are low stability of these salts and hence of the compositions thereof.
• lubricants disclosed present sticking problems such as stearic acid and gyceryl dibehenate.
• sodium stearyl fumarate which is in theory one preferred lubricant according to IP.com disclosure, has surprisingly been found to be non-compatible with clopidogrel hydrobromide.
• compositions with an efficient lubrication consisting of pharmaceutical compositions in the form of a coated tablet comprising clopidogrel hydrobromide, at least one filler and at least one lubricant selected from the group consisting of calcium stearate, zinc stearate and magnesium stearate.
• a robust composition is one which is capable of producing reproducible results in key parameters such as the dissolution profile of the pharmaceutical composition. Slight variations of process parameters such as the percentage of coating or the compression force should not influence the dissolution profile of the drug in order to have a robust composition. In manufacturing plants such slight deviations occur, and this should not compromise the reproducibility of the features of the tablets.
• the present inventors have found robust pharmaceutical compositions in the form of coated tablet comprising clopidogrel hydrobromide, at least one disaccharide alcohol as filler and at least one lubricant, preferably calcium stearate, zinc stearate or magnesium stearate.
• compositions of superior hardness, improved sensory and fracture proprieties can be produced while using the lowest possible compression pressures.
• compositions comprising clopidogrel hydrobromide Another problem faced in the development of compositions comprising clopidogrel hydrobromide is to achieve a suitable dissolution profile of the formulation, which would translate into a suitable therapeutic effect over time.
• compositions in the form of coated tablet comprising clopidogrel hydrobromide, at least one filler, at least one lubricant, wherein the average particle size of the clopidogrel hydrobromide is between 25 ⁇ m and 0.1 ⁇ m as measured by laser light diffraction.
• Clopidogrel hydrobromide is to be understood in the present invention as comprising anhydrous forms, hydrated forms, such as clopidogrel hydrobromide monohydrate, as described in EP 281459 and other publications, or solvated forms of the hydrobromide salt of clopidogrel. These forms could be in amorphous forms, crystalline forms or mixtures thereof.
• a disaccharide alcohol is to be understood as a disaccharide wherein at least one of the monosaccharide units has its carbonyl group reduced to alcohol.
• Disaccharide alcohols useful as fillers or diluents in pharmaceutical compositions include lactitol, lactitol monohydrate, maltitol and isomalt. These compound are also useful a sweeteners.
• Lactitol consists of galactose and a sorbitol units bound together and is produced by catalytic hydrogenation of lactose. Its chemical name is 4-O-( ⁇ -D-Galactopyranosyl)-D-glucitol and is sold in anhydrous and monohydrate forms.
• Maltitol consists of glucose and sorbitol units bound together and is produced by catalytic hydrogenation of maltose syrup. Its chemical name is 4-O- ⁇ -D-Glucopyranosyl-D-glucitol. lsomalt is a mixture of two stereoisomers: 6-0- ⁇ -D-glucopyranosyl-D-sorbitol (1,6-GPS) and 1-0- ⁇ -D- glucopyranosyl-D-mannitol dihydrate (1,1 -GPM). By shifting the ratio of the two components, the solubility and crystal water content can be adjusted.
• Colloidal silicon dioxide used in the examples of the invention is in anhydrous form, also known as colloidal anhydrous silica or silica colloidalis anhydrica. This excipient is useful as glidant agent.
• Suitable coatings for the tablets of the invention include HPMC based coatings, such as for example Opadry Il white, or polyvinyl alcohol based coatings such as Opadry AMB.
• D50 and d90 are the particle size below which at least 50 and 90 % of the particles are found.
• a first aspect of the present invention relates to a pharmaceutical composition in the form of a coated tablet comprising clopidogrel hydrobromide, at least one filler and at least one lubricant selected from the group consisting of calcium stearate, zinc stearate and magnesium stearate.
• the total amount of lubricant ranges from 0.25 to 5% by weight of the tablet. More preferably, it ranges from 0.5 % to 2%, and even more preferably, it ranges from 1 to 1.5% by weight.
• compositions comprise calcium stearate as a lubricant.
• compositions comprise a disaccharide alcohol as a filler.
• the disaccharide alcohol is isomalt.
• a second aspect of the present invention relates to a pharmaceutical composition in the form of coated tablet comprising clopidogrel hydrobromide, at least one disaccharide alcohol as a filler and at least one lubricant, preferably calcium stearate, zinc stearate or magnesium stearate.
• the total amount of disaccharide alcohol ranges from 10% to 90% by weight. More preferably, it ranges from 20 to 70 %, and even more preferably from 30 to 60% by weight.
• compositions comprise isomalt as a disaccharide alcohol.
• compositions comprise at least one lubricant selected from the group consisting of calcium stearate, zinc stearate and magnesium stearate.
• compositions further comprise at least one binder and at least one glidant.
• the binder is a modified starch and the glidant is colloidal silicon dioxide.
• a third aspect of the present invention relates to A pharmaceutical composition in the form of coated tablet comprising clopidogrel hydrobromide, at least one filler, at least one lubricant, wherein the average particle size of the clopidogrel hydrobromide is between 25 ⁇ m and 0.1 ⁇ m as measured by laser light diffraction.
• the average particle size is from 1 to 15 microns; preferably, from 1 to 10 microns, more preferably, from 1 to 6 microns.
• Suitable d50 values are from 1 to 25 microns. In a preferred embodiment, d50 values is from 1 to 15 microns; preferably, from 1 to 10 microns, more preferably, from 1 to 6 microns.
• Suitable d90 values are from 1 to 45 microns. In a preferred embodiment, d90 values is from 1 to 25 microns; preferably, from 5 to 15 microns.
• Mannitol used was that sold under the brand name Pearlitol SD 200.
• Tablets were prepared by direct compression. All the components except the lubricants and the glidants (polyethylene glycol 6000 and hydrogenated castor oil) were blended in a double-cone blender for 15 minutes at 20 rpm. Lubricants and.glidants were added to the previous mixture and blended in a double-cone blender for 5 minutes at 20 rpm. The resulting mixture was compressed in suitable equipment in order to obtain tablets with a weight of 250 mg and hardness around 75-100 N.
• lubricants and the glidants polyethylene glycol 6000 and hydrogenated castor oil
• compositions 8 and 9 including metallic salts of stearic acid are stable and do not show sticking problems.
• compositions 8 and 9 including metallic salts of stearic acid are stable and do not show sticking problems.
• Blend 392 g of clopidogrel hydrobromide monohydrate and 20 g of colloidal silicon dioxide were mixed in a polybag and sieved through a sieve with a 0,8 mm mesh. 235 g of microcrystalline cellulose, 203 g of lactose anhydrous, 100 g of pregelatinitzed starch and 40 g of talc were sieved through a sieve with 0,8 mm mesh and then all the components were blended in a double-cone blender for 20 minutes at 20 rpm. 10 g of calcium stearate were sieved through a sieve with a 0,25 mm mesh and then were added to the previous mixture and were blended in a double-cone blender for 3 minutes at 20 rpm.
• Example 10 2% of weight increase.
• Example 11 4 % of weight increase.
• Example 12 2 % of weight increase.
• Example 13 3 % of weight increase.
• Blend 392 g of clopidogrel hydrobromide monohydrate and 20 g of colloidal silicon dioxide were mixed in a polybag and sieved through a sieve with a 0,8 mm mesh. 438 g of isomalt, 100 g of starch 1500 LM partially pregelatinitzed and 40 g of talc were sieved through a sieve with 0,8 mm mesh and then all the components were blended in a double-cone blender for 20 minutes at 20 rpm. 10 g of calcium stearate were sieved through a sieve with a 0,25 mm mesh and then were added to the previous mixture and were blended in a double-cone blender for 3 minutes at 20 rpm.
• Example 14 2,6 % of weight increase.
• Example 15 4 % of weight increase.
• Example 16 2,6 % of weight increase.
• Example 17 4 % of weight increase.
• Example 18 2,6 % of weight increase.
• Example 19 4 % of weight increase.
• Example 20 2,6 % of weight increase.
• Example 21 4 % of weight increase.
• a composition identical to example 9 but using zinc stearate is prepared showing good stability and not showing sticking problems.
• compositions prepared using disaccharide alcohols have been compared with those of compositions having as a filler microcrystalline cellulose and lactose and the results obtained have shown that the first compositions provide comparable dissolution profiles, while this is not achieved with compositions having as a filler microcrystalline cellulose and lactose. Therefore, we can conclude that compositions having a disaccharide alcohol provide robust dissolution profiles, while composition having other fillers not robust.
• a pharmaceutical composition in the form of a coated tablet comprising clopidogrel hydrobromide, at least one filler and at least one lubricant selected from the group consisting of calcium stearate, zinc stearate and magnesium stearate.
• composition according to any of the preceding clauses comprising a disaccharide alcohol, preferably isomalt, as a filler.
• a pharmaceutical composition in the form of coated tablet comprising clopidogrel hydrobromide, at least one disaccharide alcohol as a filler and at least one lubricant, preferably calcium stearate, zinc stearate or magnesium stearate.
• composition according to any of the clauses 5 to 7 comprising at least one lubricant selected from the group consisting of calcium stearate, zinc stearate and magnesium stearate.
• composition according any of the preceding clauses, wherein it further comprises at least one binder and at least one glidant.
• composition according to clause 9 comprising modified starch and colloidal anhydrous silica.
• a pharmaceutical composition in the form of coated tablet comprising clopidogrel hydrobromide, at least one filler, at least one lubricant, wherein the average particle size of the clopidogrel hydrobromide is between 25 ⁇ m and 0.1 ⁇ m as measured by laser light diffraction.
• the present invention relates to stable oral pharmaceutical formulations comprising candesartan cilexetil and to a process for the preparation thereof.
• Cardiovascular diseases are the main cause of death for both males and females in the United States, Europe, Canada and other technologically advanced countries of the world. It is also in the top five causes of death in lesser-developed countries.
• Diseases of the cardiovascular system include those that compromise the pumping ability of the heart, hypertension, failure of the valves, inflammation of the heart muscle and/or the tissue surrounding it, or narrowing or hardening of the arteries.
• Hypertension or high blood pressure occurs when the force of blood passing through blood vessels is above normal. This increase in the pressure forces the blood to hit the blood vessel walls. Consistently high blood pressure can increase no. of other complications like atherosclerosis, stroke, heart attack and may also lead to heart and kidney failure; necessitating the inclusion of drugs like Diuretics, Beta blockers , Calcium channel blockers , ACE inhibitors, Angiotensin Il receptor blockers, vasodilators, centrally-acting anti-hypertensives, Alpha blockers.
• Angiotensin Il is formed from Angiotensin I in a reaction catalyzed by angiotensin-converting enzyme. It is a very potent chemical that causes the muscles surrounding the blood vessels to contract, which thereby narrows the blood vessels. This narrowing increases the pressure within the vessels and can cause high blood pressure (hypertension).
• Angiotensin receptor blockers (ARBs) block the action of angiotensin II. As a result, the blood vessels dilate and the blood pressure is reduced. The lower blood pressure makes it easier for the heart to pump blood and can improve heart failure. In addition, the progression of kidney disease due to high blood pressure is slowed.
• Candesartan is a useful therapeutic agent approved in USA, Europe, Canada and many other countries for the treatment of hypertension and heart failure in patients with left ventricular systolic dysfunctions. Owing to its poor solubility when administered orally, it has been developed as a prodrug (i.e. candesartan cilexetil) which rapidly hydrolyzes to candesartan during absorption from the gastrointestinal tract. Even though Candesartan cilexetil is a racemic mixture containing one chiral centre; it undergoes hydrolysis at the ester link to form the active drug (i.e. candesartan) which is achiral.
• candesartan cilexetil alone is stable at room temperature; however, when it is formulated into the dosage form like tablet with various excipients, it degrades over time. This degradation leads to the generation of no. of impurities like methyl candesartan, ethyl candesartan, desethyl candesartan, benzimidazole, n-trityl candesartan and n-trityl cilexetil candesartan.
• impurities like methyl candesartan, ethyl candesartan, desethyl candesartan, benzimidazole, n-trityl candesartan and n-trityl cilexetil candesartan.
• WO 2005084648 A1 covers the stable pharmaceutical composition comprising an effective amount of candesartan cilexetil and one or more polymers like maltodextrin, polyvinyl alcohol or xanthan gum.
• Singh et al in patent publication no. WO 2005070398 A2 claims a stable pharmaceutical composition of candesartan cilexetil and one or more co-solvents like propylene glycol, polyethylene alcohol, ethanol, glycerin etc.
• Patent publication no. WO 2006122254 A2 by Kurgan et al discloses stable Form I of candesartan cilexetil which is of fine particle size.
• a stable Candesartan cilexetil oral pharmaceutical composition can be prepared by incorporation of light liquid paraffin or Polyethylene glycol 100-400 in the formulation.
• the formulations prepared by using the light liquid paraffin or Polyethylene glycol 100-400 were found to exhibit superior stability with the quantity of desethyl candesartan and other impurities generated much below the permissible limits even after exposure to the more stringent conditions i.e. 50 0 C /75 % RH (as against 40 ° C/75 % RH, which is used in the prior art);
• the present invention is directed to a surprising discovery by the inventors that a stable pharmaceutical composition can be prepared by incorporation of light liquid paraffin or polyethylene glycol 100-400 in the formulation.
• the invention provides a novel, stable oral pharmaceutical composition of candesartan cilexetil.
• the invention provides a novel, stable pharmaceutical oral pharmaceutical composition of candesartan cilexetil and wherein the stability is maintained by using light liquid paraffin or polyethylene glycol 100-400 along with other suitable excipients.
• the invention provides a novel, stable pharmaceutical oral pharmaceutical composition of candesartan cilexetil and wherein the stability is maintained even after exposure to stringent conditions during formulation like 50°C/75%, friction, abrasion, heat and compression forces by using light liquid paraffin or polyethylene glycol along with other suitable excipients.
• the invention provides a novel, stable pharmaceutical oral pharmaceutical composition of candesartan cilexetil and wherein the stability is with regard to the level of impurities like methyl candesartan, ethyl candesartan, desethyl candesartan, benzimidazole, n-trityl candesartan and n-trityl cilexetil candesartan.
• the invention provides the process for the preparation of novel, stable pharmaceutical oral pharmaceutical composition of candesartan cilexetil.
• the light liquid paraffin which is being included in the proposed composition is a hydrocarbon with 15- 40 carbon atoms and has the boiling point above 200 0 C.
• PEG 100, 200, 300, 400 are low molecular weight grades of Polyethylene glycol which can be used effectively for the stabilization of candesartan cilexetil in the formulation.
• PEG. 400 Polyethylene Glycol 400 which due to its low toxicity, as compared to higher molecular weight Polyethylene glycol (1000-6000; which are associated with the carcinogenic potential) is widely used in a variety of pharmaceutical formulations. It is strongly hydrophillic and has the melting point of 4-8 0 C
• Candesartan cilexetil which is used in the present invention, is a prodrug, which rapidly hydrolyzes to candesartan during absorption from the gastrointestinal tract.
• the dose of candesartan cilexetil administered to the patients may be between 1-50 mgs or more particularly, it may be between about 2 mg to 40 mg. However, the exact dose to be given to the patient to get the intended therapeutic effect may vary depending upon the weight, age, sex of the patient.
• compositions of candesartan cilexetil in combination with PEG 100-400 or light liquid paraffin along with other pharmaceutical excipients are preferably given orally in the form of tablet or capsule; however, the tablet dosage form are more preferred.
• the various excipients that could be employed for the preparation of the oral dosage forms are disintegrants, fillers, binders, glidants, surfactants and lubricants.
• composition of candesartan cilexetil can be prepared in tablet dosage form by the methods known in the art like direct compression, wet granulation or dry granulation.
• the tablets are prepared by blending the candesartan cilexetil and light liquid paraffin or PEG 100-400, with all the excipients like filler, diluent, glidant, disntegrant and lubricating the blend and compressing the lubricated blend.
• the tablets are prepared by mixing the candesartan cilexetil and light liquid paraffin or PEG 100-400, filler, diluent, disntegrant and granulating it with the binder solution; drying the granules, sizing and lubricating and compressing the lubricated granules.
• the tablets are prepared by blending the candesartan cilexetil and light liquid paraffin or PEG 100-400, filler, diluent, glidant, disntegrant, passing it through roller compactors to get flakes, milling the flakes to attain granules which are then lubricated and finally compressing the granules.
• the disintegrant that can be used is selected from alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polyacrilin potassium, powdered cellulose, pregelatinized starch, sodium or calcium alginate and starch.
• the filler that can be used in the present invention is selected from calcium carbonate, calcium sulfate, compressible sugars, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, glyceryl palmitostearate, hydrogenated vegetable oil (type I), kaolin, lactose, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc and tribasic calcium phosphate.
• the binder that can be used in the present invention is selected from acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil (type I), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, magnesium aluminaum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone, pregelatinized starch, sodium alginate, com starch, and zein.
• the surfactant is selected from anionic and cationic surfactants, such as sodium lauryl sulfate, docusate sodium (dioctyl sulfosuccinate sodium salt), benzalkonium chloride, benzethonium chloride, and cetrimide (alkyltrimethylammonium bromide).
• the lubricant is selected from stearate acid metal salt (magnesium stearate or calcium stearate), stearic acid, sodium lauryl sulfate, sodium lauryl magnesium, powdered gum arabic, carnauba wax, anhydrous silicic acid, magnesium oxide, silic acid hydrate, boric acid, fatty acid sodium salt and leucine.
• composition may further comprise a coloring agent.
• Example 1 Candesartan Cilexetil (16 mg) Tablets prepared and stabilized using PEG 400
• PEG 400 and hydroxyl propyl cellulose were dissolved in water.
• Dry mix was granulated with the solution of step b in RMG.
• the wet granules were then dried in a vacuum drier, passed through the sieve and subjected to sizing.
• Example 2 Candesartan Cilexetil (16 mg) Tablets prepared and stabilized using PEG 400
• Candesartan cilexetil and PEG 400 were dispersed in water. Lactose, Pregelatinised starch and Povidone were mixed in rapid mix granulator and granulated with dispersion of step a.
• the wet granules were then dried in a vacuum drier, passed through the sieve and subjected to sizing.
• Example 3 Candesartan Cilexetil (4 mg) Tablets prepared and stabilized using PEG 100
• Candesartan cilexetil and PEG 100 were dispersed in water.
• Microcrystalline cellulose, pregelatinised starch and povidone were mixed in rapid mix granulator and granulated with dispersion of step a.
• the wet granules were then dried in a vacuum drier, passed through the sieve and subjected to sizing.
• Example 4 Candesartan Cilexetil (8 mg) Tablets prepared and stabilized using PEG 200
• Candesartan cilexetil, microcrystalline cellulose and povidone were dry mixed in rapid mix granulator.
• PEG 200 was dissolved in water. Dry mix comprising candesartan cilexetil, microcrystalline cellulose and povidone was granulated with the solution obtained from step b in rapid mixer granulator.
• the wet granules were then dried in a vacuum drier, passed through the sieve and subjected to sizing.
• Sodium starch glycolate and ferric oxide were added to the granules of step d after passing it through sieve.
• Example 5 Candesartan Cilexetil (16 mg) Tablets prepared and stabilized using Light liquid paraffin
• Dry mix was granulated with water, dried and sized.
• Candesartan cilexetil was blended with light liquid paraffin in a stainless steel vessel.
• the granules obtained from step b were mixed with Candesartan cilexetil-light liquid paraffin blend obtained from step c.
• Crosspovidone and ferric oxide were added to the granules of step d after passing it through sieve.
• magnesium stearate was added after passing it through sieve, mixed with the blend of step e and compressed to get tablets.
• Example 6 Candesartan Cilexetil (32mg) Tablets prepared and stabilized using Light liquid paraffin
• Lactose monohydrate, povidone and microcrystalline cellulose were dried mixed in rapid mix granulator.
• Candesartan cilexetil was blended with light liquid paraffin in a stainless steel vessel.
• step b The granules obtained from step b were blended with Candesartan cilexetil-light liquid paraffin blend obtained from step c.
• Sodium starch glycolate and ferric oxide were added to the granules of step d after passing it through sieve.
• a novel, stable pharmaceutical composition comprising an effective amount of candesartan cilexetil and a stabilizing agent selected from light liquid paraffin or polyethylene glycol 100-400.
• a novel pharmaceutical composition according to clause 1 wherein the stability is maintained even after exposure to stringent conditions during formulation like 50°C/75%, friction, abrasion, heat and compression forces by using light liquid paraffin or polyethylene glycol along with other suitable excipients.
• suitable pharmaceutical excipients are selected from disintegrants, fillers, binders, surfactants and lubricants.
• the present invention relates to pharmaceutical compositions in the form of tablets comprising a high content of levetiracetam as the active ingredient provided that it does not contain a disintegrant and methods for the manufacture thereof by granulation techniques. It further relates to a wet granulation process. In addition, the present invention relates to a method of coating tablets comprising a high content of levetiracetam.
• levetiracetam is a pyrrolidone derivative useful as antiepileptic. It is indicated as adjunctive therapy in the treatment of partial onset seizures with or without secondary generalization in patients with epilepsy. The precise mechanism of action by which levetiracetam induces seizure protection is unknown, but it appears to be unrelated to the mechanisms identified for current drugs.
• the chemical name is S-enantiomer of ⁇ -ethyl-2-oxo-1 -pyrrolidine acetamide, (UCB L059) chemically unrelated to existing antiepileptic active substances. Its molecular formula is C8H14N2O2 and its molecular weight is 170.21.
• the structural formula is:
• Levetiracetam is a white to off-white crystalline powder with a faint odour and a bitter taste. It has one chiral centre and is the S-enantiomer of the pair of stereoisomers.
• Levetiracetam tablets are commercially available under the trade name KEPPRA® and have the following excipients: a common superdisintegrant as sodium croscarmellose, macrogol 6000, colloidal anhydrous silica, magnesium stearate, opadry comprising polyvinyl alcohol-partially hydrolyzed.
• WO 2007012439 A1 relates to pharmaceutical compositions comprising levetiracetam and a process to prepare thereof by dry granulation.
• levetiracetam tablet must comprise a disintegrant between 2.0 % and 9.0 % per weight.
• WO 20070868991 A1 further relates to pharmaceutical compositions comprising levetiracetam formulations wherein the composition is free of any extra-granular glidant.
• the examples disclosed contain croscarmellose sodium or starch as the disintegrant.
• the tablet comprising the disintegrant is exposed to moisture in the pack can cause premature break up of the tablets.
• the water can be in the form of moisture vapour or liquid, if there is sufficient amount present; the tablet disintegrating process is initiated leading to rough tablets, crumbly tablets, swollen and even broken tablets in addition to the cost intensive production process.
• a disintegrant used in granulated formulation processes can be more effective if used both "intragranularly” and “extragranularly”, thereby acting to break the tablet up into granules and having the granules further disintegrate to release the drug substance into solution.
• the portion of disintegrant added intragranularly is usually not as effective as that added extragranularly due to the fact that it is exposed to wetting and drying (as part of the granulation process) which reduces the activity of the disintegrant.
• the aim of the present invention is to provide alternative pharmaceutical compositions of levetiracetam, especially in the form of tablets and methods of preparation thereof.
• a first aspect of the present invention relates to a pharmaceutical composition in the form of a tablet comprising levetiracetam, characterized in that it shows a very rapid in vitro dissolution of more than 85 % of dissolved levetiracetam within 15 minutes, according to guideline CPMP/EWP/QWP/1401/98 Rev.1, paddle dissolution apparatus 2 at pH of 1.0, 4.5 and 6.8 in a volume of 900 mL at a speed of 50 rpm and at temperature of 37 0 C, provided that the pharmaceutical composition does not contain a disintegrant.
• a second aspect of the present invention relates to an immediate release tablet comprising levetiracetam in an amount ranging from about 65% to about 85% w/w, preferably from about 70% to about 80% w/w, and at least one pharmaceutical acceptable excipient, provided that the pharmaceutical composition does not contain a disintegrant.
• a third aspect of the present invention relates to a method for the manufacture of a pharmaceutical composition as defined in any one of the preceding aspects by granulation techniques.
• the present inventors have found that defects (such as wall adhesion and capping) produced during the tabletting process have been eliminated.
• friability has been improved in the tablets, which improve physical resistance of the tablets in standard blister packs.
• a fourth aspect of the present invention relates to a method to prepare a pharmaceutical composition as defined in the second aspect comprising the steps of: i) mixing the active ingredient with at least one pharmaceutically acceptable excipient, preferably a diluent, ii) granulating the blend obtained in step (i) with a solvent, preferably water, iii) drying the wet granulate.
• the new manufacturing process improves the cohesiveness and compressibility of powders, there is a good distribution and uniform content of levetiracetam and excipients. It further reduces a great deal of dust and airborne contamination; for example, the glidant silicon dioxide is extremely fluffy and bulky and often require a sieving stage producing airborne particles. It also prevents the segregation of components.
• a fifth aspect of the present invention relates to a method for coating pharmaceutical compositions comprising more than 65% w/w of levetiracetam wherein the coating solution comprises water and an alcoholic solvent. It has been observed that conventional coating techniques employing water solution furnishes tablets with orange peel effect. This drawback is surprisingly solved in the present invention by using a hydro alcoholic solvent.
• a sixth aspect of the present invention relates to a granulate comprising levetiracetam and a pharmaceutical acceptable excipient, provided that it is not a disintegrant, wherein the granulate is prepared by wet granulation methods having a water content of below 4% after drying.
• a granulate with disintegrant and a higher concentration of water content leads to different kinds of problems, such as having poorer compressibility properties. Additionally more drying time is required with the consequent increase in impurities and a poor stability of the final oral solid dosage form comprising such granulate. For this reason, the granule of the present invention has optimal properties for the manufacture of oral solid dosage forms, preferably in the form of tablets.
• disintegrant means a substance or a mixture of substances added to a tablet to facilitate its breakup or disintegration after administration.
• Other miscellaneous disintegrants include surfactants, natural sponge, resins, effervescent mixtures, and hydrous aluminum silicate.
• Suitable disintegrants include one or more of water-soluble disintegrants, such as pregelatinized starch, sodium carboxymethyl cellulose and sodium alginate, and water- insoluble cross-linked polymers, such as cross-linked carboxymethylcellulose, croscarmellose sodium also ⁇ known as crosslinked sodium carboxymethylcellulose, sodium starch glycolate and cross-linked povidone also known as crosslinked polyvinylpyrrolidone.
• water-soluble disintegrants such as pregelatinized starch, sodium carboxymethyl cellulose and sodium alginate
• water- insoluble cross-linked polymers such as cross-linked carboxymethylcellulose, croscarmellose sodium also ⁇ known as crosslinked sodium carboxymethylcellulose, sodium starch glycolate and cross-linked povidone also known as crosslinked polyvinylpyrrolidone.
• super disintegrants are completely effective when used at low relative amounts (2 to 4% w/w of the tablet). It is postulated that the rate, force, and extent of swelling play an important role in these disintegrants that work by
• glidant as used herein is defined as an agent improving the fluidity of the powder and thus the of the chamber of the tablet press.
• the glidant may be present in the pharmaceutical composition in the form of a single compound or in the form of a mixture of compounds.
• examples of glidants are anhydrous colloidal silica, talc, starches and stearic acid.
• the glidant used in the present invention is colloidal silicon dioxide.
• binder as used herein is defined as an agent able to bind particles which cannot be bound only by a compression force.
• the binder may be present in the pharmaceutical composition in the form of a single compound or in the form of a mixture of compounds.
• binders are hydroxyprpopyl cellulose, hydroxyprpopyl methyl cellulose, macrogols, saccharose, starch or povidone.

Priority Applications (1)

Applications Claiming Priority (8)

Publications (1)

Family

ID=40851992

Family Applications (1)

Country Status (2)

Families Citing this family (21)

Family Cites Families (12)

• 2009
  • 2009-05-05 EP EP09741865A patent/EP2291177A2/de not_active Withdrawn
  • 2009-05-05 WO PCT/EP2009/003211 patent/WO2009135646A2/en active Application Filing

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events