Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2009—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • 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
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/14—Decongestants or antiallergics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents

Definitions

• the present invention relates to a novel composition comprising non-micronized bilastine, a preparation process thereof and the use of the composition in the treatment of histamine-mediated disease processes and allergic reactions.
• Bilastine is the international common name of 4-[2-[4-[1 -(2-ethoxyethyl)-1 h-benzimidazol-2-yl]-1 - piperidinyl)ethyl]-o,a-dimethyl-benzeneacetic acid, whose structure corresponds to the compound of formula (I):
• Bilastine is a selective H1 receptor antagonist, meaning that it is useful for treating histamine-mediated disease processes and allergic reactions, and especially for treating rhinoconjunctivitis and urticaria.
• Bilastine as a product perse, as well as the preparation and use thereof as an H1 receptor antagonist has been described in the European patent number EP0818454B1 .
• the European patent EP1505066B1 describes three crystalline forms of bilastine. Specifically, it describes the crystalline forms 1, 2 and 3 of bilastine, which are characterized by the infrared absorption spectrum and crystallographic parameters in the case of form 1.
• preparation methods of crystalline form 1 from a mixture of crystalline forms 2 and 3 are described. However, crystalline forms 2 and 3 of bilastine are easily converted into crystalline form 1.
• the European patent application EP16829901 A1 describes other crystalline forms of bilastine including Eta crystalline form which is characterized by X-ray diffractogram.
• Bilastine is actually present in the market with the commercial drug name Bilaxten, which is in form of inmediate-release and orodispersible tablets. Particularly, Bilaxten contains crystalline form 1 of bilastine in micronized form, having a particle size distribution D90 about 6.8 pm.
• the different solid forms of a pharmaceutical active ingredient may have different characteristics and offer certain advantages, for example, with respect to stability, bioavailability, ease of the formulation and ease of administration, among others. Since some solid forms are more suitable for one type of formulation, and other forms for other different formulations, the development of novel solid forms makes it possible to improve the characteristics of pharmaceutical formulations that comprise them. Furthermore, depending on therapeutic indications, one or another pharmaceutical formulation may be preferable.
• the particle size of the active ingredient may be also critical for having the appropriate dissolution profile and bioavailabilty.
• a reduction of the particle size of the active ingredient may be advantegeous for increasing its therapeutic efficacy.
• Micronization is the process of reducing the average diameter of a solid material's particles.
• the term micronization refers to the reduction of average particle diameters to the micrometer range.
• micronized active ingredients for the preparation of solid pharmaceutical compositions entails some processability problems.
• the first problems is related to wettability and reagglomeration by electrostatic phenomena.
• a mixture containing micronized active ingredients is compressed into tablets, there is a possibility of agglomeration of the micronized particles together within the tablet due to their high surface area and high surface free energy during compression; and also a modification of the physical and chemical properties of the ingredients including the active ingredients and the excipients or carriers.
• a change of the polymorphisms of the active ingredient may occur during the micronization process or during its compression, resulting in a possible modification of crucial bioavailability properties (such as stability, dissolution and absorption).
• the second problem is that micronization processes employ higher financial resources and therefore their production is more costly, due to an extra process needed to obtain the desired particle size, affecting the yield and generating more problems from a security and process control point of view. Therefore, from what is known in the art it is derived that there is still the need of providing compositions comprising non-micronized bilastine having the apropriate dissolution rate and bioavailability by an easy industrially-scaling up and reproducible process.
• compositions comprising a therapeutically effective amount of non-micronized bilastine in combination with a pyrrolidone-based polymer, allows having comparable pharmacokinetic parameters on bioavailability (e.g. C m ax, AUCo-t, AUCo- ⁇ , AUCO-T.SS, C m ax, ss, and Cmin. ss) as commercially available Bilaxten containing bilastine micronized.
• bioavailability e.g. C m ax, AUCo-t, AUCo- ⁇ , AUCO-T.SS, C m ax, ss, and Cmin. ss
• composition of the invention which comprises the combination of a therapeutically effective amount of bilastine having a particle size distribution D90 from 15 to 90 pm with a pyrrolidone-based polymer allows having the appropriate dissolution rate and availability for being used in therapy and being considered equivalent to Bilaxten which contains micronized bilastine.
• compositions of the present invention containing non-micronized bilastine can be prepared by a costless, simple, industrially scale-up and reproducible method without the processability problems disclosed in the state of the art associated to the use of micronized active ingredients (such as wettability and reagglomeration by electrostatic phenomena).
• a first aspect of the invention relates to a composition
• a composition comprising: a therapeutically effective amount of bilastine having a particle size distribution D90 from 15 to 90 pm measured by laser diffraction; and a pyrrolidone-based polymer; together with one or more pharmaceutically acceptable excipients or carriers.
• the second aspect of the invention relates to a preparation process of the composition of the first aspect of the invention.
• the third aspect of the invention relates to the use of the composition of the first aspect of the invention in the treatment of histamine-mediated disease processes and allergic reactions.
• FIG. 1 pattern of X-ray powder diffraction (intensity (counts) vs. angle 2-theta (°)) of crystalline form Eta of bilastine.
• FIG. 2 pattern of X-ray powder diffraction (intensity (counts) vs. angle 2-theta (°)) of crystalline form 1 of bilastine.
• any ranges given include both the lower and the upper end-points of the range. Ranges given, such as temperatures, times, weights, and the like, should be considered approximate, unless specifically stated.
• the term “about” or “around” as used herein refers to a range of values ⁇ 10% of a specified value. For example, the expression “about 15” includes ⁇ 10% of 15, i.e. from 13.5 to 16.5.
• percentage (%) by weight refers to the percentage of each ingredient of the composition in relation to the total weight of the composition.
• the composition comprises a therapeutically effective amount of bilastine having a particle size distribution D90 from 15 to 90 m.
• a "therapeutically effective amount” of bilastine relates to the amount of bilastine that provides a therapeutic effect after the administration thereof.
• the therapeutically effective amount of bilastine is from about 5 to 50 mg, particularly from about 10 to 40 mg, particularly from about 10 to 30 mg and particularly from about 10 to 20 mg.
• the bilastine in the compositions of the invention is not micronized, and particular, the particle size distribution D90 of bilastine is from about 15 to 90 pm. In an embodiment, the particle size distribution D90 of bilastine is from about 25 to 80 pm, particularly from about 25 to 75 pm.
• particle size refers to the size of the particles measured in pm. The measurement was performed with an appropriate apparatus by conventional analytical techniques such as, for example, laser diffraction. In the present invention the particle size was measured by a Mastersizer 3000 particle size analyzer. Such apparatus uses a technique of laser diffraction to measure the size of particles. It operates by measuring the intensity of light scattered, as a laser beam passes through a dispersed particles sample.
• This data is then analyzed using the general purpose model to calculate the size of the particles that created the scattering pattern, assuming a spherical particle shape.
• microscopic determination utilizing a scanning electron microscope (SEM) may be used. But laser diffraction is preferred.
• particle size distribution or “PSD” have the same meaning and are used interchangeably. They refer to the percentage of the particles within a certain size range.
• D90 refers to the value of particle size distribution where at least 90% of the particles have a size less or equal to the given value.
• D50 refers to the value of particle size distribution where at least 50% of the particles have a size less or equal to the given value.
• a particle size distribution D90 from about 15 to 90 m means that the 90% of the particles of bilastine have a size less or equal to the given value within the range from about 15 to 90 pm.
• composition of the invention also comprises a pyrrolidone-based polymer.
• pyrrolidone-based polymer means that the chemical structure of the monomer of the backbone of the polymer, from which the pyrrolidone-based polymer is made, contains a pyrrolidone.
• a "pyrolidonebased polymer” refers to a polymer that comprises more than 50% by weight of polymerized pyrrolidone units (also named monomer).
• the composition is one wherein the pyrrolidone-based polymer comprises 1 -vinyl-2- pyrrolidone units, which mean that the pyrrolidone-based polymer is a polyvinylpyrrolidone.
• the terms “polyvinylpyrrolidone”, “polyvidone”, “povidone” and “PVP” have the same meaning and they are used interchangeable.
• the polyvinylpyrrolidone is the polymer made from the monomer N- vinylpyrroiidone.
• Polyvinylpyrrolidone is the common name of the compound 1-ethenylpyrrolidin-2-one with the CAS number 9003-39-8 having the following structure:
• the composition is one wherein the pyrrolidone-based polymer is a cross-linked polyvinylpyrrolidone.
• the terms “cross-linked polyvinylpyrrolidone”, “polyvinylpolypyrrolidone”, “polyvinyl polypyrrolidone”, “PVPP”, “crospovidone” and “crospolividone” have the same meaning and they are used interchangeable.
• the crospovidone is a crosslinked polymer made from the monomer N- viny Ipy rrolidone.
• Crospovidone is the common name of the crosslinked polyvinylpyrrolidone (PVP) named crosslinked 1 -ethenylpyrrolidin-2-one with has the CAS number 25249-54-1.
• cross-linked refers to the use of cross-links to promote a difference in the physical properties of the polymers.
• cross-links refers to bonds that link one polymer chain to another or differents parts of the same polymer and these bonds can be covalent or ionic bonds.
• cross-linker or “cross-linking agent” refers to compounds having the ability to cross-link the polymer chains.
• percentage of crosslinking refers to the amount of cross-links present in the polymer.
• the pyrrolidone-based polymer may be any cross-linked polyvinylpyrrolidone with any percentage of crosslinking as measured by ASTM D2765 or by ASTM F2214.
• the composition comprises from 1 to 10 % by weigth of the pyrrolidone-based polymer. In an embodiment, the composition comprises from 1 and 8 % by weigth of the pyrrolidone-based polymer. In an embodiment, the composition comprises from 2 and 8 % by weigth of the pyrrolidone-based polymer. In an embodiment, the composition comprises from 3 and 5 % by weigth of the pyrrolidone-based polymer.
• the composition comprises bilastine having an X-ray diffractogram that comprises characteristic peaks at 8.4; 9.6; 12.2; 13.2; 15.1; and 19.2 ⁇ 0.2 degrees 2 theta measured with an X-ray diffractometer with Cu Ko radiation (1.5418 A) called crystalline Eta form of bilastine.
• the composition comprises Eta crystalline form of bilastine which further contains characteristic peaks at 19.7; 20.3; 21 .5; and 23.4 ⁇ 0.2 degrees 2 theta measured with an X-ray diffractometer with Cu Ko radiation
• the composition comprises Eta crystalline form of bilastine which further also contains peaks at 14.0; 16.8; 17.5; 18.2 and 25.5 ⁇ 0.2 degrees 2 theta measured with an X-ray diffractometer with Cu Ko radiation (1.5418 A).
• the composition comprises Eta crystalline form of bilastine having the X-ray diffractogram shown in FIG. 1.
• the composition comprises Eta crystalline form of bilastine characterized in that it shows the pattern of peaks, expressed in units of 2 theta degrees, 20 (°), in the X-ray powder diffractogram shown in the following table:
• the Eta crystalline form of bilastine is prepared following the processes disclosed in the European patent application EP16829901.
• the process for the preparation of the Eta crystalline form of bilastine comprising transforming the form 1 of bilastine into the Eta crystalline form, which comprises dispersing crystalline form 1 in water during the time needed for the transformation into the Eta crystalline form of bilastine of said dispersion to take place.
• the composition comprises bilastine having an X-ray diffractogram that comprises characteristic peaks at 12.51; 16.35; 17.24, 19.99 and 21.20 ⁇ 0.2 degrees 2 theta measured with an X-ray diffractometer with Cu Ko radiation (1.5418 A) called crystalline Form I of bilastine.
• the composition comprises crystalline Form I of bilastine which further contains characteristic peaks at 10.65; 12.64, 15.58 and 25.00 ⁇ 0.2 degrees 2 theta measured with an X-ray diffractometer with Cu Ko radiation (1.5418 A).
• the composition comprises crystalline Form I of bilastine which further also contains peaks at 14.14, 14.33, 1 .48, 23.40 ⁇ 0.2 degrees 2 theta measured with an X-ray diffractometer with Cu Ko radiation (1.5418 A).
• the composition comprises crystalline Form I of bilastine having the X-ray diffractogram shown in FIG. 2.
• the composition comprises crystalline Form I of bilastine characterized in that it shows the pattern of peaks, expressed in units of 2 theta degrees, 20 (°), in the X-ray powder diffractogram shown in the following table:
• the crystalline form I of bilastine is prepared following the processes disclosed in the European patent EP1505066B1.
• the process for the preparation of the crystalline Form 1 of bilastine comprises dispersing crystalline form 1 in water during the time needed for the transformation into the Eta crystalline form of bilastine of said dispersion to take place.
• composition of the present invention comprise one or more pharmaceutically acceptable excipients or carriers.
• pharmaceutically acceptable excipients or carriers refers to that excipients or carriers suitable for use in the pharmaceutical technology for preparing compositions with medical use. Said excipients or carriers must be pharmaceutically acceptable in the sense that they must be compatible with the rest of the ingredients of the pharmaceutical composition. They must also be suitable for use in contact with human or animal tissues or organs without showing excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications relating to a reasonable risk/benefit ratio.
• compositions of the invention can be formulated in any form that includes any single unit dosage form and any multiple unit dosage forms.
• single unit encompasses one entity such as a single tablet, a single granule, and a single pellet.
• single unit dosage form defines a dosage form which consists only of one unit which contains the effective amount of bilastine.
• multiple unit dosage form defines a dosage from which consists of more than one unit which contains the effective amount of bilastine.
• the multiple unit dosage forms are based on subunits such as granules, pellets or minitablets. They are usually delivered in hard capsules or transformed into tablets. Thus, it is also part of the invention a unit dosage form which comprises the composition of the present invention.
• the unit dosage from which comprises the composition of the present invention is a single unit dosage form. In an embodiment, the unit dosage from which comprises the composition of the present invention is a multiple unit dosage form.
• the appropriate excipients and/or carriers, and their amounts, can readily be determined by those skilled in the art according to the type of formulation being prepared.
• the pharmaceutically acceptable excipients or carriers are selected from the group consisting of selected from the group consisting of diluent, lubricant, binder, glidant, disintegrant and mixtures thereof.
• filler and “diluent” have the same meaning and are used interchangeably. They refer to any pharmaceutically acceptable excipient or carrier (material) that fill out the size of a composition, making it practical to produce and convenient for the consumer to use.
• Materials commonly used as filler include calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethyl cellulose, cellulose, cellulose products such as microcrystalline cellulose and its salts, dextrin derivatives, dextrin, dextrose, fructose, lactitol, lactose, starches or modified starches, magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, mannitol, sorbitol, starch, sucrose, sugar, xylitol, erythritol and mixtures thereof.
• the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprises one or more fillers. In an embodiment, the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprises one or more fillers selected from the group consisting of microcrystalline cellulose or sugar alcohols like mannitol. In an embodiment, the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprise one or more filler in an amount from about 35 to 90% by weight of the composition, particularly from about 50 to 90% by weight of the composition, particularly from about 70 to 90% by weight of the composition.
• lubricant refers to a substance that prevents composition ingredients from clumping together and from sticking to the tablet punches or capsule filling machine and improves flowability of the composition mixture.
• Materials commonly used as a lubricant include sodium oleate, sodium stearate, sodium benzoate, sodium stearate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acid, zinc, polyethylene glycol, talc and mixtures thereof.
• the presence of a lubricant is particularly preferred when the composition is a tablet to improve the tableting process.
• the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprises one or more lubricants selected from the group consisting of magnesium stearate, ascorbic acid and sodium stearyl fumarate. In an embodiment, the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprise one or more lubricants in an amount from 0.1 to 5% by weight of the composition, particularly from 0.5 to 5% by weight of the composition, particularly from about 0.5 to 3% by weight of the composition.
• binder refers to any pharmaceutically acceptable compound having binding properties.
• Materials commonly used as binders include povidone such as polyvinylpyrrolidone K30, ethyl cellulose polymers, methylcellulose polymers, hydroxyethyl cellulose, hydroxypropyl cellulose, L-hydroxypropyl cellulose (low substituted), hydroxypropylmethyl cellulose (HPMC), sodium carboxymethyl cellulose, carboxymethylene, carboxymethylhydroxyethyl cellulose and other cellulose derivatives, starches or modified starches and mixture thereof.
• the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprise one or more binders.
• the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprise one or more binders selected from the group consisting of polyvinylpyrrolidone, ethyl cellulose and hydroxypropylmethyl cellulose.
• the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprise one or more binders in an amount from 0 to 10% by weight of the composition, particularly from 1 to 10% by weight of the composition, particularly from 1 to 7% by weight of the composition, particularly from about 2.5 to 6% by weight of the composition.
• glidant refers to a substance which improves the flow characteristics of powder mixtures in the dry state.
• Materials commonly used as a glidant include magnesium stearate, colloidal silicon dioxide or talc.
• the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprises one or more glidants.
• the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprises one or more glidants selected from the group consisting of colloidal silicon dioxide and talc.
• the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprise one or more glidants in an amount from 0 to 5% by weight of the composition, particularly from 0.1 to 5% by weight of the composition, particularly from 0.2 to 5% by weight of the composition, particularly from about 0.5 to 3% by weight of the composition.
• disintegrant refers to a substance that expand and dissolve when wet causing the tablet to break apart in the body and release the active ingredient for absorption.
• Materials commonly used as disintegrants include cross-linked polymers like, for example, crospovidone and croscarmellose sodium, and modified starches like sodium starch glycolate.
• the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers further comprises at least one or more disintegrants differents from pyrrolidone-based polymer. In an embodiment, the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprises at least one disintegrant different from a pyrrolidone-based polymer selected from the group consisting of croscarmellose and sodium starch glycolate. In an embodiment, the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprise one or more disintegrants different from a pyrrolidone-based polymer in an amount from 0 to 10, particularly from 0 to 5% by weight, particularly from about 0.1 to 5 % by weight of the composition.
• composition of the present invention may contain other ingredients, such as colorants, sweeteners, aromas, and other components known in the state of the art for use in solid formulations.
• sweeteners may be selected from the group consisting of sucralose, acesulfame K, aspartame, neohesperidin and dihydrochalcone.
• Aromas may be selected from the group consisting of grape aroma, strawberry aroma and raspberry aroma.
• the composition of the present invention comprises: a therapeutically effective amount of bilastine having a particle size distribution D90 from 15 to 90 pm; and from 1 to 10 % by weight of a pyrrolidone-based polymer, particularly crospovidone; from 35 to 90 % by weight of a filler; from 0 to 5 % by weight of a glidant; from 0 to 10 % by weight of binder; from 0 to 10 % by weight of a disintegrant different from a pyrrolidone-based polymer; from 0.1 to 5 % by weight of a lubricant; and optionally other pharmaceutically acceptable excipients or carriers; being the sum of the components up to 100% by weight of the composition.
• the composition of the present invention is in a form of tablet.
• the composition of the present invention is form of a tablet and comprises: a therapeutically effective amount of bilastine having a particle size distribution D90 from 15 to 90 pm; and from 1 to 10 % by weight of a pyrrolidone-based polymer, particularly crospovidone; from 35 to 90 % by weight of a filler; from 0 to 5 % by weight of a glidant; from 0 to 10 % by weight of binder; from 0 to 10 % by weight of a disintegrant different from a pyrrolidone-based polymer; from 0.1 to 5 % by weight of a lubricant; and optionally other pharmaceutically acceptable excipients or carriers; being the sum of the components up to 100% by weight of the composition.
• composition of the present invention is in a form of immediate release tablet and an orodispersible tablet (abbreviated as ODT).
• the composition of the present invention is in a form immediate release tablet.
• immediate release composition refers to a composition which releases the active ingredient substantially immediately upon contact with gastric juices and will result in substantially complete dissolution within about 1 hour.
• Immediate release (IR) components can also be referred to as instant release.
• immediate release refers to the composition which delivers the active ingredient over a period of time less than 1 hour.
• the composition of the present invention is in form of an immediate release tablet comprising: a therapeutically effective amount of bilastine having a particle size distribution D90 from 15 to 90 pm; and from 1 to 10 % by weight of a pyrrolidone-based polymer, particularly crospovidone; from 35 to 90 % by weight of a filler; from 0.1 to 5 % by weight of a glidant; from 0.1 to 5 % by weight of a lubricant; and optionally other pharmaceutically acceptable excipients or carriers; being the sum of the components up to 100% by weight of the composition.
• the composition of the present invention is in form of an immediate release tablet comprising: a therapeutically effective amount of bilastine having a particle size distribution D90 from 15 to 90 pm; and from 2 to 8 % by weight of a pyrrolidone-based polymer, particularly crospovidone; from 50 to 90 % by weight of a filler; from 0.2 to 5 % by weight of a glidant; from 0.5 to 5 % by weight of a lubricant; and optionally other pharmaceutically acceptable excipients or carriers; being the sum of the components up to 100% by weight of the composition
• the composition of the present invention is in form of an immediate release tablet comprising: a therapeutically effective amount of bilastine having a particle size distribution D90 from 15 to 90 pm; and from 3 to 5 % by weight of a pyrrolidone-based polymer, particularly crospovidone; from 70 to 90 % by weight of a filler; from 0.5 to 3 % by weight of a glidant; from 0.5 to 3 % by weight of a lubricant; and optionally other pharmaceutically acceptable excipients or carriers; being the sum of the components up to 100% by weight of the composition
• the composition is in form of a orodispersible tablet (ODT).
• ODT orodispersible tablet
• orodispersible tablet refers to non-coated tablets for placing in the mouth which disintegrate quickly before they are swallowed.
• the orodispersible tablet of the present invention is advantageously used in cases where administration without water is necessary, cases of administration to patients who have difficulty in swallowing tablets, or cases of administration to the elderly or to children where there is a fear of blocking the throat if it is unusual tablet form.
• the composition of the present invention is in form of an orodispersible tablet comprising: a therapeutically effective amount of bilastine having a particle size distribution D90 from 15 to 90 pm; and from 1 to 10 % by weight of a pyrrolidone-based polymer, particularly crospovidone; from 35 to 90 % by weight of a filler; from 1 to 10 % by weight of a binder; from 0.1 to 5 % by weight of a lubricant; and optionally other pharmaceutically acceptable excipients or carriers; being the sum of the components up to 100% by weight of the composition.
• the composition of the present invention is in form of an orodispersible tablet comprising: a therapeutically effective amount of bilastine having a particle size distribution D90 from 15 to 90 pm; and from 2 to 8 % by weight of a pyrrolidone-based polymer, particularly crospovidone; from 50 to 90 % by weight of a filler; from 1 to 7 % by weight of a binder; from 0.5 to 5 % by weight of a lubricant; and optionally other pharmaceutically acceptable excipients or carriers; being the sum of the components up to 100% by weight of the composition.
• the composition of the present invention is in form of an orodispersible tablet comprising: a therapeutically effective amount of bilastine having a particle size distribution D90 from 15 to 90 pm; and from 3 to 5 % by weight of a pyrrolidone-based polymer, particularly crospovidone; from 70 to 90 % by weight of a filler; from 2.5 to 6 % by weight of a binder; from 0.5 to 3 % by weight of a lubricant; and optionally other pharmaceutically acceptable excipients or carriers being the sum of the components up to 100% by weight of the composition.
• the process for the preparation of the immediate release tablets of the present invention comprises: a) preparing a pre-mixture comprising bilastine or a pharmaceutically acceptable salt thereof, Crospovidone and a part of the filler (particularly about 20% of the total amount of the filler); f) optionally, sieving the pre-mixture obtained in step a) and each one of the remaining excipients (including the remaining quantity of the filler) separately by a sieve having a sieve diameter from 750 to 1250 pm; b) mixing the pre-mixture obtained in step a) with the remaining excipients including the crospovidone and except for the lubricant; c) adding the lubricant to the mixture obtained in step b); and d) compressing the mixture obtained in step (c) to form tablets; and (e) optionally, coating the tablets obtained in step (d).
• the process for the preparation of the orodispersible tablets of the present invention comprises: a') preparing a first pre-mixture comprising the flavour, the sweetener and a part of the filler (particularly about 10% of the total amount of the filler); a”) preparing a second pre-mixture comprising bilastine or a pharmaceutically acceptable salt thereof, Crospovidone and a part of the remaining part of the filler (particularly about 40-50% of the total amount of the filler); f) optionally, sieving the first and the second pre-mixture obtained in step a') and a”), and each one of the remaining excipients (including the remaining quantity of the filler) separately by a sieve having a sieve diameter from 750 to 1250 pm; b') mixing the first and the second pre-mixture with the remaining excipients including the crospovidone the remaining quantity of the filler and except for the lubricant; c') adding the lubricant to the mixture obtained in step b’
• each one of the steps (a), (a') and (a”) of the process for preparation of the composition of the invention is performed at room temperature. In an embodiment, each one of the steps (a), (a') and (a”) of the process for preparation of the composition of the invention is performed manually at lab step or in a double cone or tumbler mixer at industrial scale.
• each one of the steps (b), (b'), (c) and (c') of the process for preparation of the composition of the invention is performed at room temperature. In an embodiment, each one of the steps (b), (b'), (c) and (c’) of the process for preparation of the composition of the invention is performed in a double cone or tumbler mixer.
• the process comprises step (f) or (f).
• each one of steps (f) or (f) are performed by the use of a sieve of 1000 m for sieving the pre-mixtures, mixture and excipients excpet for the lubricant which is sieve throught a sieve of 250 pm of diameter.
• the compressing steps (d) and (d’) of the process for preparation of the composition of the invention is performed using an eccentric tableting machine for lab-scale process and rotary tableting machine for industrial scale. In an embodiment, the compressing steps (d) and (d’) of the process for preparation of the composition of the invention is performed in order to obtain tablets having a hardness about 55 to 95N.
• composition of the invention allows having the appropriate dissolution rate and availability for being used in therapy and considered equivalent to Bilaxten which include micronized bilastine.
• the composition of the invention is an immediate release tablet which exhibits a dissolution profile according to which at least 85% by weight of the bilastine or a pharmaceutically acceptable salt thereof is dissolved in 15 min, wherein: the dissolution profile is measured using a USP type I apparatus (basket), placing the composition in 900mL of phosphate buffer having pH 6.8, at 37°C and 50 rpm.
• the composition of the invention is an orodispersible tablet which exhibits a dissolution profile according to which at least 85% by weight of the bilastine or a pharmaceutically acceptable salt thereof is dissolved in 15 min, wherein: the dissolution profile is measured using a USP type I apparatus (basket), placing the composition in 900mL of phosphate buffer having pH 6.8, at 37°C and 50 rpm.
• a skilled person must differencials between disintegration (according to the Ph. Eur. 2.9.1. is 3 minutes) and dissolution profile.
• the composition of the invention exhibits a maximum plasma concentration (Cmax) and an area under the time/plasma concentration curve from time 0 to 36 hours (AUG (0-36)) from 80 to 125% refering to the Bilaxten reference product, in a confidence interval of 90% .
• Cmax refers to the maximum concentration of bilastine in the blood following a single-dose administration of the composition.
• AUG refers to the area under the time/plasma concentration curve after an oral single-dose administration of the composition of the present invention.
• AUCO-infinity denotes the area under the plasma concentration versus time curve from time 0 to infinity
• AUCo-t denotes the area under the plasma concentration versus time curve from time 0 to time t.
• composition of the invention in treatment of histamine- mediated disease processes and allergic reactions.
• This aspect could be also formulated as the use of a composition of the invention as defined above for the preparation of a medicament for the prophylaxis and/or treatment of the histamine-mediated disease processes and allergic reactions. It also relates to a method for the prophylaxis and/or treatment of a mammal suffering or is susceptible to suffer from a histamine-mediated disease processes and allergic reactions, wherein the method comprises administering to said mammal an effective amount of the composition of the present invention.
• the histamine-mediated disease processes and allergic reactions are selected from the group consisting of the symptomatic treatment of seasonal allergic rhinoconjunctivitis, the symptomatic treatment of perennial allergic rhinoconjunctivitis and the treatment of urticaria. All the embodiments disclosed above for the composition of the first aspect of the invention also apply for its use.
• the X-ray powder diffractogram has been obtained by using an X-ray diffractometer with Cu Ko radiation (1.5418 A) in a PANalytical X'Pert PRO MPD powder diffractometer with a radius of 240 millimeters, in a convergent beam configuration with a focusing mirror and transmission geometry with flat samples inserted between low absorbent films.
• the samples in powder form were inserted between polyester films with a thickness of 3.6microns.
• the diffractograms obtained show the pattern of X-ray powder diffraction (intensity (counts) vs. angle 2-theta (°)).
• Particle Type Non-spherical
• Feed hoper 0.5L
• Tablets were dispersed in water (approx. 1 :5 w/v ratio) and shaken manually for 2 minutes to dissolve the soluble contents in water. The mixture was centrifuged for 1 min at 5000 rpm. The supernatant containing soluble ingredients was discarded. Sample from the sediment was dried, mounted on glass slide, and observed under microscope for particle size analysis. The API and tablet samples were subjected to similar sample preparation and analyzed.
• Particle size of API in the tablets was determined with a pre-calibrated stage micrometer using optical/polarized hot stage microscope (Leica DMLP, Leica, Germany) equipped with a controlled heating and cooling stage (LTS350, Linkam) and an imaging system (VTO 232, JVC - Digital camera and Linksys 32 imaging software, Linkam, England). A small amount of powder was mounted on glass slide and observed under the microscope in dry state. Sample was observed at 500X magnification with a least count of 3.5 micron.
• API particles were differentiated from other ingredients present in tablets through microscopy. This was done based on difference in the melting point of the drug and excipients. API particles could be differentiated by hot-stage microscopy.
• Particle size of API was recorded by measuring the length along the longest axis of individual particles. PSD of separated individual API particles was measured and aggregated API particles were not considered for measurement. Particle size of about 300 particles was determined and data was grouped into class intervals.
• compositions of the invention are 1.1. Compositions of the invention
• Comparative Example 1 defined in Table 2 was prepared following the general process 1 as defined below using the ingredients and the amounts specified in the table, but further comprises a previous step which comprises micronizing the bilastine crystaline form I until having the D90 about 6.8 pm.
• the micronization process of the bilastine was also disclosed herein below.
• the process comprises performing the following 5 consecutive steps: 1) Pre-blending, 2) Screening, 3) Blending, 4) Lubrication and 5) Tableting.
• Pre-blending and screening steps were performed manually at laboratory scale; blending and lubrication steps were performed in a double cone mixer; and tableting step was performed in an eccentric tableting machine.
• step 2 Screening Step.
• the pre-mixture obtained in step 1 and the remaining excipients (including the remaining quantity of the filler) except for the lubricant were screened by a 1000 pm sieve.
• step 3 Blending Step.
• the pre-mixture obtained in step 2) and the excipients (including the remaining quantity of the filler) except for the lubricant were added to a 1L double cone blender and the resulting mixture was mixed during 20 minutes at 18 rpm.
• step 5 Tableting Step.
• the lubricated mixture obtained in step 4) was tableted in an eccentric tableting machine to obtain biconvex and unscored roundimmediate release tablets.
• Example 2 The orodispersible composition of the invention (Example 2) defined in Table 1 was prepared following the general process 2 as defined below using the ingredients and the amounts specified in the table.
• Comparative Example 2 the comparative orodispersible tablet (Comparative Example 2) defined in Table 2 was prepared following the general process 2 as defined below using the ingredients and the amounts specified in the table, but further comprises a previous step which comprises micronizing the bilastine crystal ine form I until having the the D90 about 6.8 pm.
• the micronization process of the bilastine was also disclosed herein below.
• the process comprises perfomring the following 5 consecutive steps: 1) Pre-blending, 2) Screening, 3) Blending, 4) Lubrication and 5) Tableting.
• Pre-blending and screening steps were performed manually at laboratory scale; blending and lubrication steps were performed in a double cone mixer; and tableting step was performed in an eccentric tableting machine.
• Pre-blending Step Two pre-mixtures were performed. The first pre-mixture was prepared by manually premixing the flavour, the sweetener and a part of the filler (10.6% of the total quantity of the filler); and the second pre-mixture was prepared by manually premixing Bilastine (10mg), Crospovidone and a second part of the filler (44.8% of the total quantity of the filler).
• step 3 Blending Step.
• the two pre-mixtures obtained in step 2) and the screened excipients (including the remaining quantity of the filler) except for the lubricant were added to a 1L drum blender and mixed during 20 minutes at 23-24 rpm.
• step 5 Tableting Step.
• the lubricated mixture obtained in step 5) was tableted in an eccentric tableting machine to obtain biconvex and unscored round orodispersible tablets.
• Table 4 shows the percentage of bilastine released from the inmediate release tablets of Examples 1 and 3, and from the commercially available inmediate release tablet of comparative Example 1, expressed as % by weight of bilastine dissolved in the time given.
• Table 5 shows the percentage of bilastine released from the orodispersible tablet of Example 2, and from the commercially available orodispersible tablet of comparative Example 2, expressed as % by weight of bilastine dissolved in the time given.
• compositions of the present invention comprising a therapeutically effective amount of non-micronized bilastine in combination with a pyrrolidone-based polymer has comparable target dissolution profile as commercially available Bilaxten containing micronized bilastine.
• target dissolution profile of the inmediate release bilastine composition comprises at least 85% dissolution at 15 minutes.
• target dissolution profile of the orodispersible tablet bilastine composition comprises at least 85% dissolution at 15 minutes.
• compositions of the present invention allows controlling the release of the non-micronized bilastine having the appropriate dissolution rate and availability for being used in therapy and considered equivalent to commercially available Bilaxten which include micronized bilastine. Furthermore, the use of the combination of non-micronized bilastine in combination with a pyrrolidone-based polymer avoids the disadvantages of processability of micronized active ingredients.

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