CA3200779A1 - A non-micronized bilastine composition - Google Patents
A non-micronized bilastine compositionInfo
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- CA3200779A1 CA3200779A1 CA3200779A CA3200779A CA3200779A1 CA 3200779 A1 CA3200779 A1 CA 3200779A1 CA 3200779 A CA3200779 A CA 3200779A CA 3200779 A CA3200779 A CA 3200779A CA 3200779 A1 CA3200779 A1 CA 3200779A1
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- composition
- weight
- bilastine
- pyrrolidone
- based polymer
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- 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
Abstract
The present invention relates to a composition comprising a therapeutically effective amount of bilastine having a particle size distribution D90 from 15 to 90 µm measured by laser diffraction; and a pyrrolidone- based polymer; together with one or more pharmaceutically acceptable excipients or carriers; and a process for its preparation. It also relates to the use of the composition in the treatment of histamine-mediated disease processes and allergic reactions.
Description
A non-micronized bilastine composition This application claims the benefit of European Patent Application EP20383149.0 filed december 23rd, 2020.
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.
Background Art Bilastine is the international common name of 4-[244-[1-(2-ethoxyethylph-benzimidazol-2-y11-1-piperidinypethy1]-a,a-dimethyl-benzeneacetic acid, whose structure corresponds to the compound of formula (I):
COOH
\N
CH.,C,I-20CH2CH;
(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 per se, as well as the preparation and use thereof as an H1 receptor antagonist has been described in the European patent number EP0818454B1. Subsequently, 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. Furthermore, in the patent EP150506661, 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. Finally, the European patent application EP16829901A1 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.
As it is known, the different solid forms of a pharmaceutical active ingredient may have different
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.
Background Art Bilastine is the international common name of 4-[244-[1-(2-ethoxyethylph-benzimidazol-2-y11-1-piperidinypethy1]-a,a-dimethyl-benzeneacetic acid, whose structure corresponds to the compound of formula (I):
COOH
\N
CH.,C,I-20CH2CH;
(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 per se, as well as the preparation and use thereof as an H1 receptor antagonist has been described in the European patent number EP0818454B1. Subsequently, 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. Furthermore, in the patent EP150506661, 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. Finally, the European patent application EP16829901A1 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.
As it is known, the different solid forms of a pharmaceutical active ingredient may have different
2 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.
However, the particle size of the active ingredient may be also critical for having the appropriate dissolution profile and bioavailabilty. In fact, 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. For the purpose of the invention, the term micronization refers to the reduction of average particle diameters to the micrometer range.
Traditional techniques for micronizing based on friction have been widely disclosed in the state of the art.
Such traditional methods include milling, bashing and grinding. Methods like crushing and cutting are also used for reducing particle diameter, but produce more rough particles compared to the two previous techniques and are therefore used as the early stages of the micronization process.
Subsequently, modern methods using supercritical fluids in the micronization process has been disclosed.
These methods induce a state of supersaturation, which leads to precipitation of individual particles. The most widely applied techniques of this category include the RESS process (Rapid Expansion of Supercritical Solutions), the SAS method (Supercritical Anti-Solvent) and the PGSS method (Particles from Gas Saturated Solutions). These modern techniques allow greater tuneability of the process.
In fact, parameters like relative pressure and temperature, solute concentration, and antisolvent to solvent ratio can be varied to be adjusted to the producer's needs. The supercritical fluid methods result in finer control over particle diameters, distribution of particle size and consistency of morphology. However, the properties of the micronized active ingredient such as particle size, size distribution, shape, surface properties, and agglomeration behaviour and powder flow are affected by the type of micronization technique used.
Furthermore, the use of 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 In particular, when 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. In particular, 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). And, 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.
However, the particle size of the active ingredient may be also critical for having the appropriate dissolution profile and bioavailabilty. In fact, 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. For the purpose of the invention, the term micronization refers to the reduction of average particle diameters to the micrometer range.
Traditional techniques for micronizing based on friction have been widely disclosed in the state of the art.
Such traditional methods include milling, bashing and grinding. Methods like crushing and cutting are also used for reducing particle diameter, but produce more rough particles compared to the two previous techniques and are therefore used as the early stages of the micronization process.
Subsequently, modern methods using supercritical fluids in the micronization process has been disclosed.
These methods induce a state of supersaturation, which leads to precipitation of individual particles. The most widely applied techniques of this category include the RESS process (Rapid Expansion of Supercritical Solutions), the SAS method (Supercritical Anti-Solvent) and the PGSS method (Particles from Gas Saturated Solutions). These modern techniques allow greater tuneability of the process.
In fact, parameters like relative pressure and temperature, solute concentration, and antisolvent to solvent ratio can be varied to be adjusted to the producer's needs. The supercritical fluid methods result in finer control over particle diameters, distribution of particle size and consistency of morphology. However, the properties of the micronized active ingredient such as particle size, size distribution, shape, surface properties, and agglomeration behaviour and powder flow are affected by the type of micronization technique used.
Furthermore, the use of 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 In particular, when 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. In particular, 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). And, 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.
3 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.
Summary of Invention The inventors have surprinsingly found that a composition 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., AUCo_t, AUCo¨, AUCo_ T,SS, - C max, ss, and Cmin, ss) as commercially available Bilaxten containing bilastine micronized.
In particular, as it is demonstrated in the Experimental data, the composition of the invention which comprises the combination of a therapeutically effective amount of bilastine having a particle size distribution 090 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.
Furthermore, the 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).
Thus, a first aspect of the invention relates to 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.
Brief Description of Drawings 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.
Summary of Invention The inventors have surprinsingly found that a composition 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., AUCo_t, AUCo¨, AUCo_ T,SS, - C max, ss, and Cmin, ss) as commercially available Bilaxten containing bilastine micronized.
In particular, as it is demonstrated in the Experimental data, the composition of the invention which comprises the combination of a therapeutically effective amount of bilastine having a particle size distribution 090 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.
Furthermore, the 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).
Thus, a first aspect of the invention relates to 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.
Brief Description of Drawings 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.
4 Detailed description of the invention All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.
For the purposes of the present invention, 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.
The terms "percentage (%) by weight", "weight/weight %" and "w/w%" have the same meaning and are used interchangeable. They refer to the percentage of each ingredient of the composition in relation to the total weight of the composition.
As it is mentioned above, the composition comprises a therapeutically effective amount of bilastine having a particle size distribution D90 from 15 to 90 pm. A "therapeutically effective amount" of bilastine relates to the amount of bilastine that provides a therapeutic effect after the administration thereof. In an embodiment, 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. The term "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.
Optionally, also microscopic determination utilizing a scanning electron microscope (SEM) may be used. But laser diffraction is preferred.
The terms "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. The term "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.
Further, the term "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. Thus, for the purpose of the invention, a particle size distribution D90 from about 15 to 90 pm 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.
For the purposes of the present invention, 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.
The terms "percentage (%) by weight", "weight/weight %" and "w/w%" have the same meaning and are used interchangeable. They refer to the percentage of each ingredient of the composition in relation to the total weight of the composition.
As it is mentioned above, the composition comprises a therapeutically effective amount of bilastine having a particle size distribution D90 from 15 to 90 pm. A "therapeutically effective amount" of bilastine relates to the amount of bilastine that provides a therapeutic effect after the administration thereof. In an embodiment, 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. The term "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.
Optionally, also microscopic determination utilizing a scanning electron microscope (SEM) may be used. But laser diffraction is preferred.
The terms "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. The term "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.
Further, the term "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. Thus, for the purpose of the invention, a particle size distribution D90 from about 15 to 90 pm 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.
5 The composition of the invention also comprises a pyrrolidone-based polymer.
The term "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. For the purpose of the invention, a "pyrolidone-based polymer' refers to a polymer that comprises more than 50% by weight of polymerized pyrrolidone units (also named monomer).
In an embodiment, 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. In particular, the polyvinylpyrrolidone is the polymer made from the monomer N-vinylpyrrolidone. Polyvinylpyrrolidone is the common name of the compound 1-ethenylpyrrolidin-2-one with the CAS number 9003-39-8 having the following structure:
4..µN 07L-- n In an embodiment, 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. In particular, the crospovidone is a crosslinked polymer made from the monomer N-vinylpyrrolidone. Crospovidone is the common name of the crosslinked polyvinylpyrrolidone (PVP) named crosslinked 1-ethenylpyrrolidin-2-one with has the CAS number 25249-54-1.
The terms "cross-linked" or "cross-linking" refers to the use of cross-links to promote a difference in the physical properties of the polymers. The term "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. The term "cross-linker' or "cross-linking agent" refers to compounds having the ability to cross-link the polymer chains.
In the present invention, the term "percentage of crosslinking" refers to the amount of cross-links present in the polymer. In an embodiment, 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 term "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. For the purpose of the invention, a "pyrolidone-based polymer' refers to a polymer that comprises more than 50% by weight of polymerized pyrrolidone units (also named monomer).
In an embodiment, 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. In particular, the polyvinylpyrrolidone is the polymer made from the monomer N-vinylpyrrolidone. Polyvinylpyrrolidone is the common name of the compound 1-ethenylpyrrolidin-2-one with the CAS number 9003-39-8 having the following structure:
4..µN 07L-- n In an embodiment, 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. In particular, the crospovidone is a crosslinked polymer made from the monomer N-vinylpyrrolidone. Crospovidone is the common name of the crosslinked polyvinylpyrrolidone (PVP) named crosslinked 1-ethenylpyrrolidin-2-one with has the CAS number 25249-54-1.
The terms "cross-linked" or "cross-linking" refers to the use of cross-links to promote a difference in the physical properties of the polymers. The term "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. The term "cross-linker' or "cross-linking agent" refers to compounds having the ability to cross-link the polymer chains.
In the present invention, the term "percentage of crosslinking" refers to the amount of cross-links present in the polymer. In an embodiment, the pyrrolidone-based polymer may be any cross-linked polyvinylpyrrolidone with any percentage of crosslinking as measured by ASTM D2765 or by ASTM
F2214.
6 In an embodiment, the composition comprises from Ito 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.
In an embodiment, 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 Ka radiation (1.5418 A) called crystalline Eta form of bilastine. In an embodiment, 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 Ka radiation (1.5418 A). In an embodiment, 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 Ka radiation (1.5418 A). In an embodiment, the composition comprises Eta crystalline form of bilastine having the X-ray diffractogram shown in FIG. 1.
In an embodiment, 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 (0), in the X-ray powder diffractogram shown in the following table:
Intensity ('') d(A) (')/0) 8.37 10.56 41.0 9.55 9.26 64.9 9.74 9.08 7.8 11.40 7.76 4.3 12.18 7.27 89.7 13.19 6.71 42.1 13.95 6.35 11.2 15.07 5.88 52.7 16.79 5.28 16.0 17.49 5.07 21.0 17.77 4.99 5.8 18.18 4.88 22.6 19.18 4.63 100 19.67 4.51 26.7 20.16 4.40 34.0 20.34 4.37 83.9 20.83 4.26 7.4
In an embodiment, 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 Ka radiation (1.5418 A) called crystalline Eta form of bilastine. In an embodiment, 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 Ka radiation (1.5418 A). In an embodiment, 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 Ka radiation (1.5418 A). In an embodiment, the composition comprises Eta crystalline form of bilastine having the X-ray diffractogram shown in FIG. 1.
In an embodiment, 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 (0), in the X-ray powder diffractogram shown in the following table:
Intensity ('') d(A) (')/0) 8.37 10.56 41.0 9.55 9.26 64.9 9.74 9.08 7.8 11.40 7.76 4.3 12.18 7.27 89.7 13.19 6.71 42.1 13.95 6.35 11.2 15.07 5.88 52.7 16.79 5.28 16.0 17.49 5.07 21.0 17.77 4.99 5.8 18.18 4.88 22.6 19.18 4.63 100 19.67 4.51 26.7 20.16 4.40 34.0 20.34 4.37 83.9 20.83 4.26 7.4
7 21.52 4.13 25.3 23.35 3.81 66.8 24.26 3.67 4.9 24.51 3.63 7.0 24.73 3.60 6.4 25.46 3.50 11.1 The Eta crystalline form of bilastine is prepared following the processes disclosed in the European patent application EP16829901. In an embodiment, 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.
In an embodiment, the composition comprises bilastine haying 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 Ka radiation (1.5418 A) called crystalline Form I of bilastine. In an embodiment, 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 Ka radiation (1.5418 A). In an embodiment, the composition comprises crystalline Form I of bilastine which further also contains peaks at 14.14, 14.33, 17.48, 23.40 0.2 degrees 2 theta measured with an X-ray diffractometer with Cu Ka radiation (1.5418 A). In an embodiment, the composition comprises crystalline Form I of bilastine haying the X-ray diffractogram shown in FIG. 2.
In an embodiment, 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:
20 (1) d(A) l(rolito;nsity 3.78 23.37347 1.85 10.65 8.30482 16.41 11.36 7.79036 5.29 12.51 7.07699 15.09 12.65 6.99799 15.29 12.88 6.87216 4.49 14.14 6.26446 14.38 14.33 6.179 14.24 14.57 6.08096 0.59 14.76 6.00242 5.31 15.16 5.84521 2.73 15.58 5.68938 9.96 16.35 5.42088 19.65
In an embodiment, the composition comprises bilastine haying 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 Ka radiation (1.5418 A) called crystalline Form I of bilastine. In an embodiment, 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 Ka radiation (1.5418 A). In an embodiment, the composition comprises crystalline Form I of bilastine which further also contains peaks at 14.14, 14.33, 17.48, 23.40 0.2 degrees 2 theta measured with an X-ray diffractometer with Cu Ka radiation (1.5418 A). In an embodiment, the composition comprises crystalline Form I of bilastine haying the X-ray diffractogram shown in FIG. 2.
In an embodiment, 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:
20 (1) d(A) l(rolito;nsity 3.78 23.37347 1.85 10.65 8.30482 16.41 11.36 7.79036 5.29 12.51 7.07699 15.09 12.65 6.99799 15.29 12.88 6.87216 4.49 14.14 6.26446 14.38 14.33 6.179 14.24 14.57 6.08096 0.59 14.76 6.00242 5.31 15.16 5.84521 2.73 15.58 5.68938 9.96 16.35 5.42088 19.65
8 16.96 5.22891 1.05 17.24 5.14283 100 17.48 5.07348 16.36 18.17 4.88233 1.24 18.52 4.79157 9.71 18.98 4.67474 3.88 19.18 4.62874 2.55 19.81 4.48233 13.59 19.99 4.44212 20.99 20.22 4.39174 2.71 20.35 4.36392 3.8 21.20 4.19182 28.2 21.46 4.14044 8.14 21.64 4.10693 1.37 22.26 3.99388 2.88 22.41 3.96769 2.08 22.68 3.92157 4.79 22,84 3.89325 1.24 23.04 3.85991 2.33 23.40 3.80223 8.78 23.91 3.7216 0.88 24.33 3.65914 1.33 24.50 3.63347 1.47 24.68 3.60783 4.18 25.00 3.56165 10.22 25.42 3.5007 2.54 25.54 3.4932 1.49 25.92 3.43473 7.2 26.36 3.37867 0.38 26.71 3.33468 1.24 27.43 3.24939 2.1 28.31 3.15014 0.51 28.54 3.12465 0.8 29.22 3.05362 7.33 29.91 2.98479 2.52 30.62 2.91733 0.4 31.00 2.88258 2.58 31.67 2.82279 0.59 31.89 2.80414 1.53 32.05 2.79766 0.99 32.25 2.77315 0.34 33.04 2.70937 1.78 33.27 2.69048 0.85 33.53 2.67076 0.84 33.76 2.65288 0.69 34.10 2.62707 1.22 34.48 2.59902 4.15
9 The crystalline form I of bilastine is prepared following the processes disclosed in the European patent EP1505066B1. In an embodiment, 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.
The composition of the present invention comprise one or more pharmaceutically acceptable excipients or carriers. The term "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.
The compositions of the invention can be formulated in any form that includes any single unit dosage form and any multiple unit dosage forms. The term "single unit" encompasses one entity such as a single tablet, a single granule, and a single pellet. The term "single unit dosage form"
defines a dosage form which consists only of one unit which contains the effective amount of bilastine. The term "multiple unit dosage form" defines a dosage from which consists of more than one unit which contains the effective amount of bilastine. Usually, 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. In an embodiment, 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.
In an embodiment, 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.
The terms "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. In an embodiment, 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 5 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.
The term "lubricant" refers to a substance that prevents composition ingredients from clumping together and
The composition of the present invention comprise one or more pharmaceutically acceptable excipients or carriers. The term "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.
The compositions of the invention can be formulated in any form that includes any single unit dosage form and any multiple unit dosage forms. The term "single unit" encompasses one entity such as a single tablet, a single granule, and a single pellet. The term "single unit dosage form"
defines a dosage form which consists only of one unit which contains the effective amount of bilastine. The term "multiple unit dosage form" defines a dosage from which consists of more than one unit which contains the effective amount of bilastine. Usually, 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. In an embodiment, 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.
In an embodiment, 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.
The terms "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. In an embodiment, 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 5 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.
The term "lubricant" refers to a substance that prevents composition ingredients from clumping together and
10 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. In an embodiment, 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.
The term "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. In an embodiment, the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprise one or more binders. In an embodiment, 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.
In an embodiment, 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.
The term "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. In an embodiment, the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprises one or more glidants. In an embodiment, the composition of the invention is one wherein
by weight of the composition, particularly from about 0.5 to 3% by weight of the composition.
The term "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. In an embodiment, the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprise one or more binders. In an embodiment, 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.
In an embodiment, 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.
The term "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. In an embodiment, the composition of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprises one or more glidants. In an embodiment, the composition of the invention is one wherein
11 the pharmaceutically acceptable excipients or carriers comprises one or more glidants selected from the group consisting of colloidal silicon dioxide and talc. In an embodiment, 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.
The term "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.
In an embodiment, 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.
Additionally, the 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. For example, 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.
In an embodiment, the composition of the present invention comprises:
a therapeutically effective amount of bilastine having a particle size distribution 090 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.
In an embodiment, the composition of the present invention is in a form of tablet.
The term "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.
In an embodiment, 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.
Additionally, the 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. For example, 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.
In an embodiment, the composition of the present invention comprises:
a therapeutically effective amount of bilastine having a particle size distribution 090 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.
In an embodiment, the composition of the present invention is in a form of tablet.
12 In an embodiment, 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.
In an embodiment the composition of the present invention is in a form of immediate release tablet and an orodispersible tablet (abbreviated as ODT).
In an embodiment, the composition of the present invention is in a form immediate release tablet. For the purpose of the invention, the term "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. When used in association with the dissolution profiles discussed herein, the term "immediate release" refers to the composition which delivers the active ingredient over a period of time less than 1 hour.
In an embodiment, 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 090 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.
In an embodiment, 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
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.
In an embodiment the composition of the present invention is in a form of immediate release tablet and an orodispersible tablet (abbreviated as ODT).
In an embodiment, the composition of the present invention is in a form immediate release tablet. For the purpose of the invention, the term "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. When used in association with the dissolution profiles discussed herein, the term "immediate release" refers to the composition which delivers the active ingredient over a period of time less than 1 hour.
In an embodiment, 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 090 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.
In an embodiment, 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
13 optionally other pharmaceutically acceptable excipients or carriers;
being the sum of the components up to 100% by weight of the composition In an embodiment, 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 090 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 In an embodiment, the composition is in form of a orodispersible tablet (ODT).
The terms "orodispersible"
tablet, "quick disintegrating" tablet, "mouth dissolving" tablet, "porous"
tablets and the abbreviature "ODT"
have the same meaning and they can be used interchangeable. In particular, the term "orodispersible" tablet refers to non-coated tablets for placing in the mouth which disintegrate quickly before they are swallowed. In particular, it is established that the time under which they must disintegrate in the disintegration test for tablets and capsules, according to the Ph. Eur. 2.9.1. 1s3 minutes (cf. European Pharmacopoeia (Ph.Eur.) 5th edition, Supplement 5.2, published in June 2004). The orodispersible tablet of the present inventionis 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.
In an embodiment, 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.
In an embodiment, 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
being the sum of the components up to 100% by weight of the composition In an embodiment, 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 090 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 In an embodiment, the composition is in form of a orodispersible tablet (ODT).
The terms "orodispersible"
tablet, "quick disintegrating" tablet, "mouth dissolving" tablet, "porous"
tablets and the abbreviature "ODT"
have the same meaning and they can be used interchangeable. In particular, the term "orodispersible" tablet refers to non-coated tablets for placing in the mouth which disintegrate quickly before they are swallowed. In particular, it is established that the time under which they must disintegrate in the disintegration test for tablets and capsules, according to the Ph. Eur. 2.9.1. 1s3 minutes (cf. European Pharmacopoeia (Ph.Eur.) 5th edition, Supplement 5.2, published in June 2004). The orodispersible tablet of the present inventionis 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.
In an embodiment, 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.
In an embodiment, 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
14 optionally other pharmaceutically acceptable excipients or carriers;
being the sum of the components up to 100% by weight of the composition.
In an embodiment, 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.
It is also part of the invention, a process for the preparation of the compositions in form of tablets of the invention. In an embodiemnt, 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).
In an embodiment, 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'); and d') compressing the mixture obtained in step (c') to form tablets; and (e') optionally, coating the tablets obtained in step (d').
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 at room temperature. In an embodiment, each one of the steps (a), (a') and (a") of 5 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.
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 at room temperature. In an embodiment, each one of the steps (b), (b'), (c) and 10 (c') of the process for preparation of the composition of the invention is performed in a double cone or tumbler mixer.
In an embodiment, the process comprises step (f) or (f'). In an embodiment, each one of steps (f) or (V) are performed by the use of a sieve of 1000 pin for sieving the pre-mixtures, mixture and excipients excpet for the lubricant which is sieve throught a sieve of 250 pm of diameter.
In an embodiment, 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.
As it is mentioned above, the 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.
In an embodiment, 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.
In an embodiment, 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 differenciate between disintegration (according to the Ph. Eur. 2.9.1. is 3 minutes) and dissolution profile.
In an embodiment, 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 (AUC (0-36)) from 80 to 125%
refering to the Bilaxten reference product, in a confidence interval of 90% .
The term "Cmax" refers to the maximum concentration of bilastine in the blood following a single-dose administration of the composition.
The term "AUC" 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 and AUCo-t denotes the area under the plasma concentration versus time curve from time 0 to time t.
Other aspect of the invention relates to the use of the 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. In an embodiment, 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.
Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps.
Furthermore, the word "comprise"
encompasses the case of "consisting of". Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Reference signs related to drawings and placed in parentheses in a claim, are solely for attempting to increase the intelligibility of the claim, and shall not be construed as limiting the scope of the claim. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.
Examples Methods:
- X-ray Powder diffractogram (XRPD) method The X-ray powder diffractogram has been obtained by using an X-ray diffractometer with Cu Ka 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 experimental conditions were as follows:
Cu Ka radiation (a= 1.5418 A).
Working power: 45 kV ¨ 40 mA.
Incident beam slits that define a beam height of 0.4 millimeters Incident and diffracted beam slits of 0.02 radian SoIler Detector PIXcel: active length = 3.347 2theta/theta scans of 2 to 40 2theta with a step size of 0.026 2theta and a measurement time of 76 seconds per step.
The diffractograms obtained show the pattern of X-ray powder diffraction (intensity (counts) vs. angle 2-theta ( )).
- Determination of the particle size distribution (PSD) of Bilastine by laser diffraction 2mg of sample were taken to measure the PSD of every API sample Instrument conditions Instrument: Malvern Laser Diffraction Masterizer 3000 Accesory: Dry Smapler Aero S
Measuring range: 0.001-3500pm Sensitivity: Normal Particle Type: Non-spherical Material Refraction Index: 1.59 Material Absorption Index: 0.01 Dispersant: Air Dispersant Air Pressure: 2 bar Background measuring time: 5 seconds Sample meauring time: 5 seconds Number of measurements: 3 Obscuration Range: 1-5%
Feed rate: 30%
Hoper opening: 2.5 Micronization method for Bilastine Form I
Wet molturation of sample Instrument: Pilot micronizer with Jetmill technology lnox 316 Feed hoper: 0.5L
Mirror polish: Ra < 0.2 pm Dosage speed: 30g/h Chamber pressure: 2.0 bar PSD analysis of the commercial tablets Bilaxten by SEM
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.
Identification of API
For particle size analysis, 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.
1. Compositions The values of the D90 of the crystalline form of Bilastine used for the preparation of the compositions of Examples 1-3 of the present invention and of the comparative Examples using the method as defined above were disclosed below in each one of the Tables 1 and 2.
1.1. Compositions of the invention The qualitative and quantitative composition of the immediate release tablets (IR-tablets of Examples 1 and 3) and orodispersible tablets (ODT of Example 2) of the present invention are shown in Table 1, wherein the amount of each of the components are expressed in weight percent:
Table 1 Examples (% w/w) Function Ingredient/D90 (pm) Example 1 Example 2 Example 3 (IR-Tablet) (ODT) (IR-Tablet) Bilastine crystaline form I
(090: 57 pm) Active ingredient Bilastine crystaline form Eta 6.7 16 (D90: 29.9 pm) Disintegrant-Crospovidone pyrrolidone-based 5 3.0 (type A) polymer Ethylcellulose binder 4.0 (ethocel std 10 FP) microcrystalline cellulose 77.6 77.6 Filler (Avicel PH-102) Mannitol CD 85.1 Glidant colloidal silicon dioxide 0.5 0.5 Lubricant Magnesium stearate 0.9 1.0 0.9 Sweetener Sucralose granular 0.1 aroma Red grapes aroma 0.1 Total weight 100 100 1.2. Comparative compositions The qualitative and quantitative comparative composition of the commercially available immediate realease tablet of micronized bilastine (Bilaxten) (Comparative Example 1) and the qualitative comparative composition of the commercially available orodispersible tablet of micronized bilastine (Bilaxten) (Comparative Example 2) falling outside the scope of the present invention are shown in Table 2, wherein the amount of each of the components are expressed in weight percent:
Table 2 Examples ( /0 w/w) Function Ingredient/D90 (pm) IR-Comparative Example 1 Bilastine crystaline form I
Active ingredient/ 16 (D90: 6.8 pm) Disintegrant Sodium starch glycolate 5 Filler Microcrystalline cellulose 77.6 Glidant Colloidal silicon dioxide 0.5 Lubricant Magnesium stearate 0.9 Total weight 100 Table2-cont.
ODT-Comparative Example 2 Function (% w/w) Bilastine crystaline form I
Active ingredient/
(D90: 6.8 pm) Disintegrant Croscarmellose sodium Filler Mannitol Lubricant Sodium stearyl fumarate Sweetener Sucralose flavour Red grade flavour 1.3. Preparation process 1.3.1. Immediate release compositions The immediate release compositions of the invention (Examples 1 and 3) defined in Table 1 were prepared following the general process 1 as defined below using the ingredients and the amounts specified in the 5 table.
Meanwhile, the comparative immediate realease tablet (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
10 until having the D90 about 6.8 pm. The micronization process of the bilastine was also disclosed herein below.
General process 1 The process comprises performing the following 5 consecutive steps: 1) Pre-blending, 2) Screening, 3)
being the sum of the components up to 100% by weight of the composition.
In an embodiment, 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.
It is also part of the invention, a process for the preparation of the compositions in form of tablets of the invention. In an embodiemnt, 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).
In an embodiment, 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'); and d') compressing the mixture obtained in step (c') to form tablets; and (e') optionally, coating the tablets obtained in step (d').
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 at room temperature. In an embodiment, each one of the steps (a), (a') and (a") of 5 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.
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 at room temperature. In an embodiment, each one of the steps (b), (b'), (c) and 10 (c') of the process for preparation of the composition of the invention is performed in a double cone or tumbler mixer.
In an embodiment, the process comprises step (f) or (f'). In an embodiment, each one of steps (f) or (V) are performed by the use of a sieve of 1000 pin for sieving the pre-mixtures, mixture and excipients excpet for the lubricant which is sieve throught a sieve of 250 pm of diameter.
In an embodiment, 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.
As it is mentioned above, the 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.
In an embodiment, 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.
In an embodiment, 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 differenciate between disintegration (according to the Ph. Eur. 2.9.1. is 3 minutes) and dissolution profile.
In an embodiment, 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 (AUC (0-36)) from 80 to 125%
refering to the Bilaxten reference product, in a confidence interval of 90% .
The term "Cmax" refers to the maximum concentration of bilastine in the blood following a single-dose administration of the composition.
The term "AUC" 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 and AUCo-t denotes the area under the plasma concentration versus time curve from time 0 to time t.
Other aspect of the invention relates to the use of the 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. In an embodiment, 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.
Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps.
Furthermore, the word "comprise"
encompasses the case of "consisting of". Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Reference signs related to drawings and placed in parentheses in a claim, are solely for attempting to increase the intelligibility of the claim, and shall not be construed as limiting the scope of the claim. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.
Examples Methods:
- X-ray Powder diffractogram (XRPD) method The X-ray powder diffractogram has been obtained by using an X-ray diffractometer with Cu Ka 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 experimental conditions were as follows:
Cu Ka radiation (a= 1.5418 A).
Working power: 45 kV ¨ 40 mA.
Incident beam slits that define a beam height of 0.4 millimeters Incident and diffracted beam slits of 0.02 radian SoIler Detector PIXcel: active length = 3.347 2theta/theta scans of 2 to 40 2theta with a step size of 0.026 2theta and a measurement time of 76 seconds per step.
The diffractograms obtained show the pattern of X-ray powder diffraction (intensity (counts) vs. angle 2-theta ( )).
- Determination of the particle size distribution (PSD) of Bilastine by laser diffraction 2mg of sample were taken to measure the PSD of every API sample Instrument conditions Instrument: Malvern Laser Diffraction Masterizer 3000 Accesory: Dry Smapler Aero S
Measuring range: 0.001-3500pm Sensitivity: Normal Particle Type: Non-spherical Material Refraction Index: 1.59 Material Absorption Index: 0.01 Dispersant: Air Dispersant Air Pressure: 2 bar Background measuring time: 5 seconds Sample meauring time: 5 seconds Number of measurements: 3 Obscuration Range: 1-5%
Feed rate: 30%
Hoper opening: 2.5 Micronization method for Bilastine Form I
Wet molturation of sample Instrument: Pilot micronizer with Jetmill technology lnox 316 Feed hoper: 0.5L
Mirror polish: Ra < 0.2 pm Dosage speed: 30g/h Chamber pressure: 2.0 bar PSD analysis of the commercial tablets Bilaxten by SEM
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.
Identification of API
For particle size analysis, 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.
1. Compositions The values of the D90 of the crystalline form of Bilastine used for the preparation of the compositions of Examples 1-3 of the present invention and of the comparative Examples using the method as defined above were disclosed below in each one of the Tables 1 and 2.
1.1. Compositions of the invention The qualitative and quantitative composition of the immediate release tablets (IR-tablets of Examples 1 and 3) and orodispersible tablets (ODT of Example 2) of the present invention are shown in Table 1, wherein the amount of each of the components are expressed in weight percent:
Table 1 Examples (% w/w) Function Ingredient/D90 (pm) Example 1 Example 2 Example 3 (IR-Tablet) (ODT) (IR-Tablet) Bilastine crystaline form I
(090: 57 pm) Active ingredient Bilastine crystaline form Eta 6.7 16 (D90: 29.9 pm) Disintegrant-Crospovidone pyrrolidone-based 5 3.0 (type A) polymer Ethylcellulose binder 4.0 (ethocel std 10 FP) microcrystalline cellulose 77.6 77.6 Filler (Avicel PH-102) Mannitol CD 85.1 Glidant colloidal silicon dioxide 0.5 0.5 Lubricant Magnesium stearate 0.9 1.0 0.9 Sweetener Sucralose granular 0.1 aroma Red grapes aroma 0.1 Total weight 100 100 1.2. Comparative compositions The qualitative and quantitative comparative composition of the commercially available immediate realease tablet of micronized bilastine (Bilaxten) (Comparative Example 1) and the qualitative comparative composition of the commercially available orodispersible tablet of micronized bilastine (Bilaxten) (Comparative Example 2) falling outside the scope of the present invention are shown in Table 2, wherein the amount of each of the components are expressed in weight percent:
Table 2 Examples ( /0 w/w) Function Ingredient/D90 (pm) IR-Comparative Example 1 Bilastine crystaline form I
Active ingredient/ 16 (D90: 6.8 pm) Disintegrant Sodium starch glycolate 5 Filler Microcrystalline cellulose 77.6 Glidant Colloidal silicon dioxide 0.5 Lubricant Magnesium stearate 0.9 Total weight 100 Table2-cont.
ODT-Comparative Example 2 Function (% w/w) Bilastine crystaline form I
Active ingredient/
(D90: 6.8 pm) Disintegrant Croscarmellose sodium Filler Mannitol Lubricant Sodium stearyl fumarate Sweetener Sucralose flavour Red grade flavour 1.3. Preparation process 1.3.1. Immediate release compositions The immediate release compositions of the invention (Examples 1 and 3) defined in Table 1 were prepared following the general process 1 as defined below using the ingredients and the amounts specified in the 5 table.
Meanwhile, the comparative immediate realease tablet (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
10 until having the D90 about 6.8 pm. The micronization process of the bilastine was also disclosed herein below.
General process 1 The process comprises performing the following 5 consecutive steps: 1) Pre-blending, 2) Screening, 3)
15 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.
The general process 1 is disclosed herein below.
1) Pre-blending Step. Bilastine (20mg), Crospovidone and a part of the filler (20.6% of the total quantity of the 20 filler) were premixed to obtain a pre-mixture.
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.
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.
4) Lubricating Step. The lubricant (previously screened by a 250 pm sieve) was added to the mixture obtained in step 3) and mixed for 5 minutes at 18 rpm in the same double cone mixer.
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.
1.3.2. Orodispersible compositions 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.
Meanwhile, 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 crystaline form I until having the the D90 about 6.8 pm. The micronization process of the bilastine was also disclosed herein below.
General process 2 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.
The process is disclosed herein below.
1) 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).
2) Screening Step. The first and the second pre-mixtures obtained in previous step and the remaining excipients (including the remaining quantity of the filler) except for the lubricant were screened by a 1000 pm sieve.
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.
4) Lubricating Step. The lubricant (previously screened by a 250 pm sieve) was added to the mixture obtained in step 3) and mixed for 5 minutes at 23-24 rpm in the same blender.
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.
2. Dissolution Test The dissolution profile of the compositions of Examples 1-3 of the present invention and the comparative Examples 1 and 2 was measured.
Conditions of the dissolution bath - Paddle speed: 50 rpm - Temperature of dissolution medium: 37.0 C - 0.5 C
- Dissolution Medium: sodium acetate buffer - Vessel volume: 900 mL
- Vessel pH: 4.5 - Sample volume: 10 mL
-Time point (min): 5, 10, 15, 20 and 30.
-no of units: 1 Method:
To the set dissolution apparatus having a 900mL of dissolution medium as defined above to each of 6 glass vessels and under the above mentioned conditions, a tablet of the test sample was added into each basket lower down hood, taking care to exclude the air bubbles from the surface of the tablet and immediately start the apparatus.
After that, at each time point, 10 mL of the test sample from each of 6 glass vessels were withdrawn and filtered through 0.22p polyvinylidene fluoride filter (PVDF filter). Further, the withdrawn volume at each time point is replaced by adding an equal quantity of fresh dissolution medium at 37.0 C 0.5 C.
Conditions of the chromatographic analysis - Column: Acquity BEH C18 1.7 pm (100 x 2.1 mm) or equivalent - Mobile Phase A: Acetonitrile HPLC grade: Methanol HPLC grade (50:50) - Mobile Phase B: 5 mM Ammonium hydrogen carbonate (pH=10) Dissolve 0.40 g of ammonium hydrogen carbonate in about 900 mL of water of water, HPLC grade. Stir it until complete dissolution and adjust to pH=10.0 0.5 with 30% ammonium hydroxide.
Dilute to 1000 mL with water, HPLC grade and filter through 0.22 pm GHP filter.
- Mobile phase: Mobile Phase A/Mobile Phase B (55:45) (isocratic) - Flow: 0.4 mL/min - Column temperature: 30 C
- Wavelength detection: 220 nm - Injection volume: 2 pL- Loop: 2 pL
- Sample Loop Option: Full loop - Sample temperature: Room temperature - Retention time: Bilastine: about1.1 min - Run time: 2 min Results The weight percent of bilastine released from the compositions of Example 1-3 of the present invention and the comparative Examples 1 and 2 submitted to the above-mentioned dissolution conditions at the time points; as well as the relative standard deviation is shown in Tables below.
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 4 Time Points Bilastine release (Y0) / RSD (%) (minutes) Example 1 Example 3 Comparative Example 1 70.4 70.4 59.6 85.9 81.5 77.7 93.3 87.3 87.4 97.1 91.1 92.1 100.4 95.4 97.4 ND = not determined Table 5 shows the percentage of bilastine released from the orodispersible tablet of Example 2, and from the 5 commercially available orodispersible tablet of comparative Example 2, expressed as % by weight of bilastine dissolved in the time given.
Table 5 Time Points Bilastine release ('%) I RSD (%) (minutes) Example 2 Comparative Example 2 5 43.75 58.9 10 81.83 85.0 15 91.3 93.2 20 94.45 96.6 30 97.11 99.4 45 98.12 100.7 The results of the dissolution profile disclosed in the above-mentioned Tables showed that the compositions 10 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. In particular, the target dissolution profile of the inmediate release bilastine composition comprises at least 85% dissolution at 15 minutes. And, the target dissolution profile of the orodispersible tablet bilastine composition comprises at least 85% dissolution at 15 minutes.
Thus, the 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.
The general process 1 is disclosed herein below.
1) Pre-blending Step. Bilastine (20mg), Crospovidone and a part of the filler (20.6% of the total quantity of the 20 filler) were premixed to obtain a pre-mixture.
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.
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.
4) Lubricating Step. The lubricant (previously screened by a 250 pm sieve) was added to the mixture obtained in step 3) and mixed for 5 minutes at 18 rpm in the same double cone mixer.
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.
1.3.2. Orodispersible compositions 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.
Meanwhile, 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 crystaline form I until having the the D90 about 6.8 pm. The micronization process of the bilastine was also disclosed herein below.
General process 2 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.
The process is disclosed herein below.
1) 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).
2) Screening Step. The first and the second pre-mixtures obtained in previous step and the remaining excipients (including the remaining quantity of the filler) except for the lubricant were screened by a 1000 pm sieve.
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.
4) Lubricating Step. The lubricant (previously screened by a 250 pm sieve) was added to the mixture obtained in step 3) and mixed for 5 minutes at 23-24 rpm in the same blender.
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.
2. Dissolution Test The dissolution profile of the compositions of Examples 1-3 of the present invention and the comparative Examples 1 and 2 was measured.
Conditions of the dissolution bath - Paddle speed: 50 rpm - Temperature of dissolution medium: 37.0 C - 0.5 C
- Dissolution Medium: sodium acetate buffer - Vessel volume: 900 mL
- Vessel pH: 4.5 - Sample volume: 10 mL
-Time point (min): 5, 10, 15, 20 and 30.
-no of units: 1 Method:
To the set dissolution apparatus having a 900mL of dissolution medium as defined above to each of 6 glass vessels and under the above mentioned conditions, a tablet of the test sample was added into each basket lower down hood, taking care to exclude the air bubbles from the surface of the tablet and immediately start the apparatus.
After that, at each time point, 10 mL of the test sample from each of 6 glass vessels were withdrawn and filtered through 0.22p polyvinylidene fluoride filter (PVDF filter). Further, the withdrawn volume at each time point is replaced by adding an equal quantity of fresh dissolution medium at 37.0 C 0.5 C.
Conditions of the chromatographic analysis - Column: Acquity BEH C18 1.7 pm (100 x 2.1 mm) or equivalent - Mobile Phase A: Acetonitrile HPLC grade: Methanol HPLC grade (50:50) - Mobile Phase B: 5 mM Ammonium hydrogen carbonate (pH=10) Dissolve 0.40 g of ammonium hydrogen carbonate in about 900 mL of water of water, HPLC grade. Stir it until complete dissolution and adjust to pH=10.0 0.5 with 30% ammonium hydroxide.
Dilute to 1000 mL with water, HPLC grade and filter through 0.22 pm GHP filter.
- Mobile phase: Mobile Phase A/Mobile Phase B (55:45) (isocratic) - Flow: 0.4 mL/min - Column temperature: 30 C
- Wavelength detection: 220 nm - Injection volume: 2 pL- Loop: 2 pL
- Sample Loop Option: Full loop - Sample temperature: Room temperature - Retention time: Bilastine: about1.1 min - Run time: 2 min Results The weight percent of bilastine released from the compositions of Example 1-3 of the present invention and the comparative Examples 1 and 2 submitted to the above-mentioned dissolution conditions at the time points; as well as the relative standard deviation is shown in Tables below.
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 4 Time Points Bilastine release (Y0) / RSD (%) (minutes) Example 1 Example 3 Comparative Example 1 70.4 70.4 59.6 85.9 81.5 77.7 93.3 87.3 87.4 97.1 91.1 92.1 100.4 95.4 97.4 ND = not determined Table 5 shows the percentage of bilastine released from the orodispersible tablet of Example 2, and from the 5 commercially available orodispersible tablet of comparative Example 2, expressed as % by weight of bilastine dissolved in the time given.
Table 5 Time Points Bilastine release ('%) I RSD (%) (minutes) Example 2 Comparative Example 2 5 43.75 58.9 10 81.83 85.0 15 91.3 93.2 20 94.45 96.6 30 97.11 99.4 45 98.12 100.7 The results of the dissolution profile disclosed in the above-mentioned Tables showed that the compositions 10 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. In particular, the target dissolution profile of the inmediate release bilastine composition comprises at least 85% dissolution at 15 minutes. And, the target dissolution profile of the orodispersible tablet bilastine composition comprises at least 85% dissolution at 15 minutes.
Thus, the 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.
Claims (12)
1. A composition comprising:
a therapeutically effective arnount 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.
a therapeutically effective arnount 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.
2. The composition according to claim 1, wherein the pyrrolidone-based polymer comprises 1-viny1-2-pyrrolidone units.
3. The composition according to any of the claims 1 or 2, wherein the pyrrolidone-based polymer is a cross-linked 1-viny1-2-pyrrolidone.
4. The composition according to any of the claims 1-3, which comprises from 1 to 10 % by weigth of the pyrrolidone-based polymer.
5. The composition according to any of the claims 1-4, wherein the particle size distribution D90 is from 25 to 80 pm.
6. The composition according to any of the claims 1-5, wherein the bilastine has an X-ray diffractogram that comprises:
Bilastine crystaline form eta defined by 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 Ka radiation (1.5418 A); or alternatively Bilastine crystalline forml defined by 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 Ka radiation (1.5418 A).
Bilastine crystaline form eta defined by 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 Ka radiation (1.5418 A); or alternatively Bilastine crystalline forml defined by 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 Ka radiation (1.5418 A).
7. The composition according to any of the claims 1-6, which is in a form of tablet; particularly selected from the group consisting of an immediate release tablet and an orodispersible tablet.
8. The composition according to any of the claims 1-7, wherein 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.
9. The composition according to any of the claims 1-8, which comprises:
a therapeutically effective arnount 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.
a therapeutically effective arnount 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.
10. The composition according to claim 9, wherein:
the composition is in form of an immediate release tablet and the composition 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 0.1 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;
or alternatively, the composition is in form of a orodispersible tablet and the composition 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 1 to 10 % by weight of 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 is in form of an immediate release tablet and the composition 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 0.1 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;
or alternatively, the composition is in form of a orodispersible tablet and the composition 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 1 to 10 % by weight of 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.
11. The composition according to any of the claims 1-10, for use in the treatment of histamine-mediated disease processes and allergic reactions.
12. The composition for use according to claim 11, wherein 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
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP20383149.0 | 2020-12-23 | ||
| EP20383149 | 2020-12-23 | ||
| PCT/EP2021/083930 WO2022135863A1 (en) | 2020-12-23 | 2021-12-02 | A non-micronized bilastine composition |
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| Publication Number | Publication Date |
|---|---|
| CA3200779A1 true CA3200779A1 (en) | 2022-06-30 |
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ID=74194484
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| CA3200779A Pending CA3200779A1 (en) | 2020-12-23 | 2021-12-02 | A non-micronized bilastine composition |
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| EP (1) | EP4267109A1 (en) |
| CA (1) | CA3200779A1 (en) |
| WO (1) | WO2022135863A1 (en) |
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| ES2124167B1 (en) | 1996-06-04 | 1999-09-16 | Espanola Prod Quimicos | NEW DERIVATIVES OF BENZMIDAZOLE WITH ANTIHISTAMINE ACTIVITY. |
| EP1505066B1 (en) | 2002-04-19 | 2006-12-06 | Faes Farma, S.A. | Polymorph of acid 4-[2-[4-[1-(2-ethoxyethyl)-1h-benzimidazole-2-il]-1-piperidinyl]ethyl]-alpha, alpha-dimethyl-benzeneacetic |
| CN103356616A (en) * | 2013-06-29 | 2013-10-23 | 北京万全德众医药生物技术有限公司 | Bilastine-containing pharmaceutical composition and preparation method thereof |
| CN106606486A (en) * | 2015-10-22 | 2017-05-03 | 天津市汉康医药生物技术有限公司 | Bilastine tablet and preparation method thereof |
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2021
- 2021-12-02 WO PCT/EP2021/083930 patent/WO2022135863A1/en unknown
- 2021-12-02 CA CA3200779A patent/CA3200779A1/en active Pending
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| EP4267109A1 (en) | 2023-11-01 |
| WO2022135863A1 (en) | 2022-06-30 |
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