WO2022023463A1 - Système d'administration de médicaments décongestionnants - Google Patents

Système d'administration de médicaments décongestionnants Download PDF

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Publication number
WO2022023463A1
WO2022023463A1 PCT/EP2021/071244 EP2021071244W WO2022023463A1 WO 2022023463 A1 WO2022023463 A1 WO 2022023463A1 EP 2021071244 W EP2021071244 W EP 2021071244W WO 2022023463 A1 WO2022023463 A1 WO 2022023463A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
core
layer
decongestant
composition according
Prior art date
Application number
PCT/EP2021/071244
Other languages
English (en)
Inventor
Gonzalo HERNÁNDEZ HERRERO
Ignacio Ortega Azpitarte
Patricia MARCIANES MORENO
Paloma Tato Cerdeiras
José María Suñé Negre
Francisco Gual Pujol
Manuel Roig Carreras
Original Assignee
Faes Farma, S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Faes Farma, S.A. filed Critical Faes Farma, S.A.
Priority to CR20230109A priority Critical patent/CR20230109A/es
Priority to EP21755715.6A priority patent/EP4188339A1/fr
Publication of WO2022023463A1 publication Critical patent/WO2022023463A1/fr
Priority to DO2023000017A priority patent/DOP2023000017A/es
Priority to CONC2023/0002166A priority patent/CO2023002166A2/es

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention is related to an oral dosage system comprising a decongestant drug and optionally bilastine, with a reproducible controlled release profile of decongestant and, if present, an immediate release of bilastine.
  • the release profile of the delivery system of the invention is such that it may be administered once daily, thus improving patient compliance.
  • Decongestants are vasoconstrictors that help reduce the swelling in nasal passages and ease the stuffiness and sinus pressure.
  • Known decongestant drugs include pseudephedrine and phenylephrine.
  • Some decongestants, such as pseudephedrine (as well as pharmaceutically acceptable acid additional salts, e.g., those of HCI or H 2 SO 4 ) are recognized as safe therapeutic agents, effective for treating nasal congestion and are commonly administered comcomitantly with an antihistamine for treatment of nasal congestion associated with allergic rhinitis.
  • U.S. Patent No. 5,314,697 describes a formulation of a pseudoephedrine-loratadine once-a-day product, achieving a release rate profile for pseudoephedrine component over an extended period in excess of twelve hours while maintaining the safety and effectiveness of the antihistamine loratadine.
  • a particular compound with the above properties is the second-generation antihistamine 2-[4-(2- ⁇ 4-[1-(2-ethoxyethyl)-1 H-benzimidazol-2-yl]-1-piperidinyl ⁇ ethyl)phenyl]-2-methyl propanoic acid, also known as bilastine, having formula: and developed by Faes Farma, Spain.
  • Bilastine is a Hi antagonist benzimidazole compound with no sedative side effects, no cardiotoxic effects, and no hepatic metabolism.
  • bilastine has proved to be effective for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria.
  • U.S. Patent Nos. 4,990,535 and 5,100,675 disclose a twice-a-day sustained release coated tablet wherein the tablet coating comprises descarbethoxyloratadine and a hydrophilic polymer and polyethylene glycol, and the tablet core comprises acetaminophen, pseudoephedrine or a salt thereof, a swellable hydrophilic polymer and pharmaceutically acceptable excipients.
  • U.S. Patent No. 5,314,697 and international PCT publication WO0145668A2 disclose a once-daily extended release tablet, containing a matrix core comprising pseudoephedrine sulfate and a coating comprising loratadine and desloratadine, respectively.
  • Mexican patent application MX 2011 005 899 A describes microspheres encapsulated in gelatin capsules. The microspheres comprise inert cores coated with a polymeric matrix comprising phenylephrine, in turn coated with an immediate release layer of bilastine.
  • the present invention provides an oral dosage form comprising a decongestant drug and optionally bilastine, with a reproducible profile characterized by a controlled release of the decongestant over a period in excess of twelve hours and preferably at least 16 hours and, if present, an immediate release of bilastine after oral administration.
  • the oral dosage form of the invention further provides a short burst release of up to 50 wt% of the total amount of the decongestant drug within the first hour after ingestion.
  • the present invention provides a multi-layer oral pharmaceutical composition comprising:
  • a matrix core comprising a decongestant and a combination of at least two cellulose derivatives selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose; and
  • a first layer covering said core comprising a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose.
  • the pharmaceutical composition of the invention comprises at least two pharmaceutical ingredients. Therefore, in a second aspect, the invention is directed at the pharmaceutical composition of the invention, for use in medicine.
  • the oral pharmaceutical composition of the invention is useful for treating patients showing the signs and symptoms associated with allergic and/or inflammatory conditions such as the common cold, as well as signs and symptoms associated with allergic and/or inflammatory conditions of the skin or upper and lower airway passages such as allergic rhinitis, seasonal allergic rhinitis and nasal congestion, to name a few.
  • the present invention is directed at the pharmaceutical composition of the invention, for use in the treatment and/or prevention of a disorder or disease susceptible to amelioration by antagonism of Hi histamine receptor and/or decongestant responsive disease.
  • the present invention is referred a process of preparation of the multi layer oral pharmaceutical composition of the invention.
  • Figure 1 shows the average of the pseudoephedrine release profiles of 6 comparative tablets obtained according to Example 1 ( ⁇ ).
  • Figure 2 shows the average of the pseudoephedrine release profiles of 6 tablets obtained according to Example 2 ( ⁇ ).
  • Figure 3 shows the average of the bilastine release profiles of 6 tablets obtained as explained in Example 3 (x).
  • Figure 4 shows the average of the pseudoephedrine release profiles of 6 tablets obtained according to Example 4 ( ⁇ ).
  • Figure 5 shows the average of the bilastine release profiles of 6 tablets obtained according to Example 4 (x).
  • Figure 7 shows the average of the pseudoephedrine release profiles of tablets of the invention for each concentration of Ethylcellulose in the first layer: 1 ,20 wt% “o”; 1,30 wt% “D” and 1 ,40 wt% “D”.
  • Figure 7 also shows the release profile of the tablets according to example Detailed description of invention
  • the present invention provides a multi-layer oral pharmaceutical composition comprising:
  • a matrix core comprising a decongestant and a combination of at least two cellulose derivatives selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C 1-3 carboxyalkyl celluloses and microcrystalline cellulose; and
  • a first layer covering said core comprising a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1- 3 carboxyalkyl celluloses and microcrystalline cellulose.
  • the pharmaceutical composition of the invention comprises at least two pharmaceutical ingredients, one being bilastine and the other being a decongestant.
  • the matrix core of the pharmaceutical composition of the invention comprises a decongestant.
  • said decongestant is selected from the group consisting of pseudephedrine, phenylephrine and pharmaceutical salts thereof.
  • Pharmaceutical salts include sulfate or hydrochloride salts.
  • the decongestant is pseudephedrine or pharmaceutical salts thereof.
  • a particularly preferred decongestant is the hydrochloride salt of pseudephedrine.
  • the matrix core comprises the total amount of decongestant. In another particular embodiment, the matrix core comprises at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt% or at least 90 wt% of the total amount of the decongestant, preferably at least 50 wt%. In another particular embodiment, the matrix core comprises between 60 wt% and 100 wt% of the total amount of the decongestant. In a particular embodiment, the matrix core comprises between 50 wt% and 80 wt% of the total amount of the decongestant, preferably between 50 wt% and 70 wt% or between 60 wt% and 80 wt% of the total amount of the decongestant.
  • the matrix core comprises between 60 wt% and 80 wt% of the total amount of the decongestant, more preferably between 65 wt% and 75 wt%. In a particular embodiment, the matrix core comprises at least 20 wt% of a decongestant, preferably at least 30 wt%, the weight percentage being expressed with respect to the total weight of the core. In another particular embodiment, the matrix core comprises no more than 50 wt% of a decongestant, preferably no more than 40 wt%, the weight percentage being expressed with respect to the total weight of the core. In a preferred embodiment, the matrix core comprises between 20 and 50 % of a decongestant, more preferably between 20 and 40 %, even more preferably between 30 and 40 %, the weight percentage being expressed with respect to the total weight of the core.
  • the matrix core comprises at least 30 mg of decongestant, preferably at least 40 mg.
  • the matrix core comprises at least 120 mg, at least 130 mg, at least 140 mg or at least 150 mg of decongestant. In another particular embodiment, the matrix core comprises less than 280 mg, less than 270 mg, less than 260 mg or less than 250 mg of decongestant. Preferably, the matrix core comprises between 30 and 250 mg of decongestant, more preferably the matrix core comprises between 140 and 250 mg of decongestant, even more preferably between 150 mg and 240 mg of decongestant. In a most preferred embodiment, the matrix core comprises 40 mg or 180 mg of decongestant, more preferably of phenylephrine or pseudoephedrine, respectively.
  • the core of the pharmaceutical composition is formulated as a matrix core, wherein the decongestant drug is homogeneously dispersed in a hydrophilic polymer matrix.
  • the inventors have surprisingly found that the composition of the hydrophilic polymer matrix has an effect on the release profile of the decongestant.
  • the hydrophilic polymer matrix is a combination of at least two cellulose derivatives selected from the group consisting of Ci- 6 alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose.
  • said cellulose derivatives of the matrix core are each independently selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose and microcrystalline cellulose.
  • said cellulose derivatives are each independently selected from the group consisting of ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose and microcrystalline cellulose.
  • said cellulose derivates are each independently selected from the group consisting of ethylcellulose, hydroxypropyl methylcellulose and microcrystalline cellulose.
  • the matrix core does not comprise ethylcellulose.
  • the matrix core comprises at least 40 wt%, preferably at least 45 wt%, more preferably at least 50 wt% of the at least two cellulose derivatives, the weight percentage being expressed with respect to the total weight of the core.
  • the matrix core comprises at least 60 wt%, preferably at least 65 wt%, more preferably at least 67 wt% of the at least two cellulose derivatives, the weight percentage being expressed with respect to the total weight of the core.
  • the matrix core comprises between 40 wt% and 80 wt% of the at least two cellulose derivatives, the weight percentage being expressed with respect to the total weight of the core. In a preferred embodiment, the matrix core comprises between 40 wt% and 70 wt% of the at least two cellulose derivatives, the weight percentage being expressed with respect to the total weight of the core. In another preferred embodiment, the matrix core comprises between 50 wt% and 70 wt% of the at least two cellulose derivatives, the weight percentage being expressed with respect to the total weight of the core. In a more preferred embodiment, the matrix core comprises between 60 wt% and 70 wt% of the at least two cellulose derivatives, the weight percentage being expressed with respect to the total weight of the core.
  • the matrix core comprises between 15 and 40 wt% of hydroxypropyl methylcellulose, preferably between 15 and 35 wt%, more preferably between 15 and 32 wt%, even more preferably between 20 and 30 wt%, the weight percentage being expressed with respect to the total weight of the core.
  • the matrix core comprises between 20 and 60 wt% of microcrystalline cellulose, preferably between 20 and 50 wt%, more preferably between 30 and 50 wt%, the weight percentage being expressed with respect to the total weight of the core.
  • the matrix core comprises from 15 to 40 wt% of hydroxypropyl methylcellulose and/or from 20 to 60 wt% of microcrystalline cellulose, the weight percentage being expressed with respect to the total weight of the core. In another preferred embodiment, the matrix core comprises from 15 to 40 wt% of hydroxypropyl methylcellulose and/or from 20 to 50 wt% of microcrystalline cellulose, the weight percentage being expressed with respect to the total weight of the core. More preferably, the matrix core comprises between 20 to 30 wt% of hydroxypropyl methylcellulose and/or from 30 to 50 wt% of microcrystalline cellulose, the weight percentage being expressed with respect to the total weight of the core.
  • the matrix core comprises between 50 and 400 mg of a combination of said at least two cellulose derivatives.
  • the matrix core comprises between 200 and 400 mg of a combination of said at least two cellulose derivatives.
  • the matrix core comprises between 200 and 400 mg of a combination of said at least two cellulose derivatives when the decongestant is pseudoephedrine.
  • the matrix core comprises between 50 and 100 mg of a combination of said at least two cellulose derivatives.
  • the matrix core comprises between 50 and 100 mg of a combination of said at least two cellulose derivatives when the decongestant is phenylephrine.
  • the matrix core comprises between 100 and 150 mg of hydroxypropyl methylcellulose, preferably between 120 and 140 mg, more preferably between 125 and 135 mg of hydroxypropyl methylcellulose.
  • the matrix core comprises between 100 and 250 mg of microcrystalline cellulose, preferably between 110 and 230 mg, more preferably between 115 and 200 mg of microcrystalline cellulose. In a particular embodiment, preferably when the decongestant is pseudoephedrine, the matrix core weights from 300 to 600 mg, preferably from 400 to 550 mg, more preferably from 450 to 550 mg. In a particularly preferred embodiment, the matrix core weights between 490 and 500 mg.
  • the matrix core comprises between 10 and 40 mg of hydroxypropyl methylcellulose, preferably between 15 and 35 mg, more preferably between 20 and 30 mg of hydroxypropyl methylcellulose.
  • the matrix core comprises between 40 and 75 mg of microcrystalline cellulose, preferably between 45 and 70 mg, more preferably between 50 and 65 mg of microcrystalline cellulose.
  • the matrix core weights from 75 to 175 mg, preferably from 100 to 150 mg, more preferably from 115 to 135 mg. In a particularly preferred embodiment, the matrix core weights between 120 and 130 mg.
  • the pharmaceutical composition comprises a matrix core, which is coated by a first layer.
  • said first layer is in direct contact with the matrix core.
  • the inventors have surprisingly found that the first layer is also responsible for providing the decongestant reproducible release profiles. Further, the inventors have surprisingly found that the first layer is also responsible for obtaining an adequate release profile of the decongestant found in the matrix core. The inventors have also found that the composition of the first layer acts in combination with the composition of the matrix core, to produce an adequate release profile of the decongestant found in the matrix core.
  • the first layer comprises a cellulose derivative selected from the group consisting of Ci- 6 alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose.
  • said cellulose derivative in the first layer is selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose and microcrystalline cellulose.
  • said cellulose derivative is selected from the group consisting of ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose and microcrystalline cellulose. More preferably, said cellulose derivative is selected from the group consisting of ethylcellulose, hydroxypropyl methylcellulose and microcrystalline cellulose. In a most preferred embodiment, said cellulose derivative is ethylcellulose.
  • the first layer comprises from 0,2 to 3 wt% of a cellulose derivative.
  • the first layer comprises from 0,2 to 2 wt% of a cellulose derivative, preferably from 0,2 to 1 ,75 wt% or from 0,5 to 2 wt%, even more preferably from 0,75 to 1,75 wt% and most preferably from 1,1 to 1,5 wt%, and even more preferably from 0,75 to 1,5 wt% and most preferably from 1,1 to 1,4 wt%, the weight percentage being expressed with respect to the total weight of the core without coating.
  • the first layer comprises an inner and an outer layer, and the concentrations identified therein refer to the inner layer.
  • the first layer comprises from 0,2 to 1 ,25 wt% of a cellulose derivative, the weight percentage being expressed with respect to the total weight of the core without coating.
  • the first layer comprises from 0,6 to 1 ,25 wt% of a cellulose derivative, the weight percentage being expressed with respect to the total weight of the core without coating, even more preferably, from 0,9 to 1 ,20 wt%.
  • the first layer comprises from 0,2 mg to 6,25 mg of a cellulose derivative.
  • the first layer comprises from 1 mg to 7 mg of a cellulose derivative, preferably from 3 mg to 7 mg, more preferably from 5 mg to 7 mg, even more preferably from 5,5 mg to 6,7 mg.
  • the first layer comprises from 1 mg to 7 mg of a cellulose derivative, preferably from 1 mg to 5 mg, more preferably from 1 mg to 3 mg, even more preferably from 1,5 mg to 2,0 mg.
  • the first layer also comprises a decongestant, preferably selected from the group consisting of oxymetazoline, xylometazoline, synephrine, tetryzoline, tramazoline, naphazoline, propylhexedrine, ephedrine, pseudephedrine, phenylephrine, and pharmaceutical salts thereof.
  • the decongestant is selected form the group consisting of pseudephedrine, phenylephrine, and pharmaceutical salts thereof. More preferably, the decongestant is pseudephedrine or a pharmaceutical salt thereof.
  • the decongestant in the first layer if present, is the same decongestant as the one of the matrix core. In another particular embodiment, the decongestant in the first layer, if present, is different from the decongestant of the matrix core. Preferably, it is the same.
  • the first layer comprises from 0 to 40 wt% of the total amount of the decongestant. In another particular embodiment, the first layer comprises at least 10 wt%, at least 20 wt%, at least 30 wt%, at least 40 wt% or at least 50 wt% of the total amount of the decongestant. Preferably, the first layer comprises between 20 wt% and 50 wt% of the total amount of the decongestant, preferably between 30 wt% and 50 wt% or between 20 wt% and 40 wt%, of the total amount of the decongestant. . In a particularly preferred embodiment, the first layer comprises between 20 wt% and 40 wt% of the total amount of the decongestant, more preferably between 25 wt% and 35 wt%.
  • the first layer comprises at least 5 wt% of a decongestant, preferably at least 10 wt%, the weight percentage being expressed with respect to the total weight of the core. In another particular embodiment, the first layer comprises no more than 30 wt% of a decongestant, preferably no more than 25 wt%, the weight percentage being expressed with respect to the total weight of the core. In a preferred embodiment, the first layer comprises between 5 and 30 wt% of a decongestant, more preferably between 10 and 25 wt%, even more preferably between 10 and 18 wt%, the weight percentage being expressed with respect to the total weight of the core.
  • the first layer comprises at least 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg or at least 90 mg of a decongestant.
  • the first layer comprises between 10 and 95 mg of a decongestant, even more preferably between 10 and 70 mg of a decongestant.
  • the first layer comprises from 50 to 70 mg of pseudoephedrine, more preferably 60 mg.
  • the first layer comprises from 10 to 30 mg of phenylephrine, more preferably 20 mg.
  • Said first layer may be a homogeneous layer, or may alternative comprise further layers. Therefore, in a preferred embodiment, said first layer comprises:
  • an inner layer comprising a cellulose derivative selected from the group consisting of O e alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose; and/or
  • a further excipient selected from a coating system comprising a cellulose derivative, said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, and a decongestant, preferably selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • the inner layer is preferably a sealing layer.
  • the outer layer is preferably an immediate release layer of the decongestant.
  • the outer layer comprises:
  • a further excipient selected from a coating system comprising a cellulose derivative, said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably hydroxypropyl methylcellulose; and
  • a decongestant selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • the outer layer comprises:
  • a further excipient selected from a coating system comprising a cellulose derivative, said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably hydroxypropyl methylcellulose; and
  • a decongestant selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • the outer layer comprises:
  • a further excipient selected from a coating system comprising a cellulose derivative, said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably hydroxypropyl methylcellulose; and - from 25 to 35 wt% of a decongestant, with respect to the total weight of decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • the outer layer comprises:
  • a further excipient selected from a coating system comprising a cellulose derivative, said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably hydroxypropyl methylcellulose; and/or
  • the outer layer comprises:
  • a further excipient selected from a coating system comprising a cellulose derivative, said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably hydroxypropyl methylcellulose; and/or
  • the outer layer comprises:
  • a further excipient selected from a coating system comprising a cellulose derivative, said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably hydroxypropyl methylcellulose; and/or
  • the outer layer comprises: - from 3 to 10 wt%, with respect to the total weight of the core, of a further excipient selected from a coating system comprising a cellulose derivative, said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably hydroxypropyl methylcellulose; and/or
  • said first layer comprises:
  • an inner layer comprising from 0,1 to 1,5 wt%, with respect to the total weight of the core, of a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose; and/or
  • an outer layer comprising from 0,1 to 1,5 wt%, with respect to the total weight of the core, of a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose, and from 20 to 40 wt% of a decongestant, with respect to the total weight of decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose, and from 20 to 40 wt% of a decongestant, with respect to the total weight of decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • said first layer consists of:
  • an inner layer comprising from 0,1 to 1,5 wt%, with respect to the total weight of the core, of a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose; and
  • an outer layer comprising from 0,1 to 1,5 wt%, with respect to the total weight of the core, of a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose, and from 20 to 40 wt% of a decongestant, with respect to the total weight of decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose, and from 20 to 40 wt% of a decongestant, with respect to the total weight of decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • said first layer comprises: - an inner layer comprising from 0,2 to 3 wt%, with respect to the total weight of the core without coating, of a cellulose derivative selected from the group consisting of Ci- 6 alkyl celluloses, C e hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose; and/or
  • an outer layer comprising from 3 to 15 wt%, with respect to the total weight of the core, of a further excipient selected from a coating system comprising a cellulose derivative, said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably hydroxypropyl methylcellulose, and from 20 to 40 wt% of a decongestant, with respect to the total weight of decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • a further excipient selected from a coating system comprising a cellulose derivative, said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably hydroxypropyl methylcellulose, and from 20 to 40 wt% of a decongestant, with
  • said first layer comprises:
  • an inner layer comprising from 0,5 to 2 wt%, with respect to the total weight of the core without coating, of a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose; and/or
  • an outer layer comprising from 3 to 15 wt%, with respect to the total weight of the core, of a further excipient selected from a coating system comprising a cellulose derivative, said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably hydroxypropyl methylcellulose, and from 20 to 40 wt% of a decongestant, with respect to the total weight of decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • a further excipient selected from a coating system comprising a cellulose derivative, said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably hydroxypropyl methylcellulose, and from 20 to 40 wt% of a decongestant, with
  • said first layer comprises:
  • an inner layer comprising from 0,75 to 1 ,5 wt%, with respect to the total weight of the core without coating, of a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose; and/or
  • an outer layer comprising from 3 to 15 wt%, with respect to the total weight of the core, of a further excipient selected from a coating system comprising a cellulose derivative, said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably hydroxypropyl methylcellulose, and from 20 to 40 wt% of a decongestant, with respect to the total weight of decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • a further excipient selected from a coating system comprising a cellulose derivative, said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably hydroxypropyl methylcellulose, and from 20 to 40 wt% of a decongestant, with
  • said first layer comprises:
  • an inner layer comprising from 0,75 to 1 ,5 wt%, with respect to the total weight of the core without coating, of a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose; and/or
  • an outer layer comprising from 3 to 15 wt%, with respect to the total weight of the core, of a further excipient selected from a coating system selected from VIVACOAT ® A, and from 20 to 40 wt% of a decongestant, with respect to the total weight of decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • the further excipient selected from a coating system of the outer layer, said coating comprising a cellulose derivative is a coating system such as VIVACOAT ® A, from JRS Pharma.
  • a coating system such as VIVACOAT ® A, from JRS Pharma.
  • VIVACOAT ® A from JRS Pharma.
  • Vivacoat ® PA-1 P-000 comprising hydroxypropyl methylcellulose (HPMC).
  • said first layer weighs from 0,2 mg to 140 mg, from 0,2 mg to 140 mg, from 0,2 mg to 130 mg, from 0,2 mg to 120 mg, from 0,2 mg to 100 mg, preferably from 0,2 mg to 100 mg, even more preferably from 0,2 mg to 95 mg.
  • the first layer weight from 90 to 140 mg or, from 20 to 35 mg or, from 0,2 to 6 mg.
  • the first layer does not comprise a decongestant.
  • the first layer weighs preferably from 0,2 to 10 mg, preferably from 0,2 to 6 mg.
  • said cellulose derivative in the first layer and said cellulose derivative in the matrix core act synergistically to yield a reproducible release profile of the decongestant.
  • the pharmaceutical composition comprises a matrix core, which is coated by a first layer.
  • said first layer is in turn coated by a second layer comprising bilastine.
  • said second layer is in direct contact with the first layer.
  • said second layer is an immediate release layer of bilastine.
  • the second layer comprises from 1 to 20 wt% of bilastine, preferably from 2 to 18 wt% of bilastine, the weight percentage being expressed with respect to the total weight of the core.
  • the second layer comprises from 1 to 5 wt% of bilastine, preferably from 2,5 to 4,5 wt% of bilastine, the weight percentage being expressed with respect to the total weight of the core, and the decongestant is optionally pseudoephedrine.
  • the second layer comprises from 10 to 20 wt% of bilastine, preferably from 14 to 18 wt% of bilastine, the weight percentage being expressed with respect to the total weight of the core, and the decongestant is optionally phenylephrine.
  • the bilastine is micronized bilastine.
  • the second layer further comprises a further excipient.
  • said further excipient is a coating system comprising a cellulose derivative, preferably HPMC.
  • An exemplary excipient would be a coating system such as VIVACOAT ® A, from JRS Pharma. Preferably it is Vivacoat ® PA-1 P-000.
  • the second layer comprises from 2 to 25 wt% of a further excipient, the weight percentage being expressed with respect to the total weight of the core. More preferably, the second layer comprises from 2 to 16 wt% of a further excipient, even more preferably from 3 to 15 wt% of a further excipient, the weight percentage being expressed with respect to the total weight of the core. In an even more preferred embodiment, the second layer further comprises from 4 to 14 wt% of a coating system comprising a cellulose derivative, preferably HPMC, the weight percentage being expressed with respect to the total weight of the core. Most preferably, the second layer further comprises from 4 to 14 wt% of Vivacoat ® PA-1 P-000, the weight percentage being expressed with respect to the total weight of the core.
  • the second layer comprises from 15 to 30 wt% of a further excipient, the weight percentage being expressed with respect to the total weight of the core. In another particular embodiment, the second layer comprises from 18 to 20 wt% of a further excipient, the weight percentage being expressed with respect to the total weight of the core.
  • the second layer further comprises from 18 to 20 wt% of Vivacoat ® , the weight percentage being expressed with respect to the total weight of the core.
  • the second layer comprises from 4 mg to 150 mg of a further excipient, preferably, from 4 to 100 mg of a further excipient. Even more preferably, the second layer comprises from 4 to 100 mg of Vivacoat ® .
  • the pharmaceutical composition of the invention comprises a therapeutically effective amount of bilastine.
  • therapeutically effective amount means that amount of a medicament which when administered supplies an amount of one or more pharmaceutically active agents contained therein to provide a therapeutic benefit in the treatment or management of a disease or disease state.
  • the second layer comprises at least 10 mg of bilastine, at least 15 mg of bilastine, or at least 20 mg of bilastine.
  • the second layer comprises between 10 mg and 25 mg of bilastine. More preferably, the second layer comprises between 10 mg and 20 mg of bilastine.
  • said second layer further comprises said decongestant.
  • the first layer does not comprise said decongestant and the second layer further comprises the ingredients and concentrations in the embodiments described above for said outer layer in said first layer.
  • the second layer can either comprise said decongestant homogenously distributed with the bilastine and any further excipients, or the second layer comprises two layers, an inner layer comprising bilastine and any further excipients as described herein, and an outer layer, which is as described above for the outer layer in said first layer.
  • the decongestant in the second layer if present, is the same decongestant as the one of the matrix core.
  • the decongestant in the second layer is different from the decongestant of the matrix core.
  • the second layer comprises said decongestant homogenously distributed with the bilastine and said any further excipients
  • said second layer comprises from 6 to 20 wt% of a further excipient, the weight percentage being expressed with respect to the total weight of the core.
  • the second layer comprises from 6 to 14 wt% of a further excipient, even more preferably from 10 to 14 wt% of a further excipient or from 6 to 10 wt% of a further excipient, the weight percentage being expressed with respect to the total weight of the core.
  • the second layer further comprises from 10 to 14 wt%, or from 6 to 10 wt% of a further excipient, of a coating system comprising a cellulose derivative, preferably HPMC, the weight percentage being expressed with respect to the total weight of the core.
  • the second layer further comprises from 10 to 14 wt%, or from 6 to 10 wt% of a further excipient, of Vivacoat ® PA-1 P-000, the weight percentage being expressed with respect to the total weight of the core.
  • the pharmaceutical composition of the invention may optionally comprise an external coating layer, selected from a coating system comprising a cellulose derivative, preferably HPMC.
  • Said coating system can be VIVACOAT ® A, from JRS Pharma. Preferably it is Vivacoat ® PA-1 P-000, comprising hydroxypropyl methylcellulose (HPMC).
  • said external coating layer is present in an amount equal to or greater than 1, 2, 4, 5, 8 or 10 wt%, the weight percentage being expressed with respect to the total weight of the core.
  • said external coating layer is present in an amount of from 1 to 15 wt%, more preferably from 2 to 14 wt%, the weight percentage being expressed with respect to the total weight of the core.
  • the pharmaceutical composition of the invention is a tablet.
  • the matrix core of the pharmaceutical composition of the invention comprises: - from 20 to 50 wt% of the decongestant; and from 40 to 80 wt% of a combination of said at least two cellulose derivatives; the weight percentages being expressed with respect to the total weight of the core.
  • the matrix core of the pharmaceutical composition of the invention comprises: - from 20 to 40 wt% of the decongestant; and from 60 to 70 wt% of a combination of said at least two cellulose derivatives; the weight percentages being expressed with respect to the total weight of the core.
  • the matrix core of the pharmaceutical composition of the invention comprises: - between 30 and 250 mg of decongestant; and between 50 and 400 mg of a combination of said at least two cellulose derivatives.
  • the matrix core of the pharmaceutical composition of the invention comprises: - between 150 and 240 mg of decongestant, preferably selected from pseudoephedrine or pharmaceutically acceptable salts thereof; and between 200 and 400 mg of a combination of said at least two cellulose derivatives.
  • the matrix core of the pharmaceutical composition of the invention comprises: between 30 and 50 mg of decongestant, preferably selected from phenylephrine or pharmaceutically acceptable salts thereof; and between 50 and 100 mg of a combination of said at least two cellulose derivatives.
  • the pharmaceutical composition of the invention may comprise further pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipient refers to a vehicle, diluent, or adjuvant that is administered with the active ingredient. Suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences” by E.W. Martin, 21st Edition, 2005.
  • excipients and auxiliary substances necessary to manufacture the desired pharmaceutical form of administration of the pharmaceutical composition of the invention will depend, among other factors, on the elected administration pharmaceutical form.
  • Said pharmaceutical forms of administration of the pharmaceutical composition will be manufactured according to conventional methods known by the skilled person in the art. A review of different active ingredient administration methods, excipients to be used and processes for producing them can be found in “Tratado de Farmacia Galenica”, C. Fauli i Trillo, Luzan 5, S.A. de Ediations, 1993.
  • pharmaceutically acceptable refers to compositions and molecular entities that are physiologically tolerable and do not typically produce an allergic reaction or a similar unfavourable reaction as gastric disorders, dizziness and suchlike, when administered to a human or animal.
  • pharmaceutically acceptable means it is approved by a regulatory agency of a state or federal government or is included in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • the matrix core of the pharmaceutical composition of the invention comprises: from 20 wt% to 50 wt% of the decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; from 15 to 40 wt% of hydroxypropyl methylcellulose; and from 20 to 60 wt% of microcrystalline cellulose; the weight percentages being expressed with respect to the total weight of the core.
  • the matrix core of the pharmaceutical composition of the invention comprises: from 30 wt% to 50 wt% of the decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; from 15 to 35 wt% of hydroxypropyl methylcellulose; and from 20 to 50 wt% of microcrystalline cellulose; the weight percentages being expressed with respect to the total weight of the core.
  • the matrix core of the pharmaceutical composition of the invention comprises: from 60 wt% to 100 wt% of the total amount of the decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; from 20 to 40 wt% of hydroxypropyl methylcellulose; from 30 to 50 wt% of microcrystalline cellulose; from 0,1 to 2 wt% of magnesium stearate; and optionally, from 0,1 to 1 wt% of polyvinylpyrrolidone; the weight percentages of the excipients being expressed with respect to the total weight of the core.
  • the decongestant selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof
  • from 20 to 40 wt% of hydroxypropyl methylcellulose from 30 to 50 wt% of microcrystalline cellulose; from 0,1 to 2 wt% of magnesium stearate; and optionally, from 0,1 to 1 wt% of
  • the expression “the weight percentages of the excipients” is to be interpreted as the the weight percentages of all ingredients which are not an active pharmaceutical ingredient, for example, a decongestant selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof or bilastine.
  • the matrix core of the pharmaceutical composition of the invention comprises: from 20 wt% to 50 wt% of the decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; from 15 to 40 wt% of hydroxypropyl methylcellulose; from 20 to 60 wt% of microcrystalline cellulose; from 0,1 to 2 wt% of magnesium stearate, preferably from 0,5 to 1,5 wt%; and optionally, from 0,1 to 1 wt% of a binder, preferably polyvinylpyrrolidone; the weight percentages being expressed with respect to the total weight of the core.
  • the decongestant selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof
  • from 15 to 40 wt% of hydroxypropyl methylcellulose from 20 to 60 wt% of microcrystalline cellulose; from 0,1 to 2 wt% of magnesium stearate, preferably from 0,5
  • the matrix core of the pharmaceutical composition of the invention consists of: from 20 wt% to 50 wt% of the decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; from 15 to 40 wt% of hydroxypropyl methylcellulose; from 20 to 60 wt% of microcrystalline cellulose; from 0,1 to 2 wt% of magnesium stearate, preferably from 0,5 to 1,5 wt%; and optionally, from 0,1 to 1 wt% of a binder, preferably polyvinylpyrrolidone; the weight percentages being expressed with respect to the total weight of the core.
  • the decongestant selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof
  • from 15 to 40 wt% of hydroxypropyl methylcellulose from 20 to 60 wt% of microcrystalline cellulose; from 0,1 to 2 wt% of magnesium stearate, preferably from
  • the matrix core of the pharmaceutical composition of the invention consists of: from 60 wt% to 100 wt% of the total amount of the decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; from 20 to 40 wt% of hydroxypropyl methylcellulose; from 30 to 50 wt% of microcrystalline cellulose; from 0,1 to 2 wt% of magnesium stearate; and optionally, from 0,1 to 1 wt% of polyvinylpyrrolidone; the weight percentages of the excipients being expressed with respect to the total weight of the core and the total sum being 100%.
  • the matrix core of the pharmaceutical composition of the invention comprises: between 150 and 250 mg of decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof, preferably pseudoephedrine; between 100 and 150 mg of hydroxypropyl methylcellulose; and between 100 and 250 g of microcrystalline cellulose;
  • the matrix core of the pharmaceutical composition of the invention comprises: between 150 and 250 mg of decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof, preferably pseudoephedrine; between 100 and 150 mg of hydroxypropyl methylcellulose; between 100 and 250 mg of microcrystalline cellulose; between 1 and 10 mg of magnesium stearate; and optionally, between 1 and 5 mg of polyvinylpyrrolidone.
  • decongestant selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof, preferably pseudoephedrine
  • between 100 and 150 mg of hydroxypropyl methylcellulose between 100 and 250 mg of microcrystalline cellulose
  • between 1 and 10 mg of magnesium stearate between 1 and 5 mg of polyvinylpyrrolidone.
  • the matrix core of the pharmaceutical composition of the invention comprises: between 30 and 50 mg of decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof, preferably phenylephrine; between 10 and 40 mg of hydroxypropyl methylcellulose; and between 40 and 75 mg of microcrystalline cellulose.
  • the matrix core of the pharmaceutical composition of the invention comprises: between 30 and 50 mg of decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof, preferably phenylephrine; between 10 and 40 mg of hydroxypropyl methylcellulose; - between 40 and 75 mg of microcrystalline cellulose; between 1 and 2 mg of magnesium stearate; and optionally, between 0,5 and 5 mg of polyvinylpyrrolidone.
  • said first layer consists of an inner layer and of an outer layer.
  • said first layer comprises: an inner layer, comprising from 0,2 to 3 wt%, with respect to the total weight of the core, of ethylcellulose; and an outer layer, comprising from 3 to 15 wt%, with respect to the total weight of the core, of VIVACOAT ® PA-1 P-000 and from 20 to 40 wt% of a decongestant, with respect to the total weight of decongestant, preferably selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • said first layer comprises: an inner layer, comprising from 0,75 to 1 ,5 wt%, with respect to the total weight of the core, of ethylcellulose; and an outer layer, comprising from 3 to 15 wt%, with respect to the total weight of the core, of ethylcellulose and from 25 to 35 wt% of a decongestant, with respect to the total weight of decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • the pharmaceutical composition of the invention comprises:
  • a matrix core comprising: from 20 wt% to 50 wt% of the decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; from 15 to 40 wt% of hydroxypropyl methylcellulose; and from 20 to 60 wt% of microcrystalline cellulose; and
  • a first layer comprising from 0,2 to 3 wt% of ethylcellulose; the weight percentages being expressed with respect to the total weight of the core.
  • composition of the invention comprises:
  • a matrix core comprising: from 20 wt% to 50 wt% of the decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; from 15 to 40 wt% of hydroxypropyl methylcellulose; and from 20 to 60 wt% of microcrystalline cellulose; and
  • a first layer comprising: an inner layer, comprising from 0,2 to 3 wt% of ethylcellulose; and an outer layer, comprising from 3 to 15 wt% of VIVACOAT ® PA-1 P-000 and from 10 to 18 wt% of a decongestant, preferably selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; the weight percentages being expressed with respect to the total weight of the core.
  • composition of the invention comprises:
  • a matrix core comprising: from 20 wt% to 50 wt% of the decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; from 15 to 40 wt% of hydroxypropyl methylcellulose; and from 20 to 60 wt% of microcrystalline cellulose;
  • a first layer comprising from 0,2 to 3 wt% of ethylcellulose
  • a second layer comprising from 1 to 20 wt% of bilastine. the weight percentages being expressed with respect to the total weight of the core.
  • composition of the invention comprises:
  • a matrix core comprising: from 20 wt% to 50 wt% of the decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; from 15 to 40 wt% of hydroxypropyl methylcellulose; and from 20 to 60 wt% of microcrystalline cellulose;
  • a first layer comprising: an inner layer, comprising from 0,2 to 3 wt% of ethylcellulose; and an outer layer, comprising from 3 to 15 wt% of VIVACOAT ® PA-1 P-000 and from 10 to 18 wt% of a decongestant, preferably selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; and
  • a second layer comprising from 1 to 20 wt% of bilastine; the weight percentages being expressed with respect to the total weight of the core.
  • composition of the invention comprises:
  • a matrix core comprising: - from 20 wt% to 50 wt% of the decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; from 15 to 40 wt% of hydroxypropyl methylcellulose; and from 20 to 60 wt% of microcrystalline cellulose;
  • a first layer comprising: - an inner layer, comprising from 0,2 to 3 wt% of ethylcellulose; and an outer layer, comprising from 3 to 15 wt% of VIVACOAT ® PA-1 P-000 and from 10 to 18 wt% of a decongestant, preferably selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; and
  • a second layer comprising from 1 to 20 wt% of bilastine and from 2 to 16 wt% of VIVACOAT ® PA-1 P-000; the weight percentages being expressed with respect to the total weight of the core.
  • the pharmaceutical composition of the invention comprises:
  • a matrix core comprising: from 20 wt% to 50 wt% of the decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; from 15 to 40 wt% of hydroxypropyl methylcellulose; and from 20 to 60 wt% of microcrystalline cellulose;
  • a first layer comprising from 0,2 to 3 wt% of ethylcellulose
  • a second layer comprising from 1 to 20 wt% of bilastine, from 2 to 25 wt% of VIVACOAT ® PA-1 P-000 and from 10 to 18 wt% of a decongestant, preferably selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof. the weight percentages being expressed with respect to the total weight of the core.
  • composition of the invention comprises:
  • a matrix core comprising: from 20 wt% to 50 wt% of the decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; from 15 to 40 wt% of hydroxypropyl methylcellulose; and from 20 to 60 wt% of microcrystalline cellulose;
  • a first layer comprising from 0,2 to 3 wt% of ethylcellulose
  • a second layer comprising: an inner layer, comprising from 1 to 20 wt% of bilastine and from 2 to 16 wt% of VIVACOAT ® PA-1 P-000; and an outer layer, comprising from 3 to 15 wt% of VIVACOAT ® PA-1 P-000 and from 10 to 18 wt% of a decongestant, preferably selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof; the weight percentages being expressed with respect to the total weight of the core.
  • a decongestant preferably selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof
  • the present invention concerns a process of preparation of the multi layer oral pharmaceutical composition of the invention comprising the steps of a) preparing a matrix core, comprising a decongestant and a combination of at least two cellulose derivatives selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose; b) coating said core with a first layer, wherein said first layer comprises a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose; and c) coating said core with said first layer with a second layer, said second layer comprising bilastine.
  • the decongestant will be coated in an intermediate step (b1), between steps (b) and (c).
  • the second layer is to comprise a decongestant in an outer layer of the second layer, as described above, then the decongestant will be coated in a further step (c1), after step (c).
  • step (c) comprises coating said core with said first layer with a second layer, said second layer comprising both bilastine and the decongestant.
  • the cores are obtained by a direct compression method.
  • the process of preparation of the cores is a wet granulation method.
  • the coating in step (b) is conducted by spraying.
  • the coating in step (c) is conducted by a pan-coating process.
  • the pharmaceutical composition of the invention is such that a retarded release profile is achieved for the decongestant while an immediate release occurs for the bilastine after oral administration.
  • At least 60 wt% of the total amount of decongestant is released within 16 hours after oral administration, preferably, 80 wt% of the total amount of decongestant is released within the first 16 hours after oral administration.
  • the pharmaceutical composition of the invention comprises an immediate release layer of decongestant as well.
  • the composition is such that less than 50 wt% of the total amount of decongestant immediately releases from the multi-layer oral pharmaceutical composition while the rest is released following a retarded release profile after oral administration.
  • less than 40 wt% of the total amount of decongestant is released within the first hour, preferably between 10 and 30 wt%, more preferably between 15 and 25 wt%.
  • from 10 to 35 wt% of the total amount of decongestant is released within the first hour and from 80 to 98wt% of the total amount of decongestant is released within the first 18 hours after oral administration.
  • no more than 85 wt% of the total amount of decongestant is released within the first 12 hours after oral administration.
  • no more than 95 wt% of the total amount of decongestant is released within 16 hours after oral administration.
  • At least 80 wt% of the total amount of bilastine is released within the first hour after oral administration, preferably, at least 90 wt% of the total amount of bilastine is released within the first hour after oral administration.
  • the pharmaceutical composition of the invention comprises at least two pharmaceutical ingredients. Therefore, in a second aspect, the invention is directed at the pharmaceutical composition of the invention, for use in medicine. This aspect may also be formulated as the pharmaceutical composition of the invention as described above, to prepare a medicament.
  • the oral pharmaceutical composition of the invention is useful for treating patients showing the signs and symptoms associated with allergic and/or inflammatory conditions such as the common cold, as well as signs and symptoms associated with allergic and/or inflammatory conditions of the skin or upper and lower airway passages such as allergic rhinitis, seasonal allergic rhinitis and nasal congestion, to name a few.
  • a third aspect of the invention is addressed to the pharmaceutical composition of the invention, for use in the treatment and/or prevention of a disorder or disease susceptible to amelioration by antagonism of Hi histamine receptor and/or decongestant responsive disease.
  • This aspect may also be formulated as the use of the composition of the invention as described above, in the manufacture of a medicament for the treatment and/or prevention of a disorder or disease susceptible to amelioration by antagonism of Hi histamine receptor and/or decongestant responsive disease.
  • This aspect may also be formulated as a method of treating and / or preventing a disorder or disease susceptible to amelioration by antagonism of Hi histamine receptor and/or decongestant responsive disease, comprising administering to a subject in need of such treatment the composition of the invention as described above.
  • a decongestant responsive disease is a disease known to ameliorate by stimulation of the a1 -adrenergic receptor.
  • treat and treatment mean reversing, alleviating, inhibiting progression of the disease or condition to which said term or one or more symptoms of said disease or condition applies.
  • prevent and “prevention,” as used herein, mean the inhibition of the occurrence of the disease or condition to which this term applies or one or more symptoms of such disease or condition.
  • the composition of the invention may be administered 1, 2, 3, 4 or 5 times / day, preferably 1 or 2 times / day, even more preferably once daily.
  • the composition of the invention may be administered until the symptoms of the disease or conditions to be treated are reversed, alleviated, or inhibited in their progress.
  • the pharmaceutical composition as described above is a pharmaceutical composition for use in the treatment and/or prevention of a disorder or disease susceptible to amelioration by antagonism of Hi histamine receptor and/or decongestant responsive disease, wherein said disorder or disease susceptible to amelioration by antagonism of Hi histamine receptor and/or decongestant responsive disease is an allergic disease, asthma, non-malignant proliferative and inflammatory diseases.
  • said disorder or disease susceptible to amelioration by antagonism of Hi histamine receptor and/or decongestant responsive disease is selected from nasal congestion, sinus congestion, rhinorrhea, eustachian tube congestion, vasomotor rhinitis, allergic rhinitis, rhinoconjunctivitis, allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, giant papillary conjunctivitis, ocular irritation, allergic dermatitis, atopic dermatitis, urticaria, asthma, itchiness, redness, tearing, chemosis, keratitis sicca, keratoconjunctivitis sicca, dysfunctional tear syndrome, croup, sinusitis, otitis media, tracheobronchitis, urinary incontinence, retinopathy and small vessel diseases.
  • Multi-layer oral pharmaceutical composition comprising:
  • a matrix core comprising a decongestant selected from the group consisting of pseudoephedrine, phenylephrine and pharmaceutical salts thereof, and a combination of at least two cellulose derivatives selected from the group consisting of Ci- 6 alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose;
  • a first layer covering said core comprising a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1- 3 carboxyalkyl celluloses and microcrystalline cellulose; and
  • Embodiment 2 The pharmaceutical composition according to embodiment 1 , wherein said cellulose derivatives are each independently selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose and microcrystalline cellulose.
  • Embodiment 3 The pharmaceutical composition according to any one of embodiments 1 to 2, wherein said first layer further comprises a decongestant selected from the group consisting of pseudoephedrine, phenylephrine and pharmaceutical salts thereof.
  • a decongestant selected from the group consisting of pseudoephedrine, phenylephrine and pharmaceutical salts thereof.
  • Embodiment 4 The pharmaceutical composition according to any one of embodiments 1 to 3, wherein the first layer comprises from 0,2 to 3 wt% of said cellulose derivative, preferably from 0,2 to 1,25 wt% the weight percentage being expressed with respect to the total weight of the core.
  • Embodiment 5 The pharmaceutical composition according to any one of embodiments 1 to 4, wherein said first layer comprises:
  • an inner layer comprising a cellulose derivative selected from the group consisting of Ci- 6 alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose; and
  • an outer layer comprising a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, and a decongestant selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • Embodiment 6 The pharmaceutical composition according to any one of embodiments 1 to 5, wherein said first layer comprises an inner sealing layer and an outer immediate release layer of a decongestant.
  • Embodiment 7 The pharmaceutical composition according to any one of embodiments 1 to 6, further comprising a pharmaceutically acceptable excipient.
  • Embodiment 8 The pharmaceutical composition according to any one of embodiments 1 to 7, wherein the matrix core comprises:
  • Embodiment 9 The pharmaceutical composition according to any one of embodiments 1 to 8, wherein the matrix core comprises: - from 60 wt% to 100 wt% of the total amount of the decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof;
  • Embodiment 10 The pharmaceutical composition according to any one of embodiments 1 to 9, wherein said first layer comprises:
  • an inner layer comprising from 0,1 to 1 ,5 wt%, with respect to the total weight of the core, of a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose; and
  • an outer layer comprising from 0,1 to 1 ,5 wt%, with respect to the total weight of the core, of a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose, and from 20 to 40 wt% of a decongestant, with respect to the total weight of decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose, and from 20 to 40 wt% of a decongestant, with respect to the total weight of decongestant, selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof
  • Embodiment 11 The pharmaceutical composition according to any one of embodiments 1 to 10, wherein at least 60 wt% of the total amount of decongestant is released within 16 hours after oral administration.
  • Embodiment 12 The pharmaceutical composition according to any one of embodiments 1 to 11 , for use in medicine.
  • Embodiment 13 The pharmaceutical composition according to any one of embodiments 1 to 11 , for use in the treatment and/or prevention of a disorder or disease susceptible to amelioration by antagonism of Hi histamine receptor and/or decongestant responsive disease.
  • Embodiment 14 The pharmaceutical composition for use according to embodiment 13, wherein said disorder or disease susceptible to amelioration by antagonism of Hi histamine receptor and/or decongestant responsive disease is an allergic disease, asthma, non-malignant proliferative and inflammatory diseases.
  • Embodiment 15 The pharmaceutical composition for use according to embodiment 13, wherein the use is in the treatment and/or prevention of nasal congestion, sinus congestion, rhinorrhea, eustachian tube congestion, vasomotor rhinitis, allergic rhinitis, rhinoconjunctivitis, allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, giant papillary conjunctivitis, ocular irritation, allergic dermatitis, atopic dermatitis, urticaria, asthma, itchiness, redness, tearing, chemosis, keratitis sicca, keratoconjunctivitis sicca, dysfunctional tear syndrome, croup, sinusitis, otitis media, tracheobronchitis, urinary incontinence, retinopathy and small vessel diseases.
  • Multi-layer oral pharmaceutical composition comprising: a matrix core, comprising a decongestant selected from the group consisting of pseudoephedrine, phenylephrine and pharmaceutical salts thereof, and a combination of at least two cellulose derivatives selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose; and a first layer covering said core, comprising a cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose.
  • Preferred embodiment 2 The pharmaceutical composition according to preferred embodiment 1 , wherein said cellulose derivatives in the matrix core are each independently selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose and microcrystalline cellulose.
  • Preferred embodiment 3 The pharmaceutical composition according to any one of preferred embodiments 1 or 2, wherein said cellulose derivatives in the matrix core are each independently selected from the group consisting of ethylcellulose, hydroxypropyl methylcellulose and microcrystalline cellulose, preferably a combination of hydroxypropyl methylcellulose and microcrystalline cellulose.
  • Preferred embodiment 4 The pharmaceutical composition according to any one of preferred embodiments 1 to 3, wherein the matrix core comprises at least 40 wt% of the at least two cellulose derivatives, the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 5 The pharmaceutical composition according to any one of preferred embodiments 1 to 4, wherein the matrix core comprises at least 50 wt% of the at least two cellulose derivatives, the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 6 The pharmaceutical composition according to any one of preferred embodiments 1 to 5, wherein the matrix core comprises between 40 wt% and 80 wt% of the at least two cellulose derivatives, the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 7 The pharmaceutical composition according to any one of preferred embodiments 1 to 6, wherein the matrix core comprises between 60 wt% and 70 wt% of the at least two cellulose derivatives, the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 8 The pharmaceutical composition according to any one of preferred embodiments 1 to 7, wherein the matrix core comprises between 15 and 40 wt% of hydroxypropyl methylcellulose, the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 9 The pharmaceutical composition according to any one of preferred embodiments 1 to 8, wherein the matrix core comprises between 20 and 30 wt% of hydroxypropyl methylcellulose, the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 10 The pharmaceutical composition according to any one of preferred embodiments 1 to 9, wherein the matrix core comprises between 20 and 60 wt% of microcrystalline cellulose, the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 11 The pharmaceutical composition according to any one of preferred embodiments 1 to 10, wherein the matrix core comprises between 30 and 50 wt% of microcrystalline cellulose, the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 12 The pharmaceutical composition according to any one of preferred embodiments 1 to 11, wherein the matrix core comprises: at least 20 wt% of said decongestant; and from 40 to 80 wt% of a combination of said at least two cellulose derivatives, the weight percentages being expressed with respect to the total weight of the core.
  • Preferred embodiment 13 The pharmaceutical composition according to any one of preferred embodiments 1 to 12, wherein the matrix core comprises: from 20 wt% to 50 wt% of said decongestant; from 15 to 40 wt% of hydroxypropyl methylcellulose; and from 20 to 60 wt% of microcrystalline cellulose; and optionally from 0,1 to 2 wt% of magnesium stearate; and from 0,1 to 1 wt% of a binder; the weight percentages being expressed with respect to the total weight of the core.
  • Preferred embodiment 14 The pharmaceutical composition according to any one of preferred embodiments 1 to 12, wherein the matrix core comprises: from 30 wt% to 40 wt% of said decongestant; from 20 to 30 wt% of hydroxypropyl methylcellulose; and from 30 to 50 wt% of microcrystalline cellulose; and optionally from 0,5 to 1 ,5 wt% of magnesium stearate; and from 0,1 to 1 wt% of a binder; the weight percentages being expressed with respect to the total weight of the core.
  • Preferred embodiment 15 The pharmaceutical composition according to any one of preferred embodiments 1 to 14, wherein said cellulose derivative in the first layer is selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose and microcrystalline cellulose.
  • Preferred embodiment 16 The pharmaceutical composition according to any one of preferred embodiments 1 to 15, wherein said cellulose derivative in the first layer is selected from the group consisting of ethylcellulose, hydroxypropyl methylcellulose and microcrystalline cellulose, preferably ethylcellulose.
  • Preferred embodiment 17 The pharmaceutical composition according to any one of preferred embodiments 1 to 16, wherein the first layer comprises from 0,2 to 3 wt% of said cellulose derivative, the weight percentage being expressed with respect to the total weight of the core without coating.
  • Preferred embodiment 18 The pharmaceutical composition according to any one of preferred embodiments 1 to 17, wherein the first layer comprises from 1,1 to 1 ,5 wt% of said cellulose derivative, the weight percentage being expressed with respect to the total weight of the core without coating.
  • Preferred embodiment 19 The pharmaceutical composition according to any one of preferred embodiments 1 to 18, further comprising a second layer covering said first layer, wherein said second layer is an immediate release layer comprising bilastine.
  • Preferred embodiment 20 The pharmaceutical composition according to preferred embodiment 19, wherein said second layer comprises from 1 to 20 wt% of bilastine, the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 21 The pharmaceutical composition according to any one of preferred embodiments 19 or 20, wherein said second layer comprises from 2 to 18 wt% of bilastine, the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 22 The pharmaceutical composition according to any one of preferred embodiments 19 to 21, wherein said second layer further comprises a further excipient selected from a coating system comprising a cellulose derivative, preferably selected from hydroxypropyl methylcellulose.
  • Preferred embodiment 23 The pharmaceutical composition according to any one of preferred embodiments 19 to 22, wherein said second layer further comprises from 2 to 25 wt% of a further excipient selected from a coating system comprising a cellulose derivative, preferably selected from hydroxypropyl methylcellulose, the weight percentage being expressed with respect to the total weight of the core.
  • a further excipient selected from a coating system comprising a cellulose derivative, preferably selected from hydroxypropyl methylcellulose, the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 24 The pharmaceutical composition according to any one of preferred embodiments 19 to 23, wherein said second layer further comprises from 4 to 14 wt% of a further excipient selected from a coating system comprising a cellulose derivative, preferably selected from hydroxypropyl methylcellulose, the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 25 The pharmaceutical composition according to any one of preferred embodiments 1 to 24, wherein said first layer further comprises a decongestant selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • Preferred embodiment 26 The pharmaceutical composition according to preferred embodiment 25, wherein said first layer comprises: an inner layer, comprising said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose; and an outer layer, comprising said decongestant.
  • said first layer comprises: an inner layer, comprising said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose; and an outer layer, comprising said decongestant.
  • Preferred embodiment 27 The pharmaceutical composition according to any one of preferred embodiments 25 or 26, wherein said first layer comprises: an inner layer, comprising said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose; and an outer layer, comprising said decongestant, further comprising a further excipient selected from a coating system comprising a cellulose derivative, preferably selected from hydroxypropyl methylcellulose.
  • said first layer comprises: an inner layer, comprising said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose; and an outer layer, comprising said decongestant, further comprising a further excipient selected from a coating system comprising a cellulose derivative, preferably selected from hydroxypropyl methylcellulose.
  • Preferred embodiment 28 The pharmaceutical composition according to any one of preferred embodiments 25 to 27, wherein said first layer comprises: an inner layer, comprising said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose; and an outer layer, comprising between 5 and 30 wt% of said decongestant, further comprising a further excipient selected from a coating system comprising a cellulose derivative, preferably selected from hydroxypropyl methylcellulose, the weight percentage being expressed with respect to the total weight of the core.
  • said first layer comprises: an inner layer, comprising said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose; and an outer layer, comprising between 5 and 30 wt% of said decongestant, further comprising a further ex
  • Preferred embodiment 29 The pharmaceutical composition according to any one of preferred embodiments 25 to 28, wherein said first layer comprises: an inner layer, comprising from 0,2 to 3 wt% of said cellulose derivative selected from the group consisting of Cre alkyl celluloses, Cre hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably ethylcellulose; and an outer layer, comprising between 10 and 18 wt% of said decongestant, further comprising from 3 to 15 wt% of a further excipient selected from a coating system comprising a cellulose derivative, preferably selected from hydroxypropyl methylcellulose, the weight percentage being expressed with respect to the total weight of the core.
  • a further excipient selected from a coating system comprising a cellulose derivative, preferably selected from hydroxypropyl methylcellulose, the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 30 The pharmaceutical composition according to any one of preferred embodiments 25 to 29, wherein said first layer comprises an inner sealing layer and an outer immediate release layer of a decongestant.
  • Preferred embodiment 31 The pharmaceutical composition according to any one of preferred embodiments 19 to 24, wherein said second immediate release layer further comprises a decongestant selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • a decongestant selected from the group consisting of pseudoephedrine, phenylephrine, and pharmaceutical salts thereof.
  • Preferred embodiment 32 The pharmaceutical composition according to preferred embodiment 31, wherein said second layer comprises from 1 to 20 wt% of bilastine and between 5 and 30 wt% of said decongestant, further comprising from 2 to 25 wt% of a further excipient selected from a coating system comprising a cellulose derivative, preferably selected from hydroxypropyl methylcellulose, the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 33 The pharmaceutical composition according to any one of preferred embodiments 31 or 32, wherein said second layer comprises from 2 to 18 wt% of bilastine and between 10 and 18 wt% of said decongestant, further comprising from 6 to 14 wt% of a further excipient selected from a coating system comprising a cellulose derivative, preferably selected from hydroxypropyl methylcellulose, the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 34 The pharmaceutical composition according to any one of preferred embodiments 31 to 33, wherein said second layer comprises: an inner layer, comprising from 1 to 20 wt% of bilastine, further comprising from 2 to 16 wt% of a further excipient selected from a coating system comprising a cellulose derivative, preferably selected from hydroxypropyl methylcellulose; and an outer layer, comprising said decongestant. the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 35 The pharmaceutical composition according to any one of preferred embodiments 31 to 34, wherein said second layer comprises: an inner layer, comprising from 1 to 20 wt% of bilastine, further comprising from 2 to 16 wt% of a further excipient selected from a coating system comprising a cellulose derivative, preferably selected from hydroxypropyl methylcellulose; and an outer layer, comprising said decongestant, further comprising a further excipient selected from a coating system comprising a cellulose derivative, preferably selected from hydroxypropyl methylcellulose. the weight percentage being expressed with respect to the total weight of the core.
  • Preferred embodiment 36 The pharmaceutical composition according to any one of preferred embodiments 31 to 35, wherein said second layer comprises: an inner layer, comprising from 1 to 20 wt% of bilastine, further comprising from
  • Preferred embodiment 37 The pharmaceutical composition according to any one of preferred embodiments 31 to 36, wherein said second layer comprises: an inner layer, comprising from 2 to 18 wt% of bilastine, further comprising from
  • Preferred embodiment 38 The pharmaceutical composition according to any one of preferred embodiments 1 to 37, further comprising a pharmaceutically acceptable excipient.
  • Preferred embodiment 39 The pharmaceutical composition according to any one of preferred embodiments 1 to 38, wherein at least 60 wt% of the total amount of decongestant is released within 16 hours after oral administration.
  • Preferred embodiment 40 The pharmaceutical composition according to any one of preferred embodiments 1 to 39, wherein no more than 95 wt% of the total amount of decongestant is released within 16 hours after oral administration.
  • Preferred embodiment 41 The pharmaceutical composition according to any one of preferred embodiments 1 to 40, for use in medicine.
  • Preferred embodiment 42 The pharmaceutical composition according to any one of preferred embodiments 1 to 40, for use in the treatment and/or prevention of a disorder or disease susceptible to amelioration by antagonism of Hi histamine receptor and/or decongestant responsive disease.
  • Preferred embodiment 43 The pharmaceutical composition for use according to preferred embodiment 42, wherein said disorder or disease susceptible to amelioration by antagonism of Hi histamine receptor and/or decongestant responsive disease is an allergic disease, asthma, non-malignant proliferative and inflammatory diseases.
  • Preferred embodiment 44 The pharmaceutical composition for use according to preferred embodiment 43, wherein the use is in the treatment and/or prevention of nasal congestion, sinus congestion, rhinorrhea, eustachian tube congestion, vasomotor rhinitis, allergic rhinitis, rhinoconjunctivitis, allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, giant papillary conjunctivitis, ocular irritation, allergic dermatitis, atopic dermatitis, urticaria, asthma, itchiness, redness, tearing, chemosis, keratitis sicca, keratoconjunctivitis sicca, dysfunctional tear syndrome, croup, sinusitis, otitis media, tracheobronchitis, urinary incontinence, retinopathy and small vessel diseases.
  • Metolose® 90 SH 4000 SR was obtained from Shin etsu Chemical Co Ltd. It is Hydroxypropyl Methylcellulose (Hypromellose) at a viscosity grade of 4000 mPa-s, substitution type 2208. Metolose® 90 SH 100000 SR has a viscosity grade of 100000 mPa-s.
  • Ethylcellulose N-100 was obtained from Ashland and N-100 corresponds to an ethoxyl substitution of 48.0-49.5%, a weight average molecular weight of 215000 and a typical Brookfield viscosity of 80-105.
  • Vivapur® 101 was obtained from JRS Pharma. It is microcrystalline cellulose (particle size 50 pm).
  • PVP K30 was obtained from Ashland. It is povidone (also known as polyvinylpyrrolidone).
  • Pharmacoat® 606 was obtained from Shin etsu Chemical Co Ltd. It is Hydroxypropyl Methylcellulose (Hypromellose) at a viscosity grade of 6 mPa-s, substitution type 2910.
  • PEG 3350 was obtained from Dow chemical.
  • Vivacoat® PA-1 P-000 was obtained from JRS Pharma. It is a coating composition comprising hydroxypropyl methylcellulose (HPMC).
  • Eudragit RS 30 D is, according to the manufacturer Evonik Nutrition & Care GmbH, a copolymer of ethyl acrylate, methyl methacrylate and a low content of a methacrylic acid ester with quaternary ammonium groups (trimethylammonioethyl methacrylate chloride).
  • Example 1 Comparative composition
  • Deionized water for binding were prepared according to the following wet granulation procedure:
  • the cores were coated with the following layer composition,
  • Deionized water evaporates
  • the coating was prepared and applied as follows: 1) The PEG was dissolved in water by paddle stirring;
  • Pseudoephedrine Dissolution test 20,0 ml_ of hydrochloric acid (5N) in 1 L of deionized water so that the pH value of the resulting aqueous solution was 1,20 ⁇ 0,05.
  • HPLC conditions were as follows:
  • the buffer used in the mobile phase was prepared as follows:
  • Results Figure 1 shows the average of the pseudoephedrine release profiles (RSD £ 1,05 wt% for t 3 4 h) of 6 tablets obtained as explained above ( ⁇ ).
  • Metolose® 90 SH 100000 SR 125 25,51
  • the ingredients of the core were screened and sieved before being blended. Then, the magnesium stearate was applied in the lubrication step and the mixture was compressed.
  • the cores were then coated with a 4 wt% Ethylcellulose N-100 ethanol (96 °) solution and coated granules were dried. The coating was conducted so that the weight of the cores increased from 500 g to 505 mg. These granules correspond to an Ethylcellulose N-100 coating concentration of 1 wt%, the weight percentage being calculated on the basis of the final weight of the cores without coating.
  • Pseudoephedrine Dissolution test 6,805 g of KH 2 PO 4 and 0,898 g of NaOH pellets were dissoled in 1000 ml_ of purified water so that the pH value of the resulting aqueous solution was 6,80 ⁇ 0,05.
  • the UPLC conditions were as follows: - Stationary phase: BEH C18 1,7um 2,1 x 100 mm
  • the buffer used in the mobile phase was prepared as follows:
  • Figure 2 shows the average of the pseudoephedrine release profiles of 6 tablets obtained as explained in this example ( ⁇ ).
  • Example 3 Coated formulation 1, according to the invention
  • Deionized water for binding were prepared according to the procedure of example 1 , except that ethylcellulose was not added in the preparation of the cores.
  • the cores were then coated with a 4 wt% Ethylcellulose N-100 ethanol (96 °) solution and coated granules were dried. The coating was conducted so that the weight of the cores increased from 500 mg to 506.25 mg. These granules correspond to an Ethylcellulose N-100 coating concentration of 1,25 wt%, the weight percentage being calculated on the basis of the final weight of the cores without coating.
  • the coated cores were then submitted to a second coating, comprising bilastine.
  • the procedure was conducted as follows:
  • Results Figure 3 shows the average of the bilastine release profiles of 6 tablets obtained as explained in this example (x).
  • Deionized water for binding were prepared according to the procedure of example 1, except that ethylcellulose was not added in the preparation of the cores.
  • the cores were then coated with Ethylcellulose N-100 so that the coating concentration was 1,25 wt%, the weight percentage being calculated on the basis of the final weight of the cores without coating.
  • the coating procedure was as follows:
  • Second layer The coated cores were then submitted to a second coating, comprising bilastine.
  • the procedure was conducted as follows:
  • Results Figure 4 shows the average of the pseudoephedrine release profiles of 6 tablets obtained as explained in this example ( ⁇ ).
  • Figure 5 shows the average of the bilastine release profiles of 6 tablets obtained as explained in this example (x).
  • Metolose 135 (27) 135 (27) 135 (27) 135 (27) 135 (27) 135 (27)
  • API Pseudoephedrine hydrochloride
  • Metolose Metolose® 90 SH 4000 SR
  • Vivapur Vivapur® 101
  • Mg St magnesium stearate
  • Eudragit Eudragit RS 30 D
  • Vivacoat
  • Figure 6 shows the pseudoephedrine release profiles of the tablets prepared according to the invention (identified herein as tablet 1 , described in example 4 as formulation 2) and of comparative tablets.
  • comparative tablets 2, 3, 4 and 5 were prepared according to the procedure of example 3 except for their composition, which varied slightly as shown in detail in the table above and summarized as follows: Comparative tablets 2 (pseudoephedrine release profile depicted in figure 6 as “o”) corresponds to tablets that did not have ethylcellulose in the first layer. In this case, the pseudoephedrine profile was not controlled and almost all pseudoephedrine was released within the first 4 hours. The release profile was therefore not adequate. Comparative tablets 3 (pseudoephedrine release profile depicted in figure 6 as “ ⁇ ”) corresponds to tablets that did not have hydroxypropyl methylcellulose in the core.
  • Comparative tablets 4 corresponds to tablets that were prepared with ethylcellulose in the core (mixed with HPMC) but without ethylcellulose in the first layer. This sample is similar to comparative sample 2 in the sense that it did not have ethylcellulose in the first layer. In this case, just as for sample 2, the pseudoephedrine profile was not controlled and almost all pseudoephedrine was released within the first 4 hours. The release profile was therefore not adequate.
  • Comparative tablets 5 corresponds to tablets that had the ethylcellulose in the first layer replaced with Eudragit RS 30 D.
  • the pseudoephedrine profile was not controlled and more than 80% of the total pseudoephedrine was released within the first 6 hours. The release profile was therefore not adequate.
  • Deionized water for binding were prepared according to the procedure of example 1, except that ethylcellulose was not added in the preparation of the cores.
  • the cores were then coated with three Ethylcellulose N-100 concentrations, so that the coating concentrations were 1,20 wt%, 1,30 wt%, and 1,40 wt%, the weight percentage being calculated on the basis of the final weight of the cores without coating.
  • the coating procedure was as follows:
  • the coated cores were then submitted to a second coating, comprising bilastine and pseudoefedrine.
  • the procedure was conducted as follows:
  • the final tablets comprised bilastine 4 wt%, pseudoefedrine 12 wt% and Vivacoat 12,2 wt%, the weights calculated on the basis of the final weight of the cores without coating.
  • Figure 7 shows the pseudoephedrine release profiles of the tablets prepared according to the present example for each concentration of Ethylcellulose: 1 ,20 wt% “o”; 1,30 wt% and 1 ,40 wt% “D”. The profiles of these tablets were characterized by an immediate release of pseudoephedrine followed by the controlled release of the pseudoephedrine.
  • Figure 7 also shows the release profile of the tablets according to example 4 (identified in Figure 7 as tablet 1 ( ⁇ ), described in example 4 as formulation 2).

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Abstract

La présente invention concerne une composition pharmaceutique orale multicouches comprenant un noyau matriciel, composé d'un décongestionnant et d'une combinaison d'au moins deux dérivés de cellulose, une première couche comprenant un dérivé de cellulose et une seconde couche facultative comprenant de la bilastine. La présente invention fournit une forme posologique orale comprenant un médicament décongestionnant et de la bilastine avec un profil reproductible caractérisé par une libération contrôlée du décongestionnant sur une période supérieure à 12 heures et de préférence d'au moins 16 heures et une libération immédiate de la bilastine après administration orale. L'invention concerne en outre des utilisations médicales de celle-ci.
PCT/EP2021/071244 2020-07-30 2021-07-29 Système d'administration de médicaments décongestionnants WO2022023463A1 (fr)

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CR20230109A CR20230109A (es) 2020-07-30 2021-07-29 Sistema de liberación de fármacos descongestivos y bilastina
EP21755715.6A EP4188339A1 (fr) 2020-07-30 2021-07-29 Système d'administration de médicaments décongestionnants
DO2023000017A DOP2023000017A (es) 2020-07-30 2023-01-27 Sistema de liberación de fármacos descongestivos y bilastina
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