Decongestant controlled release drug delivery system

Abstract

The present invention relates to a controlled release pharmaceutical composition comprising a decongestant, an acrylate copolymer, a cellulose derivative and a crosslinked acrylic acid polymer. The present invention provides an oral dosage form exhibiting 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 after oral administration. The invention further contemplates medical uses thereof. The release profile of the delivery system of the invention is highly reproducible and can be administered once daily, thus improving patient compliance.

Description

[0001] DECONGESTANT CONTROLLED RELEASE DRUG DELIVERY SYSTEM Field of invention

[0002] 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, optionally, an immediate release of bilastine and decongestant. The release profile of the delivery system of the invention is highly reproducible and can be administered once daily, thus improving patient compliance.

[0003] Background of the invention

[0004] 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 H2SO4) 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.

[0005] 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.

[0006] It has long been known that histamine plays a very important role in allergic-type diseases, such as allergic rhinitis, conjunctivitis, rhinoconjunctivitis, dermatitis, urticaria and asthma. Antihistaminic compounds acting at the H1-receptor histamine level are useful for treating such conditions. In this sense, documents EP 0818454 A1 and EP 0580541 A1 as well as patent application EP14382576.8 disclose benzimidazole compounds with selective H1antihistaminic activity and devoid of arrhythmogenic effects.

[0007] A particular compound with the above properties is the second-generation antihistamine 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl}ethyl)phenyl]-2-methyl propanoic acid, also known as bilastine, having formula:

[0008]

[0009] and developed by Faes Farma, Spain. Bilastine is a H1antagonist benzimidazole compound with no sedative side effects, no cardiotoxic effects, and no hepatic metabolism. In addition, bilastine has proved to be effective for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria.

[0010] 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.

[0011] 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.

[0012] 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.

[0013] International PCT application WO 94 / 09761 A1 discloses tablets containing a matrix core comprising pseudoephedrine wherein the core is coated with an acrylate coating and a coating comprising desloratadine.

[0014] JP2005015371A2 discloses bilayer tablets comprising pseudoephedrine and antihistamines.

[0015] However, no solution exists to the problem of providing a drug system comprising a decongestant drug as a once-daily formulation capable of a highly reproducible and adequate release profile. of invention

[0016] In a first aspect, the present invention provides a controlled release pharmaceutical composition comprising:

[0017] - a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof;

[0018] - an acrylate copolymer of C1-6 alkyl acrylates, C1-6 alkyl methacrylates and trimethylammonium C1-6 alkyl methacrylates;

[0019] - a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose; and

[0020] - a crosslinked acrylic acid polymer.

[0021] In a second aspect, the invention is directed at a multi-layer pharmaceutical composition comprising:

[0022] - a first layer comprising the controlled release pharmaceutical composition of the invention; and

[0023] - a second layer, in contact with the first layer, comprising

[0024] - bilastine or a pharmaceutical salt thereof; and

[0025] - a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof.

[0026] In a third aspect, the invention is directed at a process for the preparation of the controlled release pharmaceutical composition of the first aspect, comprising the steps of:

[0027] a) blending at least

[0028] i. a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof;

[0029] ii. an acrylate copolymer of C1-6 alkyl acrylates, C1-6 alkyl methacrylates and trimethylammonium C1-6 alkyl methacrylates;

[0030] iii. a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose; and

[0031] iv. a crosslinked acrylic acid polymer;

[0032] b. submit the blend of the previous step to a dry granulation process, preferably a slugging process;

[0033] c. sieving the granules obtained in the previous step; and d. optionally submit the sieved granules to a lubrication step.

[0034] In a fourth aspect, the invention is directed at a process for the preparation of the multilayer pharmaceutical composition of the second aspect, comprising the steps of:

[0035] A. Preparation of a controlled release pharmaceutical composition by,

[0036] a) blending at least,

[0037] i. a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof;

[0038] ii. an acrylate copolymer of C1-6 alkyl acrylates, C1-6 alkyl methacrylates and trimethylammonium C1-6 alkyl methacrylates;

[0039] iii. a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose; and

[0040] iv. a crosslinked acrylic acid polymer;

[0041] b. submit the blend of the previous step to a dry granulation process, preferably a slugging process;

[0042] c. sieving the granules obtained in the previous step; and

[0043] d. optionally submit the sieved granules to a lubrication step;

[0044] B. Preparation of an immediate release composition by sieveing bilastine or a pharmaceutical salt thereof with a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof, and optionally further excipients, blending the ingredients, and optionally lubricate the blend; and C. Compressing the granule composition of step A to obtain a first layer, and compressing the blend composition of step B on said first layer, to obtain a multilayer tablet.

[0045] In a fifth aspect, the invention is directed at the controlled release pharmaceutical composition of the first aspect, or the multi-layer pharmaceutical composition of the second aspect, for use in medicine.

[0046] Furthermore, the compositions of the invention are 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. In a sixth aspect, the present invention is directed at the controlled release pharmaceutical composition of the first aspect, or the multi-layer pharmaceutical composition of the second aspect, for use in the treatment and / or prevention of a disorder or disease susceptible to amelioration by antagonism of H1histamine receptor and / or decongestant responsive disease.

[0047] Brief description of the drawings

[0048] Figure 1 shows the curves of pseudoephedrine release profiles of four batches of compressed granule formulations obtained as explained in example 1 (average results of 6 tablets for each batch).

[0049] Figure 2 shows the curve of bilastine release profile of one batch of a compressed blend formulation using sodium carboxymethyl starch type A, obtained as explained in example 2, wherein the total weight is 160 mg (average results of 6 tablets).

[0050] Figure 3 shows the curve of bilastine release profile of one batch of a compressed blend formulation using sodium carboxymethyl starch type A, obtained as explained in example 2, wherein the total weight is 365 mg (average results of 6 tablets).

[0051] Figure 4 shows the curves of pseudoephedrine release profiles of comparative compositions obtained as explained in example 6. Comparative composition 1 (□), comparative composition 2 (A), comparative composition 3 (A) and comparative composition 4 (■), together with the pseudoephedrine dissolution curve of the averaged curves of figure 1 wherein (•) is the composition according to the present invention.

[0052] Detailed description of invention

[0053] In a first aspect, the present invention provides a controlled release pharmaceutical composition comprising:

[0054] - a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof;

[0055] - an acrylate copolymer of C1-6 alkyl acrylates, C1-6 alkyl methacrylates and trimethylammonium C1-6 alkyl methacrylates;

[0056] - a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, Ci- 6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose; and a crosslinked acrylic acid polymer.

[0057] The decongestant is classified as BCS (Biopharmaceutics Classification System) class I (high permeability and solubility) and yet, the inventors have surprisingly found that the combination of the three excipients (acrylate copolymer, cellulose derivative, and crosslinked acrylic acid polymer) allows for a sustained 24 hour controlled release of the decongestant.

[0058] Controlled release pharmaceutical composition

[0059] The controlled release composition of the invention comprises a decongestant selected from the group consisting of pseudephedrine and pharmaceutical salts thereof. Pharmaceutical salts include sulfate or hydrochloride salts.

[0060] Preferably, the decongestant is the hydrochloride salt of pseudephedrine.

[0061] In a particular embodiment, the controlled release composition of the invention comprises at least 20 wt% of the decongestant, preferably at least 25 wt% of the decongestant, the weight percentage being expressed with respect to the total weight of the composition.

[0062] In the context of the present invention, the expression “the weight percentage” refers to wt%, and the expression “the weight percentage being expressed with respect to the total weight of the composition” is to be interpreted as the weight of the ingredient to which it refers to multiplied by 100 and divided by the total weight of the controlled release composition.

[0063] In a preferred embodiment, the controlled release composition of the first aspect is a granule composition. In this preferred embodiment, the expression “weight percentage being expressed with respect to the total weight of the composition” is to be interpreted as “weight percentage being expressed with respect to the total weight of the granule composition”.

[0064] In a most preferred embodiment, the controlled release composition of the first aspect is a compressed granule composition, i.e., a tablet. In this most preferred embodiment, the expression “weight percentage being expressed with respect to the total weight of the composition” is to be interpreted as “weight percentage being expressed with respect to the total weight of the compressed granule composition”. When expressed as wt%, the sum of the wt% of all ingredients must never be greater than 100% and the skilled person will readily understand which ranges are workable to provide, when necessary, the amounts so that there is a 100% sum of the wt% values. In another particular embodiment, the controlled release composition of the invention comprises no more than 35 wt% of the decongestant, preferably no more than 30 wt% of the decongestant, the weight percentage being expressed with respect to the total weight of the composition.

[0065] In a particular embodiment, the controlled release composition of the invention comprises between 20 wt% and 35 wt% of the decongestant, preferably between 25 wt% and 30 wt% of the decongestant, the weight percentage being expressed with respect to the total weight of the composition.

[0066] In a particular embodiment, the controlled release composition of the invention comprises at least 120 mg of the decongestant, preferably at least 150 mg of the decongestant, more preferably at least 160 mg of decongestant.

[0067] In another particular embodiment, the controlled release composition of the invention comprises no more than 240 mg of the decongestant, preferably no more than 210 mg of the decongestant, more preferably no more than 200 mg of decongestant.

[0068] In a particular embodiment, the controlled release composition of the invention comprises between 120 mg and 200 mg of the decongestant, preferably between 150 mg and 210 mg of the decongestant, and more preferably between 160 mg and 200 mg of decongestant.

[0069] The controlled release composition of the invention comprises at least three excipients. A first excipient is an acrylate copolymer of C1-6 alkyl acrylates, C1-6 alkyl methacrylates and trimethylammonium C1-6 alkyl methacrylates.

[0070] Several acrylate copolymers are known under the trade name Eudragit®.

[0071] In a particular embodiment, the controlled release composition of the invention comprises an acrylate copolymer of:

[0072] - a C1-6 alkyl acrylate selected from the group consisting of methyl acrylate, ethyl acrylate and propyl acrylate, preferably ethyl acrylate;

[0073] - a C1-6 alkyl methacrylate selected from the group consisting of methyl methacrylate, ethyl methacrylate and propyl methacrylate, preferably methyl methacrylate; and - a trimethylammonium C1-6 alkyl methacrylate selected from the group consisting of trimethylammonium methyl methacrylate, trimethylammonium ethyl methacrylate and trimethylammonium propyl methacrylate, preferably trimethylammonium ethyl methacrylate.

[0074] In a preferred embodiment, the trimethylammonium C1-6 alkyl methacrylate is trimethylammonium C1-6 alkyl methacrylate chloride.

[0075] In a particular embodiment, the controlled release composition of the invention comprises at least 17 wt% of the acrylate copolymer, preferably at least 20 wt%, the weight percentage being expressed with respect to the total weight of the composition In another particular embodiment, the controlled release composition of the invention comprises no more than 28 wt% of the acrylate copolymer, preferably no more than 25 wt%, the weight percentage being expressed with respect to the total weight of the composition.

[0076] In a particular embodiment, the controlled release composition of the invention comprises between 17 wt% and 28 wt% of the acrylate copolymer, preferably between 20 wt% and 25 wt%, the weight percentage being expressed with respect to the total weight of the composition.

[0077] In a preferred embodiment, the controlled release composition of the invention comprises an acrylate copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate, more preferably as a 1:2:0.1 mixture. This copolymer is sold under the tradename Eudragit® RS PO and RS 30 D and more information can be found in textbooks, for example, at the Handbook of Pharmaceutical Excipients, 6th Ed., 2009, editors: Raymond C Rowe, Paul J Sheskey, and Marian E Quinn.

[0078] Therefore, in a preferred embodiment the controlled release composition of the invention comprises between 17 wt% and 28 wt%, more preferably between 20 wt% and 25 wt%, of an acrylate copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate, the weight percentage being expressed with respect to the total weight of the composition.

[0079] In a particular embodiment, the controlled release composition of the invention comprises at least 100 mg, preferably at least 120 mg, more preferably at least 130 mg, of the acrylate copolymer. In a particular embodiment, the controlled release composition of the invention comprises no more than 190 mg, preferably no more than 170 mg, more preferably no more than 160 mg, of the acrylate copolymer.

[0080] In a particular embodiment, the controlled release composition of the invention comprises between 100 mg and 190 mg, preferably between 120 mg and 170 mg, more preferably between 130 mg and 160 mg, of the acrylate copolymer.

[0081] In a preferred embodiment, the controlled release composition of the invention comprises between 100 mg and 190 mg, more preferably between 120 mg and 170 mg, even more preferably between 130 mg and 160 mg, of an acrylate copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate.

[0082] A second excipient in the controlled release composition of the invention is a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose.

[0083] In a particular embodiment, said cellulose derivative is selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose and microcrystalline cellulose. Preferably, said cellulose derivative is selected from the group consisting of ethylcellulose, hydroxypropyl methylcellulose and microcrystalline cellulose.

[0084] More preferably, said cellulose derivative is hydroxypropyl methylcellulose. A particularly preferred hydroxypropyl methylcellulose (HPMC) is Metolose® 90SH 4000 SR, which according to the Ph. Eur. is characterized by a substitution type 2208, a viscosity of 4000 mPa.s, a d10, d50and d90of 18.8 μm, 80.4 μm, and 208.5 μm, respectively, a span of 2.4 and a density (g / cm3) of 1.32.

[0085] In a particular embodiment, the controlled release composition of the invention comprises at least 5 wt% of the cellulose derivative, preferably at least 10 wt%, the weight percentage being expressed with respect to the total weight of the composition. In a particular embodiment, the controlled release composition of the invention comprises no more than 20 wt% of the cellulose derivative, preferably no more than 15 wt%, the weight percentage being expressed with respect to the total weight of the composition.

[0086] In a particular embodiment, the controlled release composition of the invention comprises between 5 wt% and 20 wt% of the cellulose derivative, preferably between 10 wt% and 15 wt%, the weight percentage being expressed with respect to the total weight of the composition.

[0087] In a preferred embodiment, the controlled release composition of the invention comprises between 5 wt% and 20 wt% of hydroxypropyl methylcellulose, preferably between 10 wt% and 15 wt%, the weight percentage being expressed with respect to the total weight of the composition.

[0088] In a particular embodiment, the controlled release composition of the invention comprises at least 50 mg of the cellulose derivative, preferably at least 65 mg, more preferably at least 75 mg.

[0089] In a particular embodiment, the controlled release composition of the invention comprises no more than 105 mg of the cellulose derivative, preferably no more than 90 mg, more preferably no more than 80 mg.

[0090] In a particular embodiment, the controlled release composition of the invention comprises between 50 mg and 105 mg of the cellulose derivative, preferably between 65 mg and 90 mg, more preferably between 75 mg and 80 mg.

[0091] In a preferred embodiment, the controlled release composition of the invention comprises between 50 mg and 105 mg of hydroxypropyl methylcellulose, more preferably between 65 mg and 90 mg, even more preferably between 75 mg and 80 mg.

[0092] A third excipient in the controlled release composition of the invention is a crosslinked acrylic acid polymer. Such a crosslinked acrylic acid polymer is known as carbomer, or Carbopol, well known and characterised in the United States Pharmacopeia / National Formulary (USP / NF) monograph for Carbomers and the European Pharmacopeia (Ph. Eur.) monograph for Carbomers.

[0093] These polymers may be cross-linked by polyalcohol allyl ethers, for example, allyl sucrose or allyl pentaerythritol. Thus, in a particular embodiment, the crosslinked acrylic acid polymer is crosslinked with allyl sucrose or allyl ethers of pentaerythritol.

[0094] In a particular embodiment, the carbomer is a homopolymer, for example 910, 934P, 940GE, 941 GE, 971 P, 974P, wherein " GE" refers to medical grade and " P" oral grade. The carbomer may have a viscosity of from 4,000 to 70,000, for example 10,000 to 60,000, for 20,000 to 50,000, 25,000 to 45,000 or 29,400 to 39,400 cP, wherein the viscosity is that of a 0.5 wt% solution of the carbomer in water, neutralised to pH 7.3 -7.8 at 25°C, measured using a Brookfield RVT, 20 rpm, spindle #6. In a particular embodiment, the carbomer comprises from 56% to 68.0 % by weight carboxylic acid (-COOH) groups, measured by titrating an aqueous solution or dispersion of the polymer against NaOH.

[0095] In a preferred embodiment, the crosslinked acrylic acid polymer is Carbopol 974P ®. This carbomer, of CAS number 151687-96-6, has a viscosity of 29400 to 39400 cP (0.5% solution in water neutralized to pH 7.3 - 7.8 and measured at 25°C using a Brookfield RVT, 20 rpm with spindle #6). The carbomer typically has a carboxylic acid content of from 56 to 68%.

[0096] In a particular embodiment, the controlled release composition of the invention comprises at least 20 wt% of the crosslinked acrylic acid polymer, preferably at least 25 wt%, the weight percentage being expressed with respect to the total weight of the composition.

[0097] In a particular embodiment, the controlled release composition of the invention comprises no more than 40 wt% of the crosslinked acrylic acid polymer, preferably no more than 35 wt%, the weight percentage being expressed with respect to the total weight of the composition.

[0098] In a particular embodiment, the controlled release composition of the invention comprises between 20 wt% and 40 wt% of the crosslinked acrylic acid polymer, preferably between 25 wt% and 35 wt%, the weight percentage being expressed with respect to the total weight of the composition.

[0099] In a preferred embodiment, the controlled release composition of the invention comprises between 20 wt% and 40 wt% of Carbopol 974P ®, preferably between 25 wt% and 35 wt%, the weight percentage being expressed with respect to the total weight of the composition.

[0100] In a particular embodiment, the controlled release composition of the invention comprises at least 130 mg of the crosslinked acrylic acid polymer, preferably at least 160 mg, more preferably at least 170 mg.

[0101] In a particular embodiment, the controlled release composition of the invention comprises no more than 250 mg of the crosslinked acrylic acid polymer, preferably no more than 220 mg, more preferably no more than 210 mg.

[0102] In a particular embodiment, the controlled release composition of the invention comprises between 130 mg and 250 mg of the crosslinked acrylic acid polymer, preferably between 160 mg and 220 mg, more preferably between 170 mg and 210 mg. In a preferred embodiment, the controlled release composition of the invention comprises between 130 mg and 250 mg of Carbopol 974P ®, more preferably between 160 mg and 220 mg, even more preferably between 170 mg and 210 mg.

[0103] In a preferred embodiment, the controlled release composition of the invention comprises:

[0104] - between 20 wt% and 35 wt% of pseudoephedrine or a pharmaceutical salt thereof; - between 17 wt% and 28 wt% of an acrylate copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate;

[0105] - between 5 wt% and 20 wt% of a cellulose derivative selected from the group consisting of ethylcellulose, hydroxypropyl methylcellulose and microcrystalline cellulose, preferably hydroxypropyl methylcellulose; and

[0106] - between 20 wt% and 40 wt% of a crosslinked acrylic acid polymer, preferably Carbopol 974P ®;

[0107] the weight percentages being expressed with respect to the total weight of the composition.

[0108] In a more preferred embodiment, the controlled release composition of the invention comprises:

[0109] - between 25 wt% and 30 wt% of pseudoephedrine or a pharmaceutical salt thereof; - between 20 wt% and 25 wt% of an acrylate copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate;

[0110] - between 10 wt% and 15 wt% of hydroxypropyl methylcellulose; and

[0111] - between 25 wt% and 35 wt% of Carbopol 974P ®;

[0112] the weight percentages being expressed with respect to the total weight of the composition.

[0113] In addition to the at least three excipients described above, the controlled release composition of the invention may comprise further pharmaceutically acceptable excipients.

[0114] The expression "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.

[0115] The expression "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. Preferably, the term "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.

[0116] Thus, in a particular embodiment, the controlled release composition of the invention further comprises a vinylpyrrolidone-based polymer.

[0117] In a particular embodiment, the vinylpyrrolidone-based polymer is selected from the group consisting of povidone and copovidone, preferably copovidone. Povidone is a linear, water-soluble polymer made from N-vinylpyrrolidone. Copovidone (also known as copolyvidone) is a linear, water-soluble copolymer of 1-vinyl-2-pyrrolidone (povidone) and vinyl acetate in a ratio of 6:4 by mass. Copovidone may be procured from BASF (Kollidon VA 64).

[0118] In a particular embodiment, the controlled release composition of the invention comprises from 1 wt% to 10 wt% of a vinylpyrrolidone-based polymer, preferably copovidone, the weight percentage being expressed with respect to the total weight of the composition.

[0119] In a preferred embodiment, the controlled release composition of the invention comprises from 4 wt% to 8 wt% of a vinylpyrrolidone-based polymer, more preferably copovidone, the weight percentage being expressed with respect to the total weight of the composition.

[0120] In a particular embodiment, the controlled release composition of the invention comprises from 25 mg to 50 mg of a vinylpyrrolidone-based polymer, preferably copovidone.

[0121] In a preferred embodiment, the controlled release composition of the invention comprises from 35 mg to 42 mg of a vinylpyrrolidone-based polymer, more preferably copovidone. In another particular embodiment, the controlled release composition of the invention further comprises a lubricant excipient, preferably selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, polyethylene glycol, colloidal silicon dioxide, sodium stearyl fumarate, carnauba wax and mixtures thereof. Preferably the lubricant is magnesium stearate.

[0122] In a particular embodiment, the controlled release composition of the invention further comprises a lubricant excipient, in an amount of at least 0.1 wt%, preferably at least 0.3 wt%, more preferably at least 0.4 wt%, the weight percentage being expressed with respect to the total weight of the composition.

[0123] In a particular embodiment, the controlled release composition of the invention further comprises a lubricant excipient, in an amount of no more than 2.0 wt%, preferably no more than 1.0 wt%, more preferably no more than 0.6 wt%, the weight percentage being expressed with respect to the total weight of the composition.

[0124] In a preferred embodiment, the controlled release composition of the invention further comprises a lubricant excipient, in an amount of from 0.1 wt% to 2.0 wt%, preferably from 0.3 wt% to 1.0 wt%, more preferably from 0.4 wt% to 0.6 wt%, the weight percentage being expressed with respect to the total weight of the composition.

[0125] In a particular embodiment, the controlled release composition of the invention further comprises a lubricant excipient, in an amount of at least 2 mg, preferably at least 2.5 mg, more preferably at least 3 mg.

[0126] In another particular embodiment, the controlled release composition of the invention further comprises a lubricant excipient, in an amount of no more than 5 mg, preferably no more than 4.5 mg, more preferably no more than 4 mg.

[0127] In a preferred embodiment, the controlled release composition of the invention further comprises a lubricant excipient, in an amount of from 2 mg to 5 mg, preferably from 2.5 mg to 4.5 mg, more preferably from 3 mg to 4 mg.

[0128] In a particular embodiment, the controlled release composition of the invention weighs from 427 mg to 838 mg, preferably from 530 mg to 740 mg, more preferably from 560 mg to 700 mg, even more preferably from 600 mg to 650 mg.

[0129] The inventors have surprisingly found that the particular combination of excipients in the controlled release composition of the invention allows for a blend with good compressibility and adequate hardness.

[0130] Therefore, in a preferred embodiment the controlled release composition of the invention is a granule composition, more preferably a compressed granule composition, i.e., a tablet. In a particular embodiment, the granule composition of the invention exhibit a hardness of at least 100 N, preferably of at least 150 N, more preferably of at least 200 N.

[0131] In a further particular embodiment, the granule composition of the invention comprises a pharmaceutically acceptable coloring agent. Coloring agents are added to the granule composition to yield a desired color. Suitable coloring agents are known in the art and include iron oxide red (Fe2O3, E172), sunset yellow FCF (E-110), indigo carmine (E-132), erythrosine (E-127), quinoline yellow (E-104), and the like. Preferably, the granule composition comprises iron oxide red. If present, the amounts of colorant are comprised between 0.1 to 0.5 wt%, preferably between 0.2 and 0.5 wt%, more preferably between 0.3 and 0.5 wt%, the weight percentage being expressed with respect to the total weight of the granule composition of the invention.

[0132] Multi-layer pharmaceutical composition

[0133] In a preferred embodiment, the controlled release pharmaceutical composition of the invention is a compressed granule composition forming a first layer, which can further comprise a second layer of a composition comprising bilastine. In this way, in a second aspect, the invention is directed at a multi-layer pharmaceutical composition comprising: - a first layer comprising the controlled release pharmaceutical composition of the invention; and

[0134] - a second layer, in contact with the first layer, comprising

[0135] - bilastine or a pharmaceutical salt thereof; and

[0136] - a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof.

[0137] In a preferred embodiment, multi-layer pharmaceutical composition is a tablet, preferably a bilayer tablet. In a particularly preferred embodiment, the first layer consists of the granule composition as described above, which means that the first layer is a controlled release layer.

[0138] The particular and preferred embodiments described above for the controlled release pharmaceutical composition of the invention also apply to the first layer.

[0139] In a particular embodiment, said second layer is in direct contact with the first layer. Said second layer is a pharmaceutical composition. In a preferred embodiment, said second layer is an immediate release layer.

[0140] In a particular embodiment, the second layer comprises between 2 and 20 wt% of bilastine, preferably between 3 and 18 wt%, more preferably between 7 and 18 wt%, even more preferably between 10 and 15 wt%, the weight percentage being expressed with respect to the total weight of the second layer. In another particular embodiment, the second layer comprises between 2 and 10 wt% of bilastine, preferably between 3 and 10 wt%, more preferably between 4 and 10 wt%, even more preferably between 4 and 7 wt%, the weight percentage being expressed with respect to the total weight of the second layer.

[0141] In another particular embodiment, the second layer comprises between 13 and 27 mg of bilastine, preferably between 15 and 25 mg, more preferably between 18 and 22 mg. In a preferred embodiment, the decongestant in the second layer is selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof. A particularly preferred decongestant is the hydrochloride salt of pseudephedrine.

[0142] In a particular embodiment, the second layer comprises at least 10 wt% of the decongestant, at least 15 wt% of the decongestant, at least 25 wt% of the decongestant, preferably at least 30 wt%, more preferably at least 35 wt%, of the decongestant, the weight percentage being expressed with respect to the total weight of the second layer. In a particular embodiment, the second layer comprises no more than 45 wt% of the decongestant, preferably no more than 43 wt%, more preferably no more than 40 wt%, of the decongestant, the weight percentage being expressed with respect to the total weight of the second layer.

[0143] In another particular embodiment, the second layer comprises between 10 wt% and 45 wt% of the decongestant, between 15 wt% and 45 wt% of the decongestant, between 25 wt% and 45 wt% of the decongestant, preferably between 30 wt% and 43 wt% of the decongestant, more preferably between 35 wt% and 40 wt% of the decongestant, the weight percentage being expressed with respect to the total weight of the second layer. In a preferred embodiment, the second layer comprises between 10 wt% and 45 wt% of pseudoephedrine, between 15 wt% and 45 wt% of pseudoephedrine, between 25 wt% and 45 wt% of pseudoephedrine, more preferably between 30 wt% and 43 wt% of pseudoephedrine, even more preferably between 35 wt% and 40 wt% of pseudoephedrine, the weight percentage being expressed with respect to the total weight of the second layer.

[0144] In a particular embodiment, the second layer comprises at least 40 mg of the decongestant, preferably at least 50 mg, more preferably at least 55 mg, of the decongestant. In a particular embodiment, the second layer comprises no more than 80 mg of the decongestant, preferably no more than 70 mg, more preferably no more than 65 mg, of the decongestant.

[0145] In another particular embodiment, the second layer comprises between 40 mg and 80 mg of the decongestant, preferably between 50 mg and 70 mg of the decongestant, more preferably between 55 mg and 65 mg of the decongestant.

[0146] In a preferred embodiment, the second layer comprises between 40 mg and 80 mg of the pseudoephedrine, preferably between 50 mg and 70 mg of the pseudoephedrine, more preferably between 55 mg and 65 mg of the pseudoephedrine.

[0147] In a particular embodiment, the second layer comprises at least a further pharmaceutically acceptable excipient.

[0148] Thus, in a particular embodiment, the second layer further comprises a desintegrant. A desintegrant is defined as a pharmaceutically acceptable excipient that swells in contact with water and helps to the dispersion and to the solubilization of the immediate release second layer.

[0149] In a preferred embodiment, said desintegrant is selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, sodium starch glycolate, low substituted hydroxypropylcellulose, crosslinked polyvinylpyrrolidinone and mixtures thereof, more preferably carboxymethylcellulose, carboxy methyl starch and mixtures thereof, and even more preferably carboxymethylcellulose sodium, carboxy methyl starch and mixtures thereof.

[0150] In a particular embodiment, the second layer comprises at least 5 wt%, preferably at least 6 wt%, of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, sodium starch glycolate, low substituted hydroxypropylcellulose, crosslinked polyvinylpyrrolidinone and mixtures thereof, the weight percentage being expressed with respect to the total weight of the second layer. In another particular embodiment, the second layer comprises no more than 15 wt%, preferably no more than 9 wt%, of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, sodium starch glycolate, low substituted hydroxypropylcellulose, crosslinked polyvinylpyrrolidinone and mixtures thereof, the weight percentage being expressed with respect to the total weight of the second layer. In a preferred embodiment, the second layer comprises between 5 wt% and 15 wt% of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, and mixtures thereof, the weight percentage being expressed with respect to the total weight of the second layer.

[0151] In a preferred embodiment, the second layer comprises between 6 wt% and 9 wt% of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, and mixtures thereof, the weight percentage being expressed with respect to the total weight of the second layer.

[0152] In a particular embodiment, the second layer comprises at least 8 mg, preferably at least 10 mg, of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, sodium starch glycolate, low substituted hydroxypropylcellulose, crosslinked polyvinylpyrrolidinone and mixtures thereof.

[0153] In another particular embodiment, the second layer comprises no more than 35 mg, no more than 30 mg, preferably no more than 17 mg, more preferably no more than 15 mg, of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, sodium starch glycolate, low substituted hydroxypropylcellulose, crosslinked polyvinylpyrrolidinone and mixtures thereof.

[0154] In a preferred embodiment, the second layer comprises between 8 mg and 35 mg, more preferably between 8 mg and 17 mg of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, and mixtures thereof.

[0155] In a preferred embodiment, the second layer comprises between 10 mg and 30 mg, more preferably, between 10 mg and 15 mg of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, and mixtures thereof. In yet another particular embodiment, the second layer comprises a cellulose derivative as a pharmaceutically acceptable excipient, further to those described above.

[0156] In this way, in a particular embodiment, the second layer comprises a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose. Preferably, a cellulose derivative selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose and microcrystalline cellulose. More preferably, said cellulose derivative is microcrystalline cellulose.

[0157] In a particular embodiment, the second layer comprises at least 30 wt%, preferably at least 35 wt%, of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose, the weight percentage being expressed with respect to the total weight of the second layer.

[0158] In another particular embodiment, the second layer comprises no more than 70 wt%, no more than 50 wt%, preferably no more than 40 wt% of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose, the weight percentage being expressed with respect to the total weight of the second layer.

[0159] In a particular embodiment, the second layer comprises between 30 wt% and 70 wt%, preferably between 30 wt% and 50 wt% of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose, the weight percentage being expressed with respect to the total weight of the second layer.

[0160] In a preferred embodiment, the second layer comprises between 35 wt% and 70 wt%, more preferably between 35 wt% and 40 wt% of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, more preferably microcrystalline cellulose, the weight percentage being expressed with respect to the total weight of the second layer. In a particular embodiment, the second layer comprises at least 40 mg, preferably at least 55 mg, of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose.

[0161] In another particular embodiment, the second layer comprises no more than 250 mg, no more than 245 mg, preferably no more than 80 mg, more preferably no more than 70 mg of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose.

[0162] In a particular embodiment, the second layer comprises between 40 mg and 250 mg, preferably between 40 mg and 80 mg of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose.

[0163] In a preferred embodiment, the second layer comprises between 55 mg and 245 mg, more preferably between 55 mg and 70 mg of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, more preferably microcrystalline cellulose. In yet another particular embodiment, the second layer comprises a lubricant as a pharmaceutically acceptable excipient, further to those described above.

[0164] Thus, in another particular embodiment, the second layer comprises a lubricant excipient, preferably selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, polyethylene glycol, colloidal silicon dioxide, sodium stearyl fumarate, carnauba wax and mixtures thereof. Preferably the lubricant is magnesium stearate.

[0165] In a particular embodiment, the second layer comprises a lubricant excipient, in an amount of at least 0.5 wt%, preferably at least 1.0 wt%, more preferably at least 1.3 wt%, the weight percentage being expressed with respect to the total weight of the second layer.

[0166] In a particular embodiment, the second layer comprises a lubricant excipient, in an amount of no more than 2.5 wt%, preferably no more than 2.1 wt%, more preferably no more than 1.9 wt%, the weight percentage being expressed with respect to the total weight of the second layer.

[0167] In a preferred embodiment, the second layer comprises a lubricant excipient, in an amount of from 0.5 wt% to 2.5 wt%, preferably from 1.0 wt% to 2.1 wt%, more preferably from 1.3 wt% to 1.9 wt%, the weight percentage being expressed with respect to the total weight of the second layer.

[0168] In a particular embodiment, the second layer comprises a lubricant excipient, in an amount of at least 1.6 mg, preferably at least 2.0 mg, more preferably at least 2.2 mg. In another particular embodiment, the second layer comprises a lubricant excipient, in an amount of no more than 6.5 mg, preferably 3.3 mg, more preferably no more than 2.9 mg and even more preferably no more than 2.8 mg.

[0169] In a preferred embodiment, the second layer comprises a lubricant excipient, in an amount of from 1.6 mg to 6.5 mg, preferably from 1.6 mg to 3.3 mg, more preferably from 2.0 mg to 2.9 mg and even more preferably from 2.2 mg to 2.8 mg.

[0170] In a particular embodiment, the second layer weighs from 100 mg to 400 mg, preferably from 130 mg to 380 mg, more preferably from 140 mg to 375 mg, even more preferably from 150 mg to 375 mg. In another particular embodiment, the second layer weighs from 100 mg to 210 mg, preferably from 130 mg to 180 mg, more preferably from 140 mg to 175 mg, even more preferably from 150 mg to 170 mg.

[0171] In yet another particular embodiment, the second layer weighs from 250 mg to 400 mg, preferably from 300 mg to 380 mg, more preferably from 320 mg to 375 mg, even more preferably from 355 mg to 375 mg.

[0172] In a particular embodiment, the second layer comprises:

[0173] - between 2 and 20 wt%, preferably between 3 and 18 wt%, of bilastine or a pharmaceutical salt thereof;

[0174] - between 10 wt% and 45 wt%, preferably between 15 wt% and 43 wt%, of a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof;

[0175] - between 5 wt% and 15 wt%, preferably between 6 wt% and 9 wt%, of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, and mixtures thereof; and

[0176] - between 30 wt% and 70 wt%, preferably between 35 wt% and 70 wt%, of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C 6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose;

[0177] the weight percentage being expressed with respect to the total weight of the second layer.

[0178] In another particular embodiment, the second layer comprises:

[0179] - between 2 and 20 wt%, preferably between 7 and 18 wt%, of bilastine or a pharmaceutical salt thereof;

[0180] - between 25 wt% and 45 wt%, preferably between 30 wt% and 43 wt%, of a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof;

[0181] - between 5 wt% and 15 wt%, preferably between 6 wt% and 9 wt%, of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, and mixtures thereof; and

[0182] - between 30 wt% and 50 wt%, preferably between 35 wt% and 40 wt%, of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1- 6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose; the weight percentage being expressed with respect to the total weight of the second layer.

[0183] In yet another particular embodiment, the second layer comprises:

[0184] - between 2 and 10 wt%, preferably between 4 and 7 wt%, of bilastine or a pharmaceutical salt thereof;

[0185] - between 10 wt% and 20 wt%, preferably between 12 wt% and 18 wt%, of a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof;

[0186] - between 5 wt% and 15 wt%, preferably between 6 wt% and 9 wt%, of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, and mixtures thereof; and

[0187] - between 50 wt% and 70 wt%, preferably between 60 wt% and 70 wt%, of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C 6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose;

[0188] the weight percentage being expressed with respect to the total weight of the second layer.

[0189] In a further particular embodiment, the second layer comprises a pharmaceutically acceptable coloring agent. Coloring agents are added to the composition to yield a desired color. Suitable coloring agents are known in the art and include iron oxide red (Fe2C>3, E172), sunset yellow FCF (E-110), indigo carmine (E-132), erythrosine (E-127), quinoline yellow (E-104), and the like, preferably, iron oxide red. If present, the amounts of colorant are comprised between 0.1 to 0.5 wt%, preferably between 0.2 and 0.5 wt%, more preferably between 0.3 and 0.5 wt%, the weight percentage being expressed with respect to the total weight of the second layer.

[0190] In a particular embodiment, the multi-layer pharmaceutical composition of the second aspect comprises:

[0191] - a first layer of a controlled release pharmaceutical composition comprising - between 25 wt% and 30 wt% of pseudoephedrine or a pharmaceutical salt thereof;

[0192] - between 20 wt% and 25 wt% of an acrylate copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate;

[0193] - between 10 wt% and 15 wt% of hydroxypropyl methylcellulose; and

[0194] - between 25 wt% and 35 wt% of Carbopol 974P ®; the weight percentages being expressed with respect to the total weight of the first layer; - a second layer, in contact with the first layer, comprising

[0195] - between 2 and 20 wt% of bilastine or a pharmaceutical salt thereof;

[0196] - between 10 wt% and 45 wt% of pseudoephedrine or a pharmaceutical salt thereof;

[0197] - between 5 wt% and 15 wt% of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, and mixtures thereof; and - between 30 wt% and 70 wt% of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose;

[0198] the weight percentage being expressed with respect to the total weight of the second layer.

[0199] In another particular embodiment, the multi-layer pharmaceutical composition of the second aspect comprises:

[0200] - a first layer of a controlled release pharmaceutical composition comprising - between 12 wt% and 30 wt%, preferably between 15 wt% and 26 wt%, of pseudoephedrine or a pharmaceutical salt thereof;

[0201] - between 10 wt% and 24 wt%, preferably between 12 wt% and 21 wt%, of an acrylate copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate;

[0202] - between 5 wt% and 13 wt%, preferably between 7 wt% and 12 wt%, of hydroxypropyl methylcellulose; and

[0203] - between 13 wt% and 32 wt%, preferably between 16 wt% and 28 wt%, of Carbopol 974P ®;

[0204] - a second layer, in contact with the first layer, comprising

[0205] - between 1 and 5 wt%, preferably between 1 wt% and 4 wt%, of bilastine or a pharmaceutical salt thereof;

[0206] - between 4 wt% and 10 wt%, preferably between 5 wt% and 9 wt%, of pseudoephedrine or a pharmaceutical salt thereof;

[0207] - between 1 wt% and 4 wt% of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, and mixtures thereof; and - between 5 wt% and 30 wt%, preferably between 6 wt% and 26 wt%, of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose;

[0208] the weight percentage being expressed with respect to the total weight of the first and second layers.

[0209] In a preferred embodiment, the multi-layer pharmaceutical composition of the second aspect comprises:

[0210] - a first layer of a controlled release pharmaceutical granule composition comprising - between 16 wt% and 25 wt% of pseudoephedrine or a pharmaceutical salt thereof;

[0211] - between 13 wt% and 20 wt% of an acrylate copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate;

[0212] - between 7 wt% and 11 wt% of hydroxypropyl methylcellulose; and

[0213] - between 17 wt% and 27 wt% of Carbopol 974P ®;

[0214] - a second layer, in contact with the first layer, comprising

[0215] - between 1 and 3 wt% of bilastine or a pharmaceutical salt thereof;

[0216] - between 5 wt% and 8 wt% of pseudoephedrine or a pharmaceutical salt thereof; - between 1 wt% and 3 wt% of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, and mixtures thereof; and - between 7 wt% and 25 wt% of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose;

[0217] the weight percentage being expressed with respect to the total weight of the first and second layers.

[0218] In another embodiment, the multi-layer pharmaceutical composition of the second aspect comprises:

[0219] - a first layer of a controlled release pharmaceutical composition comprising - between 150 mg and 210 mg of pseudoephedrine or a pharmaceutical salt thereof;

[0220] - between 120 mg and 170 mg of an acrylate copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate;

[0221] - between 65 mg and 90 mg of hydroxypropyl methylcellulose; and

[0222] - between 160 mg and 220 mg of Carbopol 974P ®;

[0223] - a second layer, in contact with the first layer, comprising - between 15 and 25 mg of bilastine or a pharmaceutical salt thereof;

[0224] - between 50 mg and 70 mg of pseudoephedrine or a pharmaceutical salt thereof; - between 10 mg and 35 mg of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, and mixtures thereof; and - between 55 mg and 250 mg of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose.

[0225] In a preferred embodiment of the latter, the multi-layer pharmaceutical composition of the second aspect comprises:

[0226] - a first layer of a controlled release pharmaceutical composition comprising - between 150 mg and 210 mg of pseudoephedrine or a pharmaceutical salt thereof;

[0227] - between 120 mg and 170 mg of an acrylate copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate;

[0228] - between 65 mg and 90 mg of hydroxypropyl methylcellulose; and

[0229] - between 160 mg and 220 mg of Carbopol 974P ®;

[0230] - a second layer, in contact with the first layer, comprising

[0231] - between 15 and 25 mg of bilastine or a pharmaceutical salt thereof;

[0232] - between 50 mg and 70 mg of pseudoephedrine or a pharmaceutical salt thereof; - between 10 mg and 15 mg of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, and mixtures thereof; and - between 55 mg and 70 mg of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose.

[0233] In another preferred embodiment of the former, the multi-layer pharmaceutical composition of the second aspect comprises:

[0234] - a first layer of a controlled release pharmaceutical composition comprising - between 150 mg and 210 mg of pseudoephedrine or a pharmaceutical salt thereof;

[0235] - between 120 mg and 170 mg of an acrylate copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate;

[0236] - between 65 mg and 90 mg of hydroxypropyl methylcellulose; and - between 160 mg and 220 mg of Carbopol 974P ®;

[0237] - a second layer, in contact with the first layer, comprising

[0238] - between 15 and 25 mg of bilastine or a pharmaceutical salt thereof;

[0239] - between 50 mg and 70 mg of pseudoephedrine or a pharmaceutical salt thereof; - between 25 mg and 35 mg of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, and mixtures thereof; and - between 235 mg and 250 mg of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose.

[0240] In a further particular embodiment, the multi-layer pharmaceutical composition of the second aspect, comprises a pharmaceutically acceptable coloring agent. Coloring agents are added to the composition to yield a desired color. Suitable coloring agents are known in the art and include iron oxide red (Fe2O3, E172), sunset yellow FCF (E-110), indigo carmine (E-132), erythrosine (E-127), quinoline yellow (E-104), and the like, preferably, iron oxide red. If present, the amounts of colorant are comprised between 0.1 to 0.5 wt%, preferably between 0.2 and 0.5 wt%, more preferably between 0.3 and 0.5 wt%, the weight percentage being expressed with respect to the total weight of the first and second layers.

[0241] General Process of preparation

[0242] In a further aspect, the present invention is directed at a dry granulation process for the preparation of the controlled release pharmaceutical composition, selected from the group consisting of roller compaction and slugging. Thus, in this aspect, the process is for the preparation of the controlled release pharmaceutical composition of the invention, wherein the composition is a granule composition.

[0243] Said aspect is a process for the preparation of the controlled release pharmaceutical composition comprising the following steps:

[0244] a) blending at least

[0245] i. a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof;

[0246] ii. an acrylate copolymer of C1-6 alkyl acrylates, C1-6 alkyl methacrylates and trimethylammonium C1-6 alkyl methacrylates; iii. a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose; and

[0247] iv. a crosslinked acrylic acid polymer;

[0248] b. submit the blend of the previous step to a dry granulation process, preferably a slugging process;

[0249] c. sieving the granules obtained in the previous step; and

[0250] d. optionally submit the sieved granules to a lubrication step.

[0251] Preferably, the dry granulation process is made by slugging (also known as precompression or double compression).

[0252] In a further aspect, the present invention is directed at a process for the preparation of the multi-layer pharmaceutical composition of the invention comprising the following steps:

[0253] A. Preparation of a controlled release pharmaceutical granule composition by, a) blending at least,

[0254] i. a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof;

[0255] ii. an acrylate copolymer of C1-6 alkyl acrylates, C1-6 alkyl methacrylates and trimethylammonium C1-6 alkyl methacrylates;

[0256] iii. a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose; and

[0257] iv. a crosslinked acrylic acid polymer;

[0258] b. submit the blend of the previous step to a dry granulation process, preferably a slugging process;

[0259] c. sieving the granules obtained in the previous step; and

[0260] d. optionally submit the sieved granules to a lubrication step;

[0261] B. Preparation of an immediate release composition by sieveing bilastine or a pharmaceutical salt thereof with a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof, and optionally further excipients, blending the ingredients, and optionally lubricate the blend; and C. Compressing the granule composition of step A to obtain a first layer, and compressing the blend composition of step B on said first layer, to obtain a multilayer tablet. In a particular embodiment, the process for the preparation of the second layer immediate release composition comprises the steps of sieveing the ingredients, blending them and optionally lubricate the blend. Preferably, said ingredients are a combination of bilastine or a pharmaceutical salt thereof with a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof, and optionally further excipients.

[0262] Release profile

[0263] The controlled release pharmaceutical composition of the invention, preferably granule composition, and the multi-layer pharmaceutical composition of the invention are characterized by a low deviation of the release profile amongs different batches.

[0264] The entirety of the embodiments described herein below regarding the release profile and / or RSD are based on a USP 2 (paddles) dissolution test in 700 mL of pH 6.8 USP medium stirring at 50 rpm at 37.0 ± 0.5°C and measured via UPLC / DAD detector (210 nm).

[0265] In a particular embodiment, the Relative Standard Deviation (RSD) at any given percentage of release versus elapsed time from administration is not greater than 6%, preferably not greater than 5%, more preferably not greater than 4.5%, most preferably not greater than 3.5%. In a preferred embodiment, the RSD values are for n = 6.

[0266] In a particular embodiment, the controlled release pharmaceutical composition of the invention releases no more than 20 wt%, preferably no more than 18 wt%, and more preferably no more than 15 wt%, of the total amount of decongestant within the first 15 minutes.

[0267] In a particular embodiment, the controlled release pharmaceutical composition of the invention releases no more than 22 wt%, preferably no more than 20 wt%, of the total amount of decongestant within the first 30 minutes.

[0268] In a particular embodiment, the controlled release pharmaceutical composition of the invention releases between 10 and 40 wt%, preferably between 20 and 30 wt%, and more preferably between 25 and 27 wt%, of the total amount of decongestant within the first hour.

[0269] In a particular embodiment, the controlled release pharmaceutical composition of the invention releases between 45 and 75 wt%, preferably between 50 and 70 wt%, and more preferably between 55 and 65 wt%, of the total amount of decongestant within the first six hours. In a preferred embodiment, the controlled release pharmaceutical composition of the invention releases less than 62 wt%, more preferably less than 60 wt%, of the total amount of decongestant within the first six hours.

[0270] In a particular embodiment, the controlled release pharmaceutical composition of the invention releases between 60 and 85 wt%, preferably between 60 and 80 wt%, and more preferably between 65 and 75 wt%, of the total amount of decongestant within the first ten hours.

[0271] In a particular embodiment, the controlled release pharmaceutical composition of the invention releases at least 75 wt%, preferably at least 80 wt%, more preferably at least 85 wt%, of the total amount of decongestant within the first 16 hours. In another particular embodiment, the controlled release pharmaceutical composition of the invention releases no more than 95 wt%, preferably no more than 90 wt%, of the total amount of decongestant within the first 16 hours.

[0272] In a particular embodiment, the controlled release pharmaceutical composition of the invention releases no more than 96 wt%, preferably no more than 94 wt%, of the total amount of decongestant within the first 20 hours.

[0273] In a preferred embodiment, the controlled release pharmaceutical composition of the invention releases:

[0274] - no more than 20 wt% of the total amount of decongestant within the first 15 minutes

[0275] - no more than 22 wt% of the total amount of decongestant within the first 30 minutes

[0276] - between 10 and 40 wt% of the total amount of decongestant within the first hour; - between 45 and 75 wt% of the total amount of decongestant within the first six hours; and

[0277] - at least 75 wt%, and preferably no more than 95 wt%, of the total amount of decongestant within the first 16 hours.

[0278] The multi-layer pharmaceutical composition of the invention is such that a first immediate release followed by a controlled release profile is achieved for the decongestant while an immediate release occurs for the bilastine after oral administration.

[0279] In this way, in a particular embodiment, the multi-layer pharmaceutical composition of the invention releases at least 15 wt%, preferably at least 20 wt%, and more preferably at least 21 wt%, of the total amount of decongestant within the first 15 minutes. In a particular embodiment, the multi-layer pharmaceutical composition of the invention releases between 10 and 40 wt%, preferably between 20 and 25 wt%, of the total amount of decongestant within the first hour.

[0280] In a particular embodiment, the multi-layer pharmaceutical composition of the invention releases between 30 and 60 wt%, preferably between 35 and 55 wt%, and more preferably between 40 and 50 wt%, of the total amount of decongestant within the first six hours.

[0281] In a particular embodiment, the multi-layer pharmaceutical composition of the invention releases at least 75 wt%, preferably at least 80 wt%, of the total amount of decongestant within the first 16 hours.

[0282] In a preferred embodiment, the multi-layer pharmaceutical composition of the invention releases:

[0283] - at least 15 wt% of the total amount of decongestant within the first 15 minutes; - between 10 and 40 wt% of the total amount of decongestant within the first hour; - between 30 and 60 wt% of the total amount of decongestant within the first six hours; and

[0284] - at least 75 wt% of the total amount of decongestant within the first 16 hours.

[0285] In another particular embodiment, the multi-layer pharmaceutical composition of the invention releases at least 80 wt% of the total amount of bilastine within the first hour, preferably at least 90 wt%.

[0286] In a preferred embodiment, the embodiments of the release profile described above, are after oral administration.

[0287] Medical uses

[0288] In the description that follows, any reference to pharmaceutical compositions of the invention is to be understood as a reference to the controlled release composition of the first aspect, preferably a granule composition, more preferably a compressed granule composition, and to the multi-layer composition of the second aspect.

[0289] The pharmaceutical compositions of the invention comprise at least one pharmaceutical ingredient. Therefore, in another aspect, the invention is directed at the pharmaceutical compositions of the invention, for use in medicine.

[0290] This aspect may also be formulated as the pharmaceutical compositions of the invention as described above, to prepare a medicament. The pharmaceutical compositions of the invention are preferably for oral administration. Furthermore, the oral pharmaceutical compositions of the invention are 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 further aspect of the invention is addressed to the pharmaceutical compositions of the invention, for use in the treatment and / or prevention of a disorder or disease susceptible to amelioration by antagonism of H1histamine receptor and / or decongestant responsive disease.

[0291] This aspect may also be formulated as the use of the compositions 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 H1histamine receptor and / or decongestant responsive disease.

[0292] This aspect may also be formulated as a method of treating and I or preventing a disorder or disease susceptible to amelioration by antagonism of H1histamine receptor and / or decongestant responsive disease, comprising administering to a subject in need of such treatment the compositions of the invention as described above.

[0293] In the context of the present invention, in a particular embodiment, a decongestant responsive disease is a disease known to ameliorate by stimulation of the α1-adrenergic receptor.

[0294] The terms "treat" and "treatment", as used herein, 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.

[0295] The terms "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.

[0296] The compositions of the invention may be administered 1, 2, 3, 4 or 5 times I day, preferably 1 or 2 times I day, even more preferably once daily. The compositions 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. In a particular embodiment, the pharmaceutical compositions as described above are for use in the treatment and / or prevention of a disorder or disease susceptible to amelioration by antagonism of H1histamine receptor and / or decongestant responsive disease, wherein said disorder or disease susceptible to amelioration by antagonism of H1histamine receptor and / or decongestant responsive disease is an allergic disease, asthma, non-malignant proliferative and inflammatory diseases. Preferably, said disorder or disease susceptible to amelioration by antagonism of H1histamine 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.

[0297] The following non-limiting examples are intended to illustrate the present invention and should not be considered as limitations of the scope of the same.

[0298] Materials

[0299] Pseudoephedrine hydrochloride was obtained from Farmaquimica Espanola S. A supplier (manufacturer: Embio).

[0300] Bilastine was obtained from Faes Farma.

[0301] Eudragit RS PO 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) at a ratio of 1:2:0.1, respectively. It was obtained from Evonik Nutrition & Care GmbH. Eudragit L 100 is a 1:1 copolymer of methacrylic acid and methyl methacrylate. It was obtained from Evonik Nutrition & Care GmbH.

[0302] 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. Carbopol 974P and 971 P were obtained from Lubrizol. These polymers are a mixture of carboxypolymethylene and carbomers. Carbopol 971 P has lower viscosity.

[0303] Kollidon VA64 was obtained from Basf. It is a spray-dried polymer powder of a copolymer derived from the monomers N-vinylpyrrolidone (NVP) and vinyl acetate (VAc) with a weight ratio of approx. 6:4.

[0304] Magnesium stearate was obtained from Mallinckrodt.

[0305] Croscarmellose sodium was obtained from IMCD Espana. This excipient has an internally cross-linked sodium carboxymethyl cellulose (NaCMC).

[0306] Microcrystalline cellulose was obtained from Rettenmaier Iberica, S. L y CIA. S.

[0307] Hydroxypropyl cellulose was obtained from Nippon soda Co., LTD.

[0308] Yellow iron oxide was obtained from Oxerra Italy SpA.

[0309] Example 1. Preparation of the controlled release pharmaceutical composition according to the invention.

[0310] In this example, 635 mg compressed granules with the composition,

[0311] Ingredient Mass (mg) Weight percentage (wt%) Pseudoephedrine hydrochloride 180.02 28.35 Eudragit RS PO 144.15 22.70 Metolose® 90 SH 4000 SR 78.74 12.40 Carbopol 974P 190.50 30.00 Kollidon VA64 38.10 6.00 Magnesium stearate 3.49 0.55 were prepared according to the following procedure:

[0312] The ingredients were sieved (though a sieve of 1,5R) and were added to a mixer and mixed for 7 minutes at 20 rpm. The mixture was then processed through vaccum to a dry granulation process (slugging). The mixture was compressed ata compression force < 11 kN and tablets with a friability of 0.4-0.6% were obtained. Then these tablets were sieved (through a sieve of 1.5R), thus obtaining granules with adequate rheological fluidity characteristics. The granules were then added by vacuum to a mixer (10 minutes at 20 rpm) to obtain a homogeneous powder and compressed again to obtain the final tablets. Example 2. Preparation of the second layer of the multi-layer pharmaceutical composition of the invention.

[0313] In this example, a first blend of total weight 160 mg comprising,

[0314] Ingredient Mass (mg) Weight percentage (wt%) Pseudoephedrine hydrochloride 60.0 37.50 Bilastine 20.0 12.50 Croscarmellose sodium 12.8 8.00 Microcrystalline cellulose 61.5 38.44 Magnesium stearate 2.5 1.56 Yellow iron oxide 3.2 2.00 was prepared according to the following procedure:

[0315] The ingredients (except magnesium stearate) were sieved and mixed for 7 minutes at 20 rpm. Magnesium stearate was then added (through sieve of 0.6 mm) for 3 minutes at 20 rpm.

[0316] A second blend was prepared following the same procedure but using sodium carboxymethyl starch type A instead of croscarmellose sodium.

[0317] A third blend was prepared as above, but of a total weight of 365 mg, comprising Ingredient Mass (mg) Weight percentage (wt%) Pseudoephedrine hydrochloride 60.0 16.44 Bilastine 20.0 5.50 Croscarmellose sodium 29.2 8.00 Microcrystalline cellulose 242.3 66.38 Magnesium stearate 6.2 1.69 Yellow iron oxide 7.3 2.00 And a fourth blend was prepared following the same procedure but using sodium carboxymethyl starch type A instead of croscarmellose sodium.

[0318] Example 3. Preparation of the multi-layer pharmaceutical composition of the invention.

[0319] In this example, the compressed granules of Example 1 and the first blend of Example 2 were compressed to yield bi-layer tablets weighing 795 mg, comprising a first layer of the granules (635 mg) and a second layer of said blend of Example 2 (160 mg). The controlled release layer exhibited a hardness of 250-350 N and thickness of 5.0 to 5.2 mm, while the immediate release layer exhibited a hardness of 150-250 N and thickness of 3.2 to 3.5 mm.

[0320] The multi-layer pharmaceutical composition of the invention exhibits a hardness of 250-350 and thickness of 7.1 to 7.3 mm.

[0321] Example 4. Dissolution tests.

[0322] 6.805 g of KH2PO4and 0.898 g of NaOH pellets were dissolved in 1000 mL of purified water so that the pH value of the resulting aqueous solution was 6.80 ± 0.05.

[0323] Each dissolution test was conducted according to the following conditions:

[0324] - Volume: 900 mL

[0325] - Temperature: 37.0 ± 0.5 °C

[0326] - Dissolution medium: KH2PO4pH 6.8

[0327] - Aliquot sampling volume: 3 mL

[0328] - Compensation for lost volume after sampling: negative

[0329] - Stirring speed: 50 rpm

[0330] - Accessories: Japanese sinker (for floating tablets)

[0331] - Sampling time: 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 16 h, 20 h, and 24 h.

[0332] Each aliquot was filtered through a polyethylene filter and then by PVDF 0,45 pm filters, prior to insertion into HPLC vials.

[0333] The UPLC conditions were as follows:

[0334] - Stationary phase: BEH C181,7um 2,1 x 100 mm

[0335] - Mobile phase A: NaH2PO4·H2O pH = 2.5

[0336] - Mobile pase B: Acetonitrile

[0337] - Gradient:

[0338] Time (min) %A %B Curve

[0339] 0.0 90.0 10.0 —

[0340] 1.5 70.0 30.0 Lineal 2.5 10.0 90.0 Lineal 2.6 90.0 10.0 Lineal

[0341]

[0342] 4.0 90.0 10.0 Lineal

[0343] - Seal Washing: MeOH:water (50:50 v / v)

[0344] - Wash Solvent: MeOH:water (50:50 v / v) - Purge: MeOH:water (50:50 v / v)

[0345] - Flow: 0.45 mL / min

[0346] - Injection Volume: 1.0 pL

[0347] - Column Temperature: 33°C

[0348] - Injector Temperature: 20°C

[0349] - Measured wavelength: 210 nm

[0350] - Stoptime: 4 min

[0351] The buffer used in the mobile phase was prepared as follows:

[0352] 2.76 g of anhydrous monosodium phosphate were disolved in 1 L of HPLC-grade water. The pH value was adjusted to 2.5 by addition of a phosphoric acid solution (85 wt%). Detection was performed using a DAD detector at 210 nm.

[0353] Results

[0354] Figure 1 shows the curves of pseudoephedrine controlled release profiles of four batches of compressed granule formulations obtained as explained in example 1 (average results of 6 tablets for each batch). For each of the curves, the RSD value at each data point was less than 3.1%, indication of an excellent reproducibility.

[0355] Also, when averaging the four curves of Figure 1, i.e., average of four batches, each an average of 6 tablets (data shown in Figure 2, see below), the RSD value obtained for each data point was lower than 4% (at t=0.25 h) and lower than 2% (at t>1 h), again indicating a remarkable reproducibility not only between tablets of a same batch, but also between batches.

[0356] Figures 2 and 3 show the curve of bilastine immediate release profile of one batch of a compressed blend formulation using sodium carboxymethyl starch type A obtained as explained in example 2, wherein the total weight is 160 mg and 365 mg respectively (average results of 6 tablets for each batch).

[0357] Example 5. Comparative formulations

[0358] In this example, comparative compositions 1 to 4 were prepared, tested and compared with a composition of Example 1, according to the invention. Comparing to the composition of Example 1, comparative composition: comparative composition 1 does not comprise an acrylate copolymer; comparative composition 2 does not comprise a cellulose derivative; comparative composition 3 does not comprise a crosslinked acrylic acid polymer; and

[0359] comparative composition 4 is based on prior art disclosure JP2005015371 (table 5, paragraph 26).

[0360] In comparative compositions 1 to 3, microcrystalline cellulose was added as replacement of Eudragit RS PO, Metolose® 90 SH 4000 SR, and Carbopol 974P, respectively, so that the total weight and wt% was kept constant. This excipient is known as being a filler. The comparative compositions were as follows:

[0361] mg (wt%)

[0362] ingredient

[0363] Comp. 1 Comp. 2 Comp. 3 Comp. 4n.... 180.02 180.02 180.02 144 Pseudoephedrine HCI (28.35) (28.35) (28.35) (14.46)c144.15 144.15

[0364] Eudragit RS PO — (22.70) (22.70)

[0365] Eudragit L 100 — — — (17.67)

[0366] Metolose® 90 SH 4000 SR 78.74 (12.40) --- 78.74 (12.40) 480 (48.19) C

[0367]

[0368] arbopol 974P (30.00) (30.00)

[0369] Carbopol 971P — — — (2.01)

[0370] Kollidon VA64 (38.10

[0371] 68

[0372] 01

[0373] 00

[0374] ) (3

[0375] 68

[0376] Q1

[0377] Q0

[0378] ) (3

[0379] 68

[0380] .01

[0381] 00

[0382] )

[0383] .., 3.49 3.49 3.49 4 Magnesium stearate(0 55) (0 55) (0 55) (0 40)

[0384] Microcrystalline cellulose 144.15 (22.70) 78.74 (12.40) 190.50 (30.00) 143 (14.36)

[0385]

[0386] Hydroxypropyl cellulose — — — 29

[0387] (2.91)

[0388] The granules were prepared according to the procedure described in Example 1. The flowability of Comparative compositions 1, 2 and 4 was poor, and the hardness of comparative compositions 1 to 4 was under 150 N. Dissolution tests of comparative compositions 1 to 4 were conducted in a similar fashion as that explained above under Example 4.

[0389] Figure 4 shows the pseudoephedrine dissolution curves of comparative composition 1 (□), comparative composition 2 (A), comparative composition 3 (A) and comparative composition 4 (■), together with the pseudoephedrine dissolution curve of the averaged curves of figure 1 wherein (•) is the composition according to the present invention. The results show that:

[0390] - within the first 30 minutes comparative compositions 3 and 4 released more than 30 wt% of the total amount of decongestant;

[0391] - within the first 6 hours comparative compositions 2, 3 and 4 released over 75 wt% of the total amount of decongestant;

[0392] - within the first 16 hours, all of the comparative compositions released the total amount of decongestant.

[0393] Conversely, the composition according to the invention showed an improved controlled release of the decongestant, in particular:

[0394] - within the first 30 minutes less than 20 wt% of the total amount of decongestant; - within the first 6 hours less than 60 wt% of the total amount of decongestant; - within the first 16 hours, less than 90 wt% of the total amount of decongestant; - within the first 20 hours, less than 95 wt% of the total amount of decongestant;

[0395] and

[0396] - within the first 24 hours, around 97 wt% of the total amount of decongestant. The results lead to the conclusion that the combination of an acrylate copolymer, a cellulose derivative and a crosslinked acrylic acid polymer, according to the invention, leads to the surprising effect of a controlled release profile of decongestant, with adequate hardness and flowability.

Claims

1. CLAIMS1. A controlled release pharmaceutical composition comprising:3.a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof;4.an acrylate copolymer of C1-6 alkyl acrylates, C1-6 alkyl methacrylates and trimethylammonium C1-6 alkyl methacrylates;5.a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose; and6.a crosslinked acrylic acid polymer.

2. The composition according to claim 1, comprising between 10 wt% and 15 wt% of the cellulose derivative, preferably hydroxypropyl methylcellulose, the weight percentage being expressed with respect to the total weight of the composition.

3. The composition according to any one of claims 1 or 2, comprising between 20 wt% and 25 wt% of the acrylate copolymer, preferably an acrylate copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate, the weight percentage being expressed with respect to the total weight of the composition.

4. The composition according to any one of claims 1 to 3, comprising between 25 wt% and 35 wt% of the crosslinked acrylic acid polymer, preferably Carbopol 974P ® which comprises a carboxylic acid content of from 56 to 68% and is characterized by a viscosity of 29400 to 39400 cP, the weight percentage being expressed with respect to the total weight of the composition.

5. The composition according to any one of claims 1 to 4, comprising:11.between 25 wt% and 30 wt% of pseudoephedrine or a pharmaceutical salt thereof;12.between 20 wt% and 25 wt% of an acrylate copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate;13.between 10 wt% and 15 wt% of hydroxypropyl methylcellulose; and between 25 wt% and 35 wt% of Carbopol 974P ®;14.the weight percentages being expressed with respect to the total weight of the composition.

6. Multi-layer pharmaceutical composition comprising:a first layer comprising the controlled release pharmaceutical composition of any one of claims 1-5; and16.a second layer, in contact with the first layer, comprising17.bilastine or a pharmaceutical salt thereof; and18.a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof.

7. The pharmaceutical composition according to claim 6, wherein the second layer further comprises between 6 wt% and 9 wt% of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, and mixtures thereof, the weight percentage being expressed with respect to the total weight of the second layer.

8. The pharmaceutical composition according to any one of claims 6 to 7, wherein the second layer further comprises between 35 wt% and 40 wt% of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose, the weight percentage being expressed with respect to the total weight of the second layer.

9. The pharmaceutical composition according to any one of claims 6 to 8, comprising:22.a first layer of a controlled release pharmaceutical granule composition comprising23.between 25 wt% and 30 wt% of pseudoephedrine or a pharmaceutical salt thereof;24.between 20 wt% and 25 wt% of an acrylate copolymer of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate; between 10 wt% and 15 wt% of hydroxypropyl methylcellulose; and between 25 wt% and 35 wt% of Carbopol 974P ®;25.the weight percentages being expressed with respect to the total weight of the first layer;26.a second layer, in contact with the first layer, comprising27.between 2 and 20 wt% of bilastine or a pharmaceutical salt thereof; between 25 wt% and 45 wt% of pseudoephedrine or a pharmaceutical salt thereof; between 6 wt% and 9 wt% of a desintegrant selected from the group consisting of carboxymethylcellulose, carboxy methyl starch, and mixtures thereof; and28.between 35 wt% and 40 wt% of a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C 3 carboxyalkyl celluloses and microcrystalline cellulose, preferably microcrystalline cellulose;29.the weight percentage being expressed with respect to the total weight of the second layer.

10. The pharmaceutical composition according to any one of claims 6 to 9, characterized by being in the form of a tablet, preferably a bilayer tablet.

11. Process for the preparation of the controlled release pharmaceutical composition of any one of claims 1 to 5, comprising the steps of:32.a) blending at least33.i. a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof;34.ii. an acrylate copolymer of C1-6 alkyl acrylates, C1-6 alkyl methacrylates and trimethylammonium C1-6 alkyl methacrylates;35.iii. a cellulose derivative selected from the group consisting of C1-6 alkyl celluloses, C1-6 hydroxyalkyl celluloses, C1-3 carboxyalkyl celluloses and microcrystalline cellulose; and36.iv. a crosslinked acrylic acid polymer;37.b. submit the blend of the previous step to a dry granulation process, preferably a slugging process;38.c. sieving the granules obtained in the previous step; and39.d. optionally submit the sieved granules to a lubrication step.

12. Process for the preparation of the multi-layer pharmaceutical composition of any one of claims 6 to 10, comprising the steps of:41.A. Preparation of a controlled release pharmaceutical granule composition by following the process of claim 11;42.B. Preparation of an immediate release composition by sieveing bilastine or a pharmaceutical salt thereof with a decongestant selected from the group consisting of pseudoephedrine and pharmaceutical salts thereof, and optionally further excipients, blending the ingredients, and optionally lubricate the blend; and43.C. Compressing the granule composition of step A to obtain a first layer, and compressing the blend composition of step B on said first layer, to obtain a multi-layer tablet.

13. The composition according to any one of claims 1 to 5, or the pharmaceutical composition according to any one of claims 6 to 10, for use in medicine.

14. The composition according to any one of claims 1 to 5, or the pharmaceutical composition according to any one of claims 6 to 10, for use in the treatment and / or prevention of a disorder or disease susceptible to amelioration by antagonism of H1histamine receptor and / or decongestant responsive disease.

15. The composition or the pharmaceutical composition for use according to claim 14, wherein said disorder or disease susceptible to amelioration by antagonism of H1histamine receptor and / or decongestant responsive disease is an allergic disease, asthma, non-malignant proliferative and inflammatory diseases.

Images