Pharmaceutical composition comprising rupatadine and montelukast

Abstract

The present invention relates to a novel pharmaceutical composition comprising rupatadine or a pharmaceutically acceptable salt thereof and montelukast or a pharmaceutically acceptable salt thereof. The novel pharmaceutical composition can be manufactured by a simple method and exhibits excellent compatibility of the two APIs while allowing the two APIs to have excellent bioavailability.

Description

Field of the Invention

[0001] The present invention relates to a pharmaceutical composition, in particular a tablet, comprising the antihistamine rupatadine or a salt thereof and the leukotriene D4 receptor antagonist montelukast or a salt thereof to improve the treatment of allergic disorders. Background of the Invention

[0003] The number of allergic disorders has increased dramatically worldwide. Recent intensive research activities have led to the recognition that allergic rhinoconjunctivitis is an inflammatory process in the sense of a persistent inflammatory response. Although histamine is still considered the most important mediator in the early stages and the most important trigger for symptoms such as redness, sneezing, itching, and hypersecretion (rhinorrhea and tearing), other mediators such as leukotrienes are also involved in the progression of nasal congestion, secretion, and inflammation (e.g., attracting pro-inflammatory cells, promoting cell infiltration, etc.). Therefore, the aim of treatment has shifted from symptomatic treatment to additional anti-inflammatory treatment that intervenes in the underlying inflammation of allergic disorders. Histamine and leukotrienes (LTs) are released both in the early and late stages of allergy.

[0004] It has been proposed to combine an antihistamine with a leukotriene D4 receptor antagonist to enhance the treatment of allergic rhinitis, vasomotor rhinitis, or allergic conjunctivitis (see CA 2337571C).

[0005] WO 2015 / 069203 A1 discloses a preparation comprising montelukast and rupatadine for the treatment of asthma and allergic rhinitis associated with allergic rhinitis. However, this document also discloses that incompatibility and stability problems often occur in the combination of active substances in the same dosage form. To solve the stability and incompatibility problems, this document proposes to combine a coated tablet containing rupatadine fumarate with granules of montelukast sodium in a capsule. Thus, the contact between the montelukast and rupatadine active substances is minimized by having each active substance in its own solid dosage form within the capsule.

[0006] WO 2017 / 182641 A1 also discloses that combining montelukast and rupatadine in a tablet presents significant challenges due to compatibility, dissolution, and stability problems. To overcome these problems, it is proposed to formulate the product in the form of a bilayer tablet preparation that includes montelukast sodium in the first layer and rupatadine fumarate in the second layer. In addition, this method minimizes the contact between montelukast and rupatadine by physical separation in different layers and thus in different pharmaceutical compositions. WO 2017 / 182641 A1 also shows that when rupatadine and montelukast are formulated together in a single-layer tablet form or capsule form, the dissolution and bioavailability of montelukast are significantly reduced.

[0007] WO 2017 / 182644 A1, which has the same filing date as WO 2017 / 182641 A1, discloses that during the study of the combination of montelukast and rupatadine, it was found that when montelukast was used together with rupatadine in tablet formulations or in capsule form, stability and dissolution problems were shown. According to the literature, the direct combination of the two APIs in the same pharmaceutical composition in tablet or capsule form results in a decrease in the dissolution of montelukast and an increase in impurities. The so-called solution to the problem proposed in the application is to formulate the two substances together only by spray granulation (e.g., in a fluidized bed dryer), thereby directly granulating rupatadine together with montelukast and excipients. However, this method requires the use of complex equipment and a large amount of energy to obtain the product. In addition, the literature does not show that the known stability and dissolution problems have indeed been overcome and that there is no further incompatibility between the two active substances.

[0008] Therefore, there remains an unmet need to develop a tablet formulation comprising rupatadine or a salt thereof and montelukast or a salt thereof, which is simple in itself, can be manufactured by a simple method, does not involve complex equipment or the use of a large amount of energy, and at the same time shows excellent bioavailability of the combined substances montelukast and rupatadine. In addition, there is a need to provide a composition of montelukast and rupatadine in which montelukast remains stable and does not decompose even in the presence of rupatadine, since the montelukast reference product has a rather short shelf life of only 2 years due to its sensitivity to moisture and light and must therefore be protected and stored at controlled room temperature. Summary of the Invention

[0009] The inventors have surprisingly found that when either rupatadine or a pharmaceutically acceptable salt thereof or montelukast or a pharmaceutically acceptable salt thereof is prepared in the form of granules containing only one of the two active substances, the two APIs can be combined even in a single-layer tablet without stability problems and at the same time show an excellent bioavailability profile of the two active ingredients. Contrary to the teachings of WO 2017 / 182641 A1, which shows that when rupatadine and montelukast are formulated together in a single-layer tablet form or in capsule form, the dissolution and bioavailability of montelukast are significantly reduced, it has surprisingly been found in the present invention that both rupatadine and montelukast can be combined even in a single-layer tablet, although the dissolution curve obtained for each active substance in the single-layer tablet is worse compared to the combination of individual tablets of montelukast and rupatadine but the formulation of the present invention compared to individual montelukast and rupatadine The co - administration of commercially available formulations is bioequivalent. In addition, the impurity profile of montelukast in the storage experiment indicates that it is at least as stable as, and even better than, its reference product and is even better.

[0010] Accordingly, in a first aspect, the present invention relates to a pharmaceutical composition in the form of a tablet, comprising rupatadine or a pharmaceutically acceptable salt thereof and montelukast or a pharmaceutically acceptable salt thereof, preferably in the form of a single - layer tablet, wherein:

[0011] a) i) rupatadine or a pharmaceutically acceptable salt thereof and ii) at least one of montelukast or a pharmaceutically acceptable salt thereof are present in particulate form together with at least one pharmaceutically acceptable excipient, and

[0012] b) the said particles do not simultaneously contain i) rupatadine or a pharmaceutically acceptable salt thereof and ii) montelukast or a pharmaceutically acceptable salt thereof.

[0013] In a second aspect, the present invention relates to the use of the pharmaceutical composition as defined in the first aspect for a medicament.

[0014] In a third aspect, the present invention relates to the use of the pharmaceutical composition as defined in the first aspect for the treatment and / or prevention of asthma and allergic rhinitis associated with allergic rhinitis.

[0015] In a fourth aspect, the present invention relates to the use of the pharmaceutical composition as defined in the first aspect in the preparation of a medicament for the treatment and / or prevention of asthma and allergic rhinitis associated with allergic rhinitis.

[0016] In a fifth aspect, the present invention relates to a method for the treatment and / or prevention of asthma and allergic rhinitis associated with allergic rhinitis in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition as defined in the first aspect.

[0017] As used herein, the term "prevention" means administering the composition of the present invention at the initial or early stage of a disease, or also refers to preventing its onset.

[0018] The term "treatment" is used to denote administering the composition of the present invention before or after the appearance of clinical signs to control the progression of the disease. The control of the progression of the disease refers to beneficial or desired clinical outcomes, including but not limited to: alleviation of symptoms, shortening of the duration of the disease, stabilization of the pathological state (especially avoiding further deterioration), delay in the progression of the disease, improvement of the pathological state, and remission (partial and complete). In a particular embodiment of the present invention, once the clinical symptoms of at least one disease appear, the composition of the present invention is used to control the progression of the disease.

[0019] As used herein, the term "medicament" refers to the composition of the present invention.

[0020] As used herein, the term "subject" refers to any animal or human suffering from one of the above diseases. Preferably, the subject is a mammal. As used herein, the term "mammal" refers to any mammalian species, including but not limited to domestic and farm animals (cows, horses, pigs, sheep, goats, dogs, cats or rodents), primates and humans. Preferably, the mammal is a human. Description of the Drawings

[0021] Figure 1 Shows the mean plasma concentration (ng / ml) of rupatadine in products P1 and P2 (co-administered with P3) obtained from the clinical trials described in the Examples section.

[0022] Figure 2 Shows the mean plasma concentration (ng / ml) of montelukast in products P1 and P3 (co-administered with P2) obtained from the clinical trials described in the Examples section.

[0023] Figure 3 Shows in the tablets of Example 1 (black) and in the combination of (gray) the dissolution curves of montelukast.

[0024] Figure 4 Shows in the tablets of Example 1 (black) and in the combination of (gray) the dissolution curves of rupatadine. Detailed Description

[0025] In one aspect, the present invention relates to a pharmaceutical composition in the form of a tablet, comprising rupatadine or a pharmaceutically acceptable salt thereof and montelukast or a pharmaceutically acceptable salt thereof, preferably in the form of a single-layer tablet, wherein:

[0026] a) i) rupatadine or a pharmaceutically acceptable salt thereof and ii) at least one of montelukast or a pharmaceutically acceptable salt thereof are present in the form of granules together with at least one pharmaceutically acceptable excipient, and

[0027] b) the granules do not simultaneously contain i) rupatadine or a pharmaceutically acceptable salt thereof and ii) montelukast or a pharmaceutically acceptable salt thereof.

[0028] In the context of the present invention, the term "granule" is used to denote a plurality of solid particles, measured using a graduated cylinder, which preferably have a bulk density of at least 0.3 g / ml, preferably at least 0.35 g / ml, and most preferably at least 0.37 g / ml.

[0029] In one embodiment, the particles of the present invention have a size such that at least 90% of the particles are retained by a sieve having round holes with a diameter of 0.1 mm, and no more than 20% of the particles are retained by a sieve having round holes with a diameter of 1.0 mm.

[0030] In the context of the present invention, the term "rupatadine" refers to rupatadine free base or any pharmaceutically acceptable salt thereof. Preferably, it refers to a pharmaceutically acceptable salt of rupatadine selected from the group consisting of: hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, phosphate, mesylate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, fumarate, oxalate, maleate, citrate, succinate. More preferably, it refers to rupatadine fumarate.

[0031] In the context of the present invention, the term "montelukast" refers to montelukast free acid or any pharmaceutically acceptable salt thereof. Preferably, it refers to a pharmaceutically acceptable salt of montelukast selected from the group consisting of: lithium salt, sodium salt, potassium salt, ammonium salt, calcium salt, magnesium salt, arginine salt, betaine salt, caffeine salt, choline salt, N,N'-dibenzylethylenediamine salt, diethylamine salt, 2-diethylaminoethanol salt, 2-dimethylaminoethanol salt, ethanolamine salt, ethylenediamine salt, N-ethylmorpholine salt, N-ethylpiperidine salt, glucamine salt, glucosamine salt, histamine salt, hydrabamine salt, isopropylamine salt, lysine salt, meglumine salt, morpholine salt, piperazine salt, piperidine salt, theophylline salt, triethylamine salt, trimethylamine salt, tripropylamine salt, tromethamine salt, dicyclohexylamine salt. More preferably, it refers to montelukast sodium salt.

[0032] In one embodiment, a tablet, preferably a single-layer tablet, comprises rupatadine or a pharmaceutically acceptable salt thereof, preferably rupatadine fumarate, in particulate form, wherein the particles do not comprise montelukast or a pharmaceutically acceptable salt thereof. In a particular embodiment, montelukast or a pharmaceutically acceptable salt thereof is added in the form of a powder outside the particles, optionally together with additional excipients, to the particles comprising rupatadine or a pharmaceutically acceptable salt thereof.

[0033] In another embodiment, a tablet, preferably a single-layer tablet, comprises montelukast or a pharmaceutically acceptable salt thereof, preferably montelukast sodium, in particulate form, wherein the particles do not comprise rupatadine or a pharmaceutically acceptable salt thereof.

[0034] In one embodiment, the particles comprising rupatadine or a pharmaceutically acceptable salt thereof or montelukast or a pharmaceutically acceptable salt thereof are prepared by a granulation method different from spray granulation.

[0035] In one embodiment, granules comprising rupatadine or a pharmaceutically acceptable salt thereof or montelukast or a pharmaceutically acceptable salt thereof are prepared by a granulation method selected from the group consisting of dry granulation, wet granulation in a low-shear or high-shear mixer, and hot-melt granulation. Most preferably, the granules are prepared by wet granulation in a high-shear mixer, which can provide one or more of the following advantages:

[0036] 1. Short processing time

[0037] 2. Reduced amount of binder solution

[0038] 3. Ability to handle highly viscous materials

[0039] 4. Higher density and reduced granule friability

[0040] 5. Reproducibility of uniform particle size distribution

[0041] 6. Dust reduction

[0042] 7. Predictable endpoint determination

[0043] In one embodiment, the pharmaceutical composition comprises one or more excipients selected from the group consisting of binders, diluents, disintegrants, lubricants, glidants, antioxidants, colorants, and flavorants.

[0044] Disintegrants can assist in the dispersion of tablets in the gastrointestinal tract, release the active ingredient, and increase the surface area for dissolution. According to one embodiment, the disintegrant can be selected from the group including: alginates such as calcium alginate and / or sodium alginate, calcium carboxymethylcellulose, calcium cellulose glycolate, calcium silicate, calcium carboxymethylcellulose, starch, croscarmellose sodium, crospovidone, sodium docusate, hydroxypropylmethylcellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, polyvinylpyrrolidone, powdered cellulose, sodium carboxymethylcellulose, sodium starch glycolate, and mixtures thereof. In an embodiment, the disintegrant is preferably croscarmellose sodium.

[0045] Binders help bind the tablet ingredients together, generating shape and mechanical strength. According to one embodiment, the binder can be selected from the group consisting of gum arabic mucilage, agar, alginates (sodium), carboxymethylcellulose (sodium or calcium), carbomer, carrageenan, chitosan, copovidone, starch (corn), ethylcellulose, gelatin, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropyl starch, magnesium aluminum silicate, methylcellulose, natural gums (agar, guar gum, tragacanth gum), pectin, polyethylene glycol, polyvinylpyrrolidone, pregelatinized starch, and mixtures thereof. In an embodiment, the binder is preferably pregelatinized starch and hydroxypropylcellulose.

[0046] Diluents (also known as fillers) provide volume and enable accurate dosing of the active ingredient. According to one embodiment, the binder is optionally selected from the group consisting of: α-lactalbumin, anhydrous lactose, calcium carbonate, calcium lactate, calcium phosphate (binary, anhydrous and binary, dehydrated), calcium sulfate, cellulose acetate, compressible sugar, glucose binder, dextrin, glucose, erythritol, ethyl acrylate and methyl methacrylate copolymer, ethyl cellulose, fructose, hydroxypropyl pea starch, isomalt, kaolin, lactitol, lactose monohydrate, magnesium carbonate, magnesium oxide, corn starch, maltodextrin, maltose, mannitol, methacrylic acid and ethyl acrylate copolymer, methacrylic acid and methyl methacrylate copolymer, microcrystalline cellulose, polydextrose, powdered cellulose, pregelatinized hydroxypropyl potato starch, pregelatinized modified starch, starch (corn, potato, maize, pea, tapioca, wheat), pullulan, siliconized microcrystalline cellulose, simethicone, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, spray-dried lactose, hydrogenated starch hydrolysate, sucrose, trehalose, tricalcium phosphate, xylitol, and mixtures thereof. In an embodiment, the diluent is preferably lactose monohydrate and microcrystalline cellulose.

[0047] Lubricants (also known as glidants) improve the flow of powders during tablet manufacture by reducing friction and adhesion between particles. According to one embodiment, the lubricant is optionally selected from the group consisting of: behenoyl polyoxyglycerol esters, calcium silicate, calcium stearate, cellulose, powdered colloidal silica, fumaric acid, glyceryl behenate, diglyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, glyceryl tristearate, hydrogenated natural oils, hydrophobic colloidal silica, lauric acid, magnesium lauryl sulfate, magnesium lauryl sulfate, magnesium oxide, magnesium silicate, magnesium stearate, myristic acid, palmitic acid, paraffin wax, poloxamer, polyethylene glycol, polyethylene glycol, polyethylene glycol, polyoxyethylene 10 oleyl ether, polyoxyethylene 15 hydroxystearate, polyoxyethylene 20 cetostearyl ether, polyoxyethylene 40 stearate, polysorbate (20, 40, 60, 80), potassium benzoate, silica, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, stearic acid, talc, tricalcium phosphate, zinc stearate, and mixtures thereof. In an embodiment, the lubricant is preferably magnesium stearate.

[0048] In one embodiment, the pharmaceutical composition of the present invention has a diluent in an amount of 20 wt% to 90 wt% w / w, preferably 35 wt% to 90 wt%, more preferably 50 wt% to 90 wt%, and even more preferably 70 wt% to 90 wt%, a binder in an amount of 2 to 14 wt%, preferably 2 wt% to 11 wt%, more preferably 3 to 9%, and even more preferably 4 wt% to 7 wt%, a disintegrant in an amount of 1 to 15 wt%, preferably 1 wt% to 13 wt%, more preferably 1 to 11%, and even more preferably 1 wt% to 8 wt%, and a lubricant in an amount of 0.2 to 2.0 wt%, preferably 0.3 wt% to 1.7 wt%, more preferably 0.5 to 1.5%, and even more preferably 0.7 wt% to 1.3 wt%, all percentages being expressed relative to the total weight of the pharmaceutical composition.

[0049] In one embodiment, the pharmaceutical composition of the present invention comprises pregelatinized starch, microcrystalline cellulose, lactose monohydrate, hydroxypropyl cellulose, croscarmellose sodium, and magnesium stearate as pharmaceutical excipients.

[0050] In one embodiment, the pharmaceutical composition of the present invention has pregelatinized starch in an amount of 1 wt% to 10 wt% w / w, preferably 1.5 wt% to 8 wt%, more preferably 2 wt% to 6 wt%, and even more preferably 2.5 wt% to 4 wt%, microcrystalline cellulose in an amount of 10 wt% to 60 wt% w / w, preferably 18 wt% to 52 wt%, more preferably 25 wt% to 45 wt%, and even more preferably 32 wt% to 38 wt%, lactose monohydrate in an amount of 15 wt% to 75 wt% w / w, preferably 23 wt% to 68 wt%, more preferably 30 wt% to 60 wt%, and even more preferably 35 wt% to 55 wt%, hydroxypropyl cellulose in an amount of 0.5 wt% to 8 wt% w / w, preferably 0.8 wt% to 8 wt%, more preferably 1 wt% to 6 wt%, and even more preferably 1.5 wt% to 3 wt%, croscarmellose sodium in an amount of 0.5 wt% to 8 wt% w / w, preferably 0.8 wt% to 8 wt%, more preferably 1 wt% to 6 wt%, and even more preferably 1.5 wt% to 3 wt%, and magnesium stearate in an amount of 0.1 wt% to 2 wt% w / w, preferably 0.3 wt% to 1.6 wt%, more preferably 0.5 wt% to 1.4 wt%, and even more preferably 0.8 wt% to 1.2 wt%.

[0051] In one embodiment, the amount of rupatadine or a pharmaceutically acceptable salt thereof per pharmaceutical composition in the tablet is from 0.5 to 22 mg, preferably from 1.5 to 20 mg, more preferably from 2 to 17 mg, more preferably from 4 to 15 mg, and even more preferably from 7 to 12 mg, expressed as the weight of rupatadine free base. In a more preferred embodiment, rupatadine or a pharmaceutically acceptable salt thereof is present in an amount of about 10 mg, expressed as rupatadine free base.

[0052] In one embodiment, the amount of montelukast or a pharmaceutically acceptable salt thereof per pharmaceutical composition in the tablet is from 1 to 22 mg, preferably from 1.5 to 20 mg, more preferably from 2 to 17 mg, more preferably from 4 to 15 mg, and even more preferably from 7 to 12 mg, expressed as the weight of montelukast free acid. In a more preferred embodiment, montelukast or a pharmaceutically acceptable salt thereof is present in an amount of about 10 mg, expressed as montelukast free acid.

[0053] In one embodiment, in the pharmaceutical composition according to the invention, the weight-to-weight ratio of rupatadine to the disintegrant, calculated based on the weight of rupatadine free base, is from 5:1 to 1:5, preferably from 3.5:1 to 1:3.5, and more preferably from 2.5:1 to 1:2.5.

[0054] In one embodiment, in the pharmaceutical composition according to the invention, the weight-to-weight ratio of montelukast to the disintegrant, calculated based on the weight of montelukast free base, is from 5:1 to 1:5, preferably from 3.5:1 to 1:3.5, and more preferably from 2.5:1 to 1:2.5.

[0055] In a preferred embodiment, the composition of the invention comprises rupatadine or a pharmaceutically acceptable salt thereof in particulate form.

[0056] The pharmaceutical composition of the invention exhibits excellent bioavailability of both APIs, namely rupatadine and montelukast, as represented by the in vivo results of the maximum plasma concentration (C 最大 ) and the area under the plasma concentration-time curve (AUC 0-t ), as described below.

[0057] In an embodiment, when administered orally, the pharmaceutical composition of the invention exhibits a maximum plasma concentration (C 最大 ) of rupatadine of from 5.00 ng / mL to 6.50 ng / mL, preferably from 5.20 ng / mL to 6.40 ng / mL, and more preferably from 5.30 ng / mL to 6.30 ng / mL, and a maximum plasma concentration (C 最大) ranges from 380 ng / mL to 530 ng / mL, preferably from 395 ng / mL to 520 ng / mL, and more preferably from 410 ng / mL to 510 ng / mL.

[0058] In an embodiment, when administered orally, the pharmaceutical composition of the present invention exhibits an area under the plasma concentration-time curve (AUC 0-t ) of rupatadine from 0 to 48 hours of 24.5 ng·h / mL to 28.5 ng·h / mL, more preferably 25.0 ng·h / mL to 28.0 ng·h / mL, and more preferably 25.5 ng·h / mL to 27.5 ng·h / mL, and an area under the plasma concentration-time curve (AUC 0-t ) of montelukast from 0 to 48 hours of 2850.0 ng·h / mL to 3450.0 ng·h / mL, more preferably 2900.0 ng·h / mL to 3400.0 ng·h / mL, and more preferably 2950.0 ng·h / mL to 3350.0 ng·h / mL.

[0059] The data given in Example 2 below show that the co-administration of the pharmaceutical composition of the present invention with the individual oral dosage forms of rupatadine and montelukast is bioequivalent (for both rupatadine and montelukast).

[0060] In an embodiment, the pharmaceutical composition of the present invention comprises rupatadine in the form of rupatadine fumarate.

[0061] In an embodiment, the pharmaceutical composition of the present invention comprises montelukast in the form of montelukast sodium.

[0062] What the compositions of the present invention have in common is that at least one active ingredient (rupatadine or its salt / montelukast or its salt) is prepared in the form of granules, and the granules do not simultaneously contain both active ingredients. This can be achieved in various ways:

[0063] a) Only rupatadine or its salt is prepared in the form of granules further comprising at least one excipient but not comprising montelukast or its salt;

[0064] b) Only montelukast or its salt is prepared in the form of granules further comprising at least one excipient but not comprising rupatadine or its salt;

[0065] c) Rupatadine or its salt is prepared in the form of granules further comprising at least one excipient but not comprising montelukast or its salt, And montelukast or its salt is prepared in the form of granules further comprising at least one excipient but not comprising rupatadine or its salt.

[0066] Thus, the compositions thus obtained have the advantage of minimizing any drug-drug interactions by physically separating them. This allows obtaining compositions that exhibit excellent drug release of the two active ingredients, which have excellent bioavailability that shows bioequivalence with each active ingredient administered alone. In addition, the compositions of the present invention do not affect the stability of montelukast and maintain at least its stability properties at the same level as the reference drug and it is known that the stability of montelukast is a critical issue.

[0067] The preparation of the granules comprising one active ingredient can be carried out by any granulation method different from spray granulation. Granulation methods selected from the group consisting of dry granulation, wet granulation in a low-shear or high-shear mixer, and hot-melt granulation are preferably used. Most preferably, the granules are prepared by wet granulation in a high-shear mixer. This is a very straightforward and simple manufacturing method that does not require any special conditions.

[0068] In an embodiment of the present invention, the granules comprising the active substance further comprise one or more binders, diluents, and disintegrants.

[0069] When only one of rupatadine (or its salt) and montelukast (or its salt) is used in particulate form for preparing a tabletable composition (i.e., for within the granules), the ingredients that are not in particulate form are referred to as extra-granular and are thus mixed with the granules and any other necessary additional excipients, such as binders, diluents, disintegrants, lubricants, or any other pharmaceutically acceptable additives.

[0070] When both rupatadine (or its salt) and montelukast (or its salt) are used in particulate form for preparing a tabletable composition (i.e., for within the granules), the two types of granules are mixed with any other necessary additional excipients, such as binders, diluents, disintegrants, lubricants, or any other pharmaceutically acceptable additives.

[0071] In a preferred embodiment of the present invention, rupatadine or its salt is mixed with a binder and one or more diluents, and the mixture is granulated with water or an aqueous solution in which the binder is dissolved. In a preferred embodiment, the granulation is carried out in a high-shear mixer.

[0072] In a preferred embodiment of the present invention, the granules comprising rupatadine or its salt are mixed extra-granularly with montelukast or its salt in dry powder form and one or more binders, diluents, disintegrants, lubricants, or any other pharmaceutical additives to obtain a pharmaceutical composition. The pharmaceutical composition thus obtained can be used as it is, filled into capsules, or compressed into tablets. Preferably, the pharmaceutical composition is compressed into tablets by using, for example, a rotary tablet press.

[0073] After tabletting, the tablets can be used directly without any coating, or they can optionally be coated with a coating solution, such as an aqueous solution comprising polyvinyl alcohol, hydroxypropyl methylcellulose, methylcellulose and a colorant or pigment. Preferably, the tablets remain uncoated.

[0074] It has been reported that rupatadine and montelukast can be used to treat asthma and allergic rhinitis accompanied by allergic rhinitis (WO 2015 / 069203 A1).

[0075] Accordingly, in a second aspect, the present invention relates to a pharmaceutical composition as defined in the first aspect, for use in medicine.

[0076] In a third aspect, the present invention relates to a pharmaceutical composition as defined in the first aspect, for use in the treatment and / or prevention of asthma and allergic rhinitis accompanied by allergic rhinitis.

[0077] In a fourth aspect, the present invention relates to the use of a pharmaceutical composition as defined in the first aspect in the manufacture of a medicament for the treatment and / or prevention of asthma and allergic rhinitis accompanied by allergic rhinitis.

[0078] In a fifth aspect, the present invention relates to a method for treating and / or preventing asthma and allergic rhinitis accompanied by allergic rhinitis in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition as defined in the first aspect.

[0079] The following examples represent specific embodiments of the present invention. They are not intended to limit in any way the scope of the present invention as defined in this specification.

[0080] Examples

[0081] Example 1

[0082] 300 mg tablets were prepared from the composition shown in Table 1 according to the following method:

[0083] Table 1

[0084]

[0085] Step 1: Preparation of rupatadine fumarate granules

[0086] 128 g of rupatadine fumarate, 100 g of pregelatinized starch, 150 g of microcrystalline cellulose and 612 g of lactose monohydrate were blended to prepare a homogeneous mixture. The mixture was then granulated with 216.81 g of water in a high-shear mixer (Mixing-Granulating Machine Lleal TRI-CHOP MGR-5 / 1). The resulting wet granules were dried in a forced-air oven at a temperature of 45 °C.

[0087] Step 2: Preparation of the intermediate mixture

[0088] 768.86 g of microcrystalline cellulose, 770.0 g of lactose monohydrate, 91 g of montelukast sodium, and 50.14 g of hydroxypropyl cellulose were blended to prepare a homogeneous mixture.

[0089] Step 3: Preparation of the product for pressing

[0090] 52.5 g of croscarmellose sodium was added to 866.25 g of the rupatadine fumarate granules prepared in Step 1, then 1680.0 g of the intermediate mixture prepared in Step 2 was added, and the mixture was blended to obtain a homogeneous mixture. Finally, 26.25 mg of magnesium stearate was added to the aforementioned mixture, and the mixture was blended to obtain a homogeneous mixture.

[0091] Step 4: Preparation of tablets

[0092] The final mixture of Step 3 was compressed into 300.0 mg tablets in a rotary tablet press equipped with a 9 mm diameter round punch at a pressure of 4 - 5 KN.

[0093] Example 2: An open - label, balanced, randomized, four - period, single - oral - dose, crossover study to evaluate the relative bioavailability of the test formulation (rupatadine 10 mg + montelukast 10 mg) versus rupatadine 10 mg and montelukast 10 mg co - administered as separate oral dosage forms in normal, healthy, adult human subjects under fasting conditions and to determine bioequivalence.

[0094] A Phase I study was conducted to evaluate (among other variables) the bioequivalence of the test formulation (rupatadine 10 mg + montelukast 10 mg) versus rupatadine 10 mg and montelukast 10 mg co - administered as separate oral dosage forms in normal, healthy, adult human subjects under fasting conditions. The following three formulations were used in this study:

[0095] P1 - Rupatadine 10 mg / Montelukast 10 mg tablets (product of Example 1)

[0096] P2 - (Rupatadine) 10 mg tablets

[0097] P3 - (Montelukast) 10 mg tablets

[0098] According to the protocol, sixty (60) volunteers were considered eligible and were enrolled on the enrollment day. Among these, only 53 subjects completed 4 dosing cycles and were included in the bioequivalence statistical analysis.

[0099] Products P1 to P3 were used for the following treatments:

[0100] Treatment - T: Administer 1 tablet of Product P1 ( rupatadine + montelukast ) per administration

[0101] Treatment - R1: Administer 1 tablet of Product P3 ( montelukast ) per administration

[0102] Treatment - R2: Administer 1 tablet of Product P2 ( rupatadine ) per administration

[0103] Treatment - R: Administer 1 tablet of Product P2 ( rupatadine ) per administration + Administer 1 tablet of Product P3 ( montelukast ) per administration

[0104] Conduct the treatment in the following order:

[0105] Table 2 Treatment Order

[0106] Phase I Phase II Phase III Phase IV Treatment - R1 Treatment - R2 Treatment - R Treatment - T Treatment - T Treatment - R1 Treatment - R2 Treatment - R Treatment - R Treatment - T Treatment - R1 Treatment - R2 Treatment - R2 Treatment - R Treatment - T Treatment - R1

[0107] After an overnight fast of at least 10 hours, at ambient temperature, administer the following single - oral dose to the seated subject together with 240 mL of drinking water: one tablet of the test product ( 10 mg rupatadine + 10 mg montelukast ) or one tablet of P3 ( 10 mg montelukast sodium ) or one tablet of P2 ( 10 mg rupatadine ) or co - administered P2 and P3. Administer the product according to the randomization scheme and under open - label conditions.

[0108] The tablets are swallowed whole, without chewing or crushing. The administration time of the investigational drug product is the time when the subject finishes drinking 240 mL of water and is recorded in the corresponding source - data form. The entire activity is carried out under a sodium - vapor lamp covered with red gelatin paper.

[0109] Oral examinations are performed after this activity to evaluate compliance with the administration.

[0110] Unless medically necessary due to adverse events or protocol requirements or natural emergencies, within the first 4 hours after administration in each cycle, the subject remains seated next to the chair. The occurrence of the above - mentioned situations is not considered a protocol deviation.

[0111] Thereafter, only normal activities are allowed for the subject, while avoiding strenuous physical activities. From 1 hour before to 2 hours after administration in each cycle, they do not drink water, except for the water given during product administration.

[0112] When montelukast and rupatadine were administered to Treatments T, R, R1, and R2, a total of twenty-five (25) blood samples, each of 5.5 mL, were collected from each subject at each period. In each cycle, venous blood samples were drawn before dosing (0.000 hours) and at 0.167, 0.250, 0.333, 0.500, 0.750, 1.000, 1.333, 1.667, 2.000, 2.333, 2.667, 3.000, 3.333, 3.667, 4.000, 4.500, 5.000, 6.000, 8.000, 12.000, 16.000, 24.000, 36.000, and 48.000 hours after dosing.

[0113] Using Version 8.1 (Certara L.P.), the pharmacokinetic parameters of montelukast and rupatadine (C 最大 and AUC 0-t ) were calculated from the plasma concentration-time curve by non-compartmental models. The pharmacokinetic parameters of the two formulations were statistically compared using Version 9.4 of PROCMIXED (SAS Institute Inc., USA) to evaluate the bioequivalence between the test formulation and the reference formulation.

[0114] The maximum measured plasma concentration (C 最大 ) was calculated from the plasma concentration-time curve of individual subjects. The unit of C 最大 is ng / mL.

[0115] The area under the plasma concentration-time curve (AUC 0-t ) was calculated from the measured data points from time zero to the time of the last observed concentration by the linear trapezoidal method. The unit of AUC 0-t is ng·h / mL.

[0116] Statistical methods:

[0117] Descriptive statistics of C 最大 and AUC 0-t of montelukast and rupatadine were calculated and reported. ANOVA, power, and ratio analysis of the ln-transformed pharmacokinetic parameters C 最大 and AUC 0-t of montelukast and rupatadine were calculated and reported.

[0118] For the ln-transformed pharmacokinetic parameters C 最大 and AUC 0-t of montelukast and rupatadine, the 90% confidence interval of the ratio of the geometric least-squares means between the drug formulations was calculated.

[0119] To determine the bioequivalence of rupatadine between co - administration of product P1 with products P2 and P3, the following are calculated:

[0120] · The ln - transformed C of rupatadine for treatment T 最大 versus the ln - transformed C of rupatadine for treatment R 最大 and the 90% confidence interval of said ratio

[0121] · The ln - transformed AUC of rupatadine for treatment - T 0-t versus the ln - transformed AUC of rupatadine for treatment R 0-t and the 90% confidence interval of said ratio

[0122] If the 90% confidence interval of the calculated corresponding ratio falls within the range of 80.00 to 125.00%, the two products are considered bioequivalent for rupatadine.

[0123] Similarly, to determine the bioequivalence of montelukast between co - administration of product P1 with products P2 and P3, the following are calculated:

[0124] · The ln - transformed C of montelukast for treatment T 最大 versus the ln - transformed C of montelukast for treatment R 最大 and the 90% confidence interval of said ratio

[0125] · The ln - transformed AUC of montelukast for treatment - T 0-t versus the ln - transformed AUC of montelukast for treatment R 0-t and the 90% confidence interval of said ratio

[0126] If the 90% confidence interval of the calculated corresponding ratio falls within the range of 80.00 to 125.00%, the two products are considered bioequivalent for montelukast.

[0127] Table 3: Pharmacokinetic Parameters of Rupatadine in Treatments T (Product P1) and R (Products P2 and P3)

[0128] PK Parameters Treatment T (Product P1 - Example 1) Treatment R (Products P2 and P3) <![CDATA[C 最大 (ng / mL)]]> 5.856±3.2636 5.617±2.7455 <![CDATA[AUC 0-t (ng·h / mL)]]> 26.345±16.6220 26.358±15.2279

[0129] Table 4: Results of relative bioavailability of rupatadine

[0130]

[0131] Since the 90% confidence interval of the calculated corresponding ratio falls within the range of 80.00 to 125.00%, co - administration of product P1 with products P2 and P3 is bioequivalent (with respect to rupatadine).

[0132] Table 5: Pharmacokinetic Parameters of Montelukast in Treatments T (Product P1) and R (Products P2 and P3)

[0133]

[0134]

[0135] Table 6: Relative bioavailability results of montelukast

[0136]

[0137] Since the 90% confidence intervals of the calculated corresponding ratios fall within the range of 80.00 to 125.00%, the co - administration of product P1 with products P2 and P3 is bioequivalent (with respect to montelukast).

[0138] When compared to the co - administration with the reference product 10 mg tablets (P2) + 10 mg tablets (P3), the product of Example 1 (P1) meets the bioequivalence criteria for C 最大 and AUC 0-t for montelukast and rupatadine under fasting conditions, as the 90% confidence interval (CI) falls within the acceptable range of 80.00 - 125.00% of the ln - transformed pharmacokinetic parameters.

[0139] Stability tests were also performed to compare the stability of the composition of Example 1 with since montelukast is a product known to be prone to degradation. The results are presented in Table 7 as the amount of increased impurities versus release.

[0140] Table 7: Stability results of the composition of Example 1 relative to

[0141]

[0142] The impurity levels were determined by UHPLC using an Acquity UPLC BEH C18 1.7 μm (100x2.1 mm) column and the following mobile phase:

[0143]

[0144]

[0145] The detection wavelength was fixed at 238 nm.

[0146] Impurity C elutes at 9.5 minutes, montelukast at 18.3 minutes, and impurity F at 19.0 minutes.

[0147] ​

[0148] As can be seen from Table 7, compared with the reference montelukast product, both impurities showed better behavior in Example 1.

[0149] Example 3. Dissolution profiles of the tablets of Example 1 and the combination.

[0150] The dissolution profiles of montelukast and rupatadine in the tablets obtained in Example 1 were compared with those of montelukast and rupatadine in combination.

[0151] Each tablet had the following composition:

[0152] - 10.00 mg montelukast (as the sodium salt)

[0153] - 5.73 mg hydroxypropyl cellulose

[0154] - 89.30 mg microcrystalline cellulose

[0155] - 89.30 mg lactose monohydrate

[0156] - 6.00 mg croscarmellose sodium

[0157] - 1.00 mg magnesium stearate

[0158] - 1.73 mg hydroxypropyl methylcellulose

[0159] - 1.50 mg titanium dioxide

[0160] - 0.004 mg iron oxide red

[0161] - 0.036 mg iron oxide yellow

[0162] - 0.006 mg carnauba wax

[0163] Each tablet had the following composition:

[0164] - 10 mg rupatadine (as the fumarate)

[0165] - pregelatinized maize starch

[0166] - microcrystalline cellulose

[0167] - iron oxide red (E-172)

[0168] - iron oxide yellow (E-172)

[0169] - lactose monohydrate, 57.57 mg

[0170] -Magnesium stearate

[0171] Dissolution tests were carried out according to the paddle method (European Pharmacopoeia, 2.9.3) at 50 rpm and 37 °C in an aqueous solution of 0.5% sodium dodecyl sulfate (SDS). The results are shown in Figure 3 and Figure 4 . It can be seen that the dissolution of montelukast in the tablets of Example 1 is slower relative to the combination of and , and does not reach 90% after 60 minutes. The dissolution of rupatadine in the tablets of Example 1 is also slower than in the combination of and . Considering the dissolution curves obtained from the tablets of Example 1 and the combination of , we did not expect the co - administration of the formulations of the present invention with the commercial formulations of montelukast and rupatadine alone to be bioequivalent.

Claims

1. A pharmaceutical composition in the form of a single-layer tablet, comprising rupatadine or a pharmaceutically acceptable salt thereof and montelukast or a pharmaceutically acceptable salt thereof, wherein: a) i) at least one of rupatadine or a pharmaceutically acceptable salt thereof or ii) montelukast or a pharmaceutically acceptable salt thereof is present in particulate form together with at least one pharmaceutically acceptable excipient, and b) the particulate does not simultaneously contain i) rupatadine or a pharmaceutically acceptable salt thereof and ii) montelukast or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein The above particulate is prepared by a granulation method different from spray granulation.

3. The pharmaceutical composition according to claim 2, wherein, The granulation method employed is selected from the group consisting of dry granulation, wet granulation in a low-shear or high-shear mixer, and hot-melt granulation.

4. The pharmaceutical composition according to claim 3, wherein, The granulation method employed is wet granulation in a high-shear mixer.

5. The pharmaceutical composition according to any one of claims 1-4, wherein, The pharmaceutical composition comprises at least one excipient selected from the group consisting of binders, diluents, disintegrants, lubricants, glidants, antioxidants, colorants, and flavoring agents.

6. The pharmaceutical composition according to any one of claims 1-5, wherein, The total amount of the diluent accounts for 20 wt% to 90 wt% w / w, the total amount of the binder accounts for 2 to 14 wt%, the total amount of the disintegrant accounts for 1 to 15 wt%, and the total amount of the lubricant accounts for 0.2 to 2.0 wt%, all percentages being expressed relative to the total weight of the pharmaceutical composition.

7. The pharmaceutical composition according to any one of claims 1-6, wherein, The amount of rupatadine or a pharmaceutically acceptable salt thereof per pharmaceutical composition in the tablet is 0.5 to 22 mg, expressed as the weight of rupatadine free base.

8. The pharmaceutical composition according to any one of claims 1-7, wherein, The amount of montelukast or a pharmaceutically acceptable salt thereof per pharmaceutical composition in the tablet is 1 to 22 mg, expressed as the weight of montelukast free acid.

9. The pharmaceutical composition according to any one of claims 1-8, wherein, The weight-to-weight ratio of rupatadine, expressed as the weight of rupatadine free base, to the disintegrant is 5:1 to 1:5, preferably 3.5:1 to 1:3.5, and more preferably 2.5:1 to 1:2.

5.

10. The pharmaceutical composition according to any one of claims 1-9, wherein, The weight-to-weight ratio of montelukast, expressed as the weight of montelukast free base, to the disintegrant is 5:1 to 1:5, preferably 3.5:1 to 1:3.5, and more preferably 2.5:1 to 1:2.

5.

11. The pharmaceutical composition according to any one of claims 1-10, wherein, Rupatadine or a pharmaceutically acceptable salt thereof is present in particulate form.

12. The pharmaceutical composition according to claim 11, wherein, Montelukast or a pharmaceutically acceptable salt thereof is present in dry powder form.

13. The pharmaceutical composition according to any one of claims 1-12, wherein, After single oral dose administration to human subjects, the pharmaceutical composition exhibits a maximum plasma concentration (C 最大 ) of rupatadine from 5.00 ng / mL to 6.50 ng / mL and a maximum plasma concentration (Cmax) of montelukast from 380 ng / mL to 530 ng / mL.

14. The pharmaceutical composition according to any one of claims 1-13, wherein, After a single oral dose administration to human subjects, the pharmaceutical composition exhibits an area under the plasma concentration-time curve (AUC 0-t ) of rupatadine from time 0 to 48 hours of 24.5 ng·h / mL to 28.5 ng·h / mL, and an area under the plasma concentration-time curve (AUC 0-t ) of montelukast from time 0 to 48 hours of 2850.0 ng·h / mL to 3450.0 ng·h / mL.

15. The pharmaceutical composition according to any one of claims 1-14, wherein, The pharmaceutically acceptable salt of rupatadine is rupatadine fumarate.

16. The pharmaceutical composition according to any one of claims 1-15, wherein, The pharmaceutically acceptable salt of montelukast is montelukast sodium.

17. Use of the pharmaceutical composition as defined in any one of claims 1-16 for a medicament.

18. Use of the pharmaceutical composition as defined in any one of claims 1-16 for the treatment and / or prevention of asthma and allergic rhinitis accompanied by allergic rhinitis.

19. Use of the pharmaceutical composition as defined in any one of claims 1-16 in the manufacture of a medicament for the treatment and / or prevention of asthma and allergic rhinitis accompanied by allergic rhinitis.

20. A method for treating and / or preventing asthma and allergic rhinitis accompanied by allergic rhinitis in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition as defined in any one of claims 1-16.

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