Bilastine Compositions for Once-Daily Parenteral Administration

Abstract

The present invention relates to an aqueous parenteral pharmaceutical composition comprising: a) 0.96-2.60% (w / v) of bilastine or a pharma- ceutically acceptable salt or solvate thereof; and b) 10-30% (w / v) of a β-cyclodextrin selected from unmodified β-cyclodextrin, C1-C6 alkyl-β-cyclodextrin, C1-C6 hydroxyalkyl β-cyclodextrin, C1-C6 carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, C1-C6 sulfoalkyl ether β-cyclodextrin, and mixtures thereof, wherein the pH value of the composition is 3.0-7.2 (both lower and upper limits of the range are included), and parenteral administration is selected from intravenous or intramuscular, and its use in the treatment and / or prevention of conditions mediated by H1 histamine receptors, such as allergic disorders or diseases and allergic symptoms, especially when an immediate effect is required.

Description

[Technical field]

[0001] The present invention relates to aqueous pharmaceutical compositions comprising bilastine and β-cyclodextrin suitable for once-daily parenteral administration and their use as antihistamine and antiallergic pharmaceutical compositions. [Background technology]

[0002] Antihistamines are compounds commonly used for the symptomatic treatment of different allergic diseases or disorders, since many of their symptoms (itchy eyes, runny nose, itchy skin, etc.) are caused by the action of histamine. Indeed, they have been known for a long time (some of them since the mid-20th century) for the treatment of many diseases and processes, such as allergic and non-allergic rhinitis and conjunctivitis, acute and chronic urticaria, control of itching and scratching of various dermatopathological causes (e.g. stings, dermatitis) and non-dermatopathological causes (e.g. metabolic itch), symptomatic treatment of catarrhal respiratory infections and non-specific cough, motion sickness, nausea and dizziness, as well as minor treatment of insomnia and anorexia (lack of appetite).

[0003] Antihistamines can typically be administered orally (as tablets, syrups, or drops) or topically (as creams, eye drops, nasal sprays, or eye drops).

[0004] Oral antihistamines can provide relief from some symptoms of allergies, but have a delayed onset of action compared to topical ocular medications.

[0005] Topical routes are suitable for eye, nose or skin diseases (eye drops, nasal sprays, creams, gels). When allergic symptoms are mainly ocular allergic symptoms, topical treatments seem to be the treatment of choice, as they have a more rapid onset of action (within minutes) than systemic drugs, and therefore can easily delay the allergic response. Topical antihistamines also have fewer adverse effects, due to the lower dose required to penetrate the conjunctiva and the non-negligible serum levels from topical use. However, the use of topical antihistamines is practically limited to ocular allergic reactions, and therefore such topical preparations cannot be applied to a larger disease spectrum with their corresponding symptoms.

[0006] The parenteral route is usually used to prevent or treat severe acute episodes of allergy. This route is possible only with some of the first generation antihistamines, which are known to cause sedation and cognitive and psychomotor impairments. At present, there are no effective and well tolerated options for parenteral treatment, especially formulations suitable for short-term treatment as monotherapy or for severe cases of histamine-mediated hypersensitivity reactions, when immediate action is required or parenteral formulations are preferred.

[0007] EP 0818454 A1 and EP 0580541 A1 disclose benzimidazole compounds having selective H1 antihistamine activity and no proarrhythmic effects. EP 3040334 A1 also discloses benzimidazole compounds having strong selective H1 antihistamine activity and lacking activity on the central nervous system and cardiovascular system.

[0008] A particular compound having the above characteristics is 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl}ethyl)phenyl]-2-methylpropanoic acid, also known as bilastine, having the formula: [ka] Developed by Faes Farma, Spain. Bilastine is a second generation H1 antagonist benzimidazole compound with no sedative side effects, no cardiotoxic effects, and no hepatic metabolism. In addition, bilastine has been proven effective in the symptomatic treatment of allergic rhinoconjunctivitis and urticaria.

[0009] WO2019 / 141563 discloses ophthalmic pharmaceutical compositions containing bilastine. These compositions require the presence of a gelling agent in order for the compositions to act long-term in the eye, and therefore would not be suitable for parenteral administration.

[0010] In allergic emergencies, i.e. in the case of severe events of histamine-mediated type I hypersensitivity reactions, immediate action is necessary because topical preparations may not be sufficiently effective, while oral antihistamines may not act within a reasonable time frame. Parenteral administration of antihistamines may be a solution to the lack of drugs for allergic emergency conditions, and in particular, intravenous and intramuscular preparations seem suitable for the rapid and effective treatment of acute episodes of allergy. To date, only three injectable antihistamines are known: dexchlorpheniramine (trade name Polaramine®), cetirizine hydrochloride (trade name Quzyttir®) and diphenhydramine (trade name Benadryl®, which has been withdrawn from the US market, and several generic preparations).

[0011] Dexchlorpheniramine is the standard antihistamine for emergency allergic events. It is the only injectable antihistamine regulated in Europe, but like other first generation H1 antihistamines, it can induce extreme drowsiness, dizziness or sleepiness. In some cases, up to four doses of dexchlorpheniramine per day may be required.

[0012] Cetirizine is a second-generation antihistamine compound approved by the FDA for intravenous administration in October 2019.

[0013] Diphenhydramine is a first-generation H1 antihistamine that is approved by the FDA as an injectable formulation at a concentration of 50 mg of diphenhydramine hydrochloride per mL, but like other first-generation H1 antihistamines, it can induce extreme drowsiness, dizziness, or sleepiness. In some cases, up to eight doses of dexchlorpheniramine per day may be required.

[0014] Other disclosures addressing the treatment of acute allergic symptoms by administering parenteral antihistamine preparations are quite rare.

[0015] EP1005865B1 discloses a process for making an antihistamine and antiallergic composition comprising 1) making a finely powdered blend of nimesulide and cetirizine, and 2) dissolving the homogenous blend in a solvent suitable for parenteral administration at a temperature of 25-35°C.

[0016] R. Corcostegui et al. (Drugs RD 2006, 7(4), 219-231) compared the in vivo antihistamine and antiallergic properties of bilastine, cetirizine and fexofenadine by different routes of administration (oral and intravenous) in various animal models. Bilastine was administered intravenously to rats in a tartaric acid solution for 5 minutes before inducing a papule by intradermal injection of histamine, and the resulting increase in capillary permeability was determined as a measure of the intensity of the histamine-mediated allergic reaction. Due to the low aqueous solubility of bilastine (approximately 0.5 mg / ml at pH 5-8), large volumes of the bilastine compositions disclosed herein would be required to administer a therapeutically effective dose, which would hinder efficient parenteral administration and development of a pharma- ceutical acceptable parenteral formulation. Of course, such compositions are not suitable for once-daily administration.

[0017] Parenteral compositions containing high concentrations of bilastine with optimal pH suitable as monotherapy or for once-daily treatment / prophylaxis for the treatment / prophylaxis of severe cases of histamine-mediated type I hypersensitivity reactions (e.g., acute urticaria, chronic urticaria, acute exacerbations of chronic urticaria, immediate hypersensitivity reactions, anaphylaxis or angioedema) are not known in the art. Summary of the Invention

[0018] The inventors of the present invention have surprisingly found that the parenteral formulation of the present invention exhibits a rapid onset of drug action, provides very high efficacy and is free of side effects (the formulation is in fact as safe as a placebo and does not cause drowsiness or sleepiness compared to known marketed formulations).

[0019] These compositions allow for very high concentrations of bilastine at a pH suitable for parenteral administration.

[0020] Surprisingly, the formulation of the present invention was found to be more efficient than known marketed formulations. In particular, the formulation of the present invention showed more effective efficacy results than intramuscular administration of Polaramine®, a powerful antihistamine for allergic emergencies that can induce extreme drowsiness, dizziness or sleepiness. In particular, the formulation of the present invention does not induce drowsiness, dizziness or sleepiness.

[0021] Also, unexpectedly, when administered by intravenous or intramuscular routes, the formulations of the present invention provide at least one of improved drug onset, improved efficacy, or fewer side effects when compared to other bilastine compositions, when compared to other routes of administration, or when compared to other antihistamine compositions administered by similar routes of administration.

[0022] In addition, the compositions of the invention have been found to be effective within 15 minutes of administration and remain effective over a 24 hour period, making them particularly useful where immediate action is required, for example in the prevention / treatment of acute Type I hypersensitivity reactions, either alone or as an adjunct therapy.

[0023] Furthermore, due to sustained efficacy for up to 24 hours, the compositions of the present invention can be used for once-daily administration, in contrast to current injectable antihistamine therapies.

[0024] Thus, in a first aspect, the present invention provides an aqueous, parenteral pharmaceutical composition comprising: a) 0.96% (w / v) to 2.60% (w / v) of bilastine or a pharma- ceutically acceptable salt or solvate thereof; b) 10% (w / v) to 30% (w / v) of a β-cyclodextrin selected from unmodified β-cyclodextrin, C1-C6 alkyl-β-cyclodextrin, C1-C6 hydroxyalkyl-β-cyclodextrin, C1-C6 carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, C1-C6 sulfoalkyl ether β-cyclodextrin, and mixtures thereof; Including, An aqueous parenteral pharmaceutical composition is provided, wherein the composition has a pH value of 3.0 to 7.2 (both the lower and upper limits of the range are included), and the parenteral administration is selected from intravenous or intramuscular.

[0025] Another aspect of the present invention relates to an aqueous, parenteral pharmaceutical composition of the present invention for use as a medicament.

[0026] In a further aspect, the present invention relates to an aqueous, parenteral pharmaceutical composition of the invention for use in the treatment and / or prevention of an allergic disease or disorder or an allergic condition.

[0027] Another aspect of the present invention relates to the use of an aqueous, parenteral pharmaceutical composition of the present invention in the manufacture of a medicament for the treatment and / or prevention of an allergic disease or disorder or an allergic condition.

[0028] Another aspect of the present invention relates to a method for the treatment and / or prevention of an allergic disease or disorder or allergic condition, the method comprising administering to a subject in need of such treatment and / or prevention a therapeutically effective amount of an aqueous, parenteral pharmaceutical composition of the present invention.

[0029] These aspects and preferred embodiments thereof are also further described in the following description and defined in the claims. [Brief description of the drawings]

[0030] [Figure 1] 1 shows the mean plasma concentration / time curves (0-24 hours) for a) oral bilastine (Bilaxten®), b) intramuscular (im) bilastine, c) intramuscular (im) Polaramine® and d) intravenous (iv) bilastine. [Diagram 2] Graph showing comparison of im bilastine, iv bilastine, imPolaramine®, oral bilastine and placebo in the % reduction vs. baseline in wheal area induced by histamine injection. Curves for im bilastine: P≦0.001 vs. imPolaramine® (time data points ≧30 min) and ns at 15 min (ns: not significant, P>0.05), P≦0.001 vs. iv bilastine (15 min, 30 min and 12 h), P>0.05 for the rest of the data points; P≦0.001 vs. placebo (all time data). Curves for iv bilastine: P≦0.001 vs. imPolaramine® (15 min to 12 h), P≦0.05 vs. placebo (24 h), P≦0.001 (15 min to 12 h), P=0.002 (24 h). Curves for oral bilastine: P ≤ 0.001 (30 min, 45 min), P ≤ 0.05 (15 min, 1 h), ns (remaining) vs. im bilastine; P ≤ 0.001 (15 min to 1 h), P ≤ 0.05 (12 h), ns (remaining) vs. iv bilastine; P ≤ 0.001 (1 h to 12 h), P ≤ 0.05 (24 h), ns (remaining) vs. imPolaramine®; P ≤ 0.001 (45 min to 24 h), P ≤ 0.05 (15 min, 30 min). Curves for imPolaramine®: P ≤ 0.001 (15 min to 4 h, 9 h), P ≤ 0.05 (12 h, 24 h), ns (6 h) vs. placebo. [Diagram 3] Graph showing comparison of im bilastine, iv bilastine, imPolaramine®, oral bilastine and placebo in the % reduction vs. baseline in flare area induced by histamine injection. Curves for im bilastine: P≦0.001 vs. imPolaramine® (45 min-24 hr), and ns at 15 min and 30 min; Curves for iv bilastine: P≦0.001 (15 min, 30 min and 45 min), P≦0.05 (1 hr), ns for the rest of the data points; Curves for placebo: P≦0.001 (all time data). Curves for iv bilastine: P≦0.001 vs. imPolaramine® (15 min-24 hr); P≦0.001 vs. placebo (15 min-24 hr). Curves for oral bilastine: vs. im bilastine, P≦0.001 (45 min, 1 hr), P≦0.05 (15 min, 30 min, 24 hr), ns (remaining); vs. iv bilastine, P≦0.001 (15 min-1 hr), P≦0.05 (2 hr, 24 hr), ns (remaining); vs. imPolaramine®, P≦0.001 (2 hr-24 hr), P≦0.05 (15 min, 30 min, 1 hr), ns (45 min); vs. placebo, P≦0.001 (45 min-24 hr), P≦0.05 (30 min), ns (15 min). Curves for imPolaramine®: vs. placebo, P≦0.001 (30 min, 45 min), P≦0.05 (15 min, 1 hr, 4 hr-24 hr), ns (2 hr). [Figure 4]Graph showing comparison of im bilastine, iv bilastine, imPolaramine®, oral bilastine and placebo in the % reduction from baseline in VAS (visual analog scale) values ​​related to itching sensation induced by histamine injection. Curves for im bilastine: P≦0.001 (2 h to 9 h) and ns (remaining) vs. imPolaramine®; ns vs. iv bilastine for all time data points; P≦0.001 (2 h, 4 h), P≦0.05 (1 h, 6 h, 9 h), ns (remaining) vs. placebo. Curves for iv bilastine: P≦0.05 (2 h, 4 h, 6 h), ns (remaining) vs. imPolaramine®; P≦0.001 (2 h), P≦0.05 (1 h, 4 h), ns (remaining) vs. placebo. Curves for oral bilastine: ns for im bilastine (all data points); ns for iv bilastine (all data points); P≦0.001 (9 hr), P≦0.05 (2, 4, 6, 12 hr), ns (remaining); P≦0.05 (2-24 hr), ns (15 min-1 hr) for placebo. Curves for imPolaramine: P≦0.05 (15 min), ns (remaining) for placebo. [Diagram 5] Absolute increase in perceived sleepiness over baseline with im bilastine, iv bilastine, imPolaramine®, oral bilastine and placebo. Curves for im bilastine: P≦0.05 vs. imPolaramine®; ns vs. iv bilastine and placebo. Curves for iv bilastine: ns vs. imPolaramine®; ns vs. placebo. Curves for oral bilastine: ns vs. im bilastine, iv bilastine and placebo (3 h and 1.5 h); P≦0.05 vs. imPolaramine® (1.5 h and 3 h). Curves for imPolaramine®: P≦0.05 vs. placebo (1.5 h), ns (3 h). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] The term "alkyl" refers to a straight or branched chain alkane derivative containing 1 to 6 ("C1-C6 alkyl"), preferably 1 to 3 ("C1-C3 alkyl") carbon atoms and attached to the remainder of the molecule by a single bond. Illustrative examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, and hexyl.

[0032] The phrase "pharmacologically acceptable" refers to compositions and molecular entities that, when administered to humans or animals, are physiologically tolerated and typically do not produce allergic reactions or similar undesirable reactions such as stomach upset, dizziness, and the like. Preferably, the term "pharmacologically acceptable" means approved by a state or government regulatory agency for use in animals, and more particularly, in humans, or therefore included in the United States Pharmacopeia or other generally recognized pharmacopoeias.

[0033] In this application, all percentages disclosed refer to w / v percentages unless otherwise specified.

[0034] Where a range is given in this document, both the lower and upper limits are included in the range.

[0035] All embodiments disclosed in relation to one aspect of the invention are applicable to the other aspects.

[0036] The inventors have unexpectedly found that the combination of bilastine with at least β-cyclodextrin is optimal for parenteral administration, exhibits a rapid onset of action, is substantially free of side effects (especially in view of the drowsiness that characterizes other injectable antihistamine formulations currently approved by regulatory authorities), and exhibits a good long-term action at the systemic level that makes it possible for the first time to provide a once-daily parenteral formulation containing bilastine.Thus, when administered by intravenous or intramuscular route, the formulation of the present invention provides at least one of improved onset of drug action, improved efficacy, or fewer side effects compared to other bilastine compositions, compared to other routes of administration, or compared to other antihistamine compositions administered by similar routes of administration.

[0037] Thus, in a first aspect, the present invention provides an aqueous, parenteral pharmaceutical composition comprising: a) 0.96% (w / v) to 2.60% (w / v) of bilastine, or a pharma- ceutically acceptable salt or solvate thereof; b) 10% (w / v) to 30% (w / v) of a β-cyclodextrin selected from unmodified β-cyclodextrin, C1-C6 alkyl-β-cyclodextrin, C1-C6 hydroxyalkyl-β-cyclodextrin, C1-C6 carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, C1-C6 sulfoalkyl ether β-cyclodextrin, and mixtures thereof; Including, An aqueous parenteral pharmaceutical composition is provided, wherein the composition has a pH value of 3.0 to 7.2 (both the lower and upper limits of the range are included), and the parenteral administration is selected from intravenous or intramuscular.

[0038] Bilastine The aqueous parenteral composition of the present invention comprises bilastine of the following formula: [ka] or a pharma- ceutically acceptable salt or solvate thereof. This compound is 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidinyl}ethyl)phenyl]-2-methylpropanoic acid, also known as bilastine. The synthesis of bilastine is described, for example, in EP0818454A1, EP0580541A1 and EP3040334A1.

[0039] Bilastine may be in the form of a salt or solvate, preferably a pharma- ceutically acceptable salt or solvate.

[0040] By way of example, the above-mentioned salts may be acid addition salts, base addition salts, or metal salts, and can be synthesized from the parent compound by conventional chemical processes known to those skilled in the art. Such salts are generally prepared by reacting the free compound with a stoichiometric amount of an appropriate base or acid, for example, in water, or in an organic solvent, or in a mixture of the two. Non-aqueous media such as ether, ethyl acetate, ethanol, acetone, isopropanol, or acetonitrile are generally preferred. Illustrative examples of acid addition salts include inorganic acid addition salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc., and organic acid addition salts, such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, camphorsulfonate, etc. Illustrative examples of base addition salts include inorganic base salts, e.g., ammonium salts, and organic base salts, e.g., ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine, glutamine, amino acid base salts, etc. Illustrative examples of metal salts include, e.g., sodium, potassium, calcium, magnesium, aluminum and lithium salts.

[0041] The term "solvate" according to the present invention is understood to mean any form of active compound with another molecule (most likely a polar solvent) connected by non-covalent bond.Examples of solvates include hydrates and alcoholates.Solvation methods are generally known in the art.

[0042] The compounds of the present invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, a hydrogen has been replaced by a deuterium or tritium, or a carbon has been replaced by a 13 C or 14 C is enriched with carbon or nitrogen 15 Compounds having the present structure except where N is replaced by an condensed nitrogen are within the scope of this invention.

[0043] In one embodiment, bilastine or a pharma- ceutically acceptable salt or solvate thereof is present in the pharmaceutical composition of the present invention at a concentration of 0.96% to 2.60% (w / v). A concentration of 0.96% to 2.60% (w / v) means that 9.6 mg to 26.0 mg of bilastine or a pharma- ceutically acceptable salt or solvate thereof is present in 1 mL of the aqueous composition. In one embodiment, bilastine or a pharma- ceutically acceptable salt or solvate thereof is present in the pharmaceutical composition of the present invention at a concentration of 1% to 2.6% (w / v). In one embodiment, bilastine or a pharma- ceutically acceptable salt or solvate thereof is present in the pharmaceutical composition of the present invention at a concentration of 1.00% to 2.60% (w / v).

[0044] In one embodiment, bilastine or a pharma- ceutically acceptable salt or solvate thereof is present in the pharmaceutical composition of the present invention at a concentration of 0.96% to 1.5% (w / v). In one embodiment, bilastine or a pharma- ceutically acceptable salt or solvate thereof is present in the pharmaceutical composition of the present invention at a concentration of 0.96% to 1.50% (w / v). In another embodiment, bilastine or a pharma- ceutically acceptable salt or solvate thereof is present in the pharmaceutical composition of the present invention at a concentration of 1.0% to 1.4% (w / v). In another embodiment, bilastine or a pharma- ceutically acceptable salt or solvate thereof is present in the pharmaceutical composition of the present invention at a concentration of 1.00% to 1.40% (w / v). In one embodiment, the composition comprises 1.05% (w / v) to 1.35% (w / v) bilastine or a pharma- ceutically acceptable salt or solvate thereof. In a further embodiment, the composition comprises 1.1% (w / v) to 1.3% (w / v), such as 1.14% (w / v) to 1.26% (w / v), or even 1.2% (w / v) of bilastine, or a pharma- ceutically acceptable salt or solvate thereof. In a further embodiment, the composition comprises 1.10% (w / v) to 1.30% (w / v), such as 1.14% (w / v) to 1.26% (w / v), or even 1.20% (w / v) of bilastine, or a pharma- ceutically acceptable salt or solvate thereof.

[0045] In the present invention, unless otherwise specified or feasible, a value is considered to be rounded to the last decimal place indicated. For example, a number such as "1.10" includes the range of 1.095 to 1.104. Similarly, a value such as "1.5" includes the range of 1.45 to 1.54, and a value such as "1.0" includes the range of 0.95 to 1.04.

[0046] Therefore, the mass of bilastine can be calculated from the % (w / v) value. In certain embodiments, the pharmaceutical composition is a unit dose. In some embodiments, the pharmaceutical composition is a unit dose containing 9.6 mg to 28.0 mg, or even 9.6 mg to 22.0 mg of bilastine. In other embodiments, the pharmaceutical composition is a unit dose containing 10 mg to 18 mg of bilastine, or 11 mg to 15 mg of bilastine.

[0047] In one embodiment, the volume of a unit dose of the composition of the invention is 0.5-1.5 mL, in another embodiment, the volume of a unit dose of the composition of the invention is 0.8-1.5 mL, or even 0.8-1.2 mL.

[0048] The term "unit dose" refers to an amount administered to a subject or patient in a single dose.

[0049] It has been found that β-cyclodextrin increases the solubility of bilastine, such that compositions containing high concentrations of bilastine can be obtained. Bilastine, or a pharma- ceutically acceptable salt or solvate thereof, dissolves completely (i.e., without any sign of significant precipitation) in the pharmaceutical compositions of the present invention.

[0050] Bilastine concentration can be determined, for example, by UV spectroscopy at 254 nm.

[0051] In one embodiment, bilastine or a salt or solvate thereof is the only active pharmaceutical ingredient in the composition of the invention.

[0052] Cyclodextrin Cyclodextrins (CDs) are ring structures composed of five or more β-D-glucopyranose units linked at the 1,4 positions, typically with six (α-cyclodextrin), seven (β-cyclodextrin), eight (γ-cyclodextrin) or nine (δ-cyclodextrin) sugar units in one cyclodextrin molecule.

[0053] The MS value (average molar substitution) is the average number of moles of substituents per mole of glucopyranose. For example, for β-cyclodextrin, the degree of substitution / modification (DS) is the average number of substituents per β-cyclodextrin core and can be calculated by multiplying the MS value by 7 (β-cyclodextrin contains 7 sugar units per cyclodextrin molecule).

[0054] Amorphous and crystalline cyclodextrins are within the scope of this application. As used herein, the term "cyclodextrin" may refer to cyclodextrin or cyclodextrin derivatives. Cyclodextrins may be commercially available or synthesized by methods well known in the art. Examples of cyclodextrins include, but are not limited to, modified or unmodified α-, β-, γ-, and δ-cyclodextrins.

[0055] The cyclodextrin of the present invention is β-cyclodextrin. Derivatives of cyclodextrin, particularly derivatives of β-cyclodextrin of the present invention, include those in which some or all of the OH groups are converted to OR groups. The above-mentioned derivatives include C 1~6 those with alkyl groups, such as methylated, ethylated, propylated and butylated cyclodextrins (where R is a methyl, ethyl, propyl or butyl group); those with C1-C6 hydroxyalkyl substituents, such as hydroxypropyl cyclodextrin or hydroxyethyl cyclodextrin (where R is a -CH2CH(OH)CH3 or -CH2CH2OH group-branched cyclodextrins, such as maltose-linked cyclodextrins; cationic cyclodextrins; quaternary ammonium; anionic cyclodextrins, such as carboxymethyl cyclodextrin, cyclodextrin sulfate and cyclodextrin succinate; amphoteric cyclodextrins, such as carboxymethyl / quaternary cyclodextrin. Other specific modifications include one or more hydroxyalkyl ethers (e.g., where R is C 1~6 alkylenehydroxy) moiety; C1-C6 sulfoalkyl ether (e.g., R is C 2~6 Alkylene SO3 - C1-C6 carboxyalkyl (e.g., R is C(O)C 1~6 The OR moiety may be an alkyl (alkyl) moiety, a substituted phenoxy moiety, a tryptophan moiety, or a mixture thereof. The total number of OR groups per cyclodextrin molecule is defined as the degree of substitution / modification.

[0056] In the present invention, the β-cyclodextrin is selected from the group consisting of unmodified β-cyclodextrin, C1-C6 alkyl-β-cyclodextrin, C1-C6 hydroxyalkyl β-cyclodextrin, C1-C6 carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, C1-C6 sulfoalkyl ether β-cyclodextrin, and mixtures thereof.

[0057] In one embodiment, the β-cyclodextrin is a C1-C6 alkyl-β-cyclodextrin. Preferred alkyl-β-cyclodextrins include methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, trimethyl-β-cyclodextrin, ethyl-β-cyclodextrin, diethyl-β-cyclodextrin, propyl-β-cyclodextrin, and butyl-β-cyclodextrin. In a more preferred embodiment, the β-cyclodextrin is selected from the group consisting of methyl-β-cyclodextrin or dimethyl-β-cyclodextrin. In the context of the present invention, when the term "alkyl-β-cyclodextrin" is used, it is meant to include β-cyclodextrins in which the alkyl portion is optionally substituted, but excluding hydroxyalkyl-β-cyclodextrins.

[0058] The C1-C6 alkyl β-cyclodextrin preferably has a substitution / modification degree of 1-18, 3-16, 4-14, or 4-12.6, and more preferably 4-6.

[0059] In another embodiment, the β-cyclodextrin is a C1-C6 hydroxyalkyl-β-cyclodextrin. Preferred hydroxyalkyl-β-cyclodextrins include hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin (equivalent to 2-hydroxypropyl-β-cyclodextrin) and 2-hydroxybutyl-β-cyclodextrin. In a more preferred embodiment, the β-cyclodextrin is hydroxypropyl-β-cyclodextrin (2-hydroxypropyl-β-cyclodextrin, HPBCD or HP-β-CD).

[0060] The C1-C6 hydroxyalkyl β-cyclodextrin, in particular hydroxypropyl-β-cyclodextrin, preferably has a degree of substitution / modification of 1 to 14, more preferably 2 to 8. In a further embodiment, it has a degree of substitution of 3 to 7, preferably 3 to 6.

[0061] In one embodiment, the hydroxyalkyl β-cyclodextrin, in particular hydroxypropyl-β-cyclodextrin, preferably has an average molar degree of substitution of 0.42 to 0.86, or 0.50 to 0.75.

[0062] In a further embodiment, the β-cyclodextrin is a C1-C6 carboxyalkyl-β-cyclodextrin. Preferred C1-C6 carboxyalkyl-β-cyclodextrins for use herein include carboxymethyl-β-cyclodextrin and (2-carboxyethyl)-β-cyclodextrin.

[0063] In a further embodiment, the β-cyclodextrin is a C1-C6 sulfoalkyl ether β-cyclodextrin.A preferred sulfoalkyl ether-β-cyclodextrin for use herein is sulfobutyl ether-β-cyclodextrin.

[0064] The sulfoalkylether-β-cyclodextrin preferably has a degree of substitution / modification of 1-14, preferably 1-7.

[0065] In some embodiments, the β-cyclodextrin is selected from the group consisting of C1-C6 alkyl-β-cyclodextrin, C1-C6 hydroxyalkyl-β-cyclodextrin, C1-C6 carboxyalkyl-β-cyclodextrin, C1-C6 sulfoalkyl ether β-cyclodextrin, and mixtures thereof.

[0066] In a preferred embodiment, the β-cyclodextrin is a pharma- ceutically acceptable β-cyclodextrin.

[0067] In certain embodiments, β-cyclodextrin is present in the composition in an amount of 10%-30% (w / v), where w / v means weight / volume percent concentration (g / 100 mL), e.g., when β-cyclodextrin is present in the composition in an amount of 10%-30% (w / v), this means that 100 mg-300 mg of β-cyclodextrin is present per mL of the aqueous composition.

[0068] In specific embodiments, the β-cyclodextrin is present in an amount of 10% to 25% (w / v). In other embodiments, the β-cyclodextrin is present in an amount of 12% to 22% (w / v), or 15% to 20% (w / v). In further embodiments, the β-cyclodextrin is present in an amount of 16% to 18% (w / v), for example, 17% (w / v).

[0069] In a further embodiment, the pharmaceutical composition is a unit dose comprising 100-330 mg of β-cyclodextrin, hi another embodiment, the pharmaceutical composition is a unit dose comprising 100-200 mg of β-cyclodextrin, or even 150-200 mg of β-cyclodextrin.

[0070] In a further embodiment, the pharmaceutical composition is a unit dose comprising 9.6-28 mg of bilastine and 100-330 mg of β-cyclodextrin, in another embodiment, the pharmaceutical composition is a unit dose comprising 10-18 mg of bilastine, or 11-15 mg of bilastine and 100-200 mg of β-cyclodextrin, or even 150-200 mg of β-cyclodextrin.

[0071] pH The aqueous pharmaceutical composition of the present invention is developed for parenteral use and / or administration, i.e., the aqueous parenteral pharmaceutical composition is suitable for these purposes. pH is an important aspect of parenteral preparations, which must have a pH close to physiological pH. However, pH can have an effect on the stability of the preparation, so a compromise can be found between a pH that ensures the stability of the drug substrate and a physiological pH. The acceptable range is pH 3-9 for intravenous and intramuscular injections, due to potential irritation challenges. Inappropriate pH can promote local irritation and increase pain during administration.

[0072] In one embodiment, the pharmaceutical composition has a pH value comprised between 3.0 and 7.2 (both ranges are included). In one embodiment, the pharmaceutical composition has a pH value comprised between 4.0 and 7.2 (both ranges are included). In another embodiment, the pharmaceutical composition has a pH value comprised between 4.0 and 7.0 (both ranges are included). In a further embodiment, the composition of the invention has a pH value comprised between 4.0 and 6.0 (both ranges are included), for example between 4.5 and 5.5. In some embodiments, the pH of a composition of the present invention is 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1 or 7.2.

[0073] In one embodiment, the pH of the composition is 5. In terms of pH value, it should be readily understood that a pH value of 5 may be specified as corresponding to a pH in the range of 4.5 to 5.4.

[0074] The composition may include a pH adjuster to obtain a desired pH value of the composition.

[0075] In one embodiment, the composition comprises a pH adjuster selected from the group consisting of hydrochloric acid, boric acid, acetic acid, sodium hydroxide, potassium hydroxide, or combinations thereof. Preferably, the pH adjuster is selected from hydrochloric acid, boric acid, acetic acid, and mixtures thereof, more preferably hydrochloric acid, e.g., concentrated hydrochloric acid (37% w / w).

[0076] The pH can be determined using conventional methods, for example by measuring the pH directly in the composition using a pH electrode, preferably at 23°C.

[0077] Further embodiments The compositions of the present invention further comprise balance water, i.e., water to reach the desired final volume of the composition.

[0078] The water in the compositions of the invention is preferably water for injection, eg, distilled and / or sterilized water for injection.

[0079] The term "water for injection" refers to water that has been purified so as to be suitable for parenteral administration, e.g., water that meets the USP (or foreign equivalent) requirements for water for injection.

[0080] The composition of the present invention may contain additional pharmaceutically acceptable parenteral carriers or excipients.Suitable pharmaceutically acceptable parenteral excipients or carriers include, but are not limited to, preservatives, including antimicrobial and chemical preservatives, isotonicity agents, buffers, antioxidants, chelating agents, bulking agents, solubilizers, surfactants, cosolvents, and combinations thereof.Suitable pharmaceutical carriers or excipients are described, for example, in "Remington's Pharmaceutical Sciences" by EW Martin, 21st Edition, 2005.

[0081] Preservatives may include benzalkonium chloride, benthezonium chloride, benzyl alcohol, benzoic acid, chlorobutanol, m-cresol, methylparaben, propylparaben, butylparaben, phenol, 2-phenoxyethanol, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, thimerosal, and mixtures thereof.

[0082] Typically used tonicity agents are sodium chloride, dextrose, glycerol, glycerin, mannitol, potassium chloride, propylene glycol, and mixtures thereof.

[0083] Buffers may include citrate / sodium / disodium / trisodium, phosphate / sodium / potassium, sodium acetate / acetic acid / glacial acetic acid / ammonium, sodium hydroxide, tris acetate, ammonium sulfate, ammonium hydroxide, arginine, benzenesulfonic acid, sodium benzoate / acid, sodium bicarbonate, boric acid / sodium, sodium carbonate, carbon dioxide, diethanolamine, glucono-delta-lactone, glycine / glycine HCl, histidine / histidine HCl, hydrochloric acid, hydrobromic acid, lysine, maleic acid, meglumine, methanesulfonic acid, monoethanolamine, sodium succinate / disodium, sulfuric acid, sodium tartrate / acid, tromethamine, and mixtures thereof.

[0084] Antioxidants may include ascorbic acid, acetylcysteine, ascorbyl palmitate, sodium ascorbate, butylated hydroxyl toluene, butylated hydroxyl anisole, citric acid, monothioglyercol, sulfites (hydrogen sulfite, metabisulfite), methionine, sodium metabisulfite, potassium metabisulfite, acetone metabisulfite, cysteine ​​hydrochloride, sodium dithionite, gentisic acid, sodium glutamate, glutathione, thioglycerol, propyl gallate, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thiourea, alpha tocopherol, and mixtures thereof.

[0085] Chelating agents may include edetate disodium, edetate sodium, edetate calcium disodium, DTPA, citric acid monohydrate, calcium versetamide, carteridol, ethylenediaminetetraacetic acid, and mixtures thereof.

[0086] Bulking agents may include mannitol, sucrose, lactose, dextran, trehalose, sorbitol, glucose, raffinose, glycine, histidine, and mixtures thereof.

[0087] Solubilizers, surfactants and co-solvents may include surfactants such as polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monooleate polyoxyethylene sorbitan monolaurate (Tween 20), lecithin, polyoxyethylene-polyoxypropylene copolymers (Pluronics), and alcohols such as ethanol, benzyl benzoate, dimethylacetamide, glycerin, sorbitol, polyethylene glycol, pyrrolidone, propylene glycol, castor oil, soybean oil, cottonseed oil, safflower oil, sesame oil, peanut oil, poppy seed oil, vegetable oils, and mixtures thereof.

[0088] In certain embodiments, the pharmaceutical composition of the present invention may comprise an additional pharma- ceutically acceptable parenteral carrier or excipient in an amount of 0-50% (w / v), 0-40% (w / v), or even 0-30% (w / v). That is, the composition may contain no additional pharma- ceutically acceptable parenteral carrier or excipient (0% (w / v)), or may contain an additional pharma- ceutically acceptable parenteral carrier or excipient in a maximum amount of 50% (w / v), 40% (w / v), or 30% (w / v), respectively. In certain embodiments, the pharmaceutical composition of the present invention may contain an additional pharma- ceutically acceptable parenteral carrier or excipient in an amount of 0-20% (w / v), or even 0-10% (w / v).

[0089] The phrase "pharmaceutically acceptable excipient" refers to a vehicle, diluent, or adjuvant with which an active ingredient is administered.

[0090] In certain embodiments, the compositions of the present invention do not include a gelling agent, such as hyaluronic acid, gellan gum, guar gum, locust bean gum, alginic acid, povidone, kappa-carrageenan, alginate gum, dextran, dextran sulfate, chitosan, or a salt thereof.

[0091] In certain embodiments, the compositions of the present invention do not comprise hyaluronic acid or a salt thereof.

[0092] In one embodiment, the composition of the present invention comprises: a) 0.96% (w / v) to 2.60% (w / v) of bilastine or a pharma- ceutically acceptable salt or solvate thereof; b) 10% (w / v) to 30% (w / v) of a β-cyclodextrin selected from unmodified β-cyclodextrin, C1-C6 alkyl-β-cyclodextrin, C1-C6 hydroxyalkyl-β-cyclodextrin, C1-C6 carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, C1-C6 sulfoalkyl ether β-cyclodextrin, and mixtures thereof; c) a pH adjuster that provides a pH value of 3.0 to 7.2 (both the lower and upper limits of the range are included); d) Water for injection; and e) optionally, one or more pharma- ceutically acceptable parenteral excipients or carriers selected from preservatives, including antimicrobial and chemical preservatives, isotonicity agents, buffers, antioxidants, chelating agents, bulking agents, solubilizers, surfactants, co-solvents, and mixtures thereof.

[0093] In certain embodiments, the additional pharma- ceutically acceptable parenteral excipient or carrier is present in the composition in an amount of 0-50% (w / v), or in an amount of 0-40% (w / v), or in an amount of 0-30% (w / v).In certain embodiments, the additional pharma-ceutically acceptable parenteral excipient or carrier is present in the composition in an amount of 0-20% (w / v), or in an amount of 0-10% (w / v).

[0094] Preferably, the term one or more refers to 1 to 5, or 1 to 4. In certain embodiments, it refers to 1, 2, or 3.

[0095] According to a particular embodiment, the composition of the present invention comprises: a) 0.96% (w / v) to 2.60% (w / v) of bilastine, or a pharma- ceutically acceptable salt or solvate thereof; b) 10% (w / v) to 30% (w / v) of a β-cyclodextrin selected from unmodified β-cyclodextrin, C1-C6 alkyl-β-cyclodextrin, C1-C6 hydroxyalkyl-β-cyclodextrin, C1-C6 carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, C1-C6 sulfoalkyl ether β-cyclodextrin, and mixtures thereof; c) a pH adjuster that provides a pH value of 3.0 to 7.2 (both the lower and upper limits of the range are included); d) Water for injection.

[0096] In one embodiment, the pharmaceutical composition of the present invention is a once-daily pharmaceutical composition.

[0097] The pharmaceutical composition of the present invention is suitable for parenteral administration, in particular for intramuscular or intravenous administration, preferably for intramuscular administration.

[0098] The term "parenteral" refers to any method of administering a medicine to a patient that does not involve the digestive tract. The term "parenteral" is derived from the Greek words "para," meaning beside or alongside, and "enteron," meaning intestine.

[0099] In the present invention, the term "parenteral" is selected from the group consisting of intramuscular administration and intravenous administration.

[0100] The present invention relates to antihistamine compositions that exhibit a rapid onset of action. In this regard, routes of administration such as intradermal will result in a slower onset of action. In such cases, the present inventors believe that the presence of excipients such as gelling agents will result in an even slower onset of action.

[0101] In certain embodiments, the pharmaceutical composition of the present invention is not suitable for subcutaneous or intradermal administration. In another particular embodiment, the pharmaceutical composition of the present invention is not suitable for at least one of subcutaneous, intrathecal, intraarterial, intradermal, intraocular, or subconjunctival administration.

[0102] Subcutaneous and intradermal routes of administration are given by injection into the skin between the epidermis and dermis layers. Subcutaneous is generally administered at an angle of 45°, while intradermal is usually administered at an angle of 10°-15°. For both subcutaneous and intradermal routes of administration, the volume injected is less than 0.5mL, usually less than 0.3mL, preferably less than 0.2mL. In contrast to the subcutaneous or intradermal routes of administration, the volume injected for intramuscular or intravenous administration is usually 0.3mL or more, 0.5mL or more, 0.75mL or more, or 1mL or more.

[0103] In a specific embodiment, the pharmaceutical composition of the present invention is for parenteral administration and the volume injected includes 0.5 to 5 mL, 0.5 to 4 mL, 0.5 to 3 mL, 0.5 to 2 mL, 0.5 to 1.5 mL, preferably 0.7 to 1.5 mL, more preferably 0.8 to 1.2 mL, and even more preferably 0.9 to 1.1 mL.

[0104] The present invention relates to parenteral administration consisting of intramuscular or intravenous administration. In contrast to the subcutaneous or intradermal administration routes, intramuscular administration is given at an angle greater than 45°, preferably 70-90°, more preferably 80-90°, and most preferably 90°, relative to the skin. A person skilled in the art will readily know the angles required to administer a composition in an intramuscular manner. Intravenous administration is usually given at an angle of 25°.

[0105] Commonly used muscle sites for intramuscular administration are the hip, thigh, or shoulder muscles.

[0106] use Bilastine has been shown to be an antagonist of the histamine H1 receptor and is therefore useful in the treatment and / or prevention of diseases known to be susceptible to amelioration by histamine H1 receptor antagonism.

[0107] Accordingly, one aspect of the present invention is directed to an aqueous, parenteral pharmaceutical composition of the present invention for use as a medicament.

[0108] Another aspect of the invention refers to an aqueous, parenteral pharmaceutical composition of the invention for use in the treatment and / or prevention of diseases, disorders or conditions susceptible to amelioration by histamine H1 receptor antagonism, such as allergic diseases, disorders and symptoms resulting from allergy.

[0109] In a preferred embodiment, the present invention relates to an aqueous parenteral pharmaceutical composition of the present invention for use in the treatment and / or prevention of an allergic disease, allergic disorder, or allergic condition. Preferably, the allergic disease, allergic disorder, or allergic condition is selected from rhinitis, conjunctivitis, rhinoconjunctivitis, hay fever, dermatitis, eczema, erythema, pruritus, itch, urticaria, chronic urticaria, asthma, anaphylaxis, acute urticaria, acute exacerbation of chronic urticaria, immediate hypersensitivity reaction, angioedema, food allergy, or drug allergy.

[0110] In one embodiment, the composition of the present invention is used for the prevention and / or treatment of histamine-mediated type I hypersensitivity reactions, such as allergic rhinitis, conjunctivitis, rhinoconjunctivitis, asthma, dermatitis, urticaria, acute urticaria, chronic urticaria, anaphylaxis, angioedema, food allergies, drug allergies, hay fever, eczema, erythema, pruritus or itching. In a preferred embodiment, the composition is used for the prevention and / or treatment of acute urticaria, chronic urticaria, acute exacerbation of chronic urticaria, immediate hypersensitivity reactions, anaphylaxis or angioedema.

[0111] In the present invention, parenteral route (IM or IV) can be used to prevent or treat acute severe episodes of allergy. In a preferred embodiment, the composition of the present invention is used for short-term treatment of histamine-mediated type I hypersensitivity reactions, preferably selected from acute urticaria. It may also be used in severe cases as an add-on therapy.

[0112] The concept of short-term treatment relating to rapid onset of action is to be understood as a treatment whose effect is noticeable within the first 20 minutes, preferably within the first 15 minutes after the start of administration.

[0113] Due to the rapid onset of action and extremely high efficacy of the compositions of the present invention, they can be used in severe or acute cases and / or cases where immediate action is required.The compositions are also useful when parenteral administration is necessary or preferred, for example, in uncooperative, nauseous, or unconscious patients.Furthermore, due to the long duration of action of the compositions of the present invention, they can be administered as a once-a-day composition.

[0114] The term "once daily" is well known to those skilled in the art and is intended to mean administration of a dose to a subject once per day, i.e., approximately once every 24 hours. In other words, once daily means that two intravenous or intramuscular injections of a pharmaceutical composition must be separated by at least 24 hours.

[0115] Thus, in one embodiment, the present invention relates to an aqueous, parenteral pharmaceutical composition of the present invention for use in the treatment and / or prevention of an allergic disease, allergic disorder or allergic condition, wherein the composition is administered once daily.

[0116] Generally, the effective amount of the compounds of the invention will depend on the severity of the disorder to be treated and / or prevented and on the weight of the affected individual, but a typical total daily dose may range from 9.6 mg to 15.0 mg of bilastine.

[0117] Thus, in one embodiment, the present invention relates to an aqueous, parenteral pharmaceutical composition of the invention for use in the treatment and / or prevention of an allergic disease, allergic disorder or allergic condition, wherein a total amount of bilastine in the range of 9.6 mg to 15.0 mg is administered per day, preferably a total amount of bilastine in the range of 9.6 mg to 15.0 mg is administered once per day.

[0118] In another embodiment, the total daily dose of bilastine may range from 10.0 mg to 14.0 mg or from 11.0 mg to 13.0 mg.

[0119] The parenteral pharmaceutical composition of the present invention can be used for the prevention and / or treatment of a disease or patient, and the subject or patient is a mammal, preferably a human, including humans of any age, race and sex. In one embodiment, the composition of the present invention is used as a monotherapy for the treatment and / or prevention of the above-mentioned disease, disorder or condition. That is, bilastine is used as the only active pharmaceutical ingredient in the prevention and / or treatment.

[0120] In another embodiment, the composition of the present invention is used as an adjunct therapy, i.e., in combination with another active pharmaceutical ingredient.In some embodiments, the composition of the present invention is used in combination with epinephrine, β2-agonists (e.g., salbutamol or albuterol), H2 antihistamines (e.g., cimetidine or famotidine), glucocorticoids (e.g., dexamethasone, methylprednisolone or hydrocortisone), hypertensives (e.g., norepinephrine (noradrenaline), phenylephrine, dopamine, dobutamine or vasopressin) or glucagon, for example, to treat severe diseases, disorders or conditions, such as anaphylaxis.

[0121] The pharmaceutical compositions of the present invention can be administered parenterally, in certain embodiments, intramuscularly or intravenously, preferably intramuscularly.

[0122] In the context of this specification, the term "treatment" or "treating" refers to the administration of a composition according to the invention to ameliorate or eliminate a disease or one or more symptoms associated with the disease. "Treatment" also encompasses ameliorating or eliminating the physiological sequelae of the disease.

[0123] The term "ameliorate" in the context of the present invention is understood to mean any improvement to the condition of the patient being treated.

[0124] In the context of this specification, the term "prevention" or "preventing" refers to the administration of a composition according to the invention to reduce the risk of acquiring or developing a disease or one or more symptoms associated with the disease.

[0125] The term "aqueous parenteral pharmaceutical composition" refers to a liquid pharmaceutical composition that contains water and is suitable for parenteral administration.

[0126] The phrase "therapeutically effective amount" refers to an amount of a pharmaceutical agent that, when administered, provides an amount of one or more pharma- ceutical active agents contained therein to provide a therapeutic benefit in the treatment or management of a disease or condition.

[0127] In certain embodiments, the pharmaceutical compositions of the present invention are not suitable for cosmetic applications, i.e., are not suitable for non-therapeutic applications.

[0128] Specific Embodiments Specific embodiment 1 An aqueous parenteral pharmaceutical composition comprising: a) 0.96% (w / v) to 2.60% (w / v) of bilastine, or a pharma- ceutically acceptable salt or solvate thereof; b) 10% (w / v) to 30% (w / v) of a β-cyclodextrin selected from unmodified β-cyclodextrin, C1-C6 alkyl-β-cyclodextrin, C1-C6 hydroxyalkyl-β-cyclodextrin, C1-C6 carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, C1-C6 sulfoalkyl ether β-cyclodextrin, and mixtures thereof; Including, An aqueous parenteral pharmaceutical composition, wherein the composition has a pH value of 3.0 to 7.2 (both the lower and upper limits of the range are included).

[0129] Certain embodiment 2 The pharmaceutical composition according to certain embodiment 1, wherein the composition does not comprise a gelling agent.

[0130] Certain embodiment 3 is a composition comprising: a) 0.96% (w / v) to 2.60% (w / v) of bilastine, or a pharma- ceutically acceptable salt or solvate thereof; b) 10% (w / v) to 30% (w / v) of a β-cyclodextrin selected from unmodified β-cyclodextrin, C1-C6 alkyl-β-cyclodextrin, C1-C6 hydroxyalkyl-β-cyclodextrin, C1-C6 carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, C1-C6 sulfoalkyl ether β-cyclodextrin, and mixtures thereof; c) a pH adjuster that provides a pH value of 3.0 to 7.2 (both the lower and upper limits of the range are included); d) water; e) optionally, one or more pharma- ceutically acceptable parenteral excipients or carriers selected from preservatives, including antimicrobial and chemical preservatives, isotonicity agents, buffers, antioxidants, chelating agents, bulking agents, solubilizers, surfactants, co-solvents, and mixtures thereof; The pharmaceutical composition according to any one of specific embodiments 1 to 2, consisting of:

[0131] Specific embodiment 4. The pharmaceutical composition according to any one of specific embodiments 1 to 3, wherein the composition comprises 1.0% (w / v) to 1.4% (w / v) of bilastine, or a pharma- ceutical acceptable salt or solvate thereof.

[0132] Specific embodiment 5. The pharmaceutical composition according to any one of specific embodiments 1 to 4, wherein the composition comprises 1.05% (w / v) to 1.35% (w / v), or 1.10% (w / v) to 1.30% (w / v) of bilastine, or a pharma- ceutical acceptable salt or solvate thereof.

[0133] Specific embodiment 6. The pharmaceutical composition according to any one of specific embodiments 1 to 5, wherein the composition comprises 10% (w / v) to 25% (w / v) of β-cyclodextrin.

[0134] Specific embodiment 7. The pharmaceutical composition according to any one of specific embodiments 1 to 6, wherein the composition comprises 12% (w / v) to 22% (w / v), or 15% (w / v) to 20% (w / v) of β-cyclodextrin.

[0135] Particular embodiment 8 The pharmaceutical composition according to any one of particular embodiments 1 to 7, wherein the β-cyclodextrin is a C1 to C6 hydroxyalkyl β-cyclodextrin, preferably a hydroxypropyl β-cyclodextrin.

[0136] Specific embodiment 9 A pharmaceutical composition according to any one of specific embodiments 1 to 8, wherein the pH value of the composition is between 4.0 and 7.0, preferably between 4.0 and 6.0.

[0137] Certain embodiments of the present invention relate to a composition comprising: a) 1.0% (w / v) to 1.4% (w / v) of bilastine, or a pharma- ceutically acceptable salt or solvate thereof; b) 10% (w / v) to 25% (w / v) of a C1 to C6 hydroxyalkyl β-cyclodextrin, such as hydroxypropyl β-cyclodextrin; The pharmaceutical composition according to any one of the specific embodiments 1 to 9, wherein the pH value of the composition is between 4 and 6 (both the lower and upper limits of the range are included).

[0138] Specific embodiment 11. A pharmaceutical composition according to any one of specific embodiments 1 to 10 for use as a medicament.

[0139] Specific embodiment 12. A pharmaceutical composition according to any one of specific embodiments 1 to 10 for use in the treatment and / or prevention of an allergic disease or disorder or an allergic condition.

[0140] Specific embodiment 13 A pharmaceutical composition according to any one of specific embodiments 11-12 for use in the treatment and / or prevention of rhinitis, conjunctivitis, rhinoconjunctivitis, hay fever, dermatitis, eczema, erythema, pruritus, itch, urticaria, asthma, anaphylaxis, acute urticaria, chronic urticaria, acute exacerbation of chronic urticaria, immediate hypersensitivity reactions, angioedema, food allergies or drug allergies.

[0141] Specific embodiment 14. The pharmaceutical composition for use according to any one of specific embodiments 11 to 13, wherein the composition is administered by intravenous or intramuscular administration.

[0142] Particular embodiment 15. The pharmaceutical composition for use according to any one of particular embodiments 11 to 14, wherein the composition is administered once a day.

[0143] The following examples are merely illustrative of certain embodiments of the invention and are not to be construed as limiting in any way. EXAMPLES

[0144] Materials and Methods The following materials were used: Bilastine (Faes Farma, batch number 5000015521), Hydroxypropyl-β-cyclodextrin (HPβCD, Kleptose parenteral Roquette Pharma, molar substitution 0.65, molecular weight 1399, batch number 1605157), HCl 37% (VWR Prolabo, batch number 11E230022), 0.22 μm membrane filter (Millex®-GS, MCE membrane, 33 mm diameter) and 0.45 μm sterile filter (Biofil®, Nylon membrane, 13 mm diameter), 2 mL clear type II glass ampoules.

[0145] The water used in the following examples was purified water obtained using an Elix® water purification system from Merck-Millipore. A WiseStir® Multipoint Magnetic Stirrer was used to stir the solutions.

[0146] The pH of the solutions was determined by a Hanna HI5222 pH meter equipped with a HI1330B micropH electrode.

[0147] The concentration of bilastine in the solubility test was determined by UV / vis spectrometer, which was a Cary® 60 UV-VIS.

[0148] The concentration of bilastine in the stability study was determined by HPLC (Merck Hitachi, Germany) equipped with a diode array detector (L-4500, Merck Hitachi), an autosampler (AS4000 A, Merck Hitachi) equipped with a compatible pump (L6200 A, Merck Hitachi) and a system injection of 100 μl volume, a control module (Model D-6500, Hitachi) and a Model D-7000 HMS version 4.0 data processing software (Merck Hitachi). Chromatographic analysis was performed using a Waters Symmetry C18 column (3.9×150 mm, 5 μm particle size) maintained at 30° C. by a column thermostat (L-5025, Merck).

[0149] The thermal stability of the formulations was determined using a Raypa Steam Sterilizer autoclave (Terrassa, Spain).

[0150] Formulation stability was tested in climatic chambers at 5°C ± 3 (Brand: ERATIS, Model: ICH2000), 40°C / 75% RH, (Brand: INELTEC, Model: CCLR-0 / 1360,) and 25°C / 60% RH (Code CAM027).

[0151] Example 1. Solubility of bilastine versus HPβCD concentration and pH The solubility of bilastine was determined at different concentrations of HPβCD and pH values.

[0152] The desired amount of HPβCD was dispersed in 40 ml of purified water in a 50 ml flask until completely dissolved and further diluted with water until the final volume was 50 ml. Each solution was divided into three solutions (15 ml each) and the pH was adjusted to the desired value (3, 5 or 7 respectively) with HCl 37%. Each solution was transferred to three vials (5 mL of solution each) so as to have several replicates for each sample. Bilastine was added in excess to each vial and the solutions were kept under magnetic stirring for 24 hours. After that time, the pH was adjusted again and stirring was kept for another 24 hours. Finally, the samples were filtered through a 0.45 μm filter (Biofil®, Nylon membrane, 13 mm φ), the final pH was checked and the concentration was determined by UV spectroscopy at a wavelength of 254 nm. Statistical analysis of the results was performed using the Centurion XVI Statgraphics program version 16.1.15. The results are shown in the table below.

[0153] [Table 1]

[0154] For the compositions assayed, very high concentrations of bilastine were obtained.

[0155] Example 2. Stability of bilastine formulations Eight batches (denoted as Formulations A-I) with different concentrations of HPβCD and pH adjustment were prepared for a 6-month preliminary stability study at three different conditions (5°C ± 3°C, 25°C / 60% RH, and 40°C / 75% RH).

[0156] Batch A was prepared as follows: 40 ml of purified water was placed in a mixing flask and 10 g of HPβCD was added under continuous stirring until completely dissolved. The solution was diluted with purified water to a final volume of 50 mL. To this solution, 1.2 g of bilastine was added and the solution was stirred for 1 hour. HCl 37% was added until the bilastine was completely solubilized. Finally, the pH was adjusted to 4 using HCl 37%.

[0157] The samples were filtered through a 0.22 μm membrane filter (sterile filtration, Millex®-GS filter, MCE membrane, 33 mm φ) and directly into the final ampoules (volume 2 ml). The process was carried out in a laminar flow hood using sterile materials. Finally, samples were taken for analysis.

[0158] Using the same method, Batches B through I were prepared having the compositions shown in the table below.

[0159] [Table 2]

[0160] A preliminary stability study was conducted over a period of 6 months, where the formulation was analyzed at 0, 1, 2, 3 and 6 months checking the following parameters: macroscopic examination of the inclusions, appearance and colour of the solution, presence or absence of visible particles, pH and bilastine concentration.

[0161] For analysis of pH and bilastine concentration, the ampoules were opened and the contents were filtered through a sterile 0.45 μm filter (Biofil®, Nylon membrane, 13 mm φ). The bilastine concentration (mg / mL) was determined by HPLC (phase A 58%: acetonitrile / methanol, phase B 42%: 10 mM bicarbonate buffer).

[0162] The bilastine concentration and pH results are shown in the table below (only 0, 3 and 6 month results are shown).

[0163] [Table 3]

[0164] All formulations were found to be stable. The best stability results after 6 months were found for formulation H (12 mg / ml bilastine, 17% HPβCD, pH 5.1) and formulation D (24 mg / ml bilastine, 25% HPβCD, pH 4.5).

[0165] Example 3. Thermal stability test To verify whether the sterilization of the samples can be achieved by a terminal sterilization process by autoclaving, a new batch of formulation H (12 mg / ml bilastine, 17% HPβCD, pH 5.1) and its placebo (same composition except without bilastine) were manufactured. Both formulations were sealed in 2 mL type I glass transparent ampoules and sterilized by autoclaving at 121° C. for 15 minutes. The samples were analyzed by HPLC. Formulation H and its placebo with and without terminal sterilization process were then compared.

[0166] No difference was found between Formulation H and the placebo formulation before and after the autoclave sterilization process. Thus, the thermal stability study indicates that terminal sterilization by autoclave does not affect the stability of the formulation.

[0167] Example 4. Preparation of pharmaceutical compositions The bilastine-containing pharmaceutical compositions used in the following examples were prepared as follows.

[0168] Batches of bilastine at a concentration of 12 mg / ml (1.2% (w / v)) and 0 mg / ml bilastine (placebo) were manufactured under GMP conditions for investigational drugs.

[0169] The clinical batch sizes of bilastine 12 mg / ml parenteral solution and placebo were 80 L each.

[0170] The manufacturing formulations of the drug products and placebo are set forth in the table below.

[0171] [Table 4]

[0172] The formulation was prepared by adding the raw materials to a pre-cleaned reactor and sterilizing in the following sequence: 75% water for injection (WFI) was added under constant nitrogen flow with stirring. Hydroxypropyl β-cyclodextrin was added slowly over about 10 minutes with stirring until completely dissolved. Bilastine was added slowly over about 30 minutes with stirring until completely dissolved. Concentrated hydrochloric acid solution was prepared with water for injection (WFI) and the required amount was added and the pH of the solution was adjusted to 4.92-5.00 with stirring for about 5-10 minutes until completely dissolved. The pH of the solution (4.92-5.00) was verified. The remaining water for injection was added under constant nitrogen flow and stirred for about 20 minutes.

[0173] The parenteral compositions containing bilastine were filtered under laminar flow and nitrogen flow (0.20 μm).

[0174] The bilastine parenteral composition was packaged in a 2 mL type I glass transparent open ampoule. First, the ampoule was cleaned and subjected to a depyrogenation process.

[0175] The ampoules were filled with the filtered bilastine composition (18-22° C.), which were then closed and sterilized by autoclaving (121° C., 20 min).

[0176] Example 5. Clinical Efficacy of Aqueous Formulations This example, together with Table 1 and Figures 1-5, present the results of a single-dose, five-arm crossover, randomized, double-blind, placebo-controlled study to evaluate the peripheral anti-H1 activity of bilastine 12 mg intravenous (iv) and intramuscular (im) formulations compared to Polaramine® 5 mg intramuscular formulation and bilastine 20 mg oral formulation in healthy volunteers.

[0177] Twenty-five subjects (10 men and 15 women), aged 18-45 years at the time of enrollment, were randomly assigned to receive the following: - Placebo (intramuscular) + Bilaxten® (oral) + placebo (intravenous) - Bilastine (intramuscular) + placebo (oral) + placebo (intravenous) - Placebo (intramuscular) + placebo (oral) + bilastine (intravenous) Polaramine® (intramuscular) + placebo (orally) + placebo (intravenously) - Placebo (intramuscular) + placebo (oral) + placebo (intravenous)

[0178] The trial included five experimental treatment periods separated by a minimum washout period of 7 days. All volunteers received all treatments. Finally, 23 subjects (9 males and 14 females) completed their participation in the study.

[0179] The primary objective of this study was to compare the peripheral anti-H1 activity of bilastine 12 mg iv, bilastine 12 mg im, bilastine 20 mg oral, and Polaramine® 5 mg im formulations against each other and against placebo.

[0180] The secondary objectives of this study were to: To assess the peripheral anti-H1 activity of the treatment (onset of action, peak effect and time to peak effect); To assess the subjective sensation of itching after ingestion of histamine; To define the pharmacokinetic profiles of the different drugs tested; To assess the potential drowsiness / somnolence effects of treatment; To assess the safety and tolerability of treatment.

[0181] An aqueous pharmaceutical composition of bilastine was prepared with a bilastine concentration of 1.2% (w / v) and a hydroxypropyl β-cyclodextrin concentration of 17% (w / v). The pH was adjusted to 4.96 with concentrated HCl. The placebo solution did not contain any bilastine.

[0182] Peripheral anti-H1 activity Subjects underwent the wheal and flare test, the most common tool used in human antihistamine pharmacodynamic studies. The wheal and flare test measures the effect of a drug on skin reactivity induced by intradermal injection of histamine. The ability to inhibit histamine-induced wheal and flare in the skin is considered to be an indicator of antihistamine potency and, therefore, potential efficacy. This test relies on the ability of histamine injected onto the skin to produce a wheal and flare, a neurovascular response with reflex vasodilation (flare) and localized swelling (wheal) caused by plasma extravasation. The first phase is called the wheal and is controlled by substances called acute phase mediators. The second phase is called the flare and is controlled by substances called late phase mediators. The wheal and flare response is a classic descriptive factor for characterizing the two-phase allergic response seen in type 1 hypersensitivity.

[0183] In this study, antihistamine activity was assessed by measuring the area of ​​wheals and flares induced by histamine skin tests performed before and after administration of a single daily dose of bilastine. Histamine skin tests were performed at the following time points: pre-dose (baseline), +15 min, +30 min, +45 min, +1 hr, +2 hr, +4 hr, +6 hr, +9 hr, +12 hr, and +24 hr after drug administration.

[0184] The histamine skin reaction test consisted of instilling 0.05 ml of a 100 mg / ml histamine solution on the ventral forearm. Each histamine instillation was administered to one of six randomly assigned areas on the ventral forearm, alternating arms each time, leaving a minimum distance of 2.0 cm between applications. 2 Surface area was quantified using the Visitrak System (or similar), which automatically completes area calculations.

[0185] To assess peripheral anti-H1 activity, the following parameters were determined: - Onset of effect: the first time point (h) at which the surface area of ​​the wheal and flare shows a statistically significant difference compared to its baseline value. - Maximum Effect: Maximum percentage reduction in surface area of ​​wheals and flares. - Time to peak effect: the time point (h) at which the maximum percentage of reduction in the surface area of ​​the wheal and flare is reached.

[0186] First, the % reduction in wheal area relative to baseline was studied in 23 healthy subjects and monitored over time from 15 minutes to 24 hours (Figure 2). Both intravenous and intramuscular bilastine showed significant reductions in wheal area compared to intramuscular Polaramine® and placebo already 15 or 30 minutes after injection, respectively. The % reduction peaked at approximately 2 hours and plateaued until 12 hours, after which the response began to decline. It is important to note that the efficacy of im and iv bilastine was at least 3 times higher than Polaramine® in reducing wheal area.

[0187] Next, the % reduction in flare area compared to baseline was also examined, with significant % reductions observed as short as 15 minutes after injection of Polaramine®, intramuscular bilastine, and intravenous bilastine formulations (Figure 3). The % reduction peaked at approximately 2 hours after intravenous and intramuscular bilastine injections and began to decline again after 12 hours, while intramuscular Polaramine® remained constant along the entire time range. It is important to note that intramuscular bilastine and intravenous bilastine reduced flare area by at least 4-fold more than Polaramine®.

[0188] Subjective sensation of itching To assess efficacy against itch experienced by subjects, a self-reported visual analog scale (VAS) for subjective itch sensation was administered after histamine ingestion. Subjective assessments of itch were performed at the following time points: pre-dose (baseline), +15 min, +30 min, +45 min, +1 hr, +2 hr, +4 hr, +6 hr, +9 hr, +12 hr, and +24 hr after drug administration.

[0189] Intramuscular bilastine, intravenous bilastine, and Polaramine® produced similar reductions in itch sensation during the first hour after injection, but intravenous and intramuscular bilastine were approximately twice as effective as Polaramine® over the ranges of 2-6 and 2-9 hours, respectively (Figure 4).

[0190] Subjective assessment of drowsiness / somnolence Another important aspect of the study concerns the potential side effects of parenteral formulations of bilastine. It is known that first generation antihistamines can cause significant drowsiness in patients.

[0191] To assess the effect of study medication on drowsiness / somnolence, a self-reported visual analog scale (VAS) for subjective drowsiness / somnolence was administered. Subjective assessments of drowsiness / somnolence were performed at the following time points: pre-dose (baseline), +1.5 hours and +3 hours after drug administration, using a visual analog scale (VAS).

[0192] FIG. 5 shows that intramuscular Polaramine® caused at least 8 times more sleepiness as perceived by the subjects than intramuscular bilastine at 1.5 hours after injection and nearly 4 times more sleepiness than intramuscular bilastine at 3 hours after injection. Intramuscular Polaramine® caused at least 4 times more sleepiness as perceived by the subjects than intravenous bilastine at 1.5 hours after injection and nearly 2 times more sleepiness than intravenous bilastine at 3 hours after injection. Perhaps the most interesting fact is that intramuscular and intravenous bilastine appear to be safe and well tolerated, similar to placebo, over the entire time range. Indeed, no statistically significant differences were detected between placebo and im bilastine, and between placebo and iv bilastine (FIG. 5). In contrast, statistically significant differences were found between imPolaramine® and im bilastine, and between imPolaramine® and placebo (FIG. 5).

[0193] Pharmacokinetic profile To obtain an accurate characterization of the kinetic curves, 5 ml blood samples were obtained at three time points.

[0194] The following pharmacokinetic profile was determined: drug plasma concentrations and pharmacokinetic parameters (AUC0 t , AUC0 ∞ , C max , t max , t 1 / 2 , Kel, Cl, Vd) were calculated from these plasma levels by Phoenix™ WinNonlin® v.8.3.

[0195] The data in Table 1 show the pharmacokinetic parameters of the various treatments used in clinical trials.

[0196] [Table 5]

[0197] As can be seen from Table 1 and Figure 1, bilastine in all pharmaceutical forms and all routes of administration (oral, im and iv) have similar AUCs (area under the curve), indicating similar body exposure to the drug. In addition, the C MAX and t MAX C varied for the three formulations depending on the route of administration, with much higher C for im and iv bilastine compared to its oral administration. MAX and lower t MAX In addition, it had an elimination half-life (t 1 / 2 ) remained very similar and stable among all pharmaceutical forms and routes of administration, indicating that bilastine is very stable in all forms.

[0198] Finally, Polaramine® has a t MAX , which indicates that the im absorption is similar.

Claims

1. 1. An aqueous parenteral pharmaceutical composition comprising: a) 0.96% (w / v) to 2.60% (w / v) of bilastine or a pharmaceutically acceptable salt or solvate thereof; b) 10% (w / v) to 30% (w / v) of unmodified β-cyclodextrin, C １ ~C ６ Alkyl-β-cyclodextrin, C １ ~C ６ Hydroxyalkyl β-cyclodextrin, C １ ~C ６ Carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, C １ ~C ６ a β-cyclodextrin selected from sulfoalkyl ether β-cyclodextrins, and mixtures thereof; Including, An aqueous parenteral pharmaceutical composition, wherein the pH value of said composition is 3.0 to 7.2 (both the lower and upper limits of the range are included), and parenteral administration is selected from intravenous or intramuscular.

2. 10. The pharmaceutical composition of claim 1, wherein the composition does not contain a gelling agent.

3. The composition comprises: a) 0.96% (w / v) to 2.60% (w / v) of bilastine or a pharmaceutically acceptable salt or solvate thereof; b) 10% (w / v) to 30% (w / v) of unmodified β-cyclodextrin, C １ ~C ６ Alkyl-β-cyclodextrin, C １ ~C ６ Hydroxyalkyl β-cyclodextrin, C １ ~C ６ Carboxyalkyl-β-cyclodextrin, carbonyl-β-cyclodextrin, C １ ~C ６ a β-cyclodextrin selected from sulfoalkyl ether β-cyclodextrins, and mixtures thereof; c) a pH adjuster that provides a pH value of 3.0 to 7.2 (both the lower and upper limits of the range are included); d) water for injection; and e) optionally, one or more pharmaceutically acceptable parenteral excipients or carriers selected from preservatives, including antimicrobial and chemical preservatives, tonicity agents, buffers, antioxidants, chelating agents, bulking agents, solubilizers, surfactants, co-solvents, and mixtures thereof; The pharmaceutical composition according to claim 1 or 2, comprising:

4. 3. The pharmaceutical composition according to claim 1, wherein the composition comprises 1.0% (w / v) to 1.4% (w / v) of bilastine or a pharmaceutically acceptable salt or solvate thereof.

5. 3. The pharmaceutical composition according to claim 1, wherein the composition comprises 10% (w / v) to 25% (w / v) of the β-cyclodextrin.

6. The β-cyclodextrin is C １ ~C ６ 3. The pharmaceutical composition according to claim 1, which is a hydroxyalkyl β-cyclodextrin.

7. 3. The pharmaceutical composition according to claim 1, wherein the pH value of the composition is 4.0 to 7.

0.

8. The composition comprises: a) 1.0% (w / v) to 1.4% (w / v) of bilastine or a pharmaceutically acceptable salt or solvate thereof; b) 10% (w / v) to 25% (w / v) of C １ ~C ６ hydroxyalkyl β-cyclodextrin, for example hydroxypropyl β-cyclodextrin; Including, 3. The pharmaceutical composition of claim 1, wherein the pH of the composition is between 4 and 6, both the lower and upper limits of the range being included.

9. 3. The pharmaceutical composition according to claim 1, wherein the volume of the unit dose is 0.5 to 1.5 mL.

10. 10. The pharmaceutical composition according to claim 1 for the treatment and / or prevention of an allergic disease or disorder or an allergic symptom.

11. 11. The pharmaceutical composition according to claim 10 for the treatment and / or prevention of acute type I hypersensitivity reactions.

12. 12. The pharmaceutical composition according to claim 10 or 11, for the treatment and / or prevention of rhinitis, conjunctivitis, rhinoconjunctivitis, hay fever, dermatitis, eczema, erythema, pruritus, itching, urticaria, asthma, anaphylaxis, acute urticaria, chronic urticaria, acute exacerbation of chronic urticaria, immediate hypersensitivity reaction, angioedema, food allergy or drug allergy.

13. 12. The pharmaceutical composition of claim 10 or 11, wherein the composition is administered once daily.

Images