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WO2015007759A1 - Composition pharmaceutique aqueuse liquide contenant des dérivés de cyclodextrine éthérifiée - Google Patents

Composition pharmaceutique aqueuse liquide contenant des dérivés de cyclodextrine éthérifiée Download PDF

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Publication number
WO2015007759A1
WO2015007759A1 PCT/EP2014/065203 EP2014065203W WO2015007759A1 WO 2015007759 A1 WO2015007759 A1 WO 2015007759A1 EP 2014065203 W EP2014065203 W EP 2014065203W WO 2015007759 A1 WO2015007759 A1 WO 2015007759A1
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Prior art keywords
pharmaceutically acceptable
derivatives
water
pharmaceutical composition
cyclodextrin
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English (en)
Inventor
Michael Aven
Tim LUKAS
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Boehringer Ingelheim Vetmedica GmbH
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Boehringer Ingelheim Vetmedica GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the invention relates to the field of medicine, particularly veterinary medicine.
  • the invention relates to a novel liquid aqueous pharmaceutical composition comprising one or more etherified cyclodextrin derivatives, at least one water-soluble polymer and at least one pharmaceutically active compound.
  • Cyclodextrins are cyclic oligosaccharides containing six, seven, or eight (a-1 ,4)-linked D- glucopyranoside units resulting in alpha(a)-, beta( )- and gamma(Y)-cyclodextrins.
  • cyclodextrins are pharmaceutical excipients that can solubilize various poorly soluble drugs/molecules through the formation of water-soluble drug-cyclodextrin complexes (Loftsson T et al., Journal of Pharmaceutical Sciences 2012, 101 (9): 3019-3032).
  • cyclodextrins in aqueous solution form inclusion complexes with water-insoluble or poorly soluble drugs by taking up the lipophilic moiety of the drug molecule into the cavity of the cyclodextrin, which is hydrophobic (Brewster ME et al., Advanced Drug Delivery Reviews 2007, 59: 645-666).
  • non-inclusion drug-cyclodextrin complexes can also be formed. The higher the cyclodextrin concentration increases, the higher the formation of aggregates of cyclodextrin molecules and self -assembled complexes.
  • a further aspect with cyclodextrin containing pharmaceutical compositions is the formation of self- assembled complexes and/or formation of aggregates (Messner M et al., International Journal of Pharmaceutics 201 1 , 408: 235-247). Excipients that solubilize and stabilize such aggregates include small ionized molecules such as salts of organic acids and bases.
  • etherified beta-cyclodextrin derivatives are known to improve solubility of sparingly soluble drugs, see WO 85/02767. However, in WO 85/02767 only the use of etherified beta-cyclodextrin derivatives up to a concentration of 10 % is described. A molar ratio of drug to etherified beta- cyclodextrin derivative of 1 :6 to 4: 1 was contemplated. The solubility of flubendazol within the above given ratio was only increased by a factor 30. However, those formulations are not suitable for the preparation of pharmaceutical compositions comprising substituted benzimidazole derivatives, such as pimobendan.
  • US 2004/152664 is directed to compositions comprising cyclodextrin derivatives and prednisolone.
  • WO 2004/089418 deals with a fluoroquinolone comprising aqueous formulations of a pH between 4 and 7.
  • EP 1 920 785 discloses a liquid preparation comprising a complex of pimobendan and cyclodextrin.
  • Brewster ME at al. (Advanced Drug Delivery Reviews 2007, 59(7): 645-666) describe cyclodextrins as pharmaceutical solubilizers.
  • Bassani VL et al. (Journal of Inclusion Phenomena and Molecular Recognition in Chemistry, 1996, 25(1-3): 149-152) refer to the enhanced water solubility of albendazole by hydroxypropyl- ⁇ - cyclodextrin complexation.
  • a pharmaceutical composition which overcomes the problems of the prior art as described above.
  • a pharmaceutical composition containing a sparingly water-soluble pharmaceutical active compound at palatable pH values e.g. > pH 3 shall be provided to be administered in adequate form to a subject in need thereof.
  • liquid aqueous pharmaceutical composition comprising
  • At least one pharmaceutically active compound which is poorly water-soluble, very poorly water-soluble or water-insoluble,
  • solubility of the at least one pharmaceutically active compound in water in the range of 15 to 25°C is defined as follows:
  • the at least one pharmaceutically active compound is poorly water-soluble if more than 100 mL of water per gram compound have to be used; it is very poorly water-soluble if more than 1 ,000 mL of water per gram compound have to be used; and it is water-insoluble if more than 10,000 mL water per gram compound have to be used to solubilise the compound, and preferably with the proviso that corticosteroids, in particular prednisolone and its prodrug prednisolone acetate (see US 2004/152664), and fluoroquinolones, in particular ciprofloxacin, gatifloxacin, moxifloxacin, sitafloxacin, lomefloxacin, grepafloxacin, gemifloxacin, norfloxacin, ofloxacin, levofloxacin, trovafloxacin and the like (see WO 2004/089418), are independently from each other excluded as pharmaceutically active compound which is poorly water
  • the present invention is also directed to the liquid pharmaceutical composition for use in a method for treating a subject in need of such treatment, preferably an animal, in particular a companion animal, even more preferred horse, dog or cat, guinea pig, hamster, cattle, goat, sheep, in particular cat or dog, selected from among the indications: heart diseases, particularly a hypertrophic cardiomyopathy, more particularly heart failure (HF), congestive heart failure (CHF), acute CHF, decompensated endocardiosis (DCE), dilated cardiomyopathy (DCM), asymptomatic (occult) CHF, asymptomatic DCM, hypertrophic cardiomyopathy (HCM), restricted cardiomyopathy (RCM), and heart failure due to HCM, RCM, DCM and/or UCM.
  • heart diseases particularly a hypertrophic cardiomyopathy, more particularly heart failure (HF), congestive heart failure (CHF), acute CHF, decompensated endocardiosis (DCE), dilated cardiomyopathy (DCM), a
  • kit of parts that comprises:
  • a) a liquid aqueous pharmaceutical composition according to the present invention a liquid aqueous pharmaceutical composition according to the present invention; and b) a package leaflet including the information that the pharmaceutical composition is to be used for the prevention and/or treatment of a heart disease, preferably heart failure and/or hypertrophic cardiomyopathy, in a subject in need of such prevention or treatment.
  • a heart disease preferably heart failure and/or hypertrophic cardiomyopathy
  • liquid aqueous pharmaceutical compositions for oral administration comprising sparingly or not water-soluble pharmaceutically active compounds, such as pimobendan, known from prior art are usually not suitable due to the low concentration of pharmaceutically active compound normally achieved.
  • a known pharmaceutically active compound is pimobendan (4,5-dihydro-6-[2-(4-methoxyphenyl)-1 H- benzimidazol-5-yl]-5-methyl-3(2H)-pyridazinone) disclosed in EP 0 008 391 , herein incorporated by reference in its entirety, and having the formula:
  • Pimobendan is a well-known compound for the treatment of congestive heart failure (CHF) originating for example from dilated cardiomyopathy (DCM) or decompensated endocardiosis (DCE) in animals, especially dogs (WO 2005/092343). Furthermore, pimobendan is also used for the treatment of hypertrophic cardiomyopathy in cats (WO 2010/060874). Pimobendan is also approved as a drug product for cardiovascular treatment of humans.
  • CHF congestive heart failure
  • DCM dilated cardiomyopathy
  • DCE decompensated endocardiosis
  • pimobendan drug substance is insoluble in water: 1 g drug substance is soluble in more than 10,000 mL. At pH 7 the solubility of pimobendan is only about 0.1 mg per 100 mL.
  • the solubility of pimobendan in aqueous solutions depends on the pH.
  • the solubility of pimobendan is significantly higher at pH 1 to 2.5 than at higher pH values (pH > 3.0).
  • pH > 3.0 the local tolerance and palatability as well as the chemical stability of such a formulation at pH 1 to 2.5 are not acceptable.
  • the target dose of pimobendan would require a drug concentration in solution which can only be achieved at a pH of about pH 2.5 and lower in simple aqueous solutions.
  • the concentration has to be significantly higher, resulting in a low volume that the animal will have to swallow, than is possible at pH > 3.0 in simple aqueous solutions.
  • a pimobendan formulation comprising up to 1 .5 mg/mL of pimobendan would need an increase in solubility at pH 7 by a factor of about 1000 to 1500, not achieved in prior art formulations for oral administration up to now.
  • liquid aqueous pharmaceutical compositions comprising at least one pharmaceutically active compound which is poorly water-soluble, very poorly water-soluble or water-insoluble with the assistance of one or more etherified cyclodextrin derivatives and at least one water-soluble polymer provide an acceptable solubility of the pharmaceutically active compound such as pimobendan in aqueous solution.
  • an acceptable concentration of the pharmaceutically active compound is present allowing for use in an oral administration form.
  • Due to the addition of at least one water-soluble polymer the concentration of the pharmaceutically active compound that is dissolved with the assistance of one or more etherified cyclodextrin derivatives is further increased.
  • liquid aqueous pharmaceutical compositions according to the present invention may be formulated for oral administration the disadvantageous side effects of parenteral administration such as inflammation in the subcutis following injections may be avoided.
  • the composition does not have to be given by a veterinarian, as is the case for parenteral administration.
  • the described formation of self-assembled complexes and/or formation of aggregates, which occurs in cyclodextrin containing pharmaceutical compositions, may be reduced or completely avoided by the presence of at least on water-soluble polymer that solubilises and stabilizes such aggregates.
  • the palatability if administered to animal patients is found to be good apparently due to a high concentration of well-palatable etherified cyclodextrin-derivatives present in the pharmaceutical composition of the present invention.
  • the addition of some excipients such as at least one antioxidant have been found to be advantageous in order to further increase the concentration of the pharmaceutically active compound to be used and/or to further stabilize the liquid pharmaceutical composition and to have a preserving (antimicrobial) effect.
  • the present invention is based on the surprising unexpected observation that in cyclodextrin containing pharmaceutical compositions the unwanted self -assembled complexes and/or aggregates may be minimized or completely prevented by the presence of at least on water-soluble polymer that solubilise and stabilize such aggregates. Furthermore, a higher solubility of the at least one pharmaceutically active compound which is poorly water-soluble, very poorly water-soluble or water- insoluble was surprisingly observed.
  • a liquid aqueous pharmaceutical composition is provided.
  • aqueous is to be understood in the meaning that the pharmaceutical composition contains water as a solvent, whereby also one or more other solvents may optionally be present.
  • water is the only solvent of such pharmaceutically composition.
  • the liquid aqueous pharmaceutical composition comprises at least one pharmaceutically active compound which is poorly water-soluble, very poorly water-soluble or water-insoluble. According to the European Pharmacopoeia the solubility of a compound in water in the range of 15 to 25°C is defined as follows:
  • the at least one pharmaceutically active compound is poorly water-soluble, very poorly water-soluble or water-insoluble.
  • the at least one pharmaceutically active compound is poorly water-soluble if more than 100 mL of water per gram compound have to be used; it is very poorly water-soluble if more than 1 ,000 mL of water per gram compound have be used; and it is water-insoluble if more than 10,000 mL water per gram compound must be used to solubilise the compound.
  • the at least one pharmaceutically active compound is preferably a benzimidazole derivative.
  • the benzimidazole derivative is preferably a substituted benzimidazole.
  • substituted benzimidazole means, but is not limited to thiabendazol, fuberidazol, oxibendazol, parbendazol, cambendazol, mebendazol, fenbendazol, flubendazol, albendazol, oxfendazol, nocodazol, astemisol and pimobendan, pharmaceutically acceptable salts, derivatives, metabolites or prodrugs thereof.
  • the term benzimidazole derivative as used herein means pimobendan, or any pharmaceutically acceptable salts thereof.
  • the at least one pharmaceutically active compound is preferably an oxicam derivative.
  • the oxicam derivative is preferably a substituted oxicam.
  • substituted oxicam means, but is not limited to ampiroxicam, droxicam, lornoxicam, piroxicam, tenoxicam and meloxicam, pharmaceutically acceptable salts, derivatives, metabolites or prodrugs thereof.
  • oxicam derivative as used herein means meloxicam, or any pharmaceutically acceptable salts thereof.
  • the at least one pharmaceutically active compound is preferably an imidazolinone derivative.
  • the imidazolinone derivative is preferably a substituted imidazolinone.
  • substituted imidazolinone means, but is not limited to 1-(4-chlorophenyl)-4-(4- morpholinyl)-2,5-dihydro-1 H-imidazol-2-one (imepitoin), pharmaceutically acceptable salts, derivatives, metabolites or prodrugs thereof.
  • imidazolinone derivative as used herein means 1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1 H-imidazol-2-one (imepitoin), or any pharmaceutically acceptable salts thereof.
  • the at least one pharmaceutically active compound is preferably a glucopyranosyl- substituted benzene derivative.
  • the glucopyranosyl-substituted benzene derivative is preferably a substituted glucopyranosyl-substituted benzene derivative.
  • substituted glucopyranosyl- substituted benzene derivative means, but is not limited to 1-cyano-2-(4-cyclopropyl- benzyl)-4-( -D-glucopyranos-1-yl)-benzene, pharmaceutically acceptable salts, derivatives, metabolites or prodrugs thereof.
  • glucopyranosyl-substituted benzene derivative as used herein means 1-cyano-2-(4-cyclopropyl-benzyl)-4-( -D-glucopyranos-1-yl)- benzene, or any pharmaceutically acceptable form and/or salt thereof, wherein the pharmaceutically acceptable form preferably is a crystalline complex between 1-cyano-2-(4-cyclopropyl-benzyl)-4-( -D- glucopyranos-1-yl)-benzene and one or more amino acids, preferably wherein the one or more amino acids is proline, more preferably L-proline.
  • the liquid aqueous pharmaceutical composition according to the present invention contains the at least one pharmaceutically active compound as disclosed herein, particularly in form of a substituted benzimidazole, more particularly pimobendan, preferably in the range of from 0.01 g/100 mL to 1 g/100 mL, more preferably from 0.05 g/100 mL to 0.5 g/100 mL, most preferably from 0.1 g/100 mL to 0.25 g/100 mL.
  • the pharmaceutically active compound as disclosed herein preferably a substituted benzimidazole such as pimobendan, at pH values that are acceptable for an oral pharmaceutical composition, one or more solubilizing excipients need to be added to the formulation.
  • solubilizing excipients are one or more etherified cyclodextrin derivatives.
  • the liquid aqueous pharmaceutical composition according to the present invention contains the one or more etherified cyclodextrin derivatives preferably in the range of from 5 g/100 mL to 40 g/100 mL more preferably from 10 g/100 mL to 35 g/100 mL, most preferably from 20 g/100 mL to 35 g/100 mL per one etherified cyclodextrin derivative.
  • etherified cyclodextrin derivative includes but is not limited to alpha-, beta- or gamma-cyclodextrin ethers.
  • the one or more etherified cyclodextrin derivatives as used herein means etherified beta-cyclodextrins, more preferably of the chemical formula I: in which the residues R are independently from each other hydroxyalkyl groups and part of the residues R may optionally independently from each other be alkyl groups.
  • a partially etherified beta- cyclodextrin of formula I is preferably used, in which the residues R are independently from each other hydroxyethyl, hydroxypropyl or di hydroxy propyl groups.
  • part of the residues R may for instance be methyl or ethyl groups.
  • beta-cyclodextrins with 7 to 14 methyl groups in the beta-cyclodextrin molecule as they are known from DE 31 18 218 does not fall under the present invention.
  • Partial ethers of beta-cyclodextrin comprising only alkyl groups, such as methyl, ethyl and the like, may be particularly suitable in accordance with the invention if they have a low degree of substitution, preferably as defined below of 0.05 to 0.2.
  • the one or more etherified cyclodextrin derivatives as used herein are hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, dihydroxypropyl-beta-cyclodextrin, sulphobutyl-ether- -cyclodextrin.
  • the one or more etherified cyclodextrin derivatives as used herein are hydroxypropyl- beta-cyclodextrin (HP CD), referred to as hydroxypropylbetadex in the European Pharmacopoeia.
  • Beta-cyclodextrin is a compound with ring structure consisting of 7 anhydro glucose units; it is also referred to as cycloheptaamylose.
  • Each of the 7 glucose rings contains in 2-, 3-, and 6-position three hydroxy groups which may be etherified.
  • one or more ⁇ -cyclodextrin derivatives used according to the invention only part of these hydroxy groups is etherified with hydroxyalkyl groups and optionally further with alkyl groups.
  • the degree of substitution is stated as molar substitution (MS), viz. in mole alkylene oxide per anhydroglucose unit (compare U.S. Patent 3,459,731 , column 4).
  • MS molar substitution
  • the molar substitution is preferably between 0.05 and 10, more preferably between 0.2 and 2. Particularly preferred is a molar substitution of about 0.40 to about 1.50.
  • the etherification with alkyl groups may be stated directly as degree of substitution (DS) per glucose unit which as stated above is 3 for complete substitution.
  • Partially etherified beta-cyclodextrins are used within the invention which preferably comprise besides hydroxyalkyl groups also alkyl groups, especially methyl or ethyl groups, up to a degree of substitution of 0.05 to 2.0, more preferably 0.2 to 1.5. Most preferably the degree of substitution with alkyl groups is between about 0.5 and about 1.2.
  • hydroxypropyl-beta-cyclodextrin ( ⁇ - ⁇ -CD) showed very advantageous effects and resulted in the largest increase in solubility of a pharmaceutically active compound to be used such as pimobendan or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a liquid aqueous pharmaceutical composition
  • a liquid aqueous pharmaceutical composition comprising one or more etherified cyclodextrin derivatives, at least one water-soluble polymer and at least one pharmaceutically active compound, particularly in form of a substituted benzimidazole, more particularly pimobendan, wherein the one or more etherified cyclodextrin derivative is selected from the group consisting of: alpha-, beta-, and/or gamma-cyclodextrin ether.
  • the present invention relates to a liquid aqueous pharmaceutical composition as described above, comprising one or more etherified cyclodextrin derivatives, at least one water-soluble polymer and at least one pharmaceutically active compound as disclosed herein, particularly in form of a substituted benzimidazole, more particularly pimobendan, wherein the one or more etherified cyclodextrin derivative is etherified beta-cyclodextrin.
  • that etherified beta- cyclodextrin is hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, or dihydroxypropyl- beta-cyclodextrin.
  • that etherified beta-cyclodextrin is hydroxypropyl-beta- cyclodextrin (HP CD), referred to as hydroxypropylbetadex in the European Pharmacopoeia.
  • the concentration of the pharmaceutically active compound as disclosed herein that is dissolved with the assistance of one or more etherified cyclodextrin derivatives is further increased by the addition of at least one water-soluble polymer.
  • the undesired formation of self -assembled complexes and/or formation of aggregates may be further reduced or completely avoided by the presence of at least one water-soluble polymer such as cellulose derivatives which solubilize and stabilize such aggregates.
  • the at least one water-soluble polymer has preferably a molar mass of 5,000 to 500,000 g/mol, more preferably 10,000 to 300,000 g/ mol, even more preferred 15,000 to 200,000 g/mol, even more preferred 20,000 to 200,000 g/mol.
  • water soluble polymer examples include hydroxypropyl methylcellulose (hypromellose, HPMC), hydroxypropyl cellulose, carboxymethylcellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, ethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinylacetate as well as combinations or copolymers thereof, preferably hydroxypropyl methylcellulose (hypromellose).
  • the liquid aqueous pharmaceutical composition according to the present invention contains the at least one water-soluble polymer preferably in the range of from 0.01 g/100 mL to 0.75 g/100 mL more preferably from 0.02 g/100 mL to 0.50 g/100 mL, most preferably from 0.05 g/100 mL to 0.30 g/100 mL.
  • the liquid aqueous pharmaceutical composition according to the present invention may contain one or more excipients.
  • the one or more excipients can be selected from the group consisting of an antioxidant, buffer, preservatives, pH adjustment agent, colorants or taste-masking/modifying ingredients including flavours.
  • At least one water-soluble antioxidant may be added as excipient. More preferably, at least one water-soluble polymer and at least one water-soluble antioxidant are coexistent in the liquid aqueous pharmaceutical composition according to the present invention.
  • the liquid aqueous pharmaceutical composition of the present invention further comprises at least one water-soluble antioxidant, so that the liquid aqueous pharmaceutical composition comprises at least one water-soluble polymer and at least one water-soluble antioxidant.
  • the liquid aqueous pharmaceutically composition comprises at least one water-soluble antioxidant in order to stabilize the pharmaceutical composition and to have a preserving (antimicrobial) effect. Only a small number of antioxidants are known which are water-soluble and come into question.
  • Water-soluble antioxidants that can be used comprise ascorbic acid or salts thereof, particularly sodium ascorbate; citric acid (anhydrous and/or monohydrate) or salts thereof, particularly sodium citrate; erythorbic acid; fumaric acid; malic acid; monothioglycerol; phosphoric acid; sodium metabisulfite; potassium metabisulfite; propionic acid; sodium bisulfite; sodium sulfite; resveratrol, butylhydroxyanisol, gallate derivatives, particularly propylgallate, or combinations thereof, preferably ascorbic acid or salts thereof, citric acid (anhydrous and/or monohydrate) or salts thereof, sodium metabisulfite, or potassium metabisulfite. Particularly preferred is ascorbic acid or salts thereof.
  • a system comprising one or more cyclodextrin derivatives, at least one water-soluble polymer and at least one water-soluble antioxidant has been shown to be particularly efficient to solubilise and stabilise the above described liquid aqueous pharmaceutical compositions without having a negative effect on the concentration of the pharmaceutically active compound in the pharmaceutical compositions.
  • the liquid aqueous pharmaceutically composition of the invention comprises one or more cyclodextrin derivatives, at least one water- soluble polymer, at least one water-soluble antioxidant and at least one pharmaceutically active compound which is poorly water-soluble, very poorly water-soluble or water-insoluble, preferably with the proviso that corticosteroids, in particular prednisolone and its prodrug prednisolone acetate (see US 2004/152664), and fluoroquinolones, in particular ciprofloxacin, gatifloxacin, moxifloxacin, sitafloxacin, lomefloxacin, grepafloxacin, gemifloxacin, norfloxacin, ofloxacin, levofloxacin, trovafloxacin and the like (see WO 2004/089418), are independently from each other excluded as pharmaceutically active compound which is poorly water-soluble, very poorly water-soluble or water- insoluble.
  • the water-soluble antioxidant preferably ascorbic acid or salts thereof, was found to chemically stabilize the formulation. Furthermore, small amounts of antioxidant, for example ascorbic acid, surprisingly provided a qualitatively small solubilising effect for the pharmaceutically active compound, such as pimobendan, this compound dissolved more quickly when antioxidant, such as ascorbic acid, was present in the solution. In addition, if excipients are used which are susceptible to oxidation an antioxidant may prevent such an oxidation so that at least one antioxidant should preferably be added.
  • the positive effects of the at least one antioxidant are observed independently of the concentration of the at least one antioxidant used. Therefore, already small amounts of antioxidant may have a benefit for the pharmaceutical composition according to the present invention.
  • liquid aqueous pharmaceutical composition according to the present invention comprises at least one water-soluble antioxidant preferably in the range 0.2 g/100 mL to 2.0 g/100 mL, in particular from 0.3 g/100 mL to 1.0 g/100 mL.
  • the pH of the pharmaceutical composition for oral use has preferably a pH value of 2 to 10, more preferably 3 to 10, more preferably 3 to 8, more preferably 3.1 to 8, more preferably 3 to 7, even more preferably 3.2 to 7, even more preferably 2.5 to 5, most preferably 3 to 5.
  • Particularly preferred is pH 3.3 to 6, particularly 3.4 to 5, especially 3.4 to 4.
  • liquid aqueous pharmaceutically composition having a pH range of 3 to 4.5, preferably 3.5, since aqueous solutions with a pH value in the acidic range have an improved antimicrobial activity even without a preservative.
  • the present invention relates to a liquid aqueous pharmaceutical composition as described above, comprising at least one pharmaceutically active compound in the form of at least one substituted benzimidazole or a pharmaceutically acceptable salt thereof or a substituted oxicam or a pharmaceutically acceptable salt thereof or a substituted imidazolinone or a pharmaceutically acceptable salt thereof or a substituted glucopyranosyl-substituted benzene derivative or a pharmaceutically acceptable form and/or salt thereof, one or more etherified cyclodextrin derivatives in the form of etherified beta-cyclodextrin, at least one water-soluble polymer and optionally at least one water-soluble antioxidant.
  • the present invention preferably relates to a liquid aqueous pharmaceutical composition as described above, comprising
  • a) at least one pharmaceutically active compound in the form of a substituted benzimidazole or a pharmaceutically acceptable salt thereof preferably thiabendazol, fuberidazol, oxibendazol, parbendazol, cambendazol, mebendazol, fenbendazol, flubendazol, albendazol, oxfendazol, nocodazol, astemisol or pimobendan, or pharmaceutical acceptable salts thereof, more preferably pimobendan or a pharmaceutically acceptable salt thereof;
  • etherified cyclodextrin derivatives in the form of etherified beta-cyclodextrin preferably hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, dihydroxypropyl- beta-cyclodextrin, more preferably hydroxypropyl-beta-cyclodextrin (HP CD);
  • At least one water-soluble polymer with a molar mass of 5,000 to 500,000 g/mol, preferably 10,000 to 300,000 g/mol, even more preferred 15,000 to 200,000 g/mol, even more preferred 20,000 to 200,000 g/mol, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, or methylcellulose, more preferably hydroxypropyl methylcellulose (hypromellose); and
  • At least one water-soluble antioxidant preferably ascorbic acid or a salt thereof; citric acid (anhydrous and/or monohydrate) or a salt thereof; sodium metabisulfite, potassium metabisulfite or resveratrol.
  • the present invention preferably relates to a liquid aqueous pharmaceutical composition as described above, comprising
  • etherified cyclodextrin derivatives in the form of etherified beta-cyclodextrin preferably hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, dihydroxypropyl- beta-cyclodextrin, more preferably hydroxypropyl-beta-cyclodextrin (HP CD);
  • At least one water-soluble polymer with a molar mass of 5,000 to 500,000 g/mol, preferably 10,000 to 300,000 g/mol, even more preferred 15,000 to 200,000 g/mol, even more preferred 20,000 to 200,000 g/mol, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, or methylcellulose, more preferably hydroxypropyl methylcellulose (hypromellose); and
  • the present invention preferably relates to a liquid aqueous pharmaceutical composition as described above, comprising
  • etherified cyclodextrin derivatives in the form of etherified beta-cyclodextrin preferably hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, dihydroxypropyl- beta-cyclodextrin, more preferably hydroxypropyl-beta-cyclodextrin (HP CD);
  • At least one water-soluble polymer with a molar mass of 5,000 to 500,000 g/mol, preferably 10,000 to 300,000 g/mol, even more preferred 15,000 to 200,000 g/mol, even more preferred 20,000 to 200,000 g/mol, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, or methylcellulose, more preferably hydroxypropyl methylcellulose (hypromellose); and
  • At least one water-soluble antioxidant preferably ascorbic acid or a salt thereof; citric acid (anhydrous and/or monohydrate) or a salt thereof; sodium metabisulfite, potassium metabisulfite or resveratrol.
  • the present invention preferably relates to a liquid aqueous pharmaceutical composition as described above, comprising
  • etherified cyclodextrin derivatives in the form of etherified beta-cyclodextrin preferably hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, dihydroxypropyl- beta-cyclodextrin, more preferably hydroxypropyl-beta-cyclodextrin (HP CD);
  • At least one water-soluble polymer with a molar mass of 5,000 to 500,000 g/mol, preferably 10,000 to 300,000 g/mol, even more preferred 15,000 to 200,000 g/mol, even more preferred 20,000 to 200,000 g/mol, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, or methylcellulose, more preferably hydroxypropyl methylcellulose (hypromellose); and
  • At least one water-soluble antioxidant preferably ascorbic acid or a salt thereof; citric acid (anhydrous and/or monohydrate) or a salt thereof; sodium metabisulfite, potassium metabisulfite or resveratrol.
  • the liquid aqueous pharmaceutical composition according to the present invention preferably comprises:
  • d) optionally, but according to a preferred embodiment, 0.2 g/100 mL to 2.0 g/100 mL of at least one water-soluble antioxidant, preferably ascorbic acid or a salt thereof.
  • liquid aqueous pharmaceutical composition preferably comprises:
  • the pH of the composition is between 2 to 10, preferably 3 to 10, more preferably 3 to 8, more preferably 3 to 7, more preferably 2.5 to 5, even more preferably 3 to 5, even more preferably 3.4 to 5 and most preferably 3.4 to 4.
  • liquid aqueous pharmaceutically composition is well accepted.
  • the liquid aqueous pharmaceutical composition provides an acceptable solubility of the pharmaceutically active compound as disclosed herein, such as pimobendan in aqueous solution, according to which a minimum concentration of the pharmaceutically active compound is present allowing for use in an oral administration form.
  • a general therapeutic effective target dose in particular for the treatment of HCM in cats, is about 0.1 mg to 0.5 mg pimobendan twice daily per kg bodyweight of the animal, preferably about 0.3 mg pimobendan twice daily per kg bodyweight of the animal.
  • the liquid aqueous pharmaceutical composition according to the present invention is intended for oral and/or parenteral administration, particularly oral solutions may be provided.
  • the liquid aqueous pharmaceutical composition comprises the pharmaceutically active compound in form of a substituted benzimidazole, preferably pimobendan, or a substituted oxicam, preferably meloxicam, or a substituted imidazolinone, preferably 1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1 H-imidazol-2-one (imepitoin) or a substituted glucopyranosyl-substituted benzene derivative, preferably 1-cyano-2-(4-cyclopropyl- benzyl)-4-( -D-glucopyranos-1-yl)-benzene, or any pharmaceutically acceptable form and/or salt thereof, wherein the pharmaceutically acceptable form preferably is a crystalline complex between 1- cyano-2
  • the present invention also relates to a method of treatment and/or prevention of diseases, wherein cardiotonic, hypotensive, anti-inflammatory and anti-thrombotic substances have a therapeutic benefit, preferably directed to a subject suffering from heart diseases, particularly a hypertrophic cardiomyopathy, comprising the step of administering to such subject in need of such treatment a therapeutically effective amount of any of the liquid aqueous pharmaceutical compositions as described herein.
  • the liquid aqueous pharmaceutical composition of the present invention is administered in a therapeutically effective amount from about 0.075 mg to about 0.5 mg in form of a substituted benzimidazole derivative, preferably pimobendan, or a substituted oxicam, preferably meloxicam, or a substituted imidazolinone preferably 1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1 H-imidazol-2-one (imepitoin) or a substituted glucopyranosyl-substituted benzene derivative, preferably 1 -cyano-2-(4- cyclopropyl-benzyl)-4-( -D-glucopyranos-1-yl)-benzene, or any pharmaceutically acceptable form and/or salt thereof, wherein the pharmaceutically acceptable form preferably is a crystalline complex between 1-cyano-2-(4-cyclopropyl-benzyl)-4-( -
  • the subject/patient in need of any such treatment mentioned above is a mammal, preferably a companion animal.
  • animal as used herein includes but is not limited to companion animals such as dogs, cats, guinea pigs, hamsters, horses, cattle, goats, sheep or the like.
  • the subject in need of such treatment is a dog, horse or cat, most preferably a cat or dog.
  • the liquid aqueous pharmaceutical composition according to the present invention is for use in a method for treating a patient in need of such treatment, preferably selected from among the indications: heart failure (HF), congestive heart failure (CHF), acute CHF, decompensated endocardiosis (DCE), dilated cardiomyopathy (DCM), asymptomatic (occult) CHF, asymptomatic DCM, hypertrophic cardiomyopathy (HCM), restricted cardiomyopathy (RCM), and heart failure due to HCM, RCM, DCM and/or UCM.
  • HF heart failure
  • CHF congestive heart failure
  • DCE decompensated endocardiosis
  • DCM dilated cardiomyopathy
  • HCM hypertrophic cardiomyopathy
  • RCM restricted cardiomyopathy
  • the liquid aqueous pharmaceutical composition according to the present invention is for use in a method for treating a subject in need of such treatment, preferably an animal, in particular a companion animal, even more preferred horse, dog or cat, guinea pig, hamster, cattle, goat, sheep, in particular cat or dog, selected from among the indications: heart diseases, particularly a hypertrophic cardiomyopathy, more particularly heart failure (HF), congestive heart failure (CHF), acute CHF, decompensated endocardiosis (DCE), dilated cardiomyopathy (DCM), asymptomatic (occult) CHF, asymptomatic DCM, hypertrophic cardiomyopathy (HCM), restricted cardiomyopathy (RCM), and heart failure due to HCM, RCM, DCM and/or UCM.
  • heart diseases particularly a hypertrophic cardiomyopathy, more particularly heart failure (HF), congestive heart failure (CHF), acute CHF, decompensated endocardiosis (DCE), dilated cardiomyopathy (DCM
  • the liquid aqueous pharmaceutical composition as defined above for use in the above mentioned methods is for oral and/or parenteral administration, preferably oral administration.
  • kit of parts that comprises:
  • a package leaflet including the information that the pharmaceutical composition is to be used for the prevention and/or treatment of a heart disease, preferably heart failure and/or hypertrophic cardiomyopathy, in a subject in need of such prevention or treatment.
  • the present invention also relates to a manufacturing process for the production of any of the liquid aqueous pharmaceutical compositions as described herein.
  • a preferable process for producing the pharmaceutical composition comprises the steps of:
  • the one or more etherified cyclodextrin derivatives and the at least one water-soluble polymer are added to the most part of the water under stirring thereby obtaining a first liquid mixture.
  • an ultrasonic treatment of such first liquid mixture preferably under stirring, may be optionally performed.
  • the obtained first liquid mixture is incubated at room temperature, preferably without stirring, for one or more minutes, preferably 10 minutes, and the desired pH value using a pH adjustment agent is adjusted.
  • the at least one pharmaceutically active compound and optionally one or more antioxidants as well as further excipients, if so desired, are added to the first liquid mixture during stirring thereby obtaining a second liquid mixture.
  • an ultrasonic treatment of the second liquid mixture, preferably under stirring, is optionally performed.
  • the obtained second liquid mixture is incubated at room temperature, preferably without stirring, for one or more minutes, preferably 10 minutes, and the desired pH value is adjusted using a pH adjustment agent.
  • the remaining water is added to the obtained second liquid mixture under stirring and the pH value is determined and adjusted, if necessary, using a pH adjustment agent to the desired pH value thereby obtaining the liquid aqueous pharmaceutical composition of the present invention.
  • the at least one pharmaceutically active compound, one or more etherified cyclodextrin derivatives, at least one water-soluble polymer and one or more antioxidants are those as already described in detail supra.
  • the pH adjustment agent is preferably hydrochloric acid and/or sodium hydroxide.
  • the amounts used depend from the at least one pharmaceutically active compound used as well as the intended treatment, administration route and the patient to be treated.
  • the person skilled in the art is readily able to select and adjust the required amounts by his general knowledge.
  • Figure 1 a schematic diagram wherein the solubility of pimobendan is shown as a function of concentration of hydroxypropyl-beta-cyclodextrin and presence of hydroxypropyl methylcellulose (HPMC).
  • Figure 1 is a schematic diagram wherein the solubility of pimobendan is shown as a function of concentration of hydroxypropyl-beta-cyclodextrin and presence of hydroxypropyl methylcellulose (HPMC). Therefore, in Figure 1 the effect of HPMC on the solubility of pimobendan was illustrated, and also the effect of concentration of hydroxypropyl-beta-cyclodextrin on the pimobendan solubility.
  • a concentration of HPMC of 0.1 % (m V) was used. The pH value was set to 4.5 using hydrochloric acid in all solutions.
  • Table 1 Exemplary pharmaceutical compositions according to the present invention
  • HPMC hydroxypropyl methylcellulose
  • HPMC hydroxypropyl methylcellulose
  • water weigh the hydroxypropyl- -cyclodextrin into a 100 mL glass bottle.
  • HPMC solution is then added to the 100 mL glass bottle.
  • the mixture is stirred until a homogenous solution is obtained. Let incubate at room temperature without stirring for about 10 minutes. Weigh the pimobendan into the mixture and mix until homogenized. Weigh the sorbic acid into the mixture and mix until homogenized. Weigh the antioxidant (for example ascorbic acid) into the mixture and mix until a homogenous solution is obtained. Let incubate at room temperature without stirring for about 10 minutes. Adjust pH to 3.5 ⁇ 0.1.

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Abstract

La présente invention concerne une composition pharmaceutique aqueuse liquide comprenant un ou plusieurs dérivés de cyclodextrine éthérifiée, au moins un polymère hydrosoluble et au moins un composé pharmaceutiquement actif qui est faiblement hydrosoluble, très faiblement hydrosoluble ou insoluble dans l'eau. Selon la présente invention, la solubilité du composé pharmaceutiquement actif peut être augmentée par la présence d'au moins un polymère hydrosoluble.
PCT/EP2014/065203 2013-07-19 2014-07-16 Composition pharmaceutique aqueuse liquide contenant des dérivés de cyclodextrine éthérifiée Ceased WO2015007759A1 (fr)

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CN106729723A (zh) * 2016-11-21 2017-05-31 青岛农业大学 一种含匹莫苯丹的药物组合物及其制备方法
US10973821B2 (en) 2016-05-25 2021-04-13 F2G Limited Pharmaceutical formulation
US11819503B2 (en) 2019-04-23 2023-11-21 F2G Ltd Method of treating coccidioides infection
CN118340910A (zh) * 2024-04-03 2024-07-16 温州肯恩大学（Wenzhou-Kean University） 一种芬苯达唑甲基-β-环糊精包合物及其制备方法

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10973821B2 (en) 2016-05-25 2021-04-13 F2G Limited Pharmaceutical formulation
CN106729723A (zh) * 2016-11-21 2017-05-31 青岛农业大学 一种含匹莫苯丹的药物组合物及其制备方法
US11819503B2 (en) 2019-04-23 2023-11-21 F2G Ltd Method of treating coccidioides infection
CN118340910A (zh) * 2024-04-03 2024-07-16 温州肯恩大学（Wenzhou-Kean University） 一种芬苯达唑甲基-β-环糊精包合物及其制备方法

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