WO2022025831A1 - Compositions pharmaceutiques pour injection comprenant de la tulathromycine - Google Patents

Compositions pharmaceutiques pour injection comprenant de la tulathromycine Download PDF

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Publication number
WO2022025831A1
WO2022025831A1 PCT/TR2020/050657 TR2020050657W WO2022025831A1 WO 2022025831 A1 WO2022025831 A1 WO 2022025831A1 TR 2020050657 W TR2020050657 W TR 2020050657W WO 2022025831 A1 WO2022025831 A1 WO 2022025831A1
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WO
WIPO (PCT)
Prior art keywords
sodium
tulathromycin
pharmaceutical composition
composition according
acid
Prior art date
Application number
PCT/TR2020/050657
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English (en)
Inventor
Vildan TOMBAYOGLU
Arzu PALANTOKEN
Mustafa PACALI
Ali Turkyilmaz
Original Assignee
Verano Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Verano Ilac Sanayi Ve Ticaret Anonim Sirketi filed Critical Verano Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority to PCT/TR2020/050657 priority Critical patent/WO2022025831A1/fr
Publication of WO2022025831A1 publication Critical patent/WO2022025831A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • 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
    • 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
    • A61K9/10—Dispersions; Emulsions

Definitions

  • the present invention relates to stable pharmaceutical compositions for injection comprising tulathromycin or pharmaceutically acceptable salts thereof which are used for treatment of diseases associated with Mannheimia haemolytica, Histophilus somni, Mycoplasma bovis, Moraxella bovis, Actinobacillus pleuropneumoniae, Pasteurella multocida, Mycoplasma hyopneumoniae, Haemophilus parasuis, Bordetella bronchiseptica and Dichelobacter nodosus in cattle, sheep and pigs.
  • Anti-infectives are medicine that are capable of inhibiting the spread of an infectious organism or killing the infectious organism outright. They encompass antibiotics, antifungals, anthelmintics, antimalarials, antiprotozoals, antituberculosis agents, and antivirals.
  • Antibiotics also known as antibacterials, are medications that destroy or slow down the growth of bacteria. They are used to treat or prevent bacterial infections, and sometimes protozoan infections. When an infection is suspected of being responsible for an illness but the responsible pathogen has not been identified, an empiric therapy is adopted. This involves the administration of a broad-spectrum antibiotic based on the signs and symptoms presented and is initiated pending laboratory results that can take several days. When the responsible pathogenic microorganism is already known or has been identified, definitive therapy can be started. This will usually involve the use of a narrow-spectrum antibiotic. The choice of antibiotic given will also be based on its cost. Identification is critically important as it can reduce the cost and toxicity of the antibiotic therapy and also reduce the possibility of the emergence of antimicrobial resistance.
  • the macrolides are antibiotics with a broad spectrum of activity against many gram-positive bacteria.
  • Several macrolide antibiotics have been linked to liver injury. The first macrolide discovered was erythromycin, which was first used in 1952. Erythromycin was widely used as a substitute to penicillin in cases where patients were allergic to penicillin or had penicillin- resistant illnesses. Later macrolides developed, including azithromycin and clarithromycin, stemmed from chemically modifying erythromycin; these compounds were designed to be more easily absorbed and have less side-effects since erythromycin is known to cause gastrointestinal side-effects in a significant proportion of users. Macrolides can be administered in a variety of ways that include tablets, capsules, suspensions, injectings and topically.
  • Tulathromycin is a semi-synthetic macrolide antimicrobial agent, which originates from a fermentation product. It differs from many other macrolides in that it has a long duration of action that is, in part, due to its three amine groups; therefore it has been given the chemical subclass designation of triamilide.
  • Macrolides are bacteriostatic acting antibiotics and inhibit essential protein biosynthesis by virtue of their selective binding to bacterial ribosomal RNA. They act by stimulating the dissociation of peptidyl-tRNA from the ribosome during the translocation process.
  • Tulathromycin possesses in vitro activity against M annheimia haemolytica, Pasteurella multocida, Histophilus somni, Mycoplasma bovis, Actinobacillus pleuropneumoniae, Pasteurella multocida, Mycoplasma hyopneumonia, Haemophilus parasuis and Bordetella bronchiseptica the bacterial pathogens most commonly associated with bovine and swine respiratory disease, respectively.
  • MIC minimum inhibitory concentration
  • Tulathromycin also possesses in vitro activity against Moraxella bovis, the bacterial pathogen most commonly associated with infectious bovine keratoconjunctivitis (IBK).
  • IBK infectious bovine keratoconjunctivitis
  • Resistance to macrolides can develop by mutations in genes encoding ribosomal RNA (rRNA) or some ribosomal proteins; by enzymatic modification (methylation) of the 23S rRNA target site, generally giving rise to cross-resistance with lincosamides and group B streptogramins (MLSB resistance); by enzymatic inactivation; or by macrolide efflux.
  • MLSB resistance may be constitutive or inducible. Resistance may be chromosomal or plasmid-encoded and may be transferable if associated with transposons or plasmids.
  • tulathromycin In addition to its antimicrobial properties, tulathromycin demonstrates immune-modulating and anti-inflammatory actions in experimental studies. In both bovine and porcine polymorphonuclear cells (PMNs; neutrophils), tulathromycin promotes apoptosis (programmed cell death) and the clearance of apoptotic cells by macrophages. It lowers the production of the pro-inflammatory mediators leukotriene B4 and CXCL-8 and induces the production of antiinflammatory and pro-resolving lipid lipoxin A4.
  • Tulathromycin exists as an equilibrium mixture of two isomeric forms, tulathromycin A and tulathromycin B. It is marketed by Pfizer Inc. under the tradename DRAXXIN®.
  • DRAXXIN® comprises an equilibrium mixture of about 90% ⁇ 4% of isomer A and about 10% ⁇ 4% of isomer B.
  • tulathromycin A is (2R,3S,4R,5R,8R I 10R,1 1 R, 12S, 13S, 14R)-13-(2,6- dideoxy-3-C-methyl-3-0-methyl-4-C- ((propylamino)-methyl)-a-L-ribo-hexopyranosyl)oxy-2- ethyl-3,4,10-trihydroxy-3,5,8,10,12,14- hexamethyl-1 1 -((3,4,6-trideoxy-3-(dimethylamino)-8- D-xylo-hexopyranosyl)oxy)-1 -oxa-6- azacyclopentadecan-15-one and it has has a chemical structure as shown in Formula I.
  • tulathromycin B is (3R, 6R8R, 9R, 10S, 1 1 S, 12R)- 1 1 -((2,6-dideoxy-3-C-methyl-3-0-methyl-4-C- ((propylamino)methyl-a-L-ribo-hexopyranosyl) oxy)2-((1 R,2R)-1 ,2-dihydroxy-1 -methylbutyl)- 8-hydroxy-3,6,8, 10,12-pentamethyl-9-((3, 4,6- trideoxy-3-(dimethylamino)- ⁇ -D- xylohexopyranosyl)oxy)-1 -oxa-4-azacyclolridecan-13-one ans its chemical structure is shown in Formula II.
  • a solid pharmaceutical composition is developed to eliminate the stability challenges seen in solution compositions.
  • Said solid composition comprises pure tulathromycin comprising tulathromycin A in an amount of more than 98% and tulathromycin B in an amount of less than 2% by weight.
  • the composition comprises salt and acids. Citric acid and hydrochloric acid are preferred for said composition.
  • aqueous forms for injection can be immediately administered and the required dose accurately reaches the systemic circulation.
  • parenteral administration is known to provide a better absorption (Pharmacokinetics and bioavailability of tulathromycin following intravenous, intramuscular and subcutaneous administrations in healthy rabbits, K. Abo-EI-Sooud, N. A. Afifi, A. M. Abd-EI-Aty, 2012).
  • tulathromycin is a veterinary drug, a parenteral dosage would be more comfortable to administer to animals with bovine respiratory disease which are likely to have swallowing difficulties.
  • the main object of the present invention is to obtain pharmaceutical compositions for injection comprising tulathromycin or pharmaceutically acceptable salts thereof eliminating all aforesaid problems and bringing additional advantages to the relevant prior art.
  • Another object of the present invention is to provide pharmaceutical compositions comprising tulathromycin which comprises tulathromycin A in an amount of 95-97% and tulathromycin B in an amount of 3-5% by weight.
  • Another object of the present invention is to provide pharmaceutical compositions of tulathromycin in the form of solution for injection.
  • Another object of the present invention is to provide pharmaceutical compositions of tulathromycin in the form of solution for injection.
  • Another object of the present invention is to provide pharmaceutical compositions of tulathromycin with high stability and solubility.
  • a further object of the present invention is to provide pharmaceutical solution compositions of tulathromycin with high potency and bioavailability.
  • Another object of the present invention is to provide pharmaceutical solution compositions of tulathromycin for injection which can be administered intravenously, subcutaneously, intramuscularly, intradermally or intracutaneously.
  • the present invention relates to pharmaceutical compositions for injection comprising tulathromycin or a pharmaceutically acceptable salt thereof as active agent, wherein said active agent comprises tulathromycin A in an amount of 95-97% and tulathromycin B in an amount of 3-5% by weight of the active agent.
  • Potency and stability are two time-varying properties which cannot be considered separately. They mainly depend on the homogeneity, pH value, preservation conditions and for this invention, also the equilibrium of the two isomers of tulathromycin. Tulathromycin A and B are known to influence the quality of the composition with respect to impurities. In the scope of the invention, it has been seen that potency and stability are enhanced and the shelf-life of the composition is extended when the weight ratios of these two isomers of tulathromycin are kept between the above-given ranges.
  • the form of the composition is selected from the group comprising powder, tablet, solution and suspension which are all suitable for reconstitution and/or injectable administration.
  • the composition is in the form of solution for injection.
  • Said injection can be administered intravenously, subcutaneously, intramuscularly, intradermally or intracutaneously for treatment of diseases associated with Mannheimia haemolytica, Histophilus somni, Mycoplasma bovis, Moraxella bovis, Actinobacillus pleuropneumoniae, Pasteurella multocida, Mycoplasma hyopneumoniae, Haemophilus parasuis, Bordetella bronchiseptica and Dichelobacter nodosus in cattle, sheep and pigs.
  • the solution subjected to the invention is administered subcutaneously or intramuscularly.
  • the active agent is tulathromycin free base.
  • the amount of tulathromycin is between 0.1 -80% by weight of the total composition. Preferably this amount is between 0.5-50% by weight of the total composition. More preferably tulathromycin is present between 1-20% by weight in the total composition.
  • the pharmaceutical composition comprises at least one pharmaceutically acceptable excipient selected from solvents, preservatives such as antimicrobial agents and antioxidants, pH adjusters or mixtures thereof.
  • the composition comprises at least one solvent which is selected from the group comprising propylene glycol, benzyl benzoate, dimethylacetamide, ethanol, glycerin, N-methyl-2-pyrrolidone, polyethylene glycol, vegetable oil or mixtures thereof.
  • the composition comprises propylene glycol as solvent.
  • the amount of propylene glycol is between 10-99%, preferably 20-95%, more preferably 40-90% by weight of the total composition.
  • the composition comprises at least one antioxidant which is selected from the group comprising monothioglycerol, acetone sodium bisulfite, ascorbyl palmitate, ascorbate, bisulfite sodium, butylated hydroxy anisole, butylated hydroxy toluene, cysteine, ditionite sodium, gentisic acid, glutamate monosodium, glutathione, formaldehyde sulfoxylate sodium, metabisulfite potassium, metabisulfite sodium, methionine, propyl gallate, sulfite sodium, alpha tocopherol, thioglycolate sodium or mixtures thereof.
  • monothioglycerol acetone sodium bisulfite, ascorbyl palmitate, ascorbate, bisulfite sodium, butylated hydroxy anisole, butylated hydroxy toluene, cysteine, ditionite sodium, gentisic acid, glutamate monosodium, glutathione, formaldeh
  • the composition comprises monothioglycerol as antioxidant.
  • the amount of monothioglycerol is between 0.01 -5%, preferably 0.02-1% by weight of the total composition.
  • the composition comprises at least one pH adjuster which is selected from the group comprising boric acid, sodium borate, ethanolic HCI, ammonium sulfate, ammonium hydroxide, arginine, aspartic acid, benzene sulfonic acid, benzoate sodium, benzoic acid, sodium bicarbonate, sodium carbonate, carbon dioxide, sodium citrate, disodium citrate, trisodium citrate, diethanolamine, glucono delta lactone, glycine, glycine HCI, histidine, histidine HCI, hydrochloric acid, hydrobromic acid, lysine, maleic acid, meglumine, methanesulfonic acid, monoethanolamine, acid phosphate, succinate sodium, succinate disosdium, sulfuric acid, tartarate sodium, tartaric acid, tromethamine or mixtures thereof.
  • pH adjuster which is selected from the group comprising boric acid, sodium borate, ethanolic HCI, ammonium sulfate,
  • the composition comprises boric acid as pH adjuster.
  • the amount of boric acid is between 0.01 -5%, preferably 0.02-1% by weight of the total composition.
  • boric acid acts as an antimicrobial as well and decreases the need of additional preservatives to provide a long-lasting stability.
  • the weight ratio of boric acid to monothioglycerol is in the range of 1 :0.01 to 1 :100, preferably 1 :0.1 to 1 :50, more preferably 1 :0.5 to 1 :2.
  • the composition further comprises ethanolic HCI as pH adjuster in an amount sufficient to make the pH of the total composition 4.0 to 8.0, preferably 4.8 to 7.0, more preferably 5.1 to 5.7.
  • ethanolic HCI is prepared by diluting 5ml of 1 M hydrochloric acid to 500ml with ethanol.
  • the composition comprises the following components by weight of the total composition.
  • the below given formulation can be used in the lyophilized pharmaceutical composition subjected to the invention.
  • This example is not limiting the scope of the present invention and should be considered under the light of the foregoing detailed disclosure.
  • Example 1 Solution for injection q.s.: quantity sufficient
  • a method for preparing the above-mentioned solution for injection comprises the following steps.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dispersion Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques stables pour injection comprenant de la tulathromycine ou des sels pharmaceutiquement acceptables de celle-ci, qui sont utilisées pour le traitement de maladies associées à Mannheimia haemolytica, Histophilus somni, Mycoplasma bovis, Moraxella bovis, Actinobacillus pleuropneumoniae, Pasteurella multocida, Mycoplasma hyopneumoniae, Haemophilus parasuis, Bordetella bronchiseptica et Dichelobacter nodosus chez les bovins, les moutons et les porcs.
PCT/TR2020/050657 2020-07-26 2020-07-26 Compositions pharmaceutiques pour injection comprenant de la tulathromycine WO2022025831A1 (fr)

Priority Applications (1)

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PCT/TR2020/050657 WO2022025831A1 (fr) 2020-07-26 2020-07-26 Compositions pharmaceutiques pour injection comprenant de la tulathromycine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2020/050657 WO2022025831A1 (fr) 2020-07-26 2020-07-26 Compositions pharmaceutiques pour injection comprenant de la tulathromycine

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115317499A (zh) * 2022-09-21 2022-11-11 湖北省农业科学院畜牧兽医研究所 知母皂苷aiii在制备抑制副猪嗜血杆菌的药物中的应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002007736A1 (fr) * 2000-07-24 2002-01-31 Cadila Pharmaceuticals Limited Fabrication d'une composition pharmaceutique liquide limpide d'azithromycine
US20060229219A1 (en) * 2005-04-11 2006-10-12 Advanced Medical Optics, Inc. Borate-polyol mixtures as a buffering system
CN101422479A (zh) * 2008-07-04 2009-05-06 青岛康地恩药业有限公司 一种用于治疗猪、牛呼吸道疾病的复方注射药物组合物
US20090232763A1 (en) * 2008-03-17 2009-09-17 Kabra Bhagwati P Aqueous pharmaceutical compositions containing borate-polyol complexes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002007736A1 (fr) * 2000-07-24 2002-01-31 Cadila Pharmaceuticals Limited Fabrication d'une composition pharmaceutique liquide limpide d'azithromycine
US20060229219A1 (en) * 2005-04-11 2006-10-12 Advanced Medical Optics, Inc. Borate-polyol mixtures as a buffering system
US20090232763A1 (en) * 2008-03-17 2009-09-17 Kabra Bhagwati P Aqueous pharmaceutical compositions containing borate-polyol complexes
CN101422479A (zh) * 2008-07-04 2009-05-06 青岛康地恩药业有限公司 一种用于治疗猪、牛呼吸道疾病的复方注射药物组合物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115317499A (zh) * 2022-09-21 2022-11-11 湖北省农业科学院畜牧兽医研究所 知母皂苷aiii在制备抑制副猪嗜血杆菌的药物中的应用
CN115317499B (zh) * 2022-09-21 2023-08-04 湖北省农业科学院畜牧兽医研究所 知母皂苷aiii在制备抑制副猪嗜血杆菌的药物中的应用

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