EP3302494A1 - Composition parentérale lyophilisée de tigécycline et procédé de préparation associé - Google Patents

Composition parentérale lyophilisée de tigécycline et procédé de préparation associé

Info

Publication number
EP3302494A1
EP3302494A1 EP16883515.5A EP16883515A EP3302494A1 EP 3302494 A1 EP3302494 A1 EP 3302494A1 EP 16883515 A EP16883515 A EP 16883515A EP 3302494 A1 EP3302494 A1 EP 3302494A1
Authority
EP
European Patent Office
Prior art keywords
tigecycline
pharmaceutical composition
amount
sulfobutyl ether
solution
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
EP16883515.5A
Other languages
German (de)
English (en)
Other versions
EP3302494A4 (fr
Inventor
Mitesh Natavarlal PATEL
Mafatlal Tribhovandas DAVE
Pranavkumar Jayesh Choksi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gufic Biosciences Ltd
Original Assignee
Gufic Biosciences Ltd
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 Gufic Biosciences Ltd filed Critical Gufic Biosciences Ltd
Publication of EP3302494A1 publication Critical patent/EP3302494A1/fr
Publication of EP3302494A4 publication Critical patent/EP3302494A4/fr
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/65—Tetracyclines
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention relates to a stable, freeze dried pharmaceutical composition of Tigecycline along with a suitable stabilizing agent and acidifying agent for parenteral administration.
  • the pharmaceutical composition provides stabilization of Tigecycline thereby improving the shelf life during storage.
  • the invention further relates to a process for preparation of said composition.
  • Tigecycline a derivative of minocycline that is modified to overcome tetracycline resistance
  • Tigecycline is the first of a novel class of glycylcyclines with expanded-spectrum properties. It is active in-vitro against a broad range of Gram-positive and Gram- negative bacteria, anaerobes, 'atypical' bacteria as well as against many species of drug-resistant strains [e.g. vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae and multidrug resistant (MDR) Acinetobacter baumannii].
  • MRSA methicillin-resistant Staphylococcus aureus
  • MDR multidrug resistant
  • Tigecycline inhibits protein translation by reversibly binding to the 30S subunit of the bacterial ribosome, which impedes amino acid synthesis.
  • the ribosomal binding sites of Tigecycline are similar to those of tetracycline, Tigecycline binds five times more effectively than tetracyclines. This allows Tigecycline to evade the common ribosomal protection mechanisms associated with resistance to tetracyclines. Because of its long side chain that blocks binding to most efflux proteins and transporters, Tigecycline also overcomes the efflux mechanisms of tetracycline resistance.
  • NDM-1 New Delhi Metallo-Lactamase-1
  • Tigecycline has received high attention and has been regarded as the last resort to treat pan drug-resistant-bacteria (International Journal of Antimicrobial Agents 41 (2013) 110- 116).
  • the first tetracycline antibiotics were discovered more than 50 years ago, and represented a significant advance in the treatment of many Gram-positive and Gram-negative bacterial infections.
  • tetracyclines following their initial widespread use, a high incidence of tetracycline resistance among many bacteria has led to tetracyclines being relegated to second- or third-line therapy.
  • Tigecycline is a tetracycline derivative (a glycylcycline) for intravenous infusion.
  • the chemical name of Tigecycline is (4S,4aS,5aR,12aS)-9-[2-(tert- butylamino)acetamido]-4,7-bis(dimethylamino)-l,4,4a,5,5a,6,l l,12a-octahydro- 3,10, 12,12a-tetrahydroxy-l,l l-dioxo-2-naphthacenecarboxamide.
  • the empirical formula is C29H39N5O8 and the molecular weight is 585.65gm/mol.
  • Tigecycline is a light-sensitive, hygroscopic orange powder that is freely soluble in water and isotonic sodium chloride solution (Daily Med). The chemical structure of Tigecycline is given below:
  • Tigecycline is marketed as lyophilized product for intravenous infusion by Wyeth Pharmaceuticals Inc. a subsidiary of Pfizer Inc. under the trade name Tygacil®. Tigecycline is indicated for the treatment of patients 18 years of age and older for: Complicated skin and skin structure infections, complicated intra-abdominal infections and Community-acquired bacterial pneumonia.
  • Tigecycline is in lyophilized vial containing lactose monohydrate as stabilizing agent which does not provide desirable stability due to the sensitivity of Tigecycline against environmental stress.
  • Tigecycline is generally unstable to light, heat, humidity, acid, and the like and forms degradation product Tigecycline epimer, hence, it is necessary to develop a pharmaceutical composition which stabilizes the active compound and salt thereof for parenteral administration.
  • Indian Patent Number 268331 has disclosed a stable pharmaceutical composition of Tigecycline in lyophilized form comprising lactose as stabilizing agent. It is further disclosed in IN'331 that suitable carbohydrates stabilize Tigecycline against epimer formation at acidic pH.
  • suitable carbohydrates include anhydrous, hydrated and solvated forms of mono and disaccharides selected from aldose monosaccharide or a disaccharide such as lactose, mannose, sucrose and glucose; preferably, a disaccharide such as lactose and sucrose. Lactose is most preferred.
  • Tigecycline marketed products and the compositions known in the art contain higher percentage of degradation impurities which includes Tigecycline epimer impurity.
  • improved/stable Tigecycline freeze-dried composition which can reduce Tigecycline epimer formation and other oxidative degradation impurities thereby making the product stable with longer shelf-life.
  • the above objective is realised in the present invention by providing a stable, freeze-dried pharmaceutical composition comprising Tigecycline and a suitable stabilizing agent which reduces the Tigecycline epimer formation and other degradation impurities with improved shelf life of the composition.
  • the present invention provides a stable, freeze dried pharmaceutical composition
  • a stable, freeze dried pharmaceutical composition comprising Tigecycline or pharmaceutically acceptable salt thereof along with a suitable stabilizing agent and acidifying agent for parenteral administration.
  • Tigecycline is stabilized by adding stabilizing agents selected from cyclodextrin derivatives, specially, Sulfobutyl ether betacyclodextrin sodium.
  • the pharmaceutical composition of Tigecycline and stabilizing agent is freeze dried and is provided as a drug concentrate.
  • the present invention provides a method for stabilization of Tigecycline in an aqueous solution.
  • the present invention discloses a stable, freeze-dried pharmaceutical composition for parenteral administration comprising Tigecycline or pharmaceutically acceptable salt thereof as an active ingredient along with stabilizing agent and acidifying agent.
  • the composition provides stabilization of Tigecycline with low degradation of the active ingredient thereby improving shelf life of the composition during storage and equally reducing Tigecycline epimer formation.
  • the present invention provides a stable, freeze dried pharmaceutical composition for parenteral administration comprising; i. Tigecycline or a pharmaceutically acceptable salt thereof, and
  • Stabilizing agent selected from cyclodextrin derivatives
  • Tigecycline or a pharmaceutically acceptable salt is present in the composition in an amount of lmg to 200mg/vial; more preferably, 50mg/vial and 150mg/vial.
  • Tigecycline is stabilized using a suitable stabilizing agent where Tigecycline can be maintained in a dissolved state in the aqueous solution thereby preventing crystallization or crystalline growth of Tigecycline.
  • the stabilizing agent is selected from the cyclodextrin derivatives preferably, Sulfobutyl ether betacyclodextrin sodium.
  • composition of the present invention comprises Sulfobutyl ether betacyclodextrin sodium as stabilizing agent present in an amount of lOOmg to 4000mg, preferably, lOOmg to 2000mg, more preferably, lOOmg tol500mg.
  • the pH of the composition is maintained within the range of 4.5 to 7 using acidifying agent, such as dilute hydrochloric acid solution.
  • acidifying agent such as dilute hydrochloric acid solution.
  • the present invention discloses a stable, freeze-dried pharmaceutical composition for parenteral administration comprising;
  • stabilizing agent such as Sulfobutyl ether betacyclodextrin sodium in an amount of lOOmg to 4000mg and
  • acidifying agent such as dilute hydrochloric acid solution for adjusting the pH in the range of 4.5 to 7.0.
  • the present invention discloses a stable, freeze-dried pharmaceutical composition
  • a stable, freeze-dried pharmaceutical composition comprising;
  • the present invention discloses a stable, freeze-dried pharmaceutical composition
  • a stable, freeze-dried pharmaceutical composition comprising;
  • composition of the present invention after freeze drying is chemically and physically stable over an extended period of time and is suitable for intended pharmaceutical use after reconstitution with sodium chloride injection or 5% dextrose injection.
  • Freeze drying process involves cooling of the desired composition at suitable temperature not less than -45°C, raising temperature to 0°C at suitable pressure of 150 mtorr to 100 mtorr in 35 hours, then at 50mtorr, further raising temperature to +35°C in 15 hrs.
  • the freeze dried Tigecycline when reconstituted with 5 ml of suitable vehicle contains final drug concentrate of 10 mg/ml.
  • the pharmaceutical composition of the invention described herein is freeze dried composition, which may also be prepared by dissolving Tigecycline first in aqueous vehicle containing stabilizing agent then filter the solution and fill in to 10 ml glass vial.
  • the freeze dried drug may be diluted with suitable diluents before administration as IV injection.
  • the final concentration of solution may be reduced to further desired level using 5% Dextrose infusion prior to administration to a patient.
  • the pharmaceutical composition of the present invention is useful in the treatment of various gram-positive and gram-negative bacterial infections such as complicated skin and skin structure infections, complicated intra-abdominal infections and community-acquired bacterial pneumonia.
  • compositions of the present invention are administered to a patient according to a dosing regimen.
  • a dosing regimen for any particular patient will depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, specific disease being treated and the severity of the condition among other factors and the judgment of the treating physician.
  • the pharmaceutical composition comprising Tigecycline as active with Sulfobutyl ether betacyclodextrin sodium without compromising stability of drug and its solution before Lyophilisation has a pH between 4.5 to 7.0.
  • composition is stable for the entire period of the shelf life.
  • Tigecycline (active) or pharmaceutically acceptable salt was added to an aqueous solution containing 2.0 gm of Sulfobutyl ether betacyclodextrin sodium and stirred for some time. Adjust the pH about 5.45 with 1.0 N HCL solution (pH limit 4.5 to 7.0). The solution was filtered and the resulting solution was loaded into 20 vials (10 ml) with each containing 2.5 ml solution. The solution in each vial was lyophilized using freeze dryer according to conventional method, thereby obtaining the lyophilized compositions each comprising 50 mg of Tigecycline. The resulting lyophilized preparation was stored at different storage temperatures at different time intervals and the content of Tigecycline was tested. The result is given in below Table 1.
  • Tigecycline (active) or pharmaceutically acceptable salt was added to an aqueous solution containing 5.0 gm of Sulfobutyl ether betacyclodextrin sodium and stirred for some time. Adjust the pH about 5.45 with 1.0 N HCL solution (pH limit 4.5 to 7.0). The solution was filtered and the resulting solution was loaded into 20 vials (10 ml) with each containing 2.5 ml solution. The solution in each vial was lyophilized using freeze dryer according to conventional method, thereby obtaining the lyophilized compositions each comprising 50 mg of Tigecycline. The resulting lyophilized preparation was stored at different storage temperatures at different time intervals and the content of Tigecycline was tested. The result is given in below Table 2.
  • Tigecycline (active) or pharmaceutically acceptable salt was added to an aqueous solution containing 10.0 gm of Sulfobutyl ether betacyclodextrin sodium and stirred for some time. Adjust the pH about 5.45 with 1.0 N HCL solution (pH limit 4.5 to 7.0). The solution was filtered and the resulting solution was loaded into 20 vials (10 ml) with each containing 5.0 ml solution. The solution in each vial was lyophilized using freeze dryer according to conventional method, thereby obtaining the lyophilized compositions each comprising 50 mg of Tigecycline. The resulting lyophilized preparation was stored at different storage temperatures at different time intervals and the content of Tigecycline was tested. The result is given in below Table 3.
  • Tigecycline (active) or pharmaceutically acceptable salt was added to an aqueous solution containing 15.0 gm of Sulfobutyl ether betacyclodextrin sodium and stirred for some time. Adjust the pH about 5.45 with 1.0 N HCL solution (pH limit 4.5 to 7.0). The solution was filtered and the resulting solution was loaded into 20 vials (10 ml) with each containing 5.0 ml solution. The solution in each vial was lyophilized using freeze dryer according to conventional method, thereby obtaining the lyophilized compositions each comprising 50 mg of Tigecycline. The resulting lyophilized preparation was stored at different storage temperatures at different time intervals and the content of Tigecycline was tested. The result is given in below Table 4.
  • vial was lyophilized using freeze dryer according to conventional method, thereby
  • the resulting lyophilized preparation was stored at different storage temperatures
  • Tigecycline (active) or pharmaceutically acceptable salt was added to an aqueous solution containing 60.0gm of Sulfobutyl ether betacyclodextrin sodium and stirred for some time. Adjust the pH about 5.45 with 1.0 N HCL solution (pH limit 4.5 to 7.0). The solution was filtered and the resulting solution was loaded into 20 vials (30 ml) with each containing 15.0 ml solution. The solution in each vial was lyophilized using freeze dryer according to conventional method, thereby obtaining the lyophilized compositions each comprising 150mg of Tigecycline. The resulting lyophilized preparation was stored at different storage temperatures at different time intervals and the content of Tigecycline was tested.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique lyophilisée stable contenant de la tigécycline ainsi que de l'éther sulfobutylique de bêta-cyclodextrine sodique comme agent stabilisant pour l'administration parentérale. La composition pharmaceutique permet la stabilisation de la tigécycline, en améliorant ainsi la durée de conservation pendant le stockage. L'invention concerne également un procédé de préparation de ladite composition.
EP16883515.5A 2016-01-08 2016-04-01 Composition parentérale lyophilisée de tigécycline et procédé de préparation associé Pending EP3302494A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201621000791 2016-01-08
PCT/IN2016/050104 WO2017118994A1 (fr) 2016-01-08 2016-04-01 Composition parentérale lyophilisée de tigécycline et procédé de préparation associé

Publications (2)

Publication Number Publication Date
EP3302494A1 true EP3302494A1 (fr) 2018-04-11
EP3302494A4 EP3302494A4 (fr) 2019-01-23

Family

ID=59273613

Family Applications (1)

Application Number Title Priority Date Filing Date
EP16883515.5A Pending EP3302494A4 (fr) 2016-01-08 2016-04-01 Composition parentérale lyophilisée de tigécycline et procédé de préparation associé

Country Status (4)

Country Link
EP (1) EP3302494A4 (fr)
EA (1) EA036750B1 (fr)
WO (1) WO2017118994A1 (fr)
ZA (1) ZA201804834B (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2018013584A (es) 2016-05-09 2019-04-01 Xellia Pharmaceuticals Aps Formulaciones de antibioticos glicopeptidicos estabilizados.
KR102022338B1 (ko) * 2018-08-06 2019-09-18 이건무 당과 아미노산을 함유하는 안정한 수액제 조성물

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2586213A1 (fr) * 2004-11-03 2006-05-26 Curagen Corporation Formulations, procedes de production et utilisations du fgf-20
AU2012327237A1 (en) * 2011-12-02 2013-06-20 University Health Network Compositions of tigecycline and uses thereof
CN103315947B (zh) * 2012-03-22 2016-01-20 上海汇伦生命科技有限公司 一种注射用替加环素组合物

Also Published As

Publication number Publication date
WO2017118994A1 (fr) 2017-07-13
EP3302494A4 (fr) 2019-01-23
EA036750B1 (ru) 2020-12-16
ZA201804834B (en) 2019-05-29
EA201891587A1 (ru) 2018-12-28

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