WO2006050631A1 - Stabilized freeze-dried formulation for cephalosporin derivatives - Google Patents

Stabilized freeze-dried formulation for cephalosporin derivatives Download PDF

Info

Publication number
WO2006050631A1
WO2006050631A1 PCT/CH2005/000665 CH2005000665W WO2006050631A1 WO 2006050631 A1 WO2006050631 A1 WO 2006050631A1 CH 2005000665 W CH2005000665 W CH 2005000665W WO 2006050631 A1 WO2006050631 A1 WO 2006050631A1
Authority
WO
WIPO (PCT)
Prior art keywords
freeze
solution
ocor
dried
formulation according
Prior art date
Application number
PCT/CH2005/000665
Other languages
French (fr)
Inventor
Markus Heubes
Wilhelm Scigalla
Original Assignee
Basilea Pharmaceutica Ag
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
Priority to CN2005800384621A priority Critical patent/CN101056623B/en
Priority to PL05798682T priority patent/PL1809253T3/en
Application filed by Basilea Pharmaceutica Ag filed Critical Basilea Pharmaceutica Ag
Priority to MX2007005677A priority patent/MX2007005677A/en
Priority to CA002585296A priority patent/CA2585296A1/en
Priority to DK05798682.0T priority patent/DK1809253T3/en
Priority to DE602005021530T priority patent/DE602005021530D1/en
Priority to SI200531069T priority patent/SI1809253T1/en
Priority to EP05798682A priority patent/EP1809253B1/en
Priority to AT05798682T priority patent/ATE468844T1/en
Priority to BRPI0517305-1A priority patent/BRPI0517305A/en
Priority to JP2007540473A priority patent/JP2008519775A/en
Priority to US11/667,535 priority patent/US20080032962A1/en
Priority to AU2005304252A priority patent/AU2005304252B2/en
Publication of WO2006050631A1 publication Critical patent/WO2006050631A1/en
Priority to US12/699,329 priority patent/US20100160278A1/en
Priority to HR20100364T priority patent/HRP20100364T1/en

Links

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
    • A61K9/14—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
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone

Definitions

  • the present invention relates to a freeze-dried formulation for cephalosporin derivatives having increased stability, a solution for obtaining and a method for preparing such a for ⁇ mulation, as well as the use of certain compounds for stabi ⁇ lizing cephalosporin derivatives in freeze-dried formula ⁇ tions.
  • freeze-drying may have a considerable effect on the degradation of the- pharmaceutically active ingredients in a formulation, as well as a strong impact on their stabil ⁇ ity in freeze-dried form.
  • the variables which affect these parameters are mainly the pH, the quantity of salts present, the type and quantity of excipients in the formulation as well as the temperatures, pressure and time chosen for the freezing, sublimation and drying operations.
  • the literature teaches that the presence of an amino acid, of a polyol, for example mannitol, of a crystalline phase or of an amorphous phase may have, besides certain advantages, disadvantages which lead, in the case of freeze-dried products containing particularly sensitive active ingredients like for example cephalosporin deriva- tives, to relatively short shelf lives and/or low storage temperatures for these freeze-dried products.
  • Alanine in crystallized form, has the advantage of prevent ⁇ ing the collapse of the freeze-dried product during sublima ⁇ tion and drying and or allowing the production of a freeze- dried product with a greater specific surface area and there ⁇ fore allows a more rapid drying (Pikal M. J., Freeze-drying of proteins, Biopharm. , 26-30 October 1990).
  • a decrease in the glass transition temperature is generally synonymous with a lower stability of a freeze-dried product (Franks F., Freeze- drying; from empiricism to predictability, Cryo-letters, 1990, 11, 93-110) .
  • mannitol in the composition of a freeze-dried protein product is generally justified as bulking agent, that is to say that it makes it possible both to maintain the solid and rigid structure of the volume of the freeze-dried product corresponding to the volume of solution to be freeze- dried, but its presence also makes it possible to adjust the isotonicity of the reconstituted solution to be injected.
  • mannitol is the predominant excipient in the composition of a freeze-dried protein product, it is most often in crys ⁇ talline form (Lyophilized formulations recombinant tumor necrosis factor, Hora M. S., Rana R. K., Smith F. W., Pharm. Res. , 1992, 9 (1) , 33-36) .
  • mannitol in freeze-drying is commonly used as car ⁇ rier or constituting agent to result in a homogenous, stable cake with good appearance, it is not known as stabilizer for nonprotein compounds, in particular cephalosporin derivatives (see e.g. Handbook of Pharmaceutical Excipients, Rowe, R.C, Sheskey, P.J, Weller, P.J, Fourth Edition, PhP, London, 373- 377.)
  • the present invention relates to a pharmaceutical formulation provided in the form of a freeze-dried product and containing at least one cephalosporin derivative as an active ingredient and at least one stabilizer selected from the group consisting of carbohydrates, polyhydric alcohols and polyvinyl pyrrolidone (PVP) .
  • the cephalosporin derivatives are stabilized at temperatures which may be as high as 25 0 C, or even higher, leading to an increased shelf life.
  • the stabilization by the inventive formulation of said cepha- losporin derivatives includes the stabilization during manu ⁇ facture of the product.
  • the stabilizer is selected from mannitol, trehalose, and PVP.
  • the active ingredient contained in the formulation according to the invention may be a single active ingredient or may be combined with another antibiotically active ingredient of protein or nonprotein nature.
  • the formulation may further comprise one or more compounds selected from buffers, amino acids, acids or bases for adjusting the pH, surfactants, salts, preservatives, antioxi ⁇ dants, chelating agents.
  • buffers and amino acids may lead to an additional sta ⁇ bilizing effect
  • further components mentioned above are well-known pharmaceutically acceptable excipients often used in freeze-dried forms.
  • Further customary additives known to a person skilled in the preparation of pharmaceutical formula ⁇ tions such as flavouring agents or dyes may be added as well.
  • buffers which may be introduced into the formula- tion according to the present invention, there may be men ⁇ tioned in particular citrate, tri(hydroxymethy1)aminomethane, _ - ⁇ _
  • surfactants which may be introduced into the formu ⁇ lation according to the present invention, there may be men ⁇ tioned polysorbates, poloxamers, tyloxapol, lecithins.
  • the salts which may be introduced into the formulation according to the present invention, there may be mentioned in particular the sodium salts such as ededate (tetrasodium EDTA), chloride, docusate (sodium 1, 4-bis (2-ethylhexyl) sul- phosuccinate) , bicarbonate, glutamate, potassium acetate, dipotassium carbonate and magnesium stearate.
  • ededate tetrasodium EDTA
  • docusate sodium 1, 4-bis (2-ethylhexyl) sul- phosuccinate
  • bicarbonate glutamate
  • potassium acetate dipotassium carbonate
  • dipotassium carbonate magnesium stearate
  • preservatives which may be introduced into the for ⁇ mulation according to the present invention, there may be mentioned in particular methyl and propyl para-hydroxybenzo- ate, benzethonium chloride, sodium mercurothiolate, phenyl- mercuric nitrate, benzyl alcohol, phenol and metacresol.
  • the formulations according to the present invention may be either reconstituted in liquid form by addition of an ade ⁇ quate solvent or reconstitution solution for its administra ⁇ tion via the parenteral, intra-muscular or oral route, or directly administered via the oral route, to man or to ani ⁇ mals.
  • the liquid or dry forms may be adminis ⁇ tered by inhalation.
  • the cephalosporin derivatives in the present invention include all pharmaceutically acceptable salts and polymorphs as well as hydrates.
  • cephalosporin derivative is also meant to include drugs as well as pro- drugs.
  • the present formulation comprises a cephalosporin derivative of the following general formula I
  • R 1 is hydrogen, Ci- 6 ⁇ alkyl, optionally substituted by fluoro, or C 3 _ 6 -cycloalkyl;
  • R 2 is hydrogen or a group selected from
  • R is hydrogen or Ci_ 6 -alkyl
  • R 4 is hydrogen or hydroxy
  • R 5 is hydrogen or ⁇ -hydroxyaIky1
  • X is CH or N
  • a particularly preferred example of the compounds of formula I is (6R,7R)-7-[ (Z) -2- (Amino- [1, 2 , 4] thiadiazol-3-yl) -2- hydroxyimino-acetylamino] -3- [ (E) - (3 'R, 5'R) -5 ' -hydroxymethyl- 1' - (5-methyl-2-oxo- [1, 3]dioxol-4-ylmethyloxycarbonyl-2-oxo- [1,3' ]bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza- bicyclo[4.2.0] oct-2-ene-2-carboxylic acid wherein R 1 , R 2 , R 4 and R 5 are all hydrogen, R 3 is
  • the formulations according to the present invention may be obtained by freeze-drying an aqueous solution comprising at least one cephalosporin derivative as an active ingredient, and at least one stabilizer selected from the group consist ⁇ ing of carbohydrates, polyhydric alcohols and PVP.
  • the stabilizer is selected from mannitol, trehalose, and PVP .
  • the stabilizer is preferably contained in the solution at a concentration within the range of 5 to 80% by weight.
  • par ⁇ ticular, mannitol, trehalose, and PVP are used at a concen- tration of 2 to 40% by weight.
  • con ⁇ centrations ranging from 10 to 25% by weight. Percent by weight in this application always refers to the dry weight.
  • the solution may also contain a pharmaceutically acceptable buffer for further stabilization and/or for adjusting the pH such as citrate, tartrate, carbonate, hydrogen carbonate, lactate, glycine, acetate or succinate buffers.
  • a pharmaceutically acceptable buffer for further stabilization and/or for adjusting the pH such as citrate, tartrate, carbonate, hydrogen carbonate, lactate, glycine, acetate or succinate buffers.
  • the preferred pH range is from 2.0 to 6.5, wherein 4.0 to 5.0 is particularly preferred.
  • the quantity of the active ingredient present is limited by its solubility in the aqueous solution.
  • the formulations of the invention indeed result from the freeze-drying of aqueous solutions in which the active ingredient is perfectly dis ⁇ solved.
  • a particularly preferred solution for forming a formulation according to the present invention comprises a cephalosporin derivative according to formula I, mannitol as a stabilizer and an aqueous citrate buffer.
  • solutions to be freeze-dried are, for example, prepared in the following manner:
  • the desired quantities of active ingredient, stabilizer and buffer, and optionally further additives like for example preservatives are added, at the appropriate dissolution tem ⁇ perature, to the quantity of water for injection or of solu- bilizing agent necessary for their solubilization until com- plete dissolution is obtained.
  • the solutions obtained are filtered in a sterile medium and distributed into containers, preferably vials or capsules.
  • freeze-drying of the solutions may then be carried out as follows:
  • the solution follows a cycle comprising freezing, then subli ⁇ mation and drying adapted to the volume to be freeze-dried and to the container containing the solution.
  • the sublimation and drying times, temperatures and pressures are adjusted according to the volumes of solution to be freeze-dried and the residual water content desired in the freeze-dried product.
  • Solution A was prepared by dissolution of 192.0 g BAL 5788 (synthesized as described in EP-A-I 087 980) and 34.38 g mannitol (obtained from Roquette America, Inc.) in a sodium hydroxide/citric acid buffer system with a pH between 4.2 - 4.8 (prepared by dissolving 2.18 g citric acid monohydrate in WFI (water for injection) and pH adaptation with sodium hydroxide) to result the final weight of 1389.5 g.
  • the solution was filtered and filled into vials.
  • Solution A was freeze-dried according to the process summa ⁇ rized in the following table to obtain formulation A.
  • the reference solution B was prepared in the same way as solution A by dissolution of an equal amount of BAL 5788, in the same sodium hydroxide/citric acid buffer system in WFI with the only difference that no mannitol was added. The solution was filtered and filled into vials.
  • the reference solution was freeze-dried as outlined above obtaining formulation B.
  • the freeze dried products resulting from Solution A and Solu ⁇ tion B were analytically characterized and a stability test ⁇ ing program was initiated covering different temperatures.
  • compositions (nominal) of Formulation A and Formulation B are Compositions (nominal) of Formulation A and Formulation B.
  • composition of Formulation B (per vial) :
  • the amount of degradation products formed during storage of the freeze-dried product (at e.g. 5 0 C, after 12 months) obtained from Solution A (with mannitol) was approximately 10% lower compared to the amount formed during storage of the freeze-dried product resulting from Solution B (without mannitol) .
  • Further formulations were prepared in the same way with trehalose or PVP, and also with other buffer systems.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention relates to a freeze-dried formulation for cephalosporin derivatives having increased stability, a solution for obtaining and a method for preparing such a formulation, as well as the use of certain compounds for stabilizing cephalosporin derivatives in freeze-dried formulations. The compounds preferably used as stabilizers according to the invention are mannitol, trehalose, and PVP.

Description

Stabilized Freeze-dried Formulation for Cephalosporin Deriva¬ tives
The present invention relates to a freeze-dried formulation for cephalosporin derivatives having increased stability, a solution for obtaining and a method for preparing such a for¬ mulation, as well as the use of certain compounds for stabi¬ lizing cephalosporin derivatives in freeze-dried formula¬ tions.
It is known that freeze-drying may have a considerable effect on the degradation of the- pharmaceutically active ingredients in a formulation, as well as a strong impact on their stabil¬ ity in freeze-dried form. The variables which affect these parameters are mainly the pH, the quantity of salts present, the type and quantity of excipients in the formulation as well as the temperatures, pressure and time chosen for the freezing, sublimation and drying operations.
For the stabilization of the freeze-dried products, amino acids, and polyols are often used; but the literature, which is highly abundant on the subject, gives no information on the solution to the general problem of obtaining a stable pharmaceutical formulation.
More particularly, the literature teaches that the presence of an amino acid, of a polyol, for example mannitol, of a crystalline phase or of an amorphous phase may have, besides certain advantages, disadvantages which lead, in the case of freeze-dried products containing particularly sensitive active ingredients like for example cephalosporin deriva- tives, to relatively short shelf lives and/or low storage temperatures for these freeze-dried products.
The role of polyols and of amino acids has been studied sepa¬ rately in the case of the human growth hormone (hGH) , but their synergistic effect is still poorly elucidated (Pikal M. J., Dellermann K. M. , Roy M. L., Riggin M. N., The effects of formulation variables on the stability of freeze-dried Human Growth Hormone, Pharm. research., 1991, 8, No. 4, 427-436).
The advantages and disadvantages linked to the presence of amino acids and of mannitol are listed below.
Advantages linked to the presence of amino acids.
It has been demonstrated that the presence of glycine in a freeze-dried product induced crystallization of the molecules present in solution during the freezing stage of the freeze- drying (Korey D. J., Schwartz J. B., Effects of excipients on the crystallization of pharmaceutical compounds during lyo- philization, J. Parenteral Sci. Tech., 1989, 43(2) : 80-83) . This crystallization of the active ingredient makes it possi¬ ble to enhance its stability.
Alanine, in crystallized form, has the advantage of prevent¬ ing the collapse of the freeze-dried product during sublima¬ tion and drying and or allowing the production of a freeze- dried product with a greater specific surface area and there¬ fore allows a more rapid drying (Pikal M. J., Freeze-drying of proteins, Biopharm. , 26-30 October 1990).
Disadvantages linked to the presence of amino acids. The addition of an amino acid to a sugar or to a polyol in a solution to be freeze-dried generally has the effect of decreasing the glass transition temperature of the sugar (te Booy M. P. W. M., de Ruiter R. A., de Meere A. L. J., Evalua- tion of the physical stability of freeze-dried sucrose con¬ taining formulations by differential scanning calorimetry, Pharm. Research., 1992, 9, 109-114) . Now, a decrease in the glass transition temperature is generally synonymous with a lower stability of a freeze-dried product (Franks F., Freeze- drying; from empiricism to predictability, Cryo-letters, 1990, 11, 93-110) .
Advantages linked to the presence of mannitol.
The presence of mannitol in the composition of a freeze-dried protein product is generally justified as bulking agent, that is to say that it makes it possible both to maintain the solid and rigid structure of the volume of the freeze-dried product corresponding to the volume of solution to be freeze- dried, but its presence also makes it possible to adjust the isotonicity of the reconstituted solution to be injected. When mannitol is the predominant excipient in the composition of a freeze-dried protein product, it is most often in crys¬ talline form (Lyophilized formulations recombinant tumor necrosis factor, Hora M. S., Rana R. K., Smith F. W., Pharm. Res. , 1992, 9 (1) , 33-36) .
Disadvantages linked to the presence of mannitol.
It has been reported that the degree of hydrolysis of methyl- prednisolone sodium succinate, in freeze-dried form, was greater in the presence of mannitol than in the presence of lactose, and that this level increased with the quantity of mannitol present in the freeze-dried product. This has been explained by the fact that the crystallization of mannitol during freeze-drying changes the distribution of water in the matrix of the freeze-dried product. The increase in the quan¬ tity of water present in the microenvironment of the active ingredient resulting therefrom enhances the hydrolysis of the active ingredient and reduces its stability {The effect of bulking agent on the solid state stability of freeze dried methylprednisolone sodium succinate, Herman B. D., Sinclair B. D., Milton N., Nail S. L., Pharma. Res., 1994, 11 (10), 1467-1473) .
The kinetics of degradation for various cephalosporin deriva¬ tives in aqueous solutions for various carbohydrates, polyhy- dric alcohols was shown to increase with increasing concen¬ tration of the hydroxyl compound concentration (The influence of carbohydrates and polyhydric alcohols on the stability of cephalosporins in aqueous solutions, Hans Bundgaard, Claus Larsen, Intl. Journal of Pharmaceutics, October 1983, 16, 3, 319-325) .
Moreover, mannitol in freeze-drying is commonly used as car¬ rier or constituting agent to result in a homogenous, stable cake with good appearance, it is not known as stabilizer for nonprotein compounds, in particular cephalosporin derivatives (see e.g. Handbook of Pharmaceutical Excipients, Rowe, R.C, Sheskey, P.J, Weller, P.J, Fourth Edition, PhP, London, 373- 377.)
In conclusion, the scientific literature on the subject of the effect of excipients on the stabilization of pharmaceuti- cal active ingredients gives contradictory information on their properties and furthermore does not make it possible to obtain some information on the subject of the relationships between the structure of a freeze-dried product and its sta- bility. Likewise, the role of the polyols and of the amino acids, alone or in combination, is not described according to a set of generalizable properties, but has been observed with contradictory results according to the active principles studied and the quantities of excipients used.
Based on the above described state of the prior art, it is the object of the present invention to provide a freeze-dried formulation for cephalosporin derivatives showing an increased stability during manufacture of the formulation and/or during subsequent storage.
This object was solved by the freeze-dried formulation according to claim 1, a solution for obtaining a freeze-dried formulation according to claim 14, a method for preparing such a formulation according to claim 15, and the use of cer¬ tain stabilizers according to claim 17.
According to the present invention, it was surprisingly found that certain substances have an unexpected stabilizing effect on freeze-dried formulations of cephalosporin derivatives.
Therefore, the present invention relates to a pharmaceutical formulation provided in the form of a freeze-dried product and containing at least one cephalosporin derivative as an active ingredient and at least one stabilizer selected from the group consisting of carbohydrates, polyhydric alcohols and polyvinyl pyrrolidone (PVP) . In this inventive formulation, the cephalosporin derivatives are stabilized at temperatures which may be as high as 250C, or even higher, leading to an increased shelf life.
The stabilization by the inventive formulation of said cepha- losporin derivatives includes the stabilization during manu¬ facture of the product.
In particularly preferred embodiments, the stabilizer is selected from mannitol, trehalose, and PVP.
The active ingredient contained in the formulation according to the invention may be a single active ingredient or may be combined with another antibiotically active ingredient of protein or nonprotein nature.
In addition to carbohydrates, polyhydric alcohols and/or PVP, the formulation may further comprise one or more compounds selected from buffers, amino acids, acids or bases for adjusting the pH, surfactants, salts, preservatives, antioxi¬ dants, chelating agents.
While buffers and amino acids may lead to an additional sta¬ bilizing effect, the further components mentioned above are well-known pharmaceutically acceptable excipients often used in freeze-dried forms. Further customary additives known to a person skilled in the preparation of pharmaceutical formula¬ tions such as flavouring agents or dyes may be added as well.
Among the buffers which may be introduced into the formula- tion according to the present invention, there may be men¬ tioned in particular citrate, tri(hydroxymethy1)aminomethane, _ -η _
maleate, succinate, tartrate, carbonate, and hydrogene car¬ bonate buffers, as well as mono-acidic buffers like lactate, glycine, or acetate buffer systems. It is being understood that the acids and bases composing said buffers may also be introduced alone, including hydrates, as well as any combina¬ tions thereof.
Among the surfactants which may be introduced into the formu¬ lation according to the present invention, there may be men¬ tioned polysorbates, poloxamers, tyloxapol, lecithins.
Among the salts which may be introduced into the formulation according to the present invention, there may be mentioned in particular the sodium salts such as ededate (tetrasodium EDTA), chloride, docusate (sodium 1, 4-bis (2-ethylhexyl) sul- phosuccinate) , bicarbonate, glutamate, potassium acetate, dipotassium carbonate and magnesium stearate.
Among the preservatives which may be introduced into the for¬ mulation according to the present invention, there may be mentioned in particular methyl and propyl para-hydroxybenzo- ate, benzethonium chloride, sodium mercurothiolate, phenyl- mercuric nitrate, benzyl alcohol, phenol and metacresol.
The formulations according to the present invention may be either reconstituted in liquid form by addition of an ade¬ quate solvent or reconstitution solution for its administra¬ tion via the parenteral, intra-muscular or oral route, or directly administered via the oral route, to man or to ani¬ mals. In addition, the liquid or dry forms may be adminis¬ tered by inhalation. The cephalosporin derivatives in the present invention include all pharmaceutically acceptable salts and polymorphs as well as hydrates. Furthermore, the term cephalosporin derivative is also meant to include drugs as well as pro- drugs.
In a preferred embodiment, the present formulation comprises a cephalosporin derivative of the following general formula I
Figure imgf000009_0001
wherein
R1 is hydrogen, Ci-6~alkyl, optionally substituted by fluoro, or C3_6-cycloalkyl;
R2 is hydrogen or a group selected from
-CH2C (=CHR) -COOR, -CH2OCOR, -CH(R)OCOR, -CH(R)OCOOR, -CH(OCOR)OCOR, -CH2COCH2OCOR and
Figure imgf000009_0002
R3 is hydrogen or group selected from -CH2C(=CH2)-
COOR,
-COOCH2C(=CHR) -COOR, -COOCH2OCOR, -COOCH(R)OCOR, -COOCH(R)OCOOR, -COOCH(OCOR)OCOR, -COOCH2COCH2OCOR, and
■COOCHZ AO ° with the proviso that one of R2 and R3 is hydro¬ gen and the other of R2 and R3 is different from hydrogen, _ Q _
R is hydrogen or Ci_6-alkyl;
R4 is hydrogen or hydroxy,
R5 is hydrogen or ω-hydroxyaIky1; and
X is CH or N,
as well as pharmaceutically acceptable salts and polymorphs of said compounds and hydrates of the compounds of formula I and of their salts .
Compounds according to the above formula I which are known to suffer from stability problems in freeze-dried formulations are for example described in European patent no. EP 1 087 980 Bl.
A particularly preferred example of the compounds of formula I is (6R,7R)-7-[ (Z) -2- (Amino- [1, 2 , 4] thiadiazol-3-yl) -2- hydroxyimino-acetylamino] -3- [ (E) - (3 'R, 5'R) -5 ' -hydroxymethyl- 1' - (5-methyl-2-oxo- [1, 3]dioxol-4-ylmethyloxycarbonyl-2-oxo- [1,3' ]bipyrrolidinyl-3-ylidenemethyl] -8-oxo-5-thia-l-aza- bicyclo[4.2.0] oct-2-ene-2-carboxylic acid wherein R1, R2, R4 and R5 are all hydrogen, R3 is
Figure imgf000010_0001
and R is methyl. In the following, this compound is referred to as BAL 5788.
The formulations according to the present invention may be obtained by freeze-drying an aqueous solution comprising at least one cephalosporin derivative as an active ingredient, and at least one stabilizer selected from the group consist¬ ing of carbohydrates, polyhydric alcohols and PVP. In parti¬ cular the stabilizer is selected from mannitol, trehalose, and PVP .
The stabilizer is preferably contained in the solution at a concentration within the range of 5 to 80% by weight. In par¬ ticular, mannitol, trehalose, and PVP are used at a concen- tration of 2 to 40% by weight. Especially preferred are con¬ centrations ranging from 10 to 25% by weight. Percent by weight in this application always refers to the dry weight.
The solution may also contain a pharmaceutically acceptable buffer for further stabilization and/or for adjusting the pH such as citrate, tartrate, carbonate, hydrogen carbonate, lactate, glycine, acetate or succinate buffers.
The preferred pH range is from 2.0 to 6.5, wherein 4.0 to 5.0 is particularly preferred.
The quantity of the active ingredient present is limited by its solubility in the aqueous solution. The formulations of the invention indeed result from the freeze-drying of aqueous solutions in which the active ingredient is perfectly dis¬ solved.
A particularly preferred solution for forming a formulation according to the present invention comprises a cephalosporin derivative according to formula I, mannitol as a stabilizer and an aqueous citrate buffer.
The solutions to be freeze-dried are, for example, prepared in the following manner:
The desired quantities of active ingredient, stabilizer and buffer, and optionally further additives like for example preservatives are added, at the appropriate dissolution tem¬ perature, to the quantity of water for injection or of solu- bilizing agent necessary for their solubilization until com- plete dissolution is obtained. The solutions obtained are filtered in a sterile medium and distributed into containers, preferably vials or capsules.
The freeze-drying of the solutions may then be carried out as follows:
The solution follows a cycle comprising freezing, then subli¬ mation and drying adapted to the volume to be freeze-dried and to the container containing the solution.
The sublimation and drying times, temperatures and pressures are adjusted according to the volumes of solution to be freeze-dried and the residual water content desired in the freeze-dried product.
The present invention will now be described by way of spe¬ cific examples which are however not intended to limit the scope of the present invention.
The following solutions were prepared, lyophilised, and the resulting formulations were tested with regard to their sta¬ bility:
Preparation of Solution A (with mannitol) :
Solution A was prepared by dissolution of 192.0 g BAL 5788 (synthesized as described in EP-A-I 087 980) and 34.38 g mannitol (obtained from Roquette America, Inc.) in a sodium hydroxide/citric acid buffer system with a pH between 4.2 - 4.8 (prepared by dissolving 2.18 g citric acid monohydrate in WFI (water for injection) and pH adaptation with sodium hydroxide) to result the final weight of 1389.5 g. The solution was filtered and filled into vials.
Lyophilisation of Solution A:
Solution A was freeze-dried according to the process summa¬ rized in the following table to obtain formulation A.
Figure imgf000013_0001
Preparation of a Reference Solution B (without mannitol) :
The reference solution B was prepared in the same way as solution A by dissolution of an equal amount of BAL 5788, in the same sodium hydroxide/citric acid buffer system in WFI with the only difference that no mannitol was added. The solution was filtered and filled into vials.
The reference solution was freeze-dried as outlined above obtaining formulation B. The freeze dried products resulting from Solution A and Solu¬ tion B were analytically characterized and a stability test¬ ing program was initiated covering different temperatures.
Compositions (nominal) of Formulation A and Formulation B
Composition of Formulation A (per vial) .•
Figure imgf000014_0001
Composition of Formulation B (per vial) :
Figure imgf000014_0002
Results:
The amount of degradation products formed during manufacture of Formulation A (with mannitol) was approximately 9% lower compared to Formulation B (without mannitol) .
The amount of degradation products formed during storage of the freeze-dried product (at e.g. 50C, after 12 months) obtained from Solution A (with mannitol) was approximately 10% lower compared to the amount formed during storage of the freeze-dried product resulting from Solution B (without mannitol) . Further formulations were prepared in the same way with trehalose or PVP, and also with other buffer systems.

Claims

Claims
1. Freeze-dried formulation for cephalosporin deriva¬ tives, which is pharmaceutically acceptable, comprising at least one cephalosporin derivative as an active ingredient and at least orie stabilizer selected from the group consist¬ ing of carbohydrates, polyhydric alcohols and polyvinyl pyr¬ rolidone (PVP) .
2. Freeze-dried formulation according to claim 1, wherein the carbohydrate is trehalose.
3. Freeze-dried formulation according to claim 1, wherein the. polyhydric alcohol is mannitol.
4. Freeze-dried formulation according to any of claims 1 to 3, further comprising an additional antibiotically active ingredient.
5. Freeze-dried formulation according to any of claims 1 to 4, further comprising one or more compounds selected from buffers, amino acids, acids or bases for adjusting the pH, surfactants, salts, preservatives, antioxidants, chelat¬ ing agents.
6. Freeze-dried formulation according to any of claims 1 to 5 for reconstitution of a solution for its administra¬ tion via the parenteral route, the intramuscular route, the oral route or via inhalation; or for direct administration via the oral route or via inhalation.
7. Freeze-dried formulation according to any of claims 1 to 6, wherein the cephalosporin is a compound of the fol-
Figure imgf000017_0001
lowing general formula I wherein
R1 is hydrogen, Ci_6-alkyl, optionally substituted by fluoro, or C3_6-cycloalkyl;
R2 is hydrogen or a group selected from
-CH2C(=CHR) -COOR, -CH2OCOR, -CH(R)OCOR, -CH(R)OCOOR, -CH(OCOR)OCOR, -CH2COCH2OCOR and
Figure imgf000017_0002
R3is hydrogen or group selected from -CH2Cf=CH2)- COOR,
-COOCH2C(=CHR)-COOR, -COOCH2OCOR, -COOCH(R)OCOR, -COOCH(R)OCOOR, -COOCH(OCOR)OCOR, -COOCH2COCH2OCOR, and
■COOCH2 Λo ° with the proviso that one of R2 and R3 is hydro¬ gen and the other of R2 and R3 is different from hydrogen,
R is hydrogen or Ci-β-alkyl; R4 is hydrogen or hydroxy,
R5 is hydrogen or ω-hydroxyalkyl; and
X is CH or N, as well as pharmaceutically acceptable salts and polymorphs of said compounds and hydrates of the compounds of formula I and of their salts.
8. Formulation according to any of claims 1 to 7 obtained after freeze-drying a solution comprising at least one cephalosporin as an active ingredient, at least one sta¬ bilizer selected from the group consisting of carbohydrates, polyhydric alcohols and PVP, and an aqueous solution.
9. Formulation according to claim 8, wherein the sta- bilizer is mannitol, trehalose or PVP.
10. Formulation according to claim 8 or 9, wherein the aqueous solution is a buffer solution, preferably a citrate, tartrate, carbonate, hydrogen carbonate, succinate, glycine, lactate or acetate buffer solution.
11. Formulation according to any of claims 8 to 10, wherein the aqueous solution is a mono-acidic buffer solution e.g. an acetate, glycine or lactate buffer solution.
12. Formulation according to any of claims 8 to 11, wherein the concentration of the stabilizer in the solution is in the range of 5 - 80% by weight.
13. Formulation according to any of claims 8 to 12, wherein the pH of the solution is in the range of 2.0 - 6.5, in particular in the range of 4.0 - 5.0.
14. Solution for obtaining a freeze-dried formulation, comprising at least one cephalosporin derivative as an active ingredient, at least one stabilizer selected from the group consisting of mannitol, trehalose and PVP in an aqueous solution.
15. Method for preparing a stabilized freeze-dried pharmaceutically acceptable formulation for cephalosporin derivatives, comprising the steps of
(a) adding at least one stabilizer selected from car¬ bohydrates, polyhydric alcohols, and PVP to an aqueous solu¬ tion of a cephalosporin derivative; and
(b) freeze-drying the above solution.
16. Method according to claim 15, characterized in that mannitol, trehalose or PVP is added as the stabilizer.
17. Use of a compound selected from the group consist¬ ing of carbohydrates, polyhydric alcohols and PVP for stabi¬ lizing cephalosporin derivatives in freeze-dried formula- tions.
18. Use according to claim 17, characterized in that the compound is mannitol, trehalose or PVP.
PCT/CH2005/000665 2004-11-10 2005-11-10 Stabilized freeze-dried formulation for cephalosporin derivatives WO2006050631A1 (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
AT05798682T ATE468844T1 (en) 2004-11-10 2005-11-10 STABILIZED FREEZE-DRIED FORMULATION FOR CEPHALOSPORINE DERIVATIVES
EP05798682A EP1809253B1 (en) 2004-11-10 2005-11-10 Stabilized freeze-dried formulation for cephalosporin derivatives
MX2007005677A MX2007005677A (en) 2004-11-10 2005-11-10 Stabilized freeze-dried formulation for cephalosporin derivatives.
PL05798682T PL1809253T3 (en) 2004-11-10 2005-11-10 Stabilized freeze-dried formulation for cephalosporin derivatives
DK05798682.0T DK1809253T3 (en) 2004-11-10 2005-11-10 Stabilized freeze-dried formulation for cephalosporin derivatives
DE602005021530T DE602005021530D1 (en) 2004-11-10 2005-11-10 STABILIZED FREEZE-DRIED FORMULATION FOR CEPHALOSPORIN DERIVATIVES
BRPI0517305-1A BRPI0517305A (en) 2004-11-10 2005-11-10 stabilized lyophilized formulation for cephalosporin derivatives
CN2005800384621A CN101056623B (en) 2004-11-10 2005-11-10 Stabilized freeze-dried formulation for cephalosporin derivatives
CA002585296A CA2585296A1 (en) 2004-11-10 2005-11-10 Stabilized freeze-dried formulation for cephalosporin derivatives
SI200531069T SI1809253T1 (en) 2004-11-10 2005-11-10 Stabilized freeze-dried formulation for cephalosporin derivatives
JP2007540473A JP2008519775A (en) 2004-11-10 2005-11-10 Stabilized lyophilized formulations of cephalosporin derivatives
US11/667,535 US20080032962A1 (en) 2004-11-10 2005-11-10 Stabilized Freeze-Dried Formulation for Cephalosporin Derivatives
AU2005304252A AU2005304252B2 (en) 2004-11-10 2005-11-10 Stabilized freeze-dried formulation for cephalosporin derivatives
US12/699,329 US20100160278A1 (en) 2004-11-10 2010-02-03 Stabilized freeze-dried formulation for cephalosporin derivatives
HR20100364T HRP20100364T1 (en) 2004-11-10 2010-06-29 Stabilized freeze-dried formulation for cephalosporin derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP04405690.1 2004-11-10
EP04405690A EP1656930A1 (en) 2004-11-10 2004-11-10 Stabilized freeze-dried formulation for cephalosporin derivatives

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/699,329 Continuation US20100160278A1 (en) 2004-11-10 2010-02-03 Stabilized freeze-dried formulation for cephalosporin derivatives

Publications (1)

Publication Number Publication Date
WO2006050631A1 true WO2006050631A1 (en) 2006-05-18

Family

ID=34932353

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CH2005/000665 WO2006050631A1 (en) 2004-11-10 2005-11-10 Stabilized freeze-dried formulation for cephalosporin derivatives

Country Status (24)

Country Link
US (2) US20080032962A1 (en)
EP (3) EP1656930A1 (en)
JP (1) JP2008519775A (en)
KR (1) KR20070084150A (en)
CN (1) CN101056623B (en)
AR (1) AR052233A1 (en)
AT (1) ATE468844T1 (en)
AU (1) AU2005304252B2 (en)
BR (1) BRPI0517305A (en)
CA (1) CA2585296A1 (en)
CY (1) CY1110731T1 (en)
DE (1) DE602005021530D1 (en)
DK (1) DK1809253T3 (en)
ES (1) ES2342833T3 (en)
HR (1) HRP20100364T1 (en)
MX (1) MX2007005677A (en)
MY (1) MY142648A (en)
PL (1) PL1809253T3 (en)
PT (1) PT1809253E (en)
RS (1) RS51380B (en)
SI (1) SI1809253T1 (en)
TW (1) TW200630118A (en)
WO (1) WO2006050631A1 (en)
ZA (1) ZA200703760B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009051626A1 (en) * 2007-10-18 2009-04-23 Janssen Pharmaceutica, N.V. Cephalosporin derivative formulation
JP2011516461A (en) * 2008-04-04 2011-05-26 イプセン ファルマ ソシエテ パール アクシオン サンプリフィエ Liquid formulations and lyophilized formulations

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI488657B (en) * 2006-12-07 2015-06-21 Daiichi Sankyo Co Ltd Pharmaceutical composition of improved storage stability and method for improve storage stability of pharmaceutical composition
BRPI0719393B8 (en) 2006-12-07 2021-05-25 Daiichi Sankyo Co Ltd pharmaceutical composition
AU2009222020A1 (en) * 2008-03-04 2009-09-11 Elan Pharma International Limited Stable liquid formulations of anti-infective agents and adjusted anti-infective agent dosing regimens
EP2236520A1 (en) * 2009-03-31 2010-10-06 Leukocare Ag Stabilizing composition for immobilized biomolecules
US20130089638A1 (en) 2011-10-11 2013-04-11 Mead Johnson Nutrition Company Compositions Comprising Maltotriose And Methods Of Using Same To Inhibit Damage Caused By Dehydration Processes
CN102727451B (en) * 2012-07-03 2013-07-03 哈药集团制药总厂 Cefmetazole-containing pharmaceutical composition
CN102716075B (en) * 2012-07-03 2013-08-21 哈药集团制药总厂 Ceftizoxime sodium-containing pharmaceutical composition
CN103271877A (en) * 2012-12-18 2013-09-04 张宏民 Cefoxitin sodium agent and preparation method thereof
DK2968446T3 (en) 2013-03-13 2017-08-28 Theravance Biopharma Antibiotics Ip Llc HCL-Salts of an antibiotic compound
CN110507619B (en) * 2019-08-19 2021-12-03 湖北美林药业有限公司 Cefoperazone sodium for injection and preparation method thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253329A2 (en) 1986-07-10 1988-01-20 Eisai Co., Ltd. Cephalosporin injection composition
EP0325112A1 (en) 1988-01-18 1989-07-26 Hoechst Aktiengesellschaft Stabilization of cephalosporin derivatives by drying with a stabilizer, and stable preparations containing cephalosporin derivatives
EP0421297A2 (en) 1989-09-30 1991-04-10 Eisai Co., Ltd. Injectable preparations containing cephalosporin medicament and the use thereof
WO1999065920A1 (en) * 1998-06-15 1999-12-23 F. Hoffmann-La Roche Ag Derivatives of 3-(2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl)-cephems
WO2003045435A1 (en) 2001-11-30 2003-06-05 Pfizer Products Inc. Formulations comprising a cephalosporin compound and their use treating bacterial infections in cats and dogs
WO2004000323A1 (en) 2002-06-21 2003-12-31 Shionogi & Co., Ltd. Medicinal cephem compound composition for injection

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0459730A (en) * 1990-06-26 1992-02-26 Dai Ichi Seiyaku Co Ltd Cephem-based antibiotic-containing lyophilized preparation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253329A2 (en) 1986-07-10 1988-01-20 Eisai Co., Ltd. Cephalosporin injection composition
EP0325112A1 (en) 1988-01-18 1989-07-26 Hoechst Aktiengesellschaft Stabilization of cephalosporin derivatives by drying with a stabilizer, and stable preparations containing cephalosporin derivatives
EP0421297A2 (en) 1989-09-30 1991-04-10 Eisai Co., Ltd. Injectable preparations containing cephalosporin medicament and the use thereof
WO1999065920A1 (en) * 1998-06-15 1999-12-23 F. Hoffmann-La Roche Ag Derivatives of 3-(2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl)-cephems
EP1087980B1 (en) 1998-06-15 2003-01-29 Basilea Pharmaceutica AG Derivatives of 3-(2-oxo- 1,3']bipyrrolidinyl-3-ylidenemethyl)-cephems
WO2003045435A1 (en) 2001-11-30 2003-06-05 Pfizer Products Inc. Formulations comprising a cephalosporin compound and their use treating bacterial infections in cats and dogs
WO2004000323A1 (en) 2002-06-21 2003-12-31 Shionogi & Co., Ltd. Medicinal cephem compound composition for injection

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 22 January 2004 (2004-01-22), MYOJYO, HIDETOSHI ET AL: "Medicinal cephem compound composition for injection", XP002325368, retrieved from STN Database accession no. 140:65205 *
OGUCHI T ET AL., CHEM. PHARM. BULL., vol. 40, 1992, pages 1061 - 1063
OGUCHI T ET AL: "EFFECTS OF SACCHARIDE ON THE DECOMPOSITION OF CEPHALOTHIN SODIUM AND BENZYLPENICILLIN POTASSIUM IN FREEZE-DRIED PREPARATIONS", CHEMICAL AND PHARMACEUTICAL BULLETIN (TOKYO), vol. 40, no. 4, 1992, pages 1061 - 1063, XP002325367, ISSN: 0009-2363 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009051626A1 (en) * 2007-10-18 2009-04-23 Janssen Pharmaceutica, N.V. Cephalosporin derivative formulation
JP2011516461A (en) * 2008-04-04 2011-05-26 イプセン ファルマ ソシエテ パール アクシオン サンプリフィエ Liquid formulations and lyophilized formulations

Also Published As

Publication number Publication date
MY142648A (en) 2010-12-15
DK1809253T3 (en) 2010-07-12
ZA200703760B (en) 2008-06-25
CY1110731T1 (en) 2015-06-10
US20080032962A1 (en) 2008-02-07
AU2005304252A1 (en) 2006-05-18
EP2210592A2 (en) 2010-07-28
PL1809253T3 (en) 2010-10-29
MX2007005677A (en) 2007-07-20
JP2008519775A (en) 2008-06-12
EP1809253A1 (en) 2007-07-25
CN101056623B (en) 2011-04-06
RS51380B (en) 2011-02-28
ES2342833T3 (en) 2010-07-15
DE602005021530D1 (en) 2010-07-08
EP2210592A3 (en) 2011-12-14
AR052233A1 (en) 2007-03-07
EP1809253B1 (en) 2010-05-26
SI1809253T1 (en) 2010-09-30
CA2585296A1 (en) 2006-05-18
TW200630118A (en) 2006-09-01
PT1809253E (en) 2010-09-03
ATE468844T1 (en) 2010-06-15
KR20070084150A (en) 2007-08-24
AU2005304252B2 (en) 2009-07-16
EP1656930A1 (en) 2006-05-17
CN101056623A (en) 2007-10-17
BRPI0517305A (en) 2008-10-07
HRP20100364T1 (en) 2010-07-31
US20100160278A1 (en) 2010-06-24

Similar Documents

Publication Publication Date Title
AU2005304252B2 (en) Stabilized freeze-dried formulation for cephalosporin derivatives
US6284277B1 (en) Stable freeze-dried pharmaceutical formulation
JP2950617B2 (en) Stabilized pharmaceutical formulation comprising growth hormone and histidine
JP2006137678A (en) Interleukin-2 composition
JP2007500191A (en) Freeze-dried formulation of CCI-779
US20090325978A1 (en) Stable lyophilized preparation
JP4142149B2 (en) Vancomycin lyophilized formulation
JP2005523329A (en) Aqueous preparation containing camptothecin derivative and pharmaceutical composition lyophilized from the same
KR100807650B1 (en) FREEZE-DRIED PREPARATION OF N-[o-p-PIVALOYLOXYBENZENESULFONYLAMINOBENZOYL]GLYCINE MONOSODIUM SALT TETRAHYDRATE AND PROCESS FOR PRODUCING THE SAME
JP4278115B2 (en) Stabilized pharmaceutical compositions based on quinupristin and dalfopristin and their production
CN115038431B (en) Daptomycin preparation
KR102413426B1 (en) Orally disintegrating film comprising naratriptan
EP0438091B1 (en) Freeze-dried preparation of etoposide-2-dimethylamino compound
US20030162711A1 (en) Pharmaceutical formulation
JP6706988B2 (en) Pharmaceutical composition containing bortezomib
RU2095061C1 (en) Pharmaceutical composition
JPH05331069A (en) Lyophilized pharmaceutical preparation for tumor necrosis factor
JP2018024584A (en) Pharmaceutical preparation comprising bortezomib
JPH04108737A (en) Corticortopin-releasing factor-containing pharmaceutical

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LC LK LR LS LT LU LV LY MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2585296

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2007/03760

Country of ref document: ZA

Ref document number: 11667535

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: MX/a/2007/005677

Country of ref document: MX

Ref document number: 200580038462.1

Country of ref document: CN

Ref document number: 2007540473

Country of ref document: JP

Ref document number: 1020077010624

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2005304252

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2005798682

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2005304252

Country of ref document: AU

Date of ref document: 20051110

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2005304252

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2507/CHENP/2007

Country of ref document: IN

WWP Wipo information: published in national office

Ref document number: 2005798682

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 11667535

Country of ref document: US

ENP Entry into the national phase

Ref document number: PI0517305

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: P-2010/0324

Country of ref document: RS