[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

EP2187867A1 - Injectable pharmaceutical formulation of taxoids - Google Patents

Injectable pharmaceutical formulation of taxoids

Info

Publication number
EP2187867A1
EP2187867A1 EP08786582A EP08786582A EP2187867A1 EP 2187867 A1 EP2187867 A1 EP 2187867A1 EP 08786582 A EP08786582 A EP 08786582A EP 08786582 A EP08786582 A EP 08786582A EP 2187867 A1 EP2187867 A1 EP 2187867A1
Authority
EP
European Patent Office
Prior art keywords
taxoid
oil
emulsion
sterile
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.)
Withdrawn
Application number
EP08786582A
Other languages
German (de)
French (fr)
Inventor
Vincenzo De Tommaso
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.)
Pharmatex Italia SRL
Original Assignee
Pharmatex Italia SRL
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 Pharmatex Italia SRL filed Critical Pharmatex Italia SRL
Priority to EP08786582A priority Critical patent/EP2187867A1/en
Publication of EP2187867A1 publication Critical patent/EP2187867A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/107Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • the present invention relates to injectable pharmaceutical formulations of Taxoids, for example Paclitaxel or Docetaxel.
  • Taxoids are antitumor agents which are usually administered by injection, but due to their poor solubility in water it is difficult to prepare formulations which are acceptable from a therapeutic stand point.
  • Paclitaxel comprises a surfactant (Cremophor ELTM or Tween 80TM) and ethanol.
  • Surfactants are very dangerous for the human body, since they produce side effects such as hypersensitivity. Furthermore, they produce the extraction of DEHP from plastic containers containing PVC. It is therefore necessary to carefully avoid the use of any plastic which contains PVC.
  • US 2006/067952 discloses an injectable oil-in-water emulsion comprising a taxoid drug, an oil component, a phospholipid component and water.
  • the application defines the emulsion as "low-oil", the ratio between oil and taxol is, in the examples, higher than 60: 1. It means that for each mg of taxol, the emulsion contains more than 60 mg of oil.
  • the present invention relates to new formulations of taxoids, wherein the taxoid is present in an oil-in-water emulsion, characterized by the fact that the ratio oihtaxoid is lower than 50: 1, preferably lower than 40: 1. More specifically, the emulsions of the present invention comprise a taxoid, water, oil, a phospholipid and a viscosity improver.
  • the emulsions according to the present invention reduce the overall amount of organic compounds present in the emulsion itself.
  • the weight ratio of Taxoid versus the sum of all organic compounds present in the emulsion is lower than 80 : 1, preferably lower than 60: 1.
  • the present invention allows the preparation of oil-in-water injectable emulsions with a concentration equal to or higher than 6 mg/ml, stable in time and easy to dilute, as it is usually done in therapy, to a final concentration comprised between 0.3 mg/ml and 1.2 mg/ml.
  • any edible oil commercially available examples include rapeseed oil, safflower oil, olive oil, soybean oil, corn oil, cottonseed oil, almond oil, peanut oil, sesame oil, coconut oil, palm oil, etc..
  • the preferred oil is soybean oil.
  • the amount of oil used in the preparation of the emulsion is typically higher than 5% by weight, preferably higher than 8% by weight, most preferably higher than 10% by weight, even more preferably higher than 15% by weight.
  • phospholipid it is intended a triester of glycerol with two fatty acids and one phosphate ion.
  • exemplary phospholipids useful in the present invention are phosphatidyl choline, lecithin (e.g. soybean lecithin and egg lecithin), phosphatidylethanolamine, phosphatidylglycerol. Any type of lecithin can be used in the preparation of the oil-in-water emulsion of the present invention.
  • a preferred phospholipid for use in the present invention is soybean lecithin.
  • the amount of phospholipid can vary in a broad range, it is however preferably comprised between 0.5 and 10 % by weight, most preferably between 1 and 5% by weight.
  • a viscosity improver is used in the preparation of the formulation. With viscosity improver it is intended a compound which is able to increase viscosity in the emulsion. In this way, the emulsion is more stable.
  • the possible viscosity improver we can cite glycerol, dimethyl sulfoxide (DMSO), propylene glycol and glycofurol.
  • Glycerol is the preferred viscosity improver.
  • the amount of viscosity improver can vary in a broad range, and preferably its concentration in the emulsion can vary from 1 to 25% by weight, preferably from 1.5 to 15% by weight, most preferably from 2 to 10 % by weight.
  • the formulation according to the present invention is preferably prepared according to the following process: a) Solubilization of the phospholipid and taxoid in oil, optionally with the aid of ethanol; b) Separately, solubilization of the viscosity improver in water; c) The solution of a) is sterilized by filtration with a PTFE hydrophobic membrane with a size of 0.22 micron, in sterile room (Class A); if ethanol is present, it is stripped under vacuum; d) In another vessel, the water solution of b) is sterilized by filtration with a PTFE hydrophilic membrane with a size of 0.22 micron, in sterile room (Class A).
  • e) The sterile solution of d) is added to the sterile solution of c) at a temperature of 40-50 0 C under vigorous stirring; f) The obtained emulsion is homogenized under pressure or by the sonication until the size of the oily droplets is lower than 1 micron; g) The taxoid emulsion is bottled sterilely.
  • the oil emulsion is obtained according to the following process: a) Solubilization of the phospholipid in oil; b) The solution of a) is sterilized by filtration with a PTFE hydrophobic membrane with a size of 0.22 micron, in sterile room (Class A); c) To the sterile solution of b) a sterile taxoid is added; d) Solubilization of the viscosity improver in water; e) In another vessel, the water solution of d) is sterilized by filtration with a PTFE hydrophilic membrane with a size of 0.22 micron, in sterile room (Class A).
  • e) The sterile solution of e) is added to the sterile solution of c) at a temperature of 40-50 0 C under vigorous stirring; g) The obtained emulsion is homogenized under pressure or by sonication until the size of the oily droplets is lower than 1 micron; h) The taxoid emulsion is sterilely filled into glass vials.
  • the solution was sterilized by filtration with a PTFE hydrophilic membrane with a size of 0.22 micron, in sterile room (Class A).
  • the solution of Paclitaxel was placed under vigorous stirring and the sterile water-glycerol solution was added.
  • the emulsion was left under vigorous stirring at a temperature comprised between 25 and 35 0 C, giving rise to an emulsion.
  • the emulsion was homogenized by using a high pressure homogeniser (850-900 bar) or by sonication. The homogenisation is repeated until all oil droplets have a size lower than 1 micron. Sterile water is added in order to bring the final volume to 100 ml.
  • the concentration of Paclitaxel was 6 mg/ml (which corresponds to the concentration of the commercially available Paclitaxel).
  • the pH of the emulsion was checked to verify that it was comprised between 4.0 and 7.5.
  • the emulsion was kept under stirring for 20' and was then sterilely filled in glass vials of 5 ml, 16.7 ml, 25 ml and 50 ml.
  • glycerol were dissolved in 65 ml of water for injectable solutions.
  • the solution was sterilized by filtration with a PTFE hydrophilic membrane with a size of 0.22 micron, in sterile room (Class A).
  • the solution of Paclitaxel was placed under vigorous stirring at a temperature of 95-100 0 C and the sterile water-glycerol solution was added.
  • the emulsion was left under vigorous stirring at a temperature comprised between 25 and 35 0 C, giving rise to an emulsion.
  • the emulsion was homogenized by using either a high pressure homogeniser (850-900 bar) or sonication. The homogenisation is repeated until all oil droplets have a size lower than 1 micron.
  • Sterile water is added in order to bring the final volume to 100 ml.
  • the concentration of Paclitaxel was 6 mg/ml (which corresponds to the concentration of the commercially available Paclitaxel).
  • the pH of the emulsion was checked to verify that it was comprised between 4.0 and 7.5.
  • the emulsion was kept under stirring for 20' and was then sterilely filled into glass vials of 5 ml, 16.7 ml, 25 ml and 50 ml.
  • a Paclitaxel solution similar to the commercial product was prepared by dissolving Paclitaxel in a 50/50 mixture of Cremophor EL TM and ethanol. The concentration of Paclitaxel was 12.5 mg/ml.
  • Example 4 In vivo effect of the formulation of the invention.
  • example 2 was used in the treatment of mice and compared with the activity of the formulation of comparative example 3.
  • the formulations were diluted immediately before use to a concentration of Paclitaxel of 2.5 mg/ml by using physiologic solution.
  • 56 female nude mice purchased from Harlan Italy approximately 7 weeks old were injected with 1OxIO 6 human ovaric tumor cells A2780. When the tumoral masses reached the weight of 150-200 mg, the mice were randomly divided into four groups treated in the following way: a) blank of example 2, b) example 2, 25 mg/kg, c) blank of comparative example 3, d) comparative example 3, 25 mg/kg.
  • Each point in the graph is the average value from 10 mice.
  • the arrows indicate the day in which the treatment took place.

Landscapes

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

Abstract

The present invention relates to injectable pharmaceutical formulations of Taxoids, for example Paclitaxel or Docetaxel, wherein the taxoid is present in an oil-in-water emulsion comprising an edible oil, a phospholipid and a viscosity improver, and wherein the weight ratio of oil to taxoid is lower to or equal than 50 : 1. The invention also relates to the process for the preparation of these emulsions.

Description

INJECTABLE PHARMACEUTICAL FORMULATION OF TAXOIDS
[0001] The present invention relates to injectable pharmaceutical formulations of Taxoids, for example Paclitaxel or Docetaxel.
[0002] Taxoids are antitumor agents which are usually administered by injection, but due to their poor solubility in water it is difficult to prepare formulations which are acceptable from a therapeutic stand point.
[0003] At the present, commercially available formulations of Paclitaxel comprise a surfactant (Cremophor EL™ or Tween 80™) and ethanol. Surfactants are very dangerous for the human body, since they produce side effects such as hypersensitivity. Furthermore, they produce the extraction of DEHP from plastic containers containing PVC. It is therefore necessary to carefully avoid the use of any plastic which contains PVC.
[0004] In the recent years many attempts have been made to prepare different formulations which do not contain surfactants. US 2006/067952 discloses an injectable oil-in-water emulsion comprising a taxoid drug, an oil component, a phospholipid component and water. Although the application defines the emulsion as "low-oil", the ratio between oil and taxol is, in the examples, higher than 60: 1. It means that for each mg of taxol, the emulsion contains more than 60 mg of oil.
[0005] The present invention relates to new formulations of taxoids, wherein the taxoid is present in an oil-in-water emulsion, characterized by the fact that the ratio oihtaxoid is lower than 50: 1, preferably lower than 40: 1. More specifically, the emulsions of the present invention comprise a taxoid, water, oil, a phospholipid and a viscosity improver.
[0006] Furthermore, the emulsions according to the present invention reduce the overall amount of organic compounds present in the emulsion itself. In a preferred embodiment, the weight ratio of Taxoid versus the sum of all organic compounds present in the emulsion is lower than 80 : 1, preferably lower than 60: 1. [0007] The present invention allows the preparation of oil-in-water injectable emulsions with a concentration equal to or higher than 6 mg/ml, stable in time and easy to dilute, as it is usually done in therapy, to a final concentration comprised between 0.3 mg/ml and 1.2 mg/ml.
[0008] In the present invention it is possible to use any edible oil commercially available. Examples of edible oils are rapeseed oil, safflower oil, olive oil, soybean oil, corn oil, cottonseed oil, almond oil, peanut oil, sesame oil, coconut oil, palm oil, etc.. The preferred oil is soybean oil. The amount of oil used in the preparation of the emulsion is typically higher than 5% by weight, preferably higher than 8% by weight, most preferably higher than 10% by weight, even more preferably higher than 15% by weight.
[0009] With the term "phospholipid" it is intended a triester of glycerol with two fatty acids and one phosphate ion. Exemplary phospholipids useful in the present invention are phosphatidyl choline, lecithin (e.g. soybean lecithin and egg lecithin), phosphatidylethanolamine, phosphatidylglycerol. Any type of lecithin can be used in the preparation of the oil-in-water emulsion of the present invention. A preferred phospholipid for use in the present invention is soybean lecithin. The amount of phospholipid can vary in a broad range, it is however preferably comprised between 0.5 and 10 % by weight, most preferably between 1 and 5% by weight.
[0010] A viscosity improver is used in the preparation of the formulation. With viscosity improver it is intended a compound which is able to increase viscosity in the emulsion. In this way, the emulsion is more stable. Amongst the possible viscosity improver we can cite glycerol, dimethyl sulfoxide (DMSO), propylene glycol and glycofurol. Glycerol is the preferred viscosity improver. The amount of viscosity improver can vary in a broad range, and preferably its concentration in the emulsion can vary from 1 to 25% by weight, preferably from 1.5 to 15% by weight, most preferably from 2 to 10 % by weight.
[0011] The formulation according to the present invention is preferably prepared according to the following process: a) Solubilization of the phospholipid and taxoid in oil, optionally with the aid of ethanol; b) Separately, solubilization of the viscosity improver in water; c) The solution of a) is sterilized by filtration with a PTFE hydrophobic membrane with a size of 0.22 micron, in sterile room (Class A); if ethanol is present, it is stripped under vacuum; d) In another vessel, the water solution of b) is sterilized by filtration with a PTFE hydrophilic membrane with a size of 0.22 micron, in sterile room (Class A). e) The sterile solution of d) is added to the sterile solution of c) at a temperature of 40-50 0C under vigorous stirring; f) The obtained emulsion is homogenized under pressure or by the sonication until the size of the oily droplets is lower than 1 micron; g) The taxoid emulsion is bottled sterilely.
[0012] In another preferred embodiment the oil emulsion is obtained according to the following process: a) Solubilization of the phospholipid in oil; b) The solution of a) is sterilized by filtration with a PTFE hydrophobic membrane with a size of 0.22 micron, in sterile room (Class A); c) To the sterile solution of b) a sterile taxoid is added; d) Solubilization of the viscosity improver in water; e) In another vessel, the water solution of d) is sterilized by filtration with a PTFE hydrophilic membrane with a size of 0.22 micron, in sterile room (Class A). f) The sterile solution of e) is added to the sterile solution of c) at a temperature of 40-50 0C under vigorous stirring; g) The obtained emulsion is homogenized under pressure or by sonication until the size of the oily droplets is lower than 1 micron; h) The taxoid emulsion is sterilely filled into glass vials.
[0013] The formulation according to the present invention presents several advantages in view of the formulations of the prior art:
1) Absence of dangerous ingredients, e.g. surfactants.
2) Easiness of use for paramedicals. 3) Absence of interaction of the emulsion with the plastic used for the intravenous administration.
4) Easiness of the production process, which does not require a specific apparatus, but it follows standard process procedures for sterile products.
Examples
Example 1
[0014] 600 mg of Paclitaxel and 2.4 g of Soybean lecithin (Epikuron 200 ™) were dissolved in 20 g of Soybean oil (purified) and 10 ml of absolute ethanol at a temperature comprised between 40 and 50 0C, under mild stirring. The solution was sterilized by filtration with a PTFE hydrophobic membrane with a size of 0.22 micron, in sterile room (Class A). Ethanol was removed under vacuum at 40-500C. In another vessel, 4.5 g of glycerol were dissolved in 65 ml of water for injectable solutions. The solution was sterilized by filtration with a PTFE hydrophilic membrane with a size of 0.22 micron, in sterile room (Class A). The solution of Paclitaxel was placed under vigorous stirring and the sterile water-glycerol solution was added. The emulsion was left under vigorous stirring at a temperature comprised between 25 and 35 0C, giving rise to an emulsion. The emulsion was homogenized by using a high pressure homogeniser (850-900 bar) or by sonication. The homogenisation is repeated until all oil droplets have a size lower than 1 micron. Sterile water is added in order to bring the final volume to 100 ml. The concentration of Paclitaxel was 6 mg/ml (which corresponds to the concentration of the commercially available Paclitaxel). The pH of the emulsion was checked to verify that it was comprised between 4.0 and 7.5. The emulsion was kept under stirring for 20' and was then sterilely filled in glass vials of 5 ml, 16.7 ml, 25 ml and 50 ml.
Example 2
[0015] 2.4 g of Soybean lecithin (Epikuron 200 ™) were dissolved in 20 g of Soybean oil (purified) at a temperature comprised between 85 and 90 0C, under mild stirring. The solution was sterilized by filtration with a PTFE hydrophobic membrane with a size of 0.22 micron at a temperature of 60 0C, in sterile room (Class A). In accordance with the European Pharmacopeia GMP Annex 1, update of September 2003, 600 mg of sterile powder of Paclitaxel were introduced in a sterile room (Class A) and solubilized at a temperature comprised between 90 and 100 0C in the oily phase. In another vessel, 4.5 g of glycerol were dissolved in 65 ml of water for injectable solutions. The solution was sterilized by filtration with a PTFE hydrophilic membrane with a size of 0.22 micron, in sterile room (Class A). The solution of Paclitaxel was placed under vigorous stirring at a temperature of 95-1000C and the sterile water-glycerol solution was added. The emulsion was left under vigorous stirring at a temperature comprised between 25 and 35 0C, giving rise to an emulsion. The emulsion was homogenized by using either a high pressure homogeniser (850-900 bar) or sonication. The homogenisation is repeated until all oil droplets have a size lower than 1 micron. Sterile water is added in order to bring the final volume to 100 ml. The concentration of Paclitaxel was 6 mg/ml (which corresponds to the concentration of the commercially available Paclitaxel). The pH of the emulsion was checked to verify that it was comprised between 4.0 and 7.5. The emulsion was kept under stirring for 20' and was then sterilely filled into glass vials of 5 ml, 16.7 ml, 25 ml and 50 ml.
Comparative Example 3
[0016] A Paclitaxel solution similar to the commercial product was prepared by dissolving Paclitaxel in a 50/50 mixture of Cremophor EL ™ and ethanol. The concentration of Paclitaxel was 12.5 mg/ml.
Example 4 In vivo effect of the formulation of the invention.
[0017] The formulation of example 2 was used in the treatment of mice and compared with the activity of the formulation of comparative example 3. The formulations were diluted immediately before use to a concentration of Paclitaxel of 2.5 mg/ml by using physiologic solution. [0018] 56 female nude mice purchased from Harlan Italy approximately 7 weeks old were injected with 1OxIO6 human ovaric tumor cells A2780. When the tumoral masses reached the weight of 150-200 mg, the mice were randomly divided into four groups treated in the following way: a) blank of example 2, b) example 2, 25 mg/kg, c) blank of comparative example 3, d) comparative example 3, 25 mg/kg.
[0019] All mice were treated 3 times after 9, 13 and 17 days from the date of injection of the cells. Tumoral growth was evaluated by measuring the size (length D and width d) with a calibre. The volume V of the tumor was calculated using the formula V = (d2xD)/2 and the weight was calculated assuming the density of the tumor equal to 1 g/cm3. Mice were sacrificed when reaching a tumoral mass of about 2 g. Figure 1 reports the results.
[0020] Each point in the graph is the average value from 10 mice. The arrows indicate the day in which the treatment took place.

Claims

Claims
1. Pharmaceutical injectable formulation of taxoids wherein the taxoid is present in an oil-in-water emulsion comprising an edible oil, a phospholipid and a viscosity improver, and wherein the weight ratio of oil to taxoid is lower to or equal than 50: 1.
2. Formulation according to claim 1 wherein the taxoid is selected from Paclitaxel and Docetaxel.
3. Formulation according to claims 1-2 wherein the viscosity improver is glycerol.
4. Formulation according to any of the preceding claims wherein the weight ratio of oil to taxoid is lower to or equal than 40: 1.
5. Formulation according to claims 1-4 wherein the phospholipid is selected from phosphatidyl choline, egg lecithin and soybean lecithin.
6. Formulation according to claims 1-5 wherein the amount of phospholipid is comprised between 0.5 and 10% by weight, preferably between 1 and 5% by weight.
7. Formulation according to claims 1-6 wherein the weight ratio of Taxoid versus the sum of all organic compounds present in the emulsion is lower than 80: 1, preferably lower than 60 : 1.
8. Formulation according to claims 1-7 wherein the amount of viscosity improver is comprised between 1 and 25% by weight.
9. Process for the preparation of the pharmaceutical injectable formulations of claims 1-8 according to the following process: a) Solubilization of the phospholipid and taxoid in oil, optionally with the aid of ethanol; b) Separately, solubilization of the viscosity improver in water; c) The solution of a) is sterilized by filtration with a PTFE hydrophobic membrane with a size of 0.22 micron, in sterile room (Class A); if ethanol is present, it is stripped under vacuum; d) In another vessel, the water solution of b) is sterilized by filtration with a PTFE hydrophilic membrane with a size of 0.22 micron, in sterile room (Class A). e) The sterile solution of d) is added to the sterile solution of c) at a temperature of 40-50 0C under vigorous stirring; f) The obtained emulsion is homogenized under pressure or by the sonication until the size of the oily droplets is lower than 1 micron; g) The taxoid emulsion is sterilely filled into glass vials
10. Process for the preparation of the pharmaceutical injectable formulations of claims 1-8 according to the following process: a) Solubilization of the phospholipid in oil; b) The solution of a) is sterilized by filtration with a PTFE hydrophobic membrane with a size of 0.22 micron, in sterile room (Class A); c) To the sterile solution of b) a sterile taxoid is added; d) Solubilization of the viscosity improver in water; e) In another vessel, the water solution of d) is sterilized by filtration with a PTFE hydrophilic membrane with a size of 0.22 micron, in sterile room (Class A). f) The sterile solution of e) is added to the sterile solution of c) at a temperature of 40-50 0C under vigorous stirring; g) The obtained emulsion is homogenized under pressure until the size of the oily droplets is lower than 1 micron; h) The taxoid emulsion is sterilely filled into glass vials.
EP08786582A 2007-08-14 2008-07-29 Injectable pharmaceutical formulation of taxoids Withdrawn EP2187867A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP08786582A EP2187867A1 (en) 2007-08-14 2008-07-29 Injectable pharmaceutical formulation of taxoids

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP07114341A EP2025333A1 (en) 2007-08-14 2007-08-14 Injectable pharmaceutical formulation of taxoids
PCT/EP2008/059946 WO2009021840A1 (en) 2007-08-14 2008-07-29 Injectable pharmaceutical formulation of taxoids
EP08786582A EP2187867A1 (en) 2007-08-14 2008-07-29 Injectable pharmaceutical formulation of taxoids

Publications (1)

Publication Number Publication Date
EP2187867A1 true EP2187867A1 (en) 2010-05-26

Family

ID=38962891

Family Applications (2)

Application Number Title Priority Date Filing Date
EP07114341A Withdrawn EP2025333A1 (en) 2007-08-14 2007-08-14 Injectable pharmaceutical formulation of taxoids
EP08786582A Withdrawn EP2187867A1 (en) 2007-08-14 2008-07-29 Injectable pharmaceutical formulation of taxoids

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP07114341A Withdrawn EP2025333A1 (en) 2007-08-14 2007-08-14 Injectable pharmaceutical formulation of taxoids

Country Status (2)

Country Link
EP (2) EP2025333A1 (en)
WO (1) WO2009021840A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011015226A1 (en) * 2009-08-03 2011-02-10 Pharmatex Italia Srl Process for the preparation of sterile powdered pharmaceutical compounds in the form of micro and nanoparticles
WO2012094020A1 (en) * 2010-01-07 2012-07-12 Innopharma, Inc. Methods and compositions for delivery of taxanes in stable oil-in-water emulsions
BR112019006949A2 (en) * 2016-10-05 2019-07-02 Tohoku University effective drug for lymphogen drug delivery method

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5407683A (en) * 1990-06-01 1995-04-18 Research Corporation Technologies, Inc. Pharmaceutical solutions and emulsions containing taxol
US5616330A (en) * 1994-07-19 1997-04-01 Hemagen/Pfc Stable oil-in-water emulsions incorporating a taxine (taxol) and method of making same
WO1998017242A1 (en) * 1996-10-24 1998-04-30 Board Of Trustees Of The University Of Illinois Unique peptides for targeting fibronectin-enriched surfaces and a method for their delivery in the treatment of metastatic cancer
DE19843968A1 (en) * 1998-09-24 2000-04-13 Hans Dietl Taxane-containing pharmaceutical preparation for intravenous administration and process for their preparation
US6676963B1 (en) * 2000-10-27 2004-01-13 Barnes-Jewish Hospital Ligand-targeted emulsions carrying bioactive agents
US8557861B2 (en) * 2004-09-28 2013-10-15 Mast Therapeutics, Inc. Low oil emulsion compositions for delivering taxoids and other insoluble drugs
US20080128314A1 (en) * 2005-03-14 2008-06-05 Koichi Takeda Pharmaceutical Composition Containing Hardly Water Soluble Medicament

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2009021840A1 *

Also Published As

Publication number Publication date
EP2025333A1 (en) 2009-02-18
WO2009021840A1 (en) 2009-02-19

Similar Documents

Publication Publication Date Title
US9339553B2 (en) Liquid compositions of insoluble drugs and preparation methods thereof
US9572818B2 (en) Pharmaceutical emulsion compositions comprising progestogen
US20110275705A1 (en) Stable injectable oil-in-water docetaxel nanoemulsion
KR101391020B1 (en) Pharmaceutical composition containing hardly water soluble medicament
KR20120027298A (en) Preparation method of drug loaded emulsion
KR20160146669A (en) Compositions of nanoemulsion delivery systems
BRPI0707421A2 (en) stabilized vitamin E succinate pharmaceutical compositions, methods for their preparation and use
JP5847722B2 (en) Taxane pharmaceutical solution containing pH regulator and method for producing the same
WO2011113301A1 (en) Self-emulsifying formulation of taxanes and preparation method thereof
WO2008042841A2 (en) Docetaxel compositions
EP2025333A1 (en) Injectable pharmaceutical formulation of taxoids
EP4117632A1 (en) Sunflower phospholipid composition containing phosphatidylcholine
ES2223571T3 (en) EMULSION OF PARENTERAL CISPLATIN.
US11571385B2 (en) Self-emulsifiable composition, production method therefor, nanoemulsion, and production method therefor
CN102228431A (en) Self-emulsified medicinal composition for taxane compounds
EP1987813A1 (en) Injectable pharmaceutical formulation of taxoids in stable liposomes

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20100216

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA MK RS

17Q First examination report despatched

Effective date: 20100701

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20130611