WO2005017079A1 - Procede de purification de solvants non ioniques pour preparations pharmaceutiques injectables stabilisees - Google Patents

Procede de purification de solvants non ioniques pour preparations pharmaceutiques injectables stabilisees Download PDF

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Publication number
WO2005017079A1
WO2005017079A1 PCT/US2003/023243 US0323243W WO2005017079A1 WO 2005017079 A1 WO2005017079 A1 WO 2005017079A1 US 0323243 W US0323243 W US 0323243W WO 2005017079 A1 WO2005017079 A1 WO 2005017079A1
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WO
WIPO (PCT)
Prior art keywords
paclitaxel
solvent
castor oil
process according
alcohol
Prior art date
Application number
PCT/US2003/023243
Other languages
English (en)
Inventor
Anand C. Burman
Rama Mukherjee
Dinesh Kumar
Dhiraj Khattar
Praveen Khullar
Ps Srinivasan
Rajesh Srivastava
Mukesh Kumar
Original Assignee
Dabur Research Foundation
Cord, Janet, I.
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 Dabur Research Foundation, Cord, Janet, I. filed Critical Dabur Research Foundation
Priority to CA002532110A priority Critical patent/CA2532110A1/fr
Priority to AU2003256786A priority patent/AU2003256786B2/en
Priority to EP03818174A priority patent/EP1648988A1/fr
Priority to PCT/US2003/023243 priority patent/WO2005017079A1/fr
Publication of WO2005017079A1 publication Critical patent/WO2005017079A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/44—Oils, 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

Definitions

  • the present invention relates to a stabilized pharmaceutical composition in a solvent system and in particular a co-solvent system suitable for preparing a stabilized injection composition containing at least one pharmaceutical agent. More particularly, the present invention relates to stabilized compositions of anti cancer drugs.
  • An ideal solvent must typically have the following properties : 1. It must be capable of solubilizing a therapeutically effective amount of the active agent to produce an effective composition. 2. It must be compatible with the active agent. 3. It should be safe i.e.
  • Cremophor EL or ELP is a condensation product of castor oil and ethylene oxide sold by BASF. Although these co-solvent systems can be effective in solubilizing many compounds, they are not without their disadvantages.
  • a commonly used co-solvent system used for many pharmaceutical agents is a 50:50 mixture of ethanol and Cremophor ELP.
  • a potential problem associated with such solvents is that acids, salts or other ionic impurities, as well as residual water in the solvent or solvent system, even if within the acceptable limits, can catalyze the degradation of the pharmaceutical agent. For example, co-solvents of ethanol and Cremophor are known to result in particulates forming upon dilution with infusion solutions.
  • US Patent 5,504, 102 discloses that paclitaxel reacts with ethanol during storage and that the decomposition of paclitaxel is catalyzed by the carboxylate anions in the solvent. They also disclose that lowering the carboxylate concentration of the solvent produced a stabilizing effect on the pharmaceutical composition.
  • the composition in question being Taxol, prepared as an injection concentrate containing 6 mg/ml paclitaxel in 50:50 by volume ethanol and polyoxyethylated castor oil.
  • the pharmaceutical agents of interest are those having an ester linkage that can be cleaved by an alcohol in the presence of carboxylate anions.
  • the solvent is a co-solvent mixture of at least one solvent and a solubilizing agent.
  • the preferred solvent includes alcohol such as dehydrated ethanol.
  • the solubilizing agent in preferred embodiments is a polyoxyethylated castor oil such as that sold under the tradename Cremophor EL or Cremophor ELP by BASF.
  • the carboxylate anion content of the solvent is lowered by a number of methods.
  • the Cremophor EL or other solvent is passed through a standard chromatography column of aluminum oxide which adsorbs the carboxylate anions as well as other impurities to reduce the carboxylate anion content of the solvent.
  • the solvent is treated by the addition of an acid in a stabilizing amount to reduce the carboxylate anion content to a sufficiently low level to substantially prevent catalyzed degradation of the pharmaceutical compound.
  • Nikolayev et al in US Patent No. 5,925,776 disclose a method of reducing the cation content in the polyethoxylated castor oil (cremophor). This is achieved by pre-treating the polyethoxylated castor oil with a strong cation exchange resin. The low cationic content polyethoxylated castor oil of the invention is then utilized to prepare formulations of various agents which are found to be sensitive to the previously commercially available polyethoxylated castor oil (cremophor EL).
  • Anevski et al in US Patent No. 6,388,112 disclose a process for purifying a non-ionic surfactant or solvent capable of dispersing and solubilizing a pharmaceutical compound. In the process, a solution of solvent and alcohol is brought in contact with an activated carbon column and an ion exchange resin column. The process is particularly adapted to the purification of polyethoxylated castor oils.
  • the purified solvent is useful in the preparation of pharmaceutical compositions having enhanced shelf life, such as for use with paclitaxel.
  • Carver et al in US Patent No. 6,306,894 disclose a pharmaceutical formulation of paclitaxel and polyethoxylated castor oil wherein the formulation is relatively acidified to a pH of less than 8.1 and preferably within a pH range of 5 to 7, inclusively. Ethanol is optionally included in the formulation.
  • a formulation method is also disclosed and includes the step of mixing an acid with a carrier material, such as polyethoxylated castor oil, to form a carrier solution after which paclitaxel is added in an amount such that the resulting pH is less than 8J and preferably in a pH range of 5 to 7.
  • Ethanol may optionally be slurried with the paclitaxel before mixing with the carrier solution.
  • acidifying agents a preferred one being anhydrous citric acid, are described. Acids in the form of powders, for example citric acid, have been preferred over those which contain water, for example sulfuric acid.
  • the most preferred acid for use in accordance with the invention disclosed in US Patent 6,306,894 is citric acid, but a wide range of acids may be used including : Citric acid-monohydrous, Citric acid-anhydrous, Citric acid-hydrous, Acetic acid, Formic acid, Ascorbic acid, Aspartic acid, Benzene sulphonic acid, Benzoic acid, Hydrochloric acid, Sulphuric acid, Phosphoric acid, Nitric acid, Tartaric acid, Diatrizoic acid, Glutamic acid, Lactic acid, Maleic acid, and Succinic acid.
  • Citric acid-monohydrous Citric acid-anhydrous
  • Citric acid-hydrous Citric acid-hydrous
  • Acetic acid Formic acid, Ascorbic acid, Aspartic acid, Benzene sulphonic acid, Benzoic acid, Hydrochloric acid, Sulphuric acid, Phosphoric acid, Nitric acid, Tartaric acid, Diatrizoic acid, Glutamic acid
  • 6,071,952 disclose a pharmaceutical composition with long term storage stability comprising a taxane or taxoid by incorporating an effective amount of an antioxidant.
  • Previous efforts to develop a shelf stable composition of some pharmaceutical compositions in various co-solvent systems have not been entirely successful.
  • a solvent or co-solvent system capable of being used for preparing stabilized compositions and, in particular, stabilized injection compositions containing a pharmaceutical agent.
  • the disadvantages and limitations of the previous injection composition and solvent systems are overcome by the present invention while providing a convenient and efficient method of producing a solvent and a method of stabilizing pharmaceutical compositions including compositions suitable for injection.
  • the present invention is primarily directed to a solvent suitable for producing a stabilized pharmaceutical composition and to a method of producing and stabilizing a pharmaceutical composition.
  • the invention is directed to a solvent suitable for preparing stabilized injection compositions containing at least one pharmaceutical agent. Accordingly, it is a primary aspect of the invention to provide a method of preparing a treated solvent which when used in a composition has a stabilizing effect on the composition and a method of preparing stabilized pharmaceutical compositions using the treated solvent.
  • the stabilized pharmaceutical compositions produced using the treated solvent of the invention have been shown to have a shelf life greater than the compositions produced from untreated solvent.
  • the solvent system of the invention is particularly suitable for use with pharmaceutical compounds that exhibit decomposition, which is catalyzed by the presence of ionic, metallic and oxidizing impurities.
  • the advantages of the invention are also attained by producing a stabilized pharmaceutical composition comprising at least one antineoplastic compound and a solvent system capable of solubilising the antineoplastic compound, the solvent system comprising a solubilizing amount of an alcohol such as absolute alcohol and a solubilizer such as polyoxyethylated castor oil having been purified to have an impurities content sufficiently low to substantially minimize degradation of the antineoplastic compound.
  • antineoplastic agents such as paclitaxel, teniposide, camptothecin and derivatives thereof.
  • the solvent system of the invention essentially comprises a purified non- ionic solvent
  • the solubilizing agent can be a condensation product of an alkylene oxide and a lipid or fatty acid.
  • the preferred solubilizing agent includes a polyoxyethylated castor oil such as that sold by M/s BASF under the tradename Cremophor EL or Cremophor ELP and an alcohol.
  • the polyoxyethylated castor oil is purified by a process of chromatography to reduce the water soluble ionic, metallic and oxidizing impurities to a sufficiently low concentration to minimize the decomposition of the pharmaceutical agent that is catalyzed by the presence of these impurities.
  • the content of impurities in the polyoxyethylated castor oil is lowered by reverse-phase chromatography using suitable mobile and stationary phases. Further advantages of the invention are attained by providing a method of stabilizing a pharmaceutical composition containing a pharmaceutical agent such as paclitaxel, teniposide, camptothecin and derivatives thereof, and a solvent containing absolute ethanol and a purified solubilizing agent as described above.
  • the invention provides a pharmaceutical stable formulation of paclitaxel made using a purified solvent.
  • the process involves purification of a non-ionic solvent such as polyethoxylated castor oil, preferably polyoxy-35-castor oil, more preferably cremophor such as Cremophor EL or Cremophor ELP using reverse-phase chromatography such that the content of ionic, metallic and oxidizing impurities of the cremophor is lowered.
  • a non-ionic solvent such as polyethoxylated castor oil, preferably polyoxy-35-castor oil, more preferably cremophor such as Cremophor EL or Cremophor ELP using reverse-phase chromatography such that the content of ionic, metallic and oxidizing impurities of the cremophor is lowered.
  • the process for purifying a non-ionic solvent comprising the steps of : (a) forming a solution of the non-ionic solvent in alcohol and water, with or without the aid of heating; (b) loading this solution on to a chromatography column packed with reverse phase silica (c) running the chromatograph using de-ionized water as the mobile phase to purify the solvent ; (d) running the chromatograph using an eluent to recover the purified solvent; and (e) evaporating the residual water and the eluent.
  • the de-ionized water is HPLC grade.
  • the aqueous fractions obtained from rum ⁇ ing the chromatograph using de-ionized water are not used and may be set aside or discarded.
  • the solvent is selected from polyethoxylated castor oil, polyoxy-35-castor oil, Cremophor EL or Cremophor ELP.
  • the alcohol is selected from methanol, ethanol, butanol, iso-propanol etc, more preferably ethanol and more preferably dehydrated ethanol.
  • the eluents may be selected from methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, tetrahydrofuran and other such solvents of similar polarities.
  • the preferred eluent is acetone. Combinations of eluents may be used.
  • the mobile phase is run for 1 to 50 minutes; preferably for 20 minutes.
  • the polyethoxylated castor oil is purified by loading it on a chromatography column packed with reverse-phase silica, preferably C-8 or C-18 and chromatographed using de-ionized water to remove or lower the concentration of water soluble impurities - both organic and inorganic.
  • the purified polyethoxylated castor oil is then recovered by eluting the column using an eluent, preferably acetone.
  • the de-ionized water is HPLC grade.
  • the weight ratio of polyethoxylated castor oil to alcohol is 10: 1.
  • the ratio of polyethoxylated castor oil to alcohol to water is 10 : 1 : 33 w/v/v.
  • the solvent purified by this method can be combined with antineoplastic compound to form a composition.
  • the compositions of this invention include an alcohol which may be added to the solvent before combining with the antineoplastic agent,t when the solvent is combined with the antineoplastic agent or after the solvent is combined with the antineoplastic agent.
  • the alcohol may be a dehydrated alcohol.
  • Compositions suitable for parenteral administration such as injection or infusion may be prepared by diluting the compositions with a suitable parenteral fluid prior to parenteral administration, injection or infusion. The following non-limiting example is intended to demonstrate the preferred embodiment of the invention.
  • Example - 1 This example was carried out to demonstrate the effect of purification of cremophor using reverse phase chromatography on the stability of Paclitaxel formulation.
  • 300 gm of Cremophor ELP (of M/s BASF) was diluted with about 30 ml of absolute ethanol and the mixture was then dissolved in one litre of HPLC grade de-ionized water pre-heated to 60°C with stirring to make uniform solution.
  • This cremophor solution was then loaded on to a chromatography column (15 cm x 30 cm) packed with reverse-phase silica, preferably C-8 or C-18, having an average particle size of 30 to 60 ⁇ .
  • Sample 4 was prepared as a control sample from unprocessed Cremophor ELP in a 50 : 50 v/v mixture of unprocessed Cremophor ELP and ethanol with paclitaxel in the amount of 6 mg/ml. The samples were then subjected to a stress temperature study at 50°C. The results obtained are summarized as below : Table -
  • the degradation products of paclitaxel include : Baccatin III, Ethyl Ester Side Chain of Paclitaxel , 10-Deacetyl Paclitaxel, 10- Deacetyl- 7- Epi-paclitaxel, and 7 Epi-paclitaxel.
  • purification of cremophor results in reduction of the pH of cremophor from about 5.70 to around 5J0.
  • Samples 1 to 3 prepared with purified cremophor are much, more stable in terms of degradation products of paclitaxel as compared to sample - 4.
  • cremophor ELP purified using the process of the invention improves the stability of paclitaxel formulation significantly as compared to the formulation made using untreated Cremophor ELP.

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  • 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)
  • Dermatology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique stabilisée contenant un médicament anticancéreux et une huile de ricin polyéthoxylée (crémophore) de type solvant contenant également un solubilisant de type alcool déshydraté pouvant être administré à un humain. Les compositions préparées à base de cette huile de ricin polyéthoxylée purifiée améliorent la stabilité du paclitaxel contenu dans ces compositions.
PCT/US2003/023243 2003-07-24 2003-07-24 Procede de purification de solvants non ioniques pour preparations pharmaceutiques injectables stabilisees WO2005017079A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002532110A CA2532110A1 (fr) 2003-07-24 2003-07-24 Procede de purification de solvants non ioniques pour preparations pharmaceutiques injectables stabilisees
AU2003256786A AU2003256786B2 (en) 2003-07-24 2003-07-24 Process for the purification of non-ionic solvents for stabilized injectable pharmaceutical formulations
EP03818174A EP1648988A1 (fr) 2003-07-24 2003-07-24 Procede de purification de solvants non ioniques pour preparations pharmaceutiques injectables stabilisees
PCT/US2003/023243 WO2005017079A1 (fr) 2003-07-24 2003-07-24 Procede de purification de solvants non ioniques pour preparations pharmaceutiques injectables stabilisees

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2003/023243 WO2005017079A1 (fr) 2003-07-24 2003-07-24 Procede de purification de solvants non ioniques pour preparations pharmaceutiques injectables stabilisees

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WO2005017079A1 true WO2005017079A1 (fr) 2005-02-24

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EP (1) EP1648988A1 (fr)
AU (1) AU2003256786B2 (fr)
CA (1) CA2532110A1 (fr)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8802095B2 (en) 2007-01-26 2014-08-12 Durect Corporation Injectable, non-aqueous suspension with high concentration of therapeutic agent
CN112778513A (zh) * 2020-12-30 2021-05-11 江苏优仿医药科技有限公司 一种聚氧乙烯蓖麻油的精制方法及其应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5504102A (en) * 1993-09-29 1996-04-02 Bristol-Myers Squibb Company Stabilized pharmaceutical composition and stabilizing solvent
WO1998057630A1 (fr) * 1997-06-13 1998-12-23 Laboratoires Thissen (L.T.B.) Forme pharmaceutique pour l'administration de paclitaxel, procede de preparation d'une composition de paclitaxel prete a l'emploi et utilisation de cette composition
WO2000023070A1 (fr) * 1998-10-20 2000-04-27 Ben Venue Laboratories, Inc. Procede de purification de solvants s'utilisant pour la preparation de compositions pharmaceutiques
WO2001052838A1 (fr) * 2000-01-20 2001-07-26 Baker Norton Pharmaceuticals, Inc. Purification d'huiles de ricin polyoxyethylees avec du charbon active et formulations pharmaceutiques correspondantes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5504102A (en) * 1993-09-29 1996-04-02 Bristol-Myers Squibb Company Stabilized pharmaceutical composition and stabilizing solvent
WO1998057630A1 (fr) * 1997-06-13 1998-12-23 Laboratoires Thissen (L.T.B.) Forme pharmaceutique pour l'administration de paclitaxel, procede de preparation d'une composition de paclitaxel prete a l'emploi et utilisation de cette composition
WO2000023070A1 (fr) * 1998-10-20 2000-04-27 Ben Venue Laboratories, Inc. Procede de purification de solvants s'utilisant pour la preparation de compositions pharmaceutiques
WO2001052838A1 (fr) * 2000-01-20 2001-07-26 Baker Norton Pharmaceuticals, Inc. Purification d'huiles de ricin polyoxyethylees avec du charbon active et formulations pharmaceutiques correspondantes

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8802095B2 (en) 2007-01-26 2014-08-12 Durect Corporation Injectable, non-aqueous suspension with high concentration of therapeutic agent
CN112778513A (zh) * 2020-12-30 2021-05-11 江苏优仿医药科技有限公司 一种聚氧乙烯蓖麻油的精制方法及其应用

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Publication number Publication date
EP1648988A1 (fr) 2006-04-26
AU2003256786B2 (en) 2010-01-07
CA2532110A1 (fr) 2005-02-24
AU2003256786A1 (en) 2005-03-07

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