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Parenteral formulations of gemcitabine derivatives

A technology of gemcitabine and its derivatives, applied in the field of pharmaceutical composition and its preparation

Inactive Publication Date: 2012-10-17
CLAVIS PHARMA ASA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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This represents a further challenge for both formulation and manufacturing process parameters

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  • Parenteral formulations of gemcitabine derivatives
  • Parenteral formulations of gemcitabine derivatives
  • Parenteral formulations of gemcitabine derivatives

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preparation example Construction

[0057] 6. Preparation of preparations

[0058] In one embodiment of the invention, the composition of the excipients, the ratio of drug to lipid and the method of preparation are selected to favor the liposomal structure. In a particularly preferred embodiment, the parameters are chosen to favor micellar nanoparticles or a combination of micelles and liposomes.

[0059] Some of the excipients of the pharmaceutical composition are selected to dissolve or increase the solubility of the compound of formula (I). In one embodiment, the excipients can be removed from the final product. In a preferred embodiment, the excipient is ethanol and is mostly removed from the final product.

[0060] The pharmaceutical compositions of the present invention are solid, semi-solid or liquid, preferably in liquid form, and may be presented in discrete units such as vials, liquid bags and the like. The pharmaceutical form of the final composition is a nanoscale suspension or dispersion of lip...

Embodiment 1

[0092] Gemcitabine-5'-elipoleate, egg phosphatidylcholine (EPC) and egg phosphatidylglycerol (EPG) in a molar ratio of 5.8:25:1 (to obtain a ratio of active ingredient to lipid of 1:4.4) Add to ethanol at a weight ratio of 1:7.2. The mixture was stirred with heating to 50 °C until all solid material dissolved.

[0093] This ethanol solution was then poured into glycerol / water solution (2.6% w / w) at 250 ml / min with stirring. The weight ratio of the ethanol solution to the glycerin solution is 1:7.6. The bulk solution was concentrated by tangential flow filtration, and the concentrated bulk was passed through a homogenizer 6 times at 15-20°C. The resulting product was further concentrated by tangential flow filtration to a final batch volume of 20 L and a final concentration of gemcitabine-5'-elaidate of 15 mg / mL. Residual ethanol was then removed by a diafiltration wash step, and the final product was sterile filtered and aseptically filled into sterile vials, purged wi...

Embodiment 2

[0095] Gemcitabine-5'-elipate, egg phosphatidylcholine (EPC) and egg phosphatidylglycerol (EPG) were mixed in a molar ratio of 13.5:25:1 (to obtain a ratio of active ingredient to lipid of 1:1.9) Add to ethanol at a weight ratio of 1:6. The mixture was stirred until all solid material was dissolved.

[0096] This ethanol solution was then poured into glycerol / water solution (2.6% w / w) with stirring. The weight ratio of the ethanol solution to the glycerol solution is 1:8.7. The bulk solution was homogenized twice and then concentrated by tangential flow filtration. The concentrated bulk was then passed through a homogenizer 4 times. The resulting product was further concentrated by tangential flow filtration to a final batch volume and a gemcitabine-5'-elaidate concentration of 35 mg / mL. Residual ethanol was then removed by a diafiltration wash step and the final product was sterile filtered and filled into sterile vials, purged with nitrogen and sealed. The measured...

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Abstract

The present invention relates to parenteral formulations for certain long chain saturated and monounsaturated fatty acid derivatives of 2',2'-difluorodeoxycytidine (Gemcitabine). In particular, the present invention relates to a parenteral pharmaceutical composition and a method of the preparation thereof, in order to accommodate therapeutically effective doses of the said derivatives ameliorating compliance in the treatment of cancer. The composition has an average particle size in the range of 2.5-30 nm and typically contains a phospholipid. A preferred active ingredient is gemcitabine-5'-elaidic acid ester.

Description

field of invention [0001] The present invention relates to pharmaceutical compositions comprising certain long chain saturated and monounsaturated fatty acid derivatives of 2',2'-difluorodeoxycytidine (gemcitabine) as active ingredients. In particular, the present invention relates to pharmaceutical compositions and methods for their preparation, suitable for parenteral administration of therapeutically effective doses of said derivatives to improve compliance with cancer therapy. Background of the invention [0002] The known cytostatic compound gemcitabine, marketed under the trade name Gemzar by Eli Lilly & Co., has the following formula: [0003] [0004] The active ingredient of the pharmaceutical composition of the present invention comprises the gemcitabine derivative of formula I: [0005] [0006] where R 1 , R 2 and R 3 independently selected from hydrogen and C 18 - and C 20 - saturated and monounsaturated acyl with the proviso that R 1 , R 2 and R ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K31/7068A61K9/133A61P35/00C07H19/06
CPCA61K9/0019A61K31/7068A61K47/24A61K9/1075A61K9/127C07H19/09C07H19/06A61P1/16A61P1/18A61P11/00A61P13/10A61P15/00A61P19/00A61P21/00A61P25/00A61P35/00A61P35/02
Inventor S·阿赫拉比F·米伦O·H·埃里克森
Owner CLAVIS PHARMA ASA
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