Nanodispersion

a technology of nano-dispersion and nitrate, which is applied in the field of nano-dispersion, can solve the problems of poor oral bioavailability or formulation, poor solubility, and limited patient administration of drugs

Inactive Publication Date: 2014-01-30
SUN PHARMA INDS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The formulation is stable for extended periods, reduces toxicity, and achieves a higher LD50 value, ensuring safe and effective intravenous administration with minimal aggregation or crystallization, enhancing therapeutic index and reducing side effects.

Problems solved by technology

Such drugs provide challenges in terms of having poor oral bioavailability or in terms of formulating them for drug delivery especially through the intravenous route.
The taxane derivatives exhibit very poor solubility in water and in most pharmaceutically acceptable solvents thus limiting their administration to patients.
However, use of solubilizer like Cremophor TM EL in large amounts lead to various adverse effects such as serious or fatal hypersensitive and hypertensive reactions, bradyarrythmia, anemia, neutropenia and / or peripheral neuropathy.
If therapeutically effective amount of drug is delivered through such compositions, it will be associated with entry of excessive amounts of ethanol, non-aqueous solvents or solubilizers in the body.
The main solubilizer used in the formulation polyethoxylated sorbitol oleic polyester which is an ethylene oxide addition product of palm olefin-derived oleic acid has an inherent property of getting solidified at temperatures below 10° C., making it unsuitable for solubilizing paclitaxel when used alone.
The application does not disclose the efficacy and toxicity profile of the formulations.
Also the stability of the formulation solutions after diluting with infusion diluent is of very short period of about 4 to 6 hours which can limit its administration efficiency.
Thus it is evident from the prior art that the major problem associated with formulating a taxane composition is hydrophobicity of taxanes, which(a) makes it difficult to formulate a composition which contains solubilized form of the drug and which is stable, without any substantial aggregation or crystallization of the drug or change in appearance of the formulation till a desired period of time(b) necessitates the use of large amount of solubilizers, phospholipids and surfactants.
Also, toxicity studies of TAXOL (marketed solution of paclitaxel in Cremophor and Alcohol) shows a LD50 value of 7.5-12.0 mg / kg as disclosed in U.S. Pat. No. 6,753,006 which is low, indicating that the drug administered in the form of solution has very low therapeutic index and even a moderate dose may show serious side effects and toxic reactions.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1-5

[0085]Nanodispersions of the present invention are described in Table 1 below.

TABLE 1S.Quantity (% w / v)No.IngredientsExample 1Example 2Example 3Example 4Example 51Paclitaxel0.150.150.150.150.152Cholesteryl sulfate0.010.010.010.020.043Caprylic acid0.01250.01250.01250.0250.054Polyvinylpyrrolidone (PVP) K-300.1250.06250.03250.1250.1255Ethanol0.148250.148250.148250.148250.148256PEG-4002.02.02.02.02.07Dextrose (5%)qs. 100.0qs. 100.0qs. 100.0qs. 100.0qs. 100.0

[0086]Procedure:[0087]Drug, cholesteryl sulfate, caprylic acid and PVP K-30 were weighed accurately in a vial.[0088]Contents were dissolved in the required quantity of absolute ethanol and PEG-400 with stirring and by heating at 45° C. to obtain a solution.[0089]The solution was filtered through 0.2μ PVDF membrane filter.[0090]Dextrose solution (5%) was then added slowly to the vial containing the solution of drug and shaken gently to get a transparent to translucent nanodispersion.[0091]pH of the nanodispersion is checked by using p...

example 6-7

[0099]Pharmaceutical compositions of the present invention as concentrated solution of taxane derivative are described in Table 3 below.

TABLE 3Quantity (% w / w)EXAMPLE 6Sr.(Drug conc:EXAMPLE 7No.Ingredients60 mg / gm)(Drug conc: 100 mg / gm)1Paclitaxel6.010.02Cholesteryl sulfate0.4000.663Caprylic acid0.5000.8304Polyvinylpyrrolidone5.04.16(PVP) K-305Ethanol6.010.06PEG-400Qs to 100.0Qs to 100.0

[0100]Procedure:[0101]Drug, cholesteryl sulfate, caprylic acid and PVP K-30 were weighed accurately in a glass vessel.[0102]Contents were dissolved in the required quantity of absolute ethanol and PEG-400 with stirring and by heating at 45° C. to obtain a concentrated drug solution.[0103]The solution was filtered through 0.2μ PVDF membrane filter.[0104]The solution of example-6 was filled in vials (1 gm per vials containing 60 mg drug) and charged for stability.

[0105]Stability samples were analyzed in the form of nanodispersion. Dextrose solution (5% w / v) (40 ml) was slowly added to the vial containi...

example 8

[0107]Pharmaceutical compositions of the invention using PVP K-12 are described in Table 5 below. The procedure for the preparation of nanodispersion is same as in example 1-7.

TABLE 5S. No.IngredientsQuantity (% w / v)1Paclitaxel0.152Cholesteryl sulfate0.013Caprylic acid0.01254Polyvinylpyrrolidone (PVP) K-120.1255Ethanol0.148256PEG-4002.07Dextrose (5%)qs. 100.0

[0108]The visual appearance, pH and the particle size of the compositions were observed and are summarized in table 6 below.

TABLE 6ObservationsAppearanceInitialAlmost transparent to translucent dispersion24 hours at RTAlmost transparent to translucent dispersionpH4.0Particle Size (nm)Initial164 1 h169 3 h179 5 h17724 h177RT: room temperature

[0109]It can be seen that the compositions of the present invention are physically stable, with no substantial aggregation or change in appearance of the formulation on storage for 24 hours at room temperature.

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Abstract

The present invention provides a nanodispersion comprising nanoparticles having a mean size less than 300 nm dispersed in a vehicle comprising a water miscible solvent and water, said nanoparticles comprising one or more taxane derivative, a polymer and a surfactant comprising a mixture of fatty acids or its salts and sterol or its derivatives or its salts.

Description

[0001]The present invention relates to a ‘nanodispersion’ of a taxane derivative and process for its preparation.BACKGROUND OF THE INVENTION[0002]There are number of pharmaceutical drugs that are poorly soluble or insoluble in aqueous solutions. Such drugs provide challenges in terms of having poor oral bioavailability or in terms of formulating them for drug delivery especially through the intravenous route. If a drug is intravenously administered, particles must be small enough to safely pass through capillaries without causing emboli. For intravenous administration, it is recognized as safe to administer drugs in the form of solution, emulsion, liposomes, nanodispersions and the like. Another requirement that should be met while formulating a drug delivery system especially for hydrophobic drugs is that the formulation should be physically stable with no substantial aggregation or crystallization of the drug or change in appearance of the formulation on storage at room temperatur...

Claims

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Application Information

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Patent Type & AuthorityApplications(United States)
IPC IPC(8): A61K9/10A61K9/08A61K9/14A61K31/337
CPCA61K9/10A61K9/146A61K9/08A61K31/337A61K9/1075A61K9/5138A61K9/5146A61P35/00
InventorKHOPADE, AJAY JAYSINGHBHOWMICK, SUBHAS BALARAMARULSUDAR, NATARAJAN
OwnerSUN PHARMA INDS