Stabilized formulation for oral administration of therapeutic agents and related methods

a technology of therapeutic agents and formulations, applied in the direction of antiparasitic agents, biocide, drug compositions, etc., can solve the problems of limited therapeutic arsenals, infusion-related side effects, and severe infection of the visceral reticuloendothelial system

Inactive Publication Date: 2014-08-14
THE UNIV OF BRITISH COLUMBIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The formulations provide improved bioavailability, thermal stability, and reduced renal toxicity, enabling effective oral administration of amphotericin B for treating visceral leishmaniasis and other infections, expanding treatment access and improving patient compliance.

Problems solved by technology

Each year in the Indian subcontinent alone, over 500,000 individuals play host to Leishmania donovani, an insidious parasite that invades macrophages, rapidly infiltrates the vital organs and ultimately leads to severe infection of the visceral reticuloendothelial system.
The therapeutic arsenal against Leishmania is limited to a small number of parenterally administered agents, with daily injections of pentavalent antimony compound.
However, drug therapy involves IV administration over 30-40 days and is associated with infusion-related side-effects (fever, chills, bone pain, thrombophlebitis).
The dose-limiting toxicity, which may even affect the ability to achieve a cure, is renal impairment.
In addition, due to the prohibitive cost and difficult route of drug administration, amphotericin B is failing to reach many patients.
While effective, the limitations of these parenteral formulations of amphotericin B are the safety issues associated with administration (infection of the indwelling catheter, patient chills and shaking due to RBC haemolysis, dose-dependent renal toxicity), feasibility of administration of parenteral products in remote locations and high drug cost.
However, the bioavailability of AmpB is negligible due to low aqueous solubility and instability at the low pH found in gastric fluid.
Such limitations also apply to a variety of other therapeutic agents for which oral formulations are desirable.

Method used

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  • Stabilized formulation for oral administration of therapeutic agents and related methods
  • Stabilized formulation for oral administration of therapeutic agents and related methods
  • Stabilized formulation for oral administration of therapeutic agents and related methods

Examples

Experimental program
Comparison scheme
Effect test

example 1

The Preparation of Representative Amphotericin B Formulations

[0215]In this example, the preparation of representative amphotericin formulations of the invention are described.

[0216]The preparation of two AmpB / TPGS formulations (AmpB / Peceol:Gelucire 44-14 (50:50 and 60:40)+5% v / v vitamin E-TPGS) are described.

[0217]Concurrent to making the AmpB in 50:50 and 60:40 Peceol / Gelucire 44-14+5% v / v vitamin E-TPGS vehicles, a single preparation each of 50:50 and 60:40 Peceol / Gelucire 44-14+5% v / v vitamin E-TPGS vehicles without AmpB were prepared.

[0218]Two formulations of the AmpB in 50:50 Peceol / Gelucire 44-14+5% v / v vitamin E-TPGS were prepared. For each preparation, 100 mg of AmpB (80%, Sigma) was measured into a 100 mL foil-wrapped round-bottomed flask. To this was added 50 mL of 100% ethanol (EtOH). The flask was attached to a rotary-evaporator and mixed for 30 min with rotation while incubated in a water bath at 48° C. Peceol (Gattéfossé), Gelucire 44-14 (Gattéfossé), and vitamin E-TPG...

example 2

The Temperature Stability of Representative Amphotericin B Formulations

[0223]In this example, the temperature stability of the two AmpB / TPGS formulations (AmpB / Peceol:Gelucire 44-14 (50:50 and 60:40)+5% v / v vitamin E-TPGS), prepared as described in Example 1, are compared to that of an AmpB / Peceol formulation.

[0224]Three formulations of AmpB were prepared. Each formulation was aliquoted and stored at three temperatures, 4° C., room temperature (RT, ranging between 23° to 30° C.), and 43° C. for time periods ranging from 0 days of incubation to 60 days of incubation. At specified time points over 39 days samples of each formulation at each temperature was diluted in methanol to fully solubilize the AmpB. The absorbance of AmpB was measured using the UV-Vis spectrophotometry (407 nm) using a background containing the lipid vehicles alone at the same dilution and compared to a standard curve prepared with the corresponding lipid vehicles. The concentration of AmpB in the samples was ca...

example 3

fsSGF Stability of Representative Amphotericin B Formulations

[0229]In this example, the stability in fasted state simulated gastric fluid (fsSGF) of the two AmpB / TPGS formulations (AmpB / Peceol:Gelucire 44-14 (50:50 and 60:40)+5% v / v vitamin E-TPGS), prepared as described in Example 1, are compared.

[0230]AmpB in Peceol / Gelucire 44-14 (50:50 and 60:40)+5% v / v vitamin E-TPGS was incubated in 1:100 v / v fsSGF over a time of 2 hrs at 37° C. Samples were extracted from incubation media at periodic intervals. The concentration of AmpB was measured using UV-Vis spectrophotometry, compared to a standard curve containing the lipid vehicles and fsSGF at the appropriate dilution in methanol. The degradation of AmpB in the 50:50 Peceol / Gelucire 44-14 / 5% v / v vitamin E-TPGS vehicle was compared to the degradation of AmpB in the 60:40 Peceol / Gelucire 44-14 / 5% v / v vitamin E-TPGS.

[0231]Fasted state simulated gastric fluid (fsSGF) was prepared by reducing the pH of 30 mM NaCl to pH 1.2 using HCl. The A...

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Abstract

Stable formulations for the oral administration of therapeutic agents, methods for administering therapeutic agents using the formulations, and methods for treating conditions and diseases using the formulations.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 13 / 456,023, filed Apr. 25, 2012, which is a continuation of PCT / CA2010 / 001687, filed Oct. 26, 2010, which claims the benefit U.S. Provisional Application No. 61 / 365,708, filed Jul. 19, 2010, and U.S. Provisional Application No. 61 / 255,008, filed Oct. 26, 2009. Each application is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0002]Each year in the Indian subcontinent alone, over 500,000 individuals play host to Leishmania donovani, an insidious parasite that invades macrophages, rapidly infiltrates the vital organs and ultimately leads to severe infection of the visceral reticuloendothelial system. Visceral leishmaniasis, also known as Kala-azar, is most prevalent in the weak and the young within a population. Left untreated, almost all infected individuals will die. Visceral leishmaniasis affects over 200 million people from 62 countries...

Claims

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Application Information

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Patent Type & AuthorityApplications(United States)
IPC IPC(8): A61K31/7048A61K47/14A61K47/22
CPCA61K31/7048A61K47/14A61K47/22A61K9/0053A61K9/1075A61P31/00A61P31/10A61P33/00A61P33/02Y02A50/30
InventorWASAN, KISHOR M.WASAN, ELLEN K.
OwnerTHE UNIV OF BRITISH COLUMBIA