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Compositions for delivery of drug combinations

a technology of compound compositions and drugs, applied in the direction of drug compositions, biocide, heterocyclic compound active ingredients, etc., can solve the problems of limited success in achieving cures with single agents, limiting their therapeutic use, and affecting the effect of the same combination of drugs

Inactive Publication Date: 2007-06-28
CELATOR PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0024] The invention relates to methods for administering non-antagonistic ratios of therapeutic agents, preferably antitumor drugs, using delivery vehicle compositions that encapsulate two or more agents, wherein the agents are present in the vehicles at ratios synergistic or additive (i.e. non-antagonistic) over a range of concentrations. Prior to encapsulation, the ratios of therapeutic agents in the combination are selected so that the combination exhibits synergy or additivity over a desired concentration range. Encapsulation in delivery vehicles allows two or more agents to be delivered to the disease site in a coordinated fashion, thereby assuring that the agents will be present at the disease site at a non-antagonistic ratio. This result will be achieved whether the agents are co-encapsulated in delivery vehicles, or are separately encapsulated in delivery vehicles administered such that non-antagonistic ratios are maintained at the disease site. The pharmacokinetics (PK) of the composition are controlled by the delivery vehicles themselves such that coordinated delivery is achieved (provided that the PK of the delivery systems are comparable).

Problems solved by technology

Due to this complexity, achieving cures with a single agent has been met with limited success.
Despite the aforementioned advantages associated with the use of synergistic drug combinations, there are various drawbacks that limit their therapeutic use.
Indeed, the same combination of drugs may be antagonistic at some ratios, synergistic at others, and additive at still others.
However, there is no teaching of any mode of administration which would maintain this ratio in vivo.
Again, the method of formulation does not ensure maintenance of this ratio after delivery.

Method used

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  • Compositions for delivery of drug combinations
  • Compositions for delivery of drug combinations
  • Compositions for delivery of drug combinations

Examples

Experimental program
Comparison scheme
Effect test

example 1

Multiple Representation of Dose-Effect Analysis

[0201] Quantitative analysis of the relationship between an amount (dose or concentration) of drug and its biological effect as well as the joint effect of drug combinations can be measured and reported in a number of ways. FIG. 2 illustrates 5 such methods using, as an example, a combination of irinotecan and carboplatin.

[0202] Based on Chou and Talalay's theory of dose-effect analysis, a “median-effect equation” has been used to calculate a number of biochemical equations that are extensively used in the art. Derivations of this equation have given rise to higher order equations such as those used to calculate Combination Index (CI). As mentioned previously, CI can be used to determine if combinations of more than one drug and various ratios of each combination are antagonistic, additive or synergistic. CI plots are typically illustrated with CI representing the y-axis versus the proportion of cells affected, or fraction affected (f...

example 2

CI is Dependent upon Concentrations

[0207] Drug combinations of irinotecan and 5-Fluorouracil (5-FU) at mole ratios of 1:1 and 1:10 and etoposide and carboplatin at mole ratios of 10:1 and 1:10 were tested for additive, synergistic or antagonistic effects using the standard tetrazolium-based calorimetric MTT cytotoxicity assay and the median-effect analysis as described in the previous example sections. HT29 or MCF-7 cells were exposed to single agents as well as agents in combination at defined ratios. Eight drug concentrations were utilized for single agents and combinations. Optical density values were obtained from the MTT assay, converted into a percentage of the control, averaged and then converted into fraction affected values. Dose and fraction affected values were entered into CalcuSyn which yielded the CI versus fa graph, shown in FIG. 3.

[0208]FIG. 3A shows that irinotecan and 5-FU at a mole ratio of 1:1 were non-antagonistic over the entire range of concentrations as mea...

example 3

Determination of CI for Various Two-Drug Combinations

[0211] Various drug combinations presented in the table below were tested for additive, synergistic or antagonistic effects using the MTT cytotoxicity assay protocol and the median-effect analysis procedure described above. Results from the CI versus fa graphs are tabulated below. The approximate percentage of the fa range that exhibited a non-antagonistic effect is reported in brackets following the ratio. Measurements were taken between fa values of 0.2 and 0.8 and the percent of that fa range exhibiting a synergistic or additive effect (non-antagonistic) was calculated by determining the percentage of the curve falling below a CI value of 1.1. Data is derived from at least one experiment performed in triplicate.

CELLMOLE RATIODRUG COMBINATIONLINE[% Synergistic or Additivea]Irinotecan:5-FUH4601:10 [83%], 1:1 [17%],10:1 [100%]Irinotecan:5-FUMCF-71:10 [48% additiveb], 1:1[58%], 10:1 [90%]Irinotecan:5-FUHT291:10 [75%], 1:1 [100%]...

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Abstract

Methods to prepare compositions which comprise delivery vehicles having stably associated therewith non-antagonistic combinations of two or more agents. The compositions exhibit non-antagonistic effects when combinations of drugs are administered.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional of U.S. Ser. No. 10 / 417,631 filed 16 Apr. 2003 which is a continuation of U.S. Ser. No. 10 / 406,913 filed 2 Apr. 2003 and now abandoned which is a continuation-in-part of U.S. Ser. No. 10 / 264,538 filed 3 Oct. 2002, which claims benefit under 35 U.S.C. § 119(e) of provisional applications U.S. Ser. No. 60 / 326,671 filed 3 Oct. 2001; Ser. No. 60 / 341,529 filed 17 Dec. 2001; Ser. No. 60 / 356,759 filed 15 Feb. 2002; Canadian informal application Serial No. CA 2,383,259 filed 23 Apr. 2002; provisional applications U.S. Ser. No. 60 / 401,984 filed 7 Aug. 2002 and U.S. Ser. No. 60 / 408,733 filed 6 Sep. 2002. The contents of these applications are incorporated herein by reference.TECHNICAL FIELD [0002] The invention relates to compositions and methods for improved delivery of synergistic or additive combinations of therapeutic agents. More particularly, the invention concerns delivery systems which ensure the maintenan...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K33/24A61K31/7072A61K31/704A61K31/4745A61K31/337A61K31/282A61K9/16A61KA61K9/00A61K9/127A61K9/14A61K9/50A61K31/00A61K31/7048A61K31/7076A61K33/243A61K45/06
CPCA61K9/0019A61K9/127A61K9/1271A61K9/1272A61K31/00A61K31/282A61K31/337A61K31/4745A61K31/704A61K31/7048A61K31/7072A61K31/7076A61K33/24A61K45/06A61K2300/00A61P35/00A61P43/00A61K33/243
Inventor TARDI, PAULHARASYM, TROYWEBB, MURRAYSHEW, CLIFFORDBALLY, MARCELMAYER, LAWRENCEJANOFF, ANDREWSHEW, TREVORSHEW, DOMINIC
Owner CELATOR PHARMA INC
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