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Peroxide removal from drug delivery vehicle

a technology for drug delivery and peroxide, which is applied in the direction of drug compositions, peptide/protein ingredients, inorganic non-active ingredients, etc., can solve the problems of drug delivery system, delivery system, and active ingredient oxidation in the formulation, so as to prolong the stability of the drug, and reduce the level of peroxide

Inactive Publication Date: 2012-12-27
DURECT CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]In another aspect of the present invention, provided are drug delivery vehicles adapted to provide prolonged stability of a drug that is to be delivered in viva comprising sucrose acetate isobutyrate having substantially reduced levels of peroxide, the drug delivery vehicle being treated with an amount of bisulfite salt effective to substantially reduce levels of peroxide in said drug delivery vehicle, the bisulfite salt comprising sodium metabisulfite, potassium metabisulfite, sodium bisulfite, or potassium bisulfite, or a combination thereof.

Problems solved by technology

Drug delivery systems, including SAIB delivery systems, are still confronted by various issues of drug instability, as such systems are considered for longer and longer drug delivery durations.
In particular, a number of excipients used to facilitate delivery and release of drugs have peroxides or are susceptible to the formation of peroxides, which may lead to oxidation of active ingredient in the formulation.
In the example of SAIB, the presence of peroxides is deleterious to a drug incorporated in an SAIB drug formulation as the drug is likely to undergo oxidative degradation.
There is no known process for removal of peroxides from SAIB at present, despite availability of processes for the removal of peroxides from other materials such as polymers.

Method used

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  • Peroxide removal from drug delivery vehicle

Examples

Experimental program
Comparison scheme
Effect test

example 1

Study I: Stability in Untreated SAIB (Lot #TD1030507) for 2 Weeks

[0041]

TABLE 4Stability of omega-interferon in untreated SAIB (lot #: 1030507)—Study IAnalysis by RP-HPLC (n = 3)**Initial (t = 0) (AR 48452)4 days7 days14 days(protein particles)***AR48424AR48562AR48450Assay (%)NA0.59* (0.02) 0.72 (0.00)0.68 (0.00)% omega-IFN Purity93.37 (0.40) 89.06 (0.46) 87.65 (0.06) 87.67 (0.26) % Oxidized2.8 (0.71)7.21 (0.88)7.79 (1.09)8.31 (0.10)% Deamidated0.8 (0.02)1.21 (0.00)1.28 (0.01)1.63 (0.03)% Unknown3.03 (0.62) 2.25 (0.66)3.27 (0.79)2.39 (0.38)Analysis by SEC (n = 3)**Initial (AR 48452)4 days7 days14 days(protein particles)***AR48424AR48562AR48450% Monomer100.00 (0.00)99.96 (0.01)99.60 (0.02) 99.40 (0.00) % DimerND 0.04 (0.00)0.38 (0.01)0.58 (0.02)UnknownNDND0.01 (0.00)0.01 (0.01)ND = Not detected,*sampled by scraping container walls, so values might not be representative of the bulk**standard deviation in parenthesis;***protein particles - t = 0 for suspension

[0042]The preliminary stabi...

example 2

Study IIa and IIb: Stability of SAIB (Lot #TD1030507) Treated with Neutral Alumina with Heating or Neutral Alumina in Presence of Ethanol for 4 Weeks

[0043]Treatment of SAIB with Neutral Alumina with Heating

[0044]SAIB was heated to 75° C. Alumina (15% w / w) was added to the heated SAIB. The mixture was stirred for 40 minutes and filtered though a 5.0 μm filter at 75° C. The treated SAIB was then collected, sampled for peroxide testing, and used for preparation of suspension for stability testing.

Treatment of SAIB with Neutral Alumina in Presence of Ethanol

[0045]SAIB was mixed with 15% absolute ethanol to reduce the viscosity. Basic alumina (15% w / w) was added to the SAIB containing ethanol. The resulting mixture was stirred for 1 hour and filtered though a 0.2 μm filter. The filtered SAIB was placed overnight under vacuum at 60° C. to remove the ethanol. This treated SAIB was then collected, sampled for peroxide testing, and used for preparation of suspension for stability testing.

TAB...

example 3

Study III: Stability in Untreated SAIB (Lot #TD2032663) for 2 Weeks

[0047]

TABLE 6Stability of omega-interferon in untreated SAIB ((lot #: 2032663)—Study IIIAnalysis by RP-HPLC (n = 3)**Initial (t = 0) (AR 48217)Initial (t = 0)1 week2 weeks(protein particles)AR 49640AR 49644AR 49647Assay (%)NA1.69 (0.01)1.70 (0.00)1.68 (0.01)% omega-IFN Purity88.98 (0.09) 88.21 (0.03) 84.95 (0.58) 83.71 (0.48) % Oxidized1.63 (0.04)3.20 (0.03)6.39 (0.05)7.21 (0.10)% Deamidated1.45 (0.01)1.66 (0.01)1.45 (0.40)1.84 (0.03)% Unknown7.94 (0.12)6.93 (0.04)7.22 (0.45)7.24 (0.45)Analysis by SEC (n = 3)**Initial (t = 0) (AR 48217)Initial (t = 0)*1 week2 weeks(protein particles)AR 49640AR 49644AR 49647% Monomer99.93 (0.01) 99.83 (0.02) 99.75 (0.01) 99.51 (0.01) % Dimer0.07 (0.01)0.17 (0.02)0.25 (0.01)0.49 (0.01)UnknownNDNDNDNDND = Not detected*n = 6**standard deviation in parenthesis

[0048]Stability of omega-interferon in untreated SAIB was again tested. The results of a two week stability study (Study III) of om...

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Abstract

The present invention is related to methods for lowering peroxide levels in sucrose acetate isobutyrate formulations and to composition used in and formed by such methods.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. provisional application No. 60 / 702,546, filed Jul. 26, 2005, which is incorporated herein in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to methods for reducing peroxide levels in non-polymeric preparations and to compositions used in and prepared by such methods.BACKGROUND OF THE INVENTION[0003]Sucrose acetate isobutyrate (“SAIB”) is a hydrophobic liquid with limited water solubility. It is soluble in a large number of biocompatible solvents. SAIB has an unusual property—it undergoes a dramatic change in viscosity with small additions of heat or with the addition of solvents. It is a very viscous liquid, having a viscosity of approximately 3200 poise at 37° C. SAIB is produced by the controlled esterification of natural sugar (sucrose) with acetic and isobutyric anhydrides. SAIB metabolizes to sucrose, acetic acid and isobutyric acid.[0004]SAIB is orally non-toxic and...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07H1/06C07H13/04
CPCA61K9/0024A61K47/26A61K31/7024A61K9/10A61K38/21A61P35/00A61K47/20A61K47/02A61K47/06A61K9/0004C07H1/06C07H13/04
Inventor JUNNARKAR, GUNJANDESJARDIN, MICHAEL A.CARR, JOHN PATRICK
Owner DURECT CORP
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