Novel encochleation methods, cochleates and methods of use

a technology of encochlease and cochlease, which is applied in the direction of instruments, salicyclic acid active ingredients, saccharide peptide ingredients, etc., can solve the problems of added manufacturing and product costs, affecting the activity and/or stability of encochleated materials, and time-consuming, so as to achieve efficient and easy scaling up

Inactive Publication Date: 2005-01-20
BIODELIVERY SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides novel methods of forming cochleates, which methods can be efficiently and easily scaled up. Additionally, the present invention provides an anhydrous cochleate including a protonized cargo moie...

Problems solved by technology

These steps are time consuming, represent added expense in manufacturing and product costs, and can in some instances affect the activity and/or stability of the encochleated material.
Additionally, cochleates are highly susceptible to aggregation, and thus particle size and particle size distribution can be highly variable and unstable after preparation and removal from the two-phase polymer system.
For example, aminoglycopeptides (e.g., vancomycin), are poorly absorbed through the GI tract and are difficult to deliver to cells harboring bacteria.
Accordingly, in order to administer an effective amount of drug against a bacterial infection, large amounts of drug are ingested to not only account for poor absorption through the GI tract, but also poor deliver...

Method used

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  • Novel encochleation methods, cochleates and methods of use
  • Novel encochleation methods, cochleates and methods of use
  • Novel encochleation methods, cochleates and methods of use

Examples

Experimental program
Comparison scheme
Effect test

example 1

Amphotericin B Cochleate (CAMB) Prepared with DMSO and Lipid:AmB Ratios of 10:1, 2:1 and 1:1 w / w

Amphotericin B cochleates (CAMB) were prepared with Soy PS and DMSO with Vitamin E, and a Lipid to AmB ratio of 10:1 as follows.

Preparation of Liposomes

20 ml of water was added to 200 mg of Soy-PS in a 50 ml plastic tube, vortexed for about 15 minutes to form a liposomal suspension, and filtered using a 0.45 μm filter. The suspension was sonicated for about 4 minutes and filtered again with a 0.22 μm filter.

Addition of Cargo Moiety and Antioxidant in Solvent

1.90 ml of DMSO solvent was added to 20 mg of Amphotericin B in a 15 ml plastic tube. To the AmB / DMSO mixture, 0.1 ml of Vitamin E (20 mg / ml in DMSO), vortexed for about 10 minutes. This solution was then added to the liposomal suspension by drop wise addition using a 1 ml pipette while vortexing. The final mixture was vortexed for about 2 minutes.

Precipitation of Cochleates

2 ml of calcium (0.1 N) was added to the liposom...

example 2

Amphotericin B Cochleates Prepared with NMP

Cochleates were prepared as described in Example 1, except N-methylpyrrolidone (NMP) solvent was used instead of DMSO, and the formulation was adjusted as indicated in the following table.

TABLE 2NMP 10:1 FormulationCAMB / NMP 10:1Soy PS (mg)200AmB (mg)20Vitamin E (mg)2DMSO (Ml)2Water (ml)20Calcium (ml)2Washings with sterile water w / 2calcium (1 mM)Final Volume20ml

Cochleates in the final formulations were observed as a yellowish suspension. Mice infected with a lethal dose of Aspergillus fumigatus were dosed with 2 mg / kg of the AmB-cochleate formulation for 14 days. The cochleates were efficacious against the A. fumigatus.

example 3

Amphotericin B Cochleates Prepared with DMSO and Lipid:AmB Ratios of 5:1, 4:1, 3:1 and 2:1 w / w

Amphotericin B cochleates (CAMB) were prepared with soy PS and DMSO with tocopherol (Vitamin E) with the following protocol: 1. Weighing and placing 300 mg of soy PS into a 50 ml pp sterile tube with 10 ml sterile water. 2. Vortexing the suspension for 2 minutes. 3. Sonicating the suspension for 3 minutes. 4. Filtering the suspension with a 0.22 μm filter and pooling liposomes into a 50 ml tube. 5. Weighing and placing 10 mg (5:1), 12.5 mg (4:1) 16.6 mg (3:1) and 25 mg (2:1), of AmB (individually) into four 15 ml pp sterile tubes with 0.5 ml DMSO and vortexing. 6. Adding 6.0 μl (5:1), 6.2 μl (4:1), 6.6 μl (3:1), and 7.5 μl (2:1) of tocopherol at 10 mg / ml in DMSO to the 15 ml tubes with AmB. (The concentration of the AmB was 20 mg / ml (5:1), 25 mg / ml (4:1), 33.2 mg / ml (3:1), and 50 mg / ml (2:1), at this time) 7. Vortexing the solution for a few minutes until the AmB completely dissolve...

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Abstract

Disclosed are novel methods for making cochleates and cochleate compositions that include introducing a cargo moiety to a liposome in the presence of a solvent. Also disclosed are cochleates and cochleate compositions that include an aggregation inhibitor, and optionally, a cargo moiety. Additionally, anhydrous cochleates that include a protonized cargo moiety, a divalent metal cation and a negatively charge lipid are disclosed. Methods of using the cochleate compositions of the invention, including methods of administration, are also disclosed.

Description

TECHNICAL FIELD The invention generally relates to cochleate delivery vehicles. More specifically, the invention relates to novel methods of making and using cochleates employing a solvent to encochleate a cargo moiety, to cochleates including one or more aggregation inhibitors, and to cochleates including a protonized cargo moiety, divalent cation and negatively charged lipid. BACKGROUND The advantages of cochleates are numerous. For example, cochleates are more stable than aqueous structures such as liposomes, they can be stored lyophilized which provides the potential to be stored for long periods of time at room temperatures, they maintain their structure even after lyophilization (whereas liposome structures are destroyed by lyophilization), and they are non-toxic. Cochleate structures have been prepared first by D. Papahadjopoulos as an intermediate in the preparation of large unilamellar vesicles. U.S. Pat. No. 4,078,052. Methods of making and using cochleates to deliver a...

Claims

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Application Information

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IPC IPC(8): A61K9/127A61K31/00A61K31/7048
CPCA61K9/1274A61K31/00A61K31/7048A61K38/14A61K38/12A61K31/395A61K31/60G01N33/5091A61K31/167A61K31/135A61K9/1277A61K31/7036
Inventor MANNINO, RAPHAEL J.GOULD-FOGERITE, SUSANKRAUSE-ELSMORE, SARA L.DELMARRE, DAVIDLU, RUYING
Owner BIODELIVERY SCI
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