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Non-aqueous single phase vehicles and formulations utilizing such vehicles

a single-phase vehicle, non-aqueous technology, applied in the direction of peptides, cardiovascular disorders, drug compositions, etc., can solve the problems of partial or complete occlusion of the delivery conduit, the difficulty of delivering beneficial agents that include biomolecular material over an extended period of time using an implantable drug delivery system, etc., to achieve high viscosity

Inactive Publication Date: 2005-01-13
DURECT CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008] In one aspect, the present invention includes materials and methods for providing vehicles useful for providing drug formulations that address the potential drawbacks of known nonaqueous formulations. In particular, the present invention includes nonaqueous vehicles that are formed using a combination of polymer and solvent that results in a vehicle that is miscible in water. As it is used herein, the term “miscible in water” refers to a vehicle that, at a temperature range representative of a chosen operational environment, can be mixed with water at all proportions without resulting in a phase separation of the polymer from the solvent such that a highly viscous polymer phase is formed. For the purposes of the present invention, a “highly viscous polymer phase” refers to a polymer containing composition that exhibits a viscosity that is greater than the viscosity of the vehicle before the vehicle is mixed with water. Because they do not form a highly viscous polymer phase upon mixture with water, vehicles according to the present invention allow the creation of drug formulations that work to reduce the occurrence of partial or complete occlusions of the delivery conduits included in delivery devices used to administer the formulations.

Problems solved by technology

However, the delivery of beneficial agents that include biomolecular material over an extended period of time using an implantable drug delivery system has proven difficult.
Among other challenges, two problems must be addressed when seeking to deliver biomolecular material over an extended period of time from an implanted delivery device.
This second challenge has proven particularly difficult where the biomolecular material is included in a flowable composition that is delivered from a device over an extended period of time at low flow rates (i.e., ≦100 μl / day).
However, under certain circumstances, the formulations taught in the '790 publication may have the potential to inhibit drug delivery into the desired environment of operation.
As the polymer partitions into the aqueous liquid, the concentration of polymer within the aqueous liquid may increase to such an extent that a highly viscous polymer gel or precipitate is formed within the delivery conduit, resulting in a partial or complete occlusion of the delivery conduit and interfering with the desired operation of the delivery device.
The potential for such occlusions increases where the geometry of the conduit is such that aqueous liquid interfaces with the drug formulation in a confined area over a relatively long period of time (e.g., hours or days).

Method used

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  • Non-aqueous single phase vehicles and formulations utilizing such vehicles
  • Non-aqueous single phase vehicles and formulations utilizing such vehicles
  • Non-aqueous single phase vehicles and formulations utilizing such vehicles

Examples

Experimental program
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Effect test

example 1

[0031] Three different exemplary vehicles according to the present invention were produced using Glycofurol (“GF”) and polyvinylpyrrolidone (“PVP”). The PVP included in each of the three vehicles was obtained from BASF (17 pf) and had a molecular weight below 18,000 MW. The first vehicle included 42% (wt / wt) GF and 58% (wt / wt) PVP. The second vehicle included 40% (wt / wt) GF and 60% (wt / wt) PVP, and the third vehicle included 50% (wt / wt) GF and 50% (wt / wt) PVP. In each instance, the vehicles were created by first charging the raw materials into a mixer. The taw materials were then blended at about 60° C. under vacuum (about −27 in Hg) for two hours to achieve a single-phase vehicle. Each of the three vehicles was miscible with water in all proportions.

example 2

[0032] A lysozyme formulation according to the present invention was manufactured using the second vehicle of Example 1 and dry, particulate lysozyme material. The lysozyme particles used in the formulation included 1 part lysozyme to two parts sucrose, and 1 part methionine, and the particles were spray dried from a solution including a 25 mM citrate buffer. The simulated drug formulation included 11.2% (wt / wt) lysozyme. The lysozyme formulation was prepared by loading appropriate amounts of the vehicle and the lysozyme particles into a mixer. The particles and vehicle were then blended at about 60° C. under vacuum (about −27 in Hg) until a formulation having a substantially uniform suspension of lysozyme particles was achieved.

example 3

[0033] The deliverability of the lysozyme formulation of Example 2 was evaluated using two groups of six osmotic pumps. The osmotic pumps were designed to deliver the lysozyme formulation at 1.5 μl / day over a three-month period of time, providing a targeted lysozyme release rate of 35 μg / day. To evaluate the release rate performance provided by the lysozyme formulation, the osmotic pumps were introduced into an aqueous media that included a phosphate buffer system (PBS) and was maintained at 37° C.

[0034] The first group of 6 osmotic pumps was prepared using the following components: [0035] Reservoir: Titanium alloy [0036] Piston:. C-flex [0037] Lubricant: silicone medical fluid [0038] Osmotic Composition: two osmotic tablets (40 mg osmotic engine tablets formed using 76.4% NaCl, 15.5% sodium carboxymethyl cellulose, 6% povidone, 0.5% Mg Stearate, and 1.6% water)+PEG 400 filler [0039] Semipermeable Membrane: polyurethane polymer, injection molded to desired plug shape [0040] Diffusi...

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Abstract

The present invention includes materials and methods for providing vehicles useful for providing drug formulations that address the potential drawbacks of known nonaqueous formulations. In particular, the present invention includes nonaqueous vehicles that are formed using a combination of polymer and solvent that results in a vehicle that is miscible in water. The nonaqueous vehicles facilitate the formulation of drug formulations that are stable over time, even when stored at, or exposed to, elevated temperatures. Moreover, the miscible vehicles of the present invention allow the preparation of drug formulations that work to reduce the occurrence of partial or complete occlusions of the delivery conduits included in delivery devices used to administer the drug formulations.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] Pursuant to the provisions of 35 U.S.C. § 119(e), this application claims the benefit of the filing date of provisional patent application Ser. No. 60 / 459,300, filed Mar. 31, 2003, for “Non-Aqueous Single Phase Vehicles and Formulations Utilizing Such Vehicles.”FIELD OF THE INVENTION [0002] This invention relates to single-phase vehicles useful in preparing drug formulations. In particular, the invention relates to single-phase vehicles that are nonaqueous, biocompatible, capable of providing a stable suspension of a particulate drug material, and are formulated to facilitate delivery of the drug material at controlled rates over extended periods of time. BACKGROUND [0003] Implantable devices capable of delivering desired doses of a beneficial agent over extended periods of time are known in the art. For example, U.S. Pat. Nos. 5,034,229, 5,557,318, 5,110,596, 5,728,396, 5,985,305, 6,113,938, 6,156,331, 6,375,978, and 6,395,292, the cont...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/00A61K9/14A61K38/00A61K38/09A61K38/18A61K38/22A61K48/00
CPCA61K47/32A61K9/0004A61K9/16A61K9/14A61K47/30
Inventor FEREIRA, PAMELA J.DESJARDIN, MICHAELROHLOFF, CATHERINEBERRY, STEPHEN A.
Owner DURECT CORP
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