In situ gelling drug delivery system

a drug delivery system and gel technology, applied in the direction of drug compositions, antibacterial agents, peptide/protein ingredients, etc., can solve the problems of low initial systemic concentration of active agents, and unsatisfactory traditional administration methods

Inactive Publication Date: 2005-03-03
PSIVIDA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The morphology of the polymer gel produced during the precipitation process is dependent upon the nature of the organic solvent, which can vary from a dense sponge-like structure to an open meshwork with numerous voids and channels (P. D. Graham et al., J. Controlled Release 58:233-245 (1999)). This morphology i

Problems solved by technology

There are many useful drugs on the market today for which traditional means of administration are far from ideal.
Bolus injections and oral unit doses typically result in a high initial systemic concentration of the active agent, in excess of the therapeutic concentration, which falls off over time and which will fall below the therapeutic concentration if another bolus is not timely administered.
The result is that the ideal therapeutic concentration is not consistently maintained, there is a risk of toxicity associated with high systemic exposure to the drug, and the maintenance of a minimally effective concentration is dependent upon repeated administration at prescribed intervals.
Patient compliance with a dosing regimen is difficult to ensure, especially where the course of therapy is long or of indeterminate or lifetime duration.
A major disadvantage of the macroscopic devices is their physical size.
Self-administration of such implants is not feasible, and the required intervention of trained medical personnel greatly raises the cost and inconvenience of such treatments.
However, if an aqueous suspension of microspheres is stored for any length of time, the drug will diffuse from the particles into the aqueous phase, furthermore the bioerodable matrix itself is prone to hydrolysis in an aqueous environment.
A secon

Method used

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  • In situ gelling drug delivery system

Examples

Experimental program
Comparison scheme
Effect test

example 1

Evaluation of Solubility of PLGA in Organic Solvents

A sample of PLGA polymer was added to the indicated solvent and rotated overnight at room temperature, and the resulting mixture was examined for undissolved material. The results are shown in Table 1 below.

TABLE 1Solubility of PLGA polymers in selected organic solventsPolymerSolventVisual AppearancePLGA (70:30), 0.2 gPEG 400, 1 mlClear solutionPLGA (70:30), 0.2 gPEG 300, 2 mlClear solutionPLGA (70:30), 0.2 gPEG 200, 2 mlClear solutionPLGA (70:30), 0.1 gDMA, 20 DropsClear solutionPLGA (55:15), 0.1 gPEG 400, 1 mlPartially soluble*PLGA (50:50), 0.1 gPEG 400, 1 mlPartially soluble*PLGA (85:15), 0.1 gDMA, 1 mlClear solutionPLGA (50:50), 0.1 gDMA, 1 m1Clear solutionPLGA (90:10), 0.1 gPEG 400, 2 mlPartially soluble*PLGA (70:30), 0.1 gCremophor EL, 2 mlPartially solublePLGA (70:30), 0.1 gCremophor EL-P, 2 mlPartially solublePLGA (70:30), 0.1 gBenzyl alcohol, 0.5 mlClear solutionPLGA (70:30), 0.1 gBenzyl benzoate, 0.5 mlMiscible soluti...

example 2

Release Profiles for Morphine-diclofenac Co-drug from PLGA (70:30) / PEG Formulations

Three formulations were evaluated to compare release profiles for morphine-diclofenac co-drug from different concentrations of PLGA (70:30): Formulation A was formulated at about 10 mg / ml morphine-diclofenac co-drug in PLGA (70:30) / PEG 400 solution (˜5% (w / v) PLGA in PEG). Formulation B was formulated at about 10 mg / ml morphine-diclofenac co-drug in PLGA (70:30) / PEG 400 solution (˜10% (w / v) PLGA in PEG). Formulation C was formulated at about 10 mg / ml morphine-diclofenac co-drug in PLGA (70:30) / PEG 400 solution (˜20% (w / v) PLGA in PEG).

Each formulation was loaded into a 1-ml syringe, and 100 μl aliquot was injected into a tube containing 10 ml of 10% plasma in HA (hyaluronic acid) phosphate buffer, pH 7.4. The samples were placed in a water bath at 37° C. for release study. At each time point, the entire release medium was removed and replaced with 10 ml fresh buffer. The removed solution was analy...

example 3

Release Rate Profile for Morphine-diclofenac Co-drug from PLGA (50:50) / PEG Formulation

The formulation was prepared with 12 mg / ml morphine-diclofenac co-drug in PLGA (50:50) / PEG 400 solution (˜5% (w / v) PLGA in PEG) and loaded into a 1-ml syringe, and 100 μl aliquot was injected into a test tube containing 10 ml of 10% plasma in HA (hyaluronic acid) phosphate buffer, pH 7.4. The samples were placed in a 37° C. water bath. At each time point, the entire release medium was removed and replaced with 10 ml fresh buffer. The removed solutions were analyzed for morphine, diclofenac and the co-drug contents by HPLC.

The results are shown graphically in FIG. 2. As compared to the results from Example 2, morphine release was much slower in this PLGA (50:50) formulation, even where the PLGA concentration was low as ˜5% (w / v). About 80% of the morphine was released over 40 days. It is most likely that the higher molecular weight of PLGA (50:50) reduces the release rate of morphine.

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Abstract

The invention provides liquid controlled-release drug delivery compositions which gel upon injection into the body to form, in situ, controlled-release drug implants. The compositions of the invention feature a gel-forming polymer that is insoluble in water, a polyethylene glycol solvent in which the polymer is dissolved, and the drug substance to be delivered.

Description

FIELD OF THE INVENTION The present invention relates to the field of controlled-release and sustained-release drug delivery systems, and particularly to the field of injectable drug delivery implants. BACKGROUND OF THE INVENTION There are many useful drugs on the market today for which traditional means of administration are far from ideal. Bolus injections and oral unit doses typically result in a high initial systemic concentration of the active agent, in excess of the therapeutic concentration, which falls off over time and which will fall below the therapeutic concentration if another bolus is not timely administered. The result is that the ideal therapeutic concentration is not consistently maintained, there is a risk of toxicity associated with high systemic exposure to the drug, and the maintenance of a minimally effective concentration is dependent upon repeated administration at prescribed intervals. Patient compliance with a dosing regimen is difficult to ensure, especia...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K31/382A61K31/485A61K31/542A61K47/48
CPCA61K9/0024A61K9/0051A61K9/0092A61K31/382A61K31/485A61K47/48784A61K47/481A61K47/48215A61K9/06A61K31/196A61K47/34A61K31/542A61K47/60A61K47/55A61K47/6903A61P25/04A61P43/00
Inventor SU, DONGLINGASHTON, PAULCHEN, JIANBING
Owner PSIVIDA INC
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