Enhancing transdermal administration of hydrophilic drugs

Abstract

Methods, formulations, and drug delivery systems are provided for enhancing the flux of a transdermally administered hydrophilic drug using a basic permeation enhancer composition. The enhancer composition contains an inorganic hydroxide and a weaker, nitrogenous base, wherein the bases are selected such that a 0.1M aqueous solution of the nitrogenous base has a pH that is about 1.0 to about 6.5 lower than the pH of a 0.1M aqueous solution of the inorganic hydroxide. Additionally, the molar ratio of the nitrogenous base to the inorganic hydroxide in the enhancer composition is in the range of about 0.5n:1 to about 20n:1, where n is the number of hydroxide ions per molecule of the inorganic hydroxide.

Description

technical field

[0001] The present invention relates generally to topical and transdermal administration of pharmacologically active drugs, and more particularly to methods and compositions for enhancing the flux of hydrophilic drugs across body surfaces using alkaline permeation enhancer compositions. Background technique

[0002] The way of drug delivery through the skin has many advantages: First, it is comfortable, convenient and non-invasive. The variability in absorption and metabolism rates encountered in oral therapy is avoided, as are other inherent nuisances such as gastrointestinal irritation and the like. Transdermal drug delivery also enables a high degree of control over the blood concentration of any particular drug.

[0003] The skin is a structurally complex and relatively thick membrane. Molecules that move into and through intact skin from the environment must first penetrate the stratum corneum and whatever is on its surface. They must then pass throug...

Examples

Embodiment 1

[0087] An in vitro skin permeation study was performed using four solutions of meloxicam, each containing sodium hydroxide and a nitrogenous base. The ingredients used to prepare each formulation are listed in Table 1 along with the actual weight and weight percent of each ingredient in each formulation. Each ingredient was added in the order listed in Table 1. The solution was placed directly on human cadaver skin as described below.

[0088] The in vitro permeability of meloxicam from formulations A, B, C and D was determined by using a diffusion area of ​​1 cm 2 A Franz-type diffusion cell was evaluated. The volume of the receptor solution was 8 ml. Human cadaver skin was cut to size and placed cuticle-side up on the receptor chamber of the diffusion cell. A donor chamber is placed on top of the stratum corneum, and the pools are clamped together. 50 [mu]l of each meloxicam formulation was added to the stratum corneum sandwiched between the donor and acceptor compartme...

Embodiment 2

[0093] In vitro skin penetration studies using four diclofenac sodium transdermal drug delivery systems. The ingredients used to prepare each system are listed in Table 2 along with the actual weight and weight percent of each ingredient (based on the total weight of the solution) in each formulation. Each formulation was coated on a release liner and dried in an oven at 65°C for two hours to remove water and other solvents. The dried adhesive coated drug / release liner film was laminated to a liner film, and the liner / adhesive coated drug / release liner sheet was cut into 9 / 16 inch diameter discs. After drying, the theoretical weight percents (calculated assuming that all volatile components were completely removed as precursors during drying) for each component weight of the system are listed in Table 3.

[0094] The in vitro permeability of diclofenac sodium from these discs to human cadaver skin was determined using a diffusion area of ​​1 cm 2 A Franz-type diffusion cell ...

Embodiment 3

[0101] In vitro skin penetration studies were performed as in Example 1 using three solutions of alendronate sodium, each solution containing sodium hydroxide and a nitrogenous base. The ingredients used to prepare each formulation are listed in Table 4 along with the actual weight and weight percent of each ingredient in each formulation. Each ingredient was added in the order listed in Table 4. The solution was placed directly on human cadaver skin as described below.

[0102] In vitro permeability of alendronic acid from formulations I, J and K using a diffusion area of ​​1 cm 2 Franz-type diffusion cell evaluation. The volume of the receptor solution was 8 ml. Human cadaver skin was cut to size and placed cuticle-side up on the receptor chamber of the diffusion cell. A donor chamber is placed on top of the stratum corneum, and the pools are clamped together. 50 [mu]l of each meloxicam formulation was added to the stratum corneum sandwiched between the donor and accept...

technical field

[0001] The present invention relates generally to topical and transdermal administration of pharmacologically active drugs, and more particularly to methods and compositions for enhancing the flux of hydrophilic drugs across body surfaces using alkaline permeation enhancer compositions. Background technique

[0002] The way of drug delivery through the skin has many advantages: First, it is comfortable, convenient and non-invasive. The variability in absorption and metabolism rates encountered in oral therapy is avoided, as are other inherent nuisances such as gastrointestinal irritation and the like. Transdermal drug delivery also enables a high degree of control over the blood concentration of any particular drug.

[0003] The skin is a structurally complex and relatively thick membrane. Molecules that move into and through intact skin from the environment must first penetrate the stratum corneum and whatever is on its surface. They must then pass throug...

Examples

Embodiment 1

[0087] An in vitro skin permeation study was performed using four solutions of meloxicam, each containing sodium hydroxide and a nitrogenous base. The ingredients used to prepare each formulation are listed in Table 1 along with the actual weight and weight percent of each ingredient in each formulation. Each ingredient was added in the order listed in Table 1. The solution was placed directly on human cadaver skin as described below.

[0088] The in vitro permeability of meloxicam from formulations A, B, C and D was determined by using a diffusion area of ​​1 cm 2 A Franz-type diffusion cell was evaluated. The volume of the receptor solution was 8 ml. Human cadaver skin was cut to size and placed cuticle-side up on the receptor chamber of the diffusion cell. A donor chamber is placed on top of the stratum corneum, and the pools are clamped together. 50 [mu]l of each meloxicam formulation was added to the stratum corneum sandwiched between the donor and acceptor compartme...

Embodiment 2

[0093] In vitro skin penetration studies using four diclofenac sodium transdermal drug delivery systems. The ingredients used to prepare each system are listed in Table 2 along with the actual weight and weight percent of each ingredient (based on the total weight of the solution) in each formulation. Each formulation was coated on a release liner and dried in an oven at 65°C for two hours to remove water and other solvents. The dried adhesive coated drug / release liner film was laminated to a liner film, and the liner / adhesive coated drug / release liner sheet was cut into 9 / 16 inch diameter discs. After drying, the theoretical weight percents (calculated assuming that all volatile components were completely removed as precursors during drying) for each component weight of the system are listed in Table 3.

[0094] The in vitro permeability of diclofenac sodium from these discs to human cadaver skin was determined using a diffusion area of ​​1 cm 2 A Franz-type diffusion cell ...

Embodiment 3

[0101] In vitro skin penetration studies were performed as in Example 1 using three solutions of alendronate sodium, each solution containing sodium hydroxide and a nitrogenous base. The ingredients used to prepare each formulation are listed in Table 4 along with the actual weight and weight percent of each ingredient in each formulation. Each ingredient was added in the order listed in Table 4. The solution was placed directly on human cadaver skin as described below.

[0102] In vitro permeability of alendronic acid from formulations I, J and K using a diffusion area of ​​1 cm 2 Franz-type diffusion cell evaluation. The volume of the receptor solution was 8 ml. Human cadaver skin was cut to size and placed cuticle-side up on the receptor chamber of the diffusion cell. A donor chamber is placed on top of the stratum corneum, and the pools are clamped together. 50 [mu]l of each meloxicam formulation was added to the stratum corneum sandwiched between the donor and accept...

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