SUBLINGUAL PERMEABILITY OF ATROPINE SULFATE USING NOVEL RAPIDLY DISINTEGRATING TABLETS FOR THE POTENTIAL TREATMENT OF ACUTE ORGANOPHOSPHATES
Abstract
Objective. In some countries, Atropine Sulphte (AS) is available as IM auto-injector for veterans as an antidote for OPs chemical attacks. We hypothesized that AS administered sublingually using rapidly disintegrating sublingual tablets (RDSTs) may have the potential as an alternative dosage form for the treatment of organophosphates toxicity. Our aim in this study was to evaluate, ex vivo, the permeation of AS using RDSTs formulation. Background. Organophosphates (OPs) are being used as pesticides and nerve agents. According to the American Association of Poison Control Center, OPs were responsible for ten thousand toxicity cases between 2011 and 2013 due to their use as pesticides in the United States. Also, OPs have been used against civilians several times as weapons of mass destruction, although prohibited by the United Nations and the Organization for the Prohibition of Chemical Weapons. For the treatment of OPs toxicity, atropine sulfate (AS) 2 mg, as antidote, should be administered intramuscularly (IM) as soon as possible, alone or with other therapeutic agents. However, AS IM injections are not readily available for civilians in most OPs toxicity cases and require a health care professional for their administration. AS auto-injectors are only available for veterans' use in some countries. These devices are expensive, bulky to carry, invasive, unavailable for civilians and veterans in many countries. Also, multiple devices are required for the administration of multiples doses of AS to treat OPs toxicity. We hypothesized that AS administered sublingually using rapidly disintegrating sublingual tablets (RDSTs) may have the potential as an alternative user-friendly dosage form for the treatment of organophosphates toxicity. Our aim in this study was to evaluate the feasibility of ex vivo permeation of AS using RDSTs formulation. Methods. Four batches of AS RDSTs, AS 2 mg RDSTs weighing 150 mg (B1), and AS 2 mg, 4 mg, and 8 mg RDSTs weighing 50 mg each (B2, B3, and B4, respectively), were manufactured by direct compression using a previously developed formulation. The ex vivo permeation of AS RDSTs was evaluated through excised porcine sublingual membrane using Franz cells (n=4). Phosphate buffer, pH 6.5, was used as a permeation medium. AS RDST was placed in the donor chamber that contained 2 mL of phosphate buffer. Aliquot samples, 200 μL, were withdrawn from the receptor chamber at several time-intervals. AS 2 mL solution, 1 mg/mL, was used as a reference (n=4). Results. Mean ± SD AUC0-90 AS permeation and influx (J) from B4 (11037 ± 3661 μg/cm2/min, 3.89 ± 1.38 μg/cm2/min, respectively) were significantly higher (p < 0.05) than B3 (7753 ± 2002 μg/cm2/min, 1.57 ± 0.69 μg/cm2/min), B2 (3650 ± 1499 μg/cm2/min, 1.22 ± 0.54 μg/cm2/min), B1 (2895 ± 370 μg/cm2/min, 0.953 ± 0.36 μg/cm2/min), and the reference (2292 ± 648 μg/cm2/min, 0.92 ± 0.28 μg/cm2/min). Mean ± SD AUC0-90 AS permeation and influx (J) from B2 and B1 was not significantly different (p > 0.05) form the reference. Increasing AS dose in the RDSTs increased the cumulative AS permeated linearly, R2=0.999. Conclusion. The permeation of AS through the sublingual mucosa was feasible and increasing AS dose increased its permeation linearly. These novel RDSTs released AS and promoted its permeability similar to the reference solution. AS RDSTs may have the potential as an alternative non-invasive, user-friendly dosage form for the treatment of organophosphate toxicity. Dose-ranging animal studies are required to confirm these results and to determine the relative sublingual bioavailability of AS. Grants. SACM
SUBLINGUAL PERMEABILITY OF ATROPINE SULFATE USING NOVEL RAPIDLY DISINTEGRATING TABLETS FOR THE POTENTIAL TREATMENT OF ACUTE ORGANOPHOSPHATES
POSTER PRESENTATIONS
Objective. In some countries, Atropine Sulphte (AS) is available as IM auto-injector for veterans as an antidote for OPs chemical attacks. We hypothesized that AS administered sublingually using rapidly disintegrating sublingual tablets (RDSTs) may have the potential as an alternative dosage form for the treatment of organophosphates toxicity. Our aim in this study was to evaluate, ex vivo, the permeation of AS using RDSTs formulation. Background. Organophosphates (OPs) are being used as pesticides and nerve agents. According to the American Association of Poison Control Center, OPs were responsible for ten thousand toxicity cases between 2011 and 2013 due to their use as pesticides in the United States. Also, OPs have been used against civilians several times as weapons of mass destruction, although prohibited by the United Nations and the Organization for the Prohibition of Chemical Weapons. For the treatment of OPs toxicity, atropine sulfate (AS) 2 mg, as antidote, should be administered intramuscularly (IM) as soon as possible, alone or with other therapeutic agents. However, AS IM injections are not readily available for civilians in most OPs toxicity cases and require a health care professional for their administration. AS auto-injectors are only available for veterans' use in some countries. These devices are expensive, bulky to carry, invasive, unavailable for civilians and veterans in many countries. Also, multiple devices are required for the administration of multiples doses of AS to treat OPs toxicity. We hypothesized that AS administered sublingually using rapidly disintegrating sublingual tablets (RDSTs) may have the potential as an alternative user-friendly dosage form for the treatment of organophosphates toxicity. Our aim in this study was to evaluate the feasibility of ex vivo permeation of AS using RDSTs formulation. Methods. Four batches of AS RDSTs, AS 2 mg RDSTs weighing 150 mg (B1), and AS 2 mg, 4 mg, and 8 mg RDSTs weighing 50 mg each (B2, B3, and B4, respectively), were manufactured by direct compression using a previously developed formulation. The ex vivo permeation of AS RDSTs was evaluated through excised porcine sublingual membrane using Franz cells (n=4). Phosphate buffer, pH 6.5, was used as a permeation medium. AS RDST was placed in the donor chamber that contained 2 mL of phosphate buffer. Aliquot samples, 200 μL, were withdrawn from the receptor chamber at several time-intervals. AS 2 mL solution, 1 mg/mL, was used as a reference (n=4). Results. Mean ± SD AUC0-90 AS permeation and influx (J) from B4 (11037 ± 3661 μg/cm2/min, 3.89 ± 1.38 μg/cm2/min, respectively) were significantly higher (p < 0.05) than B3 (7753 ± 2002 μg/cm2/min, 1.57 ± 0.69 μg/cm2/min), B2 (3650 ± 1499 μg/cm2/min, 1.22 ± 0.54 μg/cm2/min), B1 (2895 ± 370 μg/cm2/min, 0.953 ± 0.36 μg/cm2/min), and the reference (2292 ± 648 μg/cm2/min, 0.92 ± 0.28 μg/cm2/min). Mean ± SD AUC0-90 AS permeation and influx (J) from B2 and B1 was not significantly different (p > 0.05) form the reference. Increasing AS dose in the RDSTs increased the cumulative AS permeated linearly, R2=0.999. Conclusion. The permeation of AS through the sublingual mucosa was feasible and increasing AS dose increased its permeation linearly. These novel RDSTs released AS and promoted its permeability similar to the reference solution. AS RDSTs may have the potential as an alternative non-invasive, user-friendly dosage form for the treatment of organophosphate toxicity. Dose-ranging animal studies are required to confirm these results and to determine the relative sublingual bioavailability of AS. Grants. SACM