Padmanabh Pravinchandra Bhatt

Transmucosal Delivery of Oxytocin to Rabbits Using a Mucoadhesive Buccal Patch

A biocompatible, mucoadhesive buccal patch was evaluated in rabbits for transmucosal delivery of peptides. Oxytocin (OT) was incorporated into custom coformulations of Carbopol 974P and silicone polymer and the resulting plasma OT concentration versus time profiles determined following patch application. For comparative purposes, the mean values determined for the elimination half-life (t1/2), volume of distribution (Vd), and the total body clearance (CL) following intravenous injection of OT were 2.9 +/- 0.2 min, 85.3 +/- 6.7 ml, and 20.4 +/- 2.03 ml/min, respectively. Following application of oxytocin-loaded mucoadhesive patches, plasma OT concentrations remained 20- to 28-fold greater from 0.5 to 3.0 hr than control animals administered placebo patches. The steady-state plasma OT concentration (Css) following application of the buccal patches was 80.6 +/- 15.9 pg/ml. The lag-time associated with attainment of the Css was 0.45 +/- 0.18 hr. Steady-state flux (Jss) of oxytocin in vivo was 139 +/- 36.8 ng/hr/cm2. Based on the amount of OT remaining in the patches following removal, the average dose of OT released in vivo was 0.27 +/- 0.024 mg with a bioavailability of 0.1%. No significant alterations in mucosal histology were observed when underlying mucosa to which OT patches had been applied were compared to either control (no patch) mucosa or mucosa underneath placebo patches. The mucoadhesive buccal patches were easy to apply and remove, nonirritating to tissue, and able to continuously deliver a nonapeptide over 3 hr. Based on these preliminary studies, the mucoadhesive buccal patches evaluated may represent an improved transmucosal drug delivery system for peptides and conventional drug substances.

Evaluation of a Mucoadhesive Buccal Patch for Delivery of Peptides: In Vitro Screening of Bioadhesion

We have assessed the bioadhesive properties of several different mucoadhesive buccal patches. The patches consisted of custom coformulations of silicone polymers and Carbopol 974P. The contact angle of water was measured for each of the test formulations, using an ophthalmic shadow scope. The corresponding work of adhesion between the water and the patches (W1), and between the patches and freshly-excised rabbit buccal mucosa (W2) was then calculated, using a modification of Dupres equation. The bioadhesive strength between the patches and excised rabbit buccal mucosa was also assessed. The results of the contact-angle measurements indicated that the contact angle decreased with an increase in the amount of Carbopol in the formulation. Additionally, the calculated values of both W1 and W2 increased with an increase in the amount of Carbopol in the buccal-patch formulations. A correlation (r not equal to 0.9808) was found between the measured contact angle and the calculated values for W2. The direct measurement of the force required to separate a buccal patch from excised rabbit buccal mucosa with the INSTRON demonstrated that the adhesive strength increased with an increase in the amount of Carbopol. This preliminary study has shown that the measurement of contact angles alone may provide a useful technique for estimating the work of adhesion, and may serve as a convenient and rapid screening procedure to identify potential mucoadhesive buccal-patch formulations.

Absorption of Thyrotropin-Releasing Hormone in Rats Using a Mucoadhesive Buccal Patch

AbstractMucoadhesive buccal patches were evaluated in vitro and in vivo using rats for release of thyrotropin-releasing homne (TRH). TRH (10% w/w) was incorporated into mucoadhesive buccal patches that were custom coformulated with silicone and organic polymers (Dow Coming, Midland, MI) and its release profile was characterized in vitro using a modified Franz diffusion cell. TRH released into pH = 7.0 phosphate buffered saline at 37°C under sink conditions was detected using high-performance liquid chromatography (HPLC). Release of TRH in vitro from the buccal patches was rapid during the first 2 hr, with 51% of the total amount of TRH incolporated into the patches released after 24 hr. HPLC analysis indicated that TRH extracted from buccal patches thermally stressed at 40°, 55°, and 70°C showed negligible degradation after 6 months. In contrast, an aqueous TRH solution stored at 70°C showed degradation of TRH as soon as 10 days following incubation at this temperature. TRH patches placed on the buccal mu...

In Vitro Release and Permeation of Oxytocin from a Mucoadhesive Buccal Patch

A biocompatible, mucoadhesive patch was evaluated for potential use in the delivery of peptides. The model peptide oxytocin was incorporated into the polymeric patch matrix and the diffusion of oxytocin across excised rabbit buccal epithelium was studied following patch application. Penetration of oxytocin across excised mucosa from an applied patch did not exhibit a characteristic lag time for diffusion, with the steady-state flux of oxytocin being 0.062 +/- 0.019 microgram/cm2/hr. However, when finite-dose diffusion studies were conducted to quantitate transport of oxytocin across rabbit buccal mucosa, the mean apparent permeability coefficient (P), diffusion coefficient (D), partition coefficient (K), and lag time (tlag) were (1.94 +/- 0.74) x 10(-7) cm/sec, (9.20 +/- 1.65) x 10(-8) cm2/sec, 0.13 +/- 0.05 and 1.86 +/- 0.31 hr, respectively. The release of oxytocin from the mucoadhesive buccal patches in vitro proceeded very rapidly during the first 2 hr, with 72% of the amount initially incorporated into the patches released at 24 hr. The disappearance rate of intact, parent oxytocin when an oxytocin solution was placed in direct contact with the serosal and mucosal sides of freshly excised rabbit buccal mucosa was 0.74 +/- 0.34 microgram/cm2/hr and 3.38 +/- 1.07 micrograms/cm2/hr, respectively. Thus, the buccal patch evaluated in these studies appears to be suitable for transmucosal delivery of peptides.

Development of silicone-based barrier devices for controlled delivery of spermicidal agents

Abstract Intravaginal devices (diaphragm and disc) were fabricated from silicone elastomer and evaluated for controlled release of Nonoxynol-9 (N-9). These intravaginal devices have good physical properties and reproducibility. A significant amount of N-9 was released within 2 min from vaginal devices; the release profile was found to follow Q vs. t1/2 relationship. The release flux increased with increasing loading dose of N-9 from 10 to 40%, which followed a linear Q/t1/2 vs. (2A)1/2 relationship, a typical characteristic of matrix-type drug delivery systems. The optimal loading dose of N-9 in diaphragms to achieve an appropriate release rate was of the order of 35%. The release flux of N-9 increased as the device shape changed from diaphragm to disc. Release flux of N-9 also increased with decreasing thickness of devices from 75 to 10 mil-inch. The release rate of N-9 from devices decreased as the duration of storage, after blending of N-9 into polymer parts before molding, increased. Spermicide-releasing disposable vaginal diaphragms containing N-9 were physically and chemically stable under various storage conditions for 16 weeks. Spermicide-releasing disposable vaginal diaphragms can offer a promising approach for achieving a controlled release rate of N-9 and consequent fertility control.

Effect of excipient on drug release and permeation from silicone-based barrier devices

Spermicide-releasing disposable vaginal devices were fabricated from silicone elastomer and evaluated for controlled release of Nonoxynol-9 (N-9). The optimal loading dose of N-9 in the diaphragm-shaped barrier device to achieve an appropriate release rate was of the order of 35%. Vaginal permeation of N-9 from disc-shape vaginal devices was negligible over the initial 5 h, and increased in a Q vs. t pattern. Several excipients were screened for spermicidal activity and for synergistic effects on the release rate of N-9 from diaphragm-shape barrier devices. Incorporation of a cosolvent, Dow Corning silicone fluid (SF), into the vaginal devices facilitated burst release of N-9, and consequently reduced the required loading dose of N-9. Addition of 10% of SF in diaphragms loaded with 25% of N-9 increased the release rate of N-9 to the equivalent of that from diaphragms loaded with 35% of N-9. SF increased the solubility of N-9 in silicone-based vaginal devices, but did not affect the permeation rate of N-9 through vaginal mucosa. Silicone-based barrier devices can achieve a controllable release rate of N-9 within vagina, as well as a controllable permeation rate of N-9 through vaginal mucosa, and therefore offer a promising approach for achieving fertility control.