Novel Suppository Design for HIV Chemoprophylaxis

Technical Note: The authors investigated the variables important for calcium-alginate formation as well as dissolution.
Jul 02, 2010
Volume 34, Issue 7

A previous study provided supporting data for the concept that anti-human immunodeficiency virus (HIV) drugs, as represented by aurintricarboxylic acid (ATA), can be released from a calcium–alginate complex through the action of citrate derived from seminal fluid (1). This approach is especially attractive because the highest concentration of the anti-HIV drug would be released only during insemination and would, theoretically, be most effective for protecting women against infection from HIV-positive sexual partners. While the intended route of application is intravaginal, it is possible that intrarectal administration could potentially provide chemoprophylaxis for men and women.

This approach may be a useful adjunct to condoms and anti-HIV drugs in gels. The initial study provided dissolution data for a single concentration of citrate and aurintricarboxylic acid in a range of calcium–alginate formulations, where both calcium chloride and sodium alginate were used in equivalent concentrations (from 0.5–2.0% w/v). The purpose of the present study was to investigate the effect of variables (i.e., calcium and alginate) in the formulation and to investigate citrate as the most important physiological factor for dissolution. Although ATA was used in the previous study, the focus on calcium and alginate as variables is more important when considering other anti-HIV drugs (2–5).

Calcium–alginate gels may be formed readily into various sizes and shapes from dry, ultrathin films that rapidly release drug upon simple hydration (i.e., immediately after intravaginal and intrarectal application) to suppositories with sustained-release characteristics (6). The present study also investigates the ability of cellulose to enhance viscosity in the formulation without interfering with the ionic interactions between calcium, alginate, and citrate.


Calcium chloride, sodium citrate, microgranular α-cellulose, and aurintricarboxylic acid (sodium salt) were obtained from Sigma-Aldrich (St. Louis, MO). Sodium alginate as Protanal LF 200 was obtained from Protan (Portsmouth, NH). The first formulation trial examined the effect of citrate on dissolution. In this trial, two different formulations were evaluated. At a fixed concentration of ATA in alginate, where each mL of alginate (i.e., 0.5 and 2.0% w/v) contained 1 mg of ATA, the ATA was immobilized in calcium alginate with equal (w/v) concentrations of calcium chloride and sodium alginate. Beads of calcium–alginate ATA complex (~25 μL/bead) were produced by dropwise addition of the ATA–alginate mixture into aqueous solutions of calcium chloride. The beads were stored in water at 4 °C until tested. For citrate dissolution testing, 1 mL of sodium citrate (66 or 132 mM at pH 8.0) was added to five calcium–alginate ATA beads placed in each well of a 24-well Corning Costar 3473 microtiter plate (Corning, Corning, NY) and incubated at 23 °C.

The time necessary for total dissolution of the beads was gauged by visual inspection. The microtiter plates were mixed by an MS-3 digital mixer (IKA, Staufen, Germany) at 500 rpm. Procedures for the second formulation trial (for testing the effect of calcium in the formulation) were identical, except that beads were produced by adding 0.5 and 2.0% alginate solutions to 0.5, 1.0, and 2.0% (w/v) calcium-chloride solutions. A single concentration of citrate was used for dissolution testing (i.e., 132 mM). For fabrication of suppositories without ATA, 1 g of cellulose was thoroughly mixed with 20 mL of 2% (w/v) alginate solution to prepare a cellulose–alginate suspension. The suspension (2 mL) was loaded into a 10-cc syringe (No. 305482, BD, Franklin Lakes, NJ) from which the end was removed at the 1-mL index mark, yielding an open bore. The suspension was extruded from the syringe directly into 100 mL of 2% (w/v) calcium-chloride solution (at 23 °C) and stirred by oscillation for 20 min in an orbital mixer (Belly Button, Stovall, Greensboro, NC).

The suppositories contained approximately 2 mL each and were stored in distilled water at 4 °C until tested. For dissolution testing, each suppository was placed into one well of a six-well, Corning Costar 3471 microtiter plate (Corning) and incubated at 23 °C. Each well contained 5 mL of sodium citrate at a concentration of 132 mM. The microtiter plates were mixed with an MS-3 digital mixer at 250 rpm. The time necessary for total dissolution of the suppositories was gauged by visual inspection.

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