Dosage Form Effects

a. Extent of Drug Incorporation. The drug may be loaded onto the polymer matrix in a variety of ways. The most common approach is to incorporate the drug into mucoadhesive drug delivery systems, as shown in Figure 4. For water-soluble polymers, it is possible to employ the mu-coadhesive as a typical polymer to coat or to laminate a device. The contact time in such cases is rate limited by the dissolution of the polymer. Such systems, however, suffer from the disadvantage of having a short shelf life, because of the undesirable release of the drug in the aqueous environment (moisture) of the storage container.

The cross-linked mucoadhesives need to become hydrated to function as an effective mucoadhesive drug delivery device. In such cases, the adhesive often detaches itself from the rate-controlling drug delivery device and causes a premature release of the drug, especially with water-soluble drugs. One solution to such a problem is through incorporation of a sparingly soluble drug inside the mucoadhesive polymer. The device can slowly provide drug release until dissolution is complete. This approach may be used for sparingly soluble salts and lipophilic prodrugs of highly water-soluble drugs.

Figure 4 Approaches to incorporate drug into mucoadhesive drug delivery systems. Top panels: (*) mucoadhesive. Bottom panels: (*) drug.

Achieving high consistent loading compounds into mucoadhesive dosage forms continues to be a significant problem. A combination of a phase change and mucoadhesive concept may be used in some cases. For example, polycarbophil exhibits large changes in viscosity with pH and ionic strength. Thus, drugs either alone or with a small quantity of lipid can be suspended with the polycarbophil at the proper pH and ionic strength. When such a suspension is placed in the tear pocket of the eye, it rapidly gels, trapping the drug. The newly formed gel then releases the drug slowly over prolonged periods of time.

b. Vehicular Effects. A delivery system that would allow the drug to remain associated with a vehicle possessing enhanced precorneal retention may, therefore, provide for an attractive ocular drug delivery system. Most attention has been directed toward the influence of solution viscosity, although it has been shown that the maximum ocular availability increase obtained in rabbits by increasing the viscosity of the vehicle is approximately twice that from a simple aqueous solution (7). The viscosity effect of mucoadhesives on ocular delivery, therefore, needs to be addressed.

According to Swan (48), maintaining the lubricity and viscosity of the precorneal film is as important as maintaining the isotonicity and pH of the ophthalmic solutions. When aqueous solutions are instilled in the eye, the integrity of the precorneal film is altered. However, when 1% methylcellu-lose solution is instilled into the eye, it spreads evenly over the surface of the globe, imparts viscosity to the precorneal film, and causes minimal alteration in the integrity of the precorneal film. The viscosity of the methylcellu-lose solution prevents it from being washed rapidly from the eye and maintains the normal physiology, i.e., lacrimation. A combination of these effects increases contact time, which prolongs the absorption of drugs like homatropine (49). Oechsner and Keipert (50) have altered a polyacrylic acid (PAA) aqueous formulation for dry eyes by including a second polymer. Since PAA solutions have the disadvantage that PAA builds high viscous gels in the usual concentration of 0.2% and at physiological pH, the authors have included polyvinylpyrrolidone (PVP) in the ocular formation (50). After full hydration of the PAA polymer, a dispersion containing 2% PA was prepared and combined with an aqueous solution of PVP at a temperature of 30°C while stirring (50). A 10% aqueous solution of NaCl was then added, which resulted in a clear preparation and the formulations then made isotonic with mannitol and stabilized with 0.01% EDTA (50). The net effect of the addition of the PVP to the PAA solution was a significant reduction in the apparent viscosity of the formulation such that the preparation was nonirritating to ocular tissues (50). The mucoadhesion index (as a measure of bioadhesive strength) was determined for the experimental PAA/PVP formulations and found to possess greater mucoadhesivity compared to monopolymer formulations that employed PAA alone. It was postulated that perhaps sustained or prolonged delivery of both hydrophilic and lipophilic drugs may be possible by incorporation of either in a PAA complex with PVP (50).

Increasing contact time with methylcellulose ophthalmic vehicles has been found to be preportional to its viscosity for up to about 25 cps. This effect has been found to level off at 55 cps (51). In humans, a significant reduction in the drainage rates was observed with higher concentrations of polyvinyl alcohol (5.85%) and with 0.9% hydroxypropyl methylcellulose (42). However, it appears that in order to achieve the substantial reduction in drainage rate, abnormally high viscosities are required.

Physicochemical parameters of the viscosity-imparting agents, other than those related to viscosity effects, may also influence the corneal retention as well as ocular bioavailability from an ophthalmic product. Benedetto et al. (52) examined this effect using an in vitro model of the corneal surface and suggested that polyvinyl alcohol, but not hydroxypropyl methylcellu-lose, would significantly increase the thickness of the corneal tear film. However, such affects are considered to be only minimal. Davies et al., using rabbits, demonstrated not only a significant increase in the precorneal clearance, but also a significant increase in the bioavailability of pilocarpine when administered as a mucoadhesive polymeric solution (Carbopol 934P) as compared to an equivoscous, nonmucoadhesive polyvinyl alcohol (PVA) solution (53). Studies conducted to evaluate vehicle-drug (Carbopol 934P-pilocarpine) association indicated no binding of the pilocarpine to the polymer at physiological pH (53). Huupponen et al., using albino rabbits, combined the myriatic and cycloplegic agent, cyclopentolate, with either polygalacturonic or hyaluronic acid and determined whether the mydriatic response was increased compared to cyclopentolate base alone (54). Although treated eyes all demonstrated approximately the same time to reach a maximum mydriatic response when compared to cyclopentolate base alone, the cyclopentolate/polygalacturonic (CY-PGA) and cyclopento-late/hyaluronic acid (CY-HA) formulations demonstrated a significant increase in the maximal mydriatic response when compared to the base alone. However, only the CY-PGA formulation demonstrated a significant (p < 0.05) increase in the ocular bioavailability of cyclopentolate (54).

Increasing the contact time in the precorneal area appears to be governed by both the mucoadhesive agent as well as the viscosity effects of the polymer. Thus, in designing the ocular drug delivery systems using mucoad-hesives, one needs to find a vehicle that imparts good mucoadhesive strength as well as high viscosity at a low concentration.

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