Ping I. Lee

Kinetics of drug release from hydrogel matrices

Abstract The release of water soluble drugs from initially dehydrated hydrogel matrices generally involves the simultaneous absorption of water and desorption of drug via a swelling-controlled diffusion mechanism. Thus, as water penetrates a glassy hydrogel matrix containing dispersed drug, the polymer swells and its glass transition temperature is lowered. At the same time, the dissolved drug diffuses through this swollen rubbery region into the external releasing medium. Such diffusion and swelling generally do not follow a Fickian diffusion mechanism. The existence of some molecular relaxation process in addition to diffusion is believed to be responsible for the observed non-Fickian behavior. In this article, the kinetics of drug release from hydrogel matrices will be examined both experimentally and theoretically. Special emphasis will be placed on the effect of local drug concentration on the swelling behavior of hydrogel drug carriers. A novel approach to constant-rate drug delivery from glassy hydrogel matrices via an immobilized non-uniform drug concentration distribution will also be described.

Diffusional release of a solute from a polymeric matrix — approximate analytical solutions☆

Abstract A refined integral method has been successfully applied to moving boundary problems encountered in the diffusional release of a solute from a polymeric matrix. The release kinetics has been analyzed for both erodible and non-erodible matrices with perfect sink and constant, finite external volume conditions. The range of applicability of these approximate analytical solutions has been established by comparison with available exact solutions. p]The approximate analytical solutions presented here are much more accurate than the pseudosteady-state results and much easier to use routinely than the exact solutions. For a dispersed solute, the results presented here are particularly useful for cases where the solute loading is not in great excess of the solute solubility in the matrix.

Prediction of polymer dissolution in swellable controlled-release systems☆

Abstract Various experimental studies reported in recent years in the fields of controlled and sustained drug delivery and microlithography indicate that dissolution of a glassy polymer by a penetrant (solvent) is a process consisting of an initial swelling phenomenon, followed by a true dissolution phenomenon. In the initial stages of this process two distinct fronts are observed: a front separating the penetrant from the polymer, and a front separating the glassy polymer from the rubbery (swollen) state. Progressively, the rubbery/glassy interface disappears and only dissolution is observed. A new mathematical model was developed to describe this glassy polymer dissolution process by a thermodynamically compatible penetrant. Approximate solutions of the model are presented which indicate that the thickness of the gel layer and the velocity of each front can be predicted as a function of time. The theoretical predictions were verified by available experimental data from the fields of controlled release and microlithography.

pH-Dependent Swelling and Solute Diffusion Characteristics of Poly(Hydroxyethyl Methacrylate–CO–Methacrylie Acid) Hydrogels

Poly(hydroxyethyl methacrylate–co–methacrylie acid) hydrogels can swell extensively in a high-pH medium where the carboxyl groups are ionized. The swelling equilibrium is a strong function of the methacrylic acid composition of the polymer and pH of the medium. The nonionized gel structure was found to be rather insensitive to the amount of cross-linker, tetraethylene glycol dimethacrylate (TEGDMA), incorporated, within the range of 0.5 to 3%. This result is supportive of the existence of secondary interactions that shield the effect of covalent cross-links. Phenylpropanolamine (PPA) was used as a probe solute to study the diffusion characteristics of the poly (HEMA–co–MA) gels. Its diffusion coefficient in the swollen matrices of different methacrylic acid compositions at various pHs was measured via a desorption method. It is evident that these diffusion coefficients follow Yasudas free volume theory, which expresses an exponential relationship between the solute diffusivity in a swollen polymer membrane and the reciprocal of the membrane hydration. Although interactions exist between PPA and the hydrogel matrix, these interactions are not significant enough to perturb the free volume relationship established. This observation can be explained by the high ionic strength of the system.

Probing the Mechanisms of Drug Release from Hydroxypropylmethyl Cellulose Matrices

The transient dynamic swelling and dissolution behavior during drug release from hydroxypropylmethyl cellulose (HPMC) matrices was investigated using fluorescein as a model drug. A new flow-through cell capable of providing a well-defined hydrodynamic condition and a non-destructive mode of operation was designed for this purpose to assess the associated moving front kinetics. The results obtained show a continuous increase in transient gel layer thickness irrespective of the polymer viscosity grade or drug loading. This is attributed to the faster rate of swelling solvent penetration than that of polymer dissolution under the present experimental condition. On the other hand, the observed shrinkage of sample diameter over a longer time period demonstrates that polymer dissolution does indeed occur in HPMC matrices. Further, both the rates of polymer swelling and dissolution as well as the corresponding rate of drug release increase with either higher levels of drug loading or lower viscosity grades of HPMC. For water-soluble drugs, the present results suggest that the effect of HPMC dissolution on drug release is insignificant and the release kinetics are mostly regulated by a swelling-controlled diffusional process, particularly for higher viscosity grades of HPMC.

Probing the mechanisms of drug release from hydrogels

Abstract The swelling and drug release kinetics in suspension polymerized glassy poly(hydroxyethyl methacrylate/ (PHEMA) beads have been studied in detail using model drugs of both high and low water solubilities: oxprenolol HCl (sol. in H2O ≈ 77%) and diclofenac sodium (sol. in H2O ≈ 2.65%). The current results verify our previous findings that the drug loading has a definite effect on the drug release mechanism from hydrogels. The initial swelling front penetration has been observed to behave more Fickian as drug loading increases. Such a transition can be considered as a change of relative importance of the diffusion process versus the polymer relaxation as a function of drug loading. The swelling fronts have also been observed to accelerate near the core. This is shown to be the natural outcome of the associated moving boundary problem in spherical geometry and not, as proposed by some authors, a super-Case II transport behaviour. In all cases, the swelling bead dimension goes through a maximum followed by a gradual approach to an equilibrium value during the drug release. In addition, a doublefront formation (a swelling front and a drug dissolution front) has been observed for diclofenac sodium during the drug release due to the low drug solubility. We have also shown that by considering the increase in hydrogel bead dimension due to swelling and the decrease in dimension due to drug release, the swelling maximum in the transient dimensional changes can be qualitatively predicted. The osmotic contributions due to the presence of the drug can then be estimated from the differences between the experimental and calculated transient dimensional changes.

Effect of non-uniform initial drug concentration distribution on the kinetics of drug release from glassy hydrogel matrices

The effect of non-uniform initial drug concentration distribution, on the kinetics of drug release from polymer matrices has been examined theoretically. The results indicate that a constant-rate of drug release can be achieved, via a specific sigmoidal drug concentration distribution without the need to have a saturated drug reservoir as in a membrane-reservoir system. To test this concept, a novel approach has been developed, which utilizes the non-Fickian swelling behaviour in glassy hydrogels to develop an inflection-point containing drug concentration profile, followed by a freeze-drying step to rapidly remove the swelling solvent and immobilize in-situ the desired sigmoidal drug concentration distribution. The drug release from such a system generally exhibits a characteristic time-lag and a constant-rate release region similar to that of a membrane-reservoir system. The applicability of the present concept and process has been demonstrated experimentally with the release of oxprenolol HCl from hydrogel beads; based on 2-hydroxyethyl methacrylate polymerized with a polymeric crosslinking agent.

Initial concentration distribution as a mechanism for regulating drug release from diffusion controlled and surface erosion controlled matrix systems

The mathematical analyses of the effect of non-uniform initial drug concentration distribution on the release kinetics have been examined for both the diffusion controlled and surface erosion controlled matrix systems in planar, cylindrical and spherical geometries. Several idealized concentration profiles have been utilized in the analyses to illustrate the theory. In doing so, concentration profiles capable of generating zero-order release characteristics have been identified. These results further suggest that in addition to being able to achieve constant-rate drug release without the need to have a saturated reservoir, the concept of utilizing non-uniform initial drug concentration distribution as a mechanism for regulating drug release offers a unique opportunity to achieve programmable drug delivery in meeting a specific temporal therapeutic requirement.

Composite poly(vinyl alcohol) beads for controlled drug delivery.

A new method of preparing composite poly(vinyl alcohol) (PVA) beads with a double-layer structure has been developed, which involves a stepwise saponification of suspension polymerized poly (vinyl acetate) (PVAc) beads and subsequent stepwise cross-linking of the PVA core and shell with glu-taraldehyde. This process results in PVA beads with thin, highly cross-linked outer shells and lightly cross-linked inner cores of different degrees of cross-linking. In addition to structural characterization of the polymer based on equilibrium swelling measurements, the kinetics of water swelling and drug release from these beads were studied at 37°C using acetaminophen and proxyphylline as model drugs. The results show that the outer shell functions as a rate-controlling membrane upon increasing its cross-linking ratio, X, above 0.47. This aspect is reflected in the observed diffusional time lags and constant-rate regions during swelling and drug release. Based on observed time lags, the diffusion coefficient of water through the outer PVA shell with a high cross-linking ratio of X = 0.5 is estimated to be at least six times higher than that of acetaminophen and proxyphylline. In addition, drug diffusion coefficients in the lightly cross-linked PVA core appear to be at least 10 times larger than that in the highly cross-linked outer shell. At lower shell cross-linking ratios (X < 0.4), the diffusional time lags appear to be absent and the diffusion profiles are apparently first-order (Fickian) in nature.

Controlled Nitric Oxide Delivery Platform Based on S-Nitrosothiol Conjugated Interpolymer Complexes for Diabetic Wound Healing

Nitric oxide (NO) is known to play a critical role in enhancing wound healing as topical NO administration has demonstrated enhanced wound healing in diabetic animal models. However, this approach has been limited by the short duration of NO release, short half-life of NO, and instability of available NO donors. To overcome these deficiencies, we have developed a new NO delivery platform based on grafting S-nitrosothiols (RSNOs), derived from endogenous glutathione (GSH) or its oligomeric derivatives, phytochelatins (PCs), onto poly(vinyl methyl ether-co-maleic anhydride) (PVMMA), and their subsequent formation of interpolymer complexes with poly(vinyl pyrrolidone) (PVP). Such interpolymer complexes provide controlled release of NO for an extended duration (>10 days) and exhibit enhanced stability in the solid state over that of free RSNOs. The existence of intermolecular hydrogen bonding in such complexes and the formation of disulfide bonds following the NO release have been confirmed by FTIR and Raman. Preliminary wound healing study in a diabetic rat model demonstrates that, with a single topical application, the present controlled release NO delivery system can effectively accelerate wound closure as compared with the control (p < 0.05). The results suggest that the present NO releasing interpolymer complexes could be potentially useful for diabetic wound healing.