Thermo- and pH-sensitive glycosaminoglycans derivatives obtained by controlled grafting of poly(N-isopropylacrylamide).

Poly(N-isopropyl acrylamide) grafted heparin and chondroitin sulfate were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The copolymers were characterized by NMR, IR, SEC, DLS, SLS and NTA methods. High grafting densities were reached for both glycosaminoglycans. The temperature, pH and polymer concentration affected the low critical solution temperatures values. The increased pNIPAAm chain length, grafting density and concentration led to the sharp phase transition at 35 °C. Spherical nanogels were formed around this temperature. Terminal dodecyl trithiocarbonate groups of the copolymers were reduced to thiols that allowed formation of sensitive nanogels with sharp phase transitions induced by pNIPAAm chains. The copolymers showed no toxicity to the ocular cells and they provided the prolonged release of dexamethasone phosphate at 37 °C. These copolymers are interesting alternatives for ocular drug delivery.

Kinetic simulation model of protein secretion and accumulation in the cell microcapsules.

BACKGROUND: In cell therapy, microencapsulated cells secrete therapeutic protein, which is further released from the microcapsules. In principle, some secreted, but unreleased, protein may accumulate in the microcapsules. The kinetic simulation model was built to simulate the potential accumulation of the protein in the microcapsules. METHODS: The alginate microcapsules were cross-linked with divalent cations to encapsulate either flourescein isothiocyanate (FITC)-dextrans (molecular weights = 4.3, 10.5, 43 kDa) or retinal pigment epithelial cells (ARPE-19). The cells were genetically engineered to produce secreted alkaline phosphatase (SEAP). SEAP production from the cells was quantified with and without microcapsulation and, finally, the cells were killed with toxin to quantify the secreted but yet unreleased SEAP from the microcapsules. The empirical three-compartment kinetic model was constructed based on the release of FITC-dextrans of different molecular weights from the alginate microcapsules with different pore sizes. Protein secretion from the cells into the microcapsules was added to the model. The impact of the microcapsule wall permeability on the steady-state amounts of secreted protein in the microcapsules and in the hypothetical target compartment in the body was simulated. The simulations were compared to the experimental data from the microencapsulated SEAP secreting ARPE-19 cells. RESULTS: The model and the data show that substantial amounts (10-15 daily doses) of protein may accumulate in the microcapsules with poor wall permeability. At high permeability, the accumulation was insignificant. The pharmacokinetic simulations show that even a 1.5-fold increase in the wall permeability may result in a substantial peak in the drug amount in the target compartment, especially if the elimination rate of the protein is high. CONCLUSIONS: The kinetic simulation model for protein secretion from microcapsulated cells is a useful tool for the early kinetic prediction and risk assessment of cell therapy.

Pharmacokinetic simulation of biowaiver criteria: the effects of gastric emptying, dissolution, absorption and elimination rates.

In vitro dissolution tests can be used to waive in vivo bioequivalency studies (biowaiver), if drug has high solubility and high permeability according to biopharmaceutics classification system (BCS I). Then absorption of BCS I drugs is not dependent on drug dissolution or gastrointestinal transit time and the solid dosage form behaves like oral solution. Currently biowaivers are determined based on solubility, permeability and dissolution, but the factors related to the gastrointestinal tract and the dynamic nature of drug dissolution and systemic pharmacokinetics are not taken into account. We utilized pharmacokinetic simulation model to study effects of formulation types, and different rates of dissolution and gastric emptying on drug concentrations in plasma. Simulated maximum concentration in plasma (C(max)) and area under the curve (AUC) values of solid dosage forms were compared to the simulations of oral solution. Based on simulations about half of BCS I drugs have higher risk to fail in bioequivalency (BE) study than BCS III drugs. For these BCS I compounds 10-25% differences of C(max) were observed. Rest of the BCS I drugs and all BCS III drugs have lower risk to fail in BE study since less than 10% difference in C(max) and AUC were observed. Pharmacokinetic simulation model was valuable tool to evaluate biowaiver criteria and to study the effects of drug and physiology gastrointestinal related factors on C(max) and AUC.

Level A in vitro-in vivo correlation (IVIVC) model with Bayesian approach to formulation series.

In vitro-in vivo correlation (IVIVC) models for formulation series are useful in drug development, but the current models are limited by their inability to include data variability in the predictions. Our goal was to develop a level A IVIVC model that provides predictions with probabilities. The Bayesian approach was used to describe uncertainty related to the model and the data. Three bioavailability studies of levosimendan were used to develop IVIVC model. Dissolution was tested at pH 5.8 with basket. The IVIVC model with Bayesian approach consisted of prior and observed data. All observed data were fitted to the one-compartment model together with prior data. Probability distributions of pharmacokinetic parameters and concentration time profiles were obtained. To test the external predictability of IVIVC model, only dissolution data of formulations E and F were used. The external predictability was good. The possibility to utilize all observed data when constructing IVIVC model, can be considered as a major strength of Bayesian approach. For levosimendan capsule data traditional IVIVC model was not predictable. The usefulness of IVIVC model with Bayesian approach was shown with our data, but the same approach can be used more widely for formulation optimization and for dissolution based biowaivers.

Oligonucleotide-cationic liposome interactions. A physicochemical study.

Cationic liposomes are effective in delivering antisense oligonucleotides into cells in culture, but their interactions with the oligonucleotides are poorly understood. We studied the aggregation and fusion reactions during the formation of cationic lipid/oligonucleotide complexes in solution and their interactions with lipid bilayers. Phosphorothioate oligonucleotides (15-mer) were complexed with cationic liposomes composed of dimethyldioctadecylammonium bromide (DDAB) and dioleoylphosphatidylethanolamine (DOPE) at 8:15 molar ratio or of a commercial formulation DOTAP (N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammoniummethylsul fate), at different ratios with apparent -/+ charge ratios of 0.03-5.6. Mean size of the complexes increased with -/+ ratio so that at charge ratios 0.4-2.0 the size increased by at least an order magnitude due to the oligonucleotide induced aggregation. Resonance energy transfer experiments showed that in addition to aggregation oligonucleotides induced fusion of cationic liposomes, but the fusion was rate-controlled by the initial aggregation step. Rate constants for oligonucleotide induced aggregation were dependent on lipid concentration and were in the range of (0.2-1).10(7) M-1 s-1 and (1-10).10(7) M-1 s-1 for DDAB/DOPE and DOTAP, respectively. Increase in oligonucleotide concentration induced the aggregation and fusion until at high -/+ ratios electrostatic repulsion of negative surfaces inhibited further aggregation and fusion. DOTAP/oligonucleotide complexes did not induce leakage of calcein from neutral EPC liposomes, but did cause leakage at -/+ charge ratios of < 0.7 and > 2.0 from EPC/DOPE liposomes. Also at -/+ charge ratios below 0.8 DOTAP/oligonucleotide complexes induced leaking from negatively charged DPPC/DPPG liposomes. These results indicate that either phosphatidylethanolamine or negative charge are required in the cell membrane for fusion of cationic liposome-oligonucleotide complexes. The ratio of oligonucleotide to cationic lipid is critical in determining the physicochemical properties of the mixture.

Interactions of polymeric and liposomal gene delivery systems with extracellular glycosaminoglycans: physicochemical and transfection studies.

Complexes of DNA with cationic lipids and cationic polymers are frequently used for gene transfer. Extracellular interactions of the complexes with anionic glycosaminoglycans (GAGs) may interfere with gene transfer. Interactions of GAGs with the carrier-DNA complexes were studied using tests for DNA relaxation (ethidium bromide intercalation), DNA release (electrophoresis), and transfection (pCMVbetaGal transfer into RAA smooth muscle cells). Several cationic lipid formulations (DOTAP, DOTAP/Chol, DOTAP/DOPE, DOTMA/DOPE, DOGS) and cationic polymers (fractured dendrimer, polyethylene imines 25 kDa and 800 kDa, polylysines 20 kDa and 200 kDa) were tested. Polycations condensed DNA more effectively than the monovalent lipids. Hyaluronic acid did not release or relax DNA in any complex, but it inhibited the transfection by some polyvalent systems (PEI, dendrimers, DOGS). Gene transfer by the other carriers was not affected by hyaluronic acid. Sulfated GAGs (heparan sulfate, chondroitin sulfates B and C) completely blocked transfection, except in the case of the liposomes with DOPE. Sulfated GAGs relaxed and released DNA from some complexes, but these events were not prerequisites for the inhibition of transfection. In conclusion, polyvalent delivery systems with endosomal buffering capacity (DOGS, PEI, dendrimer) were most sensitive to the inhibitory effects of GAGs on gene transfer, while fusogenic liposomes (with DOPE) were the most resistant systems.

Cationic liposomes improve stability and intracellular delivery of antisense oligonucleotides into CaSki cells.

Antisense oligonucleotides (ODNs) are promising novel therapeutic agents against viral infections and cancer. However, problems with their inefficient delivery and inadequate stability have to be solved before they can be used in therapy. To circumvent these obstacles, a wide variety of improvements, including phosphorothioate ODNs and liposomes as a carrier system, have been developed. This study was designed to compare the effects of two cationic liposomes on the intracellular delivery and stability of ODNs in CaSki cell cultures. Also the stability of 3'-end phosphorothioate ODNs were investigated. The 3'-modification neither had any effect on the delivery, nor protected the ODNs against degradation. The cellular delivery and stability of ODNs was improved with both cationic liposomes, but a cationic liposomal preparations containing dimethyldioctadecylammonium bromide and dioleoylphosphatidylethanolamine (DDAB/DOPE) was more efficient than commercially available N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammoniummethylsulf ate (DOTAP). The improved cellular delivery was largely due to the stabilization of ODNs by cationic liposomes. The improved stability in the culture medium indicates that the cationic liposomes per se protect the ODNs from enzymatic degradation. Indeed, intact ODNs were found in the cytoplasm and nucleus only when delivered by cationic liposomes.

Novel cationic amphiphilic 1,4-dihydropyridine derivatives for DNA delivery.

In order to find new efficient and safe agents for gene delivery, we have designed and synthesized nine novel single- and double-charged amphiphiles on the base of 1,4-dihydropyridine (1,4-DHP) ring. Some biophysical properties of the amphiphilic dihydropyridines and their complexes with DNA were examined. We investigated the transfer of beta-galactosidase gene into fibroblasts (CV1-P) and retinal pigment epithelial (D 4O7) cell lines in vitro. The structure-property relationships of the compounds were investigated in various ways. The net surface charges of 1,4-DHP liposomes were highly positive (25-49 mV). The double-charged compounds condensed DNA more efficiently than single-charged and the condensation increases with the increasing +/- charge ratio between the carrier and DNA. Double-charged compounds showed also buffering properties at endosomal pH and these compounds were more efficient in transfecting the cells, but transfection efficiency of amphiphiles was cell type-dependent. The length of alkyl chains in double-charged compounds affected the transfection efficacy. The most active amphiphile (compound VI) was double-charged and had two C(12) alkyl chains. At optimal charge ratio (+/- 4), it was 2.5 times more effective than PEI 25 and 10 times better than DOTAP, known efficient polymeric and liposomal transfection agents. Formulation of amphiphiles with DOPE did not change their activities. Our data demonstrate some important effects of amphiphile structure on biophysics and activity. The data also suggest that cationic amphiphilic 1,4-DHP derivatives may find use as DNA delivery system.

Interaction of liposomes with human skin in vitro--the influence of lipid composition and structure.

Liposomes have been suggested as a vehicle for dermal and transdermal drug delivery, but the knowledge about the interaction between lipid vesicles and human skin is poor. Therefore, we visualized liposome penetration into the human skin by confocal laser scanning microscopy (CLSM) in vitro. Liposomes were prepared from phospholipids in different compositions and labeled with a fluorescent lipid bilayer marker, N-Rh-PE (L-alpha-phosphatidylethanolamine-N-lissamine rhodamine B sulfonyl). Fluorescently labelled liposomes were not able to penetrate into the granular layers of epidermis. However, the fluorescence from liposome compositions containing DOPE (dioleylphosphatidyl ethanolamine) was able to penetrate deeper into the stratum corneum than that from liposomes without DOPE. Pretreatment of skin with unlabeled liposomes containing DOPE or lyso-phosphatidyl choline (lyso-PC) enhanced the subsequent penetration of the fluorescent markers, N-Rh-PE and sulforhodamine B into the skin, suggesting possible enhancer activity, while most liposomes did not show such enhancement. Resonance energy transfer (RET) and calcein release assay between stratum corneum lipid liposomes (SCLLs) and the phospholipid vesicles suggested that the liposomes containing DOPE may fuse or mix with skin lipids in vitro and loosen the SCLL bilayers, respectively. Among the factors not affecting stratum corneum penetration were: negative charge, cholesterol inclusion and acyl chain length of the phospholipids. In conclusion, fusogenicity of the liposome composition appears to be a prerequisite for the skin penetration.

Improved ocular: systemic absorption ratio of timolol by viscous vehicle and phenylephrine.

Increasing the ocular absorption of timolol relative to its systemic absorption is important clinically because ophthalmic timolol may cause serious respiratory, cardiac, and central nervous system side effects. The authors evaluated the effects of phenylephrine coadministration and solution viscosity on the aqueous humor:plasma and iris ciliary body:plasma ratios of peak timolol concentrations after ocular application. Timolol eye drops (5 mg/ml, 25 microliters) were administered to the eyes of pigmented rabbits. Coadministered phenylephrine (0.8-8.2 mg/ml) decreased the systemic peak concentrations of timolol significantly. Since ocular absorption of timolol was not affected by phenylephrine, the ocular:systemic concentration ratios were improved four- to fivefold. Phenylephrine slows down the systemic absorption of timolol by constricting the conjunctival and nasal capillaries. The ratios of the aqueous humor:plasma and iris ciliary body:plasma peak concentration of timolol were improved three- to ninefold in the presence of sodium carboxymethylcellulose compared with nonviscous eye drops. The improved ocular penetration is probably due to the longer corneal contact, and the decreased rate of systemic absorption may be caused by the slower spreading of the solution on the nasal mucosa. Compared with timolol eye drops, the ratio of the eye:plasma peak timolol concentrations was improved tenfold by using viscous eye drops with phenylephrine. Systemic concentrations of ophthalmic timolol and possibly related side effects can be decreased when timolol is instilled in a viscous vehicle with a low phenylephrine concentration.

Dexmedetomidine-induced ocular hypotension in rabbits with normal or elevated intraocular pressures.

This study covered the ocular hypotensive effects of the stereoisomers of the alpha 2-adrenoceptor agonist medetomidine. The dextro-isomer, dexmedetomidine, is known from pharmacologic experiments to be a specific, potent, and selective full agonist at alpha 2-adrenoceptors, whereas the levo-enantiomer seems to be almost inactive. Thus, the levo-isomer (0.5 mg/ml, 25 microliters) had no significant effect on intraocular pressure. After unilateral topical administration, dexmedetomidine (0.5 mg/ml, 25 microliters) lowered intraocular pressure bilaterally in normal rabbits and in rabbits with intraocular pressure elevated after laser irradiation of the pigmented trabecular band of the anterior chamber angle. In the treated (ipsilateral) eye of normal rabbits, a maximum decrease of 4.6 +/- 0.6 mmHg was observed at 2 hr post treatment. In the contralateral eye, the maximum decrease was 4.1 +/- 0.5 mmHg at 1 hr after treatment. In rabbits with laser-induced elevation of intraocular pressure, the maximum decrease in treated hypertensive eyes was 13.5 +/- 0.3 mmHg 1 hr after dexmedetomidine administration. These results indicate that the selective alpha 2-adrenoceptor agonist, dexmedetomidine, is a potent and effective drug for decreasing intraocular pressure in rabbits.

Culture model of human corneal epithelium for prediction of ocular drug absorption.

PURPOSE: The main purpose of this study was to develop a cell culture model of immortalized epithelium from the human cornea for drug permeability testing. METHODS: Immortalized human corneal epithelial (HCE) cells were grown on filters, with various filter materials and coating procedures. In the optimal case, HCE cells were grown on polyester filters coated with rat tail collagen gel containing fibroblast cells. Transepithelial electrical resistance (TER) was measured during the growth of the cells to evaluate the epithelial differentiation and tightness of the epithelial cell layers. Transmission electron microscopy (TEM) was used to show the formation of tight junctions, desmosomes, and microvilli. Cellular morphology was characterized by light microscopy. Permeabilities of (3)H-mannitol and 6-carboxyfluorescein were determined, to evaluate the intercellular spaces of the epithelium. Rhodamine B was used as a lipophilic marker of transcellular permeability. Permeabilities of the excised rabbit corneas were determined in side-by-side diffusion chambers. RESULTS: The TER values of the corneal epithelial cultures were 200 to 800 Omega x cm(2), depending on the culture conditions. In optimal conditions, cultured corneal epithelium consisted of five to eight cell layers, TER was at least 400 Omega x cm(2), and the most apical cells were flat, with tight junctions, microvilli, and desmosomes. The permeability coefficients (P(cell), 10(-6) cm/sec) for (3)H-mannitol, 6-carboxyfluorescein, and rhodamine B were 1.42 +/- 0.36, 0.77 +/- 0.40, and 16.3 +/- 4.0, respectively. Corresponding values (at 10(-6) cm/sec) for the isolated rabbit corneas were 0.38 +/- 0.16, 0.46 +/- 0.27, and 18.1 +/- 4.0, respectively. CONCLUSIONS: The TER, morphology, and permeability of the cultured corneal epithelial cells resemble those of the intact cornea. This cell culture model may be useful in evaluation of corneal drug permeation and its mechanisms.

Characterization of paracellular and aqueous penetration routes in cornea, conjunctiva, and sclera.

PURPOSE: To characterize quantitatively the paracellular permeation routes in rabbit cornea, conjunctiva, and sclera using polyethylene glycol (PEG) oligomers. METHODS: Corneal, conjunctival, and scleral tissues from New Zealand white rabbits were tested individually in a modified two-chamber Ussing apparatus with the mixture of PEGs with mean molecular weights 200, 400, 600, and 1000 in glutathione bicarbonated Ringer's solution buffer on the donor side of the chamber. The samples and standards were analyzed with high-performance liquid chromatography-thermospray mass spectrometry method. The pore sizes and the pore densities of the corneal and conjunctival epithelia were calculated using an effusion-like approach. RESULTS: The conjunctival and scleral tissues were 15 to 25 times more permeable than the cornea and the molecular size affected the conjunctival permeability less than that of the cornea. The palpebral and bulbar conjunctivas had equal permeabilities. The scleral permeability was approximately half of that in the conjunctiva and approximately 10 times more than in the cornea. The conjunctival epithelia had 2 times larger pores and 16 times higher pore density than the cornea. The total paracellular space in the conjunctiva was estimated to be 230 times greater than that in the cornea. CONCLUSIONS: The conjunctival epithelium, due to its higher membrane permeability and larger absorptive and intercellular space surface areas, is the most viable route for ocular delivery of peptides and oligonucleotides.

Cationic liposomes mediated delivery of antisense oligonucleotides targeted to HPV 16 E7 mRNA in CaSki cells.

The "high risk" types 16 and 18 of human papillomavirus (HPV) are involved in the etiology of genital squamous cell carcinoma. The early genes 6 and 7 (E6-E7) of these viruses code for the major transforming proteins, capable of inducing cell transformation alone or acting synergistically with other oncogenes. Antisense oligonucleotides, recently applied to inhibit the functions of a number of cellular and viral proteins, might provide the basis for a new therapeutic strategy against HPV-induced malignancies. We studied the proliferation of CaSki cells by the MTT assay after their exposure to HPV 16 E7 mRNA antisense oligonucleotides with and without cationic liposomes (containing dimethyldioctadecylammonium bromide DDAB, and dioleylphosphatidylethanolamine, DOPE). Unmodified oligonucleotides (either 12- or 23-mers) did not have any effect on either CaSki cell proliferation or morphology when compared with the untreated cells. The cellular uptake of oligonucleotides was significantly enhanced by the cationic liposomes as assessed by confocal laser scanning microscopy (CLSM). The cationic liposomes were toxic to the cells as demonstrated by the reduced cell number and altered cell morphology. Only a slight reduction of the cell proliferation was seen when antisense 12-mer was protected from its 3'- and 5'-ends with thiolate and FITC, respectively. Both the 12- and the 23-mers with the cationic liposomes inhibited cell proliferation, the inhibitory effect being longer with the 23-mer. Overall, the MTT assay was less sensitive than light microscopy to reveal the toxic effects on CaSki cells. The results suggest that antisense oligonucleotides targeted to HPV 16 E7 mRNA can be introduced into CaSki cells with cationic liposomes.

Minimizing systemic absorption of topically administered ophthalmic drugs.

Due to absorption several ocularly applied medications give rise to systemic side-effects. The problem of systemic drug absorption should be taken into account in designing ocular drug and dosage forms so that oculospecificity of the medications is optimized. In this review we summarize the current knowledge about the systemic absorption of ocularly applied topical drugs. Special emphasis is directed to the methods that can be used to minimize systemic absorption and increase the oculospecificity of drugs, e.g., reducing volume and increasing viscosity of eyedrops, controlling drug release from depot preparations, prodrug-derivatization, and addition of vasoconstrictive agents.

Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alterations.

The outermost layer of the skin, stratum corneum (SC), provides an outstanding barrier against the external environment and is also responsible for skin impermeability toward most solutes. The barrier function is related to the unique composition of the SC lipids and their complex structural arrangement. The lipoidal matrix of the SC, therefore, is a target of penetration enhancer action. The literature on the skin barrier structure and function and on the mechanisms of action of some well established permeation promoters, with a focus on their impact on SC structural alterations, is reviewed. Data obtained from infrared, thermal, and fluorescence spectroscopic examinations of the SC and its components imply enhancer improved permeation of solutes through the SC is associated with alterations involving the hydrocarbon chains of the SC lipid components. Data obtained from electron microscopy and X-ray diffraction reveals that the disordering of the lamellar packing is also an important mechanism for increased permeation of drugs induced by penetration enhancers.

Controlled transdermal iontophoresis by ion-exchange fiber.

The objective of this study was to assess the transdermal delivery of drugs using iontophoresis with cation- and anion-exchange fibers as controlled drug delivery vehicles. Complexation of charged model drugs with the ion-exchange fibers was studied as a method to achieve controlled transdermal drug delivery. Drug release from the cation-exchange fiber into a physiological saline was dependent on the lipophilicity of the drug. The release rates of lipophilic tacrine and propranolol were significantly slower than that of hydrophilic nadolol. Permeation of tacrine across the skin was directly related to the iontophoretic current density and drug concentration used. Anion-exchange fiber was tested with anionic sodium salicylate. The iontophoretic flux enhancement of sodium salicylate from the fiber was substantial. As the drug has to be released from the ion-exchange fiber before permeating across the skin, a clear reduction in the drug fluxes from the cationic and anionic fibers were observed compared to the respective fluxes of the drugs in solution. Overall, the ion-exchange fibers act as a drug reservoir, controlling the release and iontophoretic transdermal delivery of the drug.

Phospholipids affect stratum corneum lipid bilayer fluidity and drug partitioning into the bilayers.

Phospholipids, e.g. fluid-state EPC (l-alpha-phosphatidylcholine from egg yolk), may diffuse into the stratum corneum and enhance dermal and transdermal drug penetration, while many other phospholipids, e.g. gel-state DSPC (distearoylphosphatidyl choline), are not able to do this. These effects are suggested to be due to the interactions between the phospholipids and the skin lipid bilayers, and so an in vitro method was developed to evaluate the influence of phospholipids on the distribution of drugs to stratum corneum lipids. The distribution coefficients of estradiol, progesterone and propranolol between stratum corneum lipid liposomes (SCLLs) without phospholipids or with EPC, DSPC, SPC (l-alpha-phosphatidylcholine from soybean) or DOPE (dioleylphosphatidyl ethanolamine), and pH 7.4 buffer were determined. Fluid-state phospholipids in SCLLs increased the partitioning of drugs into SCLLs, while gel-state lipid, DSPC, did not. The increased distribution of drugs into the SCLLs was at least partially due to the increased fluidity of SCLL bilayers by phospholipids, which was shown using steady-state fluorescence anisotropy. This in vitro method enables screening of the effects of phospholipids and other permeation enhancers on stratum corneum bilayer fluidity and drug partitioning.

Roles of acid/base nature and molecular weight in drug release from matrices of gelfoam and monoisopropyl ester of poly(vinyl methyl ether-maleic anhydride).

Ophthalmic drug inserts are usually placed in the conjunctival sac. Being in contact with the conjunctiva, they may provide means to deliver large and hydrophilic molecules, such as peptides and oligonucleotides into the eye. We evaluated Gelfoam and monoisopropyl ester of poly(vinyl methyl ether/maleic anhydride) (PVM/MA) as potential polymers for ocular inserts. Matrices were solvent cast with model drugs that had different pKa, molecular weight and hydrophilicity. Drug release from the matrices as well as charge and swelling of Gelfoam(R)-matrix were studied. The release of drugs from PVM/MA-matrices was by erosion of the polymer matrix. The molecular weight and other variants of the releasing compound did not affect their release. In Gelfoam(R)-matrices the release was diffusion controlled and it was affected by the pH of the external solution as well as the charge and molecular weight of the studied compound.

Transport of drugs across porous ion exchange membranes.

Porous ion exchange membranes have potential applications for drug delivery systems. Permeability of these membranes can be controlled by environmental factors like pH and ionic strength but also the drug properties have an important role in the permeation process. In this paper the influence of the drug charge, lipophilicity and molecular weight on the diffusional drug flux is demonstrated. The membranes under study were poly(acrylic acid) (PAA) grafted porous poly(vinylidene fluoride) (PVDF) membranes which are cation selective due to the partial ionization of carboxyl groups in grafted PAA chains. At low pH the membrane pores are open and the drugs can diffuse through the membrane quite easily. However, at pH 7 the grafted chains partially block the pores and the diffusional flux of bigger drug molecules (Mw9400) decreases five orders of magnitude and also the flux of smaller molecules is clearly reduced. When the influence of the drug charge on the diffusion of the drugs across the membranes was studied, it turned out that the PAA-PVDF membranes facilitate the transport of cationic drugs and repel anionic ones. The presented mathematical model, based on Donnan drugs equilibrium and measured transport number data, predicted the observed trends reasonably well.