In situ gelling xyloglucan/pectin formulations for oral sustained drug delivery

This study has examined the gelation and release characteristics of mixtures of xyloglucan, which has thermally reversible gelation characteristics, and pectin, the gelation of which is ion responsive, with the aim of formulating an in situ gelling vehicle suitable for oral sustained drug delivery. An investigation of the effect of the inclusion of pectin (0.75% (w/w)) on the rheological properties of gels formed from solutions of xyloglucan (1.5 and 2.0% (w/w)) showed a significantly greater gel strength when pectin was present in the formulation. The in vitro release of paracetamol from gels containing 1.5% (w/w) xyloglucan, and 1.5 or 2.0% (w/w) xyloglucan/0.75% (w/w) pectin was diffusion-controlled. Measurement of plasma levels of paracetamol after oral administration to rats of a solution containing 1.5% (w/w) xyloglucan and 0.75% (w/w) pectin showed that a more sustained release and higher drug bioavailability was achieved from the gels formed by the in situ gelation of this formulation compared to that of a 1.5% (w/w) xyloglucan solution; 0.75% (w/w) solutions of pectin did not form gels under these conditions. Visual observation of the contents of the rat stomach at intervals after oral administration showed that the inclusion of pectin in the xyloglucan solutions was effective in reducing gel erosion, so sustaining drug release.     

Ion-activated in situ gelling systems for sustained ophthalmic delivery of ciprofloxacin hydrochloride

The poor bioavailability and therapeutic response exhibited by the conventional ophthalmic solutions due to precorneal elimination of the drug may be overcome by the use of in situ gel forming systems that are instilled as drops into the eye and undergo a sol-gel transition in the cul-de-sac. Our present work describes the formulation and evaluation of an ophthalmic delivery system of an antibacterial agent, CPH, based on the concept of ion-activated in situ gelation. Gelrite gellan gum, a novel ophthalmic vehicle that gels in the presence of mono or divalent cations, present in the lacrimal fluid was used alone and in combinations with sodium alginate as the gelling agent. The developed formulations were therapeutically efficacious and provided sustained release of the drug over an 8-hr period in vitro.     

In situ gelling pectin formulations for oral drug delivery at high gastric pH

The aim of the study was to compare the gelation and drug release characteristics of formulations of pectin with high (31%) and low (9%) degrees of methoxylation over a wide pH range (pH 1.2-5.0). Dilute solutions of pectin (1.5%, w/v) containing complexed calcium ions formed gels in vitro at low pH (pH<2.5) as a consequence of cross-linking of the galacturonic chains by calcium ions released from the complex, but the efficiency of gelation was significantly reduced with increase of pH because of incomplete release of complexed Ca(++). Gelation of formulations of pectin with a degree of esterification of 9% (DE9) was observed over the pH range 2.5-5.0 in the presence of 1.6mM Ca(++), but was incomplete in formulations of pectin with a degree of esterification of 31% (DE31). A sustained release of ambroxol was observed following oral administration of pectin DE9 formulations to gastric-acidity controlled rabbits at pH 5.5-5.7 and visual observation of the stomach contents of these rabbits confirmed in situ gelation of these formulations. There was no evidence of in situ gelation of pectin DE31 formulations under these conditions and a rapid initial drug release was observed. Differences in gelling characteristics in this pH range were attributed to the greater susceptibility of low methoxylated pectin to cross-linking by di- and tri-valent ions present in the gastric juice. It is concluded that formulations of pectin with a low degree of esterification have potential application as in situ gelling vehicles for the sustained delivery of drugs following oral administration under conditions of high gastric pH.     

The influence of the degree of esterification on the release characteristics of in situ gelling pectin formulations for oral sustained delivery of paracetamol

The aim of this study was to examine the effect of a change of the degree of esterification of pectin on the in situ gelation and release characteristics of 1.5% (w/v) pectin solutions over a wide pH range. Formulations of pectin with degrees of esterification of 9% (DE9) and 31% (DE31) containing complexed calcium ions formed gels in vitro at pH 1.2 as a consequence of cross-linking of the pectin chains by free calcium ions released from the complex. In vitro release of paracetamol from these gels was diffusion controlled. A sustained release of paracetamol was observed following oral administration of pectin DE9 and DE31 formulations to gastric acidity-controlled rats at pH 2.5 but only with DE9 formulations at pH 5.5. Examination of the stomach contents confirmed effective in situ gelation of pectin DE9 formulations at a gastric pH of 6 but there was no evidence of the gelation of pectin DE31 formulations at this pH.     

In situ gel systems as 'smart' carriers for sustained ocular drug delivery

INTRODUCTION: In situ gel systems refer to a class of novel delivery vehicles, composed of natural, semisynthetic or synthetic polymers, which present the unique property of sol-gel conversion on receipt of biological stimulus. AREAS COVERED: The present review summarizes the latest developments in in situ gel technology, with regard to ophthalmic drug delivery. Starting with the mechanism of ocular absorption, the review expands on the fabrication of various polymeric in situ gel systems, made up of two or more polymers presenting multi-stimuli sensitivity, coupled with other interesting features, such as bio-adhesion, enhanced penetration or sustained release. Various key issues and challenges in this area have been addressed and critically analyzed. EXPERT OPINION: The advent of in situ gel systems has inaugurated a new transom for 'smart' ocular delivery. By virtue of possessing stimuli-responsive phase transition properties, these systems can easily be administered into the eye, similar to normal eye drops. Their unique gelling properties endow them with special features, such as prolonged retention at the site of administration, followed by sustained drug release. Despite the superiority of these systems as compared with conventional ophthalmic formulations, further investigations are necessary to address the toxicity issues, so as to minimize regulatory hurdles during commercialization.     

Percutaneous absorption of non-steroidal anti-inflammatory drugs from in situ gelling xyloglucan formulations in rats

The potential of gels formed in situ by dilute aqueous solutions of a xyloglucan polysaccharide derived from tamarind seed as sustained release vehicles for percutaneous administration of non-steroidal anti-inflammatory drugs has been assessed by in vitro and in vivo studies. Chilled aqueous solutions of xyloglucan that had been partially degraded by beta-galactosidase formed gels at concentrations of 1-2% w/w when warmed to 37 degrees C. The in vitro release of ibuprofen and ketoprofen at pH 7.4 from the enzyme degraded xyloglucan gels and the subsequent permeation of these fully ionized drugs through cellulose membranes followed root-time kinetics over a period of 12 h after an initial lag period. Diffusion coefficients were appreciably higher when the drugs were released from 1.5% w/w xyloglucan gels than when released from 25% w/w Pluronic F127 gels formed in situ under identical conditions. The difference in release rates was attributed to differences in the structure of the gels. The permeation rate of ibuprofen through excised skin was higher than that of ketoprofen when released from both gels, but of similar magnitude through cellulose membranes. Plasma concentrations of ibuprofen and ketoprofen from gels formed in situ following topical application of chilled aqueous solutions of xyloglucan and Pluronic F127 to the abdominal skin of rats were compared. The bioavailabilities of ibuprofen and ketoprofen were significantly higher when released from xyloglucan gels compared to Pluronic F127 gels. Occlusive dressing techniques had a greater enhancing effect on the bioavailability of ibuprofen when released from Pluronic gels.     

Comparison of in situ gelling formulations for the oral delivery of cimetidine

Three liquid formulations with in situ gelling properties have been assessed for their potential for the oral delivery of cimetidine. The formulations were dilute solutions of: (a) enzyme-degraded xyloglucan, which form thermally reversible gels on warming to body temperature; (b) gellan gum and; (c) sodium alginate both containing complexed calcium ions that form gels when these ions are released in the acidic environment of the stomach. The in vitro release of cimetidine from gels of each of the compounds followed root-time kinetics over a period of 6 h. Plasma levels of cimetidine after oral administration to rabbits of each of the formulations were compared with those resulting from administration of a commercial cimetidine/alginate suspension with an identical drug loading. In vivo release characteristics of each of the in situ gelling formulations were similar to those of the commercial preparation.     

In situ gel formulations for gene delivery: release and myotoxicity studies

The in vitro release of plasmid DNA and salmon sperm DNA from in situ gel formulations was investigated. Two in situ gel systems were studied: (a) an interpolymeric complex (IPC) of water-soluble polymers polymethacrylic acid (PMA) and polyethylene glycol (PEG) and (b) a hydroxypropylmethylcellulose-carbopol system (H:C). Two-way analysis of variance with replication demonstrated that both gel composition and medium pH influenced significantly the release of plasmid DNA from in situ gel formulations. When the release of both types of DNA was compared, higher release was observed for plasmid DNA compared to genomic salmon sperm DNA. Conformational analysis of the released plasmid DNA showed that DNA was released without degradation, but with remarkable conversion from supercoiled (SC) to open circular (OC). In addition, the tested in situ gel systems demonstrated protection from DNAse I degradation. The myotoxicity of the injectable gelling solutions was assessed by the cumulative release of creatine kinase (CK) over 120 min from the isolated rodent extensor digitorum longus (EDL) muscle. A higher level of cumulative CK was observed for IPC when compared to H:C (2:1). These results demonstrate that the in situ gelling systems can be considered as a valuable injectable controlled-delivery system for pDNA in their role to provide protection from DNAse degradation.     

The effect of taste masking agents on in situ gelling pectin formulations for oral sustained delivery of paracetamol and ambroxol

The aim of this study was to examine the influence of polyhydric alcohols (taste masking agents) on the rheological properties of in situ gelling pectin formulations and on the in vitro and in vivo release of paracetamol and ambroxol from these formulations. Gelation of orally administered pectin solutions containing calcium in complexed form occurred on release of calcium in the acidic environment of the stomach. Inclusion of 10% (w/v) sorbitol in 2% (w/v) pectin sols reduced the viscosity and ensured Newtonian flow properties. Xylitol and mannitol in similar concentrations were less effective in reducing viscosity; sucrose increased viscosity and caused non-Newtonian flow. The in vitro release of paracetamol from 2% (w/v) pectin gels formulated with 10% (w/v) of sorbitol, erythritol, xylitol or mannitol, and of ambroxol from 2% (w/v) pectin gels containing 10% (w/v) sorbitol, followed diffusion-controlled kinetics. Pectin gels (2%, w/v) containing sorbitol (10%, w/v) sustained the release of paracetamol in the rat stomach and bioavailabilities of approximately 90% of those from an orally administered paracetamol syrup were achieved. Sustained release of ambroxol from in situ gelling formulations was achieved with pectin concentrations of 1.5 and 1% (w/v) and a sorbitol concentration of 10% (w/v).     

The influence of gastric acidity and taste masking agent on in situ gelling pectin formulations for oral sustained delivery of acetaminophen

Dilute solutions of pectin containing complexed calcium ions form gels when these ions are released in the acidic environment of the stomach. The aim of this study was to examine the influence of a variation of gastric pH and the addition of a taste masking agent on the gelation of the pectin solutions and on the in vitro and in vivo release of acetaminophen from the gels. Increase of pH above 2.5 and addition of 10% (w/v) D-sorbitol significantly affected the ability of 1.5% (w/v) pectin solutions to form coherent gels in vitro. Gelation of sorbitol-free formulations was observed at pH 1.2 and in vitro release of acetaminophen from the gels followed diffusion-controlled kinetics; in vitro gelation of these formulations, however, was incomplete at pH 3.0 resulting in poor sustained release characteristics. Inclusion of 10% (w/v) D-sorbitol in the formulations inhibited the in vitro gelation of the 1.5% (w/v) pectin sols and poor sustained release properties were noted from these formulations even at pH 1.2. The bioavailability of acetaminophen from gels formed in the stomach of gastric-acidity controlled rabbits following oral administration of the liquid formulations was not, however, significantly affected either by the inclusion of 10% (w/v) D-sorbitol or increase of pH to 3.6. Visual observation showed in situ gelation of 1.5% (w/v) pectin formulations containing D-sorbitol at pH 4.3 suggesting that normal variations of gastric acidity in the fasting state will have no effect on the bioavailability of acetaminophen when delivered using these formulations.     

Ion-activated in situ gelling systems for antisense oligodeoxynucleotide delivery to the ocular surface

Ion-activated in situ gelling systems are able to cross-link with the cations present in the tear fluid, forming a gel on the ocular surface and prolonging corneal contact time. Corneal scrape wounding offers an exceptional model to investigate the efficacy of these formulations for connexin43 (Cx43) antisense oligodeoxynucleotide (AsODN) delivery used to improve wound repair. Systems based on gellan gum and carrageenan have previously been found advantageous in terms of their physicochemical properties, in vitro and in vivo release profiles and precorneal retention. The present study describes AsODN penetration into corneal tissue after wounding and determines the formulations' delivery efficacy by evaluating wound size, tissue inflammation and connexin levels. No difference was shown between the penetration patterns of the formulations, with most of the AsODN accumulating in the epithelium close to the wound leading edge and the stroma underlying the wound. However, significant differences were seen in the delivery efficacy, with gellan gum and carrageenan based systems resulting in the lowest connexin levels and subsequently in the greatest reduction in wound size, the least stromal edema and hypercellularity. This demonstrates their potential use as delivery vehicles for AsODNs to the ocular surface.     

In-vitro study of physostigmine salicylate and pilocarpine hydrochloride release from different gel formulations

Effect of methylcellulose and polyethylene glycol (PEG1 and PEG2) gel formulations on in-vitro release of combination of 0.25% w/w physostigmine salicylate and 1% w/w pilocarpine hydrochloride was investigated in comparison with a fatty base containing the same drugs by using a stationary dialysis technique. The results showed that the release of both drugs was very slow from the fatty base while a maximum release was attained from methylcellulose gel formulation followed by PEG1 and then PEG2 gel formulations as indicated by the calculated area under curves (AUC) for the amounts of drugs released from different formulations.     

Stimuli-responsive hydrogels for controlled pilocarpine ocular delivery

A series of vinyl hydrogels containing α-aminoacid (L-histidine, L-valine) residues was synthesized and their swelling properties evaluated at different pHs and temperatures. Unlike the zwitterionic compound containing only the l-histidine, a dual-stimuli responsiveness was improved in the carboxyl acid hydrogels carrying the l-valine residues (HVa). Besides the COOH functionality, the presence of either isopropyl and amido groups in the monomer structure renders the hydrogel also temperature-responsive, in a similar manner as the well-known poly(N-isopropylacrylamide) (pNIPAAm). The three HVa hydrogels (cross-linked with 1, 2, and 5 mol% of N,N'-ethylene-bisacrylamide, EBA) show a phase separation at the same critical pH4, although a different swelling was improved by the amount of EBA. In buffered solutions, the effect of increasing temperature led to decrease the swelling and, as the pH is close to the critical one, a further and sharper collapse of the hydrogel may be tuned. The release study of pilocarpine in physiological conditions showed a burst effect within the first few hours, followed by a sustained release for a week. The initial burst effect was strongly dependent on the kind of hydrogel investigated. As the pilocarpine is a basic molecule (pK(a)7.2), it may interact more strongly with the free carboxyl groups in the ionized state of the HVa hydrogels than the zwitterionic species of the histidine compounds. The releasing profile shows a three time greater release of the pilocarpine loaded in the HVa hydrogels. The hydrogels were found to be non-toxic against the mouse fibroblast NIH3T3 cells. The presence of pilocarpine strongly increased the cell proliferation even after 2 days.     

Design and evaluation of baicalin-containing in situ pH-triggered gelling system for sustained ophthalmic drug delivery

A phenomenon was observed for the behavior of hypromellose matrices during dissolution. The tablet laminated radially, with both edges curled outwards, forming a "butterfly" shape. The butterfly effect is thus coined to describe this behavior. Due to the flamboyant shape assumed by the hydrated matrix, the apparent surface area for drug release was significantly increased. This study attempted to elucidate mechanistically the cause of this butterfly effect. Two formative mechanisms were proposed based on the behavior of moving solvent fronts and the anisotropic expansion of materials in solution. It was hypothesized that the particle size of hypromellose, applied compaction force used and proportions of both insoluble and soluble excipients contributed to the butterfly effect. The influence of the expanded shape on the mechanism and rate of drug release was also investigated. Matrix formulation was an important factor. Greater drug release was observed when the butterfly-shaped hydrated matrix was formed. The drug release profiles generally fitted the Higuchi and Korsmeyer-Peppas equations, indicating a combination of both diffusion and erosional drug release mechanisms. A combination of both fine and coarse hypromellose size fractions and adequate compaction force (more than 3 kN) were necessary for the manifestation of the butterfly effect.     

Sustained release ophthalmic formulations of pilocarpine

The bioavailability of drugs from conventional ophthalmic formulations is low. To optimize the therapy, sustained release ophthalmic dosage forms are warranted. Hydrogels such as sodium-carboxymethyl cellulose, hydroxypropylmethyl cellulose, Carbopol-940, Carbopol-941 and Lutrol-FC-127 increase the duration of action of various drugs. Gels containing pilocarpine were prepared and evaluated by measuring the intensity and duration of miotic response in albino rabbits. Carbopol-940 gels, being the best of those used, were studied further for the effect of its concentration and of additives (benzalkonium chloride, phenylmercuric nitrate, chlorbutol and disodium edetate), autoclaving at 121 degrees C for 30 min and irradiation with gamma rays (2.5 Mrad), on the end product.     

Sustained ocular delivery of brimonidine tartrate using ion activated in situ gelling system

The poor bioavailability and therapeutic response exhibited by conventional eye drops due to rapid precorneal elimination of the drug may be overcome by the use of an in situ gelling systems that are instilled as drops into the eye and undergo a sol-to-gel transition in the cul-de-sac which improves patient compliance as the dosage regimen is one drop of the dosage form twice a day. The loss of drug overcomes due to the immediate gel formation between the eye membrane and the drug being entrapped simultaneously in sol-gel transition in the cul de sac. The present work describes the formulation and evaluation of an ophthalmic delivery system of an antiglaucomal agent, brimonidine tartrate based on the concept of ion-activated in situ gelation. Gelrite was used as the gelling agent, which gels in the presence of mono or divalent cations present in the lacrimal fluid. The formulations were evaluated for clarity, pH measurement, gelling capacity, drug content estimation, rheological study, in-vitro diffusion study, antibacterial activity, isotonicity testing, eye irritation testing. In the developed formulations Gelrite Brimonidine-3 (GB3) exhibited sustained release of drug from formulation over a period of 8 hrs thus increasing residence time of the drug, non-irritating with no ocular damage or abnormal clinical signs to the cornea, iris or conjunctiva, stable and sterile. These results demonstrate that the developed system is an alternative to conventional ophthalmic drops, with better patient compliance, and is industrially oriented and economical.     

Comparison of ion-activated in situ gelling systems for ocular drug delivery. Part 1: physicochemical characterisation and in vitro release

Cytarabine (1-β-D-arabinofuranosylcytosine, Ara-C), a pyrimidine nucleoside analogue, is an attractive therapeutic agent for the treatment of both acute and chronic myeloblastic leukemias. 1,1',2-tris-nor-Squalene acid (squaleneCOOH) has been conjugated to cytarabine with the formation of the squalenoyl-cytarabine prodrug, in order to improve the drug lipophilicity and, consequently, the affinity towards the environment of biological membranes, as well as of lipophilic carriers. The interaction of cytarabine and its prodrug with dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles and monolayers has been studied by the differential scanning calorimetry and the Langmuir-Blodgett techniques. The interaction has been evaluated considering the effect of the compounds on the DMPC MLV and monolayers behaviour. The aim was to have information on the interaction of the drug and the prodrug with the biological membranes and on the possibility to use liposomes as carriers for the prodrug. The results showed an improved affinity of the prodrug with MLV and monolayers with respect to the free drug.     

In situ gelling hydrogels incorporating microparticles as drug delivery carriers for regenerative medicine

Aqueous solutions of blends of biodegradable triblock copolymers, composed of poly(D,L-lactide-co-glycolide) (PLGA) and poly(ethylene glycol) (PEG) with varied D,L-lactide to glycolide ratios, displayed thermosensitivity and formed a gel at body temperature. The gel window of the blend solutions could be tuned by varying the blending ratio between the two components. Furthermore, the storage modulus of the resultant hydrogel from the copolymer blends at body temperature was higher than that of each individual component. Incorporation of poly(D,L-lactide) (PDLLA) microparticles (0.5-40% w/v) within the in situ gelling hydrogel did not change the sol-gel transition temperatures of the polymer solutions, while the mechanical strength of the resultant hydrogels was enhanced when the content of the microparticles was increased up to 30% and 40%. Incorporation of proteins into both the gel and microparticle components resulted in composites that controlled the kinetics of protein release. Protein within the gel phase was released over a 10-day period whilst protein in the microparticles was released over a period of months. This system can be used to deliver two drugs with differing release kinetics and could be used to orchestrate tissue regeneration responses over differing timescales.     

Carbopol/chitosan based pH triggered in situ gelling system for ocular delivery of timolol maleate

The poor bioavailability and therapeutic response exhibited by conventional ophthalmic preparations due to rapid precorneal elimination, dilution and nasolacrimal drainage of the drug may be vanquished by the use of in situ gelling systems that are instilled as drops in to the eye and undergo a sol-gel transition in the cul-de-sac. Timolol eye drops may cause systemic side effects in glaucoma patients due to absorption of the drug into systemic circulation. In situ gelling system of this drug can provide localized effect with reduced contraindications, improved patient compliance and better therapeutic index. The present work describes the formulation and evaluation of an ophthalmic delivery system of an antiglaucoma drug, timolol maleate (TM) based on the concept of pH-triggered in situ gelation. Polyacrylic acid (carbopol) was used as the gelling agent in combination with chitosan (amine polysaccharide), which was acted as a viscosity-enhancing agent. Formulations were evaluated for pH, viscosity, gelling capacity and drug content. The 0.4% w/v carbopol/0.5% w/v chitosan based in situ gelling system was in liquid state at room temperature and at the pH formulated (pH 6.0) and underwent rapid transition into the viscous gel phase at the pH of the tear fluid (lacrimal fluid) (pH 7.4). The in vitro drug release and in vivo effects of the developed in situ gelling system were compared with that of Glucomol® (a 0.25% TM ophthalmic solution), 0.4% w/v carbopol solution as well as liposomal formulation. The results clearly demonstrated that developed carbopol-chitosan based formulation was therapeutically efficacious and showed a fickian (diffusion controlled) type of release behaviour over 24 h periods. The developed system is thus a viable alternative to conventional eye drops and can also prevent the rapid drainage as in case of liposomes.