In situ gelling formulation based on methylcellulose/pectin system for oral-sustained drug delivery to dysphagic patients

Background: Oral-sustained release gel formulations with suitable rheological properties have been proposed as a means of improving the compliance of dysphagic and geriatric patients who have difficulties with handling and swallowing oral dosage forms. Aim: We have modified the rheological and release properties of thermally reversible methylcellulose solutions by admixture with pectin, the gelation of which is ion-responsive, with the aim of formulating an in situ gelling vehicle suitable for oral-sustained drug delivery. Method: Gels formed by solutions containing methylcellulose (1.0–2.0%) and pectin (0.5–2.0%) were assessed for suitable gel strength, and in vitro and in vivo release of paracetamol. Results: Addition of 1.5% pectin to a 2.0% methylcellulose formulation containing 20% d-sorbitol and calcium ions in complexed form increased the gel strength and provided a formulation with a suitable viscosity for ease of swallowing by dysphagic patients. Gels formed in situ after oral administration of this formulation retained their integrity in the rat stomach for sufficient time for sustained release to be achieved. In vitro release of paracetamol from methylcellulose, pectin, and methylcellulose/pectin gels was diffusion-controlled. Plasma levels of paracetamol after oral administration to rats (gastric pH 2.6 and 5.5) of a solution including 2.0% methylcellulose/1.5% pectin showed improved sustained release compared with that from both 2.0% methylcellulose and 1.5% pectin solutions. Conclusions: The addition of suitable concentrations of pectin to methylcellulose solutions produces in situ gelling formulations with suitable viscosity for administration to dysphagic patients and improved sustained release characteristics.     

Preparation and evaluation of gel formulations for oral sustained delivery to dysphagic patients

Background: Oral sustained release gel formulations may provide a means of administering drugs to dysphagic and geriatric patients who have difficulties with handling and taking oral dosage forms. Aim: We have designed gel formulations for the oral administration of paracetamol with suitable rheological characteristics for ease of administration to patients with swallowing difficulties and sufficient integrity in the acidic environment of the stomach to achieve a sustained release of this drug. Method: Gels formed by gelatin, agar, gellan, pectin, and xyloglucan were assessed for suitable gel strength and in vitro and in vivo release characteristics. Results: Gellan (1.5%?w/v) and xyloglucan gels (1.5%?w/w) had acceptable gel strengths for ease of swallowing and retained their integrity in the rat stomach sufficiently well to sustain the release of paracetamol over a period of 6 hours. Comparison of 1.5%?xyloglucan gels with a commercially available preparation with identical paracetamol concentrations demonstrated improved sustained release properties of the xyloglucan gels. Conclusions: Gels formed by gellan and xyloglucan have suitable rheological and sustained release characteristics for potential use as vehicles for oral delivery of drugs to dysphagic patients.     

Development of modified in situ gelling oral liquid sustained release formulation of dextromethorphan

Context: Alternative strategies are being employed to develop liquid oral sustained release formulation. These included ion exchange resin, sustained release suspensions and in situ gelling systems. The later mainly utilizes alginate solutions that form gels upon contact with calcium which may be administered separately or included in the alginate solution as citrate complex. This complex liberates calcium in the stomach with subsequent gellation. The formed gel can break after gastric emptying leading to dose dumping.

Objective: Development of modified in situ gelling system which sustain dextromethorphan release in the stomach and intestine.

Methods: Solutions containing alginate with calcium chloride and sodium citrate were initially prepared to select the formulation sustaining the release in the stomach. The best formulation was combined with chitosan. All formulations were characterized with respect to flow, gelling capacity, gelling strength and drug release.

Results: Increasing the concentration of alginate increased the gelling capacity and strength and reduced the rate of drug release in gastric conditions with 2% w/v alginate being the best formulation. However, these formulations failed to sustain the release in the intestinal conditions. Incorporation of chitosan with alginate increased the gelling capacity and strength and reduced the rate of drug release compared to alginate only system. The effect was optimum in formulation containing 1.5% w/v chitosan. The sustained release pattern was maintained both in the gastric and intestinal conditions and was comparable to that obtained from the marketed product.

Conclusion: Alginate-chitosan based in situ gelling system is promising for developing liquid oral sustained release.     

Thermoreversible mucoadhesive in situ nasal gel for treatment of Parkinson’s disease

Abstract

Parkinson’s disease is a degenerative disorder of the central nervous system (CNS). The most obvious symptoms are movement-related such as shaking, rigidity, slowness of movement and difficulty with walking, rigid muscular movements and difficulty in chewing and swallowing especially solid dosage forms. Ropinirole is an anti-Parkinson drug that has low oral bioavailability which is primarily due to first-pass metabolism. The objective of proposed work was to increase bioavailability of ropinirole and avoid patient discomfort by formulating thermoreversible in situ nasal gel. Thermoreversible nasal gels were prepared by cold method using Pluronic F-127 and hydroxy methyl propyl cellulose (HPMC K4M) as gelling agents. Formulations were evaluated for various parameters such as drug content, pH, gelling time, gelling temperature, gel strength, mucoadhesive force, ex vivo diffusion, histological studies and in vivo bioavailability. Formulations displayed gelation at nasal temperature and the gelation time was found to be less than mucociliary clearance time. The nasal residence time was seen to be increased due to mucoadhesion and increased gel strength. The nasal gel formulations showed ex vivo drug release between 56–100% in 5?h. Histological study of sheep nasal mucosa revealed that the gel had a protective effect on the mucosa unlike plain ropinirole which showed evidence of moderate cellular damage. A fivefold increase in bioavailability in brain was observed on nasal administration as compared to IV route. Thermoreversible in situ nasal gel was found to a promising drug delivery for Parkinsonian patients.     

Design and characterization of calcium-free in-situ gel formulation based on sodium alginate and chitosan

The aim of this study was to prepare and evaluate calcium-free sustained release drug delivery systems, based on the in-situ gelation of oral suspensions containing chitosan, sodium alginate and Ranitidine as drug model. The combined effects of polymer concentrations and their interactions on the rheological characteristics of both gels and suspensions and, on the kinetics of drug release were evaluated by using a central composite face-centered design. Rheological analysis showed that suspensions were potentially stable, with a viscosity increased by 1000 times compared to that of water. In addition, the obtained gels were consistent; their storage modulus could reach values close to 50?kPa when alginate concentration was greater than 7.5?g/100?mL and chitosan was fixed to 0.5?g/100?mL. In these conditions gels should have a higher gastric residence time, in comparison to the standard gastric emptying time (～2?h). Evaluation of the in-vitro release kinetics of Ranitidine showed that the association of the lowest concentration of chitosan (0.5?g/100?mL) with higher alginate concentrations generates sustained release kinetics profiles. The time corresponding to 63% of release was found close to 1.5?h, in which case the process is governed by Fickian diffusion. Finally, calcium-free alginate-chitosan based on the in-situ gelation of suspensions is advantageous as a drug delivery system for sustained-release.     

Oral Sustained Delivery of Theophylline and Cimetidine from In Situ Gelling Pectin Formulations in Rabbits

ABSTRACT

The aim of this study was to evaluate the potential of an in situ gelling pectin formulation as a vehicle for the oral sustained delivery of theophylline and cimetidine. In vitro studies demonstrated diffusion-controlled release of theophylline from 1, 1.5, and 2% w/v pectin gels. Release of this drug from 1.5% w/v pectin gels formed in situ in rabbit stomach was sustained over a period of 12 hours giving a theophylline bioavailability some seven fold higher than when administered from a commercial syrup. In contrast, interactions between cimetidine and pectin led to weak gelation of the pectin sols that prevented any meaningful determination of in vitro release characteristics. Similarly, in vivo release profiles from pectin formulations containing cimetidine were similar to that from a solution of this drug in buffer, indicative of weak gelation. Examination of the content of the rabbit stomach 5 hours after administration of 1.5% w/v pectin sols containing drug confirmed gel formation, but gels containing cimetidine were noticeably softer than those containing theophylline.     

In Situ Gelling Pectin Formulations for Oral Sustained Delivery of Paracetamol

The purpose of this study was to evaluate the potential of a pectin formulation with in situ gelling properties for the oral sustained delivery of paracetamol (acetaminophen). The formulations consisted of dilute aqueous solutions (1% to 2% w/v) of low methoxy pectin containing calcium ions in complexed form, which on release in the acidic environment of the stomach caused gelation of the pectin. In vitro studies demonstrated diffusion‐controlled release of paracetamol from the gels over a period of 6 h. A bioavailability of approximately 96% of that of a paracetamol solution could be achieved from gels containing an identical dose of drug formed in situ in the stomachs of rats, with appreciably lower peak plasma levels and a sustained release of drug over a period of at least 6 h.     

In situ gelling pectin formulations for oral sustained delivery of paracetamol

The purpose of this study was to evaluate the potential of a pectin formulation with in situ gelling properties for the oral sustained delivery of paracetamol (acetaminophen). The formulations consisted of dilute aqueous solutions (1% to 2% w/v) of low methoxy pectin containing calcium ions in complexed form, which on release in the acidic environment of the stomach caused gelation of the pectin. In vitro studies demonstrated diffusion-controlled release of paracetamol from the gels over a period of 6 h. A bioavailability of approximately 96% of that of a paracetamol solution could be achieved from gels containing an identical dose of drug formed in situ in the stomachs of rats, with appreciably lower peak plasma levels and a sustained release of drug over a period of at least 6 h.     

Thermosensitive bioadhesive gels for the vaginal delivery of sildenafil citrate: in vitro characterization and clinical evaluation in women using clomiphene citrate for induction of ovulation

Objective: The objective of this study is to develop and characterize in situ thermosensitive gels for the vaginal administration of sildenafil as a potential treatment of endometrial thinning occurring as a result of using clomiphene citrate for ovulation induction in women with type II eugonadotrophic anovulation. While sildenafil has shown promising results in the treatment of infertility in women, the lack of vaginal pharmaceutical preparation and the side effects associated with oral sildenafil limit its clinical effectiveness.

Methods: Sildenafil citrate in situ forming gels were prepared using different grades of Pluronic^® (PF-68 and PF-127). Mucoadhesive polymers as sodium alginate and hydroxyethyl cellulose were added to the gels in different concentrations and the effect on gel properties was studied. The formulations were evaluated in terms of viscosity, gelation temperature (T_sol-gel), mucoadhesion properties, and in vitro drug release characteristics. Selected formulations were evaluated in women with clomiphene citrate failure due to thin endometrium (Clinicaltrial.gov identifier NCT02766725).

Results: The T_sol-gel decreased with increasing PF-127 concentration and it was modulated by addition of PF-68 to be within the acceptable range of 28–37?°C. Increasing Pluronic® concentration increased gel viscosity and mucoadhesive force but decreased drug release rate. Clinical results showed that the in situ sildenafil vaginal gel significantly increased endometrial thickness and uterine blood flow with no reported side effects. Further, these results were achieved at lower frequency and duration of drug administration.

Conclusion: Sildenafil thermosensitive vaginal gels might result in improved potential of pregnancy in anovulatory patients with clomiphene citrate failure due to thin endometrium.     

Oral sustained delivery of paracetamol from in situ gelling xyloglucan formulations

The purpose of this study was to evaluate the potential of a xyloglucan formulation with in situ gelling properties for the oral sustained delivery of paracetamol. Gelation of dilute aqueous solutions of the polysaccharide xyloglucan occurred in rabbit and rat stomachs as the orally administered chilled solutions attained body temperature. In vitro studies demonstrated diffusion-controlled release of paracetamol from the gels over a period of 6 hr. The bioavailabilities of paracetamol from the xyloglucan gels formed in situ in the stomachs of rabbits after oral administration of the liquid formulations were similar to that of a commercially available suspension containing an identical dose of paracetamol.     

Formulation and development of ophthalmic in situ gel for the treatment ocular inflammation and infection using application of quality by design concept

Context: The conventional liquid ophthalmic delivery systems exhibit short pre-corneal residence time and the relative impermeability to the cornea which leads to poor ocular bioavailability.

Objective: The aim of this study was to apply quality by design (QbD) for development of dexamethasone sodium phosphate (DSP) and tobramycin sulfate (TS)-loaded thermoresponsive ophthalmic in situ gel containing Poloxamer 407 and hydroxyl propyl methyl cellulose (HPMC) K4M for prolonging the pre-corneal residence time, ocular bioavability and decreases the frequency of administration of dosage form. The material attributes and the critical quality attributes (CQA) of the in situ gel were identified. Central composite design (CCD) was adopted to optimize the formulation.

Materials and methods: The ophthalmic in situ forming gels were prepared by cold method. Materials attributes were the amount of Poloxamer 407 and HPMC and CQA identified were Gel strength, mucoadhesive index, gelation temperature and % of drug release of both drug.

Results and discussion: Optimized batch (F*) containing 16.75% poloxamer 407 and 0.54% HPMC K4M were exhibited all results in acceptable limits. Compared with the marketed formulation, optimized in situ gel showed delayed T_max, improved C_max and AUC in rabbit aqueous humor, suggesting the sustained drug release and better corneal penetration and absorption.

Conclusion: According to the study, it could be concluded that DSP and TS would be successfully formulated as in situ gelling mucoadhesive system for the treatment of steroid responsive eye infections with the properties of sustained drug release, prolonged ocular retention and improved corneal penetration.     

Sustained-release alginate-chitosan pellets prepared by melt pelletization technique

Context: Alginate-chitosan pellets prepared by extrusion-spheronization technique exhibited fast drug dissolution.

Objective: This study aimed to design sustained-release alginate pellets through rapid in situ matrix coacervation by chitosan during dissolution.

Methods: Pellets made of alginate with chitosan and/or calcium acetate were prepared using solvent-free melt pelletization technique which prevented reaction between processing materials during agglomeration and allowed such reaction to occur only in dissolution phase.

Results: Drug release was retarded in pH 2.2 medium when pellets were formulated with calcium acetate or chitosan till a change in medium pH to 6.8. The sustained-release characteristics of calcium alginate pellets were attributed to pellet dispersion and rapid cross-linking by soluble Ca²⁺ during dissolution. The slow drug release characteristics of alginate-chitosan pellets were attributed to polyelectrolyte complexation and pellet aggregation into swollen structures with reduced erosion. The drug release was, however, not retarded when both calcium acetate and chitosan coexisted in the same matrix as a result of chitosan shielding of Ca²⁺ to initiate alginate cross-linkages and rapid in situ solvation of calcium acetate induced fast pellet dispersion and chitosan losses from matrix.

Conclusion: Similar to calcium alginate pellets, alginate-chitosan pellets demonstrated sustained drug release property though via different mechanisms. Combination of alginate, chitosan and calcium acetate in the same matrix nevertheless failed to retard drug release via complementary drug release pattern.     

Oral sustained delivery of theophylline and cimetidine from in situ gelling pectin formulations in rabbits

The aim of this study was to evaluate the potential of an in situ gelling pectin formulation as a vehicle for the oral sustained delivery of theophylline and cimetidine. In vitro studies demonstrated diffusion-controlled release of theophylline from 1, 1.5, and 2% w/v pectin gels. Release of this drug from 1.5% w/v pectin gels formed in situ in rabbit stomach was sustained over a period of 12 hours giving a theophylline bioavailability some seven fold higher than when administered from a commercial syrup. In contrast, interactions between cimetidine and pectin led to weak gelation of the pectin sols that prevented any meaningful determination of in vitro release characteristics. Similarly, in vivo release profiles from pectin formulations containing cimetidine were similar to that from a solution of this drug in buffer, indicative of weak gelation. Examination of the content of the rabbit stomach 5 hours after administration of 1.5% w/v pectin sols containing drug confirmed gel formation, but gels containing cimetidine were noticeably softer than those containing theophylline.     

Evaluation of TRI-726 as a drug delivery matrix

Background: The TRI-726 polymeric drug delivery matrix is a newly-developed biocompatible hydrogel exhibiting in situ reverse-thermal gelling, mucoadhesivity, and sustained-erosion properties.

Methods: Using two model drugs, clindamycin hydrochloride and acetaminophen, we determined the gelling temperatures, in vitro release profiles, kinetics of matrix erosion, rheological properties, mucoadhesive strength, microbiological activity of released clindamycin, and biocompatibility when in contact with cells.

Results: It was demonstrated that none of the excipients contained in the TRI-726 polymer matrix caused any loss in clindamycin’s antimicrobial activity following incorporation into the polymer matrix. Thus, the new patent pending TRI-726 drug delivery matrix was both inert and non-reactive toward the incorporated clindamycin in terms of chemical degradation (<10% degradation under accelerated conditions over 6 months) and antimicrobial activity.

Conclusions: This new drug delivery matrix is capable of releasing a wide variety of water-soluble drug compounds over an approximate 10-day period, due primarily to protracted dissolution/erosion of the three-dimensional polymer matrix in an aqueous-based biophase. Additionally, TRI-726 exhibits excellent mucoadhesive properties that would allow a candidate drug/TRI-726 formulation to adhere and remain at a potential application site for an extended period of time. Lastly, the biocompatibility tests affirmed the non-toxic and biocompatible nature of TRI-726 when in contact with cells, which suggests its suitability and versatility as a drug delivery matrix for the targeted administration of a wide range of pharmaceutical compounds where in situ gelation, protracted release of the active, and mucoadhesion of the formulation are desired.     

Prolonged Release of Theophylline from Aqueous Suspensions

Abstract

The dissolution of theophylline from aqueous suspensions was measured by the U.S.P. paddle method. Theophylline release was retarded in the presence of xanthan gum, 1%, sodium alginate, 0.5%, and equi-weight mixtures of gelatin type B and iota carrageenan, 1%. These suspensions formed gels in situ in Simulated Gastric Fluid, U.S.P. Diffusion cell studies suggested that theophylline transport within the formed matrix was due to diffusion through immobilized liquid water. Evidence in support of a diffusion controlled dissolution mechanism in these systems were linearity of the initial section of plots of dissolution against the square route of time, the lack of effect of theophylline particle size on dissolution rate, and the tendency for release from a particular system to become independent of polymer concentration once a sufficiently high concentration was reached.     

Oral medication delivery in impaired swallowing: thickening liquid medications for safe swallowing alters dissolution characteristics

Acetaminophen (paracetamol) is available in a wide range of oral formulations designed to meet the needs of the population across the age-spectrum, but for people with impaired swallowing, i.e. dysphagia, both solid and liquid medications can be difficult to swallow without modification. The effect of a commercial polysaccharide thickener, designed to be added to fluids to promote safe swallowing by dysphagic patients, on rheology and acetaminophen dissolution was tested using crushed immediate-release tablets in water, effervescent tablets in water, elixir and suspension. The inclusion of the thickener, comprised of xanthan gum and maltodextrin, had a considerable impact on dissolution; acetaminophen release from modified medications reached 12–50% in 30?min, which did not reflect the pharmacopeia specification for immediate release preparations. Flow curves reflect the high zero-shear viscosity and the apparent yield stress of the thickened products. The weak gel nature, in combination with high G' values compared to G'' (viscoelasticity) and high apparent yield stress, impact drug release. The restriction on drug release from these formulations is not influenced by the theoretical state of the drug (dissolved or dispersed), and the approach typically used in clinical practice (mixing crushed tablets into pre-prepared thickened fluid) cannot be improved by altering the order of incorporation or mixing method.     

Box–Behnken experimental design for preparation and optimization of the intranasal gels of selegiline hydrochloride

Selegiline hydrochloride (SL) is chosen as an adjunct for the control of clinical signs of Parkinsonian patients. The aim of the present work is to develop and optimize thermosensitive gels using Pluronic (F-127) for enhancing transport of SL into the brain through the nasal route. SL gels were prepared using a cold method and the Box–Behnken experimental design methodology. Drug (SL), gelling agent (F-127), and emulsifier (Propylene glycol, PG) were selected as independent variables, while the gelation temperature, gel strength, pH, gel content, and gel erosion were considered as dependent variables. For further understanding of the interaction between the various variables, contour plots and surface plots were also applied. Selected formulations, like S10 (contain 25?mg SL, 20?g F-127, and 1?g PG) and S14 (contain 50?mg SL, 18?g F-127 and 1?g PG), had a clear appearance in the sol form, with gelling temperature of the nasal gel ranging between 33 and 34, respectively. The gel strength of the formulations varied from 4.67 and 0.68?mm and the drug content was 100%. The pH of the formulations ranged between 6.71 and 7.11. Detachment force was acceptable (63.69–244.16 N/cm²) to provide prolonged adhesion. In vitro, drug release studies showed that the prepared formulations could release SL for up to 8?h. Permeation flux for the S10 gel was 0.0002?mg/min/cm². Results demonstrated that the potential use of SL gels can enhance the therapeutic effect of SL through the intranasal administration.     

Formulation and ex vivo–in vivo evaluation of pH-triggered brimonidine tartrate in situ gel for the glaucoma treatment using application of 32 factorial design

Context: Short residence time, poor bioavailability and poor permeability are the major problems for conventional eye drops treatment.

Objective: The aim of this article is to develop, optimize and ex vivo–in vivo investigation of brimonidine tartrate in situ gel as compared to marketed eye drops for the treatment of glaucoma.

Materials and methods: The effect of independent variables, namely concentrations of polymers, on various dependent variables like viscosity at physiological pH and in vitro drug release were studied by using 3² factorial design. Further the optimized formulation was characterized for ex vivo and in vivo study.

Results and discussion: Experimental data demonstrated that optimized in situ gel formulation (F8) showed in vitro–ex vivo sustained release profile with polymer composites carbopol 974P and HPMC K4M. After 5?h of ex vivo transcorneal permeation study, the amount recovered from the corneal surface on the donor chamber 12.40% (124 ug) and the amount collected from the receptor chamber 76.8% (760 ug) of the initial dose 1?mg. The total amount recovered from the permeation experiment was 89.2%. Bioadhesive carbopol 974P and viscosity HPMC K4M composites optimized formulation (F 8) produce greater influence on the duration of drug action and improved intraocular pressure reduction activity as compared to marketed eye drop solution in in vivo study.

Conclusion: The developed in situ gelling system as a promising ophthalmic formulation to prolong the drug lowering effect on the intraocular pressure.     

Development and optimization of locust bean gum and sodium alginate interpenetrating polymeric network of capecitabine

Objective: The objective of the study was to develop interpenetrating polymeric network (IPN) of capecitabine (CAP) using natural polymers locust bean gum (LBG) and sodium alginate (NaAlg).

Significance: The IPN microbeads were optimized by Box–Behnken Design (BBD) to provide anticipated particle size with good drug entrapment efficiency. The comparative dissolution profile of IPN microbeads of CAP with the marketed preparation proved an excellent sustained drug delivery vehicle.

Methods: Ionotropic gelation method utilizing metal ion calcium (Ca²⁺) as a cross-linker was used to prepare IPN microbeads. The optimization study was done by response surface methodology based Box–Behnken Design. The effect of the factors on the responses of optimized batch was exhibited through response surface and contour plots. The optimized batch was analyzed for particle size, % drug entrapment, pharmacokinetic study, in vitro drug release study and further characterized by FTIR, XRD, and SEM. To study the water uptake capacity and hydrodynamic activity of the polymers, swelling studies and viscosity measurement were performed, respectively.

Results: The particle size and % drug entrapment of the optimized batch was 494.37?±?1.4?µm and 81.39?±?2.9%, respectively, closer to the value predicted by Minitab 17 software. The in vitro drug release study showed sustained release of 92% for 12?h and followed anomalous drug release pattern. The derived pharmacokinetic parameters of optimized batch showed improved results than pure CAP.

Conclusion: Thus, the formed IPN microbeads of CAP proved to be an effective extended drug delivery vehicle for the water soluble antineoplastic drug.     

Preparation of alginate–CaCl2 microspheres as resveratrol carriers

Resveratrol-loaded calcium alginate microspheres for prolonged drug release were prepared by ionic gelation of alginate with calcium chloride (CaCl₂). Further, resveratrol-loaded calcium alginate microspheres were developed using two concentrations of alginate (0.5 and 1 % w/v) and CaCl₂ (0.5 and 1 M) and an encapsulator equipped with a 300-μm nozzle. The mean particle size of the microspheres was between 175.52 and 244.03 μm, and an encapsulation efficiency (EE) of over 95 % was observed. FTIR spectroscopy indicated a polyelectrolyte interaction between alginate and CaCl₂; alginate microsphere thermograms were analyzed by differential scanning calorimetry. X-ray diffraction shows the crystalline change of microspheres by cross linking. The release profiles and EE increased depending on the CaCl₂ concentration, and a slow initial burst release was observed on freeze-dried microspheres. These results indicate that resveratrol-loaded calcium alginate microspheres can be used as a potential resveratrol delivery system in the food industry.