Chewing Gum as a Drug Delivery System for Nystatin Influence of Solubilising Agents Upon the Release of Water Insoluble Drugs

Nystatin is an antifungal drug with a poor solubility in water and saliva. Consequently, only a small amount of the drug was released from nystatin chewing gum during testing on a mastication device. The addition of solubilising agents to chewing gum increased the release of nystatin by a factor of 50-70, whereas the agents only increased the solubility of nystatin by a factor of 3-7. The solubilising agents were Cremophor® RH 40, Tween® 60 (non-ionic surfactants) and Panodan® AB 90 (an-ionic surfactant). There was no linear relationship between the amount of nystatin in chewing gum and the release. A method to estimate the content of nystatin in chewing gum was developed.     

Miconazole Chewing Gum as a Drug Delivery System Application of Solid Dispersion Technique and Lecithin

Abstract

The release of the antifungal drug miconazole from chewing gum was evaluated both in vitro and in vivo. It was proved that the addition of lecithin and the application of a miconazole polyethyleneglycol 6000 solid dispersion increased the release of miconazole from chewing gum. The in vitro results correlated well with the in vivo results. 6 healthy volunteers obtained therapeutically active concentrations of miconazole in saliva when they chewed gum. In the microbiological experiments performed, lecithin did not antagonize the anti-Candida albicans effect of miconazole at pH 7.2.     

Miconazole and Miconazolenitrate Chewing Gun as Drug Delivery Systems – A Practical Application of Solid Dispersion Technique

Abstract

Miconazole and miconazolenitrate are antifungal drugs with poor solubilities in water and saliva. The low solubilities meant that only small amounts of the drugs – incorporated by a conventional method in chewing gum-were released during mastication. The experiments were performed on a mastication device.

In this study it was shown that application of a 20% miconazole – 80% polyethyleneglycol 6000 solid dispersion drastically improved the in vitro release of miconazole from cheving gum, when a medium similar to saliva was used. In addition to polyethyleneglycol 6000, polyvinylpyrrolidone 40000, xylitol and urea were tested as carriers. It was also shown that the release rate of miconazole from chewing gum was much greater than the release rate of miconazolenitrate.

No certain correlation could be shown between the dissolution rates of the solid dispersions measured by a stirring paddle method and the release rates of miconazole from solid dispersions in chewing gum.

The solid dispersion systems were characterized by differential scanning calorimetry. The systems containing polyethyleneglycol 6000 and xylitol were eutectic. Polyvinylpyrrolidone 40000 prevented crystallisation of miconazole when the percentage of drug in the solid dispersion was less than 50%.     

Bioadhesive Polymer Buccal Patches for Buprenorphine Controlled Delivery: Solubility Consideration

Abstract

By using a two-roll milling method, a new bioadhesive polymer patch formulation for buprenorphine controlled delivery and consisting of polyisobutylene, polyisoprene, and Carbopol® 934P was prepared. Since solubility of drug in the polymer patches is the first factor which should be considered before to modify the feasibility of delivering drug through the buccal mucosa, the effects of α-cyclodextrin, β-cyclodextrin, sodium taurocholate, and sodium glycodeoxycholate on the solubility of buprenorphine were investigated, and β-cyclodextrin was found the strongest solubility enhancer of them. The drug release profiles were significantly affected by the drug loading and the existence of β-cyclodextrin. Increasing the drug loading and solubility enhancer would increase the drug release from the buccal polymer patches. The pH value change in the microenviroment of polymer patches during the hydration of Carbopol® 934P could even release 20% of drug from the polymer patches which didn't contain any solubility enhancer.     

Cetirizine release from cyclodextrin formulated compressed chewing gum

Beside the efficient effect on masking cetirizine bitter taste, the cyclodextrins (CDs) as well could have influence on the release from the formulation. In vitro release profiles of cetirizine from compressed chewing gums containing α-, β- and γ-CD were investigated using a three cell chewing apparatus. Different cetirizine/CD formulations were produced and analysed with respect to type of CD (α-, β- and γ-CD), the molar ratio between cetirizine and CD and the formulation of cetirizine (complex or physical mixture). Release experiments from all compressed chewing gum formulations gave similar release patterns, but with variations in the total amount released. Chewing gum formulated with cetirizine alone, demonstrated a release of 75% after 8?min of chewing. The presence of CDs resulted in increased cetirizine release. The analysis of variance (ANOVA) demonstrated that parameters with the most important influence on the release were the molar ratio of cetirizine/CD (P?<?0.05) and the formulation of cetirizine/CD (complex or physical mixture) (P?<?0.05). The compressed chewing gum formulations with 1:5 molar ratio of cetirizine/CD in complexed form demonstrated the highest release. Even though the statistical analysis (ANOVA) demonstrated significance in the release (P?<?0.05) for the complex/physical mixture factor, this difference was negligible compared to the release from chewing gums containing cetirizine without CD. This makes physical mixtures suitable for use in cetirizine/CD formulations instead the complexes with respect to release yield. Thus unnecessary expenses for the complex preformulation may be avoided.     

Effect of polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer on bioadhesion and release rate property of eplerenone pellets

Abstract

The present study involved the design and development of oral bioadhesive pellets of eplerenone. A solid dispersion of eplerenone was developed with a hydrophilic carrier, polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus^®). Bioadhesive pellets were prepared from this solid dispersion using a combination of HPMC K4M and Carbopol 934P. Both the solid dispersion and the pellets were evaluated for various physicochemical properties such as solubility, entrapment efficiency, drug content, surface morphology, mucoadhesion and swelling behavior. Analysis carried out using FT-IR, DSC and XRD found no interaction between the eplerenone and excipients. The solid dispersion had irregular-shaped smooth-surfaced particles of diameter 265?±?105.5?μm. In TEM analysis, eplerenone particles of size 79–120?nm were found. The solubility and dissolution of eplerenone in the Soluplus^®-based solid dispersion were 5.26 and 2.50 times greater, respectively. Investigation of the swelling behavior of the pellets showed that the thickness of the gel layer increased continuously over the duration of the study. Moreover, a correlation was observed between the thickness and strength of the gel layer and the percentage release. The mechanism of drug release was found to be non-Fickian (anomalous), with the release kinetics approaching first-order kinetics. The bioavailability of the eplerenone bioadhesive pellet formulation was studied using Wistar rats and was found to be improved. An in vivo mucoadhesion study showed that the pellets are retained for 24?h in rabbits. It was concluded that Soluplus^® had a positive effect on the solubility and dissolution of pellets without affecting the bioadhesion.     

Thermal,mechanical and drug release characteristics of an acrylic film using active pharmaceutical ingredient as non-traditional plasticizer

Abstract

The objective of this study was to investigate thermal and mechanical properties as well as in vitro drug release of Eudragit® RL (ERL) film using chlorpheniramine maleate (CPM) as either active pharmaceutical ingredient or non-traditional plasticizer. Differential scanning calorimeter was used to measure the glass transition temperature (T_g) of 0–100% w/w CPM in ERL physical mixture. Instron testing machine was used to investigate Young’s modulus, tensile stress and tensile strain (%) of ERL film containing 20–60% w/w CPM. Finally, a Franz diffusion cell was used to study drug release from ERL films obtained from four formulations, i.e. CRHP0/0, CRHP0/5, CRHP2/0 and CRHP2/5. The T_g of ERL was decreased when the weight percentage of CPM increased. The reduction of the T_g could be described by Kwei equation, indicating the interaction between CPM and ERL. Modulus and tensile stress decreased whereas tensile strain (%) increased when weight percentage of CPM increased. The change of mechanical properties was associated with the reduction of the T_g when weight percentage of CPM increased. ERL films obtained from four formulations could release the drug in no less than 10?h. Cumulative amount of drug release per unit area of ERL film containing only CPM (CRHP0/0) was lower than those obtained from the formulations containing traditional plasticizer (CRHP0/5), surfactant (CRHP2/0) or both of them (CRHP2/5). The increase of drug release was a result of the increase of drug permeability through ERL film and drug solubility based on traditional plasticizer and surfactant, respectively.     

Miconazole chewing gum as a drug delivery system test of release promoting additives

The release of the antifungal drug miconazole from chewing gum formulations was evaluated in vitro and in vivo. It was proven that the addition of the anionic surfactant Panodan® 165 and polyethyleneglycol 6000 increased the release of miconazole. The anionic surfactant made the chewing gum tacky. The addition of polyethyleneglycol 6000 reduced the tacky properties of the chewing gum. 4 healthy volunteers obtained therapeutically active concentrations of miconazole in saliva when they chewed gum. The salivary concentrations of miconazole were estimated, both by a reverse phase HPLC method and a plate microbioassay.     

Cetirizine release from cyclodextrin formulated compressed chewing gum

Beside the efficient effect on masking cetirizine bitter taste, the cyclodextrins (CDs) as well could have influence on the release from the formulation. In vitro release profiles of cetirizine from compressed chewing gums containing α-, β- and γ-CD were investigated using a three cell chewing apparatus. Different cetirizine/CD formulations were produced and analysed with respect to type of CD (α-, β- and γ-CD), the molar ratio between cetirizine and CD and the formulation of cetirizine (complex or physical mixture). Release experiments from all compressed chewing gum formulations gave similar release patterns, but with variations in the total amount released. Chewing gum formulated with cetirizine alone, demonstrated a release of 75% after 8 min of chewing. The presence of CDs resulted in increased cetirizine release. The analysis of variance (ANOVA) demonstrated that parameters with the most important influence on the release were the molar ratio of cetirizine/CD (P < 0.05) and the formulation of cetirizine/CD (complex or physical mixture) (P < 0.05). The compressed chewing gum formulations with 1:5 molar ratio of cetirizine/CD in complexed form demonstrated the highest release. Even though the statistical analysis (ANOVA) demonstrated significance in the release (P < 0.05) for the complex/physical mixture factor, this difference was negligible compared to the release from chewing gums containing cetirizine without CD. This makes physical mixtures suitable for use in cetirizine/CD formulations instead the complexes with respect to release yield. Thus unnecessary expenses for the complex preformulation may be avoided.     

Sustained-release from Layered Matrix System Comprising Chitosan and Xanthan Gum

ABSTRACT

Sustained-release tablets of propranolol HCl were prepared by direct compression using chitosan and xanthan gum as matrix materials. The effective prolongation of drug release in acidic environment was achieved for matrix containing chitosan together with xanthan gum which prolonged the drug release more extensive than that containing single polymer. Increasing lactose into matrix could adjust the drug release characteristic by enhancing the drug released. Component containing chitosan and xanthan gum at ratio 1:1 and lactose 75% w/w was selected for preparing the layered matrix by tabletting. Increasing the amount of matrix in barrier or in middle layer resulted in prolongation of drug release. From the investigation of drug release from one planar surface, the lag time for drug release through barrier layer was apparently longer as the amount of barrier was enhanced. Least square fitting the experimental dissolution data to the mathematical expressions (power law, first order, Higuchi's and zero order) was performed to study the drug release mechanism. Layering with polymeric matrix could prolong the drug release and could shift the release pattern approach to zero order. The drug release from chitosan-xanthan gum three-layer tablet was pH dependent due to the difference in charge density in different environmental pH. FT-IR and DSC studies exhibited the charge interaction between of NH₃⁺ of chitosan molecule and COO^? of acetate or pyruvate groups of xanthan gum molecule. The SEM images revealed the formation of the loose membranous but porous film that was due to the gel layer formed by the polymer relaxation upon absorption of dissolution medium. The decreased rate of polymer dissolution resulting from the decreased rate of solvent penetration was accompanied by a decrease in drug diffusion due to ionic interaction between chitosan and xanthan gum. This was suggested that the utilization of chitosan and xanthan gum could give rise to layered matrix tablet exhibiting sustained drug release.     

Formulation and Characterization of a Compacted Multiparticulate System for Modified Release of Water-Soluble Drugs—Part II Theophylline and Cimetidine

The purpose was to investigate the effectiveness of an ethylcellulose (EC) bead matrix and different film-coating polymers in delaying drug release from compacted multiparticulate systems. Formulations containing theophylline or cimetidine granulated with Eudragit^® RS 30D were developed and beads were produced by extrusion–spheronization. Drug beads were coated using 15% wt/wt Surelease^® or Eudragit^® NE 30D and were evaluated for true density, particle size, and sphericity. Lipid-based placebo beads and drug beads were blended together and compacted on an instrumented Stokes B2 rotary tablet press. Although placebo beads were significantly less spherical, their true density of 1.21 g/cm³ and size of 855 μm were quite close to Surelease^®-coated drug beads. Curing improved the crushing strength and friability values for theophylline tablets containing Surelease^®-coated beads; 5.7 ± 1.0 kP and 0.26 ± 0.07%, respectively. Dissolution profiles showed that the EC matrix only provided 3 h of drug release. Although tablets containing Surelease^®-coated theophylline beads released drug fastest overall (t_44.2% = 8 h), profiles showed that coating damage was still minimal. Size and density differences indicated a minimal segregation potential during tableting for blends containing Surelease^®-coated drug beads. Although modified release profiles >8 h were achievable in tablets for both drugs using either coating polymer, Surelease^®-coated theophylline beads released drug fastest overall. This is likely because of the increased solubility of theophylline and the intrinsic properties of the Surelease^® films. Furthermore, the lipid-based placebos served as effective cushioning agents by protecting coating integrity of drug beads under a number of different conditions while tableting.     

A novel osmotic pump-based controlled delivery system consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen: in vitro and in vivo evaluation

Abstract

In this study, a novel controlled release osmotic pump capsule consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen (FP) was developed to improve the solubility and oral bioavailability of FP and to minimize the fluctuation of plasma concentration. The pH-modulated solid dispersion containing FP, Kollidon® 12 PF and Na₂CO₃ at a weight ratio of 1/4.5/0.02 was prepared using the solvent evaporation method. The osmotic pump capsule was assembled by semi-permeable capsule shell of cellulose acetate (CA) prepared by the perfusion method. Then, the solid dispersion, penetration enhancer, and suspending agents were tableted and filled into the capsule. Central composite design-response surface methodology was used to evaluate the influence of factors on the responses. A second-order polynomial model and a multiple linear model were fitted to correlation coefficient of drug release profile and ultimate cumulative release in 12?h, respectively. The actual response values were in good accordance with the predicted ones. The optimized formulation showed a complete drug delivery and zero-order release rate. Beagle dogs were used to be conducted in the pharmacokinetic study. The in vivo study indicated that the relative bioavailability of the novel osmotic pump system was 133.99% compared with the commercial preparation. The novel controlled delivery system with combination of pH-modulated solid dispersion and osmotic pump system is not only a promising strategy to improve the solubility and oral bioavailability of poorly soluble ionizable drugs but also an effective way to reduce dosing frequency and minimize the plasma fluctuation.     

Development of novel amisulpride-loaded liquid self-nanoemulsifying drug delivery systems via dual tackling of its solubility and intestinal permeability

Objective: The aim of the current investigation was at enhancing the oral biopharmaceutical behavior; solubility and intestinal permeability of amisulpride (AMS) via development of liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) containing bioenhancing excipients.

Methods: The components of L-SNEDDS were identified via solubility studies and emulsification efficiency tests, and ternary phase diagrams were constructed to identify the efficient self-emulsification regions. The formulated systems were assessed for their thermodynamic stability, globule size, self-emulsification time, optical clarity and in vitro drug release. Ex vivo evaluation using non-everted gut sac technique was adopted for uncovering the permeability enhancing effect of the formulated systems.

Results: The optimum formulations were composed of different ratios of Capryol? 90 as an oil phase, Cremophor^® RH40 as a surfactant, and Transcutol^® HP as a co-surfactant. All tested formulations were thermodynamically stable with globule sizes ranging from 13.74 to 29.19?nm and emulsification time not exceeding 1?min, indicating the formation of homogenous stable nanoemulsions. In vitro drug release showed significant enhancement from L-SNEDDS formulations compared to aqueous drug suspension. Optimized L-SNEDDS showed significantly higher intestinal permeation compared to plain drug solution with nearly 1.6–2.9 folds increase in the apparent permeability coefficient as demonstrated by the ex vivo studies.

Conclusions: The present study proved that AMS could be successfully incorporated into L-SNEDDS for improved dissolution and intestinal permeation leading to enhanced oral delivery.     

Miconazole Chewing Gum as a Drug Delivery System Application of Solid Dispersion Technique and Lecithin

The release of the antifungal drug miconazole from chewing gum was evaluated both in vitro and in vivo. It was proved that the addition of lecithin and the application of a miconazole polyethyleneglycol 6000 solid dispersion increased the release of miconazole from chewing gum. The in vitro results correlated well with the in vivo results. 6 healthy volunteers obtained therapeutically active concentrations of miconazole in saliva when they chewed gum. In the microbiological experiments performed, lecithin did not antagonize the anti-Candida albicans effect of miconazole at pH 7.2.     

The Release Rate of Indomethacin from Solid Dispersions with Eudragite

Abstract

The coprecipitates were prepared by a solvent technique using Eudragit E as carrier and indomethacin as a model drug.

X-Ray diffractometry, differential scanning calorimetry (DSC) and wettability tests were employed to investigate the physical state of the studied formulations. Up to 50% of indomethacin can be dispersed in an amorphous state in Eudragit E.

The influence of the pH on the in vitro release of solid dispersions has been evaluated. Because of the good solubility of Eudragit E at pH 1.2 a fast dissolution rate of the drug was observed while a marked delay was noticed at pH 7.5 where the polymer is only permeable to water. At pH 5.8 the kinetics of drug release can be modulated by the drug/polymer ratio. The dissolution rate of the drug can be increased by decreasing its amount in the coevaporate.     

Development of Polysaccharide-Based Colon Targeted Drug Delivery Systems for the Treatment of Amoebiasis

ABSTRACT

The main focus of this study is to develop colon targeted drug delivery systems for metronidazole (MTZ). Tablets were prepared using various polysaccharides or indigenously developed graft copolymer of methacrylic acid with guar gum (GG) as a carrier. Various polysaccharides such as GG, xanthan gum, pectin, carrageenan, β-cyclodextrin (CD) or methacrylic acid-g-guar (MAA-g-GG) gum have been selected and evaluated. The prepared tablets were tested in vitro for their suitability as colon-specific drug delivery systems. To further improve the colon specificity, some selected tablet formulations were enteric coated with Eudragit-L 100 to give protection in an acidic environment. Drug release studies were performed in simulated gastric fluid (SGF) for 2 hr followed by simulated intestinal fluid (SIF) at pH 7.4. The dissolution data demonstrate that the rate of drug release is dependent upon the nature and concentration of polysaccharide/polymer used in the formulations. Uncoated tablets containing xanthan gum or mixture of xanthan gum with graft copolymer showed 30–40% drug release during the initial 4–5 hr, whereas for tablets containing GG with the graft copolymer, it was 70%. After enteric coating, the release was drastically reduced to 18–24%. The other polysaccharides were unable to protect drug release under similar conditions. Preparations with xanthan gum as a matrix showed the time-dependent release behavior. Further, in vitro release was performed in the dissolution media with rat caecal contents. Results indicated an enhanced release when compared to formulations studied in dissolution media without rat caecal contents, because of microbial degradation or polymer solubilization. The nature of drug transport was found to be non-Fickian in case of uncoated formulations, whereas for the coated formulations, it was found to be super-Case-II. Statistical analyses of release data indicated that MTZ release is significantly affected by the nature of the polysaccharide used and enteric coating of the tablet. Differential scanning calorimetry indicated the presence of crystalline nature of drug in the formulations.     

Soluplus/TPGS mixed micelles for dioscin delivery in cancer therapy

Background: Dioscin has shown cytotoxicity against cancer cells, but its poor solubility and stability have limited its clinical application. In this study, we designed mixed micelles composed of TPGS and Soluplus^® copolymers entrapping the poorly soluble anticancer drug dioscin.

Method: In order to improve the aqueous solubility and bioactivity of dioscin, TPGS/Soluplus^® mixed micelles with an optimal ratio were prepared using a thin-film hydration method, and their physicochemical properties were characterized. Cellular cytotoxicity and uptake of the dioscin-loaded TPGS/Soluplus^® mixed micelles were studied in MCF-7 breast cancer cells and A2780s ovarian cancer cells. The pharmacokinetics of free dioscin and dioscin-loaded TPGS/Soluplus^® mixed micelles was studied in vivo in male Sprague-Dawley rats via a single intravenous injection in the tail vein.

Results: The average size of the optimized mixed micelle was 67.15?nm, with 92.59% drug encapsulation efficiency and 4.63% drug loading efficiency. The in vitro release profile showed that the mixed micelles presented sustained release behavior compared to the anhydrous ethanol solution of dioscin. In vitro cytotoxicity assays were conducted on human cancer cell lines including A2780s ovarian cancer cells and MCF-7 breast cancer cells. The mixed micelles exhibited better antitumor activity compared to free dioscin against all cell lines, which may benefit from the significant increase in the cellular uptake of dioscin from mixed micelles compared to free dioscin. The pharmacokinetic study showed that the mixed micelle formulation achieved a 1.3 times longer mean residual time (MRT) in circulation and a 2.16 times larger area under the plasma concentration–time curve (AUC) than the free dioscin solution.

Conclusion: Our results suggest that the dioscin-loaded mixed micelles developed in this study might be a potential nano drug-delivery system for cancer chemotherapy.     

Properties of implantable pellets prepared from a biodegradable polyester

Abstract

Biodegradable pellets for implantation use were prepared from a naturally produced copolyester, poly(hydroxybutyrate-hydroxyvalerate) (PHBV), by a simple compression and melt technique. Progesterone was incorporated in the pellets. Differential scanning calorimetric (DSC) and scanning electron microscopic (SEM) examinations showed that the drug has limited solubility in the polymer and exists as crystals uniformly distributed in the matrix. However, the drug undergoes a polymorphic change during melting from a to β form. Ultraviolet and infrared spectrophotometric tests on melted drug and polymer samples detected no chemical degradation. In vitro release of the drug was faster when the amount of drug in the pellet was increased. The drug release could be slowed by increasing the the size of pellet.     

Carbamazepine Modified Release Dosage Forms

Abstract

The preparation of sustained release dosage forms of Carbamazepine (anti-epileptic drug characterized by a very low water solubility and by a short half life on chronique dosing) was carried out.

These formulations were obtained in two different steps:

a) modified release granules were prepared by the loading of cross-linked sodium carboxymethylcellulose (swellable polymer), with the drug and an enteric polymer. Cellulose acetate phthalate, methacrylic acid – methacrylic acid methyl ester copolymer (usually employed as enteric coating agents) and cellulose acetate trimellitate (a new enteric polymer) were used in different weight ratios.

b) some sustained release dosage forms were prepared tabletting physical mixtures of the modified release granules with different weight ratios of hydroxypropylmethylcellulose.

In vitro dissolution tests of modified release granules in gastric fluid (USP XXI) showed a modulation of the drug release, while in intestinal fluid (USP XXI) a quick drug dissolution was observed.

In vitro dissolution tests of sustained release dosage forms, performed varying during the test, the pH of the dissolution medium, (hydrochloric acid pH 1 from 0 to 2 hours and phosphate buffer pH 6.8 from 2 to 18 hours) showed that the determining factors in the controlling release of the drug are: the type and amount of enteric polymer constituting the granules and the amount of hydroxy-propylmethylcellulose mixed with them.     

Film Coated Pellets Containing Verapamil Hydrochloride: Enhanced Dissolution into Neutral Medium

Abstract

Weakly basic drugs, such as verapamil hydrochloride, that are poorly soluble in neutral/alkaline medium may have poor oral bioavailability due to reduced solubility in the small intestine and colon. Film coated pellets were prepared using two strategies to enhance drug release at high pH values. Firstly, pellets were coated with Eudragit® RS/hydroxypropyl methylcellulose acetate succinate (HMAS) mixtures in proportions of 10:1 and 10:3, respectively. The enteric polymer, HMAS, would dissolve in medium at pH>6 creating pores through the insoluble Eudragit RS membrane to increase drug release. Secondly, an acidic environment was created within the core by the inclusion of fumaric acid at concentrations of 5 and 10% in order to increase drug solubility. Both strategies enhanced drug release into neutral medium in dissolution studies using the pH change method to simulate GIT transit. Dissolution profiles of samples tested in pH 1.2 for 12 hr were compared with those using the pH change method (pH 1.2 for first 1.5 hr, pH raised to 6.8 for remaining 10.5 hr) using the area under the dissolution curve (AUC), the dissolution half-life (t_50%), and the amount of drug released in 3 hr (A_{3 hr}) values. Both strategies enhanced drug release into neutral medium although the strategy using HMAS in the film was more effective. The formulation least affected by pH change was a combination of the two strategies, i.e., pellets containing 5% fumaric acid coated with Eudragit RS 12% w/w and HMAS 1.2% w/w.