Controlled Release Excipient Research Articles

Mannitol-Coated Hydroxypropyl Methylcellulose as a Directly Compressible Controlled Release Excipient for Moisture-Sensitive Drugs: A Stability Perspective.

Hydroxypropyl methylcellulose (HPMC) is one of the most commonly used hydrophilic polymers in formulations of matrix tablets for controlled release applications. However, HPMC attracts moisture and poses issues with drug stability in formulations containing moisture-sensitive drugs. Herein, the moisture sorption behavior of excipients and drug stability using aspirin as the model drug in matrix tablets were evaluated, using HPMC and the newly developed mannitol-coated HPMC, under accelerated stability conditions (40 °C, 75% relative humidity) with open and closed dishes. Tablets prepared with mannitol-coated HPMC showed a slower drug degradation rate compared to tablets prepared with directly compressible HPMC. Initial moisture content and hygroscopicity were stronger predictors of drug stability compared to water activity when comparing samples without similar moisture content. In the early stage (day 0 to 30), the aspirin degradation rate was similar in both open and closed conditions, as moisture content is the main degradation contributor. In the later stage (day 30 to 90), aspirin degradation was faster under closed conditions than under open conditions, likely due to autocatalytic effects caused by the volatile acidic by-product entrapped in the closed environment. The findings from this study reinforced the importance of judicious excipient selection based on the understanding of excipient-moisture interactions to maximize the chemical stability of moisture-sensitive drugs. Mannitol-coated HPMC is a promising addition to the formulator's toolbox for the formulation of controlled release dosage forms by direct compression.

Mannitol-coated hydroxypropyl methylcellulose as an alternative directly compressible controlled release excipient

One of the most common forms of controlled release technology for oral drug delivery comprises an active ingredient dispersed in a hydrophilic matrix forming polymer such as hydroxypropyl methylcellulose (HPMC), which is tableted via direct compression. However, HPMC may pose problems in direct compression due to its poor flowability. Hence, mannitol syrup was spray-coated over fluidized HPMC particles to produce co-processed HPMC–mannitol at ratios of 20:80, 50:50, and 70:30. Particles of pure HPMC, co-processed HPMC–mannitol, and their respective physical mixtures were evaluated for powder flowability, compression profiles, and controlled release performance. It was found that co-processed HPMC–mannitol consisted of particles with improved flow compared to pure HPMC particles. Sufficiently strong tablets of >2 MPa could be produced at moderate to high compression forces of 150–200 MPa. The dissolution profile could be tuned to obtain desired release profiles by altering HPMC–mannitol ratios. Co-processed HPMC–mannitol offers an interesting addition to the formulator’s toolbox in the design of controlled release formulations for direct compression.

Formulating extended-release Meloxicam Pellets using the membrane coating technique

Background: Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) with potent anti-inflammatory and analgesic effects but is associated with various side effects such as inducing gastrointestinal ulcers. Extended-release meloxicam pellets offer several advantages, including reducing the frequency of daily medication intake and providing sustained drug release over time, thereby minimizing gastrointestinal side effects. The study was conducted to formulate and develop the manufacturing process for meloxicam pellets, while simultaneously evaluating the physicochemical properties of the formulated pellets. Materials and methods: Meloxicam, HPMC E5, and Ethyl Cellulose N7 were used in the study. Meloxicam pellets were formulated using the layering technique, initially depositing the drug onto inert pellets and subsequently extending the coating with Ethyl Cellulose N7. Results: The pellet formula utilizes EC N7 with the role of providing extended-release kinetics following zero-order kinetics. The pellets exhibit uniform and attractive appearance, with dimensions ranging from 0.7 - 1 mm. The drug content is 2.38% ± 0.11% (w/w), demonstrating the ability to release the drug according to a zero-order kinetic model. Conclusions: The study successfully formulated extended-release meloxicam pellets using a coating technique that involved a gradual deposition phase of the drug onto inert pellets, followed by an extended coating phase using a controlled-release excipient. Key words: Meloxicam, pellet, coating technology.

Controlled Release Formulation of Tofacitinib Citrate Tablets Evaluated Using Quality by Design (QBD) Approach

The goal of the project is to use the quality-by-design (QbD) method to create and optimise Tofacitinib citrate matrix tablets with controlled release excipients. The drug's physicochemical parameters, reference product characterisation, QTPP (Quality Target Product Profile), and CQAs were used to start product development (Critical Quality Attributes). Hypromellose (Methocel K100 premium LV CR), Polyethylene Oxide (SentryPolyox WSR N80 LEO), and Magnesium Stearate were used as formulation variables and were optimised together. The complete factorial design of experiment (DOE) with three centre points was used to investigate traditional monolithic controlled release matrix tablets. Using Design-expert12 programme, dissolution was assessed as CQA. At acidic pH, hypromellose with a higher viscosity grade provides a regulated release pattern by retaining the integrity of the medication and preventing rapid drug release. Due to the nonionic nature of the polymer, drug release from the polymer matrices is pH independent. Present monolithic controlled release matrix system the extensive degradation of Tofacitinib Citrate in the acidic condition can be avoided with desired in-vitro drug release.

Injection-Site Nodules Associated With the Use of Exenatide Extended-Release Reported to the U.S. Food and Drug Administration Adverse Event Reporting System.

Glucagon-like peptide-1 (GLP-1) receptor agonists are safe and effective U.S. Food and Drug Administration (FDA)-approved drug products for use in the treatment of type 2 diabetes. To date, the FDA has approved five GLP-1 receptor agonist parenteral formulations: exenatide, liraglutide, exenatide extended-release, and, most recently, albiglutide and dulaglutide. All of these formulations are administered subcutaneously. Exenatide and liraglutide are administered twice daily and once daily, respectively. Until recent approvals of albiglutide and dulaglutide, exenatide extended-release was the only formulation approved for once-weekly use. Relative to other antidiabetic pharmacotherapies, such as metformin or sulfonylureas, GLP-1 receptor agonists are not widely used drugs. A recent study of the usage patterns of antidiabetic drugs estimate that, of 16,316,580 patients prescribed a noninsulin antidiabetic drug in 2012, GLP-1 receptor agonists were dispensed to 673,367 (4.1%) (1). Exenatide extended-release is formulated to encapsulate exenatide in poly-(D,L-lactide-co-glycolide) (also known as PLG matrix) microspheres, which release the active drug over a sustained time interval (2). PLG is a biodegradable and biocompatible medical polymer with an established safety profile used as a controlled release excipient in a variety of drug products (3). PLG undergoes hydrolysis into lactic and glycolic acids, which are eventually eliminated as carbon dioxide and water. In 2012, the introduction of exenatide extended-release into the U.S. market offered GLP-1 receptor agonist users the advantage of fewer injections per week. At the time of approval, the FDA was aware of small, largely asymptomatic injection-site nodules that were associated with exenatide extended-release use. Based on the microsphere excipient, injection-site nodules could be expected with exenatide extended-release administration. However, these reactions were considered nonserious and believed to resolve quickly. Based on controlled data provided in the U.S. approved prescribing information, injection-site reactions were observed more frequently in exenatide extended-release users (17.1%) than in those using exenatide (12.7%) …

The Effect of Processing Variables on the Mechanical and Release Properties of Tramadol Matrix Tablets Incorporating Cissus Populnea Gum as Controlled Release Excipient

The Effect of Processing Variables on the Mechanical and Release Properties of Tramadol Matrix Tablets Incorporating Cissus Populnea Gum as Controlled Release Excipient

“Rolling” phenomenon in twin screw granulation with controlled-release excipients

The developed knowledge regarding use of twin screw granulators for continuous wet granulation has been primarily limited to immediate release formulations in the literature. The present study highlights an issue previously unreported for wet granulation with twin screw extruders when using formulations containing controlled-release (CR) excipients. Long (3–10 mm), twisted noodle-like granules can be produced in the presence of these excipients that are difficult to control and are anticipated to create complications in downstream unit operations to the granulator. Working with two different CR excipients, METHOCEL™ K4M and Kollidon® SR, each blended at different ratios with a mixture of 80% α-lactose monohydrate/20% microcrystalline cellulose, these unique particles were found to be produced in the conveying elements of the extruder, arising from a rolling action at the top of the screw flights. The CR excipients adhesively strengthen the wetted mass, forming this undesired granule shape such that they persisted to the exit of the machine; the shape appeared most strongly affected by screw speed, producing particles of higher aspect ratio as speed was increased. Adjusting the concentration of these CR excipients in the formulation, the flow rate or the type of compression element used in the screws proved ineffective in controlling the problem. Rather, a re-design of the extruder screws was required to prevent generation of these extended-form granules.

Evaluation of acrylamide grafted moth bean starch as controlled release excipient

Abstract The aim of this study was to investigate the applicability of acrylamide grafted moth bean starch as controlled release matrix former. Lamivudine was used as model drug and its controlled release tablets were formulated using various concentration of grafted copolymer. The grafted copolymer was tested for acute toxicity and drug–excipient compatibility study. The formulations were evaluated for physical characteristics like hardness, friability, % drug content and weight variations. The in vitro release study showed that the optimized formulation exhibited highest correlation (R) value in case of Higuchi model and the release mechanism study proved that the formulation showed a combination of diffusion and erosion based release process. There was a significant difference in the pharmacokinetic parameters (Tmax, Cmax, AUC, Vd, T1/2 and MDT) of the optimized formulation as compared to the marketed conventional tablet Lamivir®, which confirmed controlled release potential of acrylamide grafted copolymer.

Terminalia Gum as a Directly Compressible Excipient for Controlled Drug Delivery

The exudates from the incised trunk of Terminalia randii has been evaluated as controlled release excipient in comparison with xanthan gum and hydroxypropylmethylcellulose (HPMC) using carvedilol (water insoluble) and theophylline (water soluble) as model drugs. Matrix tablets were prepared by direct compression and the effects of polymer concentration and excipients-spray dried lactose, microcrystalline cellulose and dicalcium phosphate dihydrate on the mechanical (crushing strength (CS) friability (F) and crushing strength-friability ratio (CSFR)) and drug release properties of the matrix tablets were evaluated. The drug release data were fitted into different release kinetics equations to determine the drug release mechanism(s) from the matrix tablets. The results showed that the CS and CSFR increased with increase in polymer concentration while F decreased. The ranking of CS and CSFR was HPMC > terminalia > xanthan while the ranking was reverse for F. The ranking for t(25) (i.e. time for 25% drug release) at a polymer concentration of 60% was xanthan > terminalia = HPMC. The dissolution time, t(25), of theophylline matrices was significantly lower (p < 0.001) than those of carvedilol matrix tablets. Drug release from the matrices was by swelling, diffusion and erosion. The mechanical and drug release properties of the tablets were significantly (p < 0.05) dependent on the type and concentration of polymer and excipients used with the release mechanisms varying from Fickian to anomalous. Terminalia gum compared favourably with standard polymers when used in controlled release matrices and could serve as a suitable alternative to the standard polymers in drug delivery.

Characterization of a novel lyophilized chitosan hydrogel complex for the controlled release of a highly water soluble drug, niacinamide.

The purpose of this research was to prepare and characterize a novel lyophilized chitosan-based hydrogel complex (termed CS-M) for controlled drug delivery applications using a highly water soluble model drug, niacinamide. Characterization studies were undertaken to evaluate the physical-chemical properties, polymer swelling, in vitro controlled release kinetics, tissue bioadhesion, intestinal permeability and stability of the novel chitosan complex. Additionally, a comparative analysis was conducted with commercial polymers namely, Carbopol 974P-NF® and hydroxypropyl methylcellulose (HPMC K4M). FT–IR and 1H NMR studies confirmed that despite alteration in physical structure and morphology of the chitosan complex the chemical properties remained unchanged, when compared to the parent chitosan compound. Polymer swelling studies showed consistency in the structural integrity and water uptake of CS-M compared to other polymers which showed inconsistent swelling and disintegration behavior over a 5 h period. In vitro controlled release profiles of CS-M showed a slower, more controlled release rate of niacinamide than other polymers indicating the influence of polymer swelling capacity on water uptake and subsequent drug release. CS-M demonstrated an overall increase in bioadhesion to intestinal tissue when compared to commercial polymers at same concentrations. Similarly, drug transport through everted sac intestinal tissue showed enhanced absorption properties of CS-M when compared to other polymers. Finally, a 3 month accelerated stability study showed all polymers including CS-M to be stable when formulated with niacinamide. Overall, the modified chitosan-based hydrogel polymer, CS-M, demonstrated enhanced characteristics indicating its potential to be used as a controlled release excipient in oral drug formulations. Keywords: Chitosan hydrogel complex, controlled drug delivery, niacinamide, lyophilization, Carbopol 974P-NF, HPMC K4M

Synthesis of Per- and Poly-Substituted Trehalose Derivatives: Studies of Properties Relevant to Their Use as Excipients for Controlled Drug Release

Per- and poly-substituted oligosaccharide derivatives, with trehalose cores, have been prepared and assessed for their potential for use as excipients in controlled-release formulations. The synthesized compounds, generally with acyl and amido substituents, included 6,6′-N,N′ -diamido-6,6′ -dideoxy-α,α -trehalose derivatives, 6,6′ -bis(1,2,3,4-tetra-O-acetyl-β -D-glucopyranuronyl)-α, α -trehalose derivatives, 2,2′,3,3′ -tetra-O-acetyl-6,6′ -bis-(1,2,3,4-tetra-O-acetyl-β-D-glucopyranuronyl)-4,4′ -di-O-acyl-α,α-trehalose, 2, 2′, 3, 3′ -tetra-O-acetyl-6-(1,2,3,4-tetra-O-acetyl-β-D-glucopyranuronyl)-4,4′,6′ -tri-O-acyl-α,α-trehalose, and 2,2′,3,3′,4,4′ -hexa-O-acetyl-6,6′ -bis-(1,2,3,4-tetra-O-acetyl-6-O-succinyl-β-D-glucopyranuronyl)-α,α-trehalose. Compounds were characterized by NMR, IR, MS and optical rotations; elemental analyses; or HRMS. The compounds formed amorphous materials either on fast quenching of melts or on spray drying. Properties, used in the initial assessment of the potential as controlled-release excipients, were log10 P and glass transition, Tg, values.

Evaluation of Sterculia foetida Gum as Controlled Release Excipient

The purpose of the research was to evaluate Sterculia foetida gum as a hydrophilic matrix polymer for controlled release preparation. For evaluation as a matrix polymer; characterization of Sterculia foetida gum was done. Viscosity, pH, scanning electronmicrographs were determined. Different formulation aspects considered were: gum concentration (10-40%), particle size (75-420 microm) and type of fillers and those for dissolution studies; pH, and stirring speed were considered. Tablets prepared with Sterculia foetida gum were compared with tablets prepared with Hydroxymethylcellulose K15M. The release rate profiles were evaluated through different kinetic equations: zero-order, first-order, Higuchi, Hixon-Crowell and Korsemeyer and Peppas models. The scanning electronmicrographs showed that the gum particles were somewhat triangular. The viscosity of 1% solution was found to be 950 centipoise and pH was in range of 4-5. Suitable matrix release profile could be obtained at 40% gum concentration. Higher sustained release profiles were obtained for Sterculia foetida gum particles in size range of 76-125 microm. Notable influences were obtained for type of fillers. Significant differences were also observed with rotational speed and dissolution media pH. The in vitro release profiles indicated that tablets prepared from Sterculia foetida gum had higher retarding capacity than tablets prepared with Hydroxymethylcellulose K15M prepared tablets. The differential scanning calorimetry results indicated that there are no interactions of Sterculia foetida gum with diltiazem hydrochloride. It was observed that release of the drug followed through surface erosion and anomalous diffusion. Thus, it could be concluded that Sterculia foetida gum could be used a controlled release matrix polymer.

Comparative imaging of a slow-release starch excipient tablet: Evidence of membrane formation

A controlled release excipient made of chemically modified high-amylose starch (HAS) has been used to explore the surface membrane responsible for the slow release characteristics. Using scanning electron microscopy (SEM) and X-ray computed microtomography (CMT), the radial and axial surfaces of dry, swollen and freeze-dried sections observed were arranged in concentric domains. The presence of water enhances contrast in CMT imaging of the swollen tablet compared to the non-hydrated state. Freeze-dried SEM images showed a twin domain structure, thus defining membrane thickness. CMT quantified the average global porosity of the dry and swollen domains. The bird’s eye view of the latter defined a central-core with high contrast and 34% porosity while the average global porosity was 19% and the dry porosity was 10%. The overall membrane after 15 min swelling is best described as concentric hydrogel domains.

Evaluation of Selected Polysaccharide Excipients in Buccoadhesive Tablets for Sustained Release of Nicotine

Some naturally occurring biocompatible materials were evaluated as mucoadhesive controlled release excipients for buccal drug delivery. A range of tablets were prepared containing 0–50% w/w xanthan gum, karaya gum, guar gum, and glycol chitosan and were tested for swelling, drug release, and mucoadhesion. Guar gum was a poor mucoadhesive and lacked sufficient physical integrity for buccal delivery. Karaya gum demonstrated superior adhesion to guar gum and was able to provide zero‐order drug release, but concentrations greater than 50% w/w may be required to provide suitable sustained release. Xanthan gum showed strong adhesion to the mucosal membrane and the 50% w/w formulation produced zero‐order drug release over 4 hours, about the normal time interval between daily meals. Glycol chitosan produced the strongest adhesion, but concentrations greater than 50% w/w are required to produce a nonerodible matrix that can control drug release for over 4 hours. Swelling properties of the tablets were found to be a valuable indicator of the ability of the material to produce sustained release. Swelling studies also gave an indication of the adhesion values of the gum material where adhesion was solely dependent upon penetration of the polymer chains into the mucus layer.

Plasticisation of amylodextrin by moisture. Consequences for compaction behaviour and tablet properties

Purpose: Amylodextrin, a starch-based controlled release excipient, spontaneously absorbs moisture during storage. The aim of this study was to investigate plasticisation of amylodextrin by moisture and its effect on compaction and tablet characteristics. Methods: The glass transition temperature ( T g) of amylodextrin powders with moisture fractions ( x w) 0.070< x w<0.40 was studied by conventional and modulated DSC. Elastic modulus and yield stress were determined from compressive stress–strain experiments. Compaction behaviour was studied at 3 and 300 mm/s using a compaction simulator. Results: The T g of amylodextrin–water blends showed a smooth reduction with increasing x w, equalling room temperature at x w=0.19. Experimentally obtained T g values were close to temperatures as predicted by the Gordon–Taylor/Kelley–Bueche model and the modified Couchman–Karasz model. The elastic modulus decreased steeply between x w=0.17 and 0.23. Compaction experiments showed that moisture facilitated consolidation due to increasing powder compressibility and reduced compact relaxation. However, at x w=0.23, compressibility was reduced and relaxation significantly higher due to the rubbery character of this powder. Consequently, the lowest tablet porosities were obtained around x w=0.15. Although decreasing porosities enhanced tablet strengths, the maximum obtainable tablet strengths decreased with moisture due to reduced particle bonding and lowering of the elastic modulus. Conclusion: Moisture largely affects the visco-elastic and compaction characteristics of amylodextrin. Hence, control over moisture content is essential to produce tablets with reproducible porosity, strength and dissolution characteristics.

Use of a Novel Modified TSI for the Evaluation of Controlled-Release Aerosol Formulations. I

When considering the development of potential controlled-release pulmonary drug delivery systems, there is at present no standard method available for the assessment of in vitro drug release profiles necessary to understand how the drug might release following deposition in the lungs. For this purpose, the twin-stage impinger (TSI), apparatus A of the BP, has been redesigned and tested. This modified TSI was found capable of discriminating between drug release rates from conventional and different dry powder formulations consisting of model controlled-release excipients, providing information related to (a) drug diffusion properties of controlled-release dry powder blends with different excipient components and (b) the effect of varying drug concentration within a given formulation.

Characterization of a crosslinked high amylose starch excipient

A controlled release excipient based on sodium trimetaphosphate (STMP) crosslinked high amylose starch has been examined by 13C CP/MAS NMR. The dry excipient powder is pressed to a hard tablet whose volume increase in H 2O runs parallel to the STMP concentration used. The known polymorph resonances of single helix ‘V’ starch (hydrated) and double helix ‘B’ starch (hydrated) both contribute to the spectrum corresponding to the swollen tablet. The wet tablet when loaded with a pharmaceutical agent provides a near zero-order release profile for up to 20 h. The swelling and drug release behaviour is explained in terms of self-assembly of the STMP treated starch nanomolecular particles. These particles are drawn together by “self-assembly” due to formation of amylose double helices as water penetrates the tablet. An optimum level of chemical crosslinking ensures the integrity of the swollen tablet whose sponge-like structure enclosed by a membranous surface is responsible for sustained release.

Synthetic PMMA-Grafted Polysaccharides as Hydrophilic Matrix for Controlled-Release Forms

This paper describes the rheological behavior of starch and cellulose acrylic graft copolymers synthesized with the aim of obtaining controlled-release excipients. The rheological characteristics determine the final release properties of matrix tablets. The study of the storage and loss moduli (G′ and G″, respectively) and the viscosity allowed us to know if the polymer behavior was that of a gel and, hence, if it could act as a barrier to drug diffusion. Since dynamic measurements showed a storage modulus higher than the loss modulus, we assessed that all the polymers were gels. Thus, knowing that all the graft copolymers had acceptable properties for compression, the release of theophylline as a model drug at different pH was studied. Polymers with higher absorption capacity, viscosity, and compactibility allowed formulations with slower release rates.