Modified Release Characteristics Research Articles

Development and validation of the INappropriate solid oral dosaGE form modification aSsessmenT (INGEST) Algorithm using data of patients with medication dysphagia from a neurology ward and nursing home in Singapore

ObjectivesThis study aims to develop and validate a novel implicit tool to assist clinicians in resource-limited settings to promptly assess suitability for modification of solid oral dosage forms (SODFs) during...

On the usefulness of four in vitro methodologies in screening for product related differences in tacrolimus exposure after oral administration of amorphous solid dispersions with modified release characteristics in the fasted state

ObjectiveTo investigate the usefulness of four in vitro methodologies in screening for product related differences in tacrolimus exposure after oral administration of amorphous solid dispersions with modified release characteristics in the fasted state. MethodsInitially, Advagraf® (5 mg tacrolimus/capsule), Envarsus® (4 mg tacrolimus/tablet) and a modified release Test Tablet (5 mg tacrolimus/tablet) were subjected to in vitro biorelevant performance testing simulating fasted state conditions using a small-scale two-stage biphasic system, a small-scale two-stage dissolution – permeation (D-P) system, the compendial apparatus IV (open loop mode) and the biorelevant gastrointestinal transfer (BioGIT) system. Early and total exposure, after single dose administrations of the three products to twelve healthy adults in the fasted state on a crossover basis, were then evaluated. Subsequently, the usefulness of in vitro data in qualitatively predicting product related differences in early exposure and in total exposure were assessed. ResultsProduct related differences in tacrolimus early exposure were successfully predicted by data collected with compendial apparatus IV. The two-stage biphasic system was useful for predicting differences in early exposure between the non-disintegrating Envarsus® and the disintegrating products (Advagraf® or Test Tablet). BioGIT data were useful only for discussing clinical data early after administration of the two disintegrating products. Prediction of product related differences in total exposure was successful only when the compendial apparatus IV was used for comparing the two disintegrating products. ConclusionsBiorelevant in vitro performance testing with compendial apparatus IV was useful for qualitatively predicting differences in tacrolimus early and total exposure after administration of disintegrating products with modified release characteristics in the fasted state.

3D PRINTING OF PHARMACEUTICALS – LEADING TREND IN PHARMACEUTICAL INDUSTRY AND FUTURE PERSPECTIVES

3D printing technology is a rapid prototyping process based on computer-aided design software that is proficient to construct solid objects with various geometrics by depositing numerous layers in a sequence. The major advantages of three-dimensional printing (3DP) technology over the traditional manufacturing of pharmaceuticals include the customization of medications with individually adjusted doses, on-demand tailored manufacturing, unprecedented flexibility in the design, manufacturing of complex and sophisticated solid dosage forms, and economic benefits. Recently, many researchers have been invested their efforts in applying 3DP technology to the pharmaceutical development of drug products and different drug delivery systems. Selective laser sintering, fused deposition modeling, semi-solid extrusion, stereolithography, etc., are the multiple 3DP technologies that can be established in several customized and programmable medicines. Sublingual, orodispersible, and fast-dissolving drug delivery formulations by 3DP technology have been already manufactured. Controlled-release formulations with different characteristics, doughnut-shaped multi-layered tablets with linear release kinetics, and drug-loaded tablets with modified-release characteristics are recently fabricated using 3DP. However, few 3DP methods produce uneven shapes of dosage forms and comparatively porous structures. Cost of transition, adaptation to the existing facility, achieving regulatory approval, etc., are the present challenges that can restrict the extensive application of 3DP technology to pharmaceutical products. Intense research work for modifying the 3DP methods is simultaneously sustained for by-passing the flaws and current limitations of this technology. 3DP technology can act as a convenient and potential tool for the pharmaceutical industry which will set a revolutionary manufacturing style in the near future to facilitate patient-centered health care.

Regulatory Requirements of the European Medicines Agency for Evaluation of Bioequivalence of Modified-release Medicinal Products

There are no specific requirements and recommendations in the Russian Federation for evaluation of bioequivalence of modified-release medicinal products. Until recently, modified-release products were regulated in a similar manner as immediate-release products, which is unacceptable considering the active ingredient release profile and its pharmacokinetics. The modified release characteristics require a more complex approach to the assessment of equivalence of generic medicines as compared with the reference product. The number of parameters to be assessed and the scope of testing depend on many factors (release mechanism, specific features of the dosage form, linearity of pharmacokinetics, potential for ingredient accumulation, dependence on food intake, dose-dumping effects, and the number of dosage strengths to be registered). The aim of this paper was to develop recommendations for the national procedure of modified-release products authorisation based on the analysis of international regulatory experience in this field. The paper reviews the current European Medicines Agency (EMA) guidelines on evaluation of bioequivalence of generic modified-release dosage forms for oral use that were taken as a basis for the development of Eurasian Economic Union regulations on bioequivalence assessment. The analysis of the above-mentioned documents made it possible to develop recommendations for the national procedure of modified-release products authorisation. In the case of modified-release products for oral use it is recommended to perform bioequivalence studies by comparing the test product with the reference product. The authors developed a procedural algorithm for bioequivalence studies of modified-release medicinal products.

Selective laser sintering (SLS) 3D printing of medicines

Selective laser sintering (SLS) 3-dimensional printing is currently used for industrial manufacturing of plastic, metallic and ceramic objects. To date there have been no reports on the use of SLS to fabricate oral drug loaded products; therefore, the aim of this work was to explore the suitability of SLS printing for manufacturing medicines. Two thermoplastic pharmaceutical grade polymers, Kollicoat IR (75% polyvinyl alcohol and 25% polyethylene glycol copolymer) and Eudragit L100-55 (50% methacrylic acid and 50% ethyl acrylate copolymer), with immediate and modified release characteristics respectively, were selected to investigate the versatility of a SLS printer. Each polymer was investigated with three different drug loadings of paracetamol (acetaminophen) (5, 20 and 35%). To aid the sintering process, 3% Candurin® gold sheen was added to each of the powdered formulations. In total, six solid formulations were successfully printed; the printlets (3D printed tablets) were robust, and no evidence of drug degradation was observed. In biorelevant bicarbonate dissolution media, the Kollicoat formulations showed pH-independent release characteristics, with the release rate dependent on the drug content. In the case of the Eudragit formulations, these showed pH-dependent, modified-release profiles independent of drug loading, with complete release being achieved over 12h. In conclusion, this work has demonstrated that SLS is a versatile and practical 3D printing technology which can be applied to the pharmaceutical field, thus widening the armamentarium of 3D printing technologies available for the manufacture of modern medicines.

Stereolithographic (SLA) 3D printing of oral modified-release dosage forms

The aim of this work was to evaluate the suitability of stereolithography (SLA) to fabricate drug-loaded tablets with modified-release characteristics. The SLA printer creates solid objects by using a laser beam to photopolymerise monomers. In this work polyethylene glycol diacrylate (PEGDA) was used as a monomer and diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide was used as a photo-initiator. 4-aminosalicylic acid (4-ASA) and paracetamol (acetaminophen) were selected as model drugs. Tablets were successfully printed and formulations with different properties were fabricated by adding polyethylene glycol 300 (PEG 300) to the printing solution. The loading of paracetamol and 4-ASA in the printed tablets was 5.69% and 5.40% respectively. In a realistic dynamic dissolution simulation of the gastrointestinal tract, drug release from the tablets was dependent on the composition of the formulations, but independent of dissolution pH. In conclusion SLA 3DP technology allows the manufacture of drug loaded tablets with specific extended-release profiles. In the future this technology could become a manufacturing technology for the elaboration of oral dosage forms, for industrial production or even for personalised dose.

Optimization of caseinate-coated simvastatin-zein nanoparticles: improved bioavailability and modified release characteristics.

The current study focuses on utilization of the natural biocompatible polymer zein to formulate simvastatin (SMV) nanoparticles coated with caseinate, to improve solubility and hence bioavailability, and in addition, to modify SMV-release characteristics. This formulation can be utilized for oral or possible depot parenteral applications. Fifteen formulations were prepared by liquid–liquid phase separation method, according to the Box–Behnken design, to optimize formulation variables. Sodium caseinate was used as an electrosteric stabilizer. The factors studied were: percentage of SMV in the SMV-zein mixture (X1), ethanol concentration (X2), and caseinate concentration (X3). The selected dependent variables were mean particle size (Y1), SMV encapsulation efficiency (Y2), and cumulative percentage of drug permeated after 1 hour (Y3). The diffusion of SMV from the prepared nanoparticles specified by the design was carried out using an automated Franz diffusion cell apparatus. The optimized SMV-zein formula was investigated for in vivo pharmacokinetic parameters compared with an oral SMV suspension. The optimized nanosized SMV-zein formula showed a 131 nm mean particle size and 89% encapsulation efficiency. In vitro permeation studies displayed delayed permeation characteristics, with about 42% and 85% of SMV cumulative amount released after 12 and 48 hours, respectively. Bioavailability estimation in rats revealed an augmentation in SMV bioavailability from the optimized SMV-zein formulation, by fourfold relative to SMV suspension. Formulation of caseinate-coated SMV-zein nanoparticles improves the pharmacokinetic profile and bioavailability of SMV. Accordingly, improved hypolipidemic activities for longer duration could be achieved. In addition, the reduced dosage rate of SMV-zein nanoparticles improves patient tolerability and compliance.

An observational study on the influence of solvent composition on the architecture of drug-layered pellets

Pelletization for the manufacture of modified release multiparticulate drug delivery systems is often considered to be well defined and robust. However, small differences in formulation conditions can lead to surprising changes to the expected outcomes. We observed that extended release tramadol hydrochloride pellets, prepared by solution layering an ethanolic solution of drug on a non-pareil, resulted in highly unusual pellet architecture with deep indentations which prevented the application of a homogeneous outer coating of ethylcellulose and talc, and negatively influenced the desired modified release characteristics. Modification of outer coating thickness and process temperature showed no improvement in release characteristics. A solution to the problem was found in the incorporation of 10% v/v water into the ethanolic drug layering solution, resulting in the production of drug-loaded pellets with a smooth morphology which allowed the application of a coherent outer coating able to retard drug release. The surprising difference in pellet morphology between the two solvent drug layering systems may be attributed to differences in solvent evaporation rates. This demonstrates that established techniques are sometimes less straightforward than thought as small changes in formulation have significant effects on the resulting product in a way which is not always well understood.

Pharmacokinetic comparison between Conpremin® (Premarin®) and a generic preparation of conjugated estrogens

Objectives To determine the relative bioavailability of the estrogenic components of a generic brand of conjugated estrogens marketed in Chile in comparison to that of Conpremin* (Premarin* in the United States).Methods A randomized cross-over study was conducted on 16 healthy postmenopausal women receiving single oral doses of either two Conpremin 0.625-mg tablets or two 0.625-mg tablets of the generic brand, with a 14-day wash-out interval between doses. A gas chromatography tandem mass spectrometry assay was used to determine estrogen components.Results The peak plasma concentrations of unconjugated and total estrone and equilin, unconjugated 17β-dihydroequilin and 17β-estradiol were higher and occurred earlier with the generic conjugated estrogens than with Conpremin. The 90% confidence limits for both variables lay outside the accepted bioequivalence limits of 80–125%. Additionally, no measurable plasma concentration of unconjugated Δ8–9-dehydroestrone or 17 β-Δ8–9-dehydroestradiol was seen after administration of the generic conjugated estrogens.Conclusions These pharmacokinetic results indicate that the generic tablets do not have the modified-release characteristics of Conpremin tablets. In addition, the absence of Δ8–9-dehydroestrone and 17β-Δ8–9-dehydroestradiol in the plasma indicates that the generic form is not compositionally equivalent to Conpremin.

Development of Matrix Controlled Release Beads by Extrusion-Spheronization Technology Using a Statistical Screening Design

AbstractThe objective of this study was to develop beads with inherent modified release characteristics requiring no subsequent controlled release coating. Extrusion-spheronization was chosen to accomplish this goal. The model drug was a zwitterion (isoelectric point ∼pH 5.2) with poor solubility and low bulk density. Preliminary studies indicated that matrix beads with modified micro-environmental pH would result in sustained release of the drug. A Nica extruder and spheronizer were used to manufacture the beads. A Plackett-Burman screening design was employed to isolate critical variables influencing the bead characteristics and drug release. Variables studied included the type of polymeric dispersion, polymer concentration, acid type, acid concentration, plasticizer content, drug concentration and spheronizing time. Responses evaluated included capsule fill weight, drug release rate, micro-environmental pH, yield and friability. Beads were successfully manufactured according to the screening design and...