Optimization and development of a core-in-cup tablet for modulated release of theophylline in simulated gastrointestinal fluids

A triple-layer core-in-cup tablet that can release theophylline in simulated gastrointestinal (GI) fluids at three distinct rates has been developed. The first layer is an immediate-release layer; the second layer is a sustained-release layer; and the last layer is a boost layer, which was designed to coincide with a higher nocturnal dose of theophylline. The study consisted of two stages. The first stage optimized the sustained-release layer of the tablet to release theophylline over a period of 12 hr. Results from this stage indicated that 30% w/w acacia gum was the best polymer and concentration to use when compressed to a hardness of 50 N/m². The second stage of the study involved the investigation of the final triple-layer core-in-cup tablet to release theophylline at three different rates in simulated GI fluids. The triple-layer modulated core-in-cup tablet successfully released drug in simulated fluids at an initial rate of 40 mg/min, followed by a rate of 0.4085 mg/min, in simulated gastric fluid TS, 0.1860 mg/min in simulated intestinal fluid TS, and finally by a boosted rate of 0.6952 mg/min.     

Alginate-coated alginate-polyethyleneimine beads for prolonged release of furosemide in simulated intestinal fluid

Furosemide-loaded calcium alginate (ALG), calcium alginate-polyethyleneimine (ALG-PEI) and alginate-coated ALG-PEI (ALG-PEI-ALG) beads were prepared by ionotropic/polyelectrolyte complexation method to achieve controlled release of the drug. Effects of several formulation factors on the characteristics of the beads were investigated. Although variation in formulation factors did not influence the drug-loading efficiency (DLE) of ALG beads, rapid release of the drug in simulated intestinal fluid (SIF) could not be prevented. PEI treatment of ALG beads, however, prolonged the drug release considerably. Ionic interaction, as appeared from FTIR studies, between alginate and PEI led to the formation of polyelectrolyte complex membrane, the thickness of which was dependent on the conditions of PEI treatment as demonstrated by scanning electron microscopy (SEM). The membrane acted as a physical barrier to drug release from ALG-PEI beads. Alginate coating of ALG-PEI beads further prolonged the release of the drug by increasing membrane thickness and reducing swelling of the beads possibly by blocking the surface pores. Differential scanning calorimetry (DSC) study indicated that drug was not degraded by PEI treatment. The release data from ALG-PEI beads showed a good fit in power law expression, whereas the release data from ALG-PEI-ALG beads were found to fit in modified power law expression, and the mechanism of drug release changed from super case II transport to nearly Fickian transport, depending on the degree of gelation and formation of polyelectrolyte complex membrane.     

Calcium and titanium release in simulated body fluid from plasma electrolytically oxidized titanium

The release of titanium and calcium species to a simulated body fluid (SBF) at 37°C has been investigated for titanium treated by dc plasma electrolytic oxidation (PEO) in three different electrolytes, namely phosphate, silicate and calcium- and phosphorus-containing. The average rate of release of titanium over a 30 day period in immersion tests, determined by solution analysis, was in the range ~1.5–2.0 pg cm⁻² s⁻¹. Calcium was released at an average rate of ~11 pg cm⁻² s⁻¹. The passive current densities, determined from potentiodynamic polarization measurements, suggested titanium losses of a similar order to those determined from immersion tests. However, the possibility of film formation does not allow for discrimination between the metal releases due to electrochemical oxidation of titanium and chemical dissolution of the coating.     

Calcium phosphate fibres synthesized from a simulated body fluid

The biomimetic coating method was used for fabricating calcium phosphate fibres for biomedical applications such as bone defect fillers. Natural cotton substrate was pre-treated with phosphorylation and a Ca(OH)₂ saturated solution. The pre-treated samples were then soaked in simulated body fluid (SBF) of two different concentrations, 1.5 times and 5.0 times the ion concentration of blood plasma. The cotton was then burnt out via sintering of the ceramic coating at 950^∘C, 1050^∘C, 1150^∘C, and 1250^∘C. The results demonstrated that osteoblastic cells were able to cover the entire surface cotton fibres, and the cell coverage appeared to be independent of surface roughness and Ca/P ratio of fibres.     

Chitosan-alginate multilayer beads for gastric passage and controlled intestinal release of protein

Chitosan-alginate beads loaded with a model protein, bovine serum albumin (BSA) were investigated to explore the temporary protection of protein against acidic and enzymatic degradation during gastric passage. Optimum conditions were established for preparation of homogenous, spherical, and smooth chitosan-alginate beads loaded with BSA. Multilayer beads were prepared by additional treatment with either chitosan or alginate or both. The presence of chitosan in the coagulation bath during bead preparation resulted in increased entrapment of BSA. During incubation in simulated gastric fluid (SGF pH 1.2), the beads showed swelling and started to float but did not show any sign of erosion. Inclusion of pepsin in the gastric fluid did not show a further effect on the properties of the beads. Release studies were done in simulated gastric fluid (SGF pH 1.2) and subsequently in simulated intestinal fluid (SIF pH 7.5) to mimic the physiological gastrointestinal conditions. After transfer to intestinal fluid, the beads were found to erode, burst, and release the protein. Microscopic and macroscopic observations confirmed that the release of protein was brought about by the burst of beads. Chitosan-reinforced calcium-alginate beads showed delay in the release of BSA. The multilayer beads disintegrated very slowly. The enzymes pepsin and pancreatin did not change the characteristics of BSA-loaded chitosan-alginate beads. Single layer chitosan-alginate beads released 80-90% of the model protein within 12 h while multilayer beads released only 40-50% in the same period of time. The release from chitosan-alginate beads and multilayer beads in SIF was further delayed without prior incubation in SGF. It is concluded that alginate beads reinforced with chitosan offer an excellent perspective for controlled gastrointestinal passage of protein drugs.     

The influence of HPMC concentration on release of theophylline or hydrocortisone from extended release mini-tablets

Context: Mini-tablets are compact dosage forms, typically 2–3 mm in diameter, which have potential advantages for paediatric drug delivery. Extended release (ER) oral dosage forms are intended to release drugs continuously at rates that are sufficiently controlled to provide periods of prolonged therapeutic action following each administration, and polymers such as hypromelllose (HPMC) are commonly used to produce ER hydrophilic matrices.

Objective: To develop ER mini-tablets of different sizes for paediatric delivery and to study the effects of HPMC concentration, tablet diameter and drug solubility on release rate.

Methods: The solubility of Hydrocortisone and theophylline was determined. Mini-tablets (2 and 3 mm) and tablets (4 and 7 mm) comprising theophylline or hydrocortisone and HPMC (METHOCEL? K15M) at different concentrations (30, 40, 50 and 60%w/w) were formulated. The effect of tablet size, HPMC concentration and drug solubility on release rate and tensile strength was studied.

Results and Discussion: Increasing the HPMC content and tablet diameter resulted in a significant decrease in drug release rate from ER mini-tablets. In addition, tablets and mini-tablets containing theophylline produced faster drug dissolution than those containing hydrocortisone, illustrating the influence of drug solubility on release from ER matrices. The results indicate that different drug release profiles and doses can be obtained by varying the polymer content and mini-tablet diameter, thus allowing dose flexibility to suit paediatric requirements.

Conclusion: This work has demonstrated the feasibility of producing ER mini-tablets to sustain drug release rate, thus allowing dose flexibility for paediatric patients. Drug release rate may be tailored by altering the mini-tablet size or the level of HPMC, without compromising tablet strength.     

Corrosion behavior of surface-modified titanium in a simulated body fluid

We investigate the influence of micro-sandblasting and electrochemical passivation on properties such as corrosion rate and surface roughness, which are important to the biocompatibility of titanium (Ti), using surface analysis techniques and electrochemical measurements. Results of microscopy and surface profilometry experiments reveal roughened but uniform surface topography with an average surface roughness in the 0.87–1.06 μm range, depending on the alternating current passivation voltage applied to the micro-sandblasted samples. Open circuit potential versus time measurements in Hank’s Balanced Salt Solution (HBSS, a simulated body fluid) allow determination of the corrosion potential (E _corr) and reveal a shift of E _corr toward higher values upon passivation, thus pointing to increased corrosion stability. Corrosion rates in HBSS range between 0.049 and 0.288 μm year⁻¹ for micro-sandblasted and passivated Ti, as compared to that for the micro-sandblasted and non-passivated surface that is 0.785 μm year⁻¹. Results from this study demonstrate that micro-sandblasting coupled with electrochemical passivation provides a roughened surface with increased corrosion stability and a low corrosion rate in HBSS. Application of this technique to Ti in medical and dental applications may be expected to result in an improvement of biocompatibility.     

Development and mathematical simulation of theophylline pulsatile release tablets

Theophylline pulsatile release tablets consisting of a fast-swelling core with a water-insoluble ethylcellulose were developed. Effects of coating material, the amount of the plasticizer, subcoating, the type of the disintegrant, and coating level on the release profiles were investigated. Results showed that ethylcellulose was the best candidate polymer for pulsatile release tablets. Rupture time increased with increasing the amount of the plasticizer, but 15% plasticizer provided the best release profiles. Tablets with Methocel E50 as subcoating was most optimal in order to achieve a long lag time and followed by a rapid release. The lag time of tablets containing different disintegrants increased in the following order: croscarmellose (Ac-Di-Sol) < sodium starch glycolate (Explotab) < low-substituted hydroxypropyl cellulose (L-HPC) < crospovidone (Kollidon CL). And the rupture time increased with higher coating level. A mathematical model was presented to predict the lag time prior to rupture. Results of the water uptake experiment were used to estimate the apparent diffusion coefficient of the coating tablets. The prediction of the lag time based on the presented model is in good agreement with the experimental results.     

The influence of diluent on the release of theophylline from hydrophilic matrix tablets

The role of β-cyclodextrin (β-CD) on the apparent solubility of theophylline was investigated by the solubility method. Binary systems of theophylline and β-CD were prepared using the dry co-grinding method. Their characterization was performed by differential scanning calorimetry (DSC). The dissolution rate of theophylline and theophylline/β-CD and dissolution studies of matrix tablets prepared from mixtures containing theophylline and ground theophylline were carried out. It can be concluded that β-CD is related to an increase in the apparent solubility and dissolution rate of the drug, promoting improvement on the release of theophylline from matrices manufactured with hydroxypropylmethylcellulose (HPMC). This can be attributed to the amorphous state and the increased wettability of the drug.     

Self-assembly and bioactive response of a crystalline metal oxide in a simulated blood fluid

In this study we report on the bioactive response of self-assembled niobium oxide microstructures when immersed in a supersaturated solution emulating mineral content in blood. The structures were formed via electrochemical anodization in an electrolyte comprised of HF and NaF. The slow oxide formation kinetics associated with the presence of NaF in the electrolyte enabled microscopic examinations during microstructure evolution as shown via scanning electron microscopy (SEM). Apparently the slow growth kinetics encourage the development of bioactive sites on the microstructures, as these structures induced mineral formations. On the other hand, microstructures grown in the absence of salt were ineffective mineral nucleators. Analysis of nucleated mineral deposits was performed using X-ray diffraction and Raman spectroscopy. Both long-range and short-range order experiments verified the nucleated mineral phase was hydroxyapatite (HAP). Further characterization of the mineral phase was observed using SEM and revealed effective nucleation sites were predominantly isolated to loci on the ordered microbodies as opposed to locations lying within the amorphous strata.     

Drug release kinetics from tablet matrices based upon ethylcellulose ether-derivatives: a comparison between different formulations

The present study involved the preparation of ibuprofen-containing controlled release tablets formulated from either the established granular product, Ethocel®Standard Premium, or the novel finely-milled product, Ethocel®Standard FP Premium. The tablets were prepared by either direct compression or wet granulation. The aim was to explore the influence of different parameters on the kinetics and mechanisms of ibuprofen release from the tablets. These parameters were; polymer particle size, polymer molecular weight, drug : polymer ratio, preparation methodology and partial replacement of lactose with the coexcipient—hydroxypropyl methylcellulose (HPMC). The derived drug release data were analyzed with reference to various established mathematical models while the f₂-metric technique was used in order to determine profile equivalency. It was found that drug release was mostly modulated by several interactive factors apparently exhibiting crosstalk. Nevertheless, it was possible to identify some simple rules. Incorporation of Ethocel® FP polymers and application of the wet granulation technique facilitated greater efficiency in controlling ibuprofen release behavior from the matrices. Furthermore, drug release profiles could be modulated by partial substitution of the primary excipient with HPMC. Polymer concentrations and particle sizes, rather than viscosity grade, were found to be decisive factors in controlling drug release rates.     

Modeling of nuclide release from low-level radioactive paraffin waste: a comparison of simulated and real waste

Nuclide leaching models based on mass transfer theory are reviewed and evaluated to analyze the leaching test results of simulated and real paraffin waste from Korean nuclear power plants (NPPs). An empirical model (EM), bulk diffusion model (BDM), coupled diffusion/dissolution model (CDDM), shrinking core model (SCM), modified SCM (MSCM), and uniform reaction model (URM) are selected for comparison. In case of simulated paraffin waste form, the experimental results are satisfactorily explained by the SCM which is based on a diffusion-controlled dissolution reaction. Leaching behavior of real paraffin waste form is well predicted by URM that considers inter-aggregated porous medium and intra-aggregated porous medium separately. If real paraffin waste forms are manufactured with relatively uniform composition, their leaching behaviors are expected to be similar to those of simulated paraffin waste forms.     

Formulation and development of orodispersible sustained release tablet of domperidone

Abstract

Commercially available domperidone orodispersible tablets (ODT) are intended for immediate release of the drug, but none of them have been formulated for sustained action. The aim of the present research work was to develop and evaluate orodispersible sustained release tablet (ODT-SR) of domperidone, which has the convenience of ODT and benefits of controlled release product combined in one. The technology comprised of developing sustained release microspheres (MS) of domperidone, followed by direct compression of MS along with suitable excipients to yield ODT-SR which rapidly disperses within 30?seconds and yet the dispersed MS maintain their integrity to have a sustained drug release. The particle size of the MS was optimized to be less than 200?μm to avoid the grittiness in the mouth. The DSC thermograms of MS showed the absence of drug-polymer interaction within the microparticles, while SEM confirmed their spherical shape and porous nature. Angle of repose, compressibility and Hausner’s ratio of the blend for compression showed good flowability and high percent compressibility. The optimized ODT-SR showed disintegration time of 21?seconds and matrix controlled drug release for 9?h. In-vivo pharmacokinetic studies in Wistar rats showed that the ODT-SR had a prolonged MRT of 11.16?h as compared 3.86?h of conventional tablet. The developed technology is easily scalable and holds potential for commercial exploitation.     

Effect of diluents on tablet integrity and controlled drug release

The objective of this study was to evaluate the effect of diluents and wax level on tablet integrity during heat treatment and dissolution for sustained-release formulations and the resultant effect on drug release. Dibasic calcium phosphate dihydrate (DCPD), microcrystalline cellulose (MCC), and lactose were evaluated for their effect on tablet integrity during drug dissolution and heat treatment in wax matrix formulations. A newly developed direct compression diluent, dibasic calcium phosphate anhydrous (DCPA), was also evaluated. Compritol® 888 ATO was used as the wax matrix material, with phenylpropanolamine hydrochloride (PPA) as a model drug. Tablets were made by direct compression and then subjected to heat treatment at 80°C for 30 min. The results showed that MCC, lactose, and DCPA could maintain tablets intact during heat treatment above the melting point of wax (70°C-75°C). However, DCPD tablets showed wax egress during the treatment. MCC tablets swelled and cracked during drug dissolution and resulted in quick release. DCPD and lactose tablets remained intact during dissolution and gave slower release than MCC tablets. DCPA tablets without heat treatment disintegrated very quickly and showed immediate release. In contrast, heat-treated DCPA tablets remained intact through the 24-hr dissolution test and only released about 80% PPA at 6 hr. In the investigation of wax level, DCPD was used as the diluent. The drug release rate decreased as the wax content increased from 15% to 81.25%. The dissolution data were best described by the Higuchi square-root-of-time model. Diluents showed various effects during heat treatment and drug dissolution. The integrity of the tablets was related to the drug release rate. Heat treatment retarded drug release if there was no wax egress.     

Seeded growth of hydroxyapatite in simulated body fluid

The precipitation of calcium phosphates was investigated, in simulated body fluid (SBF), pH 7.40 and 37°C. The kinetics of the mineral phase forming in the SBF was measured using the constant supersaturation method. The approach provides a detailed investigation in the processes taking place in the SBF which is widely used for the study of biomineralization. The pH adjustment was done by a pH-stat instead of Tris-Buffer [Tris (hydroxymethyl) Aminomethane] to avoid the presence of organic soluble compounds. The stability of SBF was investigated and the stable supersaturated solutions were seeded. The technique of seeded precipitation was employed for the achievement of accurate and reproducible kinetics measurements. The crystal growth experiments in which SBF solutions of variable supersaturations were seeded with hydroxyapatite [Ca₅(PO₄)₃OH, HAP] crystals showed that the precipitation of calcium phosphates took place exclusively on specific active sites provided on the surface of the synthetic seed crystals. The crystal growth mechanism showed that the process was controlled by surface diffusion. The phase formed was HAP in the lattice of which CO₃²⁻ and Mg²⁺ ions were incorporated. SBF was the source of these ions. Moreover it was found that the less stable calcium phosphate dihydrate (CaHPO₄·2H₂O, DCPD) may form as a transient phase hydrolyzing rapidly into the more stable HAP. Morphological examination of the carbonated apatites formed in the SBF showed appreciable aggregation.     

Chemical reaction of bioactive glass and glass-ceramics with a simulated body fluid

Glass-ceramic A-W containing crystalline apatite and wollastonite in an MgO-CaO-SiO₂ glassy matrix bonds to living bone through an apatite layer which is formed on its surface in the body. The parent glass G of glass-ceramic A-W and glass-ceramic A, which has the same composition as glass-ceramic A-W but contains only the apatite, also bond to living bone through the surface apatite layer, whereas glass-ceramic A-W(Al), which contains the apatite and wollastonite in an MgO-CaO-SiO₂-Al₂O₃ glassy matrix, neither forms the surface apatite layer nor bonds to living bone. In the present study, in order to reveal the mechanism of formation of the surface apatite layer, changes in ion concentrations of a simulated body fluid with immersion of these four kinds of glass and glass-ceramics were investigated. Bioactive glass G and glass-ceramics A and A-W all showed appreciable increases in Ca and Si concentrations, accompanied by an appreciable decrease in P concentration, whereas non-bioactive glass-ceramic A-W(Al) hardly showed any element concentration change. It was speculated from these results that dissolution of the Ca(II) and Si(IV) ions from bioactive glass and glass-ceramics plays an important role in forming the apatite layer on their surfaces in the body.     

Formulation and in vitro studies of a fixed-dose combination of a bilayer matrix tablet containing metformin HCl as sustained release and glipizide as immediate release

The emerging new fixed dose combination of metformin hydrocholride (HCl) as sustained release and glipizide as immediate release were formulated as a bilayer matrix tablet using hydroxy propyl methyl cellulose (HPMC) as the matrix-forming polymer, and the tablets were evaluated via in vitro studies. Three different grades of HPMC (HPMC K 4M, HPMC K 15M, and HPMC K 100M) were used. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. In vitro release studies were carried out at a phosphate buffer of pH 6.8 with 0.75% sodium lauryl sulphate w/v using the apparatus I (basket) as described in the United States Pharmacopeia (2000). The release kinetics of metformin were evaluated using the regression coefficient analysis. There was no significant difference in drug release for different viscosity grade of HPMC with the same concentration. Tablet thus formulated provided sustained release of metformin HCl over a period of 8 hours and glipizide as immediate release.     

Preparation and in vitro/in vivo evaluation of a ketoprofen orally disintegrating/sustained release tablet

Context: Orally disintegrating tablets (ODTs) with sustained release profiles are a new generation of ODTs called orally disintegrating/sustained release tablets (ODSRTs), which are convenient in use and able to slowly release drugs to maintain effective blood concentrations over a prolonged period of time. Ketoprofen, one of non-steroidal anti-inflammatory drugs, is an ideal model drug for ODSRTs.

Methods: We designed a simple two-step process to develop novel ketoprofen orally disintegrating/sustained release tablets (KODSRTs). Firstly, sustained release ketoprofen fine granules were developed by spray drying the aqueous dispersions composed of Eudragit RS-30D, Starch 1500 and PEG 6000. The optimal parameters of spray drying were 100°C for inlet air temperature and 1.5 mL/min for feed rate. Subsequently, the obtained granules were directly compressed into KODSRTs after mixing with lactose, mannitol and a superdisintegrant, crosslinked polyvinylpyrrolidone (PVPP). The characteristics of KODSRTs, especially their potential for extended drug release, were evaluated.

Results: Results of an in vitro release test demonstrated that KODSRTs could slowly release ketoprofen for 24 h after disintegrating within 30 s. Extended release properties of KODSRTs were decided by the ketoprofen sustained release fine granules in tablets. Besides, the disintegration time of KODSRTs depended on the percentage of PVPP in tablets. In vivo pharmacokinetic studies in beagles also showed that KODSRTs possessed a significantly extended release profile compared with ketoprofen normal capsules.

Conclusion: KODSRTs were successfully prepared using a simple two-step process: spray drying and direct compression.     

A novel three-layered tablet for extended release with various layer formulations and in vitro release profiles

A novel three-layered tablet consisting of a water-soluble mid-layer and two barrier layers with swellable polymers was investigated to develop a preferable once-a-day formulation containing terazosin HCl as a hydrophilic model drug. When the tablet was exposed to a release medium, the medium quickly permeated to the mid-layer and the two barrier layers swelled surrounding the mid-layer rapidly. It facilitated the tablet to absorb a lot of water compared with monolithic matrix. Moreover, formation of a lot of pores in the tablet during dissolution could be observed, suggesting significant water absorption in the inner matrix and swollen polymers of the tablet. Barrier layers influenced drug release profiles significantly, potentially due to differences in viscosity after swelling that produce different diffusion coefficients and mechanical strength. The drug in the mid-layer showed the sigmoid type of release pattern because a period of time might be needed to release the drug from the mid-layer through the barrier layers, but the drug in barrier layers showed the typical release pattern of monolithic matrix. As the amount of water-soluble excipient in the mid-layer increased, the degree of swelling also increased, suggesting that its amount in the layer may affect the overall swelling properties of the tablet. It was also shown that more hydrophilic mid-layer caused faster erosion rate, which was related to the results of swelling property. The three-layered tablets showed more consistent release kinetics than the matrix tablets. These results can give good information for the development of sustained drug delivery systems, especially once-a-day administration.