Melt granulation and heat treatment for wax matrix-controlled drug release

The purpose of this study was to evaluate sustained drug release after melt granulation and heat treatment. Theophylline (anhydrous) and phenylpropanolamine hydrochloride (PPA) were used as model drugs. Compritol® 888 ATO (Glyceryl Behenate NF) was incorporated as the wax matrix material. Formulations with drug:wax in 3:1 and 1:1 ratios were evaluated. Tablets were made by dry blending or melt granulation; some of the tablets were heat treated at 80°C for 30 min. Tablets with or without heat treatment were tested for drug release using in vitro drug dissolution. The results showed that melt granulation gave slower drug release than dry blending. Heat treatment further retarded drug release for both dry blending and melt granulation. The drug release rates for theophylline were slower than for PPA at the same wax level and processing method. The drug release profiles were linear using a square root of time scale. In conclusion, melt granulation and heat treatment slowed drug release for the wax matrix-controlled release tablets. Heat treatment of the tablets made by melt granulation further retarded drug release. Heat treatment redistributed the wax, forming a new matrix system with higher tortuosity. The application of melt granulation or heat treatment can successfully retard drug release.     

Spray-dried O-carboxymethyl chitosan as potential hydrophilic matrix tablet for sustained release of drug

Objective: The aim of the present investigation was to evaluate the use of spray-dried O-carboxymethyl chitosan (OCMCS) as potential hydrophilic matrix excipient for sustained release of drug.

Methods: The polymer was synthesized from chitosan, then spray-dried and characterized. Tablets with different OCMCS concentrations (80, 50, 30, 5 and 2% w/w), containing diltiazem (DTZ) as model drug, were prepared for direct compression (DC) and after the wet granulation method (WG).

Results: The spray-dried OCMCS powder was spherical, with a smooth surface and an average size of 2.2?µm. The tablets prepared for WG disintegrated in time less than 30?min. The tablets obtained for DC presented high retention of the drug, with zero order or Higuchi release kinetic. There was a direct relationship between the OCMCS concentration and the release ratio, swelling degree and water uptake behavior. DC tablets containing 80% OCMCS presented behavior as an effective swelling-control system. The DC tablets with 5% OCMCS showed a similar release profile at formulations with 30% HPMC.

Conclusion: Spray-dried OCMCS showed great potential as hydrophilic matrices for drug-sustained release.     

Optimization of biodegradable sponges as controlled release drug matrices. I. Effect of moisture level on chitosan sponge mechanical properties

Cross-linked chitosan sponges as controlled release drug carrier systems were developed. Tramadol hydrochloride, a centrally acting analgesic, was used as a model drug. The sponges were prepared by freeze-drying 1.25% and 2.5% (w/w) high and low M.wt. chitosan solutions, respectively, using glutaraldehyde as a cross-linking agent. The hardness of the prepared sponges was a function of glutaraldehyde concentration and volume where the optimum concentration that offered accepted sponge consistency was 5%. Below or above 5%, very soft or very hard and brittle sponges were obtained, respectively. The determined drug content in the prepared sponges was uniform and did not deviate markedly from the calculated amount. Scanning electron microscopy (SEM) was used to characterize the internal structures of the sponges. The SEM photos revealed that cross-linked high M.wt. chitosan sponges have larger size surface pores that form connections (channels) with the interior of the sponge than cross-linked low M.wt. ones. Moreover, crystals of the incorporated Tramadol hydrochloride were detected on the lamellae and within pores in both chitosan sponges. Differences in pore size and dissolution medium uptake capacity were crucial factors for the more delayed drug release from cross-linked low M.wt. chitosan sponges over high M.wt. ones at pH 7.4. Kinetic analysis of the release data using linear regression followed the Higuchi diffusion model over 12 hours. Setting storage conditions at room temperature under 80-92% relative humidity resulted in soft, elastic, and compressible sponges.     

Design and evaluation of soluble ocular drug insert for controlled release of ciprofloxacin hydrochloride

Purpose: Soluble ocular inserts of ciprofloxacin hydrochloride were prepared with the aim of achieving once a day administration. Design: Drug reservoir was prepared using natural hydrophilic polymer viz. gelatin while rate-controlling membrane was prepared using hydrophobic ethyl cellulose. Ocular inserts were evaluated for their physicochemical parameters like thickness, weight uniformity, drug content, percent moisture loss, and percent moisture absorption. The in vitro drug release studies were carried out using Bi-chambered donar receiver compartment model. Since targeted prolong release was observed in formulation CF2 and CF5, these formulations were further subjected to in vivo drug release study using rabbits as an animal model. In vitro drug release kinetic data was treated according to Zero, First, and Higuchi kinetics to access the mechanism of drug release. Results: Correlation between in vitro and in vivo drug release was found to be strong revealing the efficacy of the formulation. Conclusion: Formulation CF5 has achieved target of present study such as increase residence time, prolong drug release, reduction in frequency of administration, and, thus may improve the patient compliance.     

Evaluation and comparison of five matrix excipients for the controlled release of acrivastine and pseudoephedrine

For treatment of allergic rhinitis, acrivastine with pseudoephedrine in Semprex®-D conventional capsules requires dosing every 6-8 hours. This study was designed to develop a controlled release matrix tablet of acrivastine and pseudoephedrine and evaluate 5 different matrix excipients for their in vitro controlled-release profiles. Compritol® 888ATO, Eudragit® RS, Methocel® K100M, Polyox® WSR301 and Precirol® ATO5 were used alone or in varying combinations for the formulation of controlled release matrix tablets. In vitro drug dissolution and mathematical modeling were used to characterize drug release rate and extent. All tablet formulations yielded quality matrix preparations with satisfactory tableting properties. Due to the aqueous solubility of pseudoephedrine and the size of the dose, none of the matrix excipients used alone prolonged drug release significantly to meet the desired twice-daily administration frequency. The use of two excipients in combination, however, significantly decreased the dissolution rate of both active ingredients. A combined lipid-based Compritol® and hydrophilic Methocel® produced optimal controlled drug release for longer than 8 hours for both acrivastine and pseudoephedrine.     

The use of a hydrophobic matrix for the sustained release of a highly water soluble drug

An experimental investigation into the use of a hydrophobic matrix to control the release of a highly water soluble drug was undertaken. Matrices consisting of hydrogenated vegetable oil and calcium sulfate with a 4% drug loading showed a sustained-release profile of up to 24 hr. The release mechanism from such matrices seemed to obey both root time kinetics and first-order behavior. Investigations showed that the effect of geometry had a significant effect on the drug release rate.     

The role of fillers and sodium metabisulfite on drug release from aged polyox tablets

Polyethylene oxides (PEOs) are extensively used to control the release rate of drugs from matrices. Unfortunately, polyox polymers are prone to oxidation under high temperature and relative humidity. The aim of this study was to investigate the effect of sodium metabisulfite as an antioxidant to overcome the drug release changes from polyox matrices (PEO 301 and 303) when stored at 40?°C. The effect of different types of fillers (lactose, mannitol and dicalcium phosphate dihydrate) on stability of diltiazem HCl release profiles was also investigated. Generally, the presence of sodium metabisulfite stabilized the release of drug from PEO matrices stored at 40?°C for 8 weeks. Whilst the absence of metabisulfite caused an increase in drug release from polyox matrices when stored at 40?°C. The results indicate that all three concentrations (0.25, 0.5 and 1% w/w) of sodium metabisulfite were able to overcome structural changes of polyox samples hence stabilizing the drug release. The results also showed that the incorporation of fillers in polyox matrices reduced the sensitivity of drug release when stored at elevated temperature. This indicates that when these excipients were used there was no need to incorporate additional antioxidant. DSC results showed that there was no difference in the melting points of fresh polyox samples and aged polyox samples containing sodium metabisulfite, whereas the melting point of aged polyox samples without sodium metabisulfite were lower than fresh polyox samples. This indicates that the presence of metabisulfite is essential to stabilize polyox samples.     

Dithiocarbamate chitosan as a potential polymeric matrix for controlled drug release

Objective: To develop a polymer matrix for controlled release of drugs, chitosan, a linear aminopolysaccharide, was chemically modified to dithiocarbamate chitosan (DTCC) to afford a matrix where metal–drug complexes could be attached and released in a controlled manner depending on the binding nature between the drugs and the metals.

Materials and methods: DTCC was treated with metal-tetracycline (Tc) complexes to prepare DTCC–Ca(II)–Tc, DTCC–Mg(II)–Tc, DTCC–Cu(II)–Tc and DTCC–Zn(II)–Tc.

Results: The binding amount of Tc was in the order of DTCC–Zn(II)–Tc?≈?DTCC–Mg(II)–Tc?≈ DTCC–Ca(II)–Tc?>?DTCC–Cu(II)–Tc. The biphasic binding profiles, where Tc binding increased initially and then decreased, were shown for DTCC–Cu(II)–Tc and DTCC–Zn(II)–Tc. In a flow method, Tc was released slowly from DTCC–metal–Tc complexes except for DTCC–Cu(II)–Tc compared with Tc release from DTCC–Tc. In parallel with the results of the release experiment, DTCC–metal–Tc complexes except for DTCC–Cu(II)–Tc presented a prolonged antibacterial activity in an antibacterial test. The antibacterial activity of DTCC–Ca(II)–, –Mg(II)– and –Zn(II)–Tc complexes lasted for 28–44 days, while free Tc and DTCC–Tc lasted for 7–12 days.

Discussion and conclusion: Taken together, our data suggest that DTCC could be used for a polymeric matrix for controlled release of drugs such as Tc, which possess functional groups for ionic and/or coordinate bond with metals.     

Applications of poly(ethylene oxide) in controlled release tablet systems: a review

To improve therapeutic effects and compatibility of patients, controlled release tablet systems based on polymers are of great interest for pharmaceutical technologies. Poly(ethylene oxide) (PEO) is a non-ionic linear hydrophilic and uncrosslinked polymer available in a number of molecular weights. It is synthesized by ethylene oxide and has many desirable properties for drug delivery applications. This review article aims to summary the recent developments on physicochemical properties of PEO and focus on the recent efforts and developments on PEO as oral controlled release matrix tablets, bioadhesive hydrophilic matrices and osmotic pump tablets. Commercial products employed PEO were also discussed.     

The effect of carboxymethyl chitin on sustained drug release of aspirin tablet

Carboxymethyl chitin (CM-chitin) was prepared at room temperature and characterized using ¹H NMR, FTIR and elemental analysis methods. The prepared CM-chitin was then used as a hydrophilic matrix for the preparation of the aspirin sustained release tablets via the wet granulation technique. The aspirin release profiles of the prepared tablets in a simulated gastric fluid and simulated intestinal fluid, respectively, were studied with the rotating-basket dissolution method. The results showed that the aspirin release rate in simulated gastric fluid was lower than that in simulated intestinal fluid. Thus, CM-chitin proved to be a pH-sensitive hydrophilic matrix.     

Effect of formulation composition on the properties of controlled release tablets prepared by roller compaction

This study discusses the effect of formulation composition on the physical characteristics and drug release behavior of controlled-release formulations made by roller compaction. The authors used mixture experimental design to study the effect of formulation components using diclofenac sodium as the model drug substance and varying relative amounts of microcrystalline cellulose (Avicel), hydroxypropyl methylcellulose (HPMC), and glyceryl behenate (Compritol). Dissolution studies revealed very little variability in drug release. The t₇₀ values for the 13 formulations were found to vary between 260 and 550 min. A reduced cubic model was found to best fit the t₇₀ data and gave an adjusted r-square of 0.9406. Each of the linear terms, the interaction terms between Compritol and Avicel and between all three of the tested factors were found to be significant. The longest release times were observed for formulations having higher concentrations of HPMC or Compritol. Tablets with higher concentrations of Avicel showed reduced ability to retard the release of the drug from the tablet matrix. Crushing strength showed systematic dependence on the formulation factors and could be modeled using a reduced quadratic model. The crushing strength values were highest at high concentrations of Avicel, while tablets with a high level of Compritol showed the lowest values. A predicted optimum formulation was derived by a numerical, multiresponse optimization technique. The validity of the model for predicting physical attributes of the product was also verified by experiment. The observed responses from the calculated optimum formulation were in very close agreement with values predicted by the model. The utility of a mixture experimental design for selecting formulation components of a roller compacted product was demonstrated. These simple statistical tools can allow a formulator to rationally select levels of various components in a formulation, improve the quality of products, and develop more robust processes.     

High-throughput evaluation of non-swellable controlled release matrix tablets

Drug release from controlled-release (CR) matrix tablets involves the permeation and diffusion of water through the system. In this study, a new methodology is proposed for the measurement of water permeation and simultaneous drug release from the inert, non-swellable CR matrix tablet of diltiazem (DLT) and a correlation is made between these two processes. Cylindrical matrices were readily prepared by direct compression of pellets obtained by extrusion-spheronization. Water transport was studied using tritiated water (HTO) as a permeant in a Franz-diffusion cell and simultaneously drug release was measured. Further, dissolution was performed on USP XXI/XXII dissolution apparatus I using demineralized water. Matrices showed a steady water-uptake up to 6 h and the steady state for HTO permeation lasting from 6-h to 24-h Flux of water permeated and flux of drug released correlated well. Thus, HTO permeation through the matrix tablet and the proposed methodology can be used as a tool and/or surrogate marker for evaluation of controlled release matrix tablets. This methodology can be coined as “high-throughput” in terms of amount of labor and resources required in comparison to that of dissolution.     

New cellulose-lignin hydrogels and their application in controlled release of polyphenols

Novel superabsorbant cellulose-lignin hydrogels (CL) were prepared by a new two-step procedure consisting in dissolving cellulose in an alkaline solution with further mixing with lignin, followed by the chemical crosslinking with epichlorohydrin. The crosslinking occurrence was verified by Fourier Transform Infrared spectroscopy (FT-IR). The effect of the structure features of cellulose-lignin hydrogels on their dehydration heat was evaluated by Differential Scanning Calorimetry (DSC). The Scanning Electron Microscopy (SEM) images reveal some morphological aspects of the hydrogels. The degree as well as the rate of swelling in a mixture of water:ethanol = 19:1 were estimated. The possible application of these hydrogels as controlled release systems was tested. Polyphenols known as having a wide range of biological effects were selected to be incorporated in such hydrogels by an optimal procedure. The extract of grapes seeds from the Chambourcin type was used as a source of polyphenols (PF). The amount of the incorporated polyphenols was estimated by UV-VIS measurements. Characterization of the hydrogels containing polyphenols was performed by FTIR spectroscopy. Some parameters were estimated based on the registered spectra, as H-bond energy (E_H), the asymmetric index (a/b) and the enthalpy of H-bond formation (ΔH). The modifications of the thermal behavior and morphology induced by the presence of the polyphenols in hydrogels were highlighted by DSC and SEM, respectively. The release of polyphenols from CL hydrogels depended on the lignin content from matrices, as assessed by spectral studies. Both loading with polyphenols and their release can be controlled by the composition of the hydrogels. The kinetic of polyphenols release was studied.     

D-optimal mixture design: optimization of ternary matrix blends for controlled zero-order drug release from oral dosage forms

The objective of the present study was to develop a tablet formulation with a zero-order drug release profile based on a balanced blend of three matrix ingredients. To accomplish this goal, a 17-run, three-factor, two-level D-Optimal mixture design was employed to evaluate the effect of Polyox^™ (X₁), Carbopol® (X₂), and lactose (X₃) concentrations on the release rate of theophylline from the matrices. Tablets were prepared by direct compression and were subjected to an in vitro dissolution study in phosphate buffer at pH 7.2. Polynomial models were generated for the responses Y₄ (percent released in 8 h) and Y₆ (similarity factor or f₂). Fitted models were used to predict the composition of a formulation that would have a similar dissolution profile to an ideal zero-order release at a rate of 8.33% per hour. When tested, dissolution profile of the optimized formulation was comparable to the reference profile (f₂ was 74.2, and n [release exponent] was 0.9). This study demonstrated that a balanced blend of matrix ingredients could be used to attain a zero-order release profile. Optimization was feasible by the application of response surface methodology, which proved efficient in designing controlled-release dosage forms.     

Preparation and characterization of novel sinomenine microcapsules for oral controlled drug delivery

Background: Developing a sustained release drug to cure arthritis is needed. Sinomenine (SIN) is abstracted from sinomenium acutum and widely used in the treatment of various rheumatism and arrhythmia with few side effects. The primary aim of this study is to develop SIN microcapsules with polyelectrolyte multilayers for controlled drug release. Method: SIN microcrystals were encapsulated with chitosan, gelatin, and alginate by layer-by-layer technique, such as (gelatin/alginate)₄ and (chitosan/alginate)₆. The size distribution, zeta-potential, stability, and morphology of the microcapsules were characterized by a particle size analyzer, zetasizer, ultraviolet spectroscopy, and transmission electron microscope, respectively. The in vitro controlled release pattern of SIN was studied using a diffusion cell assembly at physiological pH of 6.8 or 1.4. Results: Light stability of these microcapsules was improved after microencapsulation. Compared with release rate of the SIN microcapsules coated by the poly(dimethyldiallyl ammonium chloride)/alginate and gelatin/alginate multilayers, release rate of the SIN microcapsules coated with chitosan/alginate multilayers was fast. Release rate progressively decreased with the increase of chitosan/alginate bilayer number and the decrease of pH value of release medium. Conclusion: These novel SIN microcapsules may be developed into oral controlled drug delivery for rheumatism and arthritis.     

药物控、缓释体系的缓释同步性研究

通过插层技术合成了醋酸洗必泰-盐酸特比萘芬/蒙脱土(CA-TBNF/MMT)药物控、缓释纳米中间体,利用XRD对其结构进行了表征,结果表明CA-TBNF已进入MMT层间,层间距变化明显。最小抑菌浓度与缓释浓度匹配,从层间解析出的CA与TB-NF在协同作用下对细菌和真菌都有较好的杀菌效果。实验证明两种药物可实现同步缓释。     

A bending specimen for constant energy release rate under controlled displacement conditions

A bending specimen that gives a constant energy release rate (independent on the crack length) under controlled displacement conditions is developed. It is assumed that engineering beam theory is applicable, i.e. that among other things, small deformations and linear elastic isotropic material can be assumed.A specific geometry is analyzed numerically by use of the finite element method and experimentally by manufacturing a specimen with the actual geometry in PMMA (polymethylmetacrylate) and then determining the specimen stiffness for different crack lengths.It is found that the geometry considered gives a constant energy release rate under controlled displacement conditions.     

Fast and controlled release of triamcinolone acetonide from extrusion-spheronization pellets based on mixtures of native starch with dextrin or waxy maize starch

Pellets composed chiefly of inexpensive starches allow modulation of the rate of release of the poorly soluble drug triamcinolone acetonide in media of pH 1.2-6.8. Wheat- or maize-starch-based pellets with 20% of white dextrin release the drug in vitro almost completely within 20 min, while maize-starch-based pellets with 5-35% of waxy maize starch sustain gradual release over periods of 9-12 hr or longer when prepared using appropriate amounts of granulation fluid.     

Synthesis of silica nanoboxes via a simple hard-template method and their application in controlled release

Silica nanoboxes have been successfully synthesized via a simple hard-template method at room temperature. The MnCO₃ nanocubes are firstly employed as the hard template. Scanning electron microscopy (SEM) is used to characterize silica nanoboxes and indicates the hollow structure of products. The shell thickness of nanoboxes can be well controlled by the amount of tetraethylorthosilicate (TEOS) and the surface area is calculated through the N₂ adsorption-desorption isotherm. Based on these results, a plausible mechanism is proposed to explain the formation of silica nanoboxes. In addition, preliminary tests demonstrate that the silica nanoboxes are capable of being loaded and releasing Rhodamine B, thus showing a great potential in the controlled delivery applications.