EXPLORING MULTIFACETED ROLE OF LIGNIN AS A NATURAL EXCIPIENT IN PHARMACEUTICALS AND COSMETICS

Variability in raw materials presents a challenge for pharmaceutical companies. The varying physicochemical properties can critically influence drug release and bioavailability of the final dosage form. Therefore, a strategy to control this variability is required. In this study the well-established antiepileptic drug carbamazepine (CBZ) was selected as the model drug as it presents one example where variability in raw materials has been linked to bioinequivalence and clinical failures. CBZ shows poor solubility, low potency, and a narrow therapeutic index. Furthermore, CBZ exhibits at least four polymorphic forms and it transforms into the less soluble CBZ dihydrate in water. The purpose of this work was to study the impact of variability in CBZ samples of four different suppliers on the drug release and to suggest a strategy to deal with the sample variability. Thus, the CBZ samples were characterized at preformulation as well as at a formulation level. Polymorphism and morphology of CBZ samples were analyzed by differential scanning calorimetry, X-ray powder diffraction, sieve analysis, and scanning electron microscopy. CBZ samples were characterized by a unidirectional dissolution method measuring disc intrinsic dissolution rate (DIDR) of CBZ raw material and initial drug release in presence of the tablet fillers microcrystalline cellulose (MCC) and mannitol (30–90% drug load). Furthermore, CBZ samples were recrystallized in 1% polyvinylpyrrolidone ethanol solutions as an approach to reduce the sample variability. At the formulation level, a high-dose CBZ tablet was developed with the aim of a tablet formulation that is robust towards the variability in CBZ samples and that conforms to the USP requirements of CBZ tablets for immediate release. Therefore, the superdisintegrant crospovidone (CrosPVP) and the dry binder hydroxypropyl cellulose (HPC) were used, as both are reported to inhibit transformation to CBZ dihydrate. The tablet filler was MCC. All CBZ samples were of p-monoclinic form but differed in their polymorphic purity, particle size, morphology, and intrinsic dissolution rate. The DIDR profiles showed high variability among the CBZ samples. Two inflection points could characterize individual transformation behavior of anhydrous CBZ to CBZ dihydrate. Presence of MCC reduced drug release variability. Recrystallizing CBZ resulted in strongly reduced variability in dissolution and tablet strength and the transformation to CBZ dihydrate was inhibited. However, particle size and morphology could not be controlled and drug release from binary mixtures with MCC presented deviation for one of the recrystallized CBZ samples. For the tablet formulation the optimal condition was with 6% HPC and 5% CrosPVP, where tablet properties of all CBZ samples were at least 70 N tablet hardness, less than 1 min disintegration, and within the USP requirements for drug release. Nonetheless, dissolution curves of the various CBZ samples differed. Excluding the additive sodium laurylsulfate required by the USP monograph and analyzing the optimized tablet formulation in water only, the dissolution curves of the various CBZ samples could not be distinguished anymore (ANOVA, p > 0.05). The impact of variability in CBZ raw materials on the drug release could be characterized by an individual transformation behavior to the CBZ dihydrate. The applied unidirectional dissolution method can be suggested as a straightforward monitoring tool in preformulation studies conforming to the basic tenet of quality by design of FDA’s PAT initiative. To allow a certain variability in CBZ raw materials, it is suggested to incorporate the excipients CrosPVP, HPC, and MCC into the design of a CBZ tablet formulation. The strategy proposed of how to control the variability in CBZ samples includes the monitoring at preformulation level combined with the design of a robust tablet formulation.

Over the past decade, lignin-based porous biomaterials have been found to have strong potential applications in the areas of drug delivery, tissue engineering, wound dressing, pharmaceutical excipients, biosensors, and medical devices. Lignin-based porous biomaterials have the addition of lignin obtained from lignocellulosic biomass. Lignin as an aromatic compound is likely to modify the materials’ mechanical properties, thermal properties, antioxidant, antibacterial property, biodegradability, and biocompatibility. The size, shape, and distribution of pores can determine the materials’ porous structure, porosity, surface areas, permeability, porosity, water solubility, and adsorption ability. These features could be suitable for medical applications, especially controlled drug delivery systems, wound dressing, and tissue engineering. In this review, we provide an overview of the current status and future potential of lignin-based porous materials for medical and pharmaceutical uses, focusing on material types, key properties, approaches and techniques of modification and fabrication, and promising medical applications.

Patients have benefited greatly from the steady stream of new medical devices approved each year by the US Food and Drug Administration and by regulatory agencies in countries around the world. But the number of such devices for tissue engineering and regenerative medicine is just a small fraction of these, perhaps 7 of the 194 devices (<5%) approved by the FDA since 2008 [1]. Few new tissue engineering and regenerative medicine devices have reached the clinic despite the proliferation of biomaterial matrices/scaffolds, cells, and regulators of cell function (e.g., growth factors); i.e., the three types of tool currently available for implantation or injection into a specific type of defect to facilitate regeneration (the paradigm of regenerative medicine), or for the formation of tissues and organs in vitro for subsequent implantation (the tissue engineering plan). While the number of new tools added to the tissue engineer's toolbox each year is continuing to grow dramatically, there are few tools being implemented for the production of new medical devices undergoing human trial (figure 1). What are the bottlenecks in getting the tools out of the toolbox and into clinical use to advance patient care?

Hydrogels have emerged in various biomedical applications, including tissue engineering and medical devices, due to their ability to imitate the natural extracellular matrix (ECM) of tissues. However, conventional static hydrogels lack the ability to dynamically respond to changes in their surroundings to withstand the robust changes of the biophysical microenvironment and to trigger on-demand functionality such as drug release and mechanical change. In contrast, multifunctional dynamic hydrogels can adapt and respond to external stimuli and have drawn great attention in recent studies. It is realized that the integration of nanomaterials into dynamic hydrogels provides numerous functionalities for a great variety of biomedical applications that cannot be achieved by conventional hydrogels. This review article provides a comprehensive overview of recent advances in designing and fabricating dynamic hydrogels for biomedical applications. We describe different types of dynamic hydrogels based on breakable and reversible covalent bonds as well as noncovalent interactions. These mechanisms are described in detail as a useful reference for designing crosslinking strategies that strongly influence the mechanical properties of the hydrogels. We also discuss the use of dynamic hydrogels and their potential benefits. This review further explores different biomedical applications of dynamic nanocomposite hydrogels, including their use in drug delivery, tissue engineering, bioadhesives, wound healing, cancer treatment, and mechanistic study, as well as multiple-scale biomedical applications. Finally, we discuss the challenges and future perspectives of dynamic hydrogels in the field of biomedical engineering, including the integration of diverse technologies.

Welcome to Biomedical Materials

The purpose of present work was to formulate and characterize a floating drug delivery system for Clopidogrel bisulphate to improve bioavailability and to minimize the side‑effects of the drug such as gastric bleeding and drug resistance development. Clopidogrel floating tablets were prepared by direct compression technique by the use of xanthan gum at different concentrations (20%, 25% and 30% w/w). Sodium bicarbonate (15% w/w) and microcrystalline cellulose (MCC) (30% w/w) were used as gas generating agent and diluent respectively. The effects of sodium bicarbonate and MCC on the drug release kinetics and floating properties were investigated. A 22 factorial design was applied systematically to optimized formulation. The percentage amount of sodium bicarbonate (X1) and percentage amount of MCC (X2) were selected as independent variables. The drug release rate constant (K) and time required for 85% drug dissolution (T85) was selected as dependent variables. Factorial design revealed that the percentage amount of sodium bicarbonate and MCC had insignificant effect on drug release kinetics (K, T85) within the chosen levels and a high level of sodium bicarbonate (X1) and the low level of MCC (X2) favor the preparation of clopidogrel floating tablets. All the Clopidogrel floating formulations followed first order kinetics, Higuchi drug release kinetics with diffusion as the dominant mechanism of drug release. As per Korsmeyer‑Peppas equation, the release exponent “n” ranged 0.455‑0.654 indicating that drug release from all the formulations was by non‑fickian diffusion mechanism. Key words: Clopidogrel bisulfate, factorial study, floating tablets, release kinetics, variables

The objective of this study was to develop tablet formulations of sulphadimidine sodium (SDD-Na) and trimethoprim (TMP), evaluate and compare the efficiency of some excipients such as: superdisintegrant - croscarmellose sodium (Ac-Di-Sol), silicon dioxide (Aerosil), lactose and microcrystalline cellulose (Avicel pH-101) as base excipients for physical tablets properties and increasing the dissolution rate of SDD-Na and TMP. All tablet formulations were prepared by wet granulation process. Dissolution properties such as DP 30,45,60 (percent of drug dissolved at 30, 45 and 60 minutes), and dissolution rate constant value (K) were considered for comparing the dissolution results. The dissolution of SDD-Na and TMP from all examined tablet formulations followed Higuchi model kinetics with correlation coefficient (R) values from 0.984 to 0.995. The physical properties and in vitro drug release study revealed that tablets disintegration efficiency and drug dissolution depend on the amount of added disintegrant, the amount and presence of microcrystalline cellulose (Avicel) and lactose. Tablet formulation without addition of microcrystalline cellulose showed faster dissolution rate and shorter disintegration time as compared with that of tablets of formulations with microcrystalline cellulose. The results reveal that besides the type of diluents, the way of using superdisintegrant plays a major role in controlling disintegration of tablets. The portion of Ac-Di-Sol used as an intragranulary in the wet granulation process, is not as effective as that of the process of extragranulary addition. Tablets formulations F4 and F5 exhibited satisfactory friability, acceptable hardness, fulfilled the requirement for disintegration time for compressed tablets, and met the acceptable specifications with regard to drug release properties.

Micro crystalline cellulose (MCC) is a major derivative from the bio composite of natural materials such as D. arborea plant stem. It could be useful as a secondary binder and disintegrant in tablet formulation especially following direct compression technique anticipating it to provide high level of disintegration at low use level and utilizing dual mechanisms of wicking and swelling. Tablets of aceclofenac a BCS class II and non steroidal anti inflammatory drug (NSAID) which potently inhibits the cyclo oxygenase enzyme (COX-2) involved in prostaglandin synthesis was formulated by direct compression using MCC from D. arborea stem. Qualitative assessment of the plant extract was carried out and the presence of cellulose confirmed by the appearance of violet – blue coloration while the physicochemical and physicotechnical properties were comparatively evaluated with reference to avicel and corn starch. Three batches of aceclofenac tablets involving Batch A (D. arborea MCC), Batch B (Corn starch) and Batch C (Corn starch and D. arborea MCC in a 1:1 ratio), were implcated in the formulation. Physicochemical study of the MCC reveals a pH of 7.8, mean swelling index 1.14±0.05 ml and hydration capacity of 3.60±0.15 g while the pH of corn starch is 3.90 with swelling and hydration capacity at 5.09±0.03 ml and 8.26±0.01 g respectively. Quality control evaluation of resulting tablet was investigated and the wetting time of batch A tablets was 1.50, batch B 2.30 and batch C 1.80 with percentage moisture content (%) of 60.5, 56.56 and 57.8 and disintegration time (minutes) of 0.22±0.07, 0.35±0.051 and 1.60±0.286 respectively. The drug release profile of batch A, reveals an initial burst release within 10 minutes followed by gradual release while batch C had consistent drug release which was maintained although faster than that of batch A after 10 minutes but batch B had the least drug release rate.

Tissue engineering: the design and fabrication of living replacement devices for surgical reconstruction and transplantation

The present work was carried out to study the disintegrant property of plantago ovata mucilage. The objective of the work was to formulate Fast disintegrating tablets of Domperidon with a view to enhance patient compliances and dissolution rate by direct compression method using 3² full factorial design. Plantago ovata mucilage (2-10% w/w) was used as natural superdisintegrant and microcrystalline cellulose (0-30% w/w) was used as diluent, along with directly compressible mannitol to enhance mouth feel. The tablets were evaluated for hardness, friability, thickness, drug content uniformity, in vitro dispersion time, wetting time and water absorption ratio. Based on in vitro dispersion time (approximately 10s); the formulation containing 10% w/w Plantago ovata mucilage and 30%w/w microcrystalline cellulose was found to be promising and tested for in vitro drug release pattern (in 0.1 N HCl), short-term stability (at 40º/75% RH for 3 month) and drug-excipient interaction. Surface response plots are presented to graphically represent the effect of independent variables (concentrations of Plantago ovata mucilage and microcrystalline cellulose) on the in vitro dispersion time. The validity of the generated mathematical model was tested by preparing two extra-design check point formulations. The optimized tablet formulation was compared with conventional commercial tablet formulation for drug release profiles. This formulation showed nearly four-fold faster drug release (t50% 2.85 min) compared to the conventional commercial tablet formulation (t50% 7.85 min). Short-term stability studies on the formulation indicated that there are no significant changes in drug content and in vitro dispersion time (p &lt; 0.05).Shahidulla et al., International Current Pharmaceutical Journal, July 2015, 4(8): 415-419

Fast dissolving tablets of clonazepam were prepared by direct compression method with a view to enhance patient compliance. A 32 full factorial design was applied to investigate the combined effect of two formulation variables: amount of crospovidone and microcrystalline cellulose. Crospovidone (2-8% w/w) was used as superdisintegrant and microcrystalline cellulose (20-40% w/w) was used as diluent, along with directly compressible mannitol to enhance mouth feel. The tablets were evaluated for hardness, friability, thickness, drug content uniformity, in vitro dispersion time, wetting time and water absorption ratio. Based on in vitro dispersion time (approximately 16 s); the formulation containing 2% w/w crospovidone and 40% w/w microcrystalline cellulose was found to be promising and tested for in vitro drug release pattern (in pH 6.8 phosphate buffer). Short-term stability (at 40°/75% relative humidity for 3 mo) and drug-excipient interaction. Surface response plots are presented to graphically represent the effect of independent variables on the invitro dispersion time. The validity of the generated mathematical model was tested by preparing two extra-design checkpoints. The optimized tablet formulation was compared with conventional commercial tablet formulation for drug release profiles. This formulation showed nearly five-fold faster drug release (t50% 3.5 min) compared to the conventional commercial tablet formulation (t50% 16.4 min). Short-term stability studies on the formulation indicated that there are no significant changes in drug content and in vitro dispersion time (P<0.05).

Aim of this study was formulation matrix tablets of nimesulide with controlled release (CR) and immediately release (IR), and evaluation the influence of many types and concentrations of polymers on their in vitro release properties. Four formulations F1 – F4 were designed by wet granulation using different types and amount of polymers, and one formulation with immediately release. The CR matrix tablets formulations (F1 – F4) were composed of using different polymers such as, hydroxypropyl methylcellulose (HPMC-к100м), hydroxypropyl methylcellulose (HPMC-Е6), hydroxypropyl cellulose high viscosity (HPCh), carboxymethyl cellulose (CMC), ethylcellulose (EC-10 cps), whereas IR tablets formulation (F5) contained sodium lauryl sulfate (SLS), polyvinylpyrrolidone (PVP-к30), microcrystalline cellulose (MCC) and lactose monohydrate. The MCC and PVP-к30 were used in a fixed quantity in all CR formulations. The effect of polymer viscosity and its quantity on nimesulide release from two formulations containing the same polymer was studied. Data drug release in vitro was evaluated in phosphate buffer of pH 7.4 by analytical method. The amount of released nimesulide was calculated by preparing standard series in phosphate medium. In vitro profile release indicated that formulations F1 and F2 controlled the drug release for 18h and 10h respectively. Formulations F3 and F4 released 73.58%, 62.5% of their content during 18h consecutively, thus their effect can last for more than a day. While immediately release formulation F5 released more than 90% of its content within 1h, and more than 75% with 30 minutes. MS Excel was suggested to analyze the dissolution profile data for drug release kinetics such as first order, Zero-order, Higuchi and Korsmeyer–Peppas models. However, formulation (F1) containing (HPMC -к100м) as a matrix former showed drug release as highest correlation coefficient (r2) values obtained when first-order model was applied (r2 = 0.9524). Formulations (F2, F3) containing (HPMC -Е6, HPCh and CMC) and IR formulation F5 showed concentration-independent drug release as highest linearity was observed when zero-order model was applied (r2 = 0.9702 - 0.9773 - 0.8747). Whereas, formulation (F4) containing (HPCh and EC) as a matrix former showed the highest correlation coefficient (r2) values when Korsmeyer-peppas model was applied (R2 = 0.9846). Release mechanism of all formulations was Case II relaxation release. This study performed that cellulosic derivatives polymers can be considered ideal components for controlling immediately release of matrix tablets formulation.

Porous-based biomaterials for tissue engineering and drug delivery applications

The use of polymeric materials in biomedical applications has been growing exponentially. This phenomenon is due to progress in areas such as polymeric materials science, tissue engineering, pharmaceutical technology and combined medical devices. In particular, the development of concepts involving polymers that react to external stimuli has raised an increasing interest in the investigation of products to complement the use in medical devices and pharmaceutical formulations to drug delivery. The stimulus-sensitive polymers have the ability to respond to variations in the surrounding environment, examples are thermosensitive polymers, polymers sensitive to pH variations and ion-sensitive. By altering their properties and their microstructure, they can be used as drug delivery systems. The topical treatment of wounds includes clinical and surgical methods, among clinician, dressing are the most frequently used. The dressings are used to improve the conditions of the wound and can be, in some occasions, the definitive treatment itself. Conventional topical medical devices such as gauzes have limitations, such as sticking to the wound, which hampers therapeutic efficacy. In this paper it is presented representative examples of smart polymers that are capable of responding to stimuli and controlling the release of active molecules, and which may be used in the therapeutic area of ​​topical wound care.

A Tribute to Professor Nicholas Peppas.