Current Drug Delivery - Volume 15, Issue 5, 2018

GnRH antagonists have several clinical applications in prostate cancer, regulation of ovulation induction in females, breast cancer, male contraception and others. Antagonists differ from natural GnRH decapeptide in having five or more amino acid substitutions, whereas most of the antagonists are available as subcutaneous (SC) formula for injection some are formulated as a depot formulation for sustained release (e.g., Cetrorelix, Degarelix). Systemic delivery of cetrorelix acetate by intratracheal route can be achieved using dry powder for inhalation of the adhesive mixture when the powder deposition reaches stage four. The oral route for systemic delivery of peptide without its degradation can be achieved using gastrointestinal permeation enhancement technology GIPET® provided by acyline.

Background: The large dependence on a dental substrate type to bond strength has leveraged the research on materials and techniques that perform different clinical behavior, promoting a stable bonding over time. Bonding to tooth structure has different clinical behaviors and is dependent on several factors. Objective: The aim of this paper is to reflect on the state of the art of adhesive systems after the emergence of Buonocore's experiments in current days. Methods: An electronic search was conducted on PubMed databases and supplemented with a manual study of relevant references. Results: The choice of the ideal adhesive system remains under discussion, housing a range of studies that highlight its potential characteristics, suggesting techniques that enable improvement to boost clinical outcomes. Conclusion: It is important to know all different types of adhesive systems, as well as their indications and limitations. An attentive consideration of several factors is crucial to achieve clinical success on the restorative procedures.

Nanoscience and nanotechnology are emerging areas in the pharmaceutical sciences and the need of modernizing world. Nanoscience is the world of atoms, macromolecular assemblies, macromolecules, quantum dots, and molecules. Nanoscience is the study, and understanding control of phenomena and manipulation of material at the nanoscale. Carbon nanotubes are a tube like material mainly made up of carbon. Only carbon nanotubes are the macromolecules of graphite consisting of sheets of carbon, which is weaved into the cylinder. Graphite sheets look like a hexagonal in shape Nano carbon tubes are about 2 millimetres long and these are one hundred times as stiff as steel. The arrangement of atom in a carbon nanotube is in a form of hexagonal as like as graphite. Carrying capacity of carbon nanotube is 1000 times higher than that of copper thermal stability of it is 4000k, it can be semiconducting or metallic, depending on their diameter and chirality of the atom. These carbon nanotubes having various classifications like single walled CNT's, Multiwalled CNT's, Nano horns, Nano buds, polymerized single walled nanotubes. The review is more focused towards the methods of preparation of nanotubes and their general various applications in pharmacy and medicine along with toxicity. These carbon Nano tubes can be prepared by using various methods with successful ease or application in pharmaceuticals, i.e. gas storage, adsorption, catalyst supported, delivery of drug through targeted system, electrochemistry, bio sensing, fuel cell, photodynamic cells, etc. CNT's are advanced technology in the era of nanotechnology in pharmaceutical sciences which are more emphasizing on patient's compliance and safety. Possessing a broad area of application along with targeted drug delivery. The Scientists are still exploring the various applications of it.

Introduction: Triptorelin, the synthetic analog of gonadotrophin-releasing hormone, is used for the treatment of sex hormone dependent diseases via parenteral administration. The aim of the present study was to investigate the possibility of triptorelin pulmonary delivery and preparation of a pulmonary nanocarrier delivery system for it. Methods: Triptorelin was loaded in Pluronic-F127 grafted poly (methyl vinyl ether-alt-maleic acid) nanomicelles by direct dissolution method. Effects of the processing variables including: drug/polymer ratio, temperature, stirring rate and time on the physicochemical properties of nanomicelles including zeta potential, particle size, drug entrapment efficiency and release profiles of triptorelin loaded nanomicelles were evaluated. For animal studies 24 Wistar rats were separated into four groups of six. Group 1 received blank nanomicelles, groups 2, 3 and 4 were treated with a single dose of 250 μg.kg-1 of triptorelin solution subcutaneously (sc), pulmonary spraying of triptorelin solution (250 μg.kg-1) and pulmonary spraying of triptorelin nanomicelles (250 μg.kg-1), respectively by microsprayer. Results: The optimized micelles had particle size of 87.35 nm, zeta potential of -12.8 mV, entrapment efficiency of 84.36% and release efficiency of 65%. The area under the blood testosterone levels increment differed significantly (p<0.05) between pulmonary triptorelin nanomicelles and drug solution. The pharmacological activity of the simple solution was 59.38%, while it was 80.18% for the nanomicelles relative to sc route of administration with prolonged residence time. Conclusion: The results of this study show that not only triptorelin is absorbable from the lungs but also nanomicelles can significantly enhance its pulmonary absorption compared to its simple solution.

Background: Betamethasone Valerate (BV) is a potent topical corticosteroid. Preparation of nanostructured lipid carriers (NLC) involves process parameters optimization and formulations were developed. It is available in several conventional formulations like creams and ointments which have well-known problems of frequent dosing and consequently additional side effects. The aim is to ascertain the probability of NLC as an exclusive carrier for betamethasone valerate topical application with regard to release modulation and improved therapeutic effect. Method: Preparation of BVNLC formulations involves rigorous broad range optimization of process parameters viz. selection of lipids, surfactants, formulation technique, stirring time, stirring speed and homogenization cycles. Accordingly, optimized parameters were selected and formulation table was developed. Characterizations of developed NLC comprise particle shape, size, zeta potential, percent drug entrapment, in vitro drug release studies. The optimized NLC formulation was gelled and evaluated for ex vivo permeation studies and preclinical anti-inflammatory testing. Results: The permeation studies revealed that enhancement ratio of BVNLC based gel was 2.59 folds higher as compared to plain BV gel. Release models indicated anomalous (non-fickian) diffusion viz. drug release is controlled by more than one process i.e. superposition of both phenomenon, the diffusion controlled as well as swelling controlled release. Preclinical studies indicated a significant (P < 0.05) extended anti-inflammatory effect and 16.5% inhibition compared to plain gel. Conclusion: The outcome of entire characterization advocates that the developed formulation is efficient as once a day dosing in therapy of atopic dermatitis.

Background: Biopolymeric nanoparticles comprising chitosan-alginate have attracted interest in drug delivery due to their protective nature, biocompatibility, biodegradability and hydrophilicity. Objective: The present study was designed to encapsulate levofloxacin in chitosan-alginate hybrid gel for controlled release and to evaluate the effect of divalent alkaline earth metal ions (Mg2+, Ca2+, Sr2+, Ba2+) on encapsulation efficiency and drug release kinetics considering their role in polyelectrolyte gelation method. Method: Divalent metal ions control the rigidity and elasticity of the hydrogels and have the ability to change the shape and size of nanostructure formed by chitosan-alginate. The particle size increases and encapsulation efficiency decreases with the size of the divalent ions. Spherical shaped particles were formed by Mg2+ and Ca2+, whereas Sr2+ and Ba2+ produced non-spherical particles. Results: SEM image clearly shows transformation of sphere to truncated tetrahedron by Sr2+ and clear rod shape by Ba2+. Conclusion: Therefore, it is concluded that metal ions have significant influence on the morphology and drug encapsulation and release profile of the chitosan-alginate hybrid polymer nanoparticles.

Background: Continuous intravenous infusion of controlled drug delivery has certain risks. This could be diligently duplicated devoid of its hassles by using the skin as the port of drug entry. Transdermal drug delivery system is the main route with discrete, self-contained dosage forms when placed on the skin, transporting the medicament through the skin into the systemic circulation in a wellcontrolled manner. Objective: The rationale of the current work was to formulate and evaluate a transdermal patch of an antihypertensive drug by using different grades of polymers with a view to circumvent the hepatic first pass metabolism and also to escalate its bioavailability. Methods: Solvent-casting method was used to prepare transdermal patches of timolol maleate using Eudragit RL100, Eudragit RS100, ethyl cellulose as polymers, and dibutyl phthalate as the plasticizer. The formulated patches were evaluated for their physiochemical parameters such as folding endurance, percentage moisture content, thickness, and water vapour transmission. The formulated patches were subjected to in-vitro permeation studies by using a Franz diffusion cell with a dialysis sac. The optimized formulation chosen on the basis of physiochemical characteristics and in-vitro studies was subjected to in-vivo studies on methyl prednisolone acetate-induced hypertensive rats. Results: The data from release kinetics disclosed that the Korsmayer-Peppas could be the best fitting model. The results obtained from in-vitro studies disclosed that formulation with high proportion of Eudragit grade RL100 in acetone solvent system exhibited better drug release compared to rest of the formulations. The output obtained from in-vivo studies performed on rats revealed that the optimized formulation showed decrease in blood pressure from 158.53 ± 0.39 to 128.91 ± 0.50 mmHg. Conclusion: It was concluded that timolol maleate patch could be formulated into a matrix-type transdermal patch for the management of hypertension.

Background: Periodontitis is a localized inflammatory disorder. If not treated timely, the disease can result in loosening and subsequent loss of teeth. In situ hydrogel prepared with phase separation technique has emerged as an attractive alternative for periodontal pocket injection. Objective: Minocycline (MCL)-loaded in situ hydrogel was prepared composed of poly(lactide-coglycolide) (PLGA) and N-methylpyrrolidone (NMP) to improve the topical treatment effect of periodontitis. Method: A series of reasonable and applicable formulations were optimized by investigating their syringeability, viscosity and in vitro drug release. The rheological profiles, antimicrobial activities and pharmacodynamics were further studied to evaluate its effect on periodontitis treatment. Results: The prepared MCL/PLGA hydrogel exhibited the characteristic of Newton fluid with acceptable syringeability. Drug release could last for more than 48 hours with an acceptable “burst release”. It also had obvious antimicrobial activities and pharmacodynamics efficiency similar to the commercial product, Parocline®. Conclusion: MCL/PLGA in situ hydrogel may be a promising clinical formulation for periodontitis treatment.

Background: Nano drug delivery systems have the potential to address the challenges of delivering BCS Class II and IV drugs like furosemide. The purpose of the current study is to prepare stable nanosuspension and investigate in vitro dissolution performance of the model compound furosemide using quality by design (QbD) approach. Methods: Nanosuspension batches with uniform particle size were prepared for furosemide using the antisolvent precipitation method. A quality by design (Qbd) approach was explored to understand the impact of process parameters (stirring time, stirring speed, temperature, and injection rate) and material attributes (drug concentration, stabilizer type, drug: stabilizer ratio, and antisolvent: solvent ratio) on the quality attributes of furosemide nanosuspension using a full factorial experimental design. Multiple linear regression and ANOVA were employed to estimate and identify the critical process parameters and material attributes. Injection rate and stirring time were identified as the most critical process parameters' affecting the quality attributes of furosemide nanosuspension. Results: Individual material attributes did not show significant impact on the average particle size of the nanocrystals, however two-way interactions between material attributes (stabilizer type/drug concentration and stabilizer type/antisolvent: solvent ratio) significantly affected nanosuspension particle size distribution. Solid state characterization (PXRD, DSC and SEM) did not exhibit any changes of physical form during preparation and optimization of the furosemide nanosuspension. Dissolution of the furosemide nanocrystals in gastric media was significantly higher than that observed for micronized furosemide suspension and raw furosemide powder. Stability study data suggests that optimized batches of furosemide nanosuspensions were stable for three months at 4°C and ambient conditions. Conclusion: The antisolvent precipitation method can produce stable furosemide nanosuspensions with desirable quality attributes and enhancement of dissolution rate in the gastric medium as compared to the raw furosemide powder and microsuspension.

Background: Meloxicam is a non-steroidal anti-inflammatory drug revealing poor solubility in water and good permeability through biological membranes. It is currently administered mostly in forms exerting systemic effects, however, in some conditions topical formulations can be equally useful. Objective: The objective of the presented work was to formulate and investigate in detail the rheological behavior of non-aqueous gels containing 0.5% of meloxicam in a non-ionic, dissolved form. Method: Fumed silica and SynperonicTM PE/L 62 were used as structure forming components. Arlasolve ®, Transcutol®, ethanol and DMSO were applied as solubilizers and potential skin absorption enhancers. Three formulations were selected for further investigation and compared to placebo samples. The gels were examined in terms of rheological properties, spreadability and loss of volatile components. Results: The investigated samples revealed non-Newtonian pseudoplastic behavior with apparent impact of meloxicam on the gel strength. The oscillatory analyses showed an incomplete recovery after structure destruction. Moreover, two yield points were observed, one related to the destruction of fumed silica lattice and the other one to the changes in the spatial arrangement of polymer chains. The tendency to evaporation of volatile components was insignificant. The best spreadability parameter was observed for gels containing Transcutol®. Conclusion: In this study organogels with meloxicam in dissolved form were obtained and characterized. The performed tests showed that the mechanical properties of the investigated samples depended both on the presence of the drug and on the selection of excipients. The presented data are important in terms of semi-solid product manufacturing and further application by patients.

Background: The lack of an effective vaccine against viral infections, toxicity of the synthetic anti-viral drugs and the generation of resistant viral strains led to discover novel inhibitors. Recently, saffron and its compounds were used to treat different pathological conditions. Method: In this study, we tested the anti-HSV-1 and anti-HIV-1 activities of Iranian saffron extract and its major ingredients including crocin and picrocrocin as well as cytotoxicity in vitro. The data showed that the aqueous saffron extract was not active against HIV-1 and HSV-1 virions at certain doses (i.e., a mild activity), but crocin and picrocrocin indicated significant anti-HSV-1 and also anti-HIV-1 activities. Crocin inhibited the HSV replication at before and after entry of virions into Vero cells. Indeed, crocin carotenoid suppressed HSV penetration in the target cells as well as disturbed virus replication after entry into the cells. Picrocrocin was also effective for inhibiting virus entry and also its replication. Results: This monoterpen aldehyde showed higher anti-HSV effects after virus penetrating in the cells. Generally, these sugar-containing compounds extracted from saffron showed to be effective antiherpetic drug candidates. Conclusion: The recent study is the first report suggesting antiviral activities for saffron extract and its major ingredients. Crocin and picrocrocin could be a promising anti-HSV and anti-HIV agent for herbal therapy against viral infections.

Background: In order to prove the validity of a new formulation, a considerable amount of effort is required to study bioequivalence, which not only increases the burden of carrying out a number of bioequivalence studies but also eventually increases the cost of the optimization process. Objective: The aim of the present study was to develop sustained release matrix tablets containing diclofenac sodium using natural polymers and to demonstrate step by step process of product development till the prediction of in vivo marketed product equivalence of the developed product. Method: Different batches of tablets were prepared by direct compression. In vitro drug release studies were performed as per USP. The drug release data were assessed using model-dependent, modelindependent and convolution approaches. Results: Drug release profiles showed that extended release action were in the following order: Gum Tragacanth > Sodium Alginate > Gum Acacia. Amongst the different batches prepared, only F1 and F8 passed the USP criteria of drug release. Developed formulas were found to fit Higuchi kinetics model with Fickian (case I) diffusion-mediated release mechanism. Model- independent kinetics confirmed that total of four batches were passed depending on the similarity factors based on the comparison with the marketed Diclofenac. The results of in vivo predictive convolution model indicated that predicted AUC, Cmax and Tmax values for batch F8 were similar to that of marketed product. Conclusion: This study provides simple yet effective outline of pharmaceutical product development process that will minimize the formulation development trials and maximize the product success in bioequivalence studies.

Background: In situ gel formulations have been widely reported as a carrier for sustained release delivery systems due to certain advantages such as targeted drug delivery, minimal invasiveness and potent therapeutic activity. Objective: Herein, in situ gel system for sustained release of doxorubicin and ibuprofen for anti-cancer and anti-inflammatory activity is reported. Method: Doxorubicin-conjugated alginate (dox-alg) gel was prepared using EDC-NHS chemistry and loaded with ibuprofen encapsulated polycaprolactone (PCL) microparticles (dox-alg composite). PCL microparticles were prepared by a solvent evaporation method (size 50 - 100μm). The gel was characterized using SEM, FTIR, XRD and TGA analysis. Results: Dox-alg composite gel showed good syringeability and gel formation properties. Burst release was observed for both drugs within 24 h followed by sustained release till day 21. Doxorubicin released from composite showed considerable cytotoxic effect. Cell uptake was confirmed by confocal microscopy using MDA-MB-231 cells. Anti-inflammatory activity of ibuprofen released from composite gel was compared with the free drug. An injection of dox-alg composite gel in the tissue would fill the void created after tumor removal surgery, prevent the resuscitation of remnant cancerous cells and reduce inflammation. Conclusion: Thus, the dox-alg composite gel could be a potential agent for the dual anti-cancer and anti-inflammatory therapy.

Background: Complexes of Genipin and different water-soluble adjuvant polysaccharides, such as arabinogalactane, hydroxyethyl starch, fibergum, and oligosaccharides β-CD and HP-β-CD, were synthesized as drug delivery system using mechanochemical technology. Method: We have investigated physicochemical properties, stability, and hepatotoxicity of the synthesized complexes in solid state and aqueous solution. The formation of the complexes was evidenced by different physical and spectroscopy assays, and the stability constants of our synthesized Genipin-based complexes were also calculated. Results: The HP-β-CD inclusion complex showed the highest characteristics. We have found that the molecule of Genipin was completely included in the cyclodextrin cavity of the HP-β-CD. This complex of Genipin has shown a 6.14-fold increase of solubility compared with the original Genipin, and more stable in solvent and solid states. Conclusion: The hepatotoxicity assays showed that our investigated complexes of Genipin are much safer than the original Genipin. These results suggest that new Genipin-based preparations can be synthesized with advantageous of higher stability and safety.

Background: Melatonin release from Ethylcellulose matrix has never been studied on the whole range of compositions. Objective: To perform a comprehensive study about the influence of the melatonin loading on its release from solid ethylcellulose implants, from both a kinetic and structural point of view. Method: Cylindrical implants differing in their Melatonin:Ethylcellulose ratio were fabricated to cover a large range of compositions. Drug release was assayed by in vitro dissolution tests in CTAB micellar solutions. The 2D imaging of implant chemical composition during Melatonin release was performed by confocal Raman spectroscopy. FT-IR spectroscopy and Karl-Fisher technique were employed to study implants hydration. Results: A drug radial leakage, whatever the implant composition, is imaged. The apparent diffusion coefficient, D of melatonin was evaluated considering Fickian radial diffusion: its value ranges from 2 to 6 10-12 cm²/s depending on the EC content. The variation of the characteristic drug delivery time with composition was non-monotonous and two different regimes were identified. Conclusion: A micellar transport of Melatonin was found. The two regimes in drug release were interpreted considering the polymer barrier effect, the initial porosity and M domains connectivity.