Ketorolac tromethamine is a non-steroidal anti-inflammatory drug used in the management of severe pain. The half-life of Ketorolac tromethamine is within the range of 2.5–4 h. Hence, repeated doses of Ketorolac tromethamine are needed in a day to maintain the therapeutic level. However, taking several doses of Ketorolac tromethamine in a day generates certain complications, such as acute renal failure and gastrointestinal ulceration. Therefore, a polymeric-controlled drug delivery system is needed that could prolong the release of Ketorolac tromethamine. Therefore, in the current study, pH-responsive carbopol 934/sodium polystyrene sulfonate-co-poly(acrylic acid) (CP/SpScPAA) hydrogels were developed by the free radical polymerization technique for the controlled release of Ketorolac tromethamine. Monomer acrylic acid was crosslinked with the polymers carbopol 934 and sodium polystyrene sulfonate by the cross-linker N’,N’-methylene bisacrylamide. Various studies were conducted to evaluate and assess the various parameters of the fabricated hydrogels. The compatibility of the constituents used in the preparation of hydrogels was confirmed by FTIR analysis, whereas the thermal stability of the unreacted polymers and developed hydrogels was analyzed by TGA and DSC, respectively. A smooth and porous surface was indicated by SEM. The crystallinity of carbopol 934, sodium polystyrene sulfonate, and the prepared hydrogels was evaluated by PXRD, which revealed a reduction in the crystallinity of reactants for the developed hydrogels. The pH sensitivity of the polymeric hydrogel networks was confirmed by dynamic swelling and in vitro release studies with two different pH media i.e., pH 1.2 and 7.4, respectively. Maximum swelling was exhibited at pH 7.4 compared to pH 1.2 and, likewise, a greater percent drug release was perceived at pH 7.4. Conclusively, we can demonstrate that the developed pH-sensitive hydrogel network could be employed as a suitable carrier for the controlled delivery of Ketorolac tromethamine.

The aim of the current research work was to prepare Car934-g-poly(acrylic acid) hydrogels by the free-radical polymerization technique. Various concentrations of carbopol, acrylic acid and ethylene glycol dimethacrylate were employed for the fabrication of Car934-g-poly(acrylic acid) hydrogels. Fourier-transform infrared spectroscopy (FTIR), Thermogravimetric analysis (TGA), Differential scanning calorimetry (DSC), Scanning electron microscope (SEM) and Powder X-ray diffractometry (PXRD) studies were performed to know the structural arrangement, thermal stability, physical appearance and amorphous network of developed hydrogels. FTIR analysis revealed that carbopol reacted with acrylic acid during the process of polymerization and confirmed the grafting of acrylic acid over the backbone of carbopol. TGA and DSC studies showed that developed hydrogels were thermally stable. Surface morphology was analyzed by SEM, which confirmed a porous network of hydrogels. PXRD analysis indicated that crystallinity of the drug was reduced by the amorphous network of hydrogels. Furthermore, swelling studies for all developed hydrogels were performed at both media, i.e., pH 1.2 and 7.4, and higher swelling was exhibited at pH 7.4. Sol–gel analysis was performed to evaluate the soluble unreacted part of the fabricated hydrogels. Similarly, an in-vitro study was conducted for all hydrogel formulations at both acidic (pH 1.2) and basic (pH 7.4) mediums, and a greater drug release was observed at pH 7.4. Different kinetics such as zero-order, first-order, the Higuchi model and the Korsmeyer–Peppas model were applied to know the mechanism of release order of drugs from the hydrogels.

In recent years, the world has faced the issue of antibiotic resistance. Methicillin-resistant Staphylococcus aureus (MRSA) is a significant problem in various treatments and control of infections. Biocompatible materials with saturated fatty acids of different chain lengths (C8–C18) were studied as matrix formers of localized injectable vancomycin HCl (VCM)-loaded antisolvent-induced in situ forming matrices. The series of fatty acid-based in situ forming matrices showed a low viscosity (5.47–13.97 cPs) and pH value in the range of 5.16–6.78, with high injectability through a 27-G needle (1.55–3.12 N). The preparations exhibited low tolerance to high concentrations of KH2PO4 solution (1.88–5.42% v/v) and depicted an electrical potential change during phase transformation. Their phase transition and matrix formation at the microscopic and macroscopic levels depended on the chain length of fatty acids and solvent characteristics. The VCM release pattern depended on the nucleation/crystallization and solvent exchange behaviors of the delivery system. The 35% w/v of C12–C16 fatty acid-based in situ forming matrix prolonged the VCM release over seven days in which C12, C14, C16 –based formulation reached 56, 84, and 85% cumulative drug release at 7th day. The release data fitted well with Higuchi’s model. The developed formulations presented efficient antimicrobial activities against standard S. aureus, MRSA, Escherichia coli, and Candida albicans. Hence, VCM-loaded antisolvent-induced fatty acid-based in situ forming matrix is a potential local delivery system for the treatment of local Gram-positive infection sites, such as joints, eyes, dermis of surgery sites, etc., in the future.

Polymers that bear reversible massive, physical or chemical changes in response to little peripheral changes within the environmental conditions are Smart polymers, having versatility and tunable sensitivity. They have very promising applications in the biomedical field. This study will delve into the underlying principles along with entire features of these sensitive polymers and their most current and relevant applications to solve biological problems.

In the current study, biodegradable PHBV/PLGA blend nanoparticles (NPs) containing Teriparatide were loaded in hyaluronic acid/jeffamine (HA-JEF ED-600) hydrogel to prepare a combination delivery system (CDS) for prolonged delivery of Teriparatide. The principal purpose of the present study was to formulate an effective and prolonged Teriparatide delivery system in order to reduce the frequency of injection and thus enhance patient's compliance. Morphological properties, swelling behaviour, crosslinking efficiency and rheological characterization of HA-JEF ED-600 hydrogel were evaluated. The CDS was acquired by adding PHBV/PLGA NPs to HA-JEF ED-600 hydrogel simultaneously with crosslinking reaction. The percentage of NPs incorporation within the hydrogel as well as the loading capacity and morphology of Teriparatide loaded CDS were examined. Intrinsic fluorescence and circular dichroism spectroscopy proved that Teriparatide remains stable after processing. The release profile represented 63% Teriparatide release from CDS within 50days with lower burst release compared to NPs and hydrogel. MTT assay was conducted by using NIH3T3 cell line and no sign of reduction in cell viability was observed. Based on Miller and Tainter method, LD of Teriparatide loaded CDS was 131.8mg/kg. In vivo studies demonstrated that Teriparatide loaded CDS could effectively increase serum calcium level after subcutaneous injection in mice. Favourable results in the current study introduced CDS as a promising candidate for controlled delivery of Teriparatide and pave the way for future investigations in the field of designing prolonged delivery systems for other peptides and proteins.

Nanotechnological innovations over the last 16 years have brought about the potential to revolutionize specific therapeutic drug delivery to cancer tissue without affecting normal tissues. In addition, there are new nanotechnology-based platforms for diagnosis of cancers and for theranostics, i.e., integrating diagnosis with therapy and follow-up of effectiveness of therapy. This chapter presents an overview of these nanotechnology-based advancements in the areas of prevention, diagnosis, therapy, and theranostics for cancer. In addition, we stress the need to educate bio- and medical students in the field of nanotechnology.

The purpose of this study was the preparation, optimisation and in vitro characterisation of PHBV and PLGA blend nanoparticles (NPs) for prolonged delivery of Teriparatide. Double emulsion solvent evaporation technique was employed for the fabrication of NPs. The nanoformulation was optimised using the Box–Behnken methodology. The morphological properties of NPs were assessed by both SEM and transmission electron microscopy (TEM). Encapsulation of Teriparatide within the NPs and lacking of chemical bonds between drug and copolymers were proved by XRPD, FTIR and DSC. The structural stability of Teriparatide after processing was confirmed by fluorescence spectrometry. The average size of optimised NPs was 250.0 nm with entrapment efficiency (EE) of 89.5% and drug loading (DL) of 5.0%. Teriparatide release from optimised NPs led to 64.4% release over 30 days and it showed a diffusion-based mechanism. Based on the favourable results, PHBV/PLGA blend NPs could be a promising candidate for designing a controlled release formulation of Teriparatide.

Polymeric microparticles (MPs)-in-gel formulations for extended delivery of octreotide were developed. We investigated influence of polymer composition on acylation of octreotide and kinetics of release during in vitro release from biodegradable polymeric formulations. Polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid (PGA) and polyethylene glycol (PEG) based triblock (TB≈PCL10k-PEG2k-PCL10k) and pentablock (PBA≈PLA3k-PCL7k-PEG2k-PCL7k-PLA3k and PBB≈PGA3k-PCL7k-PEG2k-PCL7k-PGA3k) polymers were investigated. Octreotide was encapsulated in MPs using methanol-oil/water emulsion solvent evaporation method. The particles were characterized for size, morphology, encapsulation efficiency, drug loading and in vitro release. Release samples were subjected to HPLC analysis for quantitation and HPLC-MS analysis for identification of native and chemically modified octreotide adducts. Entrapment efficiency of methanol-oil/water method with TB, PBA and PBB polymers were 45%, 60%, and 82%, respectively. A significant fraction of released octreotide was acylated from lactide and glycolide based PBA (53%) and PBB (92%) polymers. Substantial amount of peptide was not released from PBB polymers after 330 days of incubation. Complete release of octreotide was achieved from TB polymer over a period of 3 months with minimal acylation of peptide (13%). PCL based polymers resulted in minimal acylation of peptide and hence may be suitable for extended peptide and protein delivery. Conversely, polymers having PLA and PGA blocks may not be appropriate for peptide delivery due to acylation and incomplete release.

A series of glycopolymers containing d-galactosyl 1,2,3-triazole groups were synthesized which exhibited thermosensitivity properties.

6-O-methacryloyl-α-d-glucoside 2 and 4-bromophenyl-6-O-methacryloyl-d-glucothioside 7, obtained by enzyme-catalyzed synthesis, have been homo-polymerized and copolymerized with styrene by a free radical process, yielding polymer materials with sugar moieties, attached to the polymer backbone via ester linkages. The results demonstrated that modifying the structural features of the monomers greatly affected the thermal and rheological properties of the polymers. The polymer materials obtained have been characterized by NMR, MALDI-MS, DSC, AFM, and EWC (equilibrium water content). The AFM images indicated the formation of spherical and core-shell polymeric microparticles.

Thermoassociative nanoparticles were obtained through the crosslinking reaction of periodate oxidized carboxymethyl pullulan with two difunctional Jeffamines: ED-600 and ED-2003. The nanoparticles were characterized through (1)H NMR spectra; their particle size, determined by dynamic light scattering (DLS) presented a bimodal distribution, with dimensions varying as a function of amount and type of crosslinking agent used; transmission electron microscopy photos confirmed the spherical shape of the nanoparticles and their dimensions determined by DLS. Their amphiphilic character was evidenced by retention of the dyes: hydrophobic (Rose Bengal), amphiphilic (Brilliant Blue) and hydrophilic (Vitamin B12). The thermosensitive properties, more pronounced for ED-2003 crosslinked nanoparticles, were evidenced through absorbance variation, fluorescence and DLS measurements as a temperature function. The nanoparticles retain important amounts of anionic (diclofenac: 40-80 mg/g), cationic (methylene blue: 70-125 mg/g) and hydrophobic (alpha-tocopherol: 220-350 mg/g) drugs. The in vitro characterization of the drug-polymer conjugates recommends the synthesized nanoparticles as supports for drug delivery.

Hydrochloric thiothixene (HT) is an antipsychotic drug used in the treatment of various psychoses including schizophrenia, mania, polar disorder, and in behavior disturbances. However, because the psychotics often could not control their behaviors, the independent administration of antipsychotic drug based on medical order was difficult. The omissions of the administration often brought an unsatisfactory therapeutic efficacy. A novel injectable long-term control-released in situ gel of HT for the treatment of schizophrenia was developed based on biodegradable material polylactic acid (PLA). The optimum formulation of the injectable PLA-based HT in situ gel containing 15% (w/w) HT and 45% (w/w) PLA with benzyl benzoate was used as a gelling solvent. The results of the in vitro and in vivo studies showed that this in situ gel had a long-term period of drug release for several weeks and a good histocompatibility without any remarkable inflammatory reactions.

The low therapeutic efficacy exhibited by conventional ophthalmic solutions owing to precorneal elimination of the drug, drainage by gravity, nasolacrimal drainage, conjunctival absorption, and the absence of controlled release and of bioadhesive properties, can be overcome by the use of in situ gelling systems. The combination in the same formulation of different in situ gelling polymers with different stimuli-responsiveness mechanisms exploiting the unique physicochemical characteristics of the ocular tissues is one such strategy that has produced improved results compared with conventional systems. As we discuss here, the recent use of biodegradable and biocompatible polymers in colloidal carrier systems has proved to be the most effective strategy, resulting in the exponential increase of the bioavailability of the ophthalmic drugs.

Dextran microparticles were chemically modified for the attachment of quaternary ammonium groups carrying substituents with different hydrophobicity, in order to obtain amphiphilic cationic hydrogels with different hydrophilic/lipophilic balance. These hydrogels retain various amounts of dyes: Rose Bengal, Brilliant Blue and Vitamin B12, used as models for hydrophobic, amphiphilic and hydrophilic drugs, as a function of their hydrophilic/hydrophobic properties. Bovine serum albumin (BSA) retention by hydrogels occurs in higher amounts at pH 6.9, and is influenced by electrostatic, hydrophobic forces and the swelling of the supports. Tetanus anatoxin is retained by the supports through electrostatic and/or hydrophobic forces, in amounts varying between 110 and 200 mg/g. Both proteins are gradually released, through increasing of the eluent ionic strengths. Alpha-tocopherol is retained by the hydrogels preponderantly through hydrophobic forces, in amounts varying between 130 and 300 mg/g. Measurement of the scavenging effect proved the antioxidant properties of the included drug. Based on the obtained results, one can appreciate the potential of the synthesized cationic hydrogels as supports for biomolecules or as vaccine adjuvants.

International audienceIn situ forming implants (ISI) based on phase separation by solvent exchange represent an attractive alternative to conventional preformed implants and microparticles for parenteral applications. They are indeed easier to manufacture and their administration does not require surgery, therefore improving patient compliance. They consist of polymeric solutions precipitating at the site of injection and thus forming a drug eluting depot. Drug release from ISI is typically divided into three phases: burst during precipitation of the depot, diffusion of drug through the polymeric matrix and finally drug release by system degradation. This review gives a comprehensive overview on (i) the theoretical bases of these three phases, (ii) the parameters influencing them and (iii) the remaining drawbacks which have to be addressed to enlarge their commercial opportunities. Indeed, although some of them are already commercialized, ISI still suffer from limitations: mainly lack of reproducibility in depot shape, burst during solidification and potential toxicity. Nevertheless, depending on the targeted therapeutic application, these shortcomings may be transformed into advantages. As a result, keys are given in order to tailor these formulations in view of the desired application so that ISI could gain further clinical importance in the following years

A poly (lactide-co-glycolide) (PLGA) implant was used to control the release profile of leuprolide acetate (LA) drug. The system is an in-situ polymeric precipitation system. And the formulation consisted of PLGA polymer, LA drug and N-methyl-2-pyrrolidon solvent with no additives. First, the formulation was injected into PBS solution for in-vitro studies and then it was administered to the animal models (female rats) for in-vivo release studies. The release profiles of leuprolide acetate were measured by UV spectrophotometry for a period of 28 days. The initial burst release of LA was 14% in in-vitro whereas it was 7% in in-vivo. In-vitro and in-vivo release profiles of LA had similar trends after 72 hours. However, the rate of LA release was slower in-vivo. This might be attributed to the limited diffusion process of solvent and the drug molecules. This could be due to presence of an additional pressure caused by the surrounding tissue and also the presence of small amount of water between cells in the subcutaneous site. Cross-section and surface of the implants were studied via scanning electron microscopy. Morphology of both in-vitro and in-vivo implants confirmed the release behaviours. No toxicity effects were reported in the histopathological assay. Furthermore, the pharmacological analysis showed more inactive ovaries due to release of LA.

Poly(3,4-ethylenedioxythiophene) (PEDOT) doped with poly(styrene sulfonate) (PSS) has a variety of chemical and biomedical applications. The application of PEDOT/PSS polymers in drug delivery has attracted attention. However, whether conducting polymers of PEDOT/PSS could be used for dopamine delivery has not clear. In the present study, the PEDOT/PSS coatings incorporated with dopamine were fabricated on 0.5 mm diameter platinum electrodes, electrochemical properties, and dopamine delivery capacities of these electrodes were evaluated in vitro and in vivo through implanting these electrodes into brain striatum area. The findings demonstrated that the PEDOT/PSS/dopamine coatings on platinum electrodes could reduce electrodes impedances, increase charge storage capacities, and release significant levels of dopamine upon electrical stimulation of these electrodes. These results indicated that polymers of PEDOT/PSS/dopamine could be used for dopamine delivery, implicating potential application of PEDOT/PSS/dopamine-coated implantable electrodes in the treatment of some diseases associated with dopamine deficits, such as, electrodes for the treatment of Parkinson's disease during deep brain stimulation.

Introduction: An ideal ophthalmic formulation is one that not only prolongs the contact time of the vehicle on the ocular surface but also slows down the drug elimination. The poor bioavailability and therapeutic response exhibited by the conventional ophthalmic solutions due to pre-corneal elimination of the drug may be overcome by the use of in situ gel forming systems. In situ gelling systems increase the viscosity by changing the pH or temperature in the pre-corneal region and lead to an increase of drug bioavailability by slowing drainage. Poloxamers are polyols with thermal gelling properties which are frequently included in ophthalmic formulations to improve the ocular bioavailability of drugs by increasing vehicle viscosity. Areas covered: An overview on the unique physiological characteristics of ocular globe and the limitations and disadvantages of the conventional ophthalmic pharmaceutical formulations. Readers will appreciate the different strategies to improve the absorption of drugs in the ocular globe, especially the incorporation of poloxamers in ophthalmic formulations, understanding the main advantages of the poloxamers and also learning about the different examples of applications of these polymers in ophthalmic pharmaceutical formulations. Expert opinion: Poloxamers offers a new strategy to improve bioavailability and decrease the side effects induced by the systemic absorption of topically applied ophthalmic drugs.

Effective formulation for peptide and protein delivery through the oral route has always been the critical effort with the advent of biotechnology. Stability, enzymatic degradation and ineffective absorption are common difficulties found for conventional dosage forms. As a result, new drug-delivery approaches are used to circumvent these limitations and enhance effective oral drug delivery. Some of these technologies have reached late stages of clinical trials and promising results will be available in the near future. This review covers, in general, the recent carriers reported in literature.

Antibiotics have significantly improved our living environments. However, overuse of antibiotics has led to the emergence of multi-drug resistant microorganisms, and the subsequent constant demand for the exploration of novel antibiotics. To this end, antimicrobial peptides (AMPs) have attracted much attention as a novel class of antibiotics. AMPs have strong antimicrobial activity against a wide-range of species, including gram-positive and gram-negative bacteria, fungi, and viruses. In addition, they are also effective against pathogenic organisms that are resistant to conventional drugs. Despite their great potential, the hemolytic activity and a highly broad spectrum of activity of AMPs dictate the need for amendments to develop safe pharmaceuticals. The human body contains commensal microflora as an integral part of complex mucosal surfaces that offers protection against pathogenic organisms. Administration of antibiotics with broad spectra of activity disrupts the indigenous microflora and increases the risks of diarrhea and other fatal infections. Therefore, it is difficult, but vital, to develop treatments capable of rapidly eliminating pathogenic organisms while maintaining the commensal microbiota. As such, novel pharmaceuticals, safe designer AMPs have been heavily researched. In this article, we review recent attempts to spatially and temporally regulate AMPs to enhance the quality-of-life of patients.

The paper studies the synthesis and characterization of crosslinked carboxymethylpullulan hydrogels containing Jeffamine (Jef) (M-600 and M-2005) [polyoxyalkyleneamines (polyethylene oxide, polypropylene oxide)] units as side chains, linked through amide bonds. These hydrogels present pH sensitive properties due to the presence of anionic functional groups and thermoassociative properties due to the Jeff units. They were characterized through FTIR spectra, swelling behavior in various media, at various pH or temperatures, retention of hydrophobic molecules, to appreciate their pH-sensitive and thermoassociative (multi-responsive) properties. The interaction with biomolecules as proteins: lysozyme, BSA and antioxidants as: lutein and alpha-tocopherol was studied, to estimate some potential application domains of these new synthesized hydrogels.

Biodegradable Poly(lactic-co-glycolic acid; PLGA), microspheres encapsulating the angiogenic protein recombinant human vascular endothelial growth factor (rhVEGF) were formed to achieve VEGF release in a sustained manner. These microspheres are a promising delivery system which can be used for therapeutic angiogenesis. The PLGA microspheres incorporating two different initial loading amounts of rhVEGF have been prepared by a modified water-in-oil-in-water (w/o/w) double emulsion/solvent evaporation technique. The microspheres have been characterized by particle size distribution, environmental scanning electron microscopy (ESEM), light microscopy, encapsulation efficiency and their degradation was studied in vitro. The rhVEGF released from microspheres was quantified by the competitive enzyme-linked immunosorbent assay (ELISA) and human umbilical vein endothelial cell (HUVEC) proliferation assay was used to assess biological activity of the released VEGF. The microspheres were spherical with diameters of 10–60 µm and the encapsulation efficiency was between 46% and 60%. The release kinetics of rhVEGF was studied for two different amounts: 5 µg VEGF (V5) and 50 µg VEGF (V50) per 500 mg starting polymer. The total protein (VEGF:BSA) release increased up to 4 weeks for two rhVEGF concentrations. The ELISA results showed that the burst release for V5 and V50 microspheres were 4 and 27 ng/mL, respectively. For V5, the microspheres showed an initial burst release, followed by a higher steady-state release until 14 days. VEGF release increased up to 2 weeks for V50 microsphere. HUVEC proliferation assay showed that endothelial cells responded to bioactive VEGF by proliferating and migrating.

NAP (NAPVSIPQ) is a short peptide derived from activity-dependent neuroprotective protein (ADNP) sequence, whose potent and direct neuroprotective capabilities have been widely accepted. However, due to the high risk and inconvenience of intraocular injections, NAP is difficult to be clinically administered as therapeutic agent in treating retinal diseases. Currently, stable transfection of this octapeptide into cells has not been reported, partly because of its small size and lacking of 5' signal sequence. Here, we have developed a novel NT4-NAP fusion gene by attaching the 5' nonfunctional preproregion of neurotrophin 4 (NT4) to NAP cDNA. Recombinant adeno-associated virus was established to introduce NT4-NAP construct into cultured rat retinal Müller cells (RMC), resulting in sustained high level NAP production from stable transfection. Functional analyses of RMC cells transfected with NAP revealed the remarkably reduced cytotoxicity and apoptosis of the cells under hypoxia. Furthermore, coculturing of transfected RMC-NAP cells with primary rat retinal neural cells offer marked protection to the latter against hypoxia induced cellular damages. Together our data indicate that stable transfection of NAP into retinal Müller cells with constant NAP production is possible. NAP produced from cellular transfection maintained its biological neuroprotective activities. This targeted gene expression may provide an effective treatment for retinal diseases in the near future.

A short review is proposed on the existing literature for the research performed in calcium phosphate (CaP) biomaterials used as drug delivery systems. In the first part, a brief update is given on the performance of both CaP ceramics and CaP cements. Second, a review of the research and clinical situation is developed for CaP materials already used as drug delivery systems. Experimental works performed for local delivery are reported. In particular, a description is given of the in vitro and in vivo studies in which these materials are loaded with various proteins and drugs.

As antibiotic resistance increases worldwide, there is an increasing pressure to develop novel classes of antimicrobial compounds to fight infectious disease. Peptide therapeutics represent a novel class of therapeutic agents. Some, such as cationic antimicrobial peptides and peptidoglycan recognition proteins, have been identified from studies of innate immune effector mechanisms, while others are completely novel compounds generated in biological systems. Currently, only selected cationic antimicrobial peptides have been licensed, and only for topical applications. However, research using new approaches to identify novel antimicrobial peptide therapeutics, and new approaches to delivery and improving stability, will result in an increased range of peptide therapeutics available in the clinic for broader applications.