Preliminary investigation on the design of biodegradable microparticles for ivermectin delivery: set up of formulation parameters

The aim was to design sterile biodegradable microparticulate drug delivery systems based on poly(dl-lactide) (PLA) and poly(?-caprolactone) (PCL) and containing ivermectin (IVM), an antiparasitic drug, for subcutaneous administration in dogs. The drug delivery system should: (i) ensure a full 12-month protection upon single dose administration; (ii) be safe with particular attention regarding IVM dosage and its release, in order to prevent over dosage side effects. This preliminary work involves: polymer selection, evaluation of the effects of γ-irradiation on the polymers and IVM, investigation and set up of suitable microparticle preparation process and parameters, IVM-loaded microparticles in vitro release evaluation.

Results of gel permeation chromatography analysis on the irradiated polymers and IVM mixtures showed that combination of IVM with the antioxidant α-tocopherol (TCP) reduces the damage extent induced by irradiation treatment, independently on the polymer type.

Solvent evaporation process was successfully used for the preparation of PLA microparticles and appropriately modified; it was recognized as suitable for the preparation of PCL microparticles. Good process yields were achieved ranging from 76.08% to 94.72%; encapsulation efficiency was between 85.76% and 91.25%, independently from the polymer used. The type of polymer and the consequent preparation process parameters affected microparticle size that was bigger for PCL microparticles (480–800?µm) and solvent residual that was >500?ppm for PLA microparticles. In vitro release test showed significantly faster IVM release rates from PCL microparticles, with respect to PLA microparticles, suggesting that a combination of the polymers could be used to obtain the suitable drug release rate.     

Mupirocin calcium microencapsulation via spray drying: feed solvent influence on microparticle properties,stability and antimicrobial activity

Objectives: The aim of this research was to design a controlled release, spray dried, mupirocin calcium-loaded microparticles (MP) with acrylic polymer and assess the influence of a feed solvent at preselected drug:polymer proportions (1:5 and 2:1 (w/w)) on the performance and stability of the prepared MP.

Methods: Physicochemical properties of MP were assessed using modulated differential scanning calorimetry (MDSC), and thermogravimetric analyses (TGA), Fourier transformed infrared spectroscopy (FTIR) and X-ray analyses and were correlated with drug release. Morphology and particle size were determined using low-angle laser light scattering and a scanning electron microscope. A time-kill assay was conducted on two strains of Staphylococcus aureus to evaluate the antimicrobial activity of MP.

Results and discussion: The MP formed solid dispersions without apparent drug crystallization. Drug-polymer miscibility, morphology, drug release and consequently antimicrobial activity were dependent on drug loading (DL) and the used solvent. The superior control of drug release from MP was achieved for the higher DL (2:1 (w/w) drug:polymer proportion) using solvents in the following order: methanol ≈ methanol:ethanol (50:50, w/w) > isopropanol:acetone (40:60, w/w). Moreover, a time-kill assay performed on S. aureus (ATCC 29213) and methicillin-resistant S. aureus strains confirmed the prolonged release and preservation of antimicrobial activity of the microencapsulated drug. The physical aging of the solid dispersion after 10 months of storage had negligible impact on the MP performance.

Conclusions: Acrylic-based MP were confirmed as suitable microcarriers for prolonged drug release using a well-established spray drying technique, while solvent influence was strongly related to the DL employed.     

In situ forming implants for the delivery of metronidazole to periodontal pockets: formulation and drug release studies

This study was performed to obtain prolonged drug release with biodegradable in situ forming implants for the local delivery of metronidazole to periodontal pockets. The effect of polymer type (capped and uncapped PLGA), solvent type (water-miscible and water-immiscible) and the polymer/drug ratio on in vitro drug release studies were investigated. In situ implants with sustained metronidazole release and low initial burst consisted of capped PLGA and N-methyl-2-pyrolidone as solvent. Mucoadhesive polymers were incorporated into the in situ implants in order to modify the properties of the delivery systems towards longer residence times in vivo. Addition of the polymers changed the adhesiveness and increased the viscosity and drug release of the formulations. However, sustained drug release over 10 days was achievable. Biodegradable in situ forming implants are therefore an attractive delivery system to achieve prolonged release of metronidazole at periodontal therapy.     

Formulation and evaluation of floating tablet of H2-receptor antagonist

Context: Conventional sustained dosage form of ranitidine hydrochloride (HCl) does not prevent frequent administration due to its degradation in colonic media and limited absorption in the upper part of GIT.

Objectives: Ranitidine HCl floating tablet was formulated with sublimation method to overcome the stated problem.

Methods: Compatibility study for screening potential excipients was carried out using Fourier transform infrared spectroscopy (FT-IR) and differential scanning chromatography (DSC). Selected excipients were further evaluated for optimizing the formulation. Preliminary screening of binder, polymer and sublimating material was based on hardness and drug release, drug release with release kinetics and floating lag time with total floatation time, respectively. Selected excipients were subjected to 3² factorial design with polymer and sublimating material as independent factors. Matrix tablets were obtained by using 16/32” flat-faced beveled edges punches followed by sublimation.

Results: FT-IR and DSC indicated no significant incompatibility with selected excipients. Klucel-LF, POLYOX WSR N 60?K and l-menthol were selected as binder, polymer and sublimating material, respectively, for factorial design batches after preliminary screening. From the factorial design batches, optimum concentration to release the drug within 12?h was found to be 420?mg of POLYOX and 40?mg of l-menthol. Stability studies indicated the formulation as stable.

Conclusion: Ranitidine HCl matrix floating tablets were formulated to release 90% of drug in stomach within 12?h. Hence, release of the drug could be sustained within narrow absorption site. Moreover, the dosage form was found to be floating within a fraction of second independent of the pH of media ensuring a robust formulation.     

Preparation and Characterization of Heparin-Loaded Polymeric Microparticles

ABSTRACT

Microparticles containing heparin were prepared by a water-in-oil-in-water emulsification and evaporation process with pure or blends of biodegradable (poly-?-caprolactone and poly(d,l-lactic-co-glycolic acid)) and of positively-charged non-biodegradable (Eudragit® RS and RL) polymers. The influence of polymers and some excipients (gelatin A and B, NaCl) on the particle size, the morphology, the heparin encapsulation rate as well as the in vitro drug release was investigated. The diameter of the microparticles prepared with the various polymers ranged from 80 to 130 µm and was found to increase significantly with the addition of gelatin A into the internal aqueous phase. Microparticles prepared with Eudragit RS and RL exhibited higher drug entrapment efficiency (49 and 80% respectively), but lower drug release within 24 h (17 and 3.5% respectively) than those prepared with PCL and PLAGA. The use of blends of two polymers in the organic phase was found to modify the drug entrapment as well as the heparin release kinetics compared with microparticles prepared with a single polymer. In addition, microparticles prepared with gelatin A showed higher entrapment efficiency, but a significant initial burst effect was observed during the heparin release. The in vitro biological activity of heparin released from the formulations affording a suitable drug release has been tested by measuring the anti-Xa activity by a colorimetric assay with a chromogenic substrate. The results confirmed that heparin remained unaltered after the entrapment process.     

Hydrophobic amino acids grafted onto chitosan: a novel amphiphilic chitosan nanocarrier for hydrophobic drugs

Abstract

Objective: The objective of this study is to develop a novel biocompatible amphiphilic drug delivery for hydrophobic drugs, chitosan (CS) was grafted to a series of hydrophobic amino acids including l-alanine (A), l-proline (P), and l-tryptophan (W) by carbodiimide mediated coupling reaction.

Materials and methods: Chemical characteristics of the modified polymers were determined and confirmed by FT-IR, ¹H NMR, and UV–vis spectroscopy and the degree of substitution was quantified by elemental analysis. The modified polymers were used to form amphiphilic chitosan nanocarriers (ACNs) by the conventional self-assembly method using ultrasound technique. The morphology and the size of ACNs were analyzed by scanning electron microscope (SEM) and Dynamic light scattering (DLS).

Results and discussion: The sizes of spherical ACNs analyzed by SEM were obviously smaller than those of determined by DLS. The ACNs effectively surrounded the hydrophobic model drug, letrozole (LTZ), and demonstrated different encapsulation efficiencies (EE), loading capacities (LC), and controlled drug release profiles. The characteristics of ACNs and the mechanism of drug encapsulation were confirmed by molecular modeling method. The modeling of the structures of LTZ, profiles of A, P, and W grafted onto CS and the wrapping process around LTZ was performed by quantum mechanics (QM) methods. There was a good agreement between the experimental and theoretical results. The cell viability was also evaluated in two cell lines compared with free drug by MTT assay.

Conclusion: The hydrophobic portion effects on ACNs’ characteristics and the proper selection of amino acid demonstrate a promising potential for drug delivery vector.     

In situ gelling nasal inserts for influenza vaccine delivery

Purpose: The objective of this study was to investigate the potential of rapidly gelling nasal inserts as vaccine delivery system. Methods: Nasal inserts were prepared by freeze-drying hydrophilic polymer solutions containing influenza split vaccine. In vitro vaccine release from polymer solutions and inserts and the vaccine hemagglutination activity were determined. In vivo immunization studies in mice and rats were performed with nasal solutions and nasal inserts. Results: The in vitro release of proteins (vaccine) from polymeric solutions and inserts was incomplete because of the high molecular weight of the proteins. The release rate was controlled by the polymer (Lutrol® F68 > PVP 90 > HPMC K15M > Carbopol® > chitosan ≥ carrageenan = xanthan gum) because of differences in solution viscosity and possible polymer–protein interactions. Xanthan gum, a negatively charged polymer with intrinsic adjuvanticity, enhanced the serum IgG as well as the nasal IgA response in in vivo studies with nasal vaccine solutions. Poly-l-arginine and cationic lipid were the best performing adjuvants. Solutions containing vaccine with xanthan gum and cationic lipid were effectively stabilized with 0.4 M NaCl. Discussion: The specific activity of the major vaccine protein, hemagglutinin, was not significantly affected by the addition of polymers and the freeze-drying process during insert preparation. The addition of cationic lipid as adjuvant decreased the hemagglutination activity, which strongly indicated inhibition of the protein binding site to erythrocytes. Inserts prepared from xanthan gum and cationic lipid stabilized with NaCl showed a reduced protein activity but were superior to the cationic lipid alone. Conclusion: Rat immunization with solid nasal inserts based on xanthan gum containing the influenza vaccine, with or without an additional cationic lipid adjuvant, resulted in similar IgG levels as the pure nasal liquid vaccine formulation.     

Injectable sustained release PLA microparticles prepared by solvent evaporation-media milling technology

The objective of this study was to develop agomelatine (AGM) intramuscular sustained release PLA microparticles by using solvent evaporation combined with wet milling technology. The final preparation had a regular and homogeneous particle size of approximately 35?µm, as measured by laser diffraction particle size analysis and scanning electron microscopy (SEM). The drug was confirmed to be within the carrier in an amorphous state through differential scanning calorimetry (DSC) and power X-ray diffraction (PXRD) experiments. Additionally, Fourier transform infrared spectroscopy (FT-IR) analysis was applied to confirm that there was hydrogen bonding between the drug and polymer at the molecular level. In vitro release experiments indicated that the drug could achieve long-term sustained release over the period of one month, with only a 3.07% burst release, due to the involvement of the polymer and removal of drug adsorbed on the surface during the wet grinding process. The dominant release mechanism was considered to be diffusion of the drugs in the initial period. Following this, with the hydrolysis of PLA to form a colloidal viscous layer, drug release is due to the combined effect of diffusion and erosion of the polymer matrix. Additionally, drug release behavior is closely related to the degradation mechanism of the polymer carrier. The results suggest that AGM could be developed as a potential delivery system for long-acting intramuscular administration with extensive application prospects.     

Solubility and solution stability studies of different amino acid prodrugs of bromhexine

Objective: The aim of the present study was to prepare the amino acid prodrugs of bromhexine hydrochloride to improve its solubility.

Methods: All the prodrugs were synthesized by first reacting bromhexine with tert-butoxycarbonyl (Boc) protected amino acid and then deprotection was carried out by using trifluoroacetic acid. These prodrugs were characterized by their melting points, NMR, mass and FTIR spectroscopy. Solubility and partition coefficient of bromhexine and various prodrugs were determined. The solution stability of various prodrugs was also determined in various buffers of pH ranging from 2 to 10. Degradation rate constants and half-life were also determined at various pH.

Results and discussion: The structures of all the synthesized prodrugs were confirmed by NMR, mass and FTIR spectra. The prodrug 2-N-l-alanyl-bromhexine hydrochloride showed maximum solubility and minimum partition coefficient value. These prodrugs may hydrolyze by one or more mechanisms. The order of decreasing rates of hydrolysis was 2-N-l-prolyl-bromhexine hydrochloride > 2-N-glycyl-bromhexine hydrochloride > 2-N-l-alanyl-bromhexine hydrochloride. All the prodrugs exhibited maximum stability in the acidic pH range and undergo base catalyzed hydrolysis.

Conclusion: Solubility studies and partition coefficient values indicated that the synthesized prodrug, 2-N-l-alanyl-bromhexine hydrochloride, was least lipophilic as compared to other synthesized prodrugs. Solution stability studies showed that this prodrug undergo minimum hydrolysis at 37°C. So, it is concluded that 2-N-l-alanyl-bromhexine hydrochloride exhibits better solubility and stability as compared to other synthesized prodrugs.     

In vitro evaluation of compression-coated glycyl-l-histidyl-l-lysine–Cu(II) (GHK–Cu2+)-loaded microparticles for colonic drug delivery

Glycyl-l-histidyl-l-lysine–Cu(II) (GHK–Cu²⁺)-loaded Zn-pectinate microparticles in the form of hydroxypropyl cellulose (HPC) compression-coated tablets were prepared and their in vitro behavior tested. GHK–Cu²⁺ delivery to colon can be useful for the inhibition of matrix metalloproteinase, with the increasing secretion of tissue inhibitors of metalloproteinases (TIMPS),which are the major factors contributing in mucosal ulceration and inflammation in inflammatory bowel disease. The concentration of peptide was determined spectrophotometrically. The results obtained implied that surfactant ratio had a significant effect on percent production yield (1.25 to 1.75 w/w; 72.22% to 80.84%), but cross-linking agent concentration had not. The entrapment efficiency (EE) was found to be in the range of 58.25–78.37%. The drug-loading factor significantly increased the EE; however, enhancement of cross-linking agent concentration decreased it. The release of GHK–Cu²⁺ from Zn-pectinate microparticles (F1–F8) in simulated intestinal fluid was strongly affected by cross-linking agent concentration and drug amount (50?mg for F1–F6; 250?mg for F7–F8), but not particularly affected by surfactant amount. Release profiles represented that the microparticles released 50–80% their drug load within 4?h. Therefore, the optimum microparticle formulation (F8) coated with a relatively hydrophobic polymer HPC to get a suitable colonic delivery system. The optimum colonic delivery tablets prepared with 700?mg HPC-SL provided the expected delayed release with a lag time of 6?h. The effects of polymer viscosity and coat weight on GHK–Cu²⁺ release were found to be crucial for the optimum delay of lag time. The invention was found to be promising for colonic delivery.     

Characterization of silicone pressure-sensitive adhesive episcleral implant for drug delivery

The development of an effective sustained ocular drug delivery system remains a challenging task. The objective of the present study was to characterize a silicone pressure sensitive adhesive (PSA) episcleral implant system for transscleral drug delivery. Silicone PSA implants for dexamethasone, atenolol, and bovine serum albumin (BSA) were prepared at different polymer-to-drug mass ratios. Implant adhesion to human cadaver sclera was measured. Drug release experiments were conducted in well-stirred containers in vitro. The results were then analyzed using a pharmacokinetic model and in vitro–in vivo data comparison from previous studies. The silicone PSA episcleral implants in the present study had an average diameter of 3.5?mm and a thickness of 0.8?mm. Drug release from the silicone PSA implants was influenced by drug solubility, implant polymer content, and implant coating. Drug release from the implants was observed to follow the receding boundary release mechanism and was solubility dependent with the higher water solubility drug showing higher release rate than the low-solubility drug. Increasing polymer content in the implants led to a significant decrease in the drug release rate. Coated implants reduced the initial burst effect and provided lower release rates than the uncoated implants. These implants provided sustained drug release that could last up to several months in vitro and demonstrated the potential to offer drug delivery for chronic ocular diseases via the transscleral route.     

In Vivo Characteristics of Injectable Poly(DL-Lactic Acid) Microspheres for Long-Acting Drug Delivery

Abstract

Poly(DL-lactic acid) (PLA) microspheres containing testosterone (T) were prepared by the solvent evaporation process to evaluate their physical properties such as size distribution, shape, drug content, in vivo controlled drug release, pharmacological influences on the prostate gland in castrated rats, and histopathological findings of tissues surrounding the implants. The in vivo release of T from PLA microspheres containing 30 mg of drug obtained with chloroform was continued over a 6-week period. This effect is attributed to high dispersibility ofT in the device when obtained with chloroform. Both serum drug levels and prostate gland weight recovery suggested the effects of a long-acting drug delivery system. The histopathological findings showed that the devices used were completely degraded 10 weeks after injection.     

Sugars as solid dispersion carrier to improve solubility and dissolution of the BCS class II drug: clotrimazole

Solid dispersion of poorly soluble BCS class II drug, clotrimazole, was prepared with the aim of enhancing its dissolution profile. Solid dispersions were prepared using various sugars as carriers at different weight ratio to drug-like d-mannitol, d-fructose, d-dextrose and d-maltose by fusion method. The solubility of plain clotrimazole in different percent of sugar solutions was measured. Also, its solubility in solid dispersion and their physical mixture were assessed. The dissolution of all the prepared SD tablets, direct compressed clotrimazole tablet and plain drug were tested using the U.S. Pharmacopeia convention (USP) apparatus II. The dissolution profiles were characterized by parameters like area under curve (AUC), mean residence time (MRT), mean dissolution time (MDT) and percent dissolution efficiency (% DE). The release kinetics study was performed using DD Solver TM software. The selected solid dispersions (SDs) were evaluated for antifungal activity. A 100% solution of mannitol showed 806-fold increases in solubility as compared with plain clotrimazole in water. It was observed that the dissolution profile of clotrimazole was improved by mannitol SD at drug to sugar ration of 1:3. The percent DE value for mannitol SD tablet was found to be 77.3516% as against plain drug and directly compressed tablet of clotrimazole at 50.9439% and 31.33%, respectively. Also the antifungal activity indicated by inhibition zone was found to be 54?mm indicating enhance activity against Candida albicans as compared with plain CTZ at 6.6?mm. Thus, it can be concluded that the sugar alcohol, that is, mannitol is a more promising hydrophilic carrier for solid dispersion preparation to improve the solubility and dissolution of poorly soluble drugs.     

Impact of surfactant selection on the formulation and characterization of microparticles for pulmonary drug delivery

The effect of suspension stabilizers, internal aqueous phase volume and polymer amount were investigated for the production of protein loaded poly(d,l?lactide-co-glycolide) (PLGA) microparticles suitable for pulmonary drug delivery. PLGA microparticles were produced adopting water-in-oil-in-water (W/O/W) solvent evaporation technique and were investigated for surface morphology, particle size, encapsulation efficiency (EE%) and in-vitro release profile. Porous surface morphologies with a narrow size distribution were observed when employing 0.5?ml internal aqueous phase; 23.04?µm (±0.98), 15.05?µm (±0.27) and 22.89?µm (±0.41) for PVA, Tween 80 and oleic acid. Porous microparticles exhibited increased size and reduction in EE% with increasing internal aqueous phase, with non-porous microparticles produced when adopting 2.0?ml internal aqueous phase. The selection of stabilizer influences the size of the pores formed thus offers potential for the aerodynamic properties of the microparticles to be manipulated to achieve suitable aerosolization characteristics for pulmonary delivery of proteins.     

Feasibility of poly (ε-caprolactone-co-DL-lactide) as a biodegradable material for in situ forming implants: evaluation of drug release and in vivo degradation

The purpose of this study was to evaluate the technical feasibility of poly (ε-caprolactone-co-DL-lactide), P (CL/DL-LA), for injectable in situ forming implants (ISFI). The ISFI was prepared by dissolving P (CL/DL-LA) in N-methyl-2-pyrrolidone (NMP), and Testosterone undecanoate (TU) was used as model drug. The effect of various polymer concentrations, molecular weights (Mws) and drug loads on the drug release from the TU-loaded ISFI systems was investigated in vitro. The release of TU-loaded ISFI was also evaluated in rats. In addition, a subcutaneous rabbit model was used to evaluate the degradation and foreign-body reaction of P (CL/DL-LA) ISFI. The use of higher concentration of P (CL/DL-LA) with higher molecule weight and larger CL:DL-LA monomer ratio for the TU-loaded ISFI gave a slower drug release. The ISFI of 80/20 P (CL/DL-LA) (Mw 61?753):NMP 20:80 with 16% TU formulation increased serum testosterone levels in rats over a period of three months. The in vivo degradation and biocompatibility study of ISFI shows that P (CL/DL-LA) degrades by a process of bulk degradation and that the foreign-body reaction of this biomaterial is relatively mild. In summary, our investigations demonstrate that in situ parenteral drug delivery systems can be obtained from P (CL/DL-LA) solutions.     

Transport Characteristics of a Beta Sheet Breaker Peptide Across Excised Bovine Nasal Mucosa

ABSTRACT

The purpose of the present study was to investigate the permeation characteristics of the beta sheet breaker peptide AS 602704 (BSB) on excised bovine nasal mucosa using an Ussing chamber model. The influence of various absorption enhancers such as sodium cholate, sodium dodecyl sulfate (SDS), cetrimidum, sodium caprate, Na₂EDTA, polycarbophil (PCP), the thiomer conjugate polycarbophil-cysteine (PCP-Cys), and poly-l-arginine (poly-l-arg; 100 kDa) was evaluated. Additionally, the influence of temperature and pH on the transport rate as well as the stability of the peptide drug against enzymatic degradation were investigated in vitro.

The effective permeability coefficient (P_eff) of BSB in Krebs-Ringer-buffer (KRB) pH 7.4 was (1.89 ± 0.44)* 10^?5, while in the presence of sodium caprate (0.5%) a P_eff of (9.58 ± 1.82)*10^?5 was achieved. Rank order of enhancement ratio was sodium caprate > SDS > sodium cholate > Na₂EDTA > poly-l-arg = PCP-Cys. In case of cetrimidum and PCP even a decrease in the absorption of BSB was determined. Na₂EDTA reduced the enzymatic degradation of BSB when exposed to a nasal tissue homogenate by more than the half. An increased lipophilicity of BSB because of a more acidic milieu (pH 5.5) did not lead to an increased transcellular transport. Permeation studies carried out at 4°C compared to 37°C demonstrated a temperature dependent permeation behaviour suggesting an additional active carrier mediated transport.

The results obtained within these studies should facilitate the development of a nasal delivery system for AS 602704 for the treatment of Alzheimer's disease.     

Development and in vitro characterization of chitosan-coated polymeric nanoparticles for oral delivery and sustained release of the immunosuppressant drug mycophenolate mofetil

Objective: To develop an oral sustained release formulation of mycophenolate mofetil (MMF) for once-daily dosing, using chitosan-coated polylactic acid (PLA) or poly(lactic-co-glycolic) acid (PLGA) nanoparticles. The role of polymer molecular weight (MW) and drug to polymer ratio in encapsulation efficiency (EE) and release from the nanoparticles was explored in vitro.

Methods: Nanoparticles were prepared by a single emulsion solvent evaporation method where MMF was encapsulated with PLGA or PLA at various polymer MW and drug: polymer ratios. Subsequently, chitosan was added to create coated cationic particles, also at several chitosan MW grades and drug: polymer ratios. All the formulations were evaluated for mean diameter and polydispersity, EE as well as in vitro drug release. Differential scanning calorimetry (DSC), surface morphology, and in vitro mucin binding of the nanoparticles were performed for further characterization.

Results: Two lead formulations comprise MMF: high MW, PLA: medium MW chitosan 1:7:7 (w/w/w), and MMF: high MW, PLGA: high MW chitosan 1:7:7 (w/w/w), which had high EE (94.34% and 75.44%, respectively) and sustained drug release over 12?h with a minimal burst phase. DSC experiments revealed an amorphous form of MMF in the nanoparticle formulations. The surface morphology of the MMF NP showed spherical nanoparticles with minimal visible porosity. The potential for mucoadhesiveness was assessed by changes in zeta potential after incubation of the nanoparticles in mucin.

Conclusion: Two chitosan-coated nanoparticles formulations of MMF had high EE and a desirable sustained drug release profile in the effort to design a once-daily dosage form for MMF.     

Protein functionalized tramadol-loaded PLGA nanoparticles: preparation,optimization, stability and pharmacodynamic studies

Poly (d,l-lactide-co-glycolide acid) (PLGA) Nanoparticles (NPs) with sustained drug release and enhanced circulation time presents widely explored non-invasive approach for drug delivery to brain. However, blood-brain barrier (BBB) limits the drug delivery to brain. This can be overcome by anchoring endogenous ligand like Transferrin (Tf) and Lactoferrin (Lf) on the surface of NPs, allowing efficient brain delivery via receptor-mediated endocytosis. The aim of the present investigation was preparation, optimization, characterization and comparative evaluation of targeting efficiency of Tf- vs. Lf-conjugated NPs. Tramadol-loaded PLGA NPs were prepared by nanoprecipitation techniques and optimized using 3³ factorial design. The effect of polymer concentration, stabilizer concentration and organic:aqueous phase ratio were evaluated on particle size (PS) and entrapment efficiency (EE). The formulation was optimized based on desirability for lower PS (<150 nm) and higher EE (>70%). Optimized PLGA NPs were conjugated with Tf and Lf, characterized and evaluated for stability study. Pharmacodynamic study was performed in rat after intravenous administration. The optimized formulation had 100 mg of PLGA, 1% polyvinyl alcohol (PVA) and 1:2 acetone:water ratio. The Lf and Tf conjugation to PLGA NPs was estimated to 186 Tf and 185 Lf molecules per NPs. Lyophilization was optimized at 1:2 ratio of NPs:trehalose. The NPs were found stable for 6 months at refrigerated condition. Pharmacodynamic study demonstrated enhanced efficacy of ligand-conjugated NPs against unconjugated NPs. Conjugated NPs demonstrated significantly higher pharmacological effect over a period of 24 h. Furthermore Lf functionalized NPs exhibited better antinociceptive effect as compared to Tf functionalized NPs.     

Mucoadhesive plasticized system of branched poly(lactic-co-glycolic acid) with aciclovir

Commercially available antibacterial semisolid preparations intended for topical application provide only short-term drug release. A sustained kinetics is possible by exploitation of a biodegradable polymer carrier. The purpose of this work is to formulate a mucoadhesive system with aciclovir (ACV) based on a solid molecular dispersion of this drug in poly(lactic-co-glycolic acid) branched on tripenterythritol (PLGA/T). The ACV incorporation into PLGA/T was carried out either by solvent method, or melting method, or plasticization method using various plasticizers. The drug–polymer miscibility, plasticizer efficiency and content of residual solvent were found out employing DSC. Viscosity was measured at the shear rate range from 0.10 to 10.00?s^?1 at three temperatures and data were analyzed by Newtonian model. The mucoadhesive properties were ascertained in the tensile test on a mucin substrate. The amount of ACV released was carried out in a wash-off dissolution test. The DSC results indicate a transformation of crystalline form of ACV into an amorphous dissolved in branched polyester carrier, and absence of methyl formate residuals in formulation. All the tested plasticizers are efficient at T_g depression and viscosity decrease. The non-conventional ethyl pyruvate possessing supportive anti-inflammatory activity was evaluated as the most suitable plasticizer. The ACV release was strongly dependent on the ethyl pyruvate concentration and lasted from 1 to 10 days. The formulated PLGA/T system with ACV exhibits increased adhesion to mucosal hydrophilic surfaces and prolonged ACV release controllable by degradation process and viscosity parameters.     

Formulation and characterization of ethylcellulose microparticles containing .l-alanyl- l-glutamine peptide

Context: The l-alanyl-l-glutamine peptide (AGP) has been effective to promote acute glycemia recovery during long-term insulin-induced hypoglycemia (IIH), and the oral administration of AGP is suggested to prevent prolonged hypoglycemia, such as nocturnal hypoglycemia.

Objective: Considering the ability of AGP on glycemia recovery and AGP’s fast metabolism, the aim of current study was to obtain and characterize ethylcellulose microparticles to deliver the drug for a prolonged time.

Materials and Methods: Microparticles were prepared by simple and double emulsification/hardening method and characterized by scanning electron microscopy, thermogravimetry (TG), differential scanning calorimetry (DSC), Fourier transform infra-red (FTIR) and FT-Raman spectroscopy and in vitro release.

Results and Discussion: Spherical structures with a mean diameter between 9.30?µm and 13.19?µm were formed. TG analysis showed that the thermal stability of AGP was even more increased by encapsulation with ethylcellulose. In addition, TG, DSC, FTIR and FT-Raman analyses proved that AGP was encapsulated in a molecular way. Higher values of encapsulation efficiency were observed for the microparticles prepared by double emulsification (57.83–83.67%) than for those prepared by simple emulsification (18.37%). However, the last ones could release the peptide in a quicker and more extensive manner than those prepared by double emulsification.

Conclusion: For the first time, microparticles containing AGP were developed and exhibited prolonged in vitro release as well as protection to the drug, and it could be considered as a dosage form for patients who suffer from insulin-induced hypoglycemia and/or nocturnal hypoglycemia.