Emulsion technology for the development of novel Alginate-based composite materials for controlled drug delivery applications

Emulsions have been used for centuries in many fields, such as pharmaceutical, cosmetic, food, and agriculture industry. Manufacturers of pharmaceutical products have recently shown great attention for multifunctional products in which different active agents can be incorporated, and for controlled drug delivery systems. Emulsion technology is a very simple, inexpensive and easy-to-scale approach. This technique is characterized by high loading capacity and encapsulation efficiency for therapeutic agents, independently from their nature (hydrophobic or hydrophilic). On the other hand, the other advantage is related to the possibility to use emulsion technology, to combine materials with different physiochemical properties. The aim of my doctoral research was focused on the development of new polymeric Alginate-based composite materials for biomedical applications, specifically, controlled delivery systems for drugs or bioactive molecules. The idea was to use biocompatible and non-toxic polymers, both of synthetic and natural origin, to produce the above-mentioned constructs. Biopolymers are widely used as scaffolds for biomedical applications, especially in tissue engineering and drug delivery systems due to their excellent properties such as biocompatibility, biodegradability to non-toxic products and bioactivity. In these fields, the biopolymers have been processed in different forms such as films, sponges, beads, hydrogels and capsules. However, emulsions containing dissolved biopolymers both in the oil and water phases are very scarce. In this thesis, we demonstrate such an emulsion, in which the oil phase contains a hydrophobic biodegradable polymeric material and the water phase is constituted by a sodium alginate solution. Emulsion technology was the main technique employed for the fabrication of composite matrices, constituted of hydrophilic and hydrophobic polymers, and for the encapsulation of model drugs (single and dual delivery of hydrophilic and hydrophobic active principles). Low cost raw materials and facile methods of fabrication were considered, in order to contain the costs of production, and obtain functional bio-composites easily scalable in an industrial setting. More detailed description about emulsions will be discussed in Chapter 1. In the first part of the thesis, as will be discussed in Chapter 2, we used an emulsion solution casting process to fabricate sodium alginate-Mater-Bi\uae polymer films that can retain both hydrophilic (a cutaneous antiseptic) and lipophilic (curcumin) model drugs. The objective was to achieve a biodegradable and biocompatible material as active dressing to promote and accelerate skin wound healing. The obtained matrices have been characterized in terms of their physio-chemical properties and their ability to release these model drugs individually or simultaneously in vitro. The novelty in this research was to demonstrate, for the first time the possibility to use Mater-Bi\uae also in the biomedical field. In fact, this commercial hydrophobic biodegradable polymer composite comprising polycaprolactone (PCL) and thermoplastic starch, obtained by a proprietary compound extrusion method is actively marketed as sustainable food packaging material as well as biodegradable material for perishable food containers. In the second part of the thesis, as will be discussed in Chapter 3, calcium alginate-Beeswax microbeads have been fabricated by a solvent free emulsion gelation technique. The objective of this study was to formulate an all-natural oral-controlled delivery system for a natural hydrophilic compound, a concentrated extract from Prunus mahaleb L. fruit (here named as mcfe) rich in anthocyanins, optimizing its encapsulation and assessing in vitro its release under simulated gastrointestinal conditions. The obtained microbeads were investigated for their morphology and physico-chemical properties under the different pH conditions that characterize the gastrointestinal tract. The novelty in this research was to demonstrate, for the first time the possibility to use Beeswax as wall material, acting as retardant in drug release of phenolic compounds. Chapter 4 summarizes the conclusions made throughout this study and suggests the fulfilment of future works

Part I: Effect of Nanomicelle Size on Trans-scleral Permeability of Dexamethasone and Part II: Strategies to Minimize Octreotide Acylation during Sustained Release from Biodegradable Polymers

Title from PDF of title page, viewed on July 8, 2015Dissertation advisor: Ashim K. MitraVitaIncludes bibliographic references (pages 214-223)Thesis (Ph.D.)--School of Pharmacy and Department of Chemistry. University of Missouri--Kansas City, 2015Our primary aim was to determine the effect of nanomicelle size on dexamethasone (DEX) transport across the sclera. Nanomicelles of various sizes were developed and characterized. Low molecular weight diblock co-polymers, mPEG₇₅₀-PCL₇₀₀ (DB1), mPEG₂₀₀₀-PCL₁₅₀₀ (DB2) and mPEG₅₀₀₀-PCL₄₀₀₀ (DB3) were synthesized by ring opening polymerization. Polymers were characterized by H¹ NMR (structure), gel permeation chromatography (molecular weights and polydispersity), critical micelle concentration (CMC) and in vitro cytotoxicity studies in corneal, conjunctival and retinal cell-lines. Newly synthesized polymers were purified and characterized for their structure and molecular weights by H¹-NMR and GPC, respectively. The CMCs were found to be 0.13, 4.48 and 6.04 μg/mL for DB1, DB2 and DB3, respectively. In order to understand the factors and interactions influencing drug solubilization in micelle core, an exploratory 2-factors 3-level response surface methodology was generated using SAS 9.02 (exploratory model). The independent factors were polymer amount (X1) and DEX amount (X2). Solubility of DEX in micelle solution was taken as response variable (Y). Micelle preparation method was modified based on the results obtained from exploratory model. The optimal drug:polymer ratio was identified by another response surface design (optimization model) to achieve DEX solubility of 1mg/mL for all the nanomicellar formulations. The optimized formulation was characterized for solubility of DEX, micelle size and polydispersity, morphology, in vitro release and in vitro transport across conjunctival cell line. Nanomicellar formulations iv (referred to as DEXM) containing >1mg/mL DEX were developed for all three polymers using design of experiment. The optimized nanomicelle formulation exhibited mean size in range of 10nm, 30nm and 60nm with unimodal size distribution and low polydispersity for DB1, DB2 and DB3 polymers, respectively. The formulation was also subjected to ex vivo transport across excised rabbit sclera to determine influence of micelle size on DEX transport across the static barrier. DEX permeability across the excised rabbit sclera for DEXM and DEX suspension (control) were found to be 2.7x10⁻⁶, 3.0x10⁻⁶, 1.5x10⁻⁶ and 1.2x10⁻⁶ cm/sec, respectively. There were 2.2, 2.5 and 1.3-fold increase in DEX permeability with nanomicelles of mean sizes 10 nm, 25 nm and 60 nm, respectively. The permeability studies across the sclera, static barrier, indicates that the nanomicelles with average sizes 10nm and 30nm may have potential to deliver therapeutic agents to the back of the eye following topical administration. Therefore, nanomicellar formulation may provide therapeutic levels in the back of the eye following topical administration.Literature review -- Hypothesis and rationale -- Polymer synthesis and characterization -- Preparation and optimization of dex-loaded nanomicelles of mean size 30nm using DB2 polymers -- Development of dex-loaded nanomicelles of mean size 60nm using DB3 polymer -- Effect of nanomicelle size on permeability -- Summary and recommendations -- Literature review: sustained protein and peptide delivery -- Statement of problem, hypothesis and objectives -- Extended release formulation of octreotide: simultaneous diffusion and acylation of peptide -- Reversible hydrophobic ion-paring complexation to minimize acylation of octreotide during long-term delivery from plga microparticles -- Summary and recommendation

Functional Polymers for Controlled Drug Release

This Special Issue focuses on the synthesis and characterization of hydrogels specifically used as carriers of biological molecules for pharmaceutical and biomedical employments. Pharmaceutical applications of hydrophilic materials has emerged as one of the most significant trends in the area of nanotechnology. To propose some of the latest findings in this field, each contribution involves an in-depth analysis including different starting materials and their physico-chemical and biological properties with the aim of synthetizing high-performing devices for specific use. In this context, intelligent polymeric devices able to be morphologically modified in response to an internal or external stimulus, such as pH or temperature, have been actively pursued. In general, hydrophilic polymeric materials lead to high in vitro and/or in vivo therapeutic efficacy, with programmed site-specific feature showing remarkable potential for targeted therapy. This Special Issue serves to highlight and capture the contemporary progress in this field. Relevant resources and people to approach - American Association Pharmaceutical Scientists (AAPS): web: www.aaps.org; email: (marketing division): [email protected]; (mmeting division): [email protected] - International Association for Pharmaceutical Technology (APV): web: apv-mainz.de; email (managing director)

Relatório de estágio em investigação na Bluepharma Indústria Farmacêutica, S.A.

This report intends to describe the work developed during the internship at Bluepharma Indústria Farmacêutica, S.A., in Research and Innovation sector. The first aim of this internship was to complete a review about long-acting injectables (LAI) and their characterization, as well as in vitro release. Thus, an overview of LAIs, their characterization methods, including in vitro release methods, possible membranes or barriers, and biorelevant characteristics is presented. The second aim was to support the development of the most appropriate methodology for assessing the release profile of LAI technology with an extended release of at least 96 hours develop internally. So, a description of developed activities is stated, presenting the rationale behind the choice of the method, the analytical development of the HPLC-PDA method to quantification of the drug substance (DS) and its pre-validation according to the authorities guidelines. Although the analytical method is already studied, the formulation development was not completed until the end of the internship, whereby the analytical method as well as the chosen method (including apparatus, barrier, ect.) to assess the in vitro release could need optimization with the final drug product.Este relatório pretende descrever o trabalho desenvolvido durante o estágio na Bluepharma Indústria Farmacêutica, S.A., no setor de Investigação e Inovação. O primeiro objetivo deste estágio consistia em realizar uma revisão da literatura sobre os injetáveis de ação prolongada (LAI) e a sua caracterização, incluindo testes de liberação in vitro. Assim, é apresentada uma visão geral sobre os LAI, os seus métodos de caracterização, incluindo métodos de libertação in vitro, possíveis membranas ou barreiras usadas e características biorelevantes aplicáveis ao estudo. O segundo objetivo envolvia o apoio ao desenvolvimento de uma metodologia adequada para avaliar o perfil de libertação de uma tecnologia LAI com libertação prolongada de pelo menos 96 horas desenvolvida internamente. Assim, na segunda parte do relatório é apresentada uma descrição das atividades desenvolvidas, expondo o racional para a escolha do método, o desenvolvimento analítico do método HPLC-PDA para quantificação do princípio ativo (DS) e sua pré-validação de acordo com as diretrizes das autoridades. Embora o método analítico já tenha sido estudado, o desenvolvimento da formulação não tinha sido concluído até o término do estágio, pelo que o método analítico, bem como o método escolhido para determinação do perfil de libertação in vitro (incluindo apparatus, barreira, etc.) podem necessitar de otimização com o produto final.Mestrado em Bioquímic

Alginate: Enhancement Strategies for Advanced Applications

Alginate is an excellent biodegradable and renewable material that is already used for a broad range of industrial applications, including advanced fields, such as biomedicine and bioengineering, due to its excellent biodegradable and biocompatible properties. This biopolymer can be produced from brown algae or a microorganism culture. This review presents the principles, chemical structures, gelation properties, chemical interactions, production, sterilization, purification, types, and alginate-based hydrogels developed so far. We present all of the advanced strategies used to remarkably enhance this biopolymer’s physicochemical and biological characteristics in various forms, such as injectable gels, fibers, films, hydrogels, and scaffolds. Thus, we present here all of the material engineering enhancement approaches achieved so far in this biopolymer in terms of mechanical reinforcement, thermal and electrical performance, wettability, water sorption and diffusion, antimicrobial activity, in vivo and in vitro biological behavior, including toxicity, cell adhesion, proliferation, and differentiation, immunological response, biodegradation, porosity, and its use as scaffolds for tissue engineering applications. These improvements to overcome the drawbacks of the alginate biopolymer could exponentially increase the significant number of alginate applications that go from the paper industry to the bioprinting of organs

Modified acrylamide hydrogel nanocomposites for varginal drug delivery system

This study conducted on the structure of modified acrylamide-based hydrogel by synthesizing the nano composites. The hydrogels employed in this study were provided through a combination of acrylamide monomers, montmorillonite clay, Sodium carboxymethylcellulose (NaCMC) and magnesium oxide (MgO) nanoparticles by crosslinking polymerization. N, N, N’, N’-tetramethyl ethylenediamine and ammonium persulfate as the initiator were applied in the structure of the polymer. In addition, the total of the polymerization and characterization were utilized based on three types of hydrogels which are acrylamide (Aam), Aam/NaCMC and Aam/NaCMC/MgO hydrogels. The properties of surface morphology of the hydrogels were characterized by swelling ratio, field emission scanning electron microscope (FESEM), texture analysis, x-ray diffraction and Fourier transform infrared spectroscopy (FTIR). Findings of the study considered the nano composites consisting of MgO have the highest swelling ratio and gel strength compared to Aam and Aam/NaCMC hydrogels. Thus, MgO is an appropriate nanoparticle to be used in the nano composites. The role of NaCMC was also studied in the swelling and consequently in drug release. The systems were characterized regarding rheological behavior of hydrogel, FTIR, and FESEM. The dispersion of the nanoparticles MgO and drug (acyclovir) inside the hydrogel was shown by transmission electron microscopy. Acyclovir, one of the famous drugs to treat the vaginal infections, was used as the drug for delivery and release in the vagina conditions. It was loaded into the polymer through the soaking method in an aqueous solution contained acyclovir. The drug release was studied in two different mediums, phosphate-buffer saline (PBS) (pH 7.4) and vaginal fluid simulant (SVF) (pH 4.5) aqueous solutions were utilized. The amount of released drug from the hydrogels was determined using high performance liquid chromatography. The best amount of NaCMC and MgO used in this study was 0.2 g and 0.01 g at pH 6, respectively. The aggregate percentage of released acyclovir diversed between 89.7% and 35.1% in SVF and 76.41% and 22.24% in PBS. In this study, the 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay test showed that the acrylamide-based hydrogel demonstrated a cytotoxicity effect at 12.5, 25,50, 100 and 200 mg/ml concentrations