Pharmaceutical Investigation

Meeting the unmet: from traditional to cutting-edge techniques for poly lactide and poly lactide-co-glycolide microparticle manufacturing Abstract Background Polylactides (PLA) and poly lactide-co-glycolides (PLGA) undoubtedly are among the major drivers in the pharmaceutical market. Their relevance in pharmaceutics and biomedicine is well established in light of their sustainability, safety, tunable biodegradability, and versatility. However, polymer degradability and plasticity can somehow restrain industrial developability of PLA and PLGA formulations, especially in the form of microparticles (MP). Area covered This review wants to deal with the known manufacturing issues of PLA/PLGA MP, debating the potential contribution of modern and cutting-edge manufacturing technologies to the solution of unmet production needs. Technological and regulatory aspects will be considered outlining the potential role of advanced manufacturing techniques in the advancement of PLA/PLGA MP production processes. Expert opinion The multifaceted complexity of PLA/PLGA MP manufacturing processes demands adequate standardization and updated guidelines covering the so far unmet industrialization requirements. Novel and evolving manufacturing technologies will surely support the future development of bench-to-production plant transfer for such products. Careful evaluation of production costs is demanded in order to ensure process sustainability and patient's outreach.

Poly(lactic acid)/poly(lactic-co-glycolic acid)-based microparticles: an overview Abstract Background Poly(glycolic acid), poly(lactic acid) and poly(lactic-co-glycolic acid) were approved by the United States Food and Drug Administration (FDA) in the 1970s as materials for the manufacturing of bioresorbable surgical sutures, but soon became the reference materials for the preparation of sustained release formulations, especially injectable microparticles. Since the 1986 approval of Decapeptyl® SR, the first product based on PLGA microspheres, more than 15 such products have been approved for clinical use. Area covered This article highlights the key steps that brought to the development of injectable poly(lactic acid)/poly(lactic-co-glycolic acid) microparticles for the sustained release of active pharmaceutical ingredients. After a brief history of some pioneering works that opened the field of controlled drug delivery, the key steps that led to the development of these polymers and the approval of the first microparticle-based medicinal products are reviewed. Finally, the general characteristics of these polymers are described and the classical preparation method is explained. Expert opinion Poly(lactic acid)/poly(lactic-co-glycolic acid) microparticles are among the most successful drug delivery systems. The recent approval of new medicinal products based on PLGA microspheres is the proof that pharmaceutical companies have continued to exploit this drug delivery technology. The possible development of generics and the continuous discovery of therapeutic peptides will hopefully further the success of microsphere technology.

Liposomal itraconazole formulation for the treatment of glioblastoma using inclusion complex with HP-β-CD Abstract Purpose Itraconazole, which has been widely used as an antifungal-agent, is revisited as an anticancer drug but its low solubility still remains a major hurdle. Methods Inclusion complex was used to enhance the solubility of itraconazole, followed by encapsulating into liposome for glioblastoma. Results Itraconazole-inclusion complex was well formed at 1:1, 1:2 and 1:3 molar ratios of itraconazole: hydroxypropyl-β-cyclodextrin (HP-β-CD) as determined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR) analyses. Itraconazole-HP-β-CD inclusion complex was then encapsulated in liposome and its size was 120.5 ± 53.1 nm in diameter with 50% encapsulation efficiency. Stem cell-like property, as determined by the population ratio of CD90+/CD133+, was decreased from 3.38 to 1.46% when the U87-MG-TL cells were treated with 100 µM itraconazole/HP-β-CD-loaded liposome. Anti-proliferative effect of itraconazole/HP-β-CD-loaded liposome on U87-MG-TL cells was slightly better than that of free itraconazole (IC50 of 17 µM vs. 26 µM). Moreover, anti-proliferative effect of Itraconazole/HP-β-CD-loaded liposome on U87-MG-TL cells was higher than that of free itraconazole when the cells were co-treated with temozolomide (IC50 of 1.58 mM vs. 2.35 mM). Conclusions Therefore, itraconazole/HP-β-CD-loaded liposomal formulation could serve as a promising strategy for targeting the glioblastoma multiforme.

Long acting injectable formulations: the state of the arts and challenges of poly(lactic-co-glycolic acid) microsphere, hydrogel, organogel and liquid crystal Abstract Background Long-acting injectable formulations (LAIFs) have received substantial attention recently due to their advantages over conventional formulations, including easy administration, continuous and controlled release of drug over months, and the ability to maintain drug concentrations within the therapeutic range. The constant advances in biotechnology produce complex active pharmaceuticals that might be difficult to administer by conventional means. In particular, peptides, proteins, and antibodies are hard to administer orally given their physicochemical instability in the gastrointestinal tract and short half lives in blood. Therefore, LAIFs are a good candidate delivery system for such drugs. LAIFs reduce the frequency of application and improve patient compliance. For instance, LAIF-based antipsychotics can be more effective in patients with bipolar disorder and schizoaffective disorder. Area covered This review provides an overview of the various drug delivery technologies using LAIFs. Poly (lactic-co-glycolic acid) microspheres, hydrogels, organogels, and liquid crystals were chosen as representative LAIFs, and their preparation methods, advantages, limitations, challenges, and prospects are discussed. Expert opinion LAIFs are an attractive delivery system for bio-macromolecules that might participate in the new drug paradigm in the future. While each LAIF-based delivery technology has its own unique advantages, there are still some limitations that need to be overcome, and studies are being performed to understand and address these limitations.

PEGylated polylactide (PLA) and poly (lactic-co-glycolic acid) (PLGA) copolymers for the design of drug delivery systems Abstract Background PEGylated polylactide (PLA) and poly (lactic-co-glycolic acid) (PLGA) copolymers are biodegradable polyesters, widely employed in the last decades for the design of drug delivery systems such as polymeric hydrogels and nanocarriers (e.g. micelles and nanoparticles). The coupling with polyethylene glycol (PEG) offers some advantages with the respect to PLA and PLGA, including a higher hydrophilicity and a prolonged retention time for nanoparticulate systems, as well as the possibility of preparing thermoresponsive hydrogels. A large variety of pharmacologically active-compounds (small molecules, natural compounds or biomolecules such as proteins, peptides, oligonucleotides) has been formulated and delivered through PEGylated PLA or PLGA copolymers. Due to the high number of papers recently published about the use of these biodegradable copolymers in drug delivery, PEGylated PLA or PLGA copolymers are being still attractive. Their potential applications have been also broadened by the developing of ligand-functionalized copolymers, enabling an "active drug targeting" for nanoparticulate systems. Area covered The present review summarizes the recent advances in drug delivery systems based on PEGylated PLA or PLGA copolymers, focusing on self-assembled micelles and thermoresponsive hydrogels as well as nanoparticles. A particular consideration has been given to functionalized PEGylated PLA/PLGA nanoparticles for active drug delivery. Expert opinion Further advances in the design of PEGylated PLA/PLGA delivery systems will be beneficial for an improved drug release and targeting in the light of novel personalised therapeutic strategies.

Poly(lactic acid)/poly(lactic-co-glycolic acid) particulate carriers for pulmonary drug delivery Abstract Background Pulmonary route is an attractive target for both systemic and local drug delivery, with the advantages of a large surface area, rich blood supply, and absence of first-pass metabolism. Numerous polymeric micro/nanoparticles have been designed and studied for controlled and targeted drug delivery to the lung. Area covered Among the natural and synthetic polymers for polymeric particles, poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) have been widely used for the delivery of anti-cancer agents, anti-inflammatory drugs, vaccines, peptides, and proteins because of their highly biocompatible and biodegradable properties. This review focuses on the characteristics of PLA/PLGA particles as carriers of drugs for efficient delivery to the lung. Furthermore, the manufacturing techniques of the polymeric particles, and their applications for inhalation therapy were discussed. Expert opinion Compared to other carriers including liposomes, PLA/PLGA particles present a high structural integrity providing enhanced stability, higher drug loading, and prolonged drug release. Adequately designed and engineered polymeric particles can contribute to a desirable pulmonary drug delivery characterized by a sustained drug release, prolonged drug action, reduction in the therapeutic dose, and improved patient compliance.

Biocompatibility, biodegradation and biomedical applications of poly(lactic acid)/poly(lactic-co-glycolic acid) micro and nanoparticles Abstract Background Poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) are among the well-documented FDA-approved polymers used for the preparation of safe and effective vaccine, drug and gene delivery systems using well-described reproducible methods of fabrication. Various nano and microparticulates are fabricated using these polymers. Their successful performance relies on PLA and PLGA biocompatibility and degradability characteristics. Area covered This review provides an overview of the biocompatibility and biodegradation of PLA, PLGA and their copolymers, with a special emphasis on tissue responses for these polymers as well as their degradation pathways and drug release models. Moreover, the potential of PLA and PLGA based nano and microparticulates in various advanced biomedical applications is highlighted. Expert opinion PLA and PLGA based delivery systems show promises of releasing different drugs, proteins and nucleic acids in a stable and controlled manner and greatly ameliorating their therapeutic efficacy. In addition, advancement in surface modification and targeting of nanoparticles has extended the scope of their utility.

PLA/PLGA nanoparticles prepared by nano spray drying Abstract Background Spray drying is a relatively simple, fast, reproducible and scalable drying technology that is suitable for drying heat-sensitive biopharmaceutical compounds. In view of the rapid progress of nanoencapsulation technologies in the pharmaceutical sector, nano spray drying is used in research to improve the powder formulation and release of active ingredients. The Nano Spray Dryer B-90 of the Swiss company Büchi Labortechnik AG extends the size of the powder particles produced into the nanometer scale with narrow size distributions and high encapsulation efficiency. Area covered This study explains the special nano spray drying technology and discusses the influence of the respective process parameters on the powder properties. Applications of nano spray drying for the formulation and encapsulation of active ingredients in PLA/PLGA biopolymers are investigated and discussed. Optimized process parameters for the application of nano spray drying of similar substances are presented. Expert opinion The analyzed studies show the possibility of producing PLGA particles from approx. 2 μm to below 200 nm by nano spray drying, as well as the encapsulation of various active ingredients in spherical particles and nano-in-nanoparticle composite structures made of PLGA polymers for controlled drug delivery systems. The researched applications are primarily in the therapeutic field, such as the treatment of inhalation diseases, inflammations, cancer, immune diseases, genetic disorders, the regulation of vasodilatation or the surface coating of medical implants with biocompatible PLGA nanoparticles.

Towards the production of monodisperse gelatin nanoparticles by modified one step desolvation technique Abstract Purpose The aim of the present study was to prepare gelatin nanoparticles (GNPs) using modified one step desolvation method to obtain small, uniformly sized, and spherical GNPs. Methods The modifications involved the preparation of high molecular weight gelatin (HMWG) by fractionation of gelatin. HMWG was freeze-dried to be used in a specified concentration for preparation of GNPs with controllable properties. Furthermore, HMWG was cationized by dissolving it in acidified deionized water at pH value less than its isoelectric point. Factorial design analysis was utilized to investigate the effect of different preparation variables (viz. HMWG concentration, pH and ratio of HMWG solution volume to non-solvent volume) on particle size, polydispersity index (PDI), zeta potential and yield of GNPs. Results Results revealed the formation of monodisperse GNPs with small particle size, low PDI values (< 0.2) and high yield. FT-IR spectroscopy and differential scanning calorimetry studies revealed that the conformational structure of HMWG chains was altered within GNPs matrices. Conclusion The suggested modifications introduced on the one-step desolvation method enable to prepare successfully monodispersed GNPs with narrow size distribution and high particle yield.

Application of diethylene glycol monoethyl ether in solubilization of poorly water-soluble drugs Abstract Background Diethylene glycol monoethyl ether (DEGEE) is produced via the O-alkylation of ethanol with two ethylene oxide units, followed by distillation. It has a long history of safe use in food and personal-care products, and is used as an effective strong solubilizer in oral, topical, transdermal, and injectable human and veterinary pharmaceutical products. It has been used as a pharmaceutical solvent for many years under the trade name transcutol. DEGEE, a hydroalcoholic solvent, is gaining interest as a penetration/permeation enhancer, solubilizer, and surfactant for drug delivery systems. Area covered The physicochemical properties of DEGEE, the solubility data for drugs in DEGEE or DEGEE-water mixtures, and the applications of DEGEE in the solubilization of poorly water-soluble drugs are summarized in this review. Expert opinion DEGEE is a promising excipient as a solubilizer for many pharmaceutical products with enhanced drug absorption via oral, parenteral, and topical administration, as well as cosmetic products.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
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6948891480

alsfakia@gmail.com