Novel preparation approach with a 2-step process for spherical particles with high drug loading and controlled size distribution using melt granulation: MALCORE®

A novel approach for preparing drug-containing particles (DCPs) with controlled size distribution and high drug loading was developed using melt granulation. This approach comprises two steps. First, melting component adsorbed particles (MAs) were prepared by mixing and heating the melting components with a porous carrier using a high shear granulator. Second, DCPs were prepared by layering the drug on MAs using a fluidized bed rotor granulator. The time taken for both steps was within 30 min. Adding the polymer in the second step remarkably increased the viscosity of the mixture of melting components and the polymer. Therefore, DCPs could be successfully loaded with a high amount of drug (70% w/w). The particle size distribution of the DCPs was narrow, and it depended on that of the MAs. The flowability of the DCPs was excellent, and the sphericity was close to 1. A unique particle formulation mechanism was suggested based on the observation of DCPs using scanning electron microscopy. The manufacturing time and DCP characteristics were not affected by the manufacturing scale. In conclusion, we have successfully developed a highly efficient novel approach for preparing optimal DCPs through melt granulation, named “Melt Adsorption and Layering with Porosity Core” (MALCORE®).     

Direct ink writing of vancomycin-loaded polycaprolactone/ polyethylene oxide/ hydroxyapatite 3D scaffolds

Novel inks were formulated by dissolving polycaprolactone (PCL), a hydrophobic polymer, in organic solvent systems; polyethylene oxide (PEO) was incorporated to extend the range of hydrophilicity of the system. Hydroxyapatite (HAp) with a weight ratio of 55–85% was added to the polymer-based solution to mimic the material composition of natural bone tissue. The direct ink writing (DIW) technique was applied to extrude the formulated inks to fabricate the predesigned tissue scaffold structures; the influence of HAp concentration was investigated. The results indicate that in comparison to other inks containing HAp (55%, 75%, and 85%w/w), the ink containing 65% w/w HAp had faster ink recovery behavior; the fabricated scaffold had a rougher surface as well as better mechanical properties and wettability. It is noted that the 65% w/w HAp concentration is similar to the inorganic composition of natural bone tissue. The elastic modulus values of PCL/PEO/HAp scaffolds were in the range of 4–12 MPa; the values were dependent on the HAp concentration. Furthermore, vancomycin as a model drug was successfully encapsulated in the PCL/PEO/HAp composite scaffold for drug release applications. This paper presents novel drug-loaded PCL/PEO/HAp inks for 3D scaffold fabrication using the DIW printing technique for potential bone scaffold applications.     

Development of silver nanoparticles‐loaded calcium alginate beads embedded in gelatin scaffolds for use as wound dressings

Silver nanoparticles (AgNPs)‐loaded calcium alginate beads embedded in gelatin scaffolds were developed to sustain and maintain the release of silver (Ag⁺) ions over an extended time period. The UV irradiation technique was used to reduce Ag⁺ ions in alginate solution to AgNPs. The average sizes of AgNPs ranged between ca 20 and ca 22 nm. The AgNPs‐loaded calcium alginate beads were prepared by electrospraying of a sodium alginate solution containing AgNPs into calcium chloride (CaCl₂) solution. The AgNPs‐loaded calcium alginate beads were then embedded into gelatin scaffolds. The release characteristics of Ag⁺ ions from both the AgNPs‐loaded calcium alginate beads and the AgNPs‐loaded calcium alginate beads embedded in gelatin scaffolds were determined in either deionized water or phosphate buffer solution at 37 °C for 7 days. Moreover, the AgNPs‐loaded calcium alginate beads embedded in gelatin scaffolds were tested for their antibacterial activity and cytotoxicity. © 2014 Society of Chemical Industry     

Poly(4‐vinyl pyridine)‐grafted graphene oxide for drug delivery and antimicrobial applications

Graphene oxide (GO) was covalently functionalized with poly(4‐vinyl pyridine) (P4VP) by atom transfer radical polymerization for drug delivery and antimicrobial applications. The physiochemical properties, chemical structure, composition and morphology of the P4VP‐functionalized GO (GO‐P4VP) were studied. Simple physisorption of a cancer drug, camptothecin (CPT), via π ? π stacking and/or hydrophobic interactions on the GO‐P4VP was tested for drug loading and its release by altering the pH. The GO‐P4VP has low cytotoxicity, and the CPT‐loaded GO‐P4VP exhibited a high potency for killing cancer cells in vitro. Prominent antimicrobial properties against Escherichia coli and Staphylococcus aureus were also observed. Thus, the GO‐P4VP can be utilized as a drug delivery vector with high biocompatibility, solubility and stability in physiological solutions, a suitable payload capacity and excellent bacterial toxicity. Owing to its small size, low cost, large specific area, ready scalability and useful non‐covalent interactions, GO‐P4VP is a novel material for biomedical, industrial and environmental applications. © 2015 Society of Chemical Industry     

Preparation of antimicrobial polycarboxybetaine‐based hydrogels for studies of drug loading and release

A series of cationic poly(N‐isopropyl acrylamide) (PNIPAM)‐g‐poly(carboxybetaine ester) (PCBMAE) hydrogels were prepared by reversible addition–fragmentation chain‐transfer polymerization with PCBMAE precursors reacting with N‐isopropyl acrylamide in the presence of N,N′‐methylene bisacrylamide. These hydrogels exhibited excellent antimicrobial activities against Staphylococcus aureus and could switch to nontoxic zwitterionic hydrogels after hydrolysis. Nonionic tetracycline hydrochloride (TCHC) and anionic sodium salicylate (SA) were selected to evaluate the loading capacities and release kinetics of the cationic hydrogels. We found that the loading efficiencies of TCHC in the PNIPAM‐g‐PCBMAE hydrogels were approximately twice as high as those of SA. However, the cumulative release amount of TCHC was lower than that of SA from the corresponding cationic hydrogel at 37°C. In addition, the PNIPAM‐g‐PCBMAE hydrogels exhibited accelerated release rates of both TCHC and SA with increasing content of (2‐carboxymethyl)?3‐acryloxyethyldimethylammonium chloride methyl ester. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 39839.     

Antitumor efficacy of doxorubicin encapsulated within PEGylated poly(amidoamine) dendrimers

We report here a general approach to using poly(amidoamine) (PAMAM) dendrimers modified with polyethylene glycol (PEG) as a platform to encapsulate an anticancer drug doxorubicin (DOX) for in vitro cancer therapy applications. In this approach, PEGylated PAMAM dendrimers were synthesized by conjugating monomethoxypolyethylene glycol with carboxylic acid end group (mPEG‐COOH) onto the surface of generation 5 amine‐terminated PAMAM dendrimer (G5.NH₂), followed by acetylation of the remaining dendrimer terminal amines. By varying the molar ratios of mPEG‐COOH/G5.NH₂, G5.NHAc‐mPEG_n (n = 5, 10, 20, and 40, respectively) with different PEGylation degrees were obtained. We show that the PEGylated dendrimers are able to encapsulate DOX with approximately similar loading capacity regardless of the PEGylation degree. The formed dendrimer/DOX complexes are water soluble and stable. In vitro release studies show that DOX complexed with the PEGylated dendrimers can be released in a sustained manner. Further cell viability assay in conjunction with cell morphology observation demonstrates that the G5.NHAc‐mPEG_n/DOX complexes display effective antitumor activity, and the DOX molecules encapsulated within complexes can be internalized into the cell nucleus, similar to the free DOX drug. Findings from this study suggest that PEGylated dendrimers may be used as a general drug carrier to encapsulate various hydrophobic drugs for different therapeutic applications. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40358.     

Polyampholyte acrylic latexes for tablet coating applications

Polyampholyte latexes can exist within a certain pH range as low‐viscosity aqueous dispersions, while upon a pH shift to the vicinity of the isoelectric point they undergo ionic coacervation. Three classes of coacervation latexes were synthesized and evaluated for their suitability for use in tablet coating applications. Pharmaceutical tablet coatings are commonly based on hydroxypropyl methyl cellulose, poly(vinyl alcohol), and acrylic polymers. Because of the high viscosity of their aqueous solutions, and to the consequent required low concentrations of the tablet coating polymers in the coating solutions to enable sufficiently low viscosity for effective spray application, the current commercial pharmaceutical tablet coating technology requires the removal of large amounts of water during the manufacturing process. In this work, films prepared from high‐solids, low‐viscosity coacervated acrylic latexes showed good hardness, very low tackiness, an excellent combination of optical properties, and very low water vapor permeability. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40049.     

Microparticles based on hydrophobically modified chitosan as drug carriers

In this work, a hydrophobically modified (HM) chitosan derivative was prepared by covalent linkage of C₁₂ groups to the chitosan backbone. HM‐chitosan microparticles were prepared according to an emulsification‐solvent evaporation method and naltrexone (NTX) was used as a model drug. For comparison, unmodified chitosan and poly lactic‐co‐glycolic acid (PLGA) microparticles were also tested as carriers for NTX. HM‐chitosan formed viscous semi‐dilute solutions, suggesting a high level of chain entanglements and hydrophobic associations. HM‐chitosan microparticles generally showed higher production yield and encapsulation efficiency, as compared with chitosan and PLGA. The burst release shown by chitosan microparticles was significantly reduced when using the HM‐chitosan derivative. An enhanced control of drug release was observed over at least 50 days. PLGA particles demonstrated inferior controlled release properties as compared to HM‐chitosan subsequent to the initial release stage. These results revealed the potential of hydrophobic modification of chitosan as a means to improve the stability and sustained delivery properties of the polymer. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40055.     

Biomineralized hyaluronic acid/poly(vinylphosphonic acid) hydrogel for bone tissue regeneration

Novel biomineralized hydrogels composed of hyaluronic acid (HA) and vinyl phosphonic acid (VPAc) were designed with the aim of developing a biomimetic hydrogel system to improve bone regeneration by local delivery of a protein drug including bone morphogenetic proteins. We synthesized crosslinked hydrogels composed of methacrylated HA and poly(VPAc) [P(VPAc)], which serves as a binding site for calcium ions during the mineralization process. The HA/P(VPAc) hydrogels were biomineralized by a urea‐mediation method to create functional polymer hydrogels that can deliver the protein drug and mimic the bone extracellular matrix. The water content of the hydrogels was influenced by the HA/P(VPAc) composition, crosslinking density, biomineralization, and ionic strength of the swelling media. All HA/P(VPAc) hydrogels maintained more than 84% water content. Enzymatic degradation of HA/P(VPAc) hydrogels was dependent on the concentration of hyaluronidase and the crosslinking density of the polymer network within the hydrogel. In addition, the release behavior of bovine serum albumin from the HA/PVPAc hydrogels was mainly influenced by the drug loading content, water content, and biomineralization of the hydrogels. In a cytotoxicity study, the HA/P(VPAc) and biomineralized HA/P(VPAc) hydrogels did not significantly affect cell viability. These results suggest that biomineralized HA/P(VPAc) hydrogels can be tailored to create a biomimetic hydrogel system that promotes bone tissue repair and regeneration by local delivery of protein drugs. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 41194.     

Controlled delivery of growth‐hormone‐releasing peptide 6 from the poly(lactic‐co‐glycolic acid)–poly(ethylene glycol)–poly(lactic‐co‐glycolic acid) copolymer and the effect of a growth‐hormone‐releasing peptide 6–copolymer hydrogel on the growth of rex rabbits

Growth‐hormone‐releasing peptide 6 (GHRP‐6) plays an important role in animal growth. However, there have been few studies focusing on the effect of GHRP‐6 on animal growth through controlled release systems. We synthesized the poly(lactic‐co‐glycolic acid) (PLGA)–poly(ethylene glycol) (PEG)–PLGA copolymer to investigate its controlled released effect on GHRP‐6 in vitro and to study the effect of a GHRP‐6–copolymer hydrogel on the growth of rex rabbits. The copolymer was synthesized with ring‐opening copolymerization and characterized by ¹H‐NMR. The interaction between GHRP‐6 and the copolymer was characterized by Fourier transform infrared spectroscopy and X‐ray diffraction. The body weight, serum level of insulin‐like growth factor 1 (IGF‐1), and hair coat quality were studied in rex rabbits. The results show that hydrogen bonds formed between the N? H group in GHRP‐6 and the C?O group in the copolymer. The release mechanism of GHRP‐6 was a combination of a diffusion‐controlled mechanism and an erosion‐controlled mechanism in the copolymer. The serum level of IGF‐1, hair coat quality, and body weight were all significantly higher in the GHRP‐6–copolymer hydrogel group than in the other groups. These results indicate that the copolymer effectively controlled the release of GHRP‐6. In addition, the GHRP‐6–copolymer hydrogel increased the synthesis of IGF‐1 for a prolonged period and, thereby, increased the rex rabbits' growth and hair coat quality. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40185.