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  • Patent Review: Preparation of Swellable and Deformable Microspheres

    United States Patent number 7,794,755 was issued on September 14, 2010, describing the process for preparation of swellable and deformable microspheres. The patent is assigned to E.I. du Pont de Nemours and cites Figuly, Mahajan, and Schiffino as inventors.

    A process for producing microspheres was developed that provides microspheres with new combined properties of high density, low fracture, high swell capacity, rapid swell, and deformability following swell. The process is reliable and high yielding, and makes use of a low temperature azo initiator and a small molecule chlorinated solvent as the organic phase. The microsphere preparation made using the process is particularly useful in medical treatments such as embolization.

    The patent describes a need for microspheres with properties that are advantageous for many types of applications, including medical applications. Microspheres with high density, yet a large capacity to swell in an aqueous environment, would be useful for absorption applications such as small-scale spill control and for delivery applications in which they would carry and release active ingredients such as fertilizers, herbicides, pesticides, cosmetics, shampoos, and medications. Microspheres with additional properties of durability and deformability would provide a valuable material for introduction into animals, including humans, for applications such as tissue augmentation, void filling, wound treatment, and embolization. Tissue augmentation involves introduction of materials in a collapsed area to provide a filling function, such as the treatment of scars or wrinkles. Void filling involves introduction of materials into an empty space, such as one created by removal of a tissue mass. Wound treatment involves introduction of materials to stop bleeding, provide padding, deliver medication, and absorb fluids. Such materials are useful especially in emergency situations including accidents and military operations. Embolization treatment involves the introduction of a material into the vasculature in order to block the blood flow in a particular region, and may be used to treat non-cancerous tumors, such as uterine fibroids, and cancerous tumors, as well as to control bleeding caused by conditions such as stomach ulcers, aneurysms, and injury. Blockage may be desired in the case of arteriovenous malformation (AVM), where abnormal connections occur between arteries and veins. Additionally, blockage may be desired for pre-surgical control of blood flow.

    The patented process makes use of a water soluble, low temperature-active azo initiator in an aqueous solution of monomer, crosslinking agent, and emulsifier. A chlorinated organic medium is used in forming a suspension with the aqueous solution. The aqueous solution and organic medium both additionally include protecting colloids. The aqueous solution and organic medium, as well as the mixture of the two, are initially held below the initiation temperature of the azo initiator. The organic medium, which may comprise a chloroform and methylene chloride mixture, should have a high enough boiling temperature that the aqueous soluble azo initiator can be activated to cause polymerization producing microspheres.

    A prevalence of the microspheres are in the size range of about 25 to about 250 microns in diameter, as seen when analyzing a small sample size of microspheres. A heterogeneous size mixture of microspheres may be separated into microsphere samples of specific size ranges, if desired, for specific applications. Microspheres may be separated by methods such as fluidized bed separation and custom sieving, also called screen filtering.

    The swell capacity (amount of water uptake) of microspheres prepared by the described process may vary depending on the amount of crosslinking agent added to the first solution. For example, crosslinking agent may be added in such an amount as to impart a swell capacity to the microspheres of about 50 grams of water per gram of microspheres, an amount to impart a swell capacity of about 70 grams per gram of microspheres, and alternatively an amount to impart a swell capacity of about 100 grams per gram of microspheres.

    An additional attribute of the microspheres prepared by the present process is the capacity to deform following swell. When placed under pressure, the swelled microspheres do not maintain their substantially spherical shape, but compress in the axis of the pressure and expand in the axis that is perpendicular to the pressure. Thus environmental factors, such as pressure of a flowing medium or from the walls of an enclosing container, may cause deformation of the microspheres. In addition, pressure of individual microspheres next to each other may cause deformation. This ability to deform is thought to be imparted and enhanced through the closed cell void structure of the microspheres.

    This ability to deform allows the microspheres to take on a shape of a containing space, and to fill that space. Additionally, deformed microspheres have increased surface area contact with each other, as compared to the contact area between spherical beads. The increased surface area contact between the deformed microspheres provides a more compact structure than is achievable with non-deforming spherical microspheres. This compact structure provides high resistance to penetration. The deformability is highly desirable in some applications such as in embolization treatment, where the deformed, compact microspheres may provide strong blockage at target vascular sites.

  • Motivations for Using Biodegradable Microspheres in Drug Delivery

    In recent years there is significant interest in using biodegradable polymeric microspheres for drug delivery. Delivering drugs through biodegradable microspheres has numerous advantages compared to conventional delivery systems. While in conventional systems the drug is usually released shortly after delivery and stops working after a brief period of time, biodegradable polymer offers a way to provide sustained release over a longer time, thus eliminating the need for multiple doses and ensuring sustained and controlled drug delivery over weeks or months. Continue reading “Motivations for Using Biodegradable Microspheres in Drug Delivery” »

  • Dual nanocomposite multihollow polymer microspheres prepared by suspension polymerization based on a multiple pickering emulsion

    Excerpts from an interesting approach to creating hollow polymer microspheres from a pickering emulsion.

    Abstract:

    A solid-stabilized multiple w/o/w or o/w/o emulsion was prepared in a two-step process. Various nanocomposite polymer microspheres with multihollow armored closed pores were fabricated easily by suspension polymerization of the multiple Pickering stabilized emulsions.

    Continue reading “Dual nanocomposite multihollow polymer microspheres prepared by suspension polymerization based on a multiple pickering emulsion” »

  • Chitosan microspheres prepared by spray drying

    Spray drying has been used in the production of fine powders from emulsions for many years, but it is not a process in which most people associate the production of microspheres.  This journal article shows how the authors were able to produce highly spherical microspheres in the 2-10um range by controlling the levels of Chitosan and crosslinking agents used.

    Chitosan MicrospheresThe key items I found of interest in this article were:

    The quality of the microspheres that were produced, as seen the the attached SEM micrograph.

    How the process variables did not affect the zeta potential of the microspheres produced (Table 4 below), and how the size can be varied by varying the concentrations of Chitosan or the Molecular weight (MW). Continue reading “Chitosan microspheres prepared by spray drying” »

  • Chitosan Coated PLGA-Microspheres – A Modular System for Targeted Drug Delivery

    During some research on PLGA microspheres we found this interesting article published in European Cells and Materials Vol 7 Suppl 2. 2004 (pages 11-12).   They were able to achieve a significant change in the zeta potential of their microspheres just by increasing the dosage of Chitosan.   The authors conclusions and a graph of their data follow.

    Discussion and Conclusions by the authors:

    The increase in zeta potential from –70.8 mV (chitosan-free PLGA particles) to +20.5 mV with increasing chitosan concentrations in the W2-phase used for particle preparation strongly suggests that the polycationic chitosan was firmly adsorbed to the particle surface. This finding was confirmed by X-ray photoelectron spectroscopy (data not shown). The coupling of biotin via a NHS-PEGlinker showed that the amino groups of  chitosan represent suitable sites for covalent bioconjugation of different ligands. The process allows the production of particles with a mean diameter between 1 and 10 um, a useful size range for the phagocytosis by  phagocytes like dendritic cells or macrophages. Continue reading “Chitosan Coated PLGA-Microspheres – A Modular System for Targeted Drug Delivery” »