Current Research and Applications

Drug Delivery Systems        Bone Research        References

Drug Delivery Systems:

During the last two decades, significant progress has been made in the areaof drug delivery systems. Drug delivery in the future will requiresophisticated devices that are controlled, self-regulated, and canrelease drugs only at target sites. With the recent developments inmicro-encapsulation technology, HAP micro-spheres are being consideredfor drug delivery applications. HAP has the advantage of being bio-compatible, bio-resorbable and highly binding to a variety of molecules (e.g. proteins, enzymes, antibody fragments, nucleic acids, and some sub-classes of IgG). This has opened the potential for using HAP to deliver a large variety of drugs in many clinical applications.

A study of HAP implants for the treatment of bone infections was recentlyperformed in collaboration with Professor A. K. Dash from theDepartment of Pharmaceutical and Administrative Sciences at Creighton University. HAP micro-spheres containing ciprofloxacin were prepared by precipitation followed by a spray drying process. The drug load in the micro-spheres ranged from 0.25-2% (w/w). SEM, powder X-ray diffraction, and Differential Scanning Calorimetry showed that the surface morphology of the micro-spheres was rough and that the drug was present at a molecularly dispersed state in the HAP. Implants (5x8 mm) were made by pressing the powder into small cylinders. The mechanism of in vitro drug release from the implant was found to be controlled by diffusion in the matrix. For this set of experiments, complete release of the drug occurred within 10 hours (see Fig. 1). The release rate can be increased by increasing the concentration of the drug and decreased by introducing diffusion barriers in the implants. Further information on this study can be found in "Preparation and characterization of novel drug delivery implants for the treatment of bone infections", by H.H. Pham, P. Luo, F. Génin, and A. K. Dash, Proceedings of the AAPS Meeting (New Orleans, November 1999).

Figure 1: In vitro release of ciprofloxacin from HAP implants containing;() 2% (w/w),() 1% (w/w), and(•) 0.5% (w/w) of theoretical drug load.

Other examples of drug delivery systems:

  • Inhibitions of tumor growth and metastasis:
    Protein: Cis-diamminedichloroplatinum (CDDP)
    Carrier: HAP or TCP
    CDDP-HAP or CDDP-TCP can be directly implanted into tumors or sub-cutaneously.

  • Vitamin D supplements for neonatal vitamin D deficiency:
    Proteins: Serum 25-hydroxyvitamin D (calcidiol) and parathyroid hormone (PTH)
    Carrier: HAP or TCP with sodium hydroxide (NaOH).

Other examples of proteins and HAP:

  • Lysine
  • Antibiotic gentamicin sulfate (GS)
  • Carboplatin (CBDCA)
  • Glutaraldehyde treated bovine pericardium
  • Bovine serum albumin (BSA)
  • Native bone morphogenetic proteins (BMP)
  • 6-mercaptopurine (6-MP)
    Multi-protein combinations can be loaded to the HAP micro-spheres; their release rates can be tailored using the binding strength and the morphology of the spheres. This constitutes one of the important aspects in being able to control drug release ratesas accurately as possible.

Bone Research:

Calcium phosphate apatite (CPA) is known to be one of the most important implantable materials due to its biocompatibility. Natural bone is approximately 70% CPA including hydroxyapatite (HAP) by weight and 50% by volume. Organic substances (such as collagen) and water are the other constituents of bones. The CPA mineral is nanocrystalline with grains less than 50 nm. These nanocrystals are connected to each other to form the connective hard tissue, (i.e. the bone skeleton).

Bone is a complex structure with macro- and micro-pores. The pores are mostly interconnected to allow body fluid to carry nutrients and provide a medium where interfacial reactions between hard tissue and soft tissue can occur. Two types of bone structures have been described: cancellous and cortical structures. Cancellous bone differs from cortical bone in being open-spaced and trabecular. Since osteons average between 180 and 250 Ám in diameter and intercommunicate through Volksmann canals, the sizeof the interconnected pores have similar dimensions.

Implant materials must provide properties that are similar to that of bone. Currently, only natural materials have been selected as bone substitute for bone grafting surgery. These include auto- or allograft, bovine, and coral blocks. Although these materials can closely replicate the structure of human bone, they present a number of disadvantages. They are typically very brittle and experience significant loss of strength during sterilization. They also can cause inflammation problems and carry the potential for disease transmission.

To address these issues, our research is focussing in developing high strength synthetic biomaterials such as CPA and HAP ceramics. The ceramics are either sintered porous, or dense calcium-based mixtures (including HAP and TCP). Our research team recently completed an extensive characterization of the sintering behavior of our narrow size distribution powder. We also have completed a study of the phase transformations that can occur in our sintered micro-porous HAP. Our research team is now designinghigh strength three-dimensional cellular biomaterials.

References:

Ping Luo, Nan Liu, and Michael Thelen, "Protein binding potential of biocompatible ceramic hydroxyapatite micro-spheres", 24th Annual Meeting of the Society for Biomaterials, Vol. 21, 278 (1998).

Hai H. Pham, Ping Luo, François Génin, and Alekha K. Dash, " Preparation and characterization of hydroxyapatite microspheres containing ciprofloxacin", AAPS Annual Meeting, New Orleans, November 14-18 1999.

P. Luo, F. Y. Génin, and T. G. Nieh, Synthetic calcium phsophate-based skeletons, Proceedings of the Fifth World Biomaterials Congress, Toronto, 627 (1996).

Ping Luo, "Methods of Treating NuclearHydroxyapatite Materials", US Patent 5994609, Nov.1999

Ping Luo, "Method of Synthesizing HydroxyapatitePowders and Bulk Materials", US patent 5858318, Jan.1999


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