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Bioceramics, towards nano-enabled drug delivery: A mini review Article in Trends in Biomaterials and Artificial Organs · January 2005
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Trends Biomater. Artif. Organs, Bioceramics, Vol 19(1), pp Towards 7-11 (2005) Nano-enabled Drug Delivery: A Mini Review
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Bioceramics, Towards Nano-enabled Drug Delivery: A Mini Review Willi Paul, Chandra P. Sharma* Division of Biosurface Technology, Biomedical Technology Wing Sree Chitra Tirunal Institute for Medical Sciences & Technology Poojappura, Trivandrum 695012 *
[email protected]
Introduction The word ceramic can be traced back to the Greek term keramos, meaning "a potter" or "pottery." Keramos in turn is related to an older Sanskrit root meaning "to burn." Thus the early Greeks used the term to mean "burned stuff" or "burned earth" when referring to products obtained through the action of fire upon earthy materials (1). "Ceramics" is defined in the Encyclopedia BRITANICA as "objects created from such naturally occurring raw materials as clay minerals and quartz sand, by shaping the material and then hardening it by firing at high temperatures to make the object stronger, harder, and less permeable to fluids". This broad classification includes structural clay products, whitewares, refractories, glasses, abrasives, cements and advanced ceramics which further divide into more specific classes, from dinnerware to the NASA's reusable, lightweight, ceramic tile for space shuttle program.
classified as bioceramics include Alumina, Zirconia, Calcium phosphates, Silica based glasses or glass ceramics and Pyrolytic carbons. Alumina and Zirconia are chemically inert and hard with an ability to be polished to a high surface finish. Therefore it is an ideal material for an articulating surface in hip and knee joints. Alumina is also used in dental crowns, cochlear implants, maxillofacial applications and as a scaffold for bone ingrowth. Zirconia is used in artificial knee, bone screws and plates, and as femoral heads. Figure 1 shows a commercial product made of aluminium oxide and zirconium oxide.
Bioceramics Bioceramics are a class of advanced ceramics which are defined as ceramic products or components employed in medical and dental applications, mainly as implants and replacements. They are biocompatible, and can be inert, bioactive and degradable in physiological environment which makes it an ideal biomaterial. However, it is brittle with poor tensile strength which makes it unsuitable for load bearing applications. Materials that are
Figure 1: BIOLOX ® delta used as femoral components for knee endoprostheses (2)
Pyrolytic carbon is mainly used as an artificial heart valve material because of its good strength, wear resistance and durability, and most importantly, thromboresistance or the ability to resist blood clotting. It is also used in orthopedics for small joints such as fingers and spinal inserts. Figure 2 shows its application in small joints.
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Willi Paul, Chandra P.Sharma
Figure 2: Pyrolytic carbon used for arthroplasty of finger joints
Calcium phosphates include tricalcium phosphates, hydroxyapatite and tetracalcium phosphates. Hydroxyapatite found in bone is a poorly crystalline non stotiometric apatite formed by nanosized needle like crystals. Unlike tetracalcium phosphates and tricalcium phosphates, hydroxyapatite does not break down under physiological conditions. In fact, it is thermodynamically stable at physiological pH and actively takes part in bone bonding, forming strong chemical bonds with surrounding bone. This property has been exploited for rapid bone repair after major trauma or surgery. Hydroxyapatite can be termed bioactive and tricalcium phosphate as bioresorbable. Bioinert materials form a fibrous capsule around the implant. Bioactive materials on the other hand form an interfacial bond with the implant, whereas bioresorbable materials will be replaced with the new tissue as the implant dissolved. Some of the bioceramic based bone graft materials include Norian SRS (3), ProOsteon (Interpore Cross International, Inc), Osteoset (4), Orthogran and Periobone-G (5). Dental and medical applications of commercial ceramics or ceramic based composites include: repair of bony defects, repair of
periodontal defects, maintenance or augmentation of alveolar ridge, ear implant, eye implant, spine fusion, adjuvant to uncoated implants etc. Since these ceramics are biocompatible, resorbable and porous, attempts have been made to utilize them as delivery systems for drugs, chemicals and biologicals. Bajpai and coworkers have initiated studies on ceramic drug delivery in early 80's by the introduction of alumino calcium phosphorous oxide (ALCAP) ceramic capsules (6,7). Low cost, ease of manufacture and biocompatibility makes ceramic materials a good candidate for drug delivery applications (8). ALCAP, HA and TCP ceramic capsules has been studied for the delivery of steroids, drugs like azidothymidine, epinephrine, anticancer drugs and antibiotics. Zinc Calcium Phosphorous Oxide Ceramic (ZCAP) has been investigated as implantable insulin delivery system for diabetes patients. An attempt has also been made by our group to develop ceramic drug delivery devices based on porous hydroxyapatite microspheres (9). Since hydroxyapatite is biocompatible and is used as a matrix for the purification of proteins, these microspheres could be utilized for protein and peptide drug delivery applications. When these microspheres loaded with albumin (as a model drug) and coated with poly lactic acid was studied in vitro, the drug released for over a period of 60 days. The same system when studied with ampicillin showed sustained release for a period of 15 days (10). These hydroxyapatite microspheres were loaded with gentamycin and made into a plastic composite using sodium alginate, and compressed into cylinders at low pressure (11). Although the release of drug was only for a period of 7 days, this system could be applied as an infection resistant plastic composite for bone filler applications. Antibacterial property of gentamycin loaded porous hydroxyapatite granules (coated with PLGA) were studied in vitro by modified Kirby-Bauer diffusion method. The released antibiotic was effective in inhibiting growth of S.aureus up to day 5 and the growth of E.coli upto only day 3 as seen from the zone of inhibition (unpublished work). Insulin loaded hydroxyapatite microspheres (coated with polyethylene vinyl alcohol) was
Bioceramics, Towards Nano-enabled Drug Delivery: A Mini Review
implanted in induced diabetic rats and the glucose level dropped to normal levels for 48 hours (12). Nanotechnology in Drug Delivery In recent years research efforts worldwide are developing nanoproducts aimed at improving health care and advancing medical research. Biomedical applications of nanotechnology are mainly suited for diagnostic techniques, nano drugs and delivery systems, and biomedical implants. Many industries are developing nanotechnology based applications for anticancer drugs, implanted insulin pumps, and gene therapy. Prostheses and implants are being developed from nanostructured materials. Carbon nanotubes and nanospheres have been studied as drug delivery vehicles as their nanometer size enables them to move easily inside the body. The drug can either be inserted in the nanotube or attached to the particle surface. It has been reported that a nanoparticle albumin-bound paclitaxel (ABRAXANE) demonstrates superior efficacy Vs taxol in a phase III clinical trial. It is a 130nm sized protein stabilized nanoparticle (13). The global drug delivery products and services market is projected to surpass US$67 billion in 2009. According to the report from NanoMarkets
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(14) nanotechnology-enabled drug delivery systems will generate over $1.7 billion ($US) in 2009 and over $4.8 billion in 2012. Nanoenabled polymeric drug delivery is projected as the single largest market opportunity. Reformulations will be possible with the nanoenabled drug delivery systems which help in protecting the patent holders. With NanoCrystal technology, Elan Pharmaceuticls has developed delivery systems for several drugs. Orally Disintegrating Tablet (ODT) dosage form is designed to disintegrate rapidly in the oral cavity, allowing patients to overcome the problems of swallowing cumbersome dosage forms, which discourages many from taking their medication. In essence, therefore, the ODT dosage form combines the ease-of-use of a liquid formulation with the convenience of a solid oral dosage form. The NanoCrystal particles (figure 3) of the drug are stabilized against agglomeration by surface adsorption of selected GRAS (Generally Regarded As Safe) stabilizers and is an aqueous dispersion of the drug substance that behaves like a solution-a NanoCrystal colloidal dispersion, which can be processed into finished dosage forms for all routes of administration.
Figure 3: NanoCrystal technology of Elan Pharmaceuticals
Willi Paul, Chandra P.Sharma
Because nanotechnology focuses on the very small, it is uniquely suited to creating systems that can better deliver drugs to tiny areas within the body. Nano-enabled drug delivery also makes it possible for drugs to permeate through cell walls, which is of critical importance to the expected growth of genetic medicine over the next few years. We have attempted to develop nanoparticles based on calcium phosphates for delivering insulin orally (15). Calcium phosphates have been approved for human use in several European countries as adjuvant. Zinc is being used for stabilizing insulin (long acting insulins). Therefore zinc phosphates and zinc calcium phosphates may be suitable candidates for developing ceramic based insulin delivery systems. Nanoparticles of zinc phosphate, zinc calcium phosphate, zinc calcium magnesium phosphate has been developed with a particle size of 300 - 800 nm. Efforts are being done to reduce its size to less than 100 nm. Oral cavity delivery is condidered to be the most desirable way of delivering drugs from patient compliance point-of-view. This will be the case with insulin also once an oral formulation has been developed. Delivered insulin in case of microspheres follows the pathway as naturally produced insulin by the pancreas - i.e. reaches directly to portal circulation and to liver, consistent with normal physiology. However, in the case of nanoparticles the absorption of nanoparticles takes place via Peyer's patches region, reaches lymphatic system, bypasses the first pass metabolism (bypasses liver: degradation of insulin is significantly reduced) and particles will be degraded and delivers the insulin in the blood stream. Concept of oral delivery of insulin utilising zinc phosphate nanoparticles seems to be promising since insulin will also be stable along with zinc.
Figure 4 shows the in vitro release kinetics of insulin from polymer coated insulin loaded ceramic nanoparticles (16,17). BioSante Pharmaceuticals, a US based company has developed calcium phosphate nanoparticles and have successfully passed the first stage of toxicity studies for administration orally, into muscles, under the skin and into the lungs by inhalation. It has been used for vaccine adjuvant and for protein delivery. Pre-clinical trials of both BioOral and BioAir indicate sustained delivery of insulin with sustained control of glucose levels. Similar formulations may be used for the delivery of other proteins, for example, human growth hormone orally or to the lungs. 6
5 Amount Released IU/100mg
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Figure 4: Release of insulin from polymer coated ceramic zinc phosphate nanoparticles in simulated gastric and intestinal medium
Conclusion From the above mini review it is concluded that ceramic nanoparticles may be utilised for delivery of antibiotics, peptides & polypeptides like insulin and protein drugs. However, the matching of drug release rate and biodegradation kinetics is a problem to be resolved.
References 1. Report of the Committee on Definition of the Term Ceramics, Journal of the American Ceramic Society, Vol. 3, No. 7, July 1920, pp. 526-542 2. http://www.ceramtec.de/intl/pgr4c/ta=pgr4c*627/la=en/le=0/index.html accessed 23 August 2005. 3. http://www.synthes.com/html/Norian_SRS.4317.0.html 4. http://www.wrightmedicalgroup.com/Physicians/Products/Biologics/OSTEOSETBoneGraftSubstitute.asp 5. http://www.dynamictechnomedicals.com/proddental.htm. 6. Bajpai PK, Graves Jr. GA, Porous ceramic carriers for controlled release of proteins, polypeptides, hormones and other substances within human and mammalian species, US Patent 4218255, 1980. 7. Bajpai PK, Benghuzzi HA, Ceramic systems for long-term delivery of chemicals and biologicals, J. Biomed.
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Mater. Res., 1988, 22, 1245-1266. 8. Hnatyszyn J.H., Kossovsky N., Gelman A., Sponsler E., Drug delivery systems for the future, PDA J. Pharm. Sci. Technol. 48, 247-254, 1994. 9. Paul W., Sharma C.P., Development of porous spherical hydroxyapatite granules: application towards protein delivery, J. Mater. Sci. Mater. Med., 10, 383-388, 1999. 10. Paul W., Sharma C.P., Antibiotic loaded hydroxyapatite osteoconductive implant material - in vitro release studies, J. Mater. Sc. Letters, 14, 1792-1794, 1995. 11. Paul W., Sharma C.P., Infection resistant hydroxyapatite/alginate plastic composite, J. Mater. Sci. Letters, 16, 2050-2051, 1997. 12. Paul W., Jerry N., Sharma C.P., Delivery of insulin from hydroxyapatite ceramic microspheres: Preliminary in vivo studies, J. Biomed. Mater. Res., 61, 660-662, 2002. 13. ABI-007 (ABRAXANE™), a nanoparticle albumin-bound (nab) paclitaxel demonstrates superior efficacy vs taxol in MBC: A phase III trial. O’Shaughnessy J, Tjulandin S, Davidson N, et al. Breast Cancer Research and Treatment, 82: Special Issue: 26th Annual San Antonio Breast Cancer Symposium. 2003; Abstract 44. 14. The Impact of Nanotechnology in Drug Delivery: Global Developments, Market Analysis and Future Prospects, NanoMarkets, LC, USA http://www.nanomarkets.net 15. Paul W., Sharma C.P., Porous hydroxyapatite nanoparticles for intestinal delivery of insulin, Trends Biomater. Artif. Organs, 14, 37-38, 2001. 16. Paul W. Sharma CP. Alginate coated zinc phosphate ceramic nanoparticles for oral insulin delivery (unpublished). 17. Paul W. Sharma CP. Zinc phosphate ceramic nanoparticles for oral insulin delivery. Proceedings of World Biomaterials Congress, May 17-21, 2004, Sydney, Australia, p 1168).
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