Research on characterization and drug release performance of hydroxyapatite-gelatin composite materials syntheted by using phenolic linker

Hydroxyapatite has a biological similarity to the mineral phase of the natural bone with the formula Ca10(PO4)6(OH)2. The good adsorption properties of hydroxyapatite provided scaffold for the production of drug delivery systems (DDS) and controlled drug delivery systems. This is due to both the powder and the porous structure of HAp. The porous HAp structures loaded with suitable drug form a system that gives the drug the sensitive area. This feature is used in the development of new DDSs in the treatment and prophylaxis of bone disorders, particularly osteoporosis, bone tumors, and bone metastases. In addition, studies have been conducted on systems that provide important antibiotics directly to hard tissues. In addition to drug delivery systems, attempts are made to use HAp as a carrier for hormones, anti-inflammatory agents and vitamins. Gelatin is used to synthesize biomaterials by incorporating into the composition of biodegradable polymers such as collagen, chitosan, starch. Gelatin is a natural biopolymer by a functional group such as amino acid. It is biodegradable, biocompatible, water-soluble and inexpensive. Gelatin can be obtained by thermal, physical or chemical denaturation of collagen. Crosslinking of gelatin increases gelatin stability (high gelation and melting temperatures) compared to non-crosslinked particles. Gelatin-based materials prepared without crosslinking are known to be unstable and tend to age. Due to its hydrophilicity, gelatin has a great interest in HAp and can be homogenized well in aqueous solution. Therefore, it is expected that gelatin and HAp will yield bioactive and biocompatible biomaterials with biocomposite. In this study, the synthesis of HAp as a matrix with using gelatin, the effect of biopolymer concentration change on the final structure and the characterization of the prepared composites have been investigated. Many studies carried out on the preparation methods, physical and chemical properties of HAp-GEL composites, as well as in vitro studies. These HAp-GEL composites prepared by conventional methods are generally in the form of irregular granules, pastes, sponges, and microspheres. Among these different forms, microspheres provided the ideal working environment for many applications at controlled rates over extended periods of time due to their ability to encapsulate more drug molecules and sustained drug release characteristics. HAp-GEL composite microspheres are also used as bone regenerative fillers or as an injectable bone substitute. Therefore, the potential for microspheres to combine their roles in drug delivery and bone repair reduces the time to recovery and regeneration of bone tissue. Polyphenols make the formation of natural cross-links in biological tissues and make them more resistant to degradation. It has been used in various synthetic and natural crosslinkers both in vivo and in vitro to strengthen collagen fibers in biological tissues such as dentin, tendon, pericardium strips and collagen grafts. In addition, polyphenols contain many phenolic groups capable of forming strong hydrogen bonds. Polyphenols, gelatin-dextran conjugate are obtained as a result of the formation of hydrogen bonds with gelatin. Glutaraldehyde, a chemical binder, is widely used to cross-link biopolymers in medical applications. However, its cytotoxicity prevents it is biocompatibility. Furthermore, it is difficult to use glutaraldehyde during crosslinking due to its strong odor and low vapor pressure. Various chemicals have been studied as alternative crosslinking agents. These include tannic acid, ferulic, genipine and citric. Tannic acid (TA) is completely biodegradable from plant and microorganisms. It is also cheaper than other chemical derivatives. It is a high molecular weight, a polyphenolic compound containing a central carbohydrate nucleus esterified by phenol acids. Tannic acid has a high antioxidant capacity and can interact with other biological macromolecules. It is a highly effective crosslinking agent for biopolymers which provides superior mechanical properties and water resistance compared to many agents. Fluorouracil (5-FU) is one of the major anti-metabolites used in various cancers such as stomach, colon, lung, ovary and breast cancer. Given the structural similarity to natural pyrimidines, 5-FU interferes with the nucleic acid synthesis, inhibits DNA synthesis and eventually halts cell growth. The targeted drug dosing of 5-FU is highly dependent on the cancer being treated. In-vitro studies showed cytotoxic effects of 5-FU at a high dose of 50 µg/mL. Because of 5-FU's narrow therapeutic index, its lifecycle in blood and body tissues is limited to a few minutes. As with most chemotherapy drugs, the side effects of 5-FU are also within the boundaries of the region where it is administered. In intravenous administration, 5-FU produces severe toxic effects from a gastrointestinal, hematological, neural, cardiac and dermatological origin. Therefore, site-specific administration of 5-FU provides an effective and safe treatment to reduce systemic side effects. There are studies in the literature examining the release profile of drug-loaded HAp-GEL composite materials. In this study, hydroxyapatite-gelatin (HAp-GEL) composite material has been produced with a phenolic linker TA in SBF (Simulated Body Fluid) solution, and 5-FU drug was loaded with a spray dryer. In the HAp-GEL composites synthesized by wet chemical method, the effect of the amount of gelatin on drug loading efficiency and release profile by using in three different ratios (w% w) 1:1, 1:2 and 1:4 gelatin was investigated. The tannic acid, the phenolic linker, has been used as the crosslinking agent. Two different TA solutions 2% and 5% have been used in terms of HAp-GEL composite materials have been obtained to investigate the effect of TA in the composites on drug loading efficiency and drug release profile. Lastly, 5-Fluorouracil (5-FU) has been used as a drug. The drug release profiles have been researched according to four different kinetic models; Zero Degrees, First Degrees, Higuchi and Korsmeyer-Peppas. The structural properties of the composites have been analyzed using instrumental analysis devices. Fourier transform infrared spectroscopy (FTIR), X-ray diffractometer (XRD), thermal gravimetric analysis (TGA) and scanning electron microscopy (SEM) with devices the results of the characterization have been analyzed. This study focused on a recent study of the preparation of HAp-GEL composite material with a biocompatible crosslinker for use in drug delivery systems. The spray dryer has been preferred for high-efficient drug loading.