HYDROXYAPATITE IN DRUG DELIVERY

-Diya Adhikary; Amity University Kolkata

Biomaterials of ceramic origin (bioceramics) are “specially designed and fabricated for the repair and reconstruction of diseased, damaged, missing or worn out parts of the body”.  Initially, the bioceramics were bioinert but afterward changed to responsive bioceramics. The era of hydroxyapatite in regenerative science dates from the 1950s when bone defects were filled by using biomaterials as an inert scaffold. In the beginning, it was used for grafting, then later it was used as a conductive scaffold for bony ingrowth and the recent advent of nanotechnology has given a different dimension to bioceramics. They are used in tissue engineering and drug delivery implants. Among a wide range of nanostructures, hydroxyapatite (HAp) has gained much attention in the field of biomedical and drug delivery due to its dual effect:-

• It can interact with body tissues.
• It ensures increased drug efficiency, controlled release, and site-specific delivery.

The properties of hydroxyapatite:-

Hydroxyapatite (HAp) (Ca₁₀(PO₄)₆(OH)₂), which is a form of calcium apatite, grows in hexagonal crystals. The pure form of hydroxyapatite is white whereas naturally occurring HA can have yellow, brown, or green colour. It generally makes up most of the human bone structure (69% minerals, 22% organic matrices, 9% water), tooth enamel, and found in part of the brain in small amounts. Amidst other ceramics, hydroxyapatite is used as a drug carrier due to some of its excelling properties:

• Bioactive (hydration shell):- It has superior bioactivity, which is the ability to interact and form a strong interface with the surrounding tissues.
• Biocompatibility:- It is highly compatible with living tissue and does not produce any toxic or immunological response.
• Bioresorbability:- It has a superior biodegradable matrix and gets absorbed by the body, that is the material disappears over time.
• Hydroxyapatite is also osteoconductive and osteoinductive. The porous nature of hydroxyapatite influences drug release.
• Low solubility:- It has a low solubility. The solubility can be controlled through the substitution of different types of ions (carbonate, chloride, or fluoride).

Types of hydroxyapatite:

• Hydroxyapatite blocks (HAb)—HA is also available as solid or porous blocks. They along with antibiotic impregnations have been used for drug delivery for osteomyelitis treatment. Shinjo et al. successfully demonstrated that it did not cause any thermal damage to the drug rather stimulated the growth of a new bone. Macroporous HAp blocks (2-2000µm pore size) maintained a slow-release of drug with a much shorter release period. However, the porosity of HA blocks was limited to 78% as with a higher porosity (82.63%), it exhibited an irregular drug release which gave rise to an irregular structure. For example- Arbekacin sulphate, Isepamicin sulphate (Anti-biotic); Methotrexate (Anticancer Drug).

• Hydroxyapatite nanoparticles (HAp NPs) – Recent development of hydroxyapatite-based biomaterials for applications in the biomedical field have been benefited from nanotechnology. HA has some disadvantages (like brittleness, fracture toughness, and low tensile strength), to solve these problems, HA nanocomposite coatings are used. The biomimetic and biocompatible nanostructured calcium apatite can attach biological molecules (eg. proteins) which can be used as functional materials. They can synthesize controlled structures of apatite to stimulate the bone structure and the structure of other calcified tissues. Nanocrystalline HA powder has improved sinterability (can be sintered at a lower temperature) and enhanced densification (due to a greater surface area) which improves the fracture toughness. They have better bioactivity and dissolution than coarser crystals and promote osteoblast adhesion, proliferation, and deposition of minerals containing calcium, on their surface. For example:- Cis-diamminedichloroplatinum(Ⅱ), Paclitaxel (Anticancer Drugs); Vancomycin, Norfloxacin (Anti-biotic).

The techniques of using HAp in drug delivery:

1. The drug is loaded on the synthesized scaffolds: Generally, biodegradable and biocompatible polymers are preferred to be used as the scaffolding material, on which the drug is loaded. Hydroxyapatite has excellent biodegradable and biocompatible properties. Post-surgery implant removal is not needed due to its bioresorbability and its superior bioactivity helps in promoting bone regeneration as well as enhances osteoconductivity.
2. Use of porous powder of hydroxyapatite: This technique helps in providing constant and continuous drug levels at specific sites with limited side effects. Porous powder of HAp is similar to the porous nature of bone, provides appropriate space for bony ingrowths, and enables in vivo administration of short half-life drugs.
3. Use of coated hydroxyapatite: In this technique, a drug is encapsulated with hydroxyapatite coating which improves the drug delivery process. For example- a Hap surface coated with layers of poly-allylamine and sodium alginate is used for alendronate loading (Alendronate is a drug for osteoporosis healing).
4. Use of hydroxyapatite as a coating material: Hap coatings have gained much attention due to their biocompatibility, non-toxicity, and superior bioactivity. For example:- Hydroxyapatite coated liposome is used for therapy of bone disease and anticancer applications.

Pharmaceutical Applications Of HA:

Hydroxyapatite is used in the preparation of drugs or medicines that are used in medical treatment. Some of its pharmaceutical applications are as follows:-

• Antibiotics:  Porous HA blocks are used for the sustained release of antibiotics.
• Antiresorptive drugs: HA is also used to develop drug delivery systems for delivering antiresorptive drugs.
• Anticancer drugs: Porous blocks of HA act as drug delivery systems for anticancer drugs, hence they can be used in cancer treatments.
• Gene therapy: HA NPs can be used as essential delivery vehicles for gene silencing and can also be used as a vector for delivering the gene of interest.
• Proteins: Protein-based hydroxyapatite materials are being used due to their enhanced properties (eco-friendly, renewable, biocompatible).
• Others (vitamins, hormones, analgesics): HA is used as a drug carrier for vitamins, hormones, and analgesics.

Future Prospect:

Increasing use of HA in dental and orthopedic implants is projected to hold a share in the global market. Researchers are now trying to develop the materials (sufficient mechanical strength) so that they can bear loads. They are combining HA with natural polymers to fabricate composite materials with properties (mechanical strength, elasticity, toughness) similar to bones and also trying to prevent infections. The use of nanotechnology has been proved to be a boon for HA production. HA coating (osteoconductive and osteoinductive approach) helps in enhancing bone formation. Their properties may be improved by grafting growth factors and other molecule addition. However, there are still certain restrictions (eg. the Robustness of HA particles to withstand loads) in the case of HA coatings. Further research might help improve the properties of HA particles thereby increasing their efficiency.

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