FORMULATION: BioSilicon

Nano-Porous BioSilicon: A Novel Biomaterial in Drug Delivery System

ABSTRACT

BioSilicon is a biomaterial with highly biocompatible properties and a defined and controllable nano-porous structure. There has been rapid growth in the number and types of BioSilicon materials synthesized and the number of patents describing potential applications has increased considerably in recent years.

This article is primarily directed at pharmaceutical applications of BioSilicon, but will develop scientific rationale to underpin many other areas of applications, e.g. diagnostics, tissue engineering and orthopedics. It can be used as a microparticle-carrier for the controlled release of a variety of therapeutics or as a porous membrane in implantable devices. The overall aim of this article is to gain new insight into BioSilicon as a drug delivery vehicle from the combined application of material science, interfacial science and pharmaceutical science.

Introduction

Fig.1: A transmission electron micrograph of highly porous BioSilicon.

Nanotechnology, let alone applications for drug delivery, is somewhat of a "catch-all" term used to describe a wide range of enabling technologies focused at the level of atoms and molecules, and is applicable to many different industry sectors. The design, production and application of structures at the 0.1 to 100 nanometer (nm) scales reach across industries as diverse as the electronics, environmental materials and health care sectors. There are many potentially valuable prospects for nanotechnology in the drug delivery area and great strides are already being made for some applications. The key areas in which nanotechnology efforts are being focused are:

• Systems that improve the solubility and bioavailability of poorly water soluble drugs;

• Delivery vehicles that can enhance the circulatory persistence of drugs and/or target drugs to specific cells;

• Controlled release delivery systems;

• Vaccine adjuvant and delivery systems;

• Nanostructured materials that can be used in a diverse range of drug delivery applications such as orthopedics and wound management.

Nanostructured Biomaterials-The Emergence of Silicon

Purposely introducing silicon wires into a pharmaceutical tablet or powdered suspension is not typically a formulator's objective. After all, silicon is the primary material in computer processor chips and wafers. Researchers at pSivida Ltd. (Perth WA, Australia), however, have patented a nanostructuring technology that modifies the structure of silicon such that the material is biodegradable and dissolves well in the body, which can make it an ideal alternative to other biomaterials such as polymers.

BioSilicon is a highly porous, silicon-based nanomaterials product, which can release an active pharmaceutical ingredient slowly over a period of time. pSivida uses its BioSilicon technology to fashion tiny ingestible capsules as well as tiny needles that can be built into a patch to invisibly pierce the skin and deliver drugs. The application of nanostructured bio-materials in drug delivery is at a relatively early stage, but already the use of one material is gaining increasing acceptance. Silicon is one of the most common elements on earth, constituting 30 percent of the planet's crust, and has been extensively studied by the semiconductor industry. Extremely pure silicon (about 99.999 percent pure) is readily available and reasonably inexpensive, and technologies to manipulate it at the micro and nano levels have been used for decades.

Silicon can be made biodegradable by nanostructuring it-an example of a top-down approach-and it safely breaks down in the body into silicic acid, which is found in everyday foodstuffs such as bread and rice. In this form, it can be used as a microparticle carrier for the controlled release of a variety of therapeutics or as a porous membrane in implantable devices. Nanostructured silicon can also be used in a range of other healthcare applications including orthopedics, tissue engineering and diagnostics.

The nanostructuring procedure, discovered by physicist Leigh Canham, of pSimedica, a subsidiary of pSivida, produces the biocompatible, honeycomb-shaped BioSilicon. Microparticle powders (typically 30 mm in size) and even three-dimensional implants (1-cm in size) are internally modified to enclose this porous structure. Just five to 10 atoms across, the silicon nanowires make up the honeycomb's walls, which surround the drug-filled cells (typically 50 to 100 nm wide). Although the BioSilicon structure can be used with various drugs, the company is initially focusing on cancer therapies, treatments for central nervous system diseases, peptides, and small proteins. As a new and unique biomaterial, BioSilicon exhibits many properties that make it an ideal material in which to develop products in these growing areas of healthcare:

• Biocompatible, biodegradable semiconductor;

• Abundant, low cost material;

• Scale up and manufacture proven over 40 years in the electronics industry;

• Micro-machineable - nm (10^-9) sized for biodegradability and for tissue engineering;

• Honeycomb structure mimics porous scaffolds found in nature;

• Natural by product, dissolves in the body to become silicic acid, the dietary form of silicon found in everyday foods such as beer, rice and wine.

BioSilicon in Oral Delivery

One of the key issues associated with oral delivery is the stability of the drug in the digestive system. Many current tablet products have enteric coatings to protect the active material in the highly acidic environment of the stomach. One of the greatest challenges in oral delivery is the effective administration and absorption of biologicals and highly insoluble therapeutic entities. BioSilicon addresses many of the current issues associated with oral drug delivery:

• Protection of the drug in the acid environment of the stomach through the fact that BioSilicon does not dissolve in acidic solutions;

• BioSilicon is designed to slow-release drugs through controllable biodegradation providing the opportunity to optimize delivery and absorption;

• Chip-based BioSilicon devices would offer processor-based delivery targeted to different parts of the gut.

BioSilicon particles are first loaded with the drug solution. Nanostructured porosity of BioSilicon enables drug loading, while the degree of porosity, pore size and particle size can all be optimized to controlled drug release. BioSilicon particles loaded with drugs are delivered using multiple methods. Degradation of BioSilicon particles is initiated in vivo, while BioSilicon walls degrade into silicic acid, the naturally occurring form of silicon found in the body. Controlled release of the drug is the based on the rate of degradation of the BioSilicon particle. As BioSilicon degrades, the drug is released.

The key benefits of BioSilicon in drug delivery are:

• The porous "honeycomb" structure provides a large surface area, which is an ideal matrix for high capacity and efficient drug loading and release;

• Controlled drug release over days, weeks or months-altering the physical properties of the BioSilicon matrix, eg. controls drug release kinetics by adjusting the level of porosity, altering the pore size or particle size;

• Applicable to a wide range of therapeutic entities from small molecules to peptides and proteins including hydrophobic and hydrophilic entities;

• Efficiency of drug loading up to 95 percent of starting material-typical formulations with 60 percent porosity have drug loadings of 35 to 40 percent w/w. Drug loading can be further enhanced by increasing the level of porosity of the matrix;

• Drug loading does not require chemical modification of the molecule-there are no changes in drug structure or activity after loading and subsequent release;

• Particularly well suited to solving formulation problems associated with hydrophobic drugs;

• BioSilicon can be produced in a wide range of physical forms.

One of the key benefits of BioSilicon in drug delivery is the ability to control the kinetics of drug release by altering the physical properties of the matrix; unlike most polymer systems no chemistry is required to control drug release kinetics. Work on novel depot formulations, e.g. subcutaneous implants and intratumoural depots, demonstrating that drug release can be controlled over periods of days, weeks and months with release profiles being tailored to meet specific therapeutic requirements. Furthermore, formulations can be tailored to produce zero order release kinetics with minimal or no burst release effects. BioSilicon has been found to be particularly well suited to improving the solubility and bioavailability of poorly water-soluble drugs. This results from the nanostructuring of the drug within the nanosized pores of the BioSilicon matrix so that drug surface area is increased thereby aiding dissolution and absorption. Many poorly water-soluble drugs (both class II and IV compounds) have been successfully formulated and their solubility improved using BioSilicon. Pre-clinical in vivo studies have demonstrated that BioSilicon can not only significantly improve the solubility of poorly water soluble drugs but also enhances the absorption and bioavailability of such compounds.

Advantages

BioSilicon material is cheap to manufacture, biodegradable, safe to administer and offers exquisite control over the rate of release of the drugs it carries. It takes the form of nanostructured porous silicon that can be machined into powders, microspheres, or just about any other structure while retaining its ability to carry and release active components. It is just about to start clinical trials as part of a brachytherapy (short range intratumoural radiotherapy) for liver cancer.

The main attractions to BioSilicon are the range of compounds it can carry, as well as the fact that it does not have to be chemically bonded to its payload. This means that there is no need to alter the manufacturing process for the drug it carries and, once a dossier has been filed with the relevant regulatory authorities, development of BioSilicon-based versions of existing drugs should be fairly straightforward. In drug delivery applications, BioSilicon has significant advantages over rival polymer slow release drug delivery systems in animal trials. For example, it boasts higher loading rates, and the rate of release (achieved as the BioSilicon breaks down in the body), can be controlled to extend from days to months.

The structure of the material prevents dose dumping-the release of a higher dose of drug after it is first administered which then gradually tails off. Moreover, unlike polymers, silicon can carry an electrical current, which can be harnessed to alter the rate of break down. In the future, this property could be used to incorporate sensors into a BioSilicon implant, which could then respond to its environment and release the drug appropriately.

The compound can also be engineered to alter the rate of biodegradation, and hence alter the kinetics of drug release. BioSilicon also provides a wide range of dosage forms and delivery routes, from micron-sized particles, micro-machined implants, woven fabrics, fibers and micro-devices. The delivery method ranges from direct injection to oral, to transdermal.

Toxicity studies have shown no adverse side effect, and the by-product is salicylic acid, which is excreted through the kidneys and is the dietary form of silicon found in everyday foods such as beer, wine and rice. Scale-up and manufacturing of silicon is proven with over 40 years experience from the electronics industry.

Applications

BioSilicon has multiple potential applications across the high growth health care sector, including controlled drug delivery, brachytherapy, tissue engineering and orthopedics and targeted cancer therapies. Potential diagnostics applications are being developed through its subsidiary AION Diagnostics Limited.

Brachytherapy: BrachySil is a micron-sized nanostructured silicon particle in which radioactive 32-phosphorus (32-P) is immobilized. It is administered as a liquid suspension through a fine-gauge needle directly into tumors. The procedure takes place under local anesthetic and without the need for shielded rooms or robotic injectors, and patients can be discharged the next day. Brachytherapy treatment utilizing BrachySil includes the following potential advantages:

• Short range - 32-P isotope has a short active range resulting in controlled exposure to radioactivity and less damage to healthy tissue.

• Immobilization - 32-P device is immobilized in the tumor, significantly reducing risk of leakage or systemic side effects.

• Ease of application - BrachySil is delivered under local anesthetic and patients can be discharged the next day.

• Direct delivery - BrachySil is delivered via fine-gauge needle, minimizing side effects and tissue trauma without the need for shielded rooms or robotic injectors, allowing treatment in hospitals without the need for investment in specialized facilities.

• Range of tumors - fine-gauge needle delivery allows potential application to several solid tumors, unlike current brachytherapy products.

• Distribution - 32-P half-life of 14 days allows convenient distribution to hospitals and application in the patient.

• Manufacture - BioSilicon is "radiation hard" allowing ease of manufacture of BrachySil from phosphorus-doped silicon used in the electronics industry without the need to build costly manufacturing facilities.

Orthopaedics

In orthopaedics, for example, porous silicon could potentially be manufactured into orthopaedic implants (pins, screws, etc.) loaded with tissue growth factors, anti-infectives and anti-inflammatory drugs, and designed to release these drugs as they degrade slowly during the healing process.

Dermatological

An additional advantage of such bio-mirrors is the ability to load the BioSilicon particle with suitable dermatological agents. Currently, there are extensive formulations servicing the multibillion-dollar sunscreen and skin protection market. Furthermore, unlike many of the current materials used in sunscreens such as zinc and titanium, bio-mirrors are biodegradable, so any material absorbed by the skin can safely dissolve.

Ophthalmic Implant

pSivida is exploring ophthalmic implants from both a drug delivery perspective and a tissue engineering aspect. Initial constructs involve biodegradable implants for drug delivery from the tissue surrounding the eye. The eye is a particularly favored target due to the safety of BioSilicon, unlike the degradation products from polymers like lactides and glycolides, silicic acid (the product from BioSilicon) is a very mild acid, expected to cause less irritation.

Diagnostics

Another potential application for the material is in diagnostics. Many cancers are detectable through chemical markers released into the bloodstream usually detected by diagnostic tests in pathology laboratories. By placing porous silicon mirror particles, smaller than a pin-head, containing quantities of targeted antibody, the antibody capture mechanism would generate a change in reflectivity as the relevant marker accumulates on the BioSilicon surface.

DNA Vaccine

Delivery and expression of DNA to cells has been challenging for many companies particularly for vaccine applications. The collaboration with the University of Pittsburgh will explore the use of BioSilicon in binding and protecting DNA during vaccine therapy in model systems. pSiMedica has developed the technology to load and release DNA from BioSilicon matrices resulting in effective production of immunogen (the antigen for which the DNA codes). The ability to load and protect DNA during vaccine regimens is vital to the production of DNA vaccine products.

Transdermal Drug Delivery

A key attraction in using BioSilicon in construction of micro arrays is the fact that the material is a biodegradable �-unlike needle constructed from conventional metal such as steel. Thus, a micro array on a transdermal delivery of a patch for the delivery of drugs through skin would enable the drug to cross skin barrier. Such needles are expected to be virtually painless due to extremely small needle size. Furthermore, any needle lost in skin is biodegradable. The technology also provides drugs for transferring in a specific site.

Conclusion

This novel class of nano-structured bio-material has exciting potential for developing a range of controllable drug delivery systems. Existing medical applications of BioSilicon deliver only small molecules for very specialized uses. Current research has not focused on understanding the pore structure and how it can be adapted for special applications. The main motive of the research will create new drug delivery systems with many innovative applications in medical, veterinary and bio-diagnostics fields. The medical and socio-economic impacts will be internationally significant. ?

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Geeta M. Patel, Gyatri C. Patel, Girish N. Patel, Jayvadan K. Patel, P.D. Bharadia and Madhabhai M. Patel, of the Department of Pharmaceutics and Pharmaceutical Technology, S. K. Patel College of Pharmaceutical Education and Research