Elsevier

Journal of Biotechnology

Volume 113, Issues 1–3, 30 September 2004, Pages 151-170
Journal of Biotechnology

Challenges and solutions for the delivery of biotech drugs – a review of drug nanocrystal technology and lipid nanoparticles

https://doi.org/10.1016/j.jbiotec.2004.06.007Get rights and content

Abstract

Biotechnology allows tailor-made production of biopharmaceuticals and biotechnological drugs; however, many of them require special formulation technologies to overcome drug-associated problems. Such potential challenges to solve are: poor solubility, limited chemical stability in vitro and in vivo after administration (i.e. short half-life), poor bioavailability and potentially strong side effects requiring drug enrichment at the site of action (targeting). This review describes the use of nanoparticulate carriers, developed in our research group, as one solution to overcome such delivery problems, i.e. drug nanocrystals, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and lipid–drug conjugate (LDC) nanoparticles, examples of drugs are given. As a recently developed targeting principle, the concept of differential protein adsorption is described (PathFinder Technology) using as example delivery to the brain.

Introduction

The introduction of biotechnological methods for the production of drugs brought a revolution to the pharmaceutical field. Nowadays, drugs like insulin are produced by recombinant technology. This reduces not only the price for injectables but makes it simultaneously so relatively cheap that enough insulin is available at a sufficiently low price to go for other, more patient friendly administration routes, i.e. pulmonary delivery. After pulmonary delivery, the bioavailability of insulin is much lower compared to injection (only approximately 10% (Brunner et al., 2001, Heinemann et al., 2000)), thus requiring higher amounts of insulin for treatment. Therefore, development of pulmonary administration was only possible after insulin was available in sufficient, relatively low price quantity as provided by biotechnological production. At present, the clinical trials are in phase 3 with the products AERx (Novo Nordisk/Aradigm) and Exubera (Aventis/Pfizer/Inhale). Of course other recombinant products are still more expensive than the natural products (e.g. albumin), but some of the natural sources are limited, in addition safety aspects are also of importance (e.g. potential contamination from blood products).

One has to differentiate between two different types of drugs:

  • 1.

    Biopharmaceutical drugs (biopharmaceuticals) and

  • 2.

    Biotechnological drugs.

Biopharmaceuticals are defined according to the Food and Drug Administration (FDA) as recombinant proteins and monoclonal antibody or nucleic acid-based products. Not included in the definition are tissue-engineering products, which the Food and Drug Administration (Rockville, MD) classifies as medical devices (Walsh, 2000, Walsh, 2003a). In a strict sense, the definition biotechnological drugs exclude drugs from plants or mammalian cells obtained by a simple extraction process without any prior biotechnological manipulation. To be precise, the group of biopharmaceuticals intercepts with the class of biotechnological drugs in case the biopharmaceuticals are produced by a technological method. In case they are produced by a classical chemical synthesis, they are not biotechnological drugs. That means by this definition only recombinant protein and some cellular isolate proteins, oligonucleotide (or nucleic acid-based products), peptides, antibodies and gene therapy products are covered, but not any other drugs produced by a biotechnological method. Therefore, the classification “biotechnological drugs” covers all drugs produced by a biotechnological process, e.g. fermentation, enzyme, hybridoma, tissue and cell culture technology and genetic engineering. By this definition, it includes also relatively old drugs such as penicillin, which was developed by Fleming in a time when the term “pharmaceutical biotechnology” was not yet invented. Penicillin is produced by a fermentation process using bacteria cultures of Penicillium chrysogenum or Aspergillus nidulans. Another, one of the recent examples is the production of aphidicolin produced by a fermentation of cultures of Cephalosporium aphidicola (Kayser, 2000). A nice condensed review about the status of biopharmaceuticals has recently been given by Walsh (2003b). Regarding to their physical properties two groups of drugs can be differentiated:
  • 1.

    Water-soluble drugs (in general biopharmaceuticals) and

  • 2.

    Poorly water-soluble drugs (many products from biotechnological processes, e.g. aphidicolin).

Depending on their physical and chemical properties, each group has different problems in delivery. These problems can be so massive that use in the clinic for the benefit of the patients is not possible. That means, a biotechnologically produced drug needs to be combined with a smart drug delivery system and/or delivery technology to make it applicable for the treatment of patients. Examples are poor solubility of drugs requiring an appropriate delivery system, or strong side effects of drugs requiring a technology for site-specific delivery (i.e. drug targeting). Especially in case drugs are poorly water soluble, delivery problems occur because in many cases absorption from the gut for such drugs is low. Alternative intravenous injection would require too large injection volumes, therefore smart delivery systems are required. This paper reviews solid nanoparticulate delivery systems developed within the last decade by our group (Lucks and Müller, 1996, Mueller et al., 2000) in combination with a targeting strategy (PathFinder®) applicable to biotechnological drugs.

Section snippets

Challenges for formulation and delivery

Of course, the challenges are manifold, basically one can differentiate between problems being very often related to these drugs and problems being more related specifically to a molecule, e.g. conformation issues. Problems frequently occurring with many drugs are:

  • 1.

    Poor solubility

  • 2.

    Insufficient in vitro stability (shelf life)

  • 3.

    Too low bioavailability

  • 4.

    Too short in vivo stability (half life)

  • 5.

    Strong side effect, need for targeted delivery

  • 6.

    Regulatory issues/hurdles

  • 7.

    Lack of large scale production

As clearly

Solutions for optimised delivery of biotechnology drugs

Traditional administration routes are oral administration or parenteral injection. The orally administered drug is absorbed from the gut and enters the blood stream, diffuses from the enteral absorption sides to blood and tissue whereas a parenterally administered drug is injected directly into the blood, which is typically only possible in form of a drug solution or emulsion. By these routes of drug administration, the drug itself is present as molecule in a solution (i.e. blood). It

Conclusion and perspective

The presented carriers are suitable to solve delivery problems with biotech drugs of different solubility. The suitability of the carriers has been proven because they are either already on the market (e.g. drug nanocrystals in products such as Rapamune® or Emend®) or they have been used in clinical phases/human studies (cyclosporine-loaded SLN). They fulfill the key prerequisites for the introduction to the clinic and the market, that means they are in line with regulatory requirements and

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