How polymeric microspheres deliver the goods

January 1, 2006
Jo Daniels

Pharmaceutical Technology Europe

Pharmaceutical Technology Europe, Pharmaceutical Technology Europe-01-01-2006, Volume 18, Issue 1

Drug delivery systems using biocompatible polymers allow controlled release of therapeutics, addressing many of the challenges of conventional administration. Polymer microspheres are attractive delivery systems, having a wide application in numerous therapeutic indications. This article reviews the current use and trends for polymer microspheres, and compares production methods and polymer characteristics.

In an increasingly competitive drug discovery market, controlled release and delivery technologies, which aim to achieve localized and sustained delivery of therapeutics in the human body, are of high importance to the pharmaceutical industry. Controlled delivery has the potential to improve drug effectiveness, reduce side-effects and increase patient acceptance. The commercial opportunity is enormous, with sales of drug delivery technologies expected to exceed £65 billion in 2006.1

As a consequence, the industry has seen an increase in the number of abbreviated new drug applications (ANDAs) approvals for controlled release versions of generic drugs. In addition, the increasing use of proteins and genetic material as therapeutics will continue to drive the need for improved drug delivery systems. New, controlled release technologies will enable a wide range of applications, including:

  • patent extension for proprietary drugs

  • new drugs for which delivery has not yet been developed

  • generics that can benefit from a new commercial life cycle

  • clinical development of cell therapies.

Polymer encapsulation is an ideal strategy for the controlled delivery and release of a wide range of therapeutics, offering many advantages compared with traditional drug delivery methods:

  • Controlled delivery — eliminates the need for repeated administration through controllable and optimized pharmacokinetic profiles. This increases patient compliance for drugs for chronic conditions and improves disease management.

  • Localized delivery — drug action at the site where it is required and not systemically. This is particularly important for toxic drugs including chemotherapies.

  • Drug stabilization — The polymer matrix protects the drug in situ. This is particularly important for liable biopharmaceuticals that typically have short half-lives in the physiological environment and cell therapies where immunoisolation is a necessity.

Market trends

With the market for drug delivery growing rapidly a significant number of companies are developing controlled release systems based on proprietary polymer technologies (Table 1).

Table 1. Companies involved in polymer delivery systems.

Small molecules. Commercial interest of polymer delivery technologies has increased considerably, especially after the success of products such as Lupron Depot, Zoladex, Norplant and Gliadel, all of which use the principles of sustained drug release. Drug delivery companies have developed proprietary polymer release systems for the development of sustained release drugs, either in collaboration with pharmaceutical partners or their own in-house compounds.

In addition to sustained release delivery of novel drugs, there is a growing opportunity for companies to develop new delivery systems for generic compounds. Through reformulation, companies can offer more attractive administration routes, improving patient compliance and acceptance (e.g. monthly rather than daily injections). Reformulation of generics is an attractive strategy as they have regulatory acceptance, reducing the burden of costly clinical trials. Notable success stories include J&J's Procardia; the controlled release version of nifedipine, which generated an extra $9 billion worth of sales; and Elan's Cardizem, which increased sales of dilitiazem to $900 million. Combination products (medical device and therapeutic) are a growth area with an estimated market size of $10 billion by 2009. Polymer microcapsules containing therapeutic agents are in development for a number of applications including liver and breast cancer, pain relief and drug eluting stents.

Biopharmaceuticals

The increase in biopharmaceutical therapeutic and prophylactic agents (e.g. gene and cell therapy, antisense oligonucleotides and monoclonal antibodies) is driving research into new drug delivery technologies. Conventional modes of administration, such as pills and injections, are inadequate for biopharmaceutical agents, which have extremely short half-lives and are toxic if administered systemically in large doses. Biopharmaceuticals are a growing class of macromolecule drugs encompassing proteins, peptides, oligonucleotides, SRNAi and antibodies. The protein therapeutic market was forecasted to grow rapidly at a compound annual growth rate of 10.5% from 2003 to 2010 — almost double in value.

The increased use, development and discovery of protein therapeutics are leading to increasing opportunities for drug delivery companies. Although effective, biological therapies present safety and efficacy issues as they are labile and have a narrow therapeutic window. Proteins are largely administered as immediate release, but there is a trend moving towards increased sustained release formulations to improve efficacy and reduce side-effects. Polymer microcapsules are attractive delivery systems for proteins. As well as providing controllable release, the polymer matrix stabilizes the labile molecule, offering protection from the physiological environment and increasing lifetime.

Cell therapies

Cell therapies secrete therapeutic proteins in response to the body's own feedback mechanisms, offering advantages compared with conventional protein administration that may require daily injections.

Cell therapy is a part of, and overlaps with, many other therapies; therefore it is difficult to separate the value of cell-based technologies from others. However it has been estimated that the market for encapsulated cell therapies will grow from $400 million in 2005 to $1.9 billion in 2008.2 Most commercial interest has been focused on diabetes, with a large number of companies (including Amcyte, Living Cell Technologies and Cerco Medical) progressing encapsulated cell therapies through clinical trials.

Tailored drug delivery

A wide range of biocompatible polymers and copolymers has been developed that are suitable for controlled release systems including polyvinyl alcohol (PVA), 2-hydroxyethyl methacrylate (HEMA), alginate, polyethylene glycol (PEG) and poly(lactic-co-glycolic acid) (PLGA). Non-biodegradable polymers can be used, but their disadvantage is that they must be surgically implanted and removed.

Table 2. Factors affecting drug release rates.

Controlled release rates are determined not only by polymer choice, but also through a combination of variable factors that can be tailored to achieve desired release rates (Table 2). In addition, factors including excipient, copolymers and drug polymer interactions affect release rates. The controlled release profiles are, therefore, controlled by the polymer selection and encapsulation methodology.

Encapsulation methods

Current encapsulation methods, although differing through starting materials and type of therapy that can be encapsulated, have common issues to address for the development and optimization of polymer microcapsules because of the following challenges:

  • Scalability under GMP conditions — production of commercial volumes of microspheres under sterile conditions as required by the pharmaceutical industry.

  • Reproducible control over microsphere size and uniformity — the desired capsule size is largely dependent on the administration method. Oral, injectable and vasculature require 25, 100 and 600 μm capsules, respectively. In addition, protein or small molecule loading needs to be consistent to ensure batch-to-batch uniformity.

  • Compatibility with therapy to be encapsulated — some methods employ organic solvents or high temperatures, which have the potential to damage the activity of biopharmaceutical drugs and are not suited to the encapsulation of living cells.

These factors impact drug release rates, in vivo localization and deliverability, and ultimately product efficacy and safety.

Interfacial polymerization is the most commonly used method for preparing microspheres from polymer precursors using suspension, dispersion or emulsion polymerizations. Depending on the method used, the monomer is either emulsified or dispersed in an immiscible continuous phase and then an interfacial polymerization reaction is allowed to take place at the surface of the microspheres.3 Although scalable, these processes suffer from poor size control that limits their utility for drug encapsulation. Preferably, the microspheres are mechanically sieved to retrieve narrower size ranges with drug encapsulation taking place post-processing by placing the microspheres in a solution of the drug and allowing equilibration.

In contrast, extrusion and emulsion-solvent extraction/evaporation methods produce polymer microcapsules from preformed polymers. Emulsion methods co-dissolve the drug with the polymer in a suitable solvent and then emulsify the mixture in a non-solvent phase. The microspheres are then recovered by solvent evaporation. Although very flexible, allowing a variety of methods for emulsification and drug encapsulation, the method is technically difficult, costly to scale-up and produces a large size range of microspheres. Extrusion methods in which microspheres are formed by forcing the polymer/drug through a nozzle have much better size control, although the shear forces created by the high velocity at the nozzle are deleterious to the encapsulated therapeutics are not well suited to biopharmaceutical encapsulation.

Many of the methods described employ organic solvents or high temperatures that have the potential to damage the activity of biopharmaceutical drugs and are not suited to the encapsulation of living cells. A milder process method is the ionic curing of alginate or chitosan, which occurs at ambient conditions without the use of harsh chemicals. The therapeutic agent or cells are mixed with a solution of alginate which is then forced through a nozzle to form droplets.4 Techniques such as jet cutting maintain the spherical shape of the droplet before it falls into a solution of either barium or calcium ions causing gelation. Although most suited to the encapsulation of biological material, the method produces a broad range of microspheres and is difficult to scale up under good manufacturing practice (GMP) conditions.

A novel method of polymer encapsulation using microfluidics is under development. The process employs assisted droplet break-up to from microspheres from a continuous stream of monomer.5 The monomer is polymerized into solid beads using either UV polymerization or chemical curing. In addition, streams of molten preformed polymers can be formed into droplets and solidified into beads across a temperature gradient. The systems are flexible allowing the drug to be encapsulated to be added as part of the monomer/polymer stream or separately so enabling controlled dosing of each microsphere. Although not currently a mainstream commercial method, the system confers several advantages:

  • A wide variety of therapeutics can be encapsulated (biopharmaceuticals, cells and small molecules).

  • Precise control over size, shape and composition.

  • Scalable process under GMP conditions.

  • Flexibility to work with a broad range of biocompatible polymers.

Summary

Polymer encapsulation is an ideal strategy for the controlled delivery and release of a wide range of therapeutics offering many advantages compared with traditional drug delivery methods. Consequently, a significant number of companies are now focused on the development of polymer delivery systems. The key issues of developing capsules with the desired release rates; achieving product uniformity and quality; maintaining drug stability; and scaling up lab-based production technologies to establish GMP production are driving the development of suitable polymer formulations and encapsulation technologies as pharmaceutical companies seek improved methods for disease management and product life cycle extension.

Dr Jo Daniels is the business development director at Q Chip Ltd, UK.

References

1. US Drug Delivery Systems Market — Emerging Technologies, Strategic Alliances, Patent Disputes, Market Size & Forecasts and R&D Activities (2003). www.researchandmarkets.com/reports/19886/

2. www.pharmabiotech.ch/articles

3. H.R. Allcock and F.W. Lampe, Contemporary Polymer Chemistry 2nd Edition (Prentice Hall Inc, Upper Saddle River, NJ, USA, 1990).

4. S. Sakai et al., Biotechnol. Bioeng. 86(2), 68–73 (2004).

5. T. Nisisako, T. Torii and T. Higuchi, "Rapid Preparation of Monodispersed Droplets with Confluent Laminar Flows," Proceedings of the 16th Annual International Conference on Micro Electro Mechanical Systems (2003) pp 331–334.

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