Review
The effects of irradiation on controlled drug delivery/controlled drug release systems

https://doi.org/10.1016/j.radphyschem.2007.06.006Get rights and content

Abstract

The research of radiation effects on drugs over the past 60 years has mainly dealt with radiation sterilization of individual active pharmaceutical ingredients (APIs) in the form of pure substances or injectable solutions. However, the emergence of novel systems for drug administration and targeting via controlled drug delivery (CDD) and/or controlled drug release (CDR) has extended the use of irradiation with respect to pharmaceuticals: the capacity of radiation to act as an initiator of crosslinking has been used in the manufacturing and modification of a number of polymeric carriers with an added advantage of reducing the microbial load of products at the same time. The application of irradiation to these novel systems requires the understanding of radiation action not only on APIs alone but also on drug carriers and on the functioning of the integral CDD/CDR systems. In this paper, the significance of CDD/CDR systems is considered with a special emphasis on the role of irradiation for sterilization and crosslinking in the developments over the past 15 years. Radiation sterilization, crosslinking and degradation of the principal forms of drug carrier systems and the effects of irradiation on the release kinetics of APIs are discussed in light of radiation chemical principles. Regulatory aspects pertaining to radiation sterilization of drugs are also considered. Relevant results are summarized in tabular form.

Introduction

Recent efforts in drug development resulted in a number of controlled drug delivery (CDD) systems consisting of a drug encapsulated within a suitable polymer carrier which enables drugs to be delivered either via novel routes or in a sustainable fashion or both. By a selection of biocompatible carriers, drugs could be made available at various locations in the body. Targeted delivery of drugs directly to various organs or tissues may be accompanied with an additional benefit of achieving at the same time both the spatial and temporal control of release which is the principle of operation of controlled drug release (CDR) systems. Targeted delivery of drugs directly to the diseased tissues and/or organs and its controlled release have important advantages over the traditional (oral) route: higher local concentration of a drug makes the therapy more effective; improved pharmacokinetics of drug release maintains the required therapy level over an extended period of time; both the duration and unwanted side effects of the therapy are reduced. Last but not least, simplified dosing and the ease of use directly contribute to the improvement of the patients’ life quality obviating the need for repeated, potentially uncomfortable, dosing and reduce the risk of incorrect dispensing (Maugh, 2006). Improved versions of patented drugs with pending expiration are also attractive to manufacturers, enabling an extension of the market life cycle of established drugs.

Drugs for parenteral delivery must be sterile and radiation sterilization is a method recognized by many pharmacopoeias to achieve sterility of drugs. Previous reviews of radiation sterilization of drugs dealt mainly with the sterilization of active pharmaceutical ingredients (APIs) alone (Dahlhelm and Boess, 2002; Gopal, 1995; Jacobs, 1995; Marciniec and Dettlaff, 2005). The reviews dealing so far with radiation sterilization of drug delivery systems were mainly focused on the sterilization of various polymeric carriers and presented but a few selected examples of loaded systems (Bhattacharya, 2000; Clough, 2001; Edlund and Albertsson, 2002; Jain et al., 2005; Sintzel et al., 1997). In this paper, we summarize the effects of irradiation on CDD/CDR systems in radiation's dual role with respect to these systems: as a sterilizing agent of loaded systems and as an initiator of polymerization and/or crosslinking in polymeric drug carriers before their being loaded with drugs. Only the developments based on the work done since 1990 are included in the text and the following tables. References to earlier work can be found in the previous reviews (Ferguson, 1988; Kabanov, 1998) and in the papers cited herein.

Section snippets

The significance of drug delivery systems

A feeling for the dimensions of the field of CDD can be obtained by performing a simple bibliometric count: there are seven journals containing keywords “encapsulation”, “controlled release” or “drug delivery” in their titles. The oldest three are about 20 or more years old, while the three most recent ones appeared since 2003. Total annual number of pages of these journals has been growing exponentially and exceeded 10,000 pages in 2005 (Fig. 1), which is no less than about 1000 papers only in

The importance of radiation sterilization of drug delivery systems

Just as the research on CDD systems is only a small fraction of the total research effort published in the pharmaceutical literature, so is the work on radiation sterilization of CDD/CDR systems only a small fraction of the total research effort published in that field. Literature search found about 150 journal papers on the subject since 1990, which should be compared with more than 70,000 pages only in dedicated journals in the same period, which are no less than 7000 papers in that type of

Radiation chemistry aspects of radiation sterilization and crosslinking

Two types of ionizing radiations are used for radiation sterilization and crosslinking: gamma rays emitted from the artificial radioactive isotopes 60Co and 137Cs and beams of energetic electrons from electron accelerators. The absorption of radiation energy from both types of sources occurs on a subatomic level. Electrons injected into matter from an electron accelerator enter into Coulombic interactions with atomic electrons of the medium, which results in numerous electronic excitations and

The effect of irradiation on the principal forms of CDD/CDR formulations

Having excluded solutions due to their inherent instability toward irradiation, the choice of formulations which can be subjected to radiation sterilization remains limited to solids, solids imbibed with liquids (hydrogels) and solids dispersed in liquids (liposomes and nanoparticles).

Irradiation of polymers leads to two main processes simultaneously: chain scission and crosslinking. The structure of the macromolecules, the presence of air and additives and irradiation conditions determine

The effects of irradiation on carrier materials

Normal reaction of an organism to a foreign substance, including a drug is to distribute it throughout the body via the blood circulation, try to burn it for energy (mainly in the liver) and finally to excrete whatever is left of it. Because of these metabolic processes the concentration of a drug in the body does not remain constant. The time profile of drug concentration at some location in the body is termed pharmacokinetics. To control pharmacokinetics, i.e. to maintain drugs in target

The effects of irradiation on drug release

CDD/CDR systems undergoing radiation sterilization have usually been manufactured in one of the two formats, microparticles or macroscopic objects. Microparticles can be administered by injection and may range in size from nano- to microspheres while macroscopic objects in the form of rods, disks, beads, plugs, sheets and wafers must be administered by surgical implantation to the target tissue or, exceptionally, by simple insertion. To be effective, drugs contained inside their microscopic or

Regulatory aspects of radiation sterilization of drugs

As a rule, early guidelines did not differentiate between drugs and medical devices. The fundamental difference between the two is that the drug has a defined chemical structure which, once the drug has been formulated, remains the same. On the other hand, a device undergoes an incremental development throughout its market lifetime (Phillips and Phillips, 2005). CDD/CDR systems can be understood as drug–device combinations: while the API remains the same, the composition and design of the

Tabular presentation of radiation effects on CDD/CDR systems containing various therapeutic classes

Comprehensive information on the effects of radiation sterilization on CDD/CDR systems published since 1990 can be found in the tables. The tables are organized according to the therapeutic classes of drugs. Twenty-six therapeutic classes have been the subjects of studies of radiation effects on CDD/CDR systems. Generic (non-proprietary) names of drugs are used, and within a given therapeutic class drugs are organized in alphabetic order. Eighty-five different drugs have been studied. The total

Concluding remarks

The value of any new drug is determined by the unmet needs and the urgency of the condition it treats. The list of the top 46 pharmaceuticals (“Drugs that changed our world”) (Baum, 2005) lists the drugs whose success apparently did not depend on the concept of controlled or targeted administration. This is not surprising given the fact that the success of most listed drugs was already established before the concepts of CDD/CDR were even developed. It should be noted that most drugs today are

Acknowledgments

The inception of this review was encouraged by Professor A.G. Chmielewski, then with the International Atomic Energy Agency, Vienna, Austria. Ms. Petra Gašparac, Faculty of Pharmacy and Biochemistry, University of Zagreb, and Ms. Marina Mayer, Ruđer Bošković Institute, are gratefully acknowledged for the help with literature. The work within the national project “Physicochemical Effects of Ionizing Radiations in Materials” (098-0982904-2954) was financially supported by the Ministry of Science,

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