Michael John Rathbone

Fundamentals and applications of controlled release drug delivery

The Need for Drugs and Drug Delivery Systems.- Overview of Controlled Release Mechanisms.- Hydrophobic Polymers of Pharmaceutical Significance.- Hydrogels.- Biodegradable Polymers in Drug Delivery Systems.- Diffusion Controlled Drug Delivery Systems.- Swelling Controlled Drug Delivery Systems.- Degradable Polymeric Carriers for Parenteral Controlled Drug Delivery Systems.- Porous Systems.- Targeted Delivery Using Biodegradable polymeric Nanoparticles.- Liposomes in Drug Delivery.- Receptor Mediated Delivery Systems for Cancer Therapeutics.- Biological Rhythms, Drug Delivery, and Chronotherapeutics.- Site Specific Controlled Release for Cardiovascular Disease - Translational Direction.- Drug Delivery Systems to Fight Cancer.- Applications of Vaccine Delivery in Infectious Diseases.- Tissue Engineering in Drug Delivery.- The Shaping of Controlled Release Drug Product Development by Emerging Trends in the Commercial, Regulatory and Political Macro-Environment

Overview of Controlled Release Mechanisms

Controlled release systems have been developed to improve the temporal and spatial presentation of drug in the body, to protect drug from physiological degradation or elimination, to improve patient compliance, and to enhance quality control in manufacturing of drug products. When designing controlled-release systems, it is important to identify and understand particular mechanisms involved in the release process. Often, more than one mechanism is involved at a given time or different mechanisms may dominate at different stages of the drug delivery process. This chapter begins with several vignettes, each highlighting a mode of controlled drug delivery and identifying associated mechanisms. An introductory description of several of the mechanisms follows. Details regarding these mechanisms are provided in subsequent chapters.

Recent advances in bovine reproductive endocrinology and physiology and their impact on drug delivery system design for the control of the estrous cycle in cattle.

When methods of drug intervention are being developed to control estrous cycles, a thorough understanding of the endocrine and functional changes together with the reproductive behavior of the animals are essential. This review presents our current knowledge on reproductive endocrinology, physiology and behavior, and the methods of drug intervention to control estrous cycles. It also describes current efforts to develop advanced drug delivery systems that meet the animal scientists demands to control the estrous cycle in cattle.

Fertility regulation in cattle.

This paper reviews the physiological, endocrinological and pharmaceutical literature pertaining to the design, development and optimisation of subcutaneous and intravaginal progestogen-containing drug delivery systems used in the control of synchrony and ovulation in cattle.

Reengineering of a commercially available bovine intravaginal insert (CIDR insert) containing progesterone

The purpose of this study was to reengineer a commercially available intravaginal insert containing 1.9 g progesterone (CIDR intravaginal insert) for a 7-day insertion period in cattle. The reengineering process resulted in a reduced initial drug load (1.38 g) and a reduction in the residual drug load following insertion, while at the same time maintaining the biological performance of the insert. The in vitro and in vivo pharmaceutical properties of the commercially available CIDR intravaginal insert were characterized initially to gain a thorough understanding of the factors that affected progesterone release from the insert. The effect of changing a selection of formulation and physical variables of the insert was also investigated (including surface area, drug load, addition of pore forming materials, silicone shore hardness and drug particle size). The knowledge gained from these studies was used to define the characteristics of the reengineered insert which was then manufactured and shown to be bioequivalent and clinically equivalent to the commercially available insert.

Conceptual and commercially available intravaginal veterinary drug delivery systems

In the veterinary area the utilization of the vagina as a route for drug delivery has focused on the systemic delivery of hormonal steroids to control synchrony, ovulation and fertility in a variety of livestock. There are several reasons for administering drugs to modify the menstrual cycle in humans and the estrous cycle in animals and this paper provides a comparison of the objectives of drug intervention to control reproduction in humans and livestock. In addition, the types of hormones and their concentrations found during the menstrual cycle in humans and during the estrous cycle in animals are compared. The paper also reviews the intravaginal drug delivery systems developed for the control of the estrous cycle in livestock and both conceptual and commercially available intravaginal drug delivery systems that have been described in the literature are described. The history of some of the delivery systems is included and the future directions of this area of research are discussed.

Development of an injection molded poly(ϵ-caprolactone) intravaginal insert for the delivery of progesterone to cattle

Abstract This paper reports experiments conducted to research, develop and clinically evaluate an injection molded intravaginal insert manufactured from the biodegradable polyester poly(ϵ-caprolactone). The study demonstrated that it is possible to engineer poly(ϵ-caprolactone) into a shape that is well retained, and can be used as a platform for the controlled delivery of progesterone via the vagina of cows. Field evaluation showed that the poly(ϵ-caprolactone) intravaginal inserts containing 10% (w/w) progesterone were at least as effective clinically as the commercially available CIDR intravaginal insert.

Modified release drug delivery in veterinary medicine.

To successfully research and develop an animal pharmaceutical dosage form, a diverse array of issues covering basic medicine, pharmacology and technology must be addressed. Societal concerns regarding animal and public health, as well as the rapidly changing farming and economic environments, provide additional challenges that require integration into an already complex web of issues. Here, we examine the drive towards reducing the frequency of administration to animals and the closing of gaps between the human and veterinary drug product development.

CRS/AAPS Joint Workshop on Critical Variables in the In Vitro and In Vivo Performance of Parenteral Sustained-Release Products

The Controlled Release Society (CRS) and the American Association of Pharmaceutical Scientists (AAPS) recently co-sponsored a workshop on the critical variables impacting the in vivo performance of parenteral controlled-release formulations. This workshop was a continuation of discussions initiated during the 2007 CRS Educational Workshop entitled “In Vitro and In Vivo and Considerations Associated with Parenteral Sustained Release Products,” the outcome of which was summarized in the Journal of Controlled Release (1). The 2008 workshop focused on the use of design-space concepts as a mechanism to identify the critical quality attributes associated with in vivo product performance and to facilitate the development and use of in vitro test methods for (1) setting batch release characteristics, (2) ensuring the equivalence of product performance when there are changes in formulations, excipients, or manufacturing methods, and (3) modifying batch release specifications. To address these complex issues, the workshop format allowed experts to present their perspectives on challenges associated with assuring the quality and performance of a range of state-of-the art parenteral delivery systems and provided an opportunity to hear and discuss a range of topics critical to parenteral product performance. The ten questions that served as the focus of breakout group discussions are provided in Table 1. It is also noteworthy that this workshop was the first opportunity for CRS membership to consider these questions and provide a response electronically by logging on to the CRS website (2). Feedback from the workshop participants included the following points: • Regardless of the type of parenteral product, some methodology should be employed to ensure that it is functioning as intended before batch release. • In some cases, quality control testing procedures necessitate the use of multiple tests to demonstrate adequate function of these complex delivery systems. • Host response may not be due solely to the bioactive in the product or to its chemical components, but may be related to dosage form size, shape, age, or surface characteristics. • It is important that product development is not hindered by the process of defining test requirements and that economic and time constraints are considered when developing in vitro release specifications. • Nontraditional tests can be developed, but relevant release specifications must be set if they are developed. That said, existing USP methods are underutilized, and it would be preferable (prudent) to develop tests that rely on USP apparatus since the specifications for the physical and experimental conditions associated with the use of USP apparatus are well-defined. • The establishment of any set of product specifications needs to be an iterative process. • There could be a difference between quality control methods and a method that is used to support a biowaiver. However, if a test is developed solely for quality control purposes and has been designed specifically to monitor critical quality attributes, then it cannot be used to predict biological performance. • If the release specification is intended to ensure therapeutic activity, it will be necessary to ascertain the biological relevance of the test results and the release specifications through studies that establish the in vivo–in vitro relationship. • For more complex dosage forms, safety concerns may extend beyond the rate and extent of drug exposure. When there are additional safety or efficacy concerns that cannot be addressed with bioequivalence trials, it may not be feasible to develop generic formulations of these products (e.g., products with safety and activity profiles based on ligand-based targeted delivery systems). • When employing the design-space concept, extremes of the proposed specifications should be tested both in vitro and in vivo (where in vivo studies can include the use of animal models). The in vivo data are needed to ensure that the in vitro test is reliable and discriminating. When using design space, aged materials need

Controlled release drug delivery systems for estrous control of domesticated livestock

Publisher Summary The need for controlled release drug delivery systems in the field of estrous control of domesticated livestock arises due to the physicochemical and pharmacokinetic characteristics of the drugs. The first use of controlled release drug delivery systems to control the estrous cycle of sheep and cattle dates back to the mid 1960s and mid 1970s, respectively. In spite of the long history associated with this area of drug delivery, the opportunity to develop and commercialize controlled release drug delivery systems to control the estrous cycle of domesticated species has never been greater. This is because of the rise in on-farm use of procedures such as embryo transfer and new assisted reproductive technologies. This chapter describes the controlled release drug delivery systems which are currently available or in development for the control of the estrous cycle in sheep, cattle, pigs, and horses. It describes some of the formulation considerations for such products and highlights recent advances in the field of estrous control in horses and pigs.