When a lead compound with excellent pharmacological effect is discovered, drug development usually starts from chemical derivatization to obtain a compound that could be developed through existing development processes using a conventional formulation. However, it has become more difficult to obtain a drug substance with sufficient properties from the viewpoint of pharmacokinetics and safety. In order to accomplish drug development from the lead compound most efficiently, it should be attempted to use DDS to cover such issues of a compound in addition to refining the compound by chemical modification. Maturing and successful paradigms of DDS application for LCM in Western countries encourage the application of DDS also to novel compounds. In this review, the options of applicable DDS to cover compound issues are summarized in the order of preference for the general pharmaceutical industry.

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This article explains how the venture business acts as a catalyst in the evolution of DDS contract research and development companies with special technology in a DDS field. The venture business prepares the DDS contract company for their research and development collaborations with pharmaceutical companies. The article is based on a large DDS database created in 1980, and maintained daily to date, involving DDS companies, venture capital, technologies and collaborations in drug delivery R&D.

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The advantages of pulmonary drug delivery are superior efficacy, safety, prolonged action and rapid onset of action, which other drug administration routes cannot achieve. In spite of long history of research for pulmonary delivery, little was known for the basic concept of inhalation therapy because there were many key factors such as drug, drug formulation and device. However, clinical character of inhaled drug has been able to be estimated by evaluating these factors totally, based on the recent reports of both basic and clinical researches on inhaled corticosteroids. Particularly, aerodynamic particle size delivered via device and particle depositions in respiratory tract and alveolus have strong relation not only to efficacy but to safety. Large particles are deposited much in mouth and oesophageal region, and ultrafine particles in alveoli. The particles is deposited in the alveoli region, probably get high deposition rate in the lung with very quick absorption. Therefore it is very important to develop new device which provide optimal aerodynamic particle size depending on the purposes of pulmonary drug delivery. New inhaled drug cannot be evaluated in animal studies since animal cannot inhale the drug as human does. So the formulated inhaled drugs are mainly evaluated by aerodynamic particle size distribution and pharmacokinetics in human. From these results, we can estimate whether the inhaled drug achieve the therapeutic purpose in clinical trials or not.

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The hepatitis C virus (HCV) is currently estimated to infect over 270 million people worldwide, with up to 4 million people newly infected each year. It is the leading cause of chronic liver disease and the most common reason for liver transplantation in the USA and Europe. The pegylated interferons (peginterferon alfa-2b: PEG-INTRON^® and peginterferon alfa-2a: PEGASYS^®), alone or in combination with ribavirin, are the current standard of care for patients with HCV. There are significant chemistry and manufacturing control (CMC) challenges in the manufacture and characterization of the pegylated interferons since these therapeutic drugs are composed of heterogeneous mixtures of mono-pegylated proteins with differing sites of attachment of polyethylene glycol (PEG) to the core interferon molecule, termed “positional isomers”. These CMC issues were comprehensively addressed during the development of PEG-INTRON^®. Extensive characterization of the pegylated interferon in the drug substance and drug product, and the establishment of appropriate manufacturing controls, served as the foundation for a successful CMC strategy to obtain regulatory approval. This study describes the analytical strategies for quantitating the positional isomer populations which comprise PEG-INTRON^®. Individual positional isomers were also isolated and characterized with respect to site of pegylation and in vitro biological potency. It was determined that different pegylation chemistries result in different mixtures of positional isomers. PEG-INTRON^® is predominantly pegylated at histidine 34, demonstrated to be the most biologically active positional isomer of the pegylated interferons. In contrast, the antiviral activities of positional isomers generated by attachment of PEG to lysine residues were significantly lower. Thus, the differences in pegylation chemistry between PEG-INTRON^® and PEGASYS^® result in different distributions of pegylated positional isomers and differential biological activity profiles in vitro.

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Clinical study plan for DDS preparations is dependent on available clinical data and design of the original non-DDS drug, overseas data, standard therapy, patient population, and so on. Most important element to be considered is to demonstrate clinical benefit over the non-DDS preparation and/or standard therapy in time course of pharmacokinetics/pharmacodynamics, clinical efficacy, and safety. In this article, general guidelines, though they are not specific to DDS preparations, to be considered for clinical developments of DDS preparations and examples of clinical Droaram on several DDS preoarations are summarized.

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Drug delivery system aims at optimization of the effect of drugs. In that sense, its benefit should be given for patients. DDS may be considered as a routine work in the process of new drug development, and it is an ideal that all new drug products will be optimized for drug therapy when they will be approved.

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Many years has already passed since the concept of DDS was first introduced into the field of pharmaceutical formulation development from the viewpoint of optimized pharmacotherapy. Recently, drug delivery technology has been attracting much attention as an effective tool for practicing the lifecycle management of pharmaceutical products. Indeed, the escalating cost of drug development and the increasing threats from generics after patent expiration necessitate aggressive lifecycle management strategies. Drug delivery has proven to be a viable and cost effective tool for extending a product's lifecycle, and many DDS products are now under development. In this paper, the importance of product lifecycle management utilizing drug delivery in the pharmaceutical production is addressed, and also the recent trend of the development of drug delivery systems are reviewed.

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Powder formulations of fluorescein were prepared with carriers, including microcrystalline cellulose (MCC), hydroxypropylcellulose (HPC), and lactose or polystyrene particles (PP), and administered to rabbits intranasally. The order of fluorescein absorption in terms of the AUC was MCC > PP > HPC > lactose. To clarify the differences between the carriers, absorption and elimination of fluorescein from the nasal cavity were simultaneously determined using a newly developed in vivo method. Elimination of carriers was also determined by the method. To quantify insoluble MCC and PP, a new image-analysis method was developed. These results, with in vitro fluorescein release studies, suggest that the schematic role of carriers in nasal delivery is as follows. Both MCC and PP are insoluble and showed rapid fluorescein release. PP was eliminated rapidly, while MCC was retained in the cavity. This suggests that bioadhesive MCC probably forms a local environment with a higher fluorescein concentration between the particles and membrane, thus resulting in enhanced absorption. In the HPC formulation, fluorescein or HPC eliminations and fluorescein release were sustained due to its gel-forming property. In the lactose formulation, lactose dissolves rapidly, and there may be no means for fluorescein to stay near the mucous membrane. As a result, fluorescein was eliminated rapidly by mucus flow, thus resulting in poor absorption.

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We prepared tablets in the form of a Core-Shell type to restrain the drug release in the gastric juice and to transport it selectively to the intestinal juice. We then evaluated the release behavior of the tablet, using a mixed powder of sodium alginate (Alg) and methyl glycol chitosan (MG) for the shell layer with theophylline (TH) as the model drug at the core. We determined absorptiometrically (271 nm) the release rate of TH in the process of transferring the tablet from artificial gastric juice (pH 1.2) to artificial intestinal juice (pH 6.8) after passage of a predetermined time. The release rate in the artificial gastric juice was restrained down to ca. 10%. When the tablet was transferred from the artificial gastric juice to the artificial intestinal juice, the “squeezing effect”, which is when the release rate increased rapidly, was observed. The “squeezing effect” reached a maximum level when Alg and MG in the shell layer were on an equimolar composition, and the release rate increased 9-fold. It was found that the “squeezing effect” was provoked by the volume contraction in the swelling layer of the tablet caused by formation of the polyion complex between Alg and MG and by the occurrence of cracks accompanied by the contraction.

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