The Pharmaceutical Journal
Vol 275 (Supplement) F28-F29
October 2005

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FIP Congress 2005

Biopharmaceutics and dosage aspects of the drug development process

A scientific symposium on 5 September focused on the pervasive role of biopharmaceutics and the drug development of different types of dosage forms, their evaluation and the conduct of bioequivalence studies.

Prediction of pharmacokinetics

Malcolm Rowland, of the University of Manchester, UK, commented that accurate preclinical prediction of pharmacokinetics in humans required insight. His presentation journeyed from allometric (body mass) scaling on to measurement of in vitro and in silico (computer) data in organs of animals and man. In the allometric approach, inter-species differences could be rationalised by scaling dose directly to body mass, whereas half-life time was proportional to a quarter-power (ie, fourth root) and clearance time to three-quarters-power of mass. These species relationships were illustrated through a series of Dedrick pharmacokinetic plots of distribution volume and clearance times — but there are limitations to this empirical approach. It is overly simplistic and ignores some species-specific parameters and innate body complexity. It cannot readily predict tissue loading, is unclear on incorporation of in vitro and in silico data, and when prediction fails it is difficult to select which component to adjust.

To explain big inter-species differences in organ metabolism, Professor Rowland described a compartmental model applicable to all mammals: a map of blood flow between all relevant organs, with the additional parameters of clearance (tissue affinity) and membrane permeability overlaid. The way forward, he said, was through physiologically based pharmacokinetics. This systems approach derived a likely profile in humans from animal in vitro data, provided better understanding of a compound and likely outcomes during clinical development, and furnished an integrated framework predicting differences in a series of compounds.

More careful examination revealed problems in inter-species scaling, taking account of factors such as enzyme activity, protein binding, tissue affinity and weight, and differences in adipose distribution.

Professor Rowland reviewed sources of variability in man (gender, diet, size, disease, age, genetics and environment), and of uncertainty (sampling, assay and model assumptions). He illustrated the greater scatter obtained with Dedrick (allometric) plot of observed versus predicted plasma concentration, compared with a much tighter envelope derived from the physiologically based pharmacokinetics approach.

Turning to quantitative aspects of structure-pharmacokinetics correlation, he presented some lipophilicity and plasma protein binding correlation charts for a homologous series of barbitone analogues, thereby confirming that lipophilicity increased regularly with the size of the 5-alkyl substituent, with a matching increase of binding up to 90 per cent. And since most medicinal substances are organic bases, he reported a similar in silico exercise for a large series of basic substances. He concluded that physiologically based models are mechanistic and highly informative, offer a systems approach to pharmacokinetics, allow integration and scaling of information from various sources to predict events in man, and, he claimed, “hasten the age of increasingly confident prediction and application”.

Problems assessing generic drugs

An impressive series of problems or challenges in the development and registration of generic products was comprehensively examined by Kamal Midha, of the University of Saskatchewan, Canada. He recognised the need in many countries to demonstrate pharmaceutical equivalence between generic formulations. The degree of bioequivalence for the same active pharmaceutical ingredient (API) may change during the formulation process — by altering the initial salt or ester, or creating different ratios of bioactive congeners in a complex naturally derived product.

In the US, the FDA expects pharmaceutical identity for generic products — the same tablet (or capsule) presentation and the same amount and molecular form of the API. Dr Midha instanced five common substances that occur in, or may be converted during formulation to, a different polymorphic form or solvate isoform. With biologicals, and also products obtained through recombinant biotechnology, they may suffer a variety of inter-batch differences, notably an aberrant aminoacid sequence, all potentially affecting generic bioequivalence.

Dr Midha wondered whether a single bioequivalence standard should apply to all classes of drugs when comparing the pharmacokinetic profile parameters of maximum concentration and area-under-the-curve. However, a statistical criterion of +10 per cent confidence interval (CI) could be too tight for many drugs. A less restrictive approach would be setting different pharmaceutical equivalence standards for different classes of product according to in vivo (pharmacodynamic) safety and efficacy properties and type of formulation. But the wider the CI, the greater number of subjects is required in the trial.

He noted that bioequivalence issues particularly arise with:

• Drugs with a long half-life, where plasma values are confounded by lipid storage

• Highly variable drugs (variation exceeding 30 per cent), although these are usually safe because of their wide therapeutic range

• Drugs with a narrow therapeutic (dose critical) range, for which their steep response curves raise concern about toxicity and interchangeability, and require narrower CIs

• Modern controlled release parenteral formulations, such as liposomes and micro-spheres for targeted delivery

There are also bioequivalence issues with endogenous drug products, notably difficulties in estimating the body’s natural “baseline” and diurnal changes. For instance, treatment with a gel formulation of testosterone is complicated by baseline values: there is a peak for a normal healthy man at around 7am but concentrations are minimal in the mid afternoon.

Trials of topical products are large, cumbersome and expensive, he said, and pose bioequivalence problems with multiple clinical end-points, while inhalation device studies are complex and involve detailed delivery parameters and huge inter-subject variability, which predicates ultra-sensitive low-level analysis in cross-over designs to assess safety equivalence.

Dr Midha concluded that there are still many bioequivalence issues to be resolved with generic versions of newer targeted forms and biogenetics. He looked to global discussion and understanding and science-based solutions.

Poor drug absorption

Navnit Shah, of Hoffmann La Roche, US, reviewed poorly absorbed drugs. Absorption is critically affected by low solubility, chemical instability, a molecular mass above 500Da, unstable enzymic complexes, low membrane permeability (which is exacerbated by excessive polar amine and hydroxyl groups), gut volume and pH, reverse transport (reflux) and first-pass effects. Dr Shah examined six distinct expedients for improving oral absorption.

Reduction of particle size significantly increases drug surface area, leading to better dissolution and, potentially, drug absorption. Size reduction techniques include low and high energy hammer mills (particles down to 20µm), air jet micronising (range 10µm to 2µm) and wet milling for the range 5µm to 0.5µm. He illustrated the influence on dissolution rate and bioavailability but warned of the need to overcome aggregation of nanoparticles, perhaps using a suitable surfactant. Salt formation improved solubility, provided rapid dissolution and normally resulted in improved bioavailability. A carefully chosen digestible lipid formulation was an excellent method for maximising absorption. Such delivery systems are single phase self-emulsifying formulations comprising a medium- or long-chain triglyceride vehicle and a variety of emulsifiers, including polyglycerol esters and polyglycolysed glycerides. Poorly soluble substances can also be efficiently solubilised by complexation within cyclodextrin cavities.

Dr Shah explained the need to convert poorly soluble crystalline forms to thermodynamically unstable hygroscopic amorphous formulations, which have the macro properties of a solid but a liquid microstructure. Absorbed moisture reduces glass transition temperature, increases molecular mobility and enhances bioavailability. In solvent controlled micro-precipitation, the pH and temperature conditions are critical for uniform embedding of sub-micron amorphous drug in a matrix formed with anionic methacrylate co-polymers. He reported trials on dogs in which bioavailability of one Roche candidate drug improved dramatically from 4 to 89 per cent.

Dr Shah concluded that an optimally selected pharmaceutical technology based on careful consideration of the physicochemical properties of the active substance should provide an effective strategy for improving the bioavailability of poorly absorbed drugs.

Hydrophilic drugs

Hans Junginger, visiting professor at Naresuan University, Thailand, provided a review of some work on the pharmaceutical delivery and absorption of hydrophilic drugs which, despite being highly soluble, could still be poorly absorbed.

He contrasted the development time and costs of various drug delivery systems: oral slow release products had the lowest development cost and shortest time to market, but these constraints increased through the sequence of rapid dissolution, transmucosal, transdermal and iontophoretic products, up to mucosal peptide systems.

“Is the difficult task of per-oral peptide delivery really feasible,” he asked. “Yes.” It seems that the only serious problem is consecutive absorption of peptides and proteins in the gastrointestinal tract. The delivery constraints result from macromolecules being too large, too labile or too polar to cope with the intestinal mucus blanket, and thus not degraded by GI enzymes or crossing the lipophilic barrier.

To increase intestinal absorption, one strategy is local modification of the enzymes, using functional polymers as protease inhibitors or permeation enhancers: polyacrylate hydrogels assist calcium binding and influence intercellular junctions. Another approach is to vary the mucosal epithelium by use of chitosan (2-amino cellulose) to ensure a high calcium gradient reversibly opens the “tight junctions” of the intestinal villi.

Polymeric microcapsules, microgranules or nanoparticles are an alternative per-oral delivery system for hydrophilic peptides. Optimal peptide delivery is achieved through attachment of the microsized muco-adhesive to the mucus layer and opening the “tight junctions” of the epithelium.

A novel way to deliver this superporous hydrogel is a small capsule that generates carbon dioxide, causing local swelling of the capsule. This super-swelling system ensured absorption of octreotide in a trial with six female pigs, followed by a human volunteer enteric release study using gammascintigraphic measurement. He said a hydrogel core system appeared promising in a current insulin trial in Iran but the final results were not yet known.

Professor Juninger summarised that new hydrogel delivery systems enhance absorption of per-oral peptides. The patented swelling system is easily constructed and can be targeted to different pH regions of the GI tract and, after hyper-swelling, the gut peristalsis readily disperses fine particles of drug.

Controlled release forms

Adel Sakr, of the University of Cincinnati, US, reported development of four successful extended release (ER) dosage forms. In pharmacokinetic studies in rabbits with bumetanide layered on sugar pellets and coated with methacrylate co-polymer, they found good agreement between experimental and predicted dissolution profiles and there was a distinct improvement in diuretic efficiency in the day following dosing.

His second project developed an optimum ER matrix form of propranolol that showed diffusion controlled release and enhanced bioavailability. But stability studies revealed some problems at elevated temperatures.

The third ER formulation successfully controlled the release of buspirone: single and multiple dose studies in man demonstrated a higher bioavailability than the immediate release marketed product.

His fourth project formulated a targeted antibiotic (nisin) system for delivery to the proximal colon, which was tested as a radio-tagged system in humans. It was noted that the in vivo disintegration largely depended on coating thickness.

Nanotechnology

Yilmaz Çapan, of Hacettepe University, Turkey, described some pharmaceutical applications of nanoparticle technology. This brought together skills in engineering, electronics, physical and material science, and manufacturing at the sub-micron level. In the tiny nanospheres, the drug is dispersed throughout the polymeric matrix and in nanocapsules there is an oily core reservoir inside a polymeric membrane.

The advantages are that the product is stable and easily freeze-dried, provides specific tissue targeting of a wide range of drug substances, protects them against premature chemical or enzymic degradation and, in some instances, he claimed, reduces side effects.

In drug delivery, the nanoparticles improve adhesion to gut wall, allow mucosal delivery of higher molecular mass substances such as proteins and oligonucleotides, and increase solubility and dissolution rate of poorly soluble drugs.

Professor Çapan discussed methods of surface modification forming biodegradable polymeric coatings.

He showed that polysorboate coated nanoparticles could penetrate the blood-brain barrier by binding to the inner endothelial lining of brain capillaries, and the large concentration gradient enhances passive diffusion take-up. For cancer therapy, they had developed stealth particles smaller than 100nm that were “invisible” to macrophages. These are characterised by a long half-life in blood, and were found to have increased antitumour activity, reduced systemic side effects and provided selective delivery of oligonucleotides.

Another design delivered an antibiotic in a form endocytosed by phagocytic cells and then released to fight intracellular infections from bacteria possessing complex defence mechanisms. It has proved effective against salmonella, listeria, brucella, legionella and Mycobacterium tuberculosis, Professor Çapan concluded.