Amnon Hoffman

Expandable gastroretentive dosage forms.

Expandable gastroretentive dosage forms (GRDFs) have been designed for the past 3 decades. They were originally created for possible veterinary use, but later the design was modified for enhanced drug therapy in humans. These GRDFs are easily swallowed and reach a significantly larger size in the stomach due to swelling or unfolding processes that prolong their gastric retention time (GRT). After drug release, their dimensions are minimized with subsequent evacuation from the stomach. Gastroretentivity is enhanced by the combination of substantial dimensions with high rigidity of the dosage form to withstand the peristalsis and mechanical contractility of the stomach. Positive results were obtained in preclinical and clinical studies evaluating GRT of expandable GRDFs. Narrow absorption window drugs compounded in such systems have improved in vivo absorption properties. These findings are an important step towards the implementation of expandable GRDFs in the clinical setting. The current review deals with expandable GRDFs reported in articles and patents, and describes the physiological basis of their design. Using the dog as a preclinical screening model prior to human studies, relevant imaging techniques and pharmacokinetic-pharmacodynamic aspects of such delivery systems are also discussed.

Rationalizing the selection of oral lipid based drug delivery systems by an in vitro dynamic lipolysis model for improved oral bioavailability of poorly water soluble drugs.

As a consequence of modern drug discovery techniques, there has been a consistent increase in the number of new pharmacologically active lipophilic compounds that are poorly water soluble. A great challenge facing the pharmaceutical scientist is making these molecules into orally administered medications with sufficient bioavailability. One of the most popular approaches to improve the oral bioavailability of these molecules is the utilization of a lipid based drug delivery system. Unfortunately, current development strategies in the area of lipid based delivery systems are mostly empirical. Hence, there is a need for a simplified in vitro method to guide the selection of a suitable lipidic vehicle composition and to rationalize the delivery system design. To address this need, a dynamic in vitro lipolysis model, which provides a very good simulation of the in vivo lipid digestion process, has been developed over the past few years. This model has been extensively used for in vitro assessment of different lipid based delivery systems, leading to enhanced understanding of the suitability of different lipids and surfactants as a delivery system for a given poorly water soluble drug candidate. A key goal in the development of the dynamic in vitro lipolysis model has been correlating the in vitro data of various drug-lipidic delivery system combinations to the resultant in vivo drug profile. In this paper, we discuss and review the need for this model, its underlying theory, practice and limitations, and the available data accumulated in the literature. Overall, the dynamic in vitro lipolysis model seems to provide highly useful initial guidelines in the development process of oral lipid based drug delivery systems for poorly water soluble drugs, and it predicts phenomena that occur in the pre-enterocyte stages of the intestinal absorption cascade.

Improving Oral Bioavailability of Peptides by Multiple N-Methylation: Somatostatin Analogues†

Low bioavailability of peptides following oral administration is attributed to their inactivation in the gastro–intestinal tract through enhanced enzymatic degradation in the gut wall by a variety of peptidases expressed at the enterocytes brush border, and to poor intestinal permeation. In addition, the instability of peptides toward peptidases in the systemic blood circulation causes rapid elimination (i.e., short half-life). These factors limit the use of peptides as therapeutic agents in the clinical setting. Several strategies have been used to reduce enzymatic cleavage and uptake into the systemic blood circulation, including prodrug approaches, peptidomimetics, and structural modifications, such as covalent attachment of polyethylene glycol (PEG), lipidation, and chemical modifications, for example, cyclization, d-amino acid substitution, and N-methylation. Cyclic peptides show improved chemical stability and thereby display longer biological half-life compared to their linear counterparts. Yet, additional modifications are required to generate peptides with enhanced enzymatic stability and improved oral bioavailability. One of the techniques suggested to improve the enzymatic stability of peptides is N-methylation. We recently developed a simplified method which allows fast and efficient multiple N-methylation of peptides on solid support. This simplified synthetic capability led us to study the influence of multiple N-methylation of the peptide backbone on its conformation and bioactivity. Inspired by the bioavailability of the highly N-methylated transplantation drug cyclosporin A, which can be administered orally although it violates all Lipinski9s rules on oral bioavailability; we assumed this bioavailability was a result of its multiple N-methylation together with cyclization. Thus, it is possible to overcome the above mentioned bioavailability drawbacks of peptides providing both the biological activity and the receptor selectivity by multiple N-methylation of cyclic peptides. Hence, we planned to screen a complete library of all the possible N-methylated analogues of the Veber–Hirschmann cyclic hexapeptide cyclo(-PFwKTF-) (1; Figure 1) which was reported to be selective towards sst2 and

Intestinal permeability of cyclic peptides: common key backbone motifs identified.

Insufficient oral bioavailability is considered as a key limitation for the widespread development of peptides as therapeutics. While the oral bioavailability of small organic compounds is often estimated from simple rules, similar rules do not apply to peptides, and even the high oral bioavailability that is described for a small number of peptides is not well understood. Here we present two highly Caco-2 permeable template structures based on a library of 54 cyclo(-D-Ala-Ala(5)-) peptides with different N-methylation patterns. The first (all-trans) template structure possesses two β-turns of type II along Ala(6)-D-Ala(1) and Ala(3)-Ala(4) and is only found for one peptide with two N-methyl groups at D-Ala(1) and Ala(6) [(NMe(1,6)]. The second (single-cis) template possesses a characteristic cis peptide bond preceding Ala(5), which results in type VI β-turn geometry along Ala(4)-Ala(5). Although the second template structure is found in seven peptides carrying N-methyl groups on Ala(5), high Caco-2 permeability is only found for a subgroup of two of them [NMe(1,5) and NMe(1,2,4,5)], suggesting that N-methylation of D-Ala(1) is a prerequisite for high permeability of the second template structure. The structural similarity of the second template structure with the orally bioavailable somatostatin analog cyclo(-Pro-Phe-NMe-D-Trp-NMe-Lys-Thr-NMe-Phe-), and the striking resemblance with both β-turns of the orally bioavailable peptide cyclosporine A, suggests that the introduction of bioactive sequences on the highly Caco-2 permeable templates may result in potent orally bioavailable drug candidates.

The solubility-permeability interplay in using cyclodextrins as pharmaceutical solubilizers: mechanistic modeling and application to progesterone.

A quasi-equilibrium mass transport analysis has been developed to quantitatively explain the solubility-permeability interplay that exists when using cyclodextrins as pharmaceutical solubilizers. The model considers the effects of cyclodextrins on the membrane permeability (P(m)) as well as the unstirred water layer (UWL) permeability (P(aq)), to predict the overall effective permeability (P(eff)) dependence on cyclodextrin concentration (C(CD)). The analysis reveals that: (1) UWL permeability markedly increases with increasing C(CD) since the effective UWL thickness quickly decreases with increasing C(CD); (2) membrane permeability decreases with increasing C(CD), as a result of the decrease in the free fraction of drug; and (3) since P(aq) increases and P(m) decreases with increasing C(CD), the UWL is effectively eliminated and the overall P(eff) tends toward membrane control, that is, P(eff) approximately P(m) above a critical C(CD). Application of this transport model enabled excellent quantitative prediction of progesterone P(eff) as a function of HP beta CD concentrations in PAMPA assay, Caco-2 transepithelial studies, and in situ rat jejunal-perfusion model. This work demonstrates that when using cyclodextrins as pharmaceutical solubilizers, a trade-off exists between solubility increase and permeability decrease that must not be overlooked; the transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption.

Pharmacokinetic Considerations of New Insulin Formulations and Routes of Administration

SummaryThere is a continuing search for improved insulin formulations in order to imitate as closely as possible the physiological pattern of insulin secretion, and thereby to minimise the complications of diabetes mellitus. The major advances achieved to date are in the area of human insulin analogue synthesis resulting from the introduction of recombinant DNA techniques, and in improved delivery systems that utilise noninvasive or minimally invasive modes of administration.To accommodate postprandial hyperglycaemia, monomeric insulin formulations have been developed, of which insulin lispro (the Lys-Pro analogue) is already approved for clinical use. These formulations have a rapid rate of absorption and, therefore, have to be administered at meal time (unlike the previous short-acting formulations). Their residence time is also about 2-fold shorter than regular human insulin; this minimises the risk of the excessive hypoglycaemic effect that characterises regular human insulin formulations. Certain proinsulin formulations with hepatoselective activity have been developed but were found to be poorly tolerated. The newer proinsulin molecules do not show hepatoselective properties.In order to generate basal insulin levels, peakless long-acting formulations have been developed, including: a soluble formulation (which upon subcutaneous administration, produces a ‘depot-like’ sustained release mechanism), albumin-bound insulin and cobalt-insulin hexamer formulations. To improve patient compliance the ‘pen’ device was developed for subcutaneous injections. Programmable infusion pumps were developed to avoid repetitive subcutaneous injections.Great efforts have been made in searching for noninvasive modes of insulin administration that will avoid the need for parenteral administration. These include: oral, colonic, rectal, nasal, ocular, buccal, pulmonary, uterine and transdermal routes of administration. Various enhancers have been tested to increase the bioavailability of each route. At present these alternative routes do not provide clinically relevant substitutes for the subcutaneous mode of administration.In conclusion, although the newer formulations provide certain advantages, there is still much to be done to further facilitate and improve insulin therapy.

Pharmacodynamic aspects of sustained release preparations

The sustained release (SR) mode of drug administration has certain features that have an important impact on the magnitude of the pharmacologic response: (a) it minimizes fluctuation in blood drug concentrations (i.e. between peak and trough). However, due to the pronounced non-linear relationship between drug concentration and pharmacologic effect (i.e. pharmacodynamics) the impact of this property differs considerably as a function of the shape of the pharmacodynamic profile and the position of the specific range of concentrations on the curve of this profile; (b) it produces a slow input rate which tends to minimize the bodys counteraction to the drugs intervening effect on regulated physiological processes; and (c) it provides a continuous mode of drug administration. This important pharmacodynamic characteristic may produce, in certain cases, an opposite clinical effect than that attained by an intermittent (pulsatile) mode of administration of the same drug. For many drugs with non-concentration-dependent pharmacodynamics, the exposure time, rather than the AUC, is the relevant parameter and it can therefore be optimized by SR preparations. The slow input function may minimize hysteresis in cases where the site of action is not in a rapid equilibrium with the blood circulation. The pharmacodynamics of the desired effect(s) and/or adverse effect(s) may also be influenced by the site of administration, especially in cases where the drug is delivered directly to its site of action. These factors demonstrate the important influence of the mode of administration on the pharmacological and clinical outcomes. In addition, they highlight the need to include these pharmacodynamic considerations in all stages from drug development to the optimization of their clinical use.

Novel levodopa gastroretentive dosage form: in-vivo evaluation in dogs.

Due to its narrow absorption window, levodopa has to be administered continuously to the upper parts of the intestine in order to maintain sustained therapeutic levels. This may be achieved by a controlled release (CR) gastroretentive dosage form (GRDF). The aim of this work was to develop a novel GRDF, based on unfolding polymeric membranes, that combines extended dimensions with high rigidity, and to examine the pharmacokinetics of levodopa compounded in the GRDF. Levodopa CR-GRDFs were administered to beagle dogs pretreated with carbidopa. The CR-GRDF location in the gastrointestinal tract was determined by X-ray, and serial blood samples were collected and assayed for levodopa. Optimization of the pharmacokinetic profile of levodopa from the CR-GRDFs was carried out based on the in-vitro in-vivo correlation following modifications of the release rates (adjusted by various membrane thicknesses) and drug loads. The successful CR-GRDF maintained therapeutic levodopa concentrations (>500 ng ml(-1)) over 9 h. In comparison to non-gastroretentive CR-particles and oral solution, mean absorption time was significantly extended. These outcomes demonstrate that the CR-GRDF may be used to improve levodopa therapy and can be applied to extend the absorption of other narrow absorption window drugs that require continuous input.

The Effect of Multiple N-Methylation on Intestinal Permeability of Cyclic Hexapeptides

Recent progress in peptide synthesis simplified the synthesis of multiple N-methylation of peptides. To evaluate how multiple N-methylation affects the bioavailability of peptides, a poly alanine cyclic hexapeptide library (n = 54), varying in the number of N-methyl (N-Me) groups (1-5 groups) and their position, was synthesized. The peptides were evaluated for their intestinal permeability in vitro using the Caco-2 model. Further evaluation of the transport route of chosen analogues was performed using rat excised viable intestinal tissue, a novel colorimetric liposomal model and the parallel artificial membrane permeability assay (PAMPA). While most members were found to have poor permeability (permeability coefficient, P(app) < 1 x 10⁻⁶ cm/s, lower than mannitol, the marker for paracellular permeability), 10 analogues were found to have high Caco-2 permeability, (P(app) > 1 x 10⁻⁵ cm/s, similar to testosterone, a marker of transcellular permeability). No correlation was found between the number of N-methylated groups and the enhanced permeability. However, 9/10 permeable peptides in the Caco-2 model included an N-Me placed adjacently to the D-Ala position. While the exact transport route was not fully characterized, the data suggests a facilitated diffusion. It can be concluded that multiple N-methylation of peptides may improve intestinal permeability, and therefore can be utilized in the design of orally available peptide-based therapeutics.

Novel Gastroretentive Dosage Forms: Evaluation of Gastroretentivity and Its Effect on Riboflavin Absorption in Dogs

AbstractPurpose. The purpose of this study was to design novel gastroretentive dosage forms (GRDFs) based on unfolding multilayer polymeric films, to investigate the mechanism of their gastroretentivity in dogs, and to assess the effect of compounding a narrow absorption window drug in a GRDF on the drugs absorption properties. Methods. Dosage forms (DFs) with different dimensions and mechanical properties were administered to beagle dogs with acidic buffer (pH=1.5), whose gastric retention time (GRT) was then determined by X-ray pictures. Concurrent administration of radiopaque markers was used to assess the effect of the GRDF and/or acidic buffer on GRT. The absorption of riboflavin from a prototype GRDF was compared with a nongastroretentive controlled-release DF and to an oral solution of the drug. Results. Large DFs (≥2.5 × 2.5 cm) containing rigid frame had prolonged GRT (>4 h). Administration of 400 mL of acidic buffer (or water) prolonged GRT whereas the GRDF did not cause additional prolongation. The extended absorption phase (>48 h) of riboflavin administered in a GRDF led to 4-fold increased bioavailability. Conclusion. The combination of large dimensions with rigidity produce gastroretentivity that can be used to improve absorption properties of a model of narrow absorption window drugs in the gastrointestinal tract.