Biopharmaceutical Evaluation and CMC Aspects of Oral Modified Release Formulations.

This article discusses the range of outcomes from biopharmaceutical studies of specific modified release (MR) product examples in preclinical models and humans. It touches upon five major biopharmaceutical areas for MR drug products: (1) evidence for regional permeability throughout the GI tract, (2) susceptibility to food-effect, (3) susceptibility to pH-effect, (4) impact of chronopharmacology in designing MR products, and (5) implications to narrow therapeutic index products. Robust bioperformance requires that product quality is met through a thorough understanding of the appropriate critical quality attributes that ensure reliable and robust manufacture of a MR dosage form. The quality-by-design (QbD) aspects of MR dosage form design and development are discussed with the emphasis on the regulatory view of the data required to support dosage form development.

Pharmaceutical development and regulatory considerations for nanoparticles and nanoparticulate drug delivery systems.

Pharmaceutical nanomaterials (NMs) encompass a wide variety of materials including drug nanoparticles (NPs), which can be amorphous or crystalline; or nanoparticulate drug delivery systems, such as micelles, microemulsions, liposomes, drug-polymer conjugates, and antibody-drug conjugates. These NMs are either transient or persistent-depending on whether the integrity of their structure and size is maintained until reaching the site of drug action. Examples of several approved drug products are included as pharmaceutical nanoparticulate systems along with a commentary on the current development issues and paradigms for various categories of NPs. This commentary discusses the preparation of nanoparticulate systems for commercial development, and the biopharmaceutical and pharmacokinetic advantages of these systems. A criterion of criticality is defined that incorporates the structure, in addition to size requirement of pharmaceutical NPs to identify systems that may require special development and regulatory considerations.

Generic development of topical dermatologic products, Part II: quality by design for topical semisolid products.

The emergence of quality by design as a relatively new systematic science and risk-based approach has added a new dimension to pharmaceutical development and manufacturing. This review attempts to discuss the quality by design elements and concepts applied for topical semisolid products. Quality by design begins with defining a quality target product profile as well as critical quality attributes. Subsequently, this is followed by risk identification/risk analysis/risk evaluation to recognize critical material attributes and critical process parameters, in conjunction with design of experiments or other appropriate methods to establish control strategies for the drug product. Several design-of-experiment examples are included as practical strategies for the development and optimization of formulation and process for topical drug products.

Generic development of topical dermatologic products: formulation development, process development, and testing of topical dermatologic products.

This review presents considerations which can be employed during the development of a semi-solid topical generic product. This includes a discussion on the implementation of quality by design concepts during development to ensure the generic drug product has similar desired quality attributes to the reference-listed drug (RLD) and ensure batch to batch consistency through commercial production. This encompasses the concept of reverse-engineering to copy the RLD as a strategy during product development to ensure qualitative (Q1) and quantitative (Q2) formulation similarity, as well as similarity in formulation microstructure (Q3). The concept of utilizing in vitro skin permeation studies as a tool to justify formulation differences between the test generic product and the RLD to ensure a successful pharmacodynamic or clinical endpoint bioequivalence study is discussed. The review concludes with a discussion on drug product evaluation and quality tests as well as in vivo bioequivalence studies.

Ion-exchange resins as drug delivery carriers.

There are many reports in the literature referring to the utilization of drug bound to ion-exchange resin (drug-resinate), especially in the drug delivery area. Ion-exchange resin complexes, which can be prepared from both acidic and basic drugs, have been widely studied and marketed. Salts of cationic and anionic exchange resins are insoluble complexes in which drug release results from exchange of bound drug ions by ions normally present in body fluids. Resins used are polymers that contain appropriately substituted acidic groups, such as carboxylic and sulfonic for cation exchangers; or basic groups, such as quaternary ammonium group for anion exchangers. Variables relating to the resin are the exchange capacity; degree of cross-linking, which determines the permeability of the resin, its swelling potential, and the access of the exchange sites to the drug ion; the effective pK(a) of the exchanging group, which determines the exchange affinity; and the resin particle size, which controls accessibility to the exchange ions. In this review, the properties of ion-exchange resins, selection of drugs that lend themselves to such an approach, selection of the appropriate resin, preparation of drug-resinate, evaluation of drug release, recent developments of drug-resinates, and applications are discussed.

Effect of a lipoidic excipient on the absorption profile of compound UK 81252 in dogs after oral administration.

PURPOSE: Effect of caprylocaproyl macrogolglycerides (Labrasol), as a lipoidic excipient/vehicle in an oral capsule formulation, on pharmacokinetic disposition of a BCS Class 3 compound, UK-81252, was investigated in vivo in a canine model. METHODS: The control and lipoidic formulations were administrated to six Beagle dogs in a crossover, single dose design with a 2-week washout period in between treatments. The plasma concentration-time profile for the lipoidic formulation was compared to that of the control formulation (lactose-based oral capsule). RESULTS: Although the lipoidic formulation resulted in a markedly increased oral bioavailability (based on mean pharmacokinetic parameters, AUC(0-48 hr) and C(max) ), a double-peaking phenomenon was observed with this formulation. The most likely cause of this double-peak effect was the gastric emptying retardation attribute of the lipoidic vehicle/excipient. The initial peak (Tmax1) was due to the absorption enhancing properties of the lipoidic formulation and the second peak (Tmax2) was most likely the result of a shutdown in gastric emptying for a period of up to 2 hours (this value varied between dogs) after which the remaining Compound UK 81252 emptied from the stomach to generate the second peak. CONCLUSIONS: Caprylocaproyl macrogolglycerides enhanced the absorption of Compound UK 81252. After oral administration, the liquid-filled formulation consistently produced a double-peak phenomenon in the plasma profile. Labrasol was determined to be the most likely culprit for this double peaking phenomenon.

Effect of hydroxypropyl beta-cyclodextrin on drug solubility in water-propylene glycol mixtures.

Combined effects of cosolvency and inclusion complexation on drug solubility were studied using a model hydrophobic compound (carbamazepine) and a model hydrophilic compound (Compound S). Propylene glycol (PG) was used as the nonaqueous solvent, and deionized water was employed for the aqueous systems. Hydroxypropyl beta-cyclodextrin (HPbetaCD) was chosen as the complexing agent and studied at concentrations up to 28% (w/v). Complex formation constants (Kc) and solubility enhancement ratios were determined for the respective compounds in various water/PG vehicles. The data suggested that the inclusion of the compounds was most favorable when water alone was used as the vehicle. However, the combined approach of cosolvency and complexation resulted in a significant increase in the total apparent solubility of carbamazepine (the hydrophobic compound). The same was not observed with Compound S (the hydrophilic model), since PG weakened the interactions between the molecule and HPbetaCD, and thus, no synergistic or additive effects were observed with the combined approach of complexation and cosolvency.

Evaluation of the in vivo disintegration of solid dosage forms of a bile acid sequestrant in dogs using gamma-scintigraphy and correlation to in vitro disintegration.

PURPOSE: [corrected] To evaluate the in vivo disintegration behavior of tablets and capsules of a bile acid sequestrant, DMP 504, in beagle dogs and to assess the significance of the in vitro disintegration of the dosage forms on subsequent in vivo behavior in order to draw possible in vitro-in vivo correlations. METHODS: Tablet and capsule formulations of a bile acid sequestrant, DMP 504, were formulated with samarium oxide and neutron activated to produce radioactive 53Sm to noninvasively evaluate their in vivo behavior in beagle dogs by gamma-scintigraphy. A four-way crossover design was completed (n = 4) in which (a) tablets from two different batches were administered under the fasted condition and manufactured using different lots of drug substance where one batch exhibited relatively faster in vitro disintegration time (30 min) than the other tablet batch, which resulted in slower disintegration (45 min), (b) a capsule formulation was administered to fasted beagles, and (c) the tablet having slower in vitro disintegration was also administered in the fed state, and its in vivo disintegration was compared to that observed in the fasted state. RESULTS: Tablets manufactured using a lot of DMP 504 having relatively fast in vitro disintegration (approximately 30 min) resulted in relatively rapid in vivo disintegration time (15 min) in the fasted condition. This in vivo disintegration time was comparable to the in vivo disintegration of the capsules (17 min) even though the in vitro capsule disintegration time was considerably faster (2 min). Tablets prepared using a drug substance that provided a longer in vitro disintegration time (approximately 45 min) resulted in a slower in vivo disintegration (63 min). There was no difference observed in the in vivo disintegration behavior in fasted and fed dogs for the tablets that provided slower in vitro disintegration. CONCLUSION: In vivo disintegration of tablets of the bile acid sequestrant DMP 504 correlated with in vitro disintegration times. Gamma-Scintigraphy continues to be a good tool to use during early stages of product development to investigate in vivo performance of dosage forms. The results of this study provided evidence that the physical chemical specifications of the drug substance may not always be indicative of in vitro or in vivo performance of tablet dosage form, even when formulation and process are not changed.

A Comparison of Free-Flowing, Segregating and Non-Free-Flowing, Cohesive Mixing Systems in Assessing the Performance of a Modified V-Shaped Solids Mixer.

The performance of a modified V-shaped solids mixer, i.e., uneven leg or offset angle, has been reassessed by using a binary cohesive mixture, made up of 1% sodium salicylate and 99% microcry stalline cellulose, as the mixing system. The performance of the mixer was defined in terms of relative standard deviation from the measured mean. The results generated from the present study were compared with the previously published data generated by using a free-flow mixing system. It appears in the present study that the free-flowing, segregating materials may be used as a mixing model to predict the trend of the performance of a modified V-shaped blender for the non-free-flowing, cohesive materials. However, in the equilibrium state, the non-free-flowing, cohesive mixture has much better quality of the mix than that of the free-flowing, segregating system in terms of the scale and intensity of segregation.