Reservoir-based drug delivery systems utilizing microtechnology.

This review covers reservoir-based drug delivery systems that incorporate microtechnology, with an emphasis on oral, dermal, and implantable systems. Key features of each technology are highlighted such as working principles, fabrication methods, dimensional constraints, and performance criteria. Reservoir-based systems include a subset of microfabricated drug delivery systems and provide unique advantages. Reservoirs, whether external to the body or implanted, provide a well-controlled environment for a drug formulation, allowing increased drug stability and prolonged delivery times. Reservoir systems have the flexibility to accommodate various delivery schemes, including zero order, pulsatile, and on demand dosing, as opposed to a standard sustained release profile. Furthermore, the development of reservoir-based systems for targeted delivery for difficult to treat applications (e.g., ocular) has resulted in potential platforms for patient therapy.

Solid-state stability of spray-dried insulin powder for inhalation: chemical kinetics and structural relaxation modeling of Exubera above and below the glass transition temperature.

The effect of temperature on the chemical stability of an amorphous spray-dried insulin powder formulation (Exubera) was evaluated in the solid state at constant moisture content. The chemical stability of the powder was assessed using reversed-phase high-performance liquid chromatography (RP-HPLC) and high-performance-size exclusion chromatography (HP-SEC). The major degradants in spray-dried insulin produced during heat stressing were identified as A21-desamidoinsulin (A21) and high molecular weight protein (HMWP). As expected, the rates of formation of A21 and HMWP were observed to increase with temperature. A stretched-time kinetic model (degradation rate is proportional to the square root of time) was applied to the degradant profiles above and below the glass transition temperature (T(g)) and apparent reaction rate constants were determined. Below T(g), isothermal enthalpy of relaxation measurements were used to assess the effect of temperature on molecular mobility. The formation of A21 and HMWP was found to follow an Arrhenius temperature dependence above and below the T(g). Comparison of reaction rate constants to those estimated from structural relaxation experiments suggests that the reaction pathways to form A21 and HMWP below the T(g) may be coupled with the molecular motions involved in structural relaxation.

Advances in peptide pharmaceuticals.

Drug delivery strategies for peptide pharmaceuticals have incorporated a wide range of structure activity relationships, analog generation to impart protease resistance and increased bioavailability, novel formulations, and delivery systems to target optimal therapeutic dosing requirements. Advances in peptide pharmaceuticals have provided products for the treatment of diabetes, obesity, Crohn's disease, osteoporosis, cancer, cardiovascular disease, immunotherapy, acromegaly, enuresis, pain, and antimicrobials. Here we review these marketed peptides and new peptidomimetic therapies currently in clinical trials.

Trileucine improves aerosol performance and stability of spray-dried powders for inhalation.

For particles to be useful medicinal aerosols, not only their aerodynamic diameter has to be on the order of a few micrometers but also they have to be chemically and physically stable. Manufacture of respirable particles is a technical challenge because as particles are reduced in size by conventional milling techniques, their cohesiveness greatly increases and physical and chemical stability is often compromised by the formation of amorphous material. In the present study, we describe the use of trileucine for the preparation of dry powders suitable for inhalation via spray drying of a wide range of drugs (i.e., asthma therapeutics such as albuterol and cromolyn, and anti-infectives such as netilmicin and gentamicin, as well as therapeutic proteins and peptides such as human growth hormone and salmon calcitonin). The glass transition of spray-dried trileucine is dependent on the pH and can be correlated with the proportion of the anion, cation, and zwitterion concentration in solution. Trileucine glass transition is relatively high ( approximately 104 degrees C) enabling long-term room temperature stability. The solubility of trileucine is dependent on the pH and is lowest at neutral pH ( approximately 6.8 mg/mL). Trileucine's low aqueous solubility enables the formation of low-density corrugated particles and promotes the formation of trileucine coated spray-dried particles, resulting in superior aerosol performance. Trileucine is surface active and promotes the formation of spray-dried powders with a reduced cohesiveness as demonstrated by a decrease in the measured surface energy which correlates with an observed improvement in aerosol performance. Additionally, trileucine competes with the protein on the air/water interface resulting in an additional depression of surface tension in solution which correlates with a decreased denaturation and aggregation in the solid state.

The design and performance of the exubera pulmonary insulin delivery system.

The Exubera system (Pfizer, New York, NY/Nektar Therapeutics, San Carlos, CA) is an integration of five major new technologies: protein formulation, powder processing, powder filling, drug packaging, and delivery device. The product provides a simple interface, where the patient interacts only with the delivery device and powder packaging. These components were designed together to assure repeatable dosing when used by a wide range of patients under real-world life-style and handling conditions. The device design is purely mechanical, using patient-generated compressed air as the energy source. Upon actuation, a sonic discharge of air through the novel release unit reproducibly extracts, de-agglomerates, and disperses the inhalation powder into a respirable aerosol. A clear holding chamber allows for patient feedback via dose visualization and separates aerosol cloud generation from the inspiratory effort. The Exubera product was tested under a wide range of typical use conditions and potential misuse scenarios and following long-term usage in clinical trials. These comprehensive characterization programs demonstrated robust aerosol and mechanical performance, confirming the design intent of the inhaler. These studies provide assurance of consistent and reliable dose delivery in a real-world use of the product.

Peptide drug delivery strategies for the treatment of diabetes.

Drug delivery strategies for diabetes have included a wide range of scientific and engineering approaches, including molecular design, formulation and device design. Molecular engineering has resulted in modified pharmacokinetics, such as rapid-acting or slow-release analogs of insulin. Long-acting insulin formulations are designed to meet the body's basal needs, whereas rapid-acting insulin formulations are designed to cover mealtime glucose spikes. Furthermore, the discovery of new therapeutic biomolecules, which like insulin need to be injected, will drive the need for more flexible and universally applicable delivery systems. Formulation design, such as particle engineering, can be used to modify pharmacokinetic profiles. In general, suspension formulations of insulin commonly demonstrate reduced solubility and result in sustained release. Similarly, depot injections can result in precipitation of insulin at the site of injection, again resulting in lower solubility and sustained release. Particle engineering also has been applied to pulmonary formulations for delivery to the deep lung. The creation of novel drug delivery methods for the treatment of diabetes should remove barriers to insulin therapy and increase patient acceptance and compliance. Eliminating routine injections with needle-free injectors, insulin pumps, inhalation, buccal sprays, intra-nasal delivery, and transdermal patches may offer increasingly attractive alternatives.

Pharmaceutical liquid crystals: the relevance of partially ordered systems.

Pharmaceutical solids have generally been characterized as either three-dimensional crystals or amorphous solids based on X-ray powder diffraction and modulated temperature differential scanning calorimetry. In contrast, fewer examples of thermotropic and lyotropic liquid crystals, or mesophases, appear in the pharmaceutical literature, and that literature teaches that the aforementioned analytical techniques should be complemented with polarized light microscopy and small-angle X-ray scattering in order to effectively identify potential liquid crystalline states. Lyotropic liquid crystals are induced by the presence of solvent, and have been extensively described elsewhere in the context of emulsion technology; however, other pharmaceutical examples are emerging. Thermotropic liquid crystals are induced by a change in temperature and are essentially free of solvent, where more pharmaceutical applications appear in the literature. In the present review the general structural characteristics that favor the formation of liquid crystalline mesophases are categorized by therapeutic target and molecular size, and the analytical means of their identification are presented.

EXUBERA: pharmaceutical development of a novel product for pulmonary delivery of insulin.

Development of a product for pulmonary delivery of insulin presented significant technology challenges for this first-in-class pharmaceutical product. These included developing (a) a chemically stabilized protein, (b) a dry powder formulation exhibiting required aerosol physical characteristics, (c) low-dose powder filling and packaging technology, and (d) a mechanical device for powder dispersal and reliable dosing to the patient. The insulin drug is formulated using a novel excipient combination to create a powder with a high glass transition temperature (Tg). The high Tg minimizes insulin mobility (thus reactivity), enabling ambient storage conditions. The formulation composition results in minimal hygroscopicity, where customized packaging produced product ruggedness to humidity. The formulated insulin powder is manufactured by spray-drying. This technology was further engineered to produce the desired reproducible powder characteristics with tight control over particle size and moisture content. A solution step prior to drying assures homogeneity and minimizes dependence on the physical form of the components. Novel low-dose filling and packaging technology reproducibly meters milligram quantities of microfine powder to meet stringent quality requirements for dose control. The technology for accurate, uniform, high-throughput metering of drug powders allows for automation and is scaleable for commercial operations. Finally, the mechanical device design provides powder deagglomeration and dispersion processes in a reusable dry powder inhaler with unique characteristics. The device was designed to rely on patient-generated compressed air as the energy source. A sonic discharge of air through the novel TransJector reproducibly extracts, deagglomerates, and disperses the inhalation powder. A clear holding (spacer-type) chamber allows for patient feedback via dose visualization, and separates powder dispersal from the inspiratory effort. The EXUBERA [Pfizer (New York, NY) and sanofi-aventis (Paris, France)] product provides insulin into the bloodstream with similar reproducibly and effectiveness as subcutaneous injections.

Properties and stability of a liquid crystal form of cyclosporine-the first reported naturally occurring peptide that exists as a thermotropic liquid crystal.

A new solid-state form of cyclosporine produced by spray-drying exhibited characteristics consistent with a liquid crystal. No sharp diffraction peaks were observed by powder X-ray diffraction; however, analysis by both small-angle X-ray diffraction (SAXR) and microscopic under polarized light (PLM) confirmed the existence of two-dimensional ordered liquid crystal. Hot stage microscopy revealed a solid-to-liquid transition, in the range of 118 to 125 degrees C. Moreover, the solid-to-liquid transition showed frequency dependence by dielectric analysis (DEA), and was coincidental with a stepwise heat capacity change measured by differential scanning Calorimetry (DSC). The two-dimensional order was maintained above the solid-to-liquid transition temperature indicated by low-angle diffraction by SAXR and birefringence by PLM. However, birefringence was lost at temperatures above 170 degrees C, indicating the conversion of the liquid crystal into an isotropic liquid. In situ annealing experiments, by DSC, revealed the presence of an endotherm, unexplained by either a phase transition or solvent loss, and it is believed to be the result of a structural rearrangement that has no impact on the macroscopic properties of the material. Spray-dried cyclosporine at room temperature is therefore a frozen thermotropic liquid crystal due to the presence of two-dimensional order and the lack of substantial residual solvent. This is, to our knowledge, the first report of the existence of a thermotropic liquid crystal of a naturally occurring peptide.

Secondary structure of cyclosporine in a spray-dried liquid crystal by FTIR.

The conformational state of cyclosporine in liquid crystalline spray-dried powders and the solution structure of cyclosporine, in a series of organic solvents where solvent dipole and hydrogen bonding ability varied, were determined. Fourier transformed infrared spectra (FTIR) were obtained on cyclosporine powders, and cyclosporine solutions in a series of organic solvents. Tetragonal crystalline cyclosporine revealed an intermolecular aggregate band at 1614 cm(-1), a beta-sheet band at 1627 cm(-1), a gamma-loop band at 1648 cm(-1), a gamma-turn band at 1658 cm(-1) (formed from a hydrogen bond between D-Ala(8)NH and MeLeu(6)Cdbond;O) and a Type II beta-turn band at 1673 cm(-1) (centered at the hydrogen bond betweenVal(5)NH to Abu(2)Cdbond;O). A similar conformation was observed in chloroform or octanol (apolar), where a second beta-sheet band emerged at 1638 cm(-1) and a turn structure associated with the beta-OH on MeBmt(1) appeared at 1685 cm(-1). However, the spray dried liquid crystal structure resembled the solution conformation in acetone or acetonitrile (hydrogen bond acceptor). The conformation in acetone suggested that the beta-sheet, gamma-loop, Type II beta-turn and MeBmt(1) turn remained intact. Interestingly, the spray-dried powder conformations did not resemble the solution structure of the solvent (ethanol) from which they had been obtained. The conformation in ethanol and methanol (hydrogen bond donor) showed only beta-sheet, gamma-turn, MeBmt(1) turn structure. Only a small population of molecules retained the Type II beta-turn. Finally, cyclosporine is essentially insoluble in water, so the water conformation has never been elucidated; however, a conformation resembling the active structure was obtained in a cosolvent solution containing both hydrogen bond donors and acceptors. This conformation is in good agreement with molecular modelling studies where cyclosporine is docked in the active site of cyclophilin. Spray-dried cyclosporine formed a liquid crystal that can be described as maintaining the Type II beta-turn, beta-sheet, and gamma-loop structures seen in crystalline material. However, the hydrogen bond between D-Ala(8)NH and MeLeu(6)Cdbond;O was disrupted.