Review of the TAIFUN multidose dry powder inhaler technology.

Although pressurized metered dose inhalers (pMDIs) currently constitute a majority of the market share in the inhalation market, dry powder inhaler (DPI) products have become increasingly popular due to their reliability and product performance. One such DPI is the TAIFUN inhaler that is a reservoir-based DPI system with the ability to produce consistent and uniform doses in vitro. Originally developed for the pulmonary delivery of salbutamol, the TAIFUN inhaler platform has since been used to develop a product for breakthrough cancer pain management using fentanyl citrate as the active drug. In vivo results show the TAIFUN inhaler is able to deliver a rapid onset of action and increased relative bioavailability compared with other fentanyl products currently on the market.

Nebulization of nanoparticulate amorphous or crystalline tacrolimus--single-dose pharmacokinetics study in mice.

Developing a pulmonary composition of tacrolimus (TAC) provides direct access to the graft in lung transplant offering the possibility of high drug levels. The objective of this study was to investigate the physicochemical and pharmacokinetic characteristics of the nanostructured aggregates containing amorphous or crystalline nanoparticles of TAC produced by ultra-rapid freezing (URF). TAC and lactose (1:1 ratio; URF-TAC:LAC) and TAC alone (URF-TAC) were investigated for pulmonary delivery and compared to unprocessed TAC. X-ray diffraction (XRD) results indicated that URF-TAC was crystalline, whereas URF-TAC:LAC was amorphous. In vitro results revealed the superior physiochemical characteristics of both URF formulations compared to unprocessed TAC. The surface area of URF processed TAC was higher (25-29 m2/g) than that of the unprocessed TAC (0.53 m2/g) and subsequently enhanced dissolution rates. In addition, URF-TAC:LAC displayed the ability to supersaturate in the dissolution media to about 11 times the crystalline equilibrium solubility. Similar aerodynamic particle sizes of 2-3 microm, and fine particle fraction between 70% and 75% were found in both formulations. The local and systemic pharmacokinetic studies in mice showed similar AUC(0-24), higher Cmax, and lower Tmax for the URF-TAC:LAC compared to the URF-TAC. Nanostructured aggregates containing amorphous or crystalline nanoparticles of TAC were demonstrated to be effectively delivered via nebulization, with similar in vitro and in vivo performances.

Effect of stabilizer on the maximum degree and extent of supersaturation and oral absorption of tacrolimus made by ultra-rapid freezing.

PURPOSE: Solid dispersions containing various stabilizers and tacrolimus (TAC) prepared by an Ultra-rapid Freezing (URF) process were investigated to determine the effect on their ability to form supersaturated solutions in aqueous media and on enhancing transport across biological membranes. MATERIALS AND METHODS: The stabilizers included poly(vinyl alcohol; PVA), poloxamer 407 (P407), and sodium dodecyl sulfate (SDS). In vivo absorption enhancement in rats was also investigated. Dissolution studies were conducted at supersaturated conditions in both acidic media for 24 h and at delayed release (enteric) conditions to simulate intestinal transit. RESULTS: The rank order of C/Ceq(max) in the dissolution studies at acidic conditions was URF-P407 > URF-SDS > Prograf (PRO) > URF-PVA:P407. For C/Ceq(max) under enteric conditions, the order was URF-SDS > PRO > URF-PVA:P407 > URF-P407, and for the extent of supersaturation (AUC) in acidic and pH shift conditions it was URF-SDS>PRO>URF-PVA:P407>URF-P407. The pharmacokinetic data suggests URF-P407 had the greatest absorption having higher C (max) with a 1.5-fold increase in AUC compared to PRO. All URF compositions had a shorter T (max) compared to PRO. CONCLUSIONS: The nanostructured powders containing various stabilizing polymers formed by the URF process offer enhanced supersaturation characteristics leading to increased oral absorption of TAC.

Novel ultra-rapid freezing particle engineering process for enhancement of dissolution rates of poorly water-soluble drugs.

An ultra-rapid freezing (URF) technology has been developed to produce high surface area powders composed of solid solutions of an active pharmaceutical ingredient (API) and a polymer stabilizer. A solution of API and polymer excipient(s) is spread on a cold solid surface to form a thin film that freezes in 50 ms to 1s. This study provides an understanding of how the solvent's physical properties and the thin film geometry influence the freezing rate and consequently the final physico-chemical properties of URF-processed powders. Theoretical calculations of heat transfer rates are shown to be in agreement with infrared images with 10ms resolution. Danazol (DAN)/polyvinylpyrrolidone (PVP) powders, produced from both acetonitrile (ACN) and tert-butanol (T-BUT) as the solvent, were amorphous with high surface areas (approximately 28-30 m2/g) and enhanced dissolution rates. However, differences in surface morphology were observed and attributed to the cooling rate (film thickness) as predicted by the model. Relative to spray-freezing processes that use liquid nitrogen, URF also offers fast heat transfer rates as a result of the intimate contact between the solution and cold solid surface, but without the complexity of cryogen evaporation (Leidenfrost effect). The ability to produce amorphous high surface area powders with submicron primary particles with a simple ultra-rapid freezing process is of practical interest in particle engineering to increase dissolution rates, and ultimately bioavailability.

Solid dispersions of itraconazole and enteric polymers made by ultra-rapid freezing.

The primary objective of the study is to investigate the influence of composition parameters including drug:polymer ratio and polymer type, and particle structure of enteric solid dispersions on the release of ITZ under sink and supersaturated dissolution conditions. Modulated differential scanning calorimetry (MDSC) was utilized to define the level of ITZ miscibility with each polymer. The compositions were completely miscible at 60% ITZ for both polymers and as high as 70% in HP-55. High potency composition glass transition temperatures (T(g)) correlated with predicted T(g)'s from the Gordon-Taylor equation, however, recrystallization exotherms revealed pure amorphous regions indicating that phase separation occurred during particle formation. Furthermore, in vitro studies including X-ray powder diffraction (XRD), scanning electron microscopy (SEM), surface area analysis (BET), and dissolution were performed to determine differences between low potency (completely miscible) and high potency (partially miscible) compositions. Dissolution studies on low potency ITZ compositions revealed that miscibility plays an active role in ITZ release under sink conditions, and square root diffusion through the enteric polymer is observed. Supersaturated dissolution profiles revealed high potency compositions had maximum saturation levels (C/Ceq(max)) between 10.6- and 8-times equilibrium solubility, but had higher cumulative extents of supersaturation, compared to low potency compositions which had C/Ceq(max) values of 15-19.6. However, these low potency compositions rapidly precipitated leading to significantly lower AUCs (p<0.05). The change in the miscibility of the solid dispersion had a pronounced effect of drug release (sink) while differences in potency influenced supersaturated dissolution profiles.

Cryogenic liquids, nanoparticles, and microencapsulation.

The biopharmaceutical classification system (BCS) is used to group pharmaceutical actives depending upon the solubility and permeability characteristics of the drug. BCS class II compounds are poorly soluble but highly permeable, exhibiting bioavailability that is limited by dissolution. The dissolution rate of BCS class II drug substances may be accelerated by enhancing the wetting of the bulk powder and by reducing the primary particle size of the drug to increase the surface area. These goals may be achieved by nucleating drug particles from solution in the presence of stabilizing excipients. In the spray freezing into liquid (SFL) process, a drug containing solution is atomized and frozen rapidly to engineer porous amorphous drug/excipient particles with high surface areas and dissolution rates. Aqueous suspensions of nanostructured particles may be produced from organic solutions by evaporative precipitation into aqueous solution (EPAS). The suspensions may be dried by lyophilization. The particle size and morphology may be controlled by the type and level of stabilizers. In vivo studies have shown increased bioavailability of a wide variety of drugs particles formed by SFL or EPAS. For both processes, increased serum levels of danazol (DAN) were observed in mice relative to bulk DAN and the commercial product, Danocrine. Orally dosed itraconazole (ITZ) compositions, formed by SFL, produce higher serum levels of the drug compared to the commercial product, Sporanox oral solution. Additionally, nebulized SFL processed ITZ particles suspended in normal saline have been dosed via the pulmonary route and led to extended survival times for mice inoculated with Aspergillis flavus. SFL and EPAS processes produce amorphous drug particles with increased wetting and dissolution rates, which will subsequently supersaturate biological fluids in vivo, resulting in increased drug bioavailability and efficacy.

Targeted high lung concentrations of itraconazole using nebulized dispersions in a murine model.

PURPOSE: The purpose of this study was to investigate the delivery of itraconazole (ITZ) particles to a murine lung model by nebulization. METHODS: Three ITZ formulations were prepared and characterized in the dry state using contact angle, dissolution, X-ray powder diffraction, scanning electron microscopy, and Brunauer-Emmett-Teller surface area analysis. Aerodynamic particle size distributions and lung deposition studies in 14 outbred male ICR mice were performed using aqueous dispersions of all the formulations. A separate dosing uniformity study was also performed to qualify use of the chamber. RESULTS: All formulations had an aggregated particle size of approximately 30 microm in diameter. Two formulations showed that 80% of the drug dissolved in less than 5 min. The remaining ITZ formulation had a slower dissolution and the lowest total emitted dose from the nebulizer used. High concentrations of ITZ were shown to be present in the mouse lung during the lung deposition study, up to 16.8 +/- 0.13 microg/g (+/- SE) were achieved. Concentrations of up to 0.76 +/- 0.03 microg/g (+/- SE) could be maintained from the single nebulized dose for at least 24 h. CONCLUSION: An effective method of targeted delivery of ITZ to the deep lung is presented that may be useful for the treatment and prevention of acute fungal infections.

In vivo efficacy of aerosolized nanostructured itraconazole formulations for prevention of invasive pulmonary aspergillosis.

Aerosolized evaporative precipitation into aqueous solution and spray freezing into liquid nanostructured formulations of itraconazole as prophylaxis significantly improved survival relative to commercial itraconazole oral solution and the control in a murine model of invasive pulmonary aspergillosis. Aerosolized administration of nanostructured formulations also achieved high lung tissue concentrations while limiting systemic exposure.

Micronized powders of a poorly water soluble drug produced by a spray-freezing into liquid-emulsion process.

The purpose of this paper is to investigate the influence of the emulsion composition of the feed liquid on physicochemical characteristics of drug-loaded powders produced by spray-freezing into liquid (SFL) micronization, and to compare the SFL emulsion process to the SFL solution process. Danazol was formulated with polyvinyl alcohol (MW 22,000), poloxamer 407, and polyvinylpyrrolidone K-15 in a 2:1:1:1 weight ratio (40% active pharmaceutical ingredient (API) potency based on dry weight). Emulsions were formulated in ratios up to 20:1:1:1 (87% API potency based on dry weight). Ethyl acetate/water or dichloromethane/water mixtures were used to produce o/w emulsions for SFL micronization, and a tetrahydrofuran/water mixture was used to formulate the feed solutions. Micronized SFL powders were characterized by X-ray diffraction, surface area, scanning and transmission electron microscopy, contact angle and dissolution. Emulsions containing danazol in the internal oil phase and processed by SFL produced micronized powders containing amorphous drug. The surface area increased as drug and excipient concentrations were increased. Surface areas ranged from 8.9 m(2)/g (SFL powder from solution) to 83.1 m(2)/g (SFL powder from emulsion). Danazol contained in micronized SFL powders from emulsion and solution was 100% dissolved in the dissolution media within 2 min, which was significantly faster than the dissolution of non-SFL processed controls investigated (<50% in 2 min). Micronized SFL powders produced from emulsion had similar dissolution enhancement compared to those produced from solution, but higher quantities could be SFL processed from emulsions. Potencies of up to 87% yielded powders with rapid wetting and dissolution when utilizing feed emulsions instead of solutions. Large-scale SFL product batches were manufactured using lower solvent quantities and higher drug concentrations via emulsion formulations, thus demonstrating the usefulness of the SFL micronization technology in pharmaceutical development.