Improving the oral absorption of compounds with low aqueous solubility is a common challenge that often requires an enabling technology. Frequently, oral absorption can be improved by formulating the ...compound as an amorphous solid dispersion (ASD). Upon dissolution, an ASD can reach a higher concentration of unbound drug than the crystalline form, and often generates a large number of sub-micrometer, rapidly dissolving drug-rich colloids. These drug-rich colloids have the potential to decrease the diffusional resistance across the unstirred water layer of the intestinal tract (UWL) by acting as rapidly diffusing shuttles for unbound drug. In a prior study utilizing a membrane flux assay, we demonstrated that, for itraconazole, increasing the concentration of drug-rich colloids increased membrane flux in vitro. In this study, we evaluate spray-dried amorphous solid dispersions (SDDs) of itraconazole with hydroxypropyl methylcellulose acetate succinate (HPMCAS) to study the impact of varying concentrations of drug-rich colloids on the oral absorption of itraconazole in rats, and to quantify their impact on in vitro flux as a function of bile salt concentration. When Sporanox and itraconazole/AFFINISOL High Productivity HPMCAS SDDs were dosed in rats, the maximum absorption rate for each formulation rank-ordered with membrane flux in vitro. The relative maximum absorption rate in vivo correlated well with the in vitro flux measured in 2% SIF (26.8 mM bile acid concentration), a representative bile acid concentration for rats. In vitro it was found that as the bile salt concentration increases, the importance of colloids for improving UWL permeability is diminished. We demonstrate that drug-containing micelles and colloids both contribute to aqueous boundary layer diffusion in proportion to their diffusion coefficient and drug loading. These data suggest that, for compounds with very low aqueous solubility and high epithelial permeability, designing amorphous formulations that produce colloids on dissolution may be a viable approach to improve oral bioavailability.
Bioavailability-enhancing formulations are often used to overcome challenges of poor gastrointestinal solubility for drug substances developed for oral administration. Conventional in vitro ...dissolution tests often do not properly compare such formulations due to the many different drug species that may exist in solution. To overcome these limitations, we have designed a practical in vitro membrane flux test, that requires minimal active pharmaceutical ingredient (API) and is capable of rapidly screening many drug product intermediates. This test can be used to quickly compare performance of bioavailability-enhancing formulations with fundamental knowledge of the rate-limiting step(s) to membrane flux. Using this system, we demonstrate that the flux of amorphous itraconazole (logD = 5.7) is limited by aqueous boundary layer (ABL) diffusion and can be increased by adding drug-solubilizing micelles or drug-rich colloids. Conversely, the flux of crystalline ketoconazole at pH 5 (logD = 2.2) is membrane-limited, and adding solubilizing micelles does not increase flux. Under certain circumstances, the flux of ketoconazole may also be limited by dissolution rate. These cases highlight how a well-designed in vitro assay can provide critical insight for oral formulation development. Knowing whether flux is limited by membrane diffusion, ABL diffusion, or dissolution rate can help drive formulation development decisions. It may also be useful in predicting in vivo performance, dose linearity, food effects, and regional-dependent flux along the length of the gastrointestinal tract.
Spray-dried dispersions (SDDs) of low-solubility drugs have been prepared using the polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS). For a variety of drug structures, these SDDs ...provide supersaturation in in vitro dissolution determinations and large bioavailability increases in vivo. In bile-salt/lecithin in vitro solutions, these SDDs provide amorphous drug/polymer colloids and an increased concentration of free drug and drug in micelles relative to crystalline or amorphous drug. As dry powders, the SDDs are a single amorphous phase in which the drug remains amorphous and dispersed and does not crystallize over storage times relevant for practical drug products. A melting temperature (T m)/glass-transition temperature (T g) (K/K) versus log P map for 139 compounds formulated as SDDs provides a perspective on an appropriate formulation strategy for low-solubility drugs with various physical properties.
We report the development of a new spray-drying and nanoparticle assembly process (SNAP) that enables the formation of stable, yet rapidly dissolving, sub-200 nm nanocrystalline particles within a ...high T g glassy matrix. SNAP expands the class of drugs that spray-dried dispersion (SDD) processing can address to encompass highly crystalline, but modestly hydrophobic, drugs that are difficult to process by conventional SDD. The process integrates rapid precipitation and spray-drying within a custom designed nozzle to produce high supersaturations and precipitation of the drug and high T g glassy polymer. Keeping the time between precipitation and drying to tens of milliseconds allows for kinetic trapping of drug nanocrystals in the polymer matrix. Powder X-ray diffraction, solid state 2D NMR, and SEM imaging shows that adding an amphiphilic block copolymer (BCP) to the solvent gives essentially complete crystallization of the active pharmaceutical ingredient (API) with sub-200 nm domains. In contrast, the absence of the block copolymer results in the API being partially dispersed in the matrix as an amorphous phase, which can be sensitive to changes in bioavailability over time. Quantification of the API–excipient interactions by 2D 13C–1H NMR correlation spectroscopy shows that the mechanism of enhanced nanocrystal formation is not due to interactions between the drug and the BCP, but rather the BCP masks interactions between the drug and hydrophobic regions of the matrix polymers. BCP-facilitated SNAP samples show improved stability during aging studies and rapid dissolution and release of API in vitro.
Reducing the absorption difference between fed and fasted states is an important goal in the development of pharmaceutical dosage forms. The goal of this work was to develop and characterize a solid ...nanocrystalline dispersion (SNCD) to improve the oral absorption of ziprasidone in the fasted state, thereby reducing the food effect observed for the commercial formulation. A solution of ziprasidone hydrochloride and the polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS) was spray-dried to form a solid amorphous spray-dried dispersion (SDD), which was then exposed to a controlled temperature and relative humidity (RH) to yield the ziprasidone SNCD. The SNCD was characterized using powder X-ray diffraction, thermal analysis, microscopy, and in vitro dissolution testing. These tools indicate the SNCD consists of a high-energy crystalline form of ziprasidone in domains approximately 100 nm in diameter but with crystal grain sizes on the order of 20 nm. The SNCD was dosed orally in capsules to beagle dogs. Pharmacokinetic studies showed complete fasted-state absorption of ziprasidone, achieving the desired improvement in the fed/fasted ratio.
Inhaled peptides and proteins have promise for respiratory and systemic disease treatment. Engineered spray-dried powder formulations have been shown to stabilize peptides and proteins and optimize ...aerosol properties for pulmonary delivery. The current study was undertaken to investigate the in vitro and in vivo inhalation performance of a model spray-dried powder of insulin and dextran 10 in comparison to Exubera™. Dextrans are a class of glucans that are generally recognized as safe with optimum glass transition temperatures well suited for spray drying. A 70% insulin particle loading was prepared by formulating with 30% (w/v) dextran 10. Physical characterization revealed a "raisin like" particle. Both formulations were generated to produce a similar bimodal particle size distribution of less than 3.5 μm MMAD. Four female Beagle dogs were exposed to each powder in a crossover design. Similar presented and inhaled doses were achieved with each powder. Euglycemia was achieved in each dog prior and subsequent to dosing and blood samples were drawn out to 245 min post-exposure. Pharmacokinetic analyses of post-dose insulin levels were similar for both powders. Respective dextran 10-insulin and Exubera exposures were similar producing near identical area under the curve (AUC), 7,728 ± 1,516 and 6,237 ± 2,621; concentration maximums (C max), 126 and 121 (μU/mL), and concentration-time maximums, 20 and 14 min, respectively. These results suggest that dextran-10 and other dextrans may provide a novel path for formulating peptides and proteins for pulmonary delivery.
Objective: Peptide YY3-36 PYY(3-36) has shown efficacy in appetite suppression when dosed by injection modalities (intraperitoneal (IP)/subcutaneous). Transitioning to needle-free delivery, towards ...inhalation, often utilizes systemic pharmacokinetics as a key endpoint to compare different delivery methods and doses. Systemic pharmacokinetics were evaluated for PYY3-36 when delivered by IP, subcutaneous, and inhalation, the systemic pharmacokinetics were then used to select doses in an appetite suppression pharmacodynamic study.
Methods: Dry-powder formulations were manufactured by spray drying and delivered to mice via nose only inhalation. The systemic plasma, lung tissue, and bronchoalveolar lavage fluid pharmacokinetics of different inhalation doses of PYY(3-36) were compared to IP and subcutaneous efficacious doses. Based on these pharmacokinetic data, inhalation doses of 70:30 PYY(3-36):Dextran T10 were evaluated in a mouse model of appetite suppression and compared to IP and subcutaneous data.
Results: Inhalation pharmacokinetic studies showed that plasma exposure was similar for a 2 × higher inhalation dose when compared to subcutaneous and IP delivery. Inhalation doses of 0.22 and 0.65 mg/kg were for efficacy studies. The results showed a dose-dependent (not dose proportional) decrease in food consumption over 4 h, which is similar to IP and subcutaneous delivery routes.
Conclusions: The pharmacokinetic and pharmacodynamics results substantiate the ability of pharmacokinetic data to inform pharmacodynamics dose selection for inhalation delivery of the peptide PYY(3-36). Additionally, engineered PYY(3-36):Dextran T10 particles delivered to the respiratory tract show promise as a non-invasive therapeutic for appetite suppression.
The structure and torsional properties of oxalyl chloride fluoride in the gas phase have been measured by electron diffraction at temperatures of 22, 81, 158, and 310 °C. The molecule may be regarded ...as a hybrid of oxalyl chloride and oxalyl fluoride. Since the former exists as a more stable periplanar anti form (ϕ = 180°) in equilibrium with a less stable gauche form (ϕ ≃ 60°) and the latter as an equilibrium between two periplanar forms, anti and syn, the second form of oxalyl chloride fluoride is an interesting question. It was found to be gauche. The system was modeled as two rotational conformers related by a potential of the form 2V = V 1(1 + cos ϕ) − V 2(1 − cos 2ϕ) + V 3(1 + cos 3ϕ). The anti/gauche bond distances and bond angles (r g/Angstroms, ∠α/degrees) with estimated 2σ uncertainties at 22 °C are ⟨r(CO)⟩ = 1.183(2)/1.182(2), Δr(CO) = 0.0036/0.0026 (assumed from theory), r(C−F) = 1.329(3)/1.335(3), r(C−Cl) = 1.738(2)/1.753(2), ∠(C−C−Cl) = 112.0(3)/111.9(3), ∠(C−CO3) = 123.0(4)/123.2(4), ∠(OC−Cl) = 125.0(2)/1.249(2), ∠(OC−F) = 123.0(3)/125.1(3), and ∠(Cl−C−C−F) = 180.0/59.8. The variation of composition with temperature afforded a determination of the standard enthalpy and entropy of the reaction anti → gauche. The results are ΔH° = 2.5(12) kcal/mol and ΔS° = −6.5(33) cal/(mol·K). The structures and equilibria are discussed.
The molecular structure and composition of gaseous oxalyl fluoride (OXF) has been investigated by electron diffraction (GED) at nozzle-tip temperatures of −10, 149, and 219 °C. The GED data were ...augmented by molecular orbital calculations, and the analysis was aided by use of rotational constants from microwave (MW) spectroscopy. As in the other oxalyl halides, there are two stable species, of which the more stable is periplanar anti (i.e., trans). However, unlike these other halides in which the second form is gauche, the second form of oxalyl fluoride was known from MW work to be periplanar syn (i.e., cis). Our results are consistent with a mixture of trans and cis forms, and yield values for the structural parameters, the composition of the system at the three temperatures cited, and the thermodynamic quantities ΔG°, ΔH°, and ΔS° for the reaction trans → cis. Some trans/cis distances (r g/Å) and angles (∠α/deg) at −10 °C are r(CO) = 1.178(2)/1.176(2), r(C−F) = 1.323(2)/1.328(2); r(C−C) = 1.533(3)/1.535(3), ∠(CCO) = 126.4(2)/124.2(2), ∠(C−C−F) = 109.8(2)/112.2(2), and ∠(O−C−F) = 123.8(2)/123.6(2). The mixture compositions (percent trans) at −10 °C/149 °C/219 °C are 75(3)/58(7)/52(8), from which ΔH° and ΔS° are found to be 1.14 kcal/mol and 2.12 cal/(mol·deg). The system properties are discussed.
Inhaled peptides and proteins have promise for respiratory and systemic disease treatment. Engineered spray-dried powder formulations have been shown to stabilize peptides and proteins and optimize ...aerosol properties for pulmonary delivery. The current study was undertaken to investigate the
in vitro
and
in vivo
inhalation performance of a model spray-dried powder of insulin and dextran 10 in comparison to Exubera™. Dextrans are a class of glucans that are generally recognized as safe with optimum glass transition temperatures well suited for spray drying. A 70% insulin particle loading was prepared by formulating with 30% (
w
/
v
) dextran 10. Physical characterization revealed a “raisin like” particle. Both formulations were generated to produce a similar bimodal particle size distribution of less than 3.5 μm MMAD. Four female Beagle dogs were exposed to each powder in a crossover design. Similar presented and inhaled doses were achieved with each powder. Euglycemia was achieved in each dog prior and subsequent to dosing and blood samples were drawn out to 245 min post-exposure. Pharmacokinetic analyses of post-dose insulin levels were similar for both powders. Respective dextran 10-insulin and Exubera exposures were similar producing near identical area under the curve (AUC), 7,728 ± 1,516 and 6,237 ± 2,621; concentration maximums (
C
max
), 126 and 121 (μU/mL), and concentration–time maximums, 20 and 14 min, respectively. These results suggest that dextran-10 and other dextrans may provide a novel path for formulating peptides and proteins for pulmonary delivery.
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