Route-Specific Challenges in the Delivery of Poorly Water-Soluble Drugs

Abstract

Poor aqueous solubility of new chemical entities presents various challenges in the development of effective drug-delivery systems for various delivery routes. Poorly soluble drugs that are delivered orally commonly result in low bioavailability and are subject to considerable food effects. In addition, poorly soluble drugs intended for parenteral delivery generally have to be solubilized with large amounts of cosolvents and surfactants, oftentimes resulting in adverse physiological reactions. Finally, successful formulation design of poorly soluble drugs intended for pulmonary administration is mainly hindered by the limited number of excipients generally recognized as safe for this route of delivery. In summary, this chapter reviews the specific challenges faced in the delivery of poorly water-soluble drugs via oral, parenteral, and pulmonary administration.

Appendices

Method Capsule 1Development of a Self-Emulsifying Formulation that Reduces the Food Effect for Torcetrapib

Based on the method reported by Perlman et al. (2008)

Objective

• To achieve a lower food effect and higher dose of torcetrapib per unit through the use of self-emulsifying formulation.

Equipment and Reagents

• Torcetrapib (Clog P 7.45; non-ionizable)

• Miglyol 812 BP (medium chain triglycerides)

• Triacetin (triacetyl glycerin)

• Polysorbate 80

• Capmul MCM (medium chain mono and diglycerides)

• Glass vessel

• Gelatin softgel shells

• Rotary-die encapsulation machine

Method

• Excipients are added to glass vessel (semisolid excipient Capmul MCM melted prior to addition).

• Mixture is stirred until it is homogeneous.

• Then the desired amount of the drug is added.

• The resulting mixture is stirred at ambient temperature with occasional scraping of the vessel walls until solution is obtained.

• Softgels are manufactured on a rotary-die machine by encapsulation using a shell prepared from gelatin, glycerin, and water.

Results

• The mean droplet size of the emulsion formed by mixing the formulation and water at a ratio of 1:100 by five times gentle inversion was determined to be 257 nm.

• Softgel capsules stored for 6 weeks at 5°C/75% RH, 30°C/60% RH, and 40°C/75% RH showed no change in potency as analyzed by HPLC. Also no sign of crystallization in the fill under any condition based on microscopic examination was found.

• The use of the lipophilic, GRAS cosolvent triacetin in the formulation allowed a twofold increase in the dose per capsule as compared to the formulation used in early clinical trials where the drug was dissolved in Mygliol 812 BP only.

• Pharmacokinetic studies in dogs demonstrated that the food effect seen with Mygliol softgels was reduced from five to threefold with the Mygliol/Triacetin/Polysorbate 80/Capmul MCM formulation.

Method Capsule 2High Bioavailability from Nebulized Itraconazole Nanoparticle Dispersions with Biocompatible Stabilizers

Based on the method reported by Yang et al. (2008)

Objective

• To develop an itraconazole nanoparticle dispersion for pulmonary delivery by nebulization that does not require the use of synthetic polymers and surfactants to achieve high supersaturation values in vitro and high bioavailability in in vivo.

Equipment and Reagents

• Itraconazole (ITZ)

• Mannitol

• Lecithin

• 1,4-Dioxane

• Ultra-rapid freezing (URF) apparatus

• Lyophilizer

Method

• Lecithin (118 mg) is dissolved in a mixture of 1,4-dioxane and purified water (65/35, v/v) cosolvent system (200 mL) using a magnetic stirrer.

• ITZ (588 mg) and mannitol (294 mg) are subsequently dissolved in the mixture; this provides a dissolved solids ratio of ITZ:mannitol:lecithin of 1:0.5:0.2 by weight.

• The solution is rapidly frozen using the URF apparatus in which the solution is applied to a cryogenic solid substrate cooled to−70°C.

• The resultant frozen solids are collected and lyophilized.

Results

• Particle-size distributions of lyophilized ITZ powder redispersed in water showed a narrow size range with a D50 and D90 (diameter at which the cumulative sample volume is under 50 and 90%, respectively) of 230 and 540 nm, respectively.

• ITZ nanoparticles were found to be amorphous as indicated by the absence of the characteristic crystalline peaks of ITZ and mannitol.

• ITZ nanoparticles produced supersaturation levels 27 times the crystalline solubility upon dissolution in simulated lung fluid.

• The colloidal dispersion obtained after redispersion of the powder in water demonstrated optimal aerodynamic properties with a fine particle fraction of 66.96% and a mass median aerodynamic diameter of nebulized droplets of 2.38 μm.

• An in vivo single-dose 24 h pharmacokinetics study of the nebulized colloidal dispersion demonstrated substantial lung deposition and systemic absorption with blood levels reaching a peak of 1.6 μg/mL serum in 2 h.

Method Capsule 3Amorphous Cyclosporin Nanodispersions for Enhanced Pulmonary Deposition and Dissolution

Based on the method reported by Tam et al. (2008)

Objective

• To nebulize stable amorphous nanoparticle dispersions of Cyclosporine A to achieve high fine particle fractions and high levels of absorption into the lung epithelium.

Equipment and Reagents

• Cyclosporin A

• Polysorbate 80

• Liquid nitrogen

• Methanol

• Glass vessel

• Temperature-controlled water bath

• Rotary evaporator

Method

• 15 g of methanol containing 3.2% w/w cyclosporine A is injected into 50 g deionized water containing an appropriate amount of polysorbate 80 and maintained at 3°C by means of a temperature-controlled water bath.

• Methanol is then separated from the aqueous dispersion via vacuum distillation.

• If the dry powder is desired, the aqueous dispersion can be frozen drop-wise into liquid nitrogen and then be lyophilized.

Results

• Static light scattering results demonstrated a cyclosporine to polysorbate 80 ratio of 1:0.1 produced particles with an average diameter of 300 nm.

• The absence of characteristic crystalline cyclosporine A peaks in XRD patterns indicated a primarily amorphous character.

• Dissolution of the aqueous cyclosporine A dispersion produced supersaturation values 18 times the aqueous equilibrium solubility of the drug.

• The sizes of the aerosolized aqueous droplets (1–4 μm) obtained by nebulization were found to be optimal for deep lung deposition.

• Nebulization of the dispersion to mice produced therapeutic lung levels and systemic concentrations below toxic limits.

Method Capsule 4Production and Characterization of a Budesonide Nanosuspension for Pulmonary Administration

Based on the method reported by Jacobs and Müller (2002)

Objective

• To develop a budesonide nanosuspension by high-pressure homogenization and to investigate the aerosolization properties of this nanosuspension

Equipment and Reagents

• Budesonide

• Soy lecithin

• Span 85

• Tyloxapol

• Cetylalcohol

• Ultra-Turrax

• High-pressure homogenizer

Method

• The surfactants are dissolved or dispersed in warm (∼40°C) bidistilled water by using an Ultra-Turrax.

• Budesonide is then dispersed in the aqueous surfactant solution/dispersion by using the Ultra-Turrax for 1 min at 9,500 rpm.

• The obtained premix is homogenized by using a Micron LAB 40 homogenizer at two cycles at 150 bar and two cycles at 500 bar as a kind of premilling and then 20 homogenization cycles at 1,500 bar to obtain the final product.

Results

• A combination of lecithin (0.5%, w/w) and tyloxapol (0.2%, w/w) proved to be most suitable to stabilize budesonide (1%, w/w) nanosuspension.

• The mean particle size of this nanosuspension was 500 nm as analyzed by photon correlation spectroscopy.

• The scale-up of the formulation from 40 to 300 mL was successful with ­similar size distributions obtained for both batch sizes.

• The mean particle size as determined by photon correlation spectroscopy did not change after nebulization of the nanosuspension indicating suitability for pulmonary delivery.

• Nanosuspension stored at room temperature was stable in terms of size distribution over 1 year period.

Method Capsule 5Trojan Particles: Large Porous Carriers of Nanoparticles for Drug Delivery

Based on the method reported by Tsapis et al. (2002)

Objective

• To combine the drug release and delivery potential of nanoparticle (NP) systems with the ease of flow, processing, and aerosolization potential of large porous particle (LPP) systems by spray-drying solutions of NPs into large porous NP (LPNP) aggregates.

Equipment and Reagents

• 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)

• 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE)

• Lactose monohydrate

• Hydroxypropylcellulose

• Bovine serum albumin (BSA)

• Ethanol

• Aqueous suspensions of surfactant-free carboxylate-modified polystyrene NP (PS-NP) or aqueous suspensions (pH 9) of Nyacol 9,950 colloidal silica NP

• Spray-dryer

Method

• Solutions of NPs were prepared by mixing ethanol and water (70:30, v/v) to the desired w/v fraction.

• If desired, additional excipients may be included, e.g., sugars, lipids such as DPPC and DMPE, polymers, or proteins.

• The resulting mixture is spray-dried under the following conditions: the inlet temperature is fixed at 110°C, the outlet temperature is about 46°C, a V24 rotary atomizer spinning at 20,000 rpm is used, and the feed rate of the solution is 70 mL/min, the drying air flow rate is 98 kg/h.

• Spray-dried particles are collected with a 6 in. cyclone.

Results

• The chemical nature of the NPs seemed to be of little importance, since LPNPs were also successfully produced with colloidal silica NPs instead of PS-NPs.

• The formation of LPNPs appears to be generally independent of the size of the NPs (25 nm and 170 nm NP were tested), provided they are much smaller than the ultimate physical dimension of the spray-dried LPNP.

• In all cases, the LPNPs had a solid deformable shell, consisting of several layers of NPs, and a wrinkled structure indicative of a low relative density, making their aerodynamic properties highly favorable.

• Additional control over LPNPs physical characteristics is achieved by adding other components to the spray-dried solutions, including sugars, lipids (DPPC, DMPE), polymers (hydroxypropylcellulose), and proteins (BSA).