Solubilized Formulations

Abstract

Co-solvent based, polyethylene glycol (PEG)-based, and lipid-based solubilization techniques for the delivery of poorly soluble drugs are discussed in this chapter. The properties of excipients and the physicochemical principles are presented for formulating each type of the solubilized formulations. Co-solvents are commonly used in combination with surface active solubilizers to increase the solubilizing capacity and to improve the in vivo emulsification of self-emulsifying formulations. In PEG-based delivery systems, drug is either dispersed as micronized crystalline particles (via the formation of eutectic mixtures) or present in its amorphous state. Improvement in absorption from PEG matrix is due to (1) fast dissolution rate of drug from the dosage forms and (2) higher transient solubility of the drug substance in gastrointestinal tract. The mechanisms of improved absorption from lipid-based solubilized formulations include (1) enhanced dissolution and solubilization in vivo; (2) prolongation of gastric residence time; (3) stimulation of lymphatic transport; and (4) reduced metabolism and efflux activities.

Various manufacturing techniques to process the solubilized formulations into oral dosage forms are also discussed in this chapter. For the formulations that are liquid under ambient conditions, encapsulation into soft gelatin or hard gelatin capsules is the most common manufacturing method. Semi-solid and solid-solubilized formulations that are liquid at a higher temperature (50–70°C) can be encapsulated into hard gelatin capsules as molten liquids at elevated temperature. Semi-solid or solid matrices are formed inside the capsules when the molten materials are cooled to ambient temperature. Spray congealing and fluidized bed melt granulation are alternative manufacturing processes to convert the solubilized formulations with high melting/softening points into granules that can be readily processed into capsules or tablets. Powdered solution technology can also be applied to transform the solubilized formulation of low-dose drug into free flowing powder by absorbing the formulation into solid carriers.

Appendices

Method Capsule 1Preformulation Support of Solubilized Formulations

Based on the method reported by Desai and Park (2004)

Objective

• To determine the solubility of valdecoxib in a variety of solid carriers, co-solvents, and surfactants.

Equipment and Reagents

• Valdecoxib

• Polyethylene Glycol 4000, 6000, 8000

• Urea

• Mannitol

• Tween 20, Tween 80

• Sodium lauryl sulfate

• Glycerol

• Ethanol

• Methanol

• Purified water

Method

• Solubility studies with 1, 2, 5, 10% wt/vol for carrier–water mixtures.

• Solubility studies with 10, 20, 30, 40, 50% wt/vol for co-solvent–water mixtures.

• Solubility studies with 0.25, 0.50, 0.75, 1.0% wt/vol for surfactant–water mixtures.

• Powder X-ray diffraction and scanning electron microscopy for characterization of valdecoxib drug substance.

Results

• The solubility of valdecoxib increased up to 8-, 7-, 6.7-, and 4.2-fold for PEG 4000, PEG 6000, PEG 8000, and urea, respectively. Mannitol provided no solubility benefit.

• Co-solvent systems through 50% wt/vol showed a rank-order increase of solubility such that ethanol>methanol>glycerol which was due to the greater polarity of the mixed solvent system.

• Anionic surfactant (sodium lauryl sulfate) provided greater solubility enhancement than nonionic surfactants (Tween) and was associated with the micelle interaction between the surfactant and valdecoxib.

Method Capsule 2Miniaturized and Automated Screening of Liquid and Semi-solid Formulations

Based on the method reported by Mansky et al. (2007)

Objective

• To apply a material sparing and efficient screening method to identify liquid and semi-solid formulations.

Equipment and Reagents

• JNJ-25894934, JNJ-3026582

• Gelucire^® 44/14

• Hydroxypropyl-β-cyclodextrin

• Tween 20, Tween 80

• Volpo 10

• Capmul^® MCM, PG8

• Captex 200

• Maisine 35–1

• Myvacet^® 9–45

• Oleic acid

• Capric acid

• Vitamin E TPGS

• TECAN Genesis Workstation (96 Well Model)

Method

• Compound and excipient stock solutions were prepared, metered, and dried to using the TECAN system into 96 well plates.

• Samples were aged as necessary by protocol.

• Microplate dissolution was performed and concentration profiles assessed by HPLC.

Results

• Testing was successfully performed using drug levels as small as 50 μg per well, allowing for multiple formulation evaluation within a material sparing design.

• Binary drug–excipient evaluation at multiple drug loadings revealed that JNJ-25894943 and JNJ-3026582 were solubilized at up to 100 mg/g by Vitamin E TPGS and Incrocas 35, with Vitamin E TPGS being the most effective stabilizer over extended durations for both compounds.

• Kinetic solubility data generated by the high-throughput methodology was highly correlated with conventional solubility screening.

Method Capsule 3Evaluating Lipid Formulation In Vitro and Ex Vivo

Based on the method reported by Dahan and Hoffman (2007)

Objective

• Investigate the impact of different lipid-based formulations on in vitro solubilization and intestinal ex vivo permeability.

Equipment and Reagents

• Dexamethasone, griseofulvin

• Peanut oil (long-chain triglyceride)

• Triacetin (short-chain triglyceride)

• Taurocholic acid

• Pancreatin

• L-a-phosphatidylcholine

• Tris maleate

• Calcium chloride

Method

• Simulated in vitro lypolysis performed using an Using diffusion cell and ultracentrifugation to separate drug phases that are available for absorption.

• Permeation was assessed using an ex vivo model by means of intestinal segments of male Wistar rats.

• In vivo oral bioavailability of formulations was assessed in male Wistar rats at a dose of 5 mg/kg with plasma concentration assessed by high-performance liquid chromatorgraphy.

Results

• In vitro lypolysis showed a correlation of improved performance for griseofulvin formulations with increasing triglyceride chain length while no major improvement was observed for dexamethasone.

• Ex vivo results showed that short-chain triglycerides improved permeability for dexamethasone and griseofulvin.

• In vivo results were well correlated with in vitro data when comparing rank order identified for each drug-formulation; however, the observed ex vivo permeability enhancement of the short-chain triglyceride was not confirmed in vivo.

• Limited changes of internal porosity were the result of elastic recovery and molecular rearrangement during the dissolution process.

Method Capsule 4Cross-linking of Soft Gelatin and Hard Gelatin Capsules

Based on the method reported by Meyer et al. (2000)

Objective

• To utilize in vitro analysis to predict bioequivalent and bioinequivalent capsules.

Equipment and Reagents

• Acetaminophen

• Lactose

• Polyethylene Glycol 600, 1000

• Hard Gelatin Capsules, Size 1

• Type B Gelatin, 150 bloom limed-bone gelatin

• Glycerin

• Sorbitol

Method

• Hard gelatin capsules were stressed by filling with lactose containing 20 ppm and 120 ppm of formaldehyde while storing for six days at room temperature and one day at 40°C/75%RH. Capsules were then emptied and manually filled with acetaminophen.

• Soft gelatin capsules were prepared containing 0, 20, and 80 ppm, with a storage period of over 30 weeks at 25°C/60%RH and 40°C/75%RH.

• In vitro dissolution was conducted using USP Apparatus II with 900 mL of simulated gastric fluid containing pepsin at 50 rpm.

• Two separate 24-subject, three-way crossover, bioequivalence studies using three different lots of hard gelatin capsules and three different lots of soft gelatin capsules, all having experienced different levels of stress.

Results

• Hard gelatin capsules exposed to increased levels of formaldehyde failed to meet USP dissolution testing requirements in SGF and water.

• Soft gelatin capsules containing 20 ppm formaldehyde met dissolution requirements; however, higher levels failed to comply with USP specifications after 55 days storage at 40°C/75%RH.

• Oral bioavailability of stressed capsules showed similar AUC when compared to nonstressed product; however, a statistically significant increase in T_max was observed for stressed product due to the cross-linked induced delayed release.