Nabumetone is a nonsteroidal anti-inflammatory drug (NSAID) for the treatment of pain and inflammation associated with rheumatoid
arthritis and osteoarthritis (1). The incidence of gastrointestinal ulceration associated with nabumetone appears to be lower
than for other NSAIDs, suggesting that the drug may be a preferential inhibitor of cyclooxygenase-2 (2). Because the drug
exhibits poor aqueous solubility, researchers have attempted to improve its solubility using various techniques (3, 4). Efforts
also have been made to elicit a rapid onset of therapeutic effect by formulating the drug as an effervescent chewable tablet
and as a compressed annular tablet with molded tablet triturate (5, 6).
Although conventional tablets are widely accepted oral solid-dosage forms, pediatric, geriatric, and bedridden patients experience
difficulties in swallowing them. Moreover, for poorly soluble drugs, dissolution of the drug from the tablet is the rate-limiting
step in the process of drug absorption (7). Because the rate and extent of drug absorption is determined by the rate and extent
of drug dissolution from tablets, drugs with poor aqueous solubility as a result of erratic or incomplete absorption from
the gastrointestinal tract are known to pose potential bioavailability problems (8).
Because nabumetone is practically insoluble in water, its absorption is expected to be dependent on dissolution rate (9).
This study attempts to resolve this problem by formulating the drug previously complexed with β-cyclodextrin (β-CD) as a porous
rapidly dispersing tablet. These tablets were intended to disintegrate quickly and dissolve completely to facilitate complete
drug absorption following oral administration. Inclusion complexes have been used successfully to improve solubility, dissolution,
and bioavailability of poorly soluble drugs (10–14).
Materials and methods
Nabumetone was donated by Micro Labs (Bangalore, India). β-CD manufactured by Roquette Freres (Lestrem cedex, France) was donated by Signet Chemical Corp., (Mumbai, India). Crospovidone (polyplasdone XL) and mannitol (Paerlitol) were samples from Zydus Health Care Ltd., (Bangalore). The other samples of ammonium bicarbonate, saccharine sodium, and polyvinyl pyrollidone-K30 (PVP-K30) were
of analytical grade and purchased from S.D. Fine Chemicals (Mumbai).
Phase solubility studies.
Phase solubility studies were performed in triplicate at room temperature (25 °C) according to the method reported in the
literature (10). Excess amounts of nabumetone were added to distilled water containing various concentrations of β-CD (0.3–1.5
mM) in a series of stoppered volumetric flasks and shaken for 72 h on a rotary shaker (Secor Laboratory Instruments, New Delhi, India). The resulting suspensions were filtered through 0.45-μm filter, diluted suitably, and assayed spectrophotometrically
(model UV 1700 PC Shimadzu Corp., Kyoto, Japan) at 270 nm using reagent blanks prepared with the same concentrations of β-CD in distilled water. The apparent
stability constant (Ks) of the complexes was calculated from the slope and the intercept of the phase solubility diagram using Equation 1:
Preparation of the complexes.
The drug β-CD complexes were prepared using the kneading method (10). Nabumetone was mixed with equimolar quantities of β-CD
in a mortar with a small amount of water and kneaded for 45 min to obtain a homogeneous paste. The resulting paste was dried
in an oven at 45 °C for 48 h, and the solid obtained was ground and sieved through a 150-μm sieve. A physical mixture of the
drug and β-CD at a 1:1 molar ratio prepared by simple mechanical admixing was used as a reference during characterization
of the kneaded complex.
Fourier transform infrared (FTIR)spectrophotometry.
The samples were powdered and mixed with dry powdered potassium bromide. The mixtures were taken in a diffuse reflectance
sampler and infrared spectra of the drug, β-CD, and the inclusion complexes were recorded by scanning the 400–4000 cm–1 wavelength region in an FTIR spectrophotometer (model 460 Plus, Jasco, Japan).