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Chronotherapeutic drug delivery systems (CRDDS) have been recognized as potentially beneficial to the chronotherapy (timeoptimized
therapy) of widespread chronic diseases that display time-dependent symptoms, such as ulcers, asthma, cardiovascular diseases
and arthritis. CRDDS control drug release according to circadian rhythms and the timing of symptoms.1 A number of CRDDS have been developed to synchronize medication with the intrinsic biorhythm of the disease; with conventional
and modifiedrelease formulations being administered at different times of the day in accordance with the circadian onset of
the disease.2People with rheumatoid arthritis (RA), usually experience peak pain in the morning, which decreases throughout the day. In
this scenario, an evening once-a-day nonsteroidal anti-inflammatory drug (NSAID) schedule is recommended. If pain is worse
during early afternoon or at night, however, a morning or an evening onceaday NSAID schedule may be recommended. The exact
dose depends on the severity of the patient's pain and their individual physiology.3 Most newly developed antiRA agents are now available as oncedaily dosage forms; the absorption kinetics of conventional
dosage forms are inadequate in the morning, which is when the need of patient is greatest, and drug levels of once-a-day formulations
that have nighttime dosing indication tend to fall off towards the end of the 24h dosing interval, resulting in reduced protection
against the pain when the need is more.
Diclofenac sodium (DS) is a potent NSAID frequently used to treat RA; however, oral administration of DS as a conventional
formulation generally fails to achieve the desired clinical effect because it elicits patient incompliance — many fail to
take the dosage early enough in the morning to coordinate with the rhythm of RA. Therefore, the development of oral controlledrelease
formulations of this drug is highly desirable.
The Pulsincap system, developed and registered by R.P. Scherer International Corp. (MI, USA), is a special dosage form comprising
a waterinsoluble capsule body enclosing a drug reservoir. The body is closed at the open end with a swellable hydrogel plug,
which consists of insoluble, but permeable and swellable polymers (e.g., polymethacrylates), erodible compressed polymers
(e.g., hydroxypropylmethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polyethylene oxide), congealed melted polymers
(e.g., saturated polyglycolated glycerides, glyceryl monooleate) and/or enzymatically controlled erodible polymers (e.g.,
pectin). When this capsule comes in to contact with the dissolution fluid, it swells and, after a lag time, the plug pushes
itself outside the capsule and rapidly releases the drug. The length of the plug and its position of insertion into the capsule
controls the lag time.4,5In our study, a modified Pulsincap device containing DS was developed to target drug release in the colon. This is a sitespecific
and timedependent formulation; by administering the formulation at 10.00 pm, symptoms that are experienced early in the morning
are avoided. This therapeutic effect is prolonged by continuously releasing the medication over an extended period of time
after administering a single dose. The study objective was to explore the time-and pHdependent controlled drug delivery of
DS using the pulsincap system.
Material and methods
Materials
DS was obtained as gift sample from Welable Parma Ltd (India). pHsensitive methacrylic acid copolymers (Acrycoat L 100 and
S 100) were supplied as gifts by Corel Pharma Ltd (India). Hydroxypropylmethyl celluloseK4M (HPMC) and hydroxypropyl cellulose
(HPCH) were obtained as a gift from Colorcon (India). Sodium carboxymethyl cellulose (NaCMC), cellulose acetate phthalate
(CAP), guar gum (GG) and sodium alginate (NaAlg) were purchased from S.D. Fine Chem. Ltd (India). All other chemicals used
were of analytical grade.
Methods
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