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Pulsatile delivery can be employed for the delivery of the drug in accordance with the required temporal pattern. Pulsatile delivery can be achieved through sophisticated devices with the release profile achieved by some form of external trigger, as will be discussed below. It is important to recognize, however, that pulsatile release per se does not necessarily mean pulsatile concentration time profiles at the site of action. Drugs with the proper pharmacokinetics, e.g. short half-life and chronopharmacology [240,241] have to be considered in order to obtain the desired concentration-time profiles at the diseased site. |
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Several pulsatile delivery systems have been designed, all of which are in the experimental stage of development. External triggers used to accomplish pulsatile release include temperature, electric current, magnetism, ultrasound, and light. |
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At least three temperature activated systems have been described in the literature. Thermosensitive hydrogels have been prepared that exhibit reversible swelling-shrinking changes induced by temperature variations. Drug loaded into the hydrogel is released on shrinking in response to a programmed temperature change [242,243]. Acrylic pressure sensitive adhesives have also been prepared with side-chain crystallizable segments. Drug loaded in the pressure sensitive adhesive cannot be released until the temperature is increased above the melting point of the side chains [244]. |
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A third concept uses the glass transition temperature of amorphous polymers as the trigger temperature. Since below the glass transition temperature no segmental rotation can take place, drug loaded in the polymer will not be released until the external temperature is brought above the glass transition temperature. By switching the external temperature above and then below the glass transition temperature of the amorphous polymer, a pulsatile on-off drug delivery can be obtained [245]. |
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Another pulsatile system incorporates the drug, as well as small magnetic beads, into the polymeric matrix. When desired, the release rate is enhanced by an external oscillating magnetic field [246,247]. Magnetic field frequency and strength, as well as polymer composition and strength, and orientation of the embedded beads influence the release [248,249]. |
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Externally applied ultrasonic irradiation has been shown to enhance the release of drugs from diffusion control membranes as well as bioerodible polymers [250,251]. The mechanism of drug release enhancement is the cavitation caused by the ultrasonic waves. The method has been tested in vivo in diabetic rats [252]. |
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Pulsatile delivery has also been accomplished by making conjugates of targetable soluble polymers, e.g. HPMA copolymers with photoactivatable drugs such as porphyrins, phthalocyanines, and chlorins. The conjugates enter the cells by pinocytosis and accumulate in the lysosomes. At the desired time, the |
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