Controlled dlievery systems are preparations designed in such a way that they release rate or location of active drug is controlled. They are needed to reduce fluctuations in [plasma] (imp. For reducing side effects of narrow therapeutic window drugs), reduce dosing frequency (imp. for patient compliance), control delivery site (colon) for optimum activity and timed release the drug (e.g. pulsatile action for hormones or angina).
There are four main mechanisms for controlling Drug Release.
The first one is Diffusion-control DDS. When diffusion takes place through a non-porous or micro-porous membrane and water-insoluble polymers coat the drug core [(s)/(l)], the device is called Reservoir and the drug goes in solution when in aqueous environment. Monolithic devices is the second type of diffusion-control DDS. Diffusion takes place through bulk water-insoluble polymer, when water penetrates, drug in solution diffuses. The drug is dissolved in polymer solution prior to device formation and dispersed throughout the device. This tends to be used for implantable devices.
The second type of CDDS is Chemically-controlled ones, where diffusion is similar to the matrix monolithic device. Drug is dissolved in (natural or synthetic and water-soluble or water degradable) polymer solution prior to device formation and is released as the polymer matrix breaks down. Predominantly for long-term implantation. There are two subtypes: monolithic devices, where either pure polymer erodes (surface erosion, decreasing ph, increases autocatalytic degradation of polymer backbone by acid addition or SAVIT delivery technology where coating is non-erodible and active erodible matrix erodes at both ends) or combination of erosion and diffusion takes place (bulk erosion, PLGA is commonly used and FDA approved). Multiple drug can be delivered at specific times and locations through the CHRONOP delivery technology and alternative pulsative release is also possible, when at fixed time drug will erode from inside. This is particularly useful for prolonged GIT absorption. The second subtype is Pendant systems where hydrolysis pendant group to break it free and be released from the backbone and diffusion of bulk polymer takes place. The rate of release depends on the hydrolysis of ester. Also in the HLB ratio. The more hydrophobic functional groups of polymer, the more slow release rate.
The third type is Water penetration- controlled DSS. The drug is being delivered through osmosis (Water transport through semipermeable membrane to form concentration solution inside, drug is pushed out through the hole) or swelling (water penetration into glossy polymer). Osmosis can be direct or indirect and more controlled, depending on the needs. An example of an osmotic device is OROS which provides CR for 24hrs, can be used for high doses of poorly and highly soluble drugs and improve bioavailability. It has been used to improve PK profile of oxybutin. Swelling controlled devices is affected by polymer structure (physichochemical properties, x-linking), hydrophobicity (polymer and drug contribute) and drug (concentration). The more concentrated, the greater gradient outside and inside. The more hydrophilic (pectin), water enters in rapidly and increases swelling, hydrophobic compounds (HPMC) decrease swelling rate. Mixture of hydroxypropyl and methyl controls swelling rate. There are also devices that can control rate by erosion, swelling and diffusion. Properties of gel can also be tailored by LBG (nice, straight polymer):Xanthan (helical polymer stabilises H-bonding) ratio. When gel formulation is wetted, water ingress allows drug to diffuse out gel. GEMINEX delivery technology combines two drugs together in a bilayer with a unique release profile. By altering polymer properties we can change where and how quickly drug is released. Distance betwee polymer chains is also important when high amylose starch is being used in formulations, such as CONTRAMID. It is safe, compressible, biogegredable, can be chemically x-linked, has a high drug capacity, fexible release profiles and can release multiple drugs. There are more complex systems to, such as GEOMATRIX. It has a hydrophilic HPMC core with drug in it, changing the properties alter parameters of device and tailored released depends on drug barrier. Both layers can expands or it can swell thinly. Water penetration controlled DSS working by swelling are capable of 0 order, quick slow, slow-quick, binary, positioned, acce;erated, delayed and pulsatile release. Burst can also take place in the swelling mechanism and the thicker the membrane, the slower the release. Alginate is an example of a polysaccharide working in this way.
There are four main mechanisms for controlling Drug Release.
The first one is Diffusion-control DDS. When diffusion takes place through a non-porous or micro-porous membrane and water-insoluble polymers coat the drug core [(s)/(l)], the device is called Reservoir and the drug goes in solution when in aqueous environment. Monolithic devices is the second type of diffusion-control DDS. Diffusion takes place through bulk water-insoluble polymer, when water penetrates, drug in solution diffuses. The drug is dissolved in polymer solution prior to device formation and dispersed throughout the device. This tends to be used for implantable devices.
The second type of CDDS is Chemically-controlled ones, where diffusion is similar to the matrix monolithic device. Drug is dissolved in (natural or synthetic and water-soluble or water degradable) polymer solution prior to device formation and is released as the polymer matrix breaks down. Predominantly for long-term implantation. There are two subtypes: monolithic devices, where either pure polymer erodes (surface erosion, decreasing ph, increases autocatalytic degradation of polymer backbone by acid addition or SAVIT delivery technology where coating is non-erodible and active erodible matrix erodes at both ends) or combination of erosion and diffusion takes place (bulk erosion, PLGA is commonly used and FDA approved). Multiple drug can be delivered at specific times and locations through the CHRONOP delivery technology and alternative pulsative release is also possible, when at fixed time drug will erode from inside. This is particularly useful for prolonged GIT absorption. The second subtype is Pendant systems where hydrolysis pendant group to break it free and be released from the backbone and diffusion of bulk polymer takes place. The rate of release depends on the hydrolysis of ester. Also in the HLB ratio. The more hydrophobic functional groups of polymer, the more slow release rate.
The third type is Water penetration- controlled DSS. The drug is being delivered through osmosis (Water transport through semipermeable membrane to form concentration solution inside, drug is pushed out through the hole) or swelling (water penetration into glossy polymer). Osmosis can be direct or indirect and more controlled, depending on the needs. An example of an osmotic device is OROS which provides CR for 24hrs, can be used for high doses of poorly and highly soluble drugs and improve bioavailability. It has been used to improve PK profile of oxybutin. Swelling controlled devices is affected by polymer structure (physichochemical properties, x-linking), hydrophobicity (polymer and drug contribute) and drug (concentration). The more concentrated, the greater gradient outside and inside. The more hydrophilic (pectin), water enters in rapidly and increases swelling, hydrophobic compounds (HPMC) decrease swelling rate. Mixture of hydroxypropyl and methyl controls swelling rate. There are also devices that can control rate by erosion, swelling and diffusion. Properties of gel can also be tailored by LBG (nice, straight polymer):Xanthan (helical polymer stabilises H-bonding) ratio. When gel formulation is wetted, water ingress allows drug to diffuse out gel. GEMINEX delivery technology combines two drugs together in a bilayer with a unique release profile. By altering polymer properties we can change where and how quickly drug is released. Distance betwee polymer chains is also important when high amylose starch is being used in formulations, such as CONTRAMID. It is safe, compressible, biogegredable, can be chemically x-linked, has a high drug capacity, fexible release profiles and can release multiple drugs. There are more complex systems to, such as GEOMATRIX. It has a hydrophilic HPMC core with drug in it, changing the properties alter parameters of device and tailored released depends on drug barrier. Both layers can expands or it can swell thinly. Water penetration controlled DSS working by swelling are capable of 0 order, quick slow, slow-quick, binary, positioned, acce;erated, delayed and pulsatile release. Burst can also take place in the swelling mechanism and the thicker the membrane, the slower the release. Alginate is an example of a polysaccharide working in this way.
The fourth and last type of DSS is responsive DSS. Drug release can be controlled by temperature (some polymers undergo a sol-gel transition upon a temp. change), ph (changes in ionisation or cleavage of functional groups due to altered ph can affect sol-gel behaviour, drugs can be loeaded in acidic branched polymers and by repleiing drug can go out), chemicals, enzymes (GIT lots of bac. espesh in colon have enzymes that can be used in delivery systems and an increased drug plasma concentration is being observed as the drug is released by degrading enzymes), ultrasound, magnetism, light, mechanical force (disrupts matrix by compression, sqeezing drug out and allowing it to be released) and IR radiation (insulin released from nanoparticles).
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