RATE- PREPROGRAMMED DDS Release of drug molecules from the delivery systems has been preprogrammed at specific rate profiles Diffusion of drug molecules into the medium is controlledCLASSIFICATION OF RATE- PREPROGRAMMED DDSA. Polymer membrane permeation-controlled drug delivery systemsB. Polymer matrix diffusion-controlled drug delivery systemsC. Micro reservoir partition-controlled drug delivery systems 6
A. POLYMER MEMBRANE PERMEATION-CONTROLLED DDS Drug release surface of the reservoir compartment is rate-controlling polymeric membrane. Polymeric membrane can be nonporous, microporous or semi permeable in nature. Encapsulation of drug in the reservoir is accomplished by injection molding, spray coating, capsulation or microencapsulation. Q/t = [(Km/r Ka/m Dd Dm)/( Km/r Dm hd + Ka/m Dd hm)] cR 7
Release of drug is controlled by controlling the partition coefficient and diffusivity of the drug molecule and the thickness of the rate-controlling membrane 8
EXAMPLES:PROGESTASERT IUD:reservoir - suspension of progesterone crystals in siliconemedical fluidMembrane- nonporous membrane of ethylene vinyl acetatecopolymerDeliver natural progesterone continuously in the uterinecavity at a daily dosage rate of at least 65 µg/day toachieve contraception for1 year. 9
OCUSERT SYSTEM thin disk of pilocarpine alginate complex sandwiched between two transparent sheets of microporous ethylene-vinyl acetate copolymer membrane. 11
Either 20 or 40 µg/hr of pilocarpine is releasedTRANSDERM-NITRO Nitroglycerin-lactose triturate in the silicone medical fluid Micro porous membrane of ethylene-vinyl acetate copolymer Thin layer of pressure-sensitive silicone adhesive polymer is coated 12
B. POLYMER MATRIX DIFFUSION-CONTROLLED DDS Reservoir is prepared by homogenously dispersing drug particles in a rate-controlling polymer matrix. 13
Q/t1/2 = (2ACRDp)1/2 release of drug is controlled by controlling the loading dose, polymer solubility of the drug, and its diffusivity in the polymer matrixEXAMPLESNITRO-DUR Nitro-glycerine transdermal patch for 24 hr to provide a continuous transdermal infusion of nitro-glycerine at a dosage rate of 0.5 mg/cm2/day for the treatment of angina pectoris. 14
C. MICRORESERVOIR PARTITION- CONTROLLED DRUG DELIVERY SYSTEMS Micro dispersion of an aqueous suspension of drug using a high-energy dispersion technique in a bio-compatible polymer,(Eg. silicone elastomers), forms a homogenous dispersion of many discrete, unleachable, microscopic drug reservoirs. device can be further coated with a layer of biocompatible polymer to modify the mechanism and the rate of drug release 16
Release of drug molecules from this type of CRDDS can follow either dissolution or a matrix diffusion-controlled process depending upon the relative magnitude of Sl and SpEXAMPLESNITRODISC SYSTEM Nitro-glycerine in silicone elastomer 0.5mg/cm2 for once-a-day 17
Activation – modulateddrug delivery systems 18
ACTIVATION MODULATED DDS Drug delivery is activated and controlled by physical, chemical or bio-chemical processes or facilitated by the energy supplied externallyClassification of activation modulated DDS Based on the nature of the process applied or the type of energy used1. Physical means2. Chemical means3. Biological means 19
1. Osmotic pressure- activated DDS drug reservoir can be a solution contained within an impermeable collapsable tube. This is covered with osmotic agent place in a rigid semi permeable housing with controlled water permeability. The rate of drug release is modulated by the gradient of osmotic pressure. Q/t = PwAm (πs-πe) /hmPw = water permeabilityAm = effective surface areahm =thickness of the semi permeable housing 21
2. Hydrodynamic pressure activated DDS hydrodynamic pressure is used as the source of energy to activate the drug release. 24
Q/t = Pf Am/hm (θs – θe)Pf = fluid permeabilityAm = effective surface areahm = thickness of the wall with annular openingsθs – θe = difference in hydrodynamic pressure between the DDS and the environment 25
3. Vapour pressure- activated drug delivery systems Drug inside infusion compartment is separated from pumping compartment by freely movable partition. Pumping compartment contains a fluorocarbon fluid that vaporizes at body temperature The vapour pressure created moves the partition upward, forcing the drug to be delivered. Eg: INFUSAID implants (heparin) 26
Q/t= d4(Ps-P-e)/40.74µld & l = the inner diameter and the length of the delivery cannula, respectivelyPs-P-e = difference between the vapour pressure in the pumping compartment and the site of implantation.µ = viscosity of the drug formulation used. 28
4. Mechanically activated drug delivery system Equipped with a mechanically activated pumping system A measured dose of drug formulation is reproducibly delivered The volume of solution delivered is controllable, as small as 10-100µl Volume of solution delivered is independent of the force & duration of activation applied as well as the solution volume in the container. Example is the development of metered dose nebulizer for the intranasal administration of a precision dose of buserelin (LHRH). 29
5. Magnetically activated drug delivery systems Drug reservoir is a dispersion of peptide or protein powders in a polymer matrix Low rate of delivery is improved by incorporating electromagnetically triggered vibration mechanism 31
Coating polymer can be a ethylene-vinyl acetate copolymer or silicon elastomers. These systems have been used to deliver protein drugs, such as bovine serum albumin6. Sonophoresis-activated drug delivery systems Utilize ultrasonic energy to activate the delivery of the drugs from a polymeric drug delivery device can be fabricated from either a non degradable polymer, such as ethylene-vinyl acetate copolymer, a bio erodible polymer such as poly[bis(p- carboxyphenoxy)alkane anhydride]. 32
Sonophoresis-activated drug delivery systems 33
7. Iontophoresis-activated drug delivery systems uses electrical current to activate and to modulate the diffusion of a charged drug molecule across the skin in a facilitated rate 34
skin permeation rate of a charged molecule i consist of 3 components Jiisp = Jp+Je+Jc Jp = passive skin permeation flux Je = electrical current driven permeation flux Jc = convection flow-driven skin permeation flux IONSYS - fentanyl iontophoretic transdermal system Example : development of an iontophoretic DDS of dexamethasone sodium phosphate 35
8. Hydration-activated drug delivery system Depends on the hydration induced swelling process to activate the release of drug Drug reservoir is homogeneously dispersed in a swellable polymer matrix fabricated from a hydrophilic polymer Release of the drug is controlled by the rate of swelling of the polymer matrix. Example is VALRELEASE tablet- diazepam in hydrocolloid and pharmaceutical excipients. In stomach absorbs the gastric fluid & forms colloidal gel that starts from the tablet surface and grows inward. 36
release of the drug is controlled by matrix diffusion through this gel barrier 37
In this group of controlled-release drug delivery systems the release of drug molecules from the delivery systems is activated by a triggering agent, such as a biochemical substance, in the body and also regulated by its concentration via some feedback mechanisms. The rate of drug release is then controlled by the concentration of triggering agent detected by a sensor in the feedback- regulated mechanism.
There are 3 different sub-type of this system : Bioerosion Regulated Drug Delivery System Bioresponsive Drug Delivery System Self-Regulating Drug Delivery System
Thefeedback regulated drug delivery concept was applied to the development of a Bioerosion- regulated drug delivery system by Heller and Trescony.
The system consists of drug-dispersed bioerodible matrix fabricated from poly(vinyl methyl ether) half-ester, which was coated with a layer of immobilized urease. In a solution with near neutral pH, the polymer only erodes very slowly.
In the presence of urea, urease at the surface of drug delivery system metabolizes urea to form ammonia. This causes the pH to increase and a rapid degradation of polymer matrix as well as the release of drug molecules.
In this system the drug reservoir is contained in a device enclosed by a Bioresponsive polymeric membrane whose drug permeability is controlled by a concentration of a biochemical agent in a tissue where the system is located.
A typical example of this Bioresponsive drug delivery system is the development of a glucose-triggered insulin delivery system in which the insulin reservoir is encapsulated in within a hydrogel membrane having pedant –NR2 groups. In alkaline solution the –NR2 groups are neutral and the membrane is unswollen and impermeable to insulin.
As glucose, a triggering agent, penetrates into the membrane, is oxidized enzymatically by the glucose oxidase entrapped in the membrane to form gluconic acid. The –NR2 groups are protonated to form – NR2H+ and hydrogel membrane then become swollen and permeable to insulin molecules. The amount of insulin delivered is thus Bioresponsive to the concentration of glucose penetrating the insulin delivery system.
This type of feedback-regulated drug delivery system depends on a reversible and competitive binding mechanism to activate and to regulate the release of drug. In this system the drug reservoir is a drug complex encapsulated within a semipermeable polymeric membrane. The release of drug from the delivery system is activated by the membrane permeation of biochemical agent from the tissue in which the system is located.
Kim et al. first applied the mechanism of reversible binding of sugar molecules by lectin into the design of self-regulating drug delivery system. It first involves the preparation of biologically active insulin derivatives in which insulin is coupled with a sugar and this into a insulin- sugar-lectin complex. The complex is then encapsulated within a semipermeable membrane.
As blood glucose diffuses into the device and competitively binds at the sugar binding sites in lectin molecules, this activates the release of bound sugar-insulin derivatives. The released insulin-sugar derivatives then diffuse out of the device, and the amount of insulin-sugar derivatives released depends on the glucose concentration. Thus a self regulating drug delivery is achieved.
However the potential problem exists: that is, the release of insulin is non-linear in response to the changes in glucose level. Further development of the self-regulating insulin delivery system utilized the complex of glycosylated insulin-concavalin A, which is encapsulated inside a polymer membrane.
As glucose, the triggering agent, penetrates the system, it activates the release of glycosylated insulin from the complex for the controlled delivery out of the system. The amount of insulin delivered is thus self- regulated by the concentration of glucose penetrating the insulin delivery system.