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Polymeric Systems for Controlled Drug Release Synopsis of the Polymeric Systems for Controlled Drug Release. [Uhrich et al. Chemical Reviews, 1999, Vol. 99, No. 11 , 3181-3198]
Polymeric Systems for Controlled Drug Release
Synopsis of the Polymeric Systems for Controlled Drug Release.
[Uhrich et al. Chemical Reviews, 1999, Vol. 99, No. 11 , 3181-3198]
Controlled Release Systems intended to improve effectiveness of therapy, by
- increasing therapeutic efficacy, - decreasing side effects, - reducing number of administrations,
- get rid of special administration (e.g., injections).
Methods of Controlled Release
(1) Temporal control
(2) Distribution control
(1) Temporal control: deliver the drug over an extended duration or at a specific time during treatment, suitable for rapidly metabolized and eliminated drugs
Methods of Controlled Release
Methods of Controlled Release (1) Temporal control
Drug concentrations at site of therapeutic action after delivery as a conventional injection (thin line) and as a temporal controlled release system (bold line).
(2) Distribution control: target the release of drug to the site of activity, suitable when the ordinary distribution (a) causes major side effects hence discontinue treatment, (often the cause of chemotherapy failure when bone marrow cell death prevents the patient from undergoing a complete drug
treatment). (b) does not allow the drug to reach the site of action e.g. cannot cross the BBB
Methods of Controlled Release
(2) Distribution control
Methods of Controlled Release
Drug delivery from an ideal distribution controlled
release system. Bold line: Drug concentrations at
site of therapeutic action. Thin line: Systemic levels at
which side effects occur.
Mechanisms of CDR Using Polymers:
(A) Temporal.
(B) Distribution.
A. Temporal CDR : The polymeric device protect drug from aqueous environment for preprogrammed periods of time. Many of these devices provide sustained release at a constant rate.
It involve: (1) delay dissolution (2) diffusion control (3) drug solutions control flow.
Delaying dissolution: slow the rate of drug exposure to aqueous environment by a polymer coating or matrix that dissolves slower than the drug. Diffusion control: inhibit drug diffusion by insoluble polymer matrix or membrane which act as a diffusion barrier. Drug solutions control flow: utilize osmotic pressure to control the flow of the drug solution out of the device
Examples of mechanisms of temporal controlled release.
Another form of temporal CDR is responsive drug delivery in which drug is released in a pulsatile manner only when required by the body. It is composed of (a) sensor that detects the environmental parameter that stimulates drug release, (b) delivery device that releases drug. e.g. Insulin delivery
B. Distribution CDR A simple technique to control distribution is to implant the drug device directly at the site of action. Direct implantation is suitable only if the site of drug action is accessible without risk to the patient and the drug is unable to leave the site, e.g. the drug is unable to pass through the blood-brain barrier. A targeting mechanism must be employed that allows the delivery system to find the desired target
Polymers used are of two types: (1) colloidal carriers: the polymer encapsulates drug within micro-or nanoparticles. (2) polymer-drug conjugates: the polymer is covalently joined to the drug as a carrier then the bond is cleaved to release the drug, biological molecules are utilized as targeting moieties.
Type of Polymers
(1) Biodegradable. (2) Nonbiodegradable.
common routes of biodegradation in vivo are hydrolysis and enzymatic cleavage, resulting in a water soluble products can be easily excreted. Degradable polymers are classified based on the mechanism of erosion. The term “degradation” refers to bond cleavage (chemical process), whereas “erosion” refers to reduction of material (physical phenomena dependent on dissolution and diffusion processes). Two mechanisms of polymer erosion occur: (1) surface erosion. (2) bulk erosion. Both mechanisms will occur, but varies with the chemical structure of the polymer backbone.
The R.O.A rule the type of CRS to be used, also the fate of polymer in the body after drug release, so naturally excreted polymers are desirable. Nondegradable polymers are accepted when the delivery system can be recovered after drug release (e.g., removal of patch or insert) or for oral applications in which the polymer passes through the GIT.
A. Poly(esters): bulk degradation, poly(L-lactic acid) (PLA), poly (caprolactone) (PCL); poly(glycolic acid) (PGA).
(1) PLA , PGA and copolymer poly (lactic acid-co-glycolic acid) (PLGA). From the enantiomeric forms of PLA the naturally occurring is L(or S),so PLLA is more biocompatible.
(2) Poly (ethyleneglycol) (PEG) block copolymers also called poly(ethylene oxide) (PEO) at high molecular weights.
B. Poly(ortho esters): release drug after surface erosion,
zero-order release.
- Chemical modification yields: (1) self-catalyzing degradation polymer. (2) pH sensitive degradation polymer. The second used for pulsatile delivery of insulin.
C. Poly(anhydrides): Nearly zero-order, polymer surface erosion.
-Types (1) Aliphatic: sebacic acid (SA), poly(fatty acid dimer-sebacic acid). (2) Aromatic: p-(carboxyphenoxy) propane(CPP), p-(carboxyphenoxy) hexane (CPH).
1. Poly(anhydride-imides): A co-polymer of poly(anhydrides) and amino acids such as glycine and alanine. It show surface erosion.
2. Poly(anhydride-esters):
Include two types of bonds:
(1) anhydride bonds rapidly hydrolyzed to the
(2) poly(ester) which degraded slowly.
A unique aspect of these polymer is that degradation of the polymer backbone yields salicylic acid , an antiinflammatory agent.
Poly(anhydride-esters) that degrade into salicylic acid, an anti-inflammatory agent.
2. Poly(anhydride-esters):
D. Poly(amides):
mildly antigenic, amide bond rely on enzymes for cleavage resulting in poor controlled release in vivo. An example is poly(lactic acid-colysine) (PLAL).
1. Poly(iminocarbonates): Poly(iminocarbonates) are currently being investigated for use in small bone fixation devices as bone screws and pins.
E. Phosphorus-Containing Polymers
1. Poly(phosphazenes): a unique inorganic phosphorus-nitrogen backbone. The side-chain is responsible for properties and biodegradation kinetics. Employed in temporal CDR of NSAIDs and peptides.
2. Poly(phosphoesters)
Co-polymer of phosphoester and poly(urethanes).
Poly(urethanes) have been used as blood-contacting biomaterials.
Biocompatibility of polymers and its degradation products are critical, so it is ideal than nonbiocompatible polymers. Metabolism of the polymer itself and its degradation products generating soluble monomers is essential for excretion. Degradable polymers possess unstable bonds within living environments such as anhydride, ester or amide .
Miscellaneous Issues Involve Polymers
Enantiomers ,especially naturally occurring are useful. Crystalline form, Taft’s steric phenomena, Molecular weight, Hydrophilic or Lipophilic nature, Surfactant properties, PH sensitivity, Thermosensitivity ,Zero-order kinetic of drug release and polymer degradation are significant.
Miscellaneous Issues Involve Polymers
the synthetic manipulation of polymers aims to improve mechanical stability, through introducing suitable side chain affecting degradation by inserting acidic or basic excipients into the polymer backbone. Also, the use of catalyst for both synthesis (FDA proved as a food stabilizer. e.g. stannous octoate)and degradation processes is helpful.
Miscellaneous Issues Involve Polymers
Synthetic pathways for a few polymers: poly(esters)are synthesized by ring- opening polymerization of cyclic lactone monomer, poly(ortho esters) are synthesized by the addition of polyols to diketene acetals, poly (anhydrides) are prepared by melt-condensation polymerization.
Miscellaneous Issues Involve Polymers
Ring-opening polymerization of selected cyclic
lactones to give the following: (a) poly(-caprolactone) (PCL); (b) poly(glycolic acid) (PGA); (c) poly(L-lactic acid)(PLA).
Conclusions The review focused on biodegradable polymers applications. There are many research’s for designing new polymer materials. One unique approach to polymer design is the use of combinatorial methods to design arrays of new polymeric materials. The ability to impart bioadhesivity, cell specificity, active transport, or other specific characteristics into a biocompatible polymer represents an important synthetic challenge. Biodegradable polymers have had a significant effect on human health care for now and the future.
