pharmaceutics 5 rassoul dinarvand professor of pharmaceutics pharmaceutics 5 1
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2Pharmaceutics 5
دارورسانی طوالنی
دارورسانی به محل اثر
دارورسانی در زمان مورد نیاز
ثبت پتنت جدید و تمدید دوران تولید انحصاری
پپتیدها و دارورسانی مواد موثره خاص(
پروتئینها(
حذف قله ها و دره های غلظت خونی و
کاهش عوارض جانبی
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Drug levels in the blood with (a) traditional drug dosing and (b) controlled-delivery dosing
Pharmaceutics 5
استفاده از حاللهای روغنیاستفاده از امالح کم محلول داروها استفاده از پیش داروها(Prodrugs) )استفاده از حاملهای غیرپلیمری )لیپوزومها استفاده از سیستمهای دارو رسانی مکانیکی )پمپهای
دارورسانی( اتصال مولکولهای دارویی به مولکولهای خاص
(PEG)منوکلونال آنتی بادی، پروتئین های خاص،
استفاده از حاملهای پلیمری
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Chemical engineering◦ Less soluble melts◦ Prodrugs◦ Targeting linkages (MAB)◦ Pegylation
Pharmaceutical engineering◦ Oil vehicles◦ Liposomes◦ Polymeric delivery◦ Cell based drug delivery
Particle engineering◦ Solid lipid particles◦ Dendrimers
Mechanical engineering◦ Mechanical pumps
• Large molecule composed of a number of sub-units
- Natural e.g. alginates,
- synthetic e.g. poly(HMPA)
- Function governed by number and arrangement of constitutional repeat units e.g. –[A-]n, -[A-B-]n, -[A-A] n-[B-B] m , --A-A-B-A-B-B-A-
• How are they made?
- Processing of natural products – alginates from seaweeds, celluloses from plants
- Synthesis from chemical feedstocks – poly(olefins), nylons, poly(esters)
• How can they help?
- Protection of therapeutic compound during passage through body, as encapsulant or carrier.
- Mediator or activator of controlled release
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• Matrix (Monolithic) devices
- films with the drug in a polymer matrix
- Easy to fabricate, typically by simple mixing of polymer and drug
- Example: Eudragit RS100 polymer, mixed with sorbitol and Flurbiprofen
• Polymer drug conjugates
- Polymer attached to drug by (covalent) sacrificial linker
- Example: Paclitaxel-albumin conjugate in the market
Docetaxel-albumin conjugate under investigation
• Reservoir devices
- Drug contained by the polymer
- Release is usually diffusion controlled (Fickian) i.e. J = -DC where J =flux, C =
component of concentration across membrane of defined area, and is a differential vector operator
- Example: PharmazomeTM Theophylline release
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• Biodegradable polymers
- Polymer degrades in vivo to release the drug
- Simple release mechanism, but difficult to obtain fine control over degradation
- Does not invoke an inflammatory or toxic response.
- Is metabolized in the body after fulfilling its purpose, leaving no trace
• Examples in use
- Resomer (PLGA)
- Vicryl (PLGA)
• Common biodegradable polymers
- Poly(lactide-co-glycolide) (PLGA)
- Poly(hydroxybutyrate-co valerate) (Biopol)
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Hydrogels
• Three-dimensional, hydrophilic polymeric networks, swollen with water
• Cross-linking between polymer chains determines swelling and gel flexibility
• Natural or synthetic derived – very large number of hydrogels have been produced
• Ionic (acidic, basic) or neutral dependent on desired application
• Inherently biocompatible – strongly hydrated
O
OOH
O
O
O
O
HEMA EGDMA>95 parts <5 parts
polymeriseO
O
OH
O
O
O
O O
O
HO[] [
]
[] [
]
Monomer (water-soluble) Cross-linker Hydrogel
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Mucoadhesives
• 2nd Major class of polymer drug delivery vehicles
- Similar in design features to hydrogels (sub-class)
- Ability to localise at mucus membrane via adhesive interactions
- Contain functional groups for binding to mucosal surfaces – primarily H-bonding
- Pendant chains for intimate contact and interdigitation with mucins
- Inherently biocompatible – strongly hydrated
O
OH
O
O
O
Methacrylic acid(MAA)
Poly(ethyleneglycol)dimethacrylatePEGDMA
polymeriseO
HO
O
O
O
O O
OH
[] [
]
[] [
]Adhesivegroups
O
[]
n
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Controlled release implies controlled release of drugs from polymer drug delivery systems (DDS)
Type of polymer◦ Non-degradable / Degradable
Type of Design
Reservoir Matrix
Release mechanisms◦ Diffusion / polymer degradation / combination
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Drug delivery from (a) reservoir and (b) matrix swelling-controlled release systems
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Molecular gates for the delivery of insulin triggered by the presence of glucose in the bloodstream
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Drug delivery from (a) bulk-eroding and (b) surface-eroding biodegradable systems
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Polymer Non-degradable Degradable
Design Reservoir Matrix Reservoir Matrix
Release √√√ √√√ √√ √√
Removal √ √
Rupture √ √
Low Mw √ √ √ √
High Mw √ √ √Duration 5 years 5 years 1-2 years Months
Examples Norplant® Jadelle® CapronorTM Microspheres
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Particulate systems◦ Nanoparticles
Nanocapsules Nanospheres
◦ Microparticles Microspheres Microcapsules
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Simultaneous drug loading and polymerisation/device fabrication
Drug loading after device fabrication◦ Drug uptake by polymeric device when immersed in
drug saturated solution◦ Mechanical drug loading
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DiffusionConcentration gradient in polymeric matrix
Chemical reactionPolymer biodegradation
Solvent effectRelease of soluble drugs in hydrogels
Mechanical releaseDrug release from mechanical devices such as
pumps
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