NOVEL DRUG DELIVERY SYSTEMS

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NOVEL DRUG DELIVERY SYSTEMS
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Introduction

• Transdermal drug delivery systems These are
  defined as self-contained, discrete dosage forms
  which when applied to the intact skin, deliver
  the drug(s) through the skin at a controlled rate
  to the systemic circulation.
• Advantages
• Transdermal medication delivers a steady infusion
  of a drug over an extended period of time.
  Adverse effects or therapeutic failures
  frequently associated with intermittent dosing
  can also be avoided.
• Transdermal delivery can increase therapeutic
  value of many drugs by avoiding specific problems
  associated with the drug (ex- GIT irritation, low
  absorption, decomposition due to hepatic first
  pass effect, formation of metabolites that causes
  side effects, short half life necessitating
  frequent dosing etc).
• Self administration is possible with these
  systems.
• The drug input can be terminated at any point of
  time by removing transdermal patch.

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Transdermal drug delivery systems

• Dis advantages
• The drug must have some desirable physicochemical
  properties for penetration through stratum conium
  if the drug dosage required for therapeutic
  value is more than 10mg/day, the transdermal
  delivery will be difficult for administration.
  Daily doses of less than 5mg/day is preferred.
• Skin irritation or contact dermatitis due to
  drug, excipients and enhancers of drug used to
  increase percutaneous absorption is another
  limitation.
• Clinical need is another area that has to be
  examined carefully before a decision is made to
  develop a transdermal product.
• The barrier function of skin changes from one
  site to another on the same person, from person
  to person with age.

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Kinetics of transdermal penetration

• Knowledge of skin permeation kinetics is vital to
  the successful development of transdermal
  therapeutic systems. Transdermal permeation of
  drug involves the following steps
• Sorption by stratum corneum
• Penetration of drug through viable epidermis
• Uptake of the drug by capillary network in the
  dermal papillary layer
• Basic components of transdermal drug delivery
  systems
• 1) Polymer matrix/matrices Natural polymers
  Cellulose, gelatin, starches.
• b) Synthetic elastomers polybutadiene,
  polysiloxane, neoprene etc.
• c) Synthetic polymers PVC, PVA, polyethylene,
  polyurea.
• 2) Drugs
• 3) Permeation enhancers These are compound
  which promote skin permeability by altering the
  skin as a barrier to the flux of a desired
  penetrant. A large no of compounds are identified
  as solvents, surfactants, binary systems
  miscellanous chemicals.
• 4) Other excipients It includes adhesives,
  backing membrane.

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Approaches used in development of transdermal
systems

• Membrane permeation controlled systems
• Nitroglycerin releasing transdermal system,
  clonidine releasing transdermal system.
• Adhesive dispersion systems
• Isosorbide dinitrate releasing transdermal system
  
• Matrix diffusion controlled
• Nitro-Dur-I, Nitro-Dur-II
• Microreservoir / Microsealed dissolution
  controlled systems
• Nitrodisc (nitroglycerine releasing transdermal
  systems).

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Ocular drug delivery systems

• The objective of the ocular drug delivery is to
• Improve ocular contact time
• Enhancing corneal permeability
• Enhancing site specificity
• Role of polymers in ocular drug delivery
• Incorporation of polymers into an aqueous medium
  of drug could increase solution viscosity and
  reduces the solution drainage. Increasing the
  solution viscosity of pilocarpine from 1 to 100
  cps by using methyl cellulose reduced the drug
  drainage and 2 fold increase in drug
  concentration in aqueous humor was obtained.
• Natural polymers such as sodium hyaluronate
  chondroitin sulfate are being investigated as
  viscosity inducing agents.
• Ophthalmic inserts It offers the potential
  advantage of improving patient compliance by
  reducing dosing frequency. The desired criteria
  for a controlled release ocular insert are
• a) Comfort b) Ease of handling c) sterility d)
  Ease of manufacture.
• Controlled release systems for ocular use
  encompass both erodible non-erodible systems.
  The non-erodible inserts are of 2 types
• Ocusert system
• Contact lens

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Ocular drug delivery systems

• Ocusert systems It is preprogrammed to release
  pilocarpine at constant rate of 20 or 40 µg/hr
  around the clock for 7 days for the treatment of
  glaucoma.
• Contact Lens Therapeutic soft lenses are often
  used to aid corneal wound healing in patients
  with infection, corneal ulcers characterised by
  thining of cornea.
• Erodible Inserts Several erodible drug inserts
  have been prepared tested for ocular use.
  Pilocarpine containing CMC wafers, PVA disc or
  rod is a classical example. The three devices of
  erodible inserts have been marketed to date are
  a) The Lacriserts b) SODI (soluble ocular drug
  insert) c) Minidisc.
• Corneal collagen shields Collagen is a protein
  that can be safely applied to the body and is
  used to promote wound healing and delivers a
  variety of medications to the cornea ocular
  tissues. A study published in 1978 showed that
  wafer shaped collagen inserts impregnated with
  gentamicin produced highest level of drug in tear
  film tissue in the rabbit eye compared to
  drops, ointment conjuctival injection.

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Buccal drug delivery systems

• Drugs administered to the oral cavity are removed
  from the site of administration by natural
  clearance mechanisms.
• For drug delivery purposes, the term bioadhesion
  implies attachment of a drug carrier system at a
  specific biological action. In most instances the
  bioadhesive polymer is in contact with the mucous
  hence the term mucoadhesion is employed.
• Buccal mucosa The buccal cavity provides a
  highly vascular mucous membrane site for
  administration of drugs.
• The epithelial lining of oral cavity differs both
  in type (keratinised non-keratinised)
  thickness in different areas the differences
  give rise to regional variations in permeability
  to drugs.
• The buccal mucosa is being perceived as an
  alternative for peptide protein drug
  administration especially when sustained delivery
  is desired.
• The future challenge in the development of
  buccoadhesive dosage forms is to modify the
  permeability barrier of the mucosa using safe and
  effective penetration enhancers.

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Buccal drug delivery systems

• Mucoadhesive buccal dosage forms have 3 desirable
  features.
• They are readily localised in the oral cavity to
  improve enhance the bioavailability of drugs.
• They facilitate intimate contact of the
  formulation with the underlying absorption
  surface.
• They also prolong residence time of the dosage
  form to permit once or twice a day dosing.
• Methods to study bioadhesion
• Study of cellular modifications during
  interpretation
• Study of adhesion on artificial media
• Study of adhesion on biological tissues
• Factors affecting bioadhesion
• The bioadhesive polymer environment both affect
  bioadhesion. The polymer related factors include
  mol.wt, polymer chain length configuration,
  concentration of active polymer swelling.
• The environment related factors are pH applied
  strength.

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Liposomes as drug carriers

• These are simple microscopic (lipid) vesicles in
  which an aqueous volume is entirely enclosed by a
  membrane composed of lipid molecule.
• The drug molecules can either be encapsulated in
  aqueous space or intercalated into the lipid
  bilayer.
• Amphipathic molecules are used to form Liposomes.
  Some examples of amphipathic molecules are
  lecithin, phosphatidyl glycerol etc.
• The exact location of drug will depend upon its
  physicochemical characteristics the
  composition of lipids.
• A standard composition of Liposome is egg
  lecithin cholesterol phosphatidyl glycerol in
  molar ratio (0.9 1.0 0.1). These lipids can
  be stored either as solids, or inorganic solution
  at -20 or -70ºC in order to reduce the chances of
  oxidation.
• Method of preparation of Liposomes It involves
  3 or 4 basic stages
• Drying down lipids from organic solvent
• Dispersion of lipids in aqueous media
• Purification of resultant Liposomes
• Analysis of final product

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Liposomes as drug carriers

• Characterisation of Liposomes
• The behaviour of Liposomes in both physical
  biological systems is governed by the factors
  such as physical size, membrane permeability,
  entrapped solutes, chemical composition as well
  as quantity purity of starting materials.
• Therefore the Liposomes are characterised for
  physical attributes (shape, size its
  distribution, drug captured, entrapped volume,
  lamellarity, drug release and chemical
  composition (estimation of phospholipids,
  cholesterol).
• Applications of Liposomes
• Liposomes prove to be efficient carrier for
  targeting the drug to site of action, because of
  being biodegradable identical to biological
  membrane.
• Liposomes can able to produce localised drug
  effect, enhanced drug uptake cell Liposome
  interaction.
• Liposomes are carriers for vaccines, antigens,
  micromolecules for site specific delivery (oral,
  topical, pulmonary ophthalmic etc).

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Niosomes as drug carriers

• Niosomes are non-ionic surfactant vesicles that
  can entrap both hydrophilic and lipophilic drugs
  either in aqueous layer or in vesicular membrane
  made of lipid materials. Niosomes can prolong the
  circulation of entrapped drugs.
• Some examples of non-ionic surfactants like
  span-40,60,80 tweens are commonly used. These
  surfactants can be combined with cholesterol to
  entrap drugs in vesicles.
• Formulation of Niosomes It can be formulated by
  lipid layer hydration method, reverse phase
  evaporation techniques or by trans membrane pH
  gradient uptake process.
• Characterisation Niosomes can be characterised
  by size distribution studies (small niosomes
  100-200 nm, large 800-900 nm, big 2-4 µm).
• Evaluation Drug entrapment efficiency, drug
  stability, drug leakage in saline plasma on
  storage, PK aspects, toxicity studies drug
  targeting efficiency.

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Niosomes as drug carriers

• Loading of drug(s) into Niosomes The use of
  niosomes as drug delivery vehicles naturally
  assumes an ability to efficiently load the
  niosomes with the drug of choice. Passive
  trapping and active trapping are 2 methods used
  to load drug(s) into niosomes.
• Benefits of Niosomal drug carrier
• Niosomes are more suitable for parenteral drug
  delivery.
• As compared to liposomes, about 50 of
  phospholipids can be replaced with non-ionic
  surfactant the vesicle stability may be
  improved.
• Due to presence of non-ionic surfactants, there
  may be improvement in permeation release of
  drugs entrapped through various barriers of body
  organs which may improve the targeting
  efficiency of drugs.
• The drug targeting efficiency of niosomes may be
  improved using suitable surface modification with
  the help of other adjuvants.

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Niosomes as drug carriers

• Applications of Niosomes
• Therapeutic agents like anticancer agents, anti
  infectives, anti HIV agents, antivirals,
  anti-inflammatory drugs can be entrapped in
  niosomes to achieve better bioavailability
  targeting properties for reducing the toxicity
  side effects of drugs.
• Niosomes can be transported by macrophages which
  are known to infiltrate tumour cells.

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Microspheres as drug carriers

• Microspheres of biodegradable non biodegradable
  polymers have been investigated for sustained
  release depending on the final application.
• The most important characteristic of microsphere
  is microphase separation morphology which endows
  it with a controllable variability in degradation
  rate also drug release.
• Preparation of Microspheres The preparation of
  microspheres from natural polymers involves 3
  steps
• In the 1st step, the solution of polymer is
  dispersed in a continuous medium such as
  vegetable oil or an organic solvent using
  suitable stabilising agent.
• Dispersion is accomplished using
  mechanical stirring or by ultrasonication or by
  high speed homogenisation depending on particle
  size required.
• The 2nd step involves hardening of polymer
  droplets either by heat denaturation or by
  chemical cross linking using suitable cross
  linking agent.
• The 3rd step involves separation of solid
  microspheres, purification drying.

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Microspheres as drug carriers

• Drugs are incorporated into the microspheres
  either during their synthesis or after the
  microsphere is formed.
• High loading can be achieved by insitu loading
  if drug is insoluble in the dispersion medium
  employed for microsphere stabilisation.
• Washing the microspheres after their preparation
  to remove surfactants, oils and other impurities
  etc using solvents in which the drug solubility
  is high may result in poor loading efficiency.
• Mechanism of drug release from microspheres
• Degradation controlled monolithic system
• Diffusion controlled monolithic system
• Diffusion controlled reservoir system
• Erodable polyagent system

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Microspheres as drug carriers

• Microspheres based on natural polymers
• Albumin microspheres
• Casein microspheres
• Gelatin microspheres
• Polysaccharide microspheres
• Microspheres based on synthetic polymers
• Polyester microspheres
• Polyanhydride microspheres
• Other biodegradable polymers

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Nanoparticles as drug carrier

• Nanoparticles are sub nanosized colloidal
  structures composed of synthetic or semisynthetic
  polymers.
• The first reported nanoparticles were based on
  non biodegradable polymeric systems
  (polyacrylamide, polymethyl methacrylate
  polystyrene etc).
• The polymeric nanoparticles can carry drug(s) or
  proteinaceous substances (antigens). The drugs
  may be added during preparation of nanoparticles
  or to the previously prepared nanoparticles.
• TYPES OF POLYMERS FOR PREPARATION OF
  NANOPARTICLES
• Natural polymers Lectins, albumin, alginate,
  dextran, chitosan etc.
• Synthetic polymers poly lactic acid, poly
  lactide co glycolide, polymethyl methacrylate,
  polybutyl cyanoacrylate.

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Nanoparticles

• Preparation of Nanoparticles
• Amphiphilic macromolecule cross linking
• a) Heat cross linking b) Chemical cross
  linking
• 2) Polymerisation based methods
• Polymerisation of monomers insitu
• Emulsion (micellar) polymerisation
• Dispersion polymerisation
• Interfacial condensation
• Interfacial complexation
• 3) Polymer precipitation methods
• Solvent extraction/evaporation
• Solvent displacement (nanoprecipitation)
• Salting out

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Nanoparticles

• Novel nanoparticulate systems
• Solid Lipid Nanoparticles (SLN), Copolymerised
  Peptide Nanoparticles
• Hydrogel nanoparticles, Nanocrystals
  Nanosuspensions
• Biomimetic nanoparticles , Magnetic nanoparticles
• Nanoparticles coated with antibodies
• Characterisation of nanoparticles
• Particle size size distribution
• Charge determination, surface hydrophobicity
• Chemical analysis of surface, carrier-drug
  interaction, drug stability
• Release profile, nanoparticle dispersion
  stability
• Applications of Nanoparticles
• 1) Cancer chemotherapy 4) DNA delivery
  
• 2) Ocular delivery 5)
  Oligonucleotide delivery
• 3) Brain delivery 6)
  Lymph targeting