Unit 8 _i_ Parenteral controlled drug delivery systems

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Unit 8 _i_ Parenteral controlled drug delivery systems Powered By Docstoc
 Routes for parentral drug delivery
 Biocampatibility
 Approaches to design controlled release parentral dosage
 Advances
Routes for Parenteral Delivery

 Intravenous-
   - used rarely for the administration of liposomes,
     nanoparticles, erythrocytes and polypeptides.
  - particle size is an important consideration.
 Intramuscular-
  - volume of injection should not exceed 2ml.
 Subcutaneous-
  - volume of injection between 0.5 to 1.5 ml
  - poorly perfused with blood.
 Intraperitonial-
  - to target antineoplastic agents into the lymphatic
 Extended duration of action for days, months or years.
 Act as circulating depots.

  - the drug cannot be easily removed if an undesirable
    action is precipitated.
 It is described in terms of acute & chronic local inflammatory
 Polyhydroxyethyl methacrylate & ethylene vinyl acetate
  copolymer were found non-inflammatory.
 Polyacrylamide & PVP produced significant inflammation.
 Also, polybutylcyanoacrylate, polymerized gelatin & poly
  lactic acid caused joint inflammation while polymerized
  albumin did not.
 It can also be measured in terms of sensitivity reactions &
 Major of the sensitivity reactions were caused by implants.
 Rough or porous surface of implants is more prone to cause
 Biocompatibility can be improved by heparinizing the
  polymer surface.
Parentral dosage forms
 Aqueous solutions
 Aqueous suspensions
 Oil solutions
 Oil suspensions
 Emulsions
 Resealed erythrocytes
 Liposomes
 Nanoparticles
 Implants
 Aqueous solutions
  The drug release from the aqueous solutions is controlled in
 three ways;
 1) Formulating high viscosity products
     - it reduces the diffusion of drug ,thereby delaying
       the drug transfer.
   examples of viscosity agents: methylcellulose,
                                   Na-CMC, PVP
2) By complex formation:
    - role of plasma protein & tissue binding in prolonging
 drug action is well known.
   - using the same principle, a dissociable complex of drugs is
 formed with MC, Na CMC, PVP for IM administration.
3) by forming complex which controls the release of drug ,
 not by dissociation but by decreasing the solubility of parent
   e.g.- protamine zinc insulin, cyanocobalamine zinc tannate,
Aqueous suspensions
 Gives longer duration of action than aqueous solution when
  given intramuscularly or subcutaneously.
 The drug is continuously dissolving to replenish what is being
 Dissolution rate of drug can be described by Noyes-Whitney
        dissolution rate= DA ( Cs-C)
         where, D- diffusion coefficient
                  A- surface area available for dissolution
      (Cs-C) – difference in conc between diffusion
                 layer & bulk solution.
             h – thickness of diffusion layer.
 - formulation parameters that can be changed to obtain the
   objective are particle size, diffusion coeff. & concentration to
   some extent.
- These parameters are subject to constraints imposed by
   stability, syringeability, pain upon injection.
- Crystalline & stable polymorphs of drug are chosen rather
   than amorphous forms for delay release
- Viscosity builders can be used to increase viscosity & reduce
   diffusion coeff of drug.
 The solid content in the parentral suspensions should fall
  between 0.5 and 5%.
 To minimize pain & irritation, it is recommended that the
  particle size should be below 10µm
Oil solutions
 Drug release is controlled by partitioning of drug out of oil
  into the surrounding aqueous medium.
 Vegetable oils like arachis oil, cottonseed oil are used.
Oil suspensions
 Drug release from oil suspensions combines the principles
  involved in aqueous suspensions & oil solution.
 Suspended particles act as drug reservoir.
 The process of drug availability consists of dissolution of drug
  particles followed by partitioning of drug from oil solution to
  aqueous medium.
 Administered IV in total parentral nutrition.
 Fortner et al obtained satisfactory results with IV emulsion of
  antineoplastic agent for the treatment of cancer.

 Limitations of cancer therapy:
 - systemic toxicity on normal replicating cells.
To reduce the drug toxicity, LDL are used as novel carriers for
 antineoplastic drugs because of greater uptake and
 metabolism of LDL by tumours than normal cells.
1) O/W or W/O emulsions:
 - Salk et al found a 10 fold rise in antibody titer using
  emulsified influenza vaccine with persistance of high titers
  upto 4 years after injection.
 - multiple emulsions have been developed to control or
  sustain the release the drug. (o/w/o emulsion or w/o/w
 - it introduces additional reservoir into which drug can
  partition thus effectively retard its release.
 - prolongation of action of chemotherapeutic agents like
  methotrexate,vinblastine sulfate & bleomycin have been
 Multiemulsion formation
2) Magnetic emulsions:
  - ideal to deliver anticancer agents only to localized tumour
  - it describes magnetically responsive o/w emulsion which
  localize the drug 1-(2-chloroethyl)-3-(trans-4-methyl
  cyclohexyl)-1-nitrosourea i.e. methyl CCNU by magnetic
  means to specified target tissues.
  - it consists of ethyl oleate based magnetic fluid as dispersed
  phase & caesin solution as continous phase.
F) Resealed erythrocytes
 The erythrocytes are ruptured by immersing them in
  hypotonic solutions & the drug is loaded into it.
 The cells are then resealed by restoring the isotonicity &
  incubation at 37˚c.
 The damaged erythrocytes are removed by liver & spleen
3)Act as circulatory depots
4) protect the entrapped drug from immunological &
  enzymatic detection
 Does not require the drug to be chemically modified.
 Drug release from these carriers may occur by:
       - phagoytosis
       - simple diffusion
       - transport out of the cell by some specific
         transport system.
 Hydrated liquid crystals formed when phospholipids are
  allowed to swell in an aqueous media
 Sphingolipids, Glycolipids & Sterols have also been used to
  prepare liposomes
 Structurally liposomes are classified as-
  1) Multilamellar Vesicles (MLV) :
          Made of series of concentric bilayers of lipid enclosing
     a small internal volume.
   2) Oligolameller Vesicles (OLV):
          Consist of 2 to 10 bilayers
3) Unilameller Vesicles (ULV):
        Made of single bilayer . It is again classified into
  i) Small unilmeller vesicle : 20 to 40 nm
  ii) Medium unilameller Vesicle : 40 to 80 nm
 iii) Large unilameller vesicle: 100 to 1000 nm
 iv) Giant unilameller vesicle : > 1000 nm
        Drug such as antineoplastic antibiotics peptides viruses,
   bacterias & enzymes can be incorporated in liposomes.
 Advantages:
1. Versatality in size & electrical charge
2. Ability to encapsulate both hydrophilic & lipophilic drugs
3. Non Toxicity
4. Protect labile drugs from inactivation in blood by isolating
   them from surrounding medium
 Product          Molecule       Year
Amelcet ®       Amphotericin B   1995
Doxil/caelyx®   Daunorubicin     1995

DaunoXome®      Daunorubicin     1996

Amphotec®       Amphotericin B   1996

Ambisome®       Amphotericin B   1997

Depocyt®        cytarabine       1999
 These are carrier for drugs & other active molecule in nm
  size range.

 Advantages:
  -capable of being stored for a period up to 1 year.
  -Can be selectively targeted to liver and to cells that
   are active phagocytically.
 - Placed subcutaneously to sustain drug release via
   the mechanism of drug diffusion, Polymer
   dissolution or both.
 - Polydimethyl siloxane, a non biodegaradable
   polymer deliver drug by simple diffusion at a rate
   dependent on drug solubility .
 - it includes: i) osmotic pumps
                ii) vapour pressure activated system.
a] Alzamer Depot Technology - consist of biodegradable
   polymer, solvent & drug particle injected subcutaneously &
   drug is released by diffusion.
  - Solvents of low water miscibility are used.
b] Atrigel Drug Delivery System
 - developed by Dunn & co-workers.
 - a drug consists is incorporated in polymer solution. This
   drug is then placed into the body using std needles &syringes
 - the polymer solution is such that it gets solidified upon
   contact with biological fluids.
 -Thus, the drug becomes trapped within the polymer matrix
  as it solidifies.
Polymers used: polyhydroxyacids, polyorthoesters,
                   polyesteramide, etc
Solvents employed:
  hydrophilic- DMSO, N-methyl-2-pyrrolidone, tetraglycol &
  glycol furol
  hydrophobic- propylene carbonate, triacetin, ethyl acetate,
  benzyl benzoate, etc.
 E.g.
 1) Atridox - peridontal treatment product with subgingival
  delivery of doxycycline.
 2) Eligard- leuprolide acetate for treatment of prostatic

c] Duros implant:
   - osmotically driven
   e.g. Viadur- leuprolide acetate implant provide zero
                 order delivery.

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