Prodrug and Drug Delivery Systems Reference books for further

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Prodrug and Drug Delivery Systems Reference books for further, Drug Delivery, Market Analysis, Drug Delivery Systems, Delivery Component, Drug Delivery Technology, Worldwide Market, Market Size, Pulmonary Drug Delivery, Delivery Markets
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posted:: 7/31/2009
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							Molecular Recognition and Drug Design

        Prodrug and Drug Delivery Systems




                                劉


        Reference books for further reading

                    The Organic Chemistry of Drug Design and Drug Action.
                    2nd ed. 2003
                                                       Author: Silverman




                     An Introduction to Medicinal Chemistry.
                     4th ed. 2009
                                                         Author: Patrick
                  An outline

1. Enzyme activation of drugs

2. Carrier-linked prodrugs

3. Bioprecursor prodrugs




                  An outline

1. Enzyme activation of drugs

2. Carrier-linked prodrugs

3. Bioprecursor prodrugs
        Rational drug discovery process




                    Hard and soft drugs

Plasma half-life:                         Plasma half-life:
9 h in dogs                               680 h in dogs
  Why do you want to design a prodrug?

 Aqueous solubility

 Absorption and distribution

 Site specificity

 Instability

 Prolonged release

 Toxicity

 Poor patient accessibility

 Formulation problems




                     Types of prodrugs
 Carrier-linked prodrugs
  A compound that contains an active drug linked to a carrier
  group that can be removed enzymatically.

 Bioprecursor prodrugs
  A compound that is metabolized by molecular modification into a
  new compound which is the active principle or which can be
  metabolized further to the active drug.
                           An outline

 1. Enzyme activation of drugs

 2. Carrier-linked prodrugs

 3. Bioprecursor prodrugs




                         Drug carrier
A ideal drug carrier must:
 protect the drug until it is at the site of action

 localize the drug at the site of action

 allow for release of the drug chemically or enzymatically

 minimize host toxicity

 be biodegradable, biochemically inert, and nonimmunogenic

 be easily prepared inexpensively

 be chemically and biochemically
  stable in its dosage form
           Types of carrier-linked prodrugs

    Bipartite prodrug
     A prodrug comprised of one carrier attached to the drug

    Tripartite prodrug
     A carrier is connected to a linker that is connected to the drug

    Mutual prodrug
      A compound consists of two, usually synergistic, drugs attached to
      each other




   Carrier linkages for various functional groups

The most common reaction for activation of carrier-linked prodrugs is
hydrolysis.

The general functional groups involved are:

 Alcohols, carboxylic acids, and related groups

 Amines

 Sulfonamides

 Carbonyl Compounds
Carrier linkages for alcohols, carboxylic acids, and
                  related groups




Carrier linkages for alcohols, carboxylic acids, and
                  related groups
  Carrier linkages for amine groups




Carrier linkages for sulfonamide groups
  Carrier linkages for carbonyl groups




Examples of carrier linked bipartite prodrugs

 Prodrugs for increased water solubility

 Prodrugs for improved absorption and distribution

 Prodrugs for site specificity

 Prodrugs for stability

 Prodrugs for slow and prolonged release

 Prodrugs to minimize toxicity

 Prodrugs to encourage patient acceptance

 Prodrugs to eliminate formulation problems
  Prodrugs for increased water solubility

              療




Prodrugs for improved absorption and distribution

                      療




                  療
                Prodrugs for site specificity

                               療




             Tumor cells contain a higher concentration of
             phosphatases and amidases than do normal cells.




              Enzyme-prodrug therapies (I)
 The prodrug-activating enzyme should be either of nonhuman origin or a
  human protein that is absent or expressed only at low concentrations in
  normal tissues.

 The prodrug-activating enzyme must achieve adequate expression in the
  targeted tumor cells and have high catalytic activity.

 The prodrug should be a good substrate for the enzyme incorporated in the
  tumors but not be activated by endogenous enzymes outside of the tumors.

 The prodrug must be able to cross the tumor cell membrane for intracellular
  activation.
               Enzyme-prodrug therapies (II)
 The cytotoxicity difference between the prodrug and its corresponding
  active drug should be high.

 The activated drug should be highly diffusible or be actively taken up by
  adjacent nonexpressing cancer cells for what is known as a bystander
  killing effect, the ability of the drug to kill neighboring nonexpressing cells.

 The half-life of the active drug should be long enough to induce a
  bystander killing effect but short enough to avoid the drug leaking out of
  the tumor cells and causing damage elsewhere.




   Antibody-directed
enzyme prodrug therapy
       (ADEPT)
            An example of ADEPT




                     Structure of the nitrogen mustard cross-link




Antibody-directed abzyme prodrug therapy (ADAPT)
              An example of ADAPT




      Doxorubicin-DNA
      complex




Gene-directed enzyme prodrug therapy (GDEPT)
           An example of GDEPT




                                DNA alkylating agent




Virus-directed enzyme prodrug therapy (VDEPT)
An example of VDEPT




Prodrugs for stability

                         療
Prodrugs for slow and prolonged release

              精神     療




     Prodrugs to minimize toxicity
     Prodrugs to encourage patient acceptance




    Prodrugs to eliminate formulation problems


       泌尿




                           Acetic acid
Formaldehyde
      Macromolecular Drug Carrier Systems (I)
 Synthetic polymers




 Aspirin prodrug
                               Ibuprofen prodrug

 Poly(-amino acids)




                                    Norethindrone prodrug




      Macromolecular Drug Carrier Systems (II)

 Proteins
                    Armed antibodies




       Types of carrier-linked prodrugs

 Bipartite prodrug
  A prodrug comprised of one carrier attached to the drug

 Tripartite prodrug
  A carrier is connected to a linker that is connected to the drug

 Mutual prodrug
  A compound consists of two, usually synergistic, drugs attached to
  each other
Tripartite prodrugs (I)




Tripartite prodrugs (II)
                         Formaldehyde




                                        -lactamase




                                 Mutual prodrugs




Site-speciﬁc drug delivery using liposomes as carriers
                      An outline

1. Enzyme activation of drugs

2. Carrier-linked prodrugs

3. Bioprecursor prodrugs




    Various activation mechanisms of
         bioprecursor prodrugs
    Proton activation

    Hydrolytic activation

    Elimination activation

    Oxidative activation

    Reductive activation

    Nucleotide activation

    Phosphorylation activation

    Sulfation activation

    Decarboxylation activation
Proton activation (I)




Proton activation (II)
Hydrolytic activation




Elimination activation


          類              療
Oxidative activation




Reductive activation

 療

                in anaerobic bacteria
  Nucleotide activation




Phosphorylation activation
   Sulfation activation




Decarboxylation activation