Rationale for controlled drug delivery

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					Rational for Controlled Drug
• Just as cars are useless without roads,
  drugs are useless without an effective
  delivery system.
• The active ingredient in a medicine is
  only part of the arsenal against
• The drug must somehow get to the
  right place at the right time. That's
  where drug delivery comes in.
• Drug delivery companies work to
  devise    new     dosage    forms  for
  medications. Historically, this has
  meant product life-cycle management,
  a process in which a pharmaceutical
  company looks for ways to set apart a
  product reaching the end of its patent
  lifetime from the inevitable generic
  competition. For example, a company
  might tinker with a drug that patients
  must take multiple times a day and
  reduce that to a single dose.
Nowadays, the competition is so intense
in the pharmaceutical marketplace that
companies look to drug delivery as a way
to gain a competitive advantage. The
value that drug delivery adds can be
improved safety, efficacy, convenience,
and patient compliance.
• As    a    result  of    biotechnology
  development, many people believe that
  proteins are going to comprise an
  increasing proportion of the new-drug
• Many existing peptide and protein
  drugs are coming off patent, fueling the
  interest in developing new dosage
• There is the equivalent of a generic industry
  that will likely be developed for peptides and
  proteins, analogous to [what evolved with]
  small molecules.

• The race is on to develop alternatives to
  injection for macromolecules. The main
  methods being explored are pulmonary
  (inhalation) and oral formulations. In
  addition, transdermal and extended-release
  injectable formulations are being targeted.
• Better control of plasma drug levels and
  less frequent dosing.
• For Linear one compartment PK drugs:
Dose interval (‫ < )דּ‬t1/2 (Ln TI)/Ln 2
TI is therapeutic index = Cmax/Cmin or
For non-linear multi-compartment PK drugs:
  t1/2 is replaced by 0.693*MRT
    The dosing interval may be
          increased by :

• Modifying the drug molecule to
  decrease the rate of elimination.
• Modifying the release rate of a
  dosage form to decrease the rate of
     Factors influencing the design and
     performance of a controlled release
1.   Drug properties: physico-chemical
     (stability- solubility- partition
2.   Route of administration
3.   Target sites
4.   Acute or chronic therapy
5.   The pateint
  Advantages of Controlled drug
        delivery systems
1. achieve more effective therapies while
   eliminating the potential for both under-
   and overdosing.
2. the maintenance of drug levels within a
   desired range.
3. the need for fewer administrations,
   optimal use of the drug in question, and
   increased patient compliance.
 Disadvantages of controlled drug
1. the possible toxicity or nonbiocompatibility of
   the materials used.
2. undesirable by-products of degradation.
3. the chance of patient discomfort from the
   delivery device for instance if any surgery
   required to implant or remove the system.
4. the higher cost of controlled-release systems
   compared with traditional pharmaceutical
Oral Controlled Release
     Drug Delivery
 Major challenges to an oral controlled
          release medication
• Unpredectable gastric emptying time.

• High variations in Gastric emptying due
  to factors such as age, race, sex, and
  disease states.

• Limited contact time at the site of
  Oral Platform Drug Delivery
• Matrix based on hydrophillic
• Diffusion-controlling
• Osmotic pumps.
• Diffussion controlled vesicle
     Matrix based on hydrophillic
• Drug and excipients are mixed with polymers
  such as Hydroxypropyl methylcellulose
  (HPMC) and Hydroxypropyl cellulose (HPC).
• Tableted by conventional compression.
• Release from the tablet takes place by
  combination of :
  - water diffuses into the tablet, swells the
  polymer and dissolves the drug.
  - drug may diffuse out to be absorbed
 Critical factors in Matrix based tablets

• The rate of drug out-diffusion should be
  slower than the rate of polymer swelling.

• Tablet porosity     affects   the   water

• Food may alter the rate of drug diffusion
  as a result of increased mechanical stress
  Diffusion-controlling membranes.

• In this type of drug
  delivery, a core of
  pure drug is coated
  with a permeable
Very rapid gelling and nearly complete hydration of OCAS delivery system in the upper GI tract ensures drug release
throughout the entire GI tract,
including the colon where water is poorly available. Reprinted from European Urology Supplements, 4(2), Michel MC,
Korstanje C, KrauwinkelW, Kuipers M,
The pharmacokinetic profile of tamsulosin oral controlled absorption system (OCAS1), pp 15–24, 2005, with permission
from European Association of
                    Osmotic pump
• Is considered a special type of the previous type in which the
   semipermeable membrane :
   - allow the water to diffuse in.
   - prevent the drug to diffuse out.
Drilling a hole in the outer membrane that allows the passage only
   of the dissolved drug.
 Diffussion controlled vesicle (DCV(

• The principal of this system is :
  - The drug core is coated with a
  suspension of a water soluble pore
  former in a solution of impenetratable
  water-insoluble polymer.
  - This process creates a macroporous
  membrane that controls the diffusion of
Bioavailability of Deltiazem DCV Drug
delivery compared with oral solution
Potential drug candidates for gastro-
retentive drug delivery systems:

a. Weakly basic drugs that are poorly soluble in
   intestinal pHs and have better dissolution in the
   acidic medium of stomach.

b. Drugs that have absorption windows in the upper
part of the small intestine. They will gradually
empty in solution form to the site of absorption.

c. All drugs that are intended for local action on the
gastro-duodenal wall e.g. therapeutic agents of
ulcerous diseases.
Drugs that are unsuitable for gastro-retentive
drug delivery system:

a. Enteric coated systems.

b. Drugs intended for selective release in the colon e.g. 5-
aminosalicylic acid and corticosteroids.

c. Drugs that have very limited acid solubility e.g.

d. Drugs that suffer instability in the gastric environment
e.g. erythromycin
    Approaches for prolonging the
       gastric residence time:
•   High-density systems.
•   Floating systems.
•   Swelling and expanding systems.
•   The use of passage delaying excipients.
•   Superporous hydrogels.
•   Mucoadhesive & Bioadhesive systems.
•   Magnetic systems
       High-density systems
• Gastric contents have a density close to water
  ( 1.004 g cm− 3). When the patient is upright
  small high-density pellets sink to the bottom of the
  stomach where they become entrapped in the folds
  of the antrum and withstand the peristaltic waves
  of the stomach wall.
• A density close to 2.5 g cm−3 seems necessary for
  significant prolongation of gastric residence time.
• Barium sulphate, zinc oxide, iron powder,and
  titanium dioxide are examples for excipients used.
         Floating systems
• These have a bulk density lower than the
  gastric content. They remain buoyant in the
  stomach for a prolonged period of time, with
  the potential for continuous release of drug.
  They Include:
   – Hydrodynamically balanced systems
   – Gas-generating systems
   – Raft-forming systems
   – Low-density systems
Schematic localization of an intragastric floating system
and a high-density system in the stomach.
Hydrodynamically balanced systems:

Schematic diagram shows the mode of action for HBSTM
(Bogentoft, 1982).
Gas-generating systems
              Floating    (continued)

       Raft-forming systems

Schematic illustration of the barrier formed by a raft-
forming system.
                Expandable systems

Different geometric forms of unfoldable systems proposed by
Caldwell et al. From Caldwell et al. (1988).
             Superporous hydrogels

On the left, superporous hydrogel in its dry (a) and water-swollen
(b) state. On the right, schematic illustration of the transit of
superporous hydrogel. From Gutierrez-Rocca, (2003).
 Mucoadhesive or bioadhesive systems
• The basis of mucoadhesion is that a dosage form can
  stick to the mucosal surface by different

• Examples for Materials commonly used for
  bioadhesion are poly(acrylic acid) (Carbopol®,
  polycarbophil), chitosan, Gantrez® (Polymethyl vinyl
  ether/maleic anhydride copolymers), cholestyramine,
  tragacanth, sodium alginate.

• the rapid turnover of mucus in the gastrointestinal
  tract is the main problem

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