Parenteral controlled drug delivery in body

							     Parenteral Controlled Drug
         Delivery Systems

Approaches for injectable controlled release formulations,

Implants development



                                            Presented by
                                          S.H. Majumdar
                                            SPTM, Shirpur
                      Why Parenterals ?

   • Para enteron:
     • Beside the intestine

Circumvents:
 – GI enzymatic activity
 – GI instability
 – Low absorption
 – Variable absorption


Provides:
 – Rapid and accurate doasge
 – Alternative to other routes of delivery
      Advantages of Parenteral
          Administration
 Fastest method of drug delivery (e.g. cardiac arrest,
asthma, shock)
 Viable alternative to unsuccessful oral therapy
 Uncooperative, nauseous, or unconscious patients
 Less patient control (i.e., return visits)
 Local effect (e.g., dentistry, anesthesiology)
 Prolonged action (e.g., intra-articular steroids, IM
  penicillins)
 Correcting serious fluid and electrolyte imbalance
 Total Parenteral Nutrition (TPN)
Need of Controlled formulation
   Rapid drug absorption also accompanied by a rapid decline
    in drug levels in systemic circulation.




   Continuous IV infusion--- entails certain health hazards,
    continuous hospitalization, close medical supervision.
   To duplicate benefits of IV infusion without potential
    hazards----Depot-type parenteral controlled release
    formulations.
Parenterally admininstered
colloidal carrier systems
Release profile(s) & Biofate of IV
administered system
P’cokinetic profile of drugs in
tissues of varying perfusion
Biofate of IM administered system
Release
 patterns
 of
 Parenteral
Depot Formulation
   An Aq. (or oleaginous) suspension or an oleaginous
    solution, into S.C. or I.M. tissue results if formation of
    depot at the site of injection.
   Drug reservoir releases drug at a rate determined by
    characteristics of the formulation.
   Nature of vehicle, Physicochemical characteristics of drug,
    interactions of drug with vehicle & tissue fluid (determine
    rate of drug absorption & hence duration of therapeutic
    activity)
   Reduced drug dose, decreased side effects, enhanced
    patient compliance, improved drug utilization.
Injectable drug delivery
   Approaches
     •   Dissolution-controlled depot formulation
     •   Adsorption-type depot preparations
     •   Encapsulation-type depot preparation
     •   Esterification-type depot preparation
   Development of Injectable controlled release formulations
     •   Long acting Penicillin preparations
     •   Long acting Insulin preparations
     •   Long acting Vit B12 preparations
     •   Long acting Adrenocorticotropic Hormone preparations
     •   Long acting Steroid preparations
     •   Long acting Antipsychotic preparations
     •   Long acting Antinarcotic preparations,
     •   Long acting contraceptive preparations
   Biopharmaceutics
     • Effect of physicochemical properties
     • Effect of physiological conditions
     • P’cokinetic basis
Implantable drug delivery
   Historical development
   Approaches to development of Implantable DDS
   Biomedical applications
   Benefits
   Medical aspects
Injectable drug delivery:
Approaches

   Use of viscous, water-miscible vehicles, such as Aq. soln of gelatin or PVP

   Utilization of water-immiscible vehicles, such as vegetable oils, plus water-
    repelling agent, such as aluminum monostearate

   Formation of thixotropic suspensions

   Preparation of water-insoluble drug derivatives, such as salts, complexes &
    esters

   Dispersion in polymeric microspheres or microcapsules, such as lactide-
    glycol-esters

   Co administration of vasoconstrictors
Injectable drug delivery:
Approaches

Classified on the basis of the process used for controlled drug
   release as:
   Dissolution-controlled depot formulation:

   Adsorption-type depot preparations

   Encapsulation-type depot preparation

   Esterification-type depot preparation
Dissolution-controlled depot
formulation


   Formation of salt or complexes with low Aq. Solubility
    (Penicillin G procaine)
   Suspension of macrocrystals (Testosterone isobutyrate IM
    injection)
   Release of drug molecules is not of zero-order kinetics as
    expected from theoretical model
Adsorption-type depot preparation
   Binding of drug molecules to adsorbents. Unbound, free
    species of the drug is available for absorption.
   Langmuir relationship



   eg. Vaccine preparations in which antigens are bound to
    aluminum hydroxide gel
Encapsulation-type depot preparation

   Encapsulating drug solids within a permeation barrier or
    dispersing drug particles in a diffusion matrix.
   Both permeation barrier & diffusion matrix are fabricated
    from biodegradable or bioabsorbable macromolecule
    (gelatin, dextran etc)
   Release of drug molecules is controlled by the rate of
    permeation across the permeation barrier & the rate of
    biodegradation of the barrier macromolecules.
   eg. Naltrexone pamoate releasing biodegradable
    microcapsule, liposome.
Esterification-type                              Drug
depot preparation                           Prodrug
                                    Ester form       Bioconvertible

                                    Injectable Formulation
                                  Drug reservoir      Site of action

    Rate of drug absorption is controlled by the interfacial
     partitioning of drug esters from the reservoir to the tissue
     fluid & the rate of bioconversion of drug esters to
     regenerate active drug molecule.
    eg. Testosterone 17β- cypionate in oleaginous solution
Development of Injectable Controlled-
Release Formulations

   Long acting Penicillin preparations
   Long acting Insulin preparations
   Long acting Vit B12 preparations
   Long acting Adrenocorticotropic Hormone preparations
   Long acting Steroid preparations
   Long acting Antipsychotic preparations
   Long acting Antinarcotic preparations,
   Long acting contraceptive preparations
Long acting Penicillin preparations

   Water-soluble sodium or potassium salt rapidly absorbed from
    SC or IM site
   Rapid urinary excretion: 80% excretion by tubular secretion &
    20% by glomerular filtration.
   Renal tubular secretion can be blocked by co-administration of
    drugs (phenylbutazone, aspirin, indomethacin) leading to ▲se in
    effective blood level of penicillin
    Two formulation approaches
     • Reduce Aq. solubility of Penicillin by converting water soluble Na, K salt
       into salts of low Aq. solubility (eg. Penicillin G procaine)---- Gelation of oily
       suspensions
     • Aq. Suspension of relatively water-insoluble salts-----thixotropic suspensions
       of Penicillin G procaine.
Penicillin
Oleaginous
Suspension

    Table 1      Dispersions of micronized
                  crystals of Penicillin G procaine
                  in vegetable oil (peanut or
                  sesame oil)----- then gelled with
                  aluminum monostearate---IM
                  injection.
                 The duration of the depot effect
                  depends on
     Fig 2        1.   Type & Size of penicillin G
                       procaine crystals
                  2.   Type & Amount of aluminum
                       stearate
Long acting Penicillin
preparations
Long acting Penicillin preparations
Long acting Penicillin preparations
Long acting Penicillin preparations
Long Acting Insulin Preparations

Need of Long-acting Insulins ……?

   Oral delivery of insulin (Inactivation by GI enzymes)

   Other (nasal, ocular, buccal, sublingual, rectal, transdermal
    etc) aim to bypass GI & hepatic metabolism (incomplete
    &/or uncertain absorption)

   Parenteral SC route:
    • Duration of action is not linearly proportional to the dosage of
      insulin injected but function of log of dose)
    • Injection technique: Improper, areas of lumpiness or swelling.
Type 2 Compensation & Exhaustion
Ideal Insulin Replacement Strategy



                          Bolus Insulin


                           Basal Insulin
  Normoglycemic activity & Duration of
  some commercial Insulin Products
                                         Normoglycemic activity
              Insulin Preparation      Onset     Peak    Duration
                                        (Hr)     (Hr)      (Hr)
Insulin Injection USP                  0.5-1.0    2-3      4-8
Insulin-Zn Complex
 Semilente                             0.5-1.0    5-7     12-16
 Lente                                 1.0-1.5   8-12      24
 Ultralente                            4.0-8.0   16-18     >36
Insulin-Zn-Protein Complex
 Globin-Zn-Insulin Injection USP        2.0      8-16      24
 Isophane insulin Suspension USP       1.0-1.5   8-12      24
 Protamine-Zn-insulin Suspension USP   4.0-8.0   14-20     36
   Long Acting Insulin Preparations




Comparative normoglycemic activity of Ultralente, Semilente & regular insulin preparation
Long Acting Insulin Preparations




24-Hr blood glucose profile after SC injection of Ultralente Insulin Suspension
Long Acting Insulin
Preparations

Novolinpen, a mechanically activated
   drug delivery system, which is
   designed as a dial-a-dose insulin
   device to inject human insulin in 2
   unit increments (with a dosage
   accuracy of 99.5%)
Long-acting Contraceptive Preparations
   Progestational steroids in high doses supresses the pitutory
    release of LH & hypothalamus release of LH-releasing
    factor, thus preventing ovulation.
   Natural progesterone in oleaginous solution
   Long-acting derivatives of progesterone
    • Medroxyprogesterone acetate in Aq. Solution
    • Dihydroxyprogesterone acetophenide & estradiol enanthate in
      oleaginous solution.
    • Norethindrone in a polymer beads
    • Norethindrone enanthate in oleaginous solution
    • Norgesterol 17 β-fatty acids esters in oleaginous solution
   Long-acting injectable contraceptive prepn contain either
    progestin alone or in combination with estrogen.
Long-acting injectable contraceptive

   Depo-Provera C-150
   Deladroxate
   Norethindrone-Releasing Biodegradable Polymer Bed
    Suspension
Depo-Provera C-150

   Aq. suspension of microcrystalline medroxyprogesterone
    acetate (150 mg)
   IM injection deep into the gluteal muscle, one dose every 3
    months
   Suppressing ovulation by inhibition of the preovulatory
    surge of LH & FSH
   Impending nourishment of the blastocyst within the
    endometrial cavity by alteration of the secretory
    transformation of endometrium.
   Reducing the penetration of spermatozoa into the uterus by
    increasing the viscosity of cervical mucus.
Depo-Provera C-150
Deladroxate

   Once in a month IM injection composed of
    dihydroxyprogesterone acetophenide (150 mg) & estradiol
    enanthate (10 mg)
   Simultaneous prolongation of progestational & estrogenic
    activities for approx 3 weeks, controls ovulation.
Norethindrone-releasing biodegradable
polymer bead suspension
Long-acting Contraceptive Preparations
Long-acting Contraceptive Preparations
Long-acting Contraceptive Preparations
Long acting Vit B12
preparations
Long acting Adrenocorticotropic
Hormone preparations

   .
Long acting Steroid preparations

   .
Long acting Antipsychotic preparations

   .
Long acting Antinarcotic preparations

   .
BIOPHARMACEUTICS

   Effect of Physicochemical properties
   Effect of Physiological conditions
   Pharmacokinetic basis