Oral Controlled Release Drug Delivery Systems OCRDDS recent trends future challenges RAJEEV S RAGHUVANSHI Ph D by ybu19157

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									       Oral Controlled Release Drug
       Delivery Systems (OCRDDS) :
      recent trends & future challenges



            RAJEEV S. RAGHUVANSHI
                                Ph.D.
               5th Oct’07, Mumbai


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 NDDS CURRENT GLOBL BUSINESS SCENARIO


                  TRANSDERMAL
                      12.3%



                                                 OCULAR & BUCCAL
                                                      0.59%


                                        NASAL
                                         7.1 %
      ORAL          TRANSMUCOSAL
      51.8%             26.3%
                                                    PULMONARY
                                                       18.5%




                          INJECTABLES
                               8%
              LIPOSOMES
                 1.5%


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              NDDS - INNOVATION THEME


      PRESENT
      ONCE-A-DAY : A WAY OF LIFE
        Greater consumer awareness
        Demand for a Quality life



      FUTURE
      4 ONCE-A-DAY + Value Addition
        Safety profile improvement
        Better therapeutic efficacy
        Better tolerability

        NDDS – A tool for product life cycle management


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                                BLOOD PROFILES
                    Controlled Release vs. Immediate Release



               30
                                       2nd dose       3rd dose
               25
                                                                             Side Effects
                                                                 4th dose
                        1st dose
               20
 Blood Conc.




               15
                                                                            Effective Therapy

               10
                                                                             Ineffective Level

               5
                                                                                                 IR
               0                                                                                 CR

                    0      2       4      6       8     10 12 14 16 18
                                                                     Hrs.




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                                          Schematic of dissolution
                                  from different types of delivery systems


                        100


                        80
      %Drug Dissolved




                        60


                        40
                                                                                             IR
                                                                                             ER
                        20
                                                                                             DR

                         0
                              0    2   4    6   8   10      12      14   16   18   20   22        24

                                                         Time (h)




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                                                   Schematic of plasma profiles
                                              from different types of delivery systems


                                     50
                                                                                                         IR
      Plasma Concentration (ng/mL)




                                     40                                                                  ER
                                                                                                         DR
                                     30


                                     20


                                     10


                                     0
                                          0    2    4   6   8   10      12      14   16   18   20   22        24

                                                                     Time (h)




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                OCRDDS: advantages



 • Reduced dosing frequency
 • Better patient convenience and compliance
 • Reduced GI side effects
 • Less fluctuating plasma drug levels
 • Improved efficacy/safety ratio
 • More uniform drug effect
 • Lesser total dose




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      Recent Trends : Matrix Tablet – Release Mechanism


      ER Tablet
              Film coating
              dissolves & matrix
              hydration starts


 Matrix Expansion                                Smooth &
    (swelling)                                   continuous
                                                 release for
                                                 extended
                                                 time
  Drug Diffusion



  Soluble matrix
     erosion
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               Recent Trends : Quetiapine OD

•   Seroquel XR Tablets, 50, 200, 300 and 400mg,
    AstraZeneca Pharmaceuticals LP, USA



•   Technology:
     – Film Coated Matrix tablets comprising Hypromellose as a release
       controlling polymer with diffusion and erosion controlled release


•   Composition patent claiming Gelling agents in combination with
    Quetiapine. Constraint of use of any of the following polymers like
    HPMC, HPC, Polyox, Carbopol, HEC, Ethylcellulose.


    R&D
Recent Trends : Extended release formulation of Bupropion




Bupropion is used in the treatment of major depressive disorder.

Conventional formulation has to be administered 3 times daily

Initially 150 mg ER formulation was introduced for bid regimen

Later on 300 mg ER formulation was introduced for once daily regimen

For ER formulation provide similar Cmax and AUC values as compared

to immediate release formulation at steady state.




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Recent Trends : Extended release formulation of Bupropion




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                      Recent trends: Geomatrix® (SKY Parma)



Products in market:
Cordicant -uno®
Madopar DR
SULAR ER




  -This technology Controls amount, timing and location of release in body.
  -Formulation with predictable and reproducible drug release profile.
 - Controls rate of drug diffusion throughout release process, ensuring
 100% release

     R&D
                        Nisoldipine OD
• Innovator – Sular ER 10, 20, 30 and 40mg

• Previous Technology: Press-coated tablet
   – Immediate release core with enteric coating
   – Sustained release coating
   – Drug is present in both core and coat
   – Film Coating

   New Technology - Geomatrix, to be developed by SkyePharma

   sNDA filed, Expected Launch – Early 2008.




   R&D
      Recent Trends : Multiparticulate drug delivery system


                                    Polymeric membrane layer



                                           Inert core

                                             Drug Layer




•   Soluble/Insoluble inert core
•   Drug layering on inert core
•   ER coat (E.g., Ethyl cellulose, Eudragits, HPMC etc.)
•   Filling of ER coated beads in suitable capsule shells
•   Advantage : COMPARTMENTALIZATION

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                          Carvedilol ER
•   Innovator – Coreg CRTM (carvedilol phosphate) extended-release
    capsules 10, 20, 40 and 80 mg GlaxoSmithKline


•   COREG CR utilizes Flamel's proprietary Micropump® technology.
    Micropump® is a controlled release and taste-masking technology for
    the oral administration of small molecule drugs.


•   COREG CR hard gelatin capsules are filled with carvedilol phosphate
    immediate-release and controlled-release microparticles that are drug-
    layered and then coated with methacrylic acid copolymers.


     – IR component as micro particle – 12.5% of dose
     – Micropump IIa – (37.5% of dose)- Releases content at pH 5.5
     – Micropump IIc – (50 % of dose)- Releases content at pH 6.4-6.8
    R&D
                            Carvedilol ER




- Technology consist of 5000- 10000 microparticles per capsule.
- 200-500 micron particles released in stomach, and pass into small
   intestine, where each microparticle release drug by osmotic pressure
   at adjustable rate over an extended period.

     R&D
               Recent Trends: Multiparticulate technology

              CODOS® ( Chrono Oral Drug Absorption System)


                                                 Products in market: Verelan®

                  Drug core coated
                                                 Filled in the capsule
                  with CR polymers
                  for timed release




Specific advantage:
• Delivery profile designed to compliment the circadian pattern of blood pressure
• Controlled onset, extended release delivery system
• Rate of release essentially independent of pH, posture and food




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      METOPROLOL PORT SYSTEM




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                   Recent Trends : LEDDS Technology



• Liquid and Emulsion Drug Delivery System (LEDDS)
• Enabling Oral Controlled Release
      • Liquids/Emulsions/Suspensions
      • Customise drug release profile
            Controlled
            Sustained
            Pulsatile
      • Format flexibility




    R&D
                               Recent Trends : LEDDS Technology
Case studies 1                                                                     700




                                                     Mean Concentration (ng/ml)
•  Human Clinical Study Goal:
                                                                                   600
     • Refn: Sandimmune™
     • Test: LEDDS™ Cyclosporine                                                   500

                                                                                   400
•       Study Design:
                                                                                   300
         • 8 male volunteers
         • Cross-over                                                              200

                                                                                   100
•       Results:
                                                                                        0
         • Safe/Effective                                                                   0        4           8           12
                                                                                                                            Time
                                                                                                                                             16         20        24

         • ↑ Bioavailability                                                                             Sand immune               LEDDS Cyclosporine
         • ↑ Rate of Uptake


                                                                                  400
    Case study 2
                                                                                  350

    •   Determine LEDDS™ dose to achieve reference                                300
        bioequivalence
                                                                                  250

    •   Anticipated results:                                                      200


            130mg Vs. 200mg                                                       150


    •   Bioequivalence at 65% (35% Less Active)                                   100


                                                                                  50


                                                                                   0
                                                                                        0       4            8            12            16         20        24
                                                                                                                         Time

                                                                                                    Sandimmune (200mg)          LEDDS Cyclosporine (130mg)

           R&D
                   Recent Trends : LEDDS Technology



 Key Clinical LEDDS benefits will include:



 •    Rapid onset of action

 •    Delivery of liquid/emulsion drug to the optimal site of action

 •    Delivery of liquid/emulsion drug to maximize absorption

 •    Controlled/Sustained release of liquid/emulsion drugs

 •    Increased residence time in the small intestine or colon

 •    Protection of active ingredient from harsh gastric and intestinal environment

 •    Broad GIT dispersion, limiting local irritation and increasing absorption co-efficient




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              Recent Trends : Gastro-Retentive Drug Delivery

Need for gastro-retentive drug delivery
A controlled drug delivery system with prolonged residence time in the stomach is of particular
    interest for drugs
•   are locally active in the stomach (e.g., misoprostol, antacids, antibiotics against Helicobacter
    pylori
•   have an absorption window in the stomach or in the upper small intestine,(e.g., L- DOPA, p-
    aminobenzoic acid, furosemide, riboflavin),
•   are unstable in the intestinal or colonic environment (e.g., captopril)
•   exhibit low solubility at high pH values(e.g., diazepam, chlordiazepoxide, verapamil HCl)



Approaches for gastro-retention
• bioadhesive delivery systems, which adhere to mucosal surfaces
• delivery systems that rapidly increase in size once they are in the stomach to slow the passage
   through the pylorus;
• density-controlled delivery systems, which either float or sink in gastric fluids




       R&D
                     Recent Trends : Gastro-Retentive Drug Delivery
•      Size-increasing drug delivery system
    Systems unfolding in the stomach:               Gastric retention of a highly swellable, gastroretentive drug delivery system




Systems unfolding in the stomach:               A) The device significantly swells on contact with gastric fluids (to a few hundred times of the original
e.g., Tetrahedron-shaped drug delivery system   volume); B – D) the gastric contraction pushes the hydrogel to the pylorus; E) the gastric contraction
formed by assembling two components: silastic   slips over the surface of the hydrogel; and F) the hydrogel is pushed back into the body of the stomach.
corners and erodible arms.


           R&D
          Recent Trends : Gastro-Retentive Drug Delivery




• Density controlled drug delivery system
    Floating system
     • Inherent low density
     • Low density due to swelling
     • Low density due to gas formation and entrapment




    R&D
Recent Trends: OROS Technology (ALZA corporation)

                             • Single layer tablet: Drug
  ELEMENTARY OSMOTIC PUMP      core (water soluble drug
                               with or without excipients)
                             • Semipermeable membrane
                               with a drilled orifice
                             • Water imbibition by the core
                               because of osmotic action
                               results in drug dissolution,
                               which is released at a
                               controlled rate through the
                               orifice
                             • Not suitable for water-
                               insoluble drugs
                             • Examples: Sudafed 24
                               hours (Pseudoephedrine);
                               Volmax (Salbutamol)


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Recent Trends: OROS Technology (ALZA corporation)



                                 Available marketed products
                                 • Alpress™ LP (prazosin)
                                 • Cardura® XL (doxazosin mesylate)
                                 • Concerta® (methylphenidate HCl) CII
                                 • Covera-HS® (verapamil)
                                 • Ditropan XL® (oxybutynin chloride)
                                 • DynaCirc CR® (isradipine)
                                 • Efidac 24® (chlorpheniramine)
                                 • Glucotrol XL® (glipizide)
                                 • Sudafed® 24 Hour (pseudoephedrine)
                                 • Procardia XL® (nifedipine)
                                 • Volmax® (albuterol)




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      Extended release formulation of Methylphenidate



Indicated for the treatment of attention Deficit Hyperactivity Disorder (ADHD)
Immediate-release overcoat provides a rapid onset of action (1-2 hours).
Controlled release of methylphenidate in the morning hours helps avoid the
troughs seen with immediate-release products.
Higher concentration of methylphenidate released in the early afternoon provides
a smooth effect through the early evening hours.




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      Extended release formulation of Methylphenidate




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      Challenges in Oral Drug Delivery


                     (A) Oral: easily administered formulations

                     (B) Stomach: gastric retention platforms

                     (C) Intestine: formulations for improved
                         absorption of poorly soluble drugs and
                         high molecular weight drugs

                     (D) Colon: colon targeted drug delivery
                         systems




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                 Challenges in Oral Drug Delivery




(A) Oral: easily administered formulations
    •   One-third of the population has pill swallowing difficulties.
    •   Orally disintegrating tablets provides a suitable solution.
    •   Bio-adhesive Buccal Tablets for avoiding FPM
    •   In-situ gelling formulation for dental therapy




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                     Challenges in Oral Drug Delivery

(B) Stomach: gastric retention platforms
    •    Many drugs get absorbed only in upper small intestine.
    •    Designing such molecules as once-daily formulations are elusive for these
         molecules. Thus GI retention platforms had emerged.
    •    One of the major challenge in developing gastric retention device is overcoming
         the house keeping waves particularly in the fasted state.


              Approaches for making gastric retention platforms
               Low density microspheres with bioadhesive coats
               Moderately swelling matrix systems
               Bioadhesives
               Superswelling hydrogel systems




        R&D
                   Challenges in Oral Drug Delivery

(C) Intestine: formulations for improved absorption of poorly soluble drugs and
    high molecular weight drugs
      •   Lack of sufficient solubility pose as major problem in oral drug delivery
      •   The other problem is delivering protein peptides due to their instability in GI
          environment


            Technologies for improving drug solubility
              Solid dispersions
              Nanocrystals and nanoparticles
              Polymeric micelles
              Self emulsifying systems




     R&D
                     Challenges in Oral Drug Delivery

(D) Colon: colon targeted drug delivery systems
•   Promising delivery of acid and enzymes labile substances thorough colon made this
    delivery route popular
•   Further local delivery to colon in certain disease state is essential


             Technologies for improving drug solubility
               Modified enteric coating
               Biodegradable swellable polymers
               pH-controlled systems
               Time delayed systems




      R&D
            Challenges in Oral Drug Delivery



•   GI PHYSIOLOGY
•   WINDOW OF ABSORPTION
•   SPATIAL DELIVERY
•   ORAL DELIVERY OF MACROMOLECULES
•   COST
•   LOW PERMEABILITY DRUGS (BCS III / IV)




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           ORAL MACROMOLECULAR DELIVERY



1.    Eligen Technology (Emisphere technologies Ltd.)


2.    CLEC Crosslinked Enzyme Crystals (Altus Pharmaceuticals)


3.    Hydroance (Lipocene inc.) [Lipid based formulations]


4.    Oral Insulin Developments




     R&D
                   OCRS Approvals Post - 2006
    Product               Drug              Company       Approval date       Technology
CLARINEX-D 12    Desloratadine (2.5 mg) +    Schering      February 01,      Bilayer tablets
HOUR tablets     Pseudoephedrine sulfate                      2006         (Desloratidine as IR
                        (120 mg)                                          and Pseudoephedrine
                                                                                 as ER)
OPANA ER            Oxymorphone HCl            Endo       June 22, 2006      Matrix tablets
tablets              (5/10/20/40 mg)
COREG CR           Carvedilol phosphate     SB Pharmco     October 20,      Multiparticulates
capsules            (10/20/40/80 mg)                          2006
INVEGA tablets   Paliperidone (3/6/9 mg)      Janssen     December 19,           OROS
                                                             2006
AMRIX ER             Cyclobenzaprine           ECR         February 01,     Multiparticulates
capsules         hydrochloride (15/30 mg)                     2007
SEROQUEL XR        Quetiapine fumarate      Astrazeneca   May 17, 2007       Matrix tablets
tablets            (50/200/300/400 mg)
ZYFLO CR             Zileuton 600 mg          Critical    May 30, 2007       Matrix tablets
tablets
SANCTURA XR      Trospium chloride 60 mg     Indevus       August 03,
tablets                                                      2007
     R&D
    OCRS under development/filed post 2006
                   Product              Company        Development stage

Jurnista tablets (OROS Hydromorphone)     J&J      Approved in EU/Out licensed
                                                              in US
Lamictal XR tablets (Lamotrigine)        GSK               Approvable

Pristiq (Desvenlafaxine succinate ER)    Wyeth             Approvable

Tacrolimus MR                           Astellas           NDA filed

Requip ER (Ropinirole)                   GSK               NDA Filed

Avandamet XR (Rosiglitazone maleate +    GSK                Phase III
metformin HCl)
Gepirone ER                              GSK                Phase III

Rosiglitazone XR                         GSK                Phase III

Coreg CR + ACE inhibitor                 GSK                Phase III

Gabapentin GR                           Depomed             Phase III

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      THANK YOU




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